Biotechnology, 2E, Vol. 12, Modern Biotechnology

Biotechnology Second Edition Volume12

Legal, Economic and Ethical Dimensions

Biotechnology Second Edition Fundamentals

Special Topics

Volume I

Volume 9 Enzymes. B ioma ss

Biological Fundamentals

,

Food and Feed

Volume 2

Volume 10 Sp ecial Processes

Volume 3

Environmental Processes

Genetic Fundamentals and Genetic E ngi n eer i ng

Volume 1 1

Bioprocessing Volume4 Me a s u r ing Modelling and Control .

.

Volume 12 Legal, Economic and

Ethical Dimensions

Products Volume 5 Genetically En gi nee red Proteins and Monoclonal Antibodies Volume 6

Products of Primary Metabolism Volume

7 Products of Secondary Metabolism Volume H Biotransformations

© VCH Verlagsgesellschaft mbH. D-69451 Weinheim (Federal Republic of Germany). 1995 Distribution:

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ISB'\ Vi27-2!!322-6 Set ISB'-i Vi27-2R310·2

A

Multi-Volume Comprehensive Treatise

Edited by H.-J. Rehm and G. Reed in cooperation with A. Piihler and P. Stadler

Volume12

Legal, Economic and Ethical Dimensions Edited by

D. Brauer

Weinheim New York Basel Cambridge Tokyo ·

·

·

Series Editors:

Prof. Dr. H.-J. Rehm lnstitut fiir Mikrobiologie Universitat Munster Corrensstra8e 3 D-48149 Munster Prof. Dr. A. PUhler

Biologie VI (Genetik)

Universitlit Bielefeld P. 0. Box 100131 D-33501 Bielefeld

Dr. G. Reed

2131 N. Summit Ave.

Apartment #304 Milwaukee, WI 53202-1347 USA

Vol ume Ed itor:

Dr. Dieter Brauer HoechstAG Head Office Corporate Res ea r ch and Development D-65926 Frankfurt am Main

Dr. P. J. W. Stadler BayerAG Verfahrensentwicklung Biochemic

Lei tung

Friedrich-Ebert-Stra8e 217

D-42096 Wuppertal

This book was carefully produced. Nevertheless. author s . editors and p ublisher do not war rant the information

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Published joint ly by VCH Verlagsgesellschaft mbH. Weinhei m (Federal Republic of G ermany) VCH Publishers Inc . . New York. NY (USA) Editorial Director: Dr. Hans-Joachim Kraus

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NE: Rehm. Han s J. [Hrsg.)

2 .. completely rev. ed. Vol. 12. Legal. Economic and E thi cal Dimensions I ed. by D. Brauer - 1995 ISBN 3-527-28322-6 NE: Brauer. Dieter [Hrsg.J

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Preface

In recognition of the enormous advances in biotechnology in recent years, we are pleased to present this Second Edition of "Biotechno­ logy" relatively soon after the introduction of the First Edition of this multi-volume com­ prehensive treatise. Since this series was ex­ tremely well accepted by the scientific com­ munity, we have maintained the overall goal of creating a number of volumes, each de­ voted to a certain topic, which provide scien­ tists in academia, industry, and public institu­ tions with a well-balanced and comprehensive overview of this growing field. We have fully revised the Second Edition and expanded it from ten to twelve volumes in order to take all recent developments into account. These twelve volumes are organized into three sections. The first four volumes consid­ er the fundamentals of biotechnology from biological , biochemical, molecular biological, and chemical engineering perspectives. The next four volumes are devoted to products of industrial relevance. Special attention is given here to products derived from genetically en­ gineered microorganisms and mammalian cells. The last four volumes are dedicated to the description of special topics. The new "Biotechnology" is a reference work, a comprehensive description of the state-of-the-art, and a guide to the original literature. It is specifically directed to micro­ biologists , biochemists, molecular biologists, bioengineers, chemical engineers, and food and pharmaceutical chemists working in indus­ try, at universities or at public institutions.

A carefully selected and disti�ished Scientific Advisory Board stands behind the series. Its members come from key institu­ tions representing scientific input from about twenty countries. The volume editors and the authors of the individual chapters have been chosen for their recognized expertise and their contribu­ tions to the various fields of biotechnology. Their willingness to impart this knowledge to their colleagues forms the basis of "Biotech­ nology" and is gratefully acknowledged. Moreover, this work could not have been brought to fruition without the foresight and the constant and diligent support of the pub­ lisher. We are grateful to VCH for publishing "Biotechnology" with their customary excel­ lence . Special thanks are due to Dr. Hans­ Joachim Kraus and Christa Schultz, without whose constant efforts the series could not be published. Finally, the editors wish to thank the members of the Scientific Advisory Board for their encouragement, their helpful sugges­ tions, and their constructive criticism. H.-J. Rehm G. Reed A. Piihler P. Stadler

Scientific Advisory Board

Prof Dr. M. J. Beker

Prof Dr. T. K. Ghose

August Kirchenstein Institute of Microbiology Latvian Academy of Sciences Riga, Latvia

Biochemical Engineering Research Centre Indian Institute of Technology New Delhi, India

Prof Dr. J. D. Bu'Lock

Prof Dr. I. Goldberg

Weizmann Microbial Chemistry Laboratory Department of Chemistry University of Manchester Manchester, UK

Department of Applied Microbiology The Hebrew University Jerusalem, Israel

Prof Dr. C. L. Cooney

Prof Dr. G. Goma

Department of Chemical Engineering Massachusetts Institute of Technology Cambridge, MA, USA

Departement de Genie Biochimique et Alimentaire Institut National des Sciences Appliquees Toulouse, France

Prof Dr. H. W. Doelle

Prof Dr. D. A. Hopwood

Department of Microbiology University of Queensland St. Lucia, Australia

Department of Genetics John Innes Institute Norwich, UK

Prof Dr. J. Drews

Prof Dr. E. H. Houwink

F.

Hoffmann-La Roche AG Basel, Switzerland

Organon International bv Scientific Development Group Oss, The Netherlands

Prof Dr. A. Fiechter

Prof Dr. A. E. Humphrey

Institut ftir Biotechnologie Eidgenossische Technische Hochschule ZUrich, Switzerland

Center for Molecular Bioscience and B iotechnology Lehigh University Bethlehem, P A, USA

VIII

Scientific

Advisory Board

Prof Dr. I. Karube

Research Center and Technology

for Advanced Science

Tokyo. J apan

M. A. Lachance

Department of

Pl ant

Schugerl

I nstitu t fiir Technische Chemic

Universitat Hannover Hannover, Germany

University of Tokyo

Proj: Dr.

Prof Dr. K.

Sciences

University of Western Ontario London, Ontario. Canada

Prof Dr.

P. Sensi

Chair of Fermentation Chemistry and Industrial Microbiology

Lepetit Research Cen ter

G e re n zano I tal y ,

Prof Dr. Y. Liu

China National Center for Biotec hnology Development

Beijing, China

Prof Dr.

J. F. Martin

Department of Microbiology University of Leon

Prof Dr. Y. H. Tan

Institute of Molecular and Cell Biology National Universit y of Singapore Singapore

Prof Dr. D. Thomas

Laboratoire de Technologic Enzymatique

Un i v e rs it e de Compi eg n e

Leon. Spain

Compiegne, France

Prof Dr. B. Mattiasson Department of B i ot ech nology

Prof Dr. W. Verstraete Laboratory of Mic rob i al Ecol ogy

University of Lund

G e nt

Chemical Center

Lund. Sweden Prof

Dr.

M. Rohr

lnstitut fUr B i ochem i sche Technologic

und Mikrobiologie

Technische Universitat Wien Wien, Austri a

Prof Dr. H. Sahm lnstitut fUr Biotechnologie Forschungszentrum J i.il ich Jiilich, Germany

Rijksuniversiteit Gent ,

B el gium

Prof Dr. E.-L. Winnacker Insti t ut fi.ir Biochemic Universitat Mi.inchen M i.inchen , Ge rmany

Contents

Introduction

D.

1

Brauer

I. Modern Biotechnology - What Is New About It?

1 The Evaluation of Technology as an

Interactive Commitment-Building Process - The Failure of Technology Assessment 5 G. Van Steendam

2 Concepts of Risk Assessment: The "Process versus Product" Controversy Put to the Rest 39 H. I. Miller

3 Biosafety in rONA Research and Production 63 D. Brauer, M. Broker, C. Kellermann, E.-L. Winnacker

4 Biotechnology and Bioethics: What is

Ethical Biotechnology? D. R. J. Macer

1 15

7 Biomedicinal Product Development 213 J.-P. Gregersen 8 Regulations for Recombinant DNA Research, Product Development and Production in the US, Japan and Europe 239 D. Brauer, H. D. Schlumberger

III. Intellectual Property and Bioinformatics 9 Biotechnology and Intellectual

Property 281 J. Straus 10 Patent Applications for Biomedicinal Products 299 J.-P. Gregersen 1 1 Databases in Biotechnology 323 E.

Poetzsch

IV. Biotechnology in a Developing World II. Product Development and Legal Requirements

12 Commercial Biotechnology: Developing World Prospects 339 G. T. Tzotzos, M. Leopold

5 Structured Risk Assessment of rONA Products and Consumer Acceptance of These Products 157

13 Biotechnology in the Asian-Pacific Region 369 R. D. Schmid, B.-H. Chung, A. J. Jones,

6 Strategic Regulations for Safe Development of Transgenic Plants

14 Biotechnology and Biological Diversity 433

C. T. Verrips

T.

L. Medley, S. L. McCammon

S. Saono, J. Scriven,

197

M. Kawai

J. H. J. Tsai

X

Content.\

V. Public Attitudes and Political Responses I.S

Ih

··oui·· or ··Non'' to Biotechnology: The

Other French Refe rendum 449 A. Millet G ov er nm e nt Researchers and Activists: The Critical Public Policy Interface 459 S. L. Huttner .

17

18

Press Coverage of Genetic Engineering in Germany: Facts, Faults and Causes 495 H. M. Kepplinger, S. C. Ehmig The Regulation of Modern Biotechnology: A Historical and European Perspective 505 M. F. Cantley

Index

683

Contributors

Dr. Dieter Brauer

Dr. Simone Christine Ehmig

Hoechst AG Head Office Corporate Research and Development D-65926 Frankfurt am Main Federal Republic of Germany

Johannes Gutenberg-Universitii.t Institut fiir Publizistik Jakob-Welder-Weg 20 D-55128 Mainz Federal Republic of Germany

Dr. Michael Broker

Dr. Jens-Peter Gregersen

Behringwerke AG Emil-von-Behring-StraBe 76 D-35041 Marburg Federal Republic of Germany

Behringwerke AG Emil-von-Behring-StraBe 76 D-35041 Marburg Federal Republic of Germany

Dr. Mark F. Cant l ey

Dr. Susanne L. Huttner

OECD (Organisation for Economic Co-operation and Development) Head of Biotechnology Unit Directorate for Science, Technology and Industry 2, rue Andre Pascal F-75775 Paris Cedex 1 6 France

Director UCLA Systemwide Biotechnology Research and Education Program Molecular Biology Institute 405 Hilgard A venue Los Angeles, CA 90024-1570 U.S.A.

Dr. Bong-Hyun Chung

Dr. Alan J. Jones

Senior Research Scientist Genetic Engineering Research Institute of KIST Taeduk Science Town Taejon, South Korea

Counsellor (Industry, Science and Technology) Australian Embassy Godesberger Allee 106--107 D-53175 Bonn Federal Republic of Germany

Chapters 3 and 8

Chapter 3

Chapter 18

Chapter 13

Chapter 17

Chapters 7 and 10

Chapter

16

Chapter 13

XII

Contributors

Prof. Dr. Marion Leopold

Dr. Sally L. McCammon

Department of Sociology Universite du Quebec P-8888 Succ A Montreal, Quebec H3C 3P8 Canada

U.S. Departme nt of Agriculture APHIS Animal and Pl an t Health Service P.O. Box 96464 Washington. DC 20090-6464

Chapter 12

U.S.A.

Chapter

6

Dr. Terry L. Medley

Dr. Masao Kawai Director

of Agriculture APHIS A nimal and Plant Health Inspe ction Service P.O. Box 96464 Washington, DC 20090-6464 U.S. Department

Japan Monkey Center Chairman of the Commi ttee on Biodiversity Tokyo 105 Jap a n Chapter 14

U.S.A.

Chapter

6

Prof. Dr. Henry I. Miller

Dr. Cornelia Kellermann

Laboratori um fi.ir Molekulare Genzentrum Am Klopferspitz 18 D-82152 Martinsried Federal Republic of Germany Chapter 3

Biologie

Prof. Dr. Hans Mathias Kepplinger

Johannes Gutenberg-llniversitiit lnstitut fiir Publizistik

Stanford Unive rsity Hoover Institution and I nstitute for Interna­ tional Studies Stanford, CA 94305-6010 U.S.A . Chapter 2 Annette Millet Biofutur 29, rue Buffon

Jakob-Welder-Weg 20 D-55128 Mainz Federal Republic of Germany Chapter 17

F-75005 Paris France Chapter 15

Prof. Dr. Darryl R. J. Macer

Dr. Eleonore Poetzsch FIZ Chemie Berlin GmbH Fachinformationszentrum Post fach 12 60 50 D-1 0593 Berlin Federal Re p ubli c o f Germany Chapter 1 1

Institute of Biological Sciences University of Tsukuba Tsukuba Science Citv 305 Japan ·

and

Eubios Et hics Institute Colwyn Street Christchurch 5 New Zealand Chapter 4 31

Inspection

Dr. Susono Saono Research and Development Centre for

Biotechnology Ir. H. Juanda 18 P.O. Box 323 Bo go r 16122 Indonesia Chapter 13

Jl.

.

Contributors

Prof. Dr. Horst Dieter Schlumberger

Dr. George T. Tzotzos

B ayer AG Geschaftsbereich Pharma Forschung und Entwicklung Postfach 10 17 09 D-42096 Wuppertal Federal Republic of Germany Chapter 8

UNIDO United Nations Industrial Development Organization ICGEB Science Coordinator ( International Centre for Genetic Engineering and Biotechnology) Vienna Office P.O. Box 400 A-1400 Wien Austria Chapter 12

Prof. Dr. Rolf D. Schmid

XIII

Prof. Dr. Guido Van Steendam

Institut fiir Technische Biochemie Universitat Stuttgart Allmandring 31 D-70569 Stuttgart Federal Republic of Germany Chapter 13

ifb International Forum for Biophilosophy Director Craenendonck 15 B-3000 Leuven Belgium Chapter 1

Jeannie Scriven, B. A.

Prof. Dr. C. Theo Verrips

GBF Gesellschaft fiir Biotechnologische Forschung mbH Mascheroder Weg 1 D-38124 Braunschweig Federal Republic of Germany Chapter 13

Unilever Research Laboratorium P.O. Box 1 14 NL-3130 AC Vlaardingen The Netherlands Chapter 5

Prof. Dr. Joseph Straus Max-Planck-Institut fUr auslandisch e s und

Prof. Dr. Ernst-Ludwig Winnacker Laboratorium fur M olekular e Biologie

internationales Patent-, Urheber- und Wettbewerbsrecht SiebertstraBe 3 D-81675 Miinchen Federal Republic of Germany Chapter 9 Dr. Jane H. J. Tsai

Kurt-Schumacher-Weg 1 1 D-37073 Gottingen Federal Republic of Germany Chapter 13

Genzentrum Am Klopferspitz 1 8 D-82152 Martinsried Federal Republic of Germany Chapter 3

Biotec/11wlogy

Ed ited by ,H.-J. Rehm a nd G. Reed in coo p eration wi th A. Puhler and P. Stad ler C o p yright © VCH Verlagsgesellscnatt mbH,1995

Introduction

DIETER BRAUER Frankfurt am Main, Federal Republic of Germany

"Biotechnology" undoubtedly is a fascinat­ ing field with far-reaching legal, economic and ethical implications for mankind. In this Volume 12 of the Second Edition of "Bio­ technology" an experienced and diverse team of authors comprising scientists from academ­ ic research and industry. regulators and jour­ nalists examines the potential implications biotechnology may have from various angles. The perspective is thoroughly international and with many critical comparisons and views expressed. It is an indispensable reading for everyone seriously concerned with the poten­ tial risks and benefits of modern biotechnolo­ gy and the more general problems associated with the introduction of a new technology into society. From about 20 different technical and scientific disciplines including biochemistry. classical genetics. protein chemistry, micro­ biology etc .. further biologically derived tools such as genetic engineering and hybridoma technology have been developed. which are often referred to as "modern biotechnology" and which represent the most exciting ad­ vance in the biological sciences this century. However. there is evidence that this new technology is not understood by the public, that there is a tendency to think of biotechno­ logy as fundamentally different from other technologies. The speed of its introduction

seems to frighten some onlookers, and the sa­ fety of genetic modification is questioned. Hence the public demands regulation for its protection. Not surprisingly therefore, since the pio­ neering phase of modern biotechnology we have seen the production of an enormous quantity of political, scientific, socio-econom­ ic and ethical literature evaluating the differ­ ent aspects of biotechnology. There are also the questions of patenting "life''- needed for the protection of investments and rejected as ''unmoral" by other interests and fears with regard to biotechnology have to be linked to ambiguous attitudes towards technology in general. The contributions compiled in the five parts of this book are an attempt to cover the mainstream of thoughts and developments with respect to biotechnology from an inter­ national and multidisciplinary perspective: Part I guides the reader into biotechnology and starts with an introduction into technolo­ gy assessment in a fundamental way and not limited to biotechnology, only. The n the dif­ ferent concepts of risk assessment applied to­ day are discussed and evaluated and are fol­ lowed by a detailed introduction to biosafety issues in research and production. The intro­ duction to biotechnology is concluded by combining the terms "biotechnology" and

2

Introduction

"bioethics" and the development of thoughts about what ethical biotechnology might be. Part II focuses on the practical aspects of applying modern biotechnology in research and to the production of goods. It addresses the different expectations and needs of users of modern biotechnology, consumers and reg­ ulators who have to serve all interests appro­ priately. The topics range from structured risk assessment of rDNA products mainly in the food sector and the regulations applied to a safe development of transgenic plants to biomedicinal product development and a comparison of the different regulatory envi­ ronments for modern biotechnology in the US, Japan and Europe. Part Ill covers both intellectual property protection and bioinformatics. One chapter focuses on what "patent protection" actually is, and why lack of patent protection prevents investment into R & D confining activities to reengineering and copying. Only an effective use of intellectual property rights enables in­ dustry to recover the enormous costs involved in developing new products and processes. B ecause modern biotechnology is highly in­ formation-dependent, the availability of high­ quality, up-to-date and comprehensive infor­ mation is an important requirement on al­ most each level of R & D, production devel­ opment and in intellectual property protec­ tion. Therefore, databases are an essential tool in biotechnology. Part IV evaluates prospects for biotechnol­ ogy in the developing world and specifically in the Asian-Pacific region. It is discussed in detail, to which extent the disjunction of pri­ orities between the industrial and developing world influences the potential of biotechnolo­ gy to solve health- and food supply-related problems in the developing world. Many countries in the Asian-Pacific region are in a state of rapid transformation from agricultur­ al to industry- and service-based economies. The data available indicate that biotechnolo­ gy has achieved a high priority status in the whole region which has become a strong con­ tender to the development of biotechnology in North America and Europe.

Part V is an attempt to analyze the role of the public in the development of biotechnolo­ gy and to compare the differing views in some key countries like France, USA and Germa­ ny. The focus is put on the activities of inter­ est groups, the role of the media and the po­ litical responses. The concluding chapter in this book is a historical review of events and decisions in time relevant to the development of modern biotechnology with specific em­ phasis on the European perspective. Howev­ er, this chapter is not limited to but goes well beyond biotechnology. In a narrative form it represents a case study in how societies cope with new knowledge in the last quarter of the twentieth century. Everybody knows the fairy-tale of the in­ nocent maiden and the ugly and horrible beast which turned out to be something hon­ est and trustworthy after being treated with goodwill and trust rather than with fear and repulsion. But, unfortunately, there is no evi­ dence for who is the beauty and who is the beast. Is it the innocent and trusting public which is confronted with a flourishing science threatening human life, the environment and the integrity of God's creation? Or is it a pure and beneficial science promising progress in many human problems which is rejected by an ignorant and distrustful public? Hopefully, this comprehensive book will provide the interested reader with sufficient evidence to make him understand that bio­ technology is neither a beauty nor a beast, and that science and technology are not a subsystem of our society in the sense that they could be regarded separately from other subsystems. Understanding this and the points made in this book may help the reader to find his own views and positions based on an educated choice not only towards biotech­ nology but also to "technology" in a broader sense.

Frankfurt am Main, November 1994 Dieter Brauer

I. Modem Biotechnology What is New About It?

-

Biotec/uwlogy

Ed ited by .H.-J. Rehm a nd G. Reed in coo p eration w ith A. Puhler and P. Stadler Copyright © VCH Verlagsgesellschatt mbH, 1995

1 The Evaluation of Technology as an

Interactive Commitment-Building

Process - The Failure of Technology Assessment

GUIDO VAN STEENDAM Leuven, Be l gi um

1 Introduction 7 2 The Benefits of Technology 7 2.1 Growing Social and Economic Welfare 8 2.2 Maintaining Peace 9 2.3 Prestige 9 3 Technology under Attack 9 3.1 Doubts on the Socia l Relevance 10 3.1.1 Prestige 10 3.1.2 Maintaining Peace 10 3.1.3 Growing Social and Economic Welfare 3.2 The Hidden Costs 10 3.2.1 Cost to t h e Natural Environment 11 3.2.2 Cost to the Soc ial Environment 11 4 The Rise of Technology Assessment 11 4.1 The T A Methodology 12 4.2 The T A Office 13 4.2.1 A Congressional Ins t itution 13 4.2.2 A Strong Institution 14 5 The End of Technology Assessment 15 5.1 A Recognized Failure 15 5.2 An Inadequate View on Technology 16 5.2.1 Predictability 17 5.2.2 Controllability 17

10

1 The Evaluation of Technology as an interactive Commitment-Building Process

6

6

7

8

9 10

5.3 An Inadequate View of Assessment 18 5.3.1 Objective Overall Assessment 18 5.3.2 Subjective Overall Assessment 20 Lessons from TA 22 6.1 The Importance of Sound Interaction 22 6.1.1 Interaction with the Initiator 22 6.1.2 A Powerful and Committed Interaction 23 6.1.3 Informed Interaction 23 6.1.4 Properly Institutionalized Interaction 24 6.1.5 Interaction Among All Partners Involved 24 6.2 The Allurement of Objective Certainty 25 The Origins of Science and Technology Policy 26 7.1 Industrial Science and Technology Policy 26 7.1.1 The First Industrial Revolution 27 7.1.2 The Second Industrial Revolution 27 7.1.3 Later Revolutions 28 7.2 Early Governmental Science and Technology Policy 28 7.2.1 Prestige and Maintaining Peace 28 7.2.2 Growing Social and Economic Welfare 29 7.3 Spread of Governmental Science and Technology Policy 29 7.3.1 Science for Policy 30 7.3.2 Policy for Science 30 Making Science and Technology Policy Interactive 30 8.1 Making Existing Policy Interactive 31 8.2 Using All Possible Social Resources 33 8.3 An Information Process 33 8.4 A Process of Shared Commitment-Building 34 8.5 Decentralized and Multi-Form Institutionalization 35 TA after TA 37 References 38

2

1 Introduction Is Technology Assessment", or "TA", the magic brew which enables governments to guarantee the to tal quality and relevance of the technological developments they approve or stimulate? Can othe r initiators of technolo­ gies, such as biotech compa n ie s or academic research labs, make use of the same tool to convi nce the authorities of how well-pre­ pared, b e nefi c i al and safe thei r p l ans are? Or does T A provide activists and envir onmental ists with an infallible instrument to collect ir­ refutable evidence of the danger of speci fic developme nts which they had since long sus­ "

­

pected?

The answer to each of these question s is a disappointing but clear No : TA is not the panacea it is still often believed to be. While bein g prepared by t he American Con­ gress in the sixties as a method with capital T and capital A. to understand and assess all as­ pects of technological develop m e nts in real­ ity it never worked that way. and it never will. Both the conception of "technology" and the ideas on '"assessment" which underlie the T A approach appear to be exceedingly objective and therefore unrealistic. The T A experiment of the US Congre s s is an e x periment that failed and was doomed to fail. This is the first point we want to make in this chapt e r The second p o i n t is t h at the T A ideals are a permanent threat to any serious attempt to monitor the relevance and harmlessness of technological developments By holding up the prospect of providing a complete and ob­ jective analysi s TA play s a long with our de eply human but utopi a n craving for making infallible decisions. and in this way diverts our a ttent i on fro m mor e realistic appr oache s to e nhanci n g t h e quality of decision m a king

r ath er

"

"

,

.

7

The Benefits of Technology

well. They are important to the extent they succeed in developing activities that go beyond T A as designed by US Congress in the sixties, but contribute to reali z ing and sus­ taining a broader social process of informed, committed and interactive policy making This chapter begins with a description of the ambiguous situation of the "golden six­ ties" during which the American Congress conceived the idea of Technology Assessment and coined the term. The sixties were domi­ nated by technology which was first seen as the d riving force behind wealth and abun­ dance (Section 2) and later as a po tentia l dan­ ger and a major source of an irrelevant and degenerating lifestyle (Section 3). Next fol­ lows a p resentation of T A, as the attempt by US Congress to identify valuable technology and to sepa r ate the wheat from the chaff (Section 4). This outline is followed by an evaluation of this enterprise, expla ining the untenability of the approach (Section 5) and paying attention to the positive lessons we can learn from the T A experiment ( Se ction 6). The chapte r concludes with an overview of a more realistic and work able, though fallible, approach to monitor technological develop­ ments. It e x plains that such endeavor should be seen as a further step in the burgeoning science and technology policy ( Se ction 7) and that it takes account of our growi ng aware­ ness and inc reasing understandin g of the falli­ bility of human deci sion mak i ng in a perma­ nent situation of uncertainty (Section 8). -

.

-

.

.

2 The B e nefits of Technology

-

under uncertainty.

The most important point of this chapter is that proper ma na gement of te c h no l o gical de­ ve lopm en ts requires a great dive r sity of activ­ ities of a l ar ge variety of i nst i tutions linked to all formal and i n fo rmal social sectors. These institutions include res e arch units, advisory bodi e s discussion groups. international and interdisciplinary forums, and strategic grou ps - many of which al r eady exist and fu nct ion ,

In the 1 960s, few would have e x pect e d that anybody would ever seri ous l y endorse the idea that new technological deve lop m ents are in fact suspicious and in need of cr i t ic al as­ sessment before they be allowed to p roceed On the contrary, technological innovation was believed to be a good thing which should be stimulated by all means. Technology ap peared to have re vitaliz ed all important as­ pects of social life. .

­

8

1

The Evaluation of Technology as an Interactive Commitment-Building Process

2.1 Growing Social and Economic Welfare

The great affluence which so characterized the sixties was unrivalled by that of any other preceding period in the history of mankind. Never before had the people in Western in­ dustrialized countries experienced a similar wealth and comfort. Since World War II, the average productivity of human labor, the Gross National Product and the GNP per capita had steadily been increasing by about 3 to 4% per year. This trend of growing pros­ perity not only resulted in more dispensable income for the families and more money to invest for national states, but also in a de­ crease in the amount of working hours, which, in its turn, allowed for more time for leisure. Technological innovation, based on strong scientific research, manifested itself to be at the heart of this new social order. It appeared that four hundred years of modern science and two hundred years of modern technology had finally reached their stage of maturity. And, as the academic and industrial world were only at the beginning of the exploration and exploitation of promising fields and pow­ erful new technologies, much faith was placed in the fact that this process of increasing pros­ perity had been set into motion for good. Four fields were expected to lead to new rev­ olutions with breathtaking new possibilities. (1) The first one was the electronic revolu­ tion with the Integrated Circuit which at the time was still in its infancy. Despite its new­ ness, however, its application had already drastically heightened economic productivity. It was expected that by the year 2000, the computer would enhance the productive ca­ pacity of human labor by another 300% , al­ lowing every person to do the work - and to earn the income - of three. (2) The second field revolved around the development of new and cheaper sources of energy. Here the promising new technology would allow the unleashing of enormous amounts of energy stored in the inner core of highly energetic material, by converting this hidden energy into electricity for everyday use. This movement is also called the nuclear revolution.

(3) Thirdly, there was a similar hope that certain traditional basic materials, like steel, whose elemental properties were difficult to engineer, could be replaced by more flexible man-made materials such as plastics. The properties of plastics present the advantage that they can be designed in a research facility and specifically adapted to their planned use, and, at a later stage, they can easily be manu­ factured in chemical plants by employing sim­ ple readily available raw materials. (4) Finally, the sixties also announced a biological revolution. Genetics was believed to be the driving force behind this revolution. This discipline was seen as the study of the core elements of life, being genes and chro­ mosomes, which encoded the characteristics of the different species and forms of life and which are used by living organisms to trans­ mit hereditary traits to later generations. Re­ search increasingly succeeded in unravelling the basic mechanisms of those mysterious units, and subsequently opened up prospects for powerful technological applications not only in the field of human health care, but also in agriculture and other fields of human activities. By the end of the sixties, science had already succeeded in isolating the first gene, but it would take until the seventies be­ fore the first technological uses of those genes would become possible. These prospects, combined with the in­ sights into the driving forces behind them not only stimulated an increased respect for aca­ demic science and technology, but went on to nurture the growth of industrial companies. Only large companies could afford to be in­ volved in the basic research which was needed to guarantee ongoing economic growth. And it was only these same large companies that could afford to develop the mechanisms to turn these basic scientific dis­ coveries and technological developments into real industrial products to be distributed in society. In taking this beneficial effect of technolo­ gy on industry into account, we cannot forget that life and the happiness of individuals and families remained at the center of those de­ velopments. New machines helped to reduce burdensome work and to organize and enrich daily life. Washing machines, dishwashers, re-

3 Technology under Attack

frigerators and freezers became available and accessible to e ach house hold. Color television opened a more vivid window on the real world and provided a priva t e entertainment center for every l i vin g room. Communication was facilitated by a growing number of tele­ phones and cars. These were the golden six­ ties. filled with new m usic, wealth and hope.

2.2 Maintaining Peace Technology also left its mark on the wide­ spread belief that there would never be an­ other war like World War II which would be staged in the Western world. It was clear that war had not disappeared from the earth. But at the beginning of the sixties. massive war, with its atrocities and mise ry. did disappear from the daily life o f Westerners. War as a concept with a capital W had become humil­ iated to the abstract notion of a mere diplo­ matic tension between two blocks - the Cold War between the E ast and the West - or to the theoretical knowledge of smaller. local conflicts in "hidden parts" o f the world. There was a general faith that Western diplo­ mats. politicians and military forces could master all existing threats because the y could rely on t he most sophisticated arsenal of high­ tech weapons then known to man. which would easily be able to s t op all attacks from the outside. Furthermore. it was clear to many that these weapons. incl uding a whole battery of nuclear weapons. were so powerful that no other power would ever dare try to attack the West. because they realized that the West could immediately re ply to any at­ tack with the utter anni hilation of the attack­ ing force and indeed its entire nation by means of a series of atomic bombs many times more pow erf u l than the bomb which destroyed Hiroshima. In t he same way that large stone walls could protect the inhabitants of a medieval town or fortress. the shield of technology wa s believed to be protecting the modern Western world. Sophisticated weap­ ons re plac e d bow and arrow while radars and sa t e l l i tes replaced the watchers· ey e .

9

2.3 Prestige In the sixties. technology was not j ust ap­ preciated as the powerful engine of economic wealth and peace . It was also a deep source of human pride and a symbol of the unlimited possibilities of human rationality and of strong Western nations. Even the most unbe­ lievable adventures appeared to be possible now. The exploration of space was the show­ piece of this evolution. The manned landing on the moon was the first dream which be­ came true. On May 26, 1961 President KEN­ NEDY earned a long and thunderous applause while explaining his projects to the Con­ gress: "I believe that this nation should commit itself to achieving the goal, before this decade is out, of landing a man on the moon and re­ turning him safely to the earth. No single space project in this period will be more im­ pressive to mankind, or more important for the long-range exploration of space; none will be so difficult or expensive to accomplish." (JOHN F. KENNEDY, 1961). As we all know, this dream became reality. On July 21, 1969, NEIL ARMSTRONG and Buzz ALDRIN spent two hours walking on the moon. The l anding on the moon was transmitted live by television all around the world. This technical feat was experienced as the clear symbol of the unlimited power and possibilities of mankind. For many, the con­ viction prevailed that man had entered a new phase in his existence, or, as NEIL ARM­ STRONG expressed it, the very moment after putting the first human foot on the lunar soil: "That's one small step for man, one giant leap for mankind."

3 Technology under Attack

Being a major symbol of the successes of science and technology in t he sixties, the lu­ nar landing and space travel in general soon became a focal point in a growing movement of mistrust and critical reappraisal. Doubt was

10

1 The Evaluation of Technology as an Interactive Commitment-Building Process

cast on the social relevance of many splendid technological and industrial developments. Furthermore, it became clear that science and technology, functi oning as the engine of our increasing prosperity were accompanied by a host of social and environmental costs to which we had been blind for many years. Science and technology came under a grow­ ing attack in each of the domains in which they had proven so successful in the sixties. 3 . 1 D oubts on the Social Relevance 3 . 1 . 1 Prestige

The landing on the moon was soon fol­ lowed by a postnatal depression. For ten years there had been a concerted effort to put an American on the moon, and several scien­ tific, techno l ogical and industrial projects de­ rived their raison d'etre from this adventure. Now that the goal had been achieved, ques­ tions began to surface concerning the true na­ ture of the project. What was the real inten­ tion behind the space program? Was the nat­ ural next step to stage a s imilar landing on the planet Mars? What was the point of the American public authorities' incorporating space travel into their main technological pri ­ orities? What had the nation - or mankind actu all y gained from its lunar expedition? Leading scientists had already considered these pr oblem s earlier. ALVIN WEINBERG, for example, a former member of the Ameri­ can President's Science Advisory Committee, wrote as early as 1 966: "A crisis of mission will face our space program during the middle seventies. The present scale and pace of our space enterprise is determined by our com­ mitment to send a man to the moon early in 1970. Now that this date is approaching, grave questions arise as to the next step. Should we go on to Mars; or should the space program revert to the scale it enjoyed before we de­ cided to send a manned expedition to the moon? The existence of a massive space es­ tablishment, including many fine laboratories, surely will tend to w eigh the balance stro n gly toward going to Mars after we have reached the moon. Yet I would hope that when the

time for this far-reaching decision comes, we shall have ready for this great scientific tech­ nical resource many other technical chal­ lenges that bear more directly on our human well-being than does a manned trip to Mars" (ALVI N M. WEINBERG, 1967). 3 . 1 .2 Maintaining Peace

The domain of military research, another priorities came under attack by the same school of criticism. After all, had not the Vietnam experience proved that the "American war machine" had not succeeded, even with the most sophisti­ cated weapons, in bringing the war to an end? This growing realization was linked to the general question as to why the Vietnam war had act u al ly been necessary. In addition, more and more members of the American Congress felt that the nation would be better served by a po li cy different from the mainte­ nance of a high-tech arms race. They also felt that research funds could be put to better use. of Americans technological

3 . 1 .3 Growing Social and Economic Welfare

Economic

growth had the history . While , in the sixties, few would deny that this growth had led to an increasing prosperity and general well-being, it also became gradually clear that it did not make sense to perceive unlimited growth as a goal in itself. These doubts dampened the evi­ dent relevance of the large investments in scientific and technological developments, de­ si gned to stimulate economic growth. and industrial

same ambiguous

3.2 The Hidden Costs There was another source of unrest and mistrust towards science and technology. The sixties marked the beginning of a growing awareness that some technologies, developed and applied with only the best of intentions, threatened our natural or cultural resources, long taken for granted.

4 The Rise of Technology Assessment

3.2. 1 Cost to the Natural Environment In 1 962 R A C H E L C A RSON publ i shed " Si­ lent Spring"' . In this dramatic and alarming report, she co nv i ncingly demonstrates how the increased use of pe s t i cide s is slowly but surely poisoning our biological environment. It is the first influential and well-documented admonition to s oc iety that. by undermining the environment. our technological civiliza­ tion could ultimately turn against humanity instead of promoting it. Her claim was fol­ lowed by many negative reports about the ef­ fects of motorways, jet aircrafts and airports, nuclear energy and many other phenomena of our modern culture. Until the beginning of the 1 960s it had always been naively pre­ sumed that the sea. rivers. groundwater, air, earth and the plant, animal and human king­ doms could withstand any conceivable shock that humans could deliver to them. Until that time, it had scarcely been thinkabl e that the increasing industrialization would ultimately lead to the w i des pread extinction of aquatic life, to heavily polluted coasts and beaches, or, inde e d to sickening and unhealthy air pol­ lution in the large cit i e s In the seventies. when biotechnological methodologies were revolutionized, the ve ry scien t ist s and tech­ nologists behind these breakthroughs had al­ ready expressed their deep concern for the potential hazards of the use and laboratory study of recombinant DNA molecules - haz­ ards to the human health as well as to the health of our environment. Leading molecu­ lar biologists even proclaimed a moratorium for all further research. This gesture of cau­ tion attracted the attention of the press and policy-makers and fue l led the widespread be­ lief that the potential dangers associated with biotechnology are of a very special nature. .

.

3 . 2 . 2 Cost to the Social

Envi ronm ent

Potential dangers, increasingly attributed to technological developments. were not lim­ ited to our natural environment. A great di-

11

versity of threats to the social enviro nment were also increasingly considered. U n employ ment was a manifest example of these social dangers. Less tangible perhaps was the dan­ ger that the ever-changing technologies in the workplace m i ght adversely influence the mo­ tivation of workers, as it could be feared that they would not want to constantly adapt to new procedures or to be i n need of perma­ nent education. Aside from the social environment in the workplace , the cultural and family-centered social environments were not spared from the technological implications of this new age. For example , it had been argued that televi­ sion had signified the death of social and cul­ tural life and even of family life. Also, the enormously increased mobility of the jet-age generation was described as a potential threat to family life. Questions also arose concerning the neces­ s i ty to adapt our legal and social mechanisms to the many new and powerful technologies, such as the broadened potentials of medicine in the fields of p renatal life and care of the elderly. Not everyone was convinced that the new social and legal order would ultimately bring out social optimal i ty in a better and more humane way than the old order did. Again the oncoming biotechnology and its multiple uses in agriculture , industry and health care stirred the imagination. What should we think e.g. about a society in which specific, newly designed, living beings obtain an economic value and are patented ? And how can our society survive in a situation where man can predefine the t raits of their own children or design "produce" and patent a genetically engineered worker or soldier? ­

,

4 The Rise of Technology Assessment

After years of economic growth and social euphoria, the 1 960s ended with a deep aware­ ness of crisis. The engine of our increasing prosperity, namely technological and indus­ trial de velop ment had p roved to be accom,

12

1

The Evaluation of Technology as a n lnteractive Commitment-Building Process

panied by a host of social and environmental costs to which we had been blind for many years. National governments, which were themselves systematically involved in large­ scale technological development programs, felt compelled to seriously examine and re­ consider their earlier carefree approach and their priorities. It was within the context of this reappraisal that the American Congress launched its own initiative, prepared by the subcommittee for "Science, Research and Development" of the "Science and Astronautics" Committee of the House of Representatives. The first report of this subcommittee, published on October 17, 1 966, described how Congress planned to deal with the growing conviction that it is ab­ solutely necessary to "keep [ . . ] tab on the potential dangers, as well as the benefits in­ herent in new technology" . Two major con­ cerns appear to form the basis of these Con­ gressional efforts. Their first objective was the ensuring of the attainability of in-depth knowledge into the potentially dangerous consequences of tech­ nologies like "technological unemployment, toxic pesticides, pollution, exhaustion of re­ sources, the disposal of radioactive wastes, and invasions of personal liberty by electronic snooping and computer data banks". They proposed reaching this objective by means of the development of a new, highly specific, scientific methodology to provide an all-en­ compassing assessment procedure of all that could be described as "technology". For this new discipline, the subcommittee coined the name "Technology Assessment" (TA). The second objective of the Congressional subcommittee was to make sure that such T A studies were actually carried out, and this in such a way that they would prevent the US Government from promoting and funding ir­ relevant or dangerous technological develop­ ments. This concern resulted in the firm belief that one had to establish some sort of institu­ tional mechanism which would organize the necessary "TA studies" on a systematic basis. Congress believed that this institution should be established within Congress itself. This clarifies why, in 1973, a new Congressional Office was established: the "Office for Tech­ nology Assessment" (OTA). .

The following sections will expose in greater detail the actual birth of both the T A methodology and the TA Office (see e.g., Sect. 6.1 .3).

4.1 The TA Methodology Unexpected troubles like the environmen­ tal crises of the 1960s had made Congress acutely aware of the importance of the ability of foresight. Only being able to recognize the destructive consequences of technological projects after they have been developed and widely used, was an embarrassing handicap Congress wanted to rid itself of. The alarming DDT experience should never happen again . Congressmen also staunchly opposed invest­ ing in the development of technological solu­ tions which afterwards would prove to be use­ less or socially irrelevant. They realized that they were in need of a methodology that could provide them with the accurate infor­ mation about future consequences of techno­ logical developments. The mechanism of foresight that was needed would have to be characterized by the following four elements: (a) Firstly, the mechanism should function as a "first alert" system which would sound the alarm bell before the hazardous technolo­ gy had gotten past the drawing board, or at least before the potential negative conse­ quences had the opportunity to take place. In other words, the information about future consequences would have to be provided when it was still possible to stop the planned technology from being implemented, or at least to redirect or restrain it. (b) Secondly, the early warning system should be systematic and exhaustive. Every consequence of the planned technologies should be explored including the "real and potential impacts of technology on social, economic, environmental, and political sys­ tems and processes" (VARY T. CoATES, 1 972). However, this analysis was not to con­ tent itself with the pure assessment of that trend or scenario, which at first glance ap­ pears to be the only or most evident one. Many technological developments can in fact follow several scenarios depending on the im-

4

pact of broad social or economic develop­ ments, specific human decisions or other ex­ ternal factors. In this case the consequences of each of these alternative scenarios should be studied. This included the special case of the consequences of the zero option . where it was decided not to i nitiate the technology at all. Finally, Congress wished that the scope of T A would be of such dimensions that all tech­ nological domains. harmless though they may appear to be, would be scrutinized . (c) Thirdly. the methodology should not just name the consequences, but also indicate to what extent and in what sense they are haz­ ardous. The methodology procedures should appraise the nature. significance and merits of the consequences. simultaneously providing a balanced appraisal of the technology under examination. B ased on the results of a T A analysis. the policy-makers should be able to understand what is really at stake when new technological programs are introduced. T A studies should become a powerful tool in pol­ icy-making. (d) Fourthly, the prognostications should not be the mere guesses of uninformed peo­ ple, or the work of lobbyists trying to stop or promote a specific technological develop­ ment. The forecast was to be reliable and ob­ jective for 1 00% and constitute an incontesta­ ble basis for sound and justified policy-mak­ ing. I n other words, the methodology of the investigations should follow some sort of ''scientific met hod '' and the result should be reliably scientific material. Congress was aware that no single e xisting scientific disci­ pline was able to deliver the required assess­ ment of all future conseq uences. So it be­ lieved that a great variety of existing analyti­ cal methods would have to be modified and combined to form a spanking brand-new dis­ cipline.

4.2 The TA Office l t was clear that the US Congress would al­ ready feel much more comfortable when a scientific methodology would be available for making complete and reliable predictions of the consequences of technological and indus­ trial developments. But the mere availability

The Rise of Technology

Assessment

13

o f a T A methodology could not completely reassure its members. Congress also wanted to regulate the institutional context of TA studies in such a way that they would be tak­ en seriously. A ccording to Congress, this would imply, first of all, that a new structure for T A studies should be created as an institu­ tionalized element of the Congressional work unto itself, and secondly, that this new struc­ ture should be given the necessary staff and funding to organize T A studies in a profes­ sional, systematic and consistent way.

4.2. 1 A Congressional Institution There are at least three reasons why Con­ gress wanted to develop the new TA i nstitu­ tion within Congress itself. ( 1 ) The basic reason is that , i n the US, it is the President and his administration who are the major initiators and promoters of national technological projects, while Congress asserts that it is the only institution that can effec­ tively put pressure on the President to stop or modify his technological proj ects, in the event the results of a T A study would have un­ masked their irrelevance or hazards. The most direct tool of Congress consisted in its power to control the budget of the President. In the United States, the White House can do relatively little without the consent of Con­ gress. which must approve the budget needed to carry out its plans. Thus the famous speech about man landing on the moon, delivered to the American Congress by President KENNE­ DY in 1 96 1 . was in fact not simply an expres­ sion of an undertaking by the President to his people . but was really a request to Congress to give financial support to his plans and to approve the budge t. As long as science and technology were generally considered to be beyond any suspicion, Congress did not feel the need for inte nsive and systematic assess­ ment studies. However, when the conviction grew that technological developments, and therefore also the technological policy of the government, might sometimes be hairy or even problematic, Congress wanted to give a clear sign to the American public that it was ready to shoulder its responsibility and to base its approval on a preliminary careful as-

14

1 The Evaluation of Technology

as

a n Interactive Commitment-Building Process

sessment of the technologies proposed. Con­ gress was naturally quite aware of the extent of the power of persuasion of public pressures (such as activists and lobbyists) in the White House. The tendencies towards a more direct democracy were understandably perceived as threatening by many members of Congress, who preferred to come up with a strong and potent plan to reassure the constituency that they were capable of and effective in fulfilling their mandate to control the executive pow­ er. (2) A second reason for Congress' desire to keep TA under its direct control, is that Con­ gress dwelt in the conviction that the impar­ tiality of the studies could only be guaranteed by relying on inhouse technical and scientific expertise. Congress did not go as far as to re­ quest that this inhouse Congressional office for TA studies be not allowed to subcontract minor or larger parts of the research needed. It felt, however, that working with external groups always carried the risk that such teams would include biased and partial experts, who might have an interest in giving an incom­ plete or distorted picture of the effects of a planned technology. In this sense it was felt that only the Congressional office itself could bear the responsibility for the final presenta­ tion of the results. (3) As a third important reason for having inhouse expertise available, Congress stressed that this method was the only means to avoid that certain studies which were relevant for policy-making would not be carried out be­ cause of lack of an interested external re­ search partner.

4.2.2 A Strong Institution There are also several reasons which help clarify why Congress was convinced that a proper functioning of TA required a strong, well-staffed and well-financed institute. The obvious reason is that the founding of such a well-established institution presents the only guarantee that technological initia­ tives funded or controlled by the US govern­ ment be assessed in a professional way. More specifically, Congress wanted to take advantage of the growing belief in the need of

TA, to strengthen its internal power and to counter the power of the White House. In fact, Congress had not (until then) ever been really involved in decision-making in the field of new technological developments. Setting the agenda for Government-funded technolo­ gy had always been the exclusive task of the President. The President had, of course, al­ ways been dependent on Congress for budget approvals, but Congress never commanded any serious means of discussing the proposals made by the President. Since the time of Pres­ ident ROOSEVELT, the White House had had the services of a special advisory body at its disposal. This body was led by the "Presi­ dential Science Advisor", and was utilized to determine the technological initiatives of the US Government. As a result, Presidential dossiers were usually well-prepared and con­ vincing. They were filled with tables, lists and figures, which authoritatively explained the supporting scientific evidence of the Presi­ dential initiatives and which illustrated the many benefits these new programs would bring to the American nation. Consequently, Congress did not see any necessity for engag­ ing in detailed discussions on the specific as­ pects of the plans of the President. Nor did it feel the need to, in doing so, prepare a tool of its own which would allow it to contest the conclusions of the Presidential experts. The result is that Congress did not dispose of the experience or expertise it required, when it gradually discovered the need to make its ap­ proval of the President's technology budget dependent upon the results of a serious as­ sessment of the long-term relevance, benefits and dangers of the new technological devel­ opments proposed by the President. On the other hand, the growing scepticism did, of course, also change the attitude of the sea­ soned Presidential advisors. They increased the strength of the scientific evidence endors­ ing their plans, they multiplied the number of pages of their reports, and they used ever more sophisticated strategies to convince Congress of the necessity of the technologi­ cal developments they proposed. R OB E RT McNAMARA, President JoHNSON's Defense Secretary, was notorious for his use of the computer in his attempts to silence members of Congress in debates and hearings. In this

5 co n t ext . Co n g r ess fe l t t he need for a s t r o n g counter-attack. which would lead to the es­ tablishment of a s t ro n g in-house office for the st ud y of te chn o logy . This is why. in 1 96 7 . re pr e s e n ta t i v e EMILIO Q. DADDARIO. chairman o f the subcommit­ tee which ex pl o re d the need for T A. i n t ro ­ duced b ill H.R. 6698. which - be i n g the result of severa l hearings an d internal deliberations and e x t e rnal studies - fi n a ll y led i n 1 973 to the e s t abl i s h m e n t of a new Co ng res s i on a l Of­ fice . the " O ffi ce of Te c h n o l o gy Assessment"". or '' OTA "". di r ec t e d by E M I L I O Q. DADDA­ RIO. It is c l ea r t h a t t h e White H o use was not incl i n e d to favo r t h i s de v el op m e n t . On the contrary. the R e p ubli ca n President N IXON . during whose Pre s i de n t i a l term OT A w a s fi­ nally set u p . did his u t m ost to combat t h is i n ­ t ern a l st re ngt h e n i ng of the t h e n pre d o m in a n t ­ ly De mocrat i c Congress i n t h e area of s c ien ce policy . But w h e n President N IXON fi nally si gne d the bill, OT A became established as an autonomous Congress ional bod y. I t was founded on the idea t hat it sho uld not h a v e any other master than the obj ective re qu ire ­ ments of its ne u tra l . scie n t i fic T A methodolo­ gy. which is a ble to monitor t he t e c h n o l og i cal i n i tiatives of the US Government. Conse­ qu e n t l y , it was accorded a l l kinds of r i ght s to guarantee its a u t o n o m y . also towards the power and influence of the P r esid e nt and his a d m i ni s tr a ti o n . It was give n the r ig h t to pub­ lish the resul t s of its s t u d ie s . w he ne ve r t h ese app e a r e d to make sense . albeit in the face of ex pl i c i t disapproval by t h e executive powers. This i s what h app e n ed in 1 988 when, under strong p ro t es t of the Pe n t a go n and the De­ pa rt m e n t of Defense . OT A p u bli sh e d its as­ sess ment of the S t ra te gi c Defense I n itiative under the title " S O l : Te c h n o l og y Survivabili­ ty and Software '". OTA was also given t he ri g ht to call w i tnesse s and to d em a nd a l l doc­ ume nts necessary for the success of its work. In this sense it h ad been given the power of a strong. p o lit i c a l . pa r l i a m e n t a r y c ommittee with the m a n date to tra ck and monitor t h e White Ho u se in its act ions.

The End of Technology Assessment

15

5 The End of Technology Assessment The T A experiment of the US Co n gress is more than 20 years u n d e rw a y b y now. OTA has b e com e a well-known a n d internationally respected body. It functions as a para d i g m for many w e ll - i n s p ired people all over the world, who are convinced t h a t technological devel­ opments re q u i re s t ri ct c o n t r o l and gu idance , but who fail to see how this ca n be d o n e . OT A gives them hope. For t h e m , OT A is a s y m bo l of success. It is the l i v in g evidence that it is n o t j u s t an unattainable dream to create an institution which can keep t e c h n olo ­ gical de ve lop m e n t s on the ri g h t track. O T A. g iv e s them the courage t o fi gh t and lobby in o rd e r to introduce a si m il a r institution in their own coun t ry , all ow i ng the l ocal politi­ c ian s to differentiate be t wee n t e ch n o l o gie s which are i r r e l e va n t and hazardous and de­ ve lopme nt s which are relevant a nd sa fe . I n sho r t , the TA i n iti a ti v e of t h e U S Co n gre ss ga i n e d wide acce p ta nc e as the ap pro p riat e way to deal with social p r o b l ems linked to technology. Many people, w h e n t h ink i n g abo u t ha n d li n g te c hn o l o gical developments p rope r ly . do not fee l the need to go any fur­ ther t h a n s tu d yi ng an d im pl e m en t ing the same m e t h odolo gy which we described in the p re v io u s section and for which the US Con­ gress c o i ned t he s pecifi c name "TA " or " ' Tec h nol o g y Assessment . "

5 . 1 A Recognized Failure D e s p i t e its initial success a n d d es pi t e the fact that the TA me t h o do l o gy appears to be unquestionably co n v i ncing and self-evident, e v e ry bo d y who has a closer look at what h ap ­ pe n ed in OT A can o nl y come to the conclu­ sion that T A. as created by the U S Co n gr e ss , did not work and never will. By t he e n d of t h e seventies. there existed a fa irly gene ral con­ s en t that OT A w a s not capable of ach i e v i n g the g o a l for which it had been founded. These ins i ghts were shared by scholars like VARY T. CO ATES . who at the beg i nni n g of the 1970s h ad worked enthusiastically on the de v el op-

16

1

The Evaluation of Technology as an Interactive Commitment-Building Process

ment of the theoretical structure of a scien­ tific "T A discipline". In 1 979 she writes: "Technology Assessment . . . had its day and has faded into the background along with planning by objectives, and Program-Plan­ ning and Budgetting Systems (PPBS), and other nonce phrases cum slogans recorded in the history of public administration" (VARY T. COATES, 1 979). Reports prepared by OTA virtually never achieved the level of scientific indisputability which had been envisaged. On the contrary, serious doubts arose at fairly regular intervals concerning the completeness or the "scien­ tific" nature of the studies carried out. Nor did OTA succeed in establishing an early warning system, coming up with wide-ranging and timely forecasts of potential social prob­ lems and environmental risks associated with the continued development of science and technology. Finally, OTA reports hardly ever affected actual policy-making. The influence of the studies on policy can in fact be de­ scribed as varying between minimal and non­ existent. For many analysts of technological devel­ opments, these rather negative observations did not come as a surprise. Even before OTA was established, as early as 1968, the National Academy of Sciences (NAS) in Washington, DC was asked by Congress to give it advice on how to organize an effective assessment of technological developments. This advice turned out to be a strong warning against any attempt to guarantee the relevance of tech­ nology by trying to install some type of agen­ cy which would function as a neutral j udge who is able to find out what is good for "so­ ciety" or for the "environment" and who is empowered to indicate which technological developments should be permitted and which prohibited. The NAS report clearly demon­ strates that this is not the way technology can develop or can be controlled. It concludes that it is simply an illusion to hope that a so­ called neutral and objective agency would be able to solve the problems linked to technolo­ gy. Proper decisions about technology require assessment procedures that differ completely from the creating of a centralized office of TA, and completely different studies than the all-encompassing TA studies OTA was

dreaming of. We will expand on this later. But first we want to analyze what exactly went wrong in the implementation of OT A. The problems appear to be very fundamental. It turns out that the concept of "Technology Assessment" as developed by the US Con­ gress was built on a complete misunderstand­ ing of what both "technology" and "assess­ ment" really are.

5.2 An Inadequate View on Technology

It is a common mistake to imagine science and technology as a totality of processes whose internal progress is determined by an implacable, strict, scientific method. In this view, technological developments can be compared to the movement of clocks which run according to their own dynamics. Once the process is started and its momentum kept up, its continued internal progress is regarded as being objectively fixed. According to this view, "external" institutions, such as public authorities, must refrain from any attempt to intervene in the "internal" dynamics of science and technology. Should they try to do this, the scientific quality of the processes can no longer be guaranteed. There is, however, another way for "external institutions" to in­ fluence the course of science and technology without endangering its internal logic. The basis of this type of interaction is the fact that many external conditions and bodies "from outside" are or can be involved in decisions about which scientific and technological pro­ cesses will be permitted, started, encouraged, held back or stopped. In all these "external interactions", the internal logic of the tech­ nological process is left untouched. This pos­ sibility formed the opportunity the US Con­ gress wanted to seize in order to prevent irrel­ evant or dangerous technological develop­ ments. This possibility was also the context for developing TA, which was believed to provide a solid basis for such "Go" or "No­ go" decisions by presenting a reliable and comprehensive analysis of what would really happen when a new technological process would be allowed to start.

5 The End

of Technology

17

Assessment

study does n o t attempt to forecast which of these scenarios will actually present itself at some time in the future. This, after all, will depend on the u n p re d i ct ab l e way in which the scientists, the decision-makers and the public will react at crucial moments in the fu­ ture. It is believed, however, that such a b roa d e r assessment of all scenarios, while be­ 5 . 2 . 1 Predictabi l ity ing of a less rigorously predictive nature, is still able to provide valuable insights in the possible future of a particular technology . Technol ogi cal d e v e l opments appear to The great problem with this "scenario have little in c o m m o n with the widespread thinking" is that it still c l i n gs to a classical idea that autonomous. homogeneous. p red i c t able processes are completely determined by view in which scientific and technological de­ some internal scientific logic. Instead, they velopments are rega rded as predictable pro­ appear to be complex social processes with cesses into which it is possible to have a con­ many poss i ble side-branches and alternatives. tinuous insi g h t. Although scenario a nalys t s I n designing and de v e lop i ng new technolo­ show themselves ready to take account of var­ gi e s scientists are continually faced by ious unpredictable in fl uences and all kinds of choices a n d are constantly forced to take social factors. they ultimately think it must be creative decisions concerning the di rection possible in principle to chart these influences th ey will follow in the fut ure. Many of these with reasonable clarity. This view, however. "internal" decisions a re co-determined by a makes no allowance for the individual nature multitude of "external" influences to which of the many conscious and unconscious con­ th e y are exposed. which feed and m on i tor trolling factors which are constantly at work their work and which are taken on board. It in scientific and technological d e v e l op m ent has been wid e ly demonstrated by now that This means that the sc e nar i o s described are the concrete form which a given scientific or those which t he client and the research group, technological development fi nally takes and possibly after wide consultation and study, the way i t is i m p l e mented in society. is not are willing and able to think of. The selection just the result of the internal logic of some of scenarios is therefore subject to their con­ clear methodology , hut also of a multitude of scious and unconscious preferences, and is individual and collective decisions and inter­ still far removed from the dreamed-of "objec­ ests. This concrete for m is anything but pre­ tive overview" of the future of a given tech­ dictable . due to t h e great number of variables nology. which a T A analysis promised to be. and the hig h measure of uncertainty inherent to t e ch no l ogic a l developments. A compre­ hensive analysis of the many types of conse­ 5 .2.2 Controllability quences of this technology for social life or the environment proves even less feasible. We have seen that the multifaceted com­ A proposed new way of avoiding this prob­ pl e x it y of real-life technological develop­ lem would be to ensure that an assessment ments precludes the possibility of providing a study does not s i m p l y entail an analysis of the ful l and reliable picture of their future conse­ co n s e q u e n ce s of a technology, but would also quences. Another aspect of this complexity is entail a whole decision-mak i n g and informa­ the impossibi l ity for outsiders, like TA an a ­ t io n process which will accompany the devel­ lysts of the members of the US C o n gres s to opme n t of that technology. A good assess­ supervise the implementation of specific tech­ ment stu d y then does not t r y to come up with nological products by the sim p l e Go/No-go a clear "prognosis" of the future technology decision giving specific technological pro­ and its consequences. Instead. it aims at pre­ cesses the gree n light, while nipping others in senting the total picture of the various possi ­ the bud. Could Congress really prevent some ble future developments (scenarios). The dangerous or undesirable future conse-

In real life technology, such solid TA p re­ appear to be unrealistic, just as much as the belief t ha t si mp le Go/No-go decisions bv external actors can determine whether or n o t spe c i fi c t echn o l ogica l developments will or wil l not he realized.

dictions

­

,

.

,

18

1 The Evaluation of Technology as an Interactive Commitment-Building Process

quences of a specific technological evolution by using all its power and authority to stop its development ? We have more reason to be pessimistic than optimistic concerning the power and the potential of such clear "No-go decisions". Obviously, it is possible for a financier to call a halt to a good many concrete research pro­ jects by turning off the flow of cash. An au­ thoritative government body can achieve the same effect in many other ways as well. And yet the influence of such decisions, even if they may be immediately successful, is always fairly limited and short-lived. Is it not suffi­ cient for the research group simply to find an­ other financial backer? Cannot the power of certain authorities be circumvented by con­ tinuing the same research in a location where the prohibiting authority has no say? There is a good chance that this could happen. After all, a decision to halt a scientific process al­ ways ends up in the midst of a complex force field in which a great number of other inter­ ests are already at work. The fact that one of the interested parties withdraws because he no longer finds the process interesting, or even feels it to be dangerous, does not neces­ sarily mean that the others will follow him and that the process will come to a standstill. It is more likely that the other partners will go in search of ways to continue the process and that they will if necessary seek out new interested partners. These are the sorts of considerations which regularly lead to the strange situation where­ by persons or institutions are genuinely con­ vinced that it would be better on the grounds of "higher motives" to halt an interesting de­ velopment, while they in reality simply carry on. The reason then given is that it is never possible to prevent the same work being done by others in another place, so that it is ulti­ mately felt to be better - if the work is to go ahead anyway - that those already involved should be the ones to reap the rewards. Moreover, scientific and technological de­ velopments do not simply follow a single straight line towards a certain goal, but rather seek their way through a multitude of pro­ cesses which in turn constantly branch out in various directions and cross each other again at various levels. In such a tangled web, an

"undesirable " effect which was revealed as a potential consequence of one specific devel­ opment may also come out of the blue as be­ ing the quasi-coincidental result of a whole series of completely unrelated technological developments.

5.3 An Inadequate View of Assessment

We mentioned that "Technology Assess­ ment", as created by the US Congress, is not only built on a completely inadequate view on technology, but also on a completely un­ workable view on assessment. In the previous section we explained that the sort of technol­ ogy the US Congress wanted to assess does not exist in real life. The manifest conclusion was that the TA methodology is totally un­ suitable for clarifying the possibilities, chal­ lenges and potential problems related to tech­ nological developments as they actually ex­ ist. We will now explain the problems of the TA methodology which are due to inadequa­ cies and ambiguities in its underlying concep­ tion of the general process of political assess­ ment. In fact, even if real-life technology proved to be the simple, straightforward and predictable process as TA assumes it to be, the TA methodology of the US Congress would still be doomed to failure. We will ex­ plain first the inadequacy of its theoretical view on assessment, and later the ambiguity of its practical view. 5 . 3 . 1 Obj ective Overall Assessment

The whole expected purpose of T A was to provide the members of Congress with an evaluation, an assessment of a specific tech­ nological project under discussion. This means that a TA report should contain the scientific evidence required to demonstrate to what extent the different facets, results and consequences of a specific technological pro­ ject will be dangerous or harmless, irrelevant or needed. EMILIO Q. DADDARIO, the driv-

5 The End

ing fo rc e beh i n d the establishment of OTA a n d its first director. put it as fo l l ows: "Technology a s sessm e n t is a fo r m of policy research w h i c h p ro v i de s a balanced appraisal to the p o Ji c y ma k e r ( E M I L I O Q. D A D D A R I O . ""

1 968 ).

This balanced evaluation is in fact why Congress o r i g i na l l y fel t t h e n e e d for c re ati n g a me c h a n i s m for obj ec t ive Tech n o l o g y As­ sessment. .. Co n gre s s created OT A i n 1 972 to meet its n e e d for a s o ur c e of technical infor­ mation that is nonpartisan. o bj ec t i v e and an­ t i c i p a t o r y . . . M e m bers of C o n g r e s s began to wonder whom to b e l i e ve as an expert because it a ppe ar ed that there were expe rt s 011 all s ides of an issue . I t b e c am e obvious that Con­ gress needed its own source of nonpartisan. in-house technical analytic help·· (CHR ISTINE LAWRENCE. 1985 ). C o n g re ss wanted to m a k e scie n tific e vide nce its only a d vi se r It was dis­ trustful of i n dust rial lo b b y i st s or P r esid ent i a l advisors who d we l l e d solely on t h e beneficial consequences of t he technology t h e y wanted to promote while d o w n p l a y in g p ote n t ial ris k s . Congress also looked w i t h distrust on activists a n d members of the a n t i t ec h n o log y lobby who come up with e n d l ess lists of r i s k y haz­ a r d o u s and bad c o n s e q u e n c es which are in­ v a r i ab l y prese n t e d as d a nge r s t o su c h i m p or tant goods as human health. the environment. the a i r , soci a l life . and many other elements. OTA was e s t a b l i s he d as a n ind e pen d e n t re­ source which w a s c a p a b l e of m a k i ng an o bj ec t i ve a ppra i s a l and allowing the m embe r s of Congress to make d ec i s i o n s based on facts. rather than on empty rhetoric. Th is is why Con g r ess wanted t h e reports of its T A o ffi ce to be explicit a n d e x h austive about a n t i c i ­ pated problems and d a n ge rs as well as about e x p e c t e d ben e fi t s and p r o m i se s I n n u r t u r i n g these beliefs the U S Con gr es s is a chi l d of i t s time. It s h are s the e x pec t at io n s which have grad ual l y g a i n e d w i de sp re a d credibil ity since the e i g h t e e n t h c e n t ury. t h e age of the E n l i g h t e n m e n t . Keywords here are notions like h a r m o n y cert a in t y '"obj ec­ tive knowle dge . . . In fac t , the ideas of a homo­ ge n e o us and predictable sc ie n c e and tec h n o l ogy are part of a p a r t icul a r embodime nt of the Enlig h te nme n t ideals. which we will call the •·certainty-based" or '"completely-objec­ tivistic" E n l i ghte nm e n t v iew . Th is E n l i g h t en .

.

-

.

,

­

­

.

'"

".

..

".

­

-

of Technology

19

Assessment

ment view embraces t h e ideas that a balanced a pp ra i s al o f c o mp l ex human situations can be achieved t h rough the meticulous comp i l i ng d ed u ci ng a n d com p a ri n g of objective facts and that responsible de c i s i o n ma k i n g is une­ q u i v oca l l y determined by these o bj ect i v e and incontestable i ns i g h t s It is cl e a r that these types of E nl i g h tenm e n t beliefs have l eft t h e ir mark on every layer of our mo d er n culture and our modern b od y of t h o u g h t The idea of a purely l og i c a l and c o nt r o l la b le science and tech n o l og y which as we have seen is an un­ realistic myth, is in fa c t only one of the many traces of this s pec i fi c E n l ig h te n m e n t view. While the ce rt a i n t y b a s ed E n li g h te nm e n t p roj ec t has nev er been wit hout i ndividual critics and w h i l e its fa ilure a l re a d y gave rise to wid e sp rea d scept i c i sm and relativism, o nl y in t h e sixties d i d a powerful and sustained process of c r i t i q u e really break t hr o u gh It is n o t difficult to see t h a t its ideals per­ t ai n i n g to strong and certain assessment and d ec is ion m a k in g are as unrealistic a s i t s co n ­ ce p t ion of science and t ech no l ogy Decisions on re sp on s i b le action and a gl ob a l assessment of a co m p l ex human situation are simply n ot as straightforward as we would h o pe and as the cert aint y -b a sed E nl ig h t e nme n t vision wants us to believe . We do not need a lot of theoretical a n a ly s i s to realize that there is something askew w i t h t h is pu re l y objectivistic view o n a ppra i s a l and decision-making. I t i s somewhat more difficult to grasp how a more rea l i s ti c u nders ta n d i n g of r a ti o n a l dec isi o n ­ m a k i ng can be d e v e l ope d We will h a ve to c om e back to t h i s later. For the m o men t we can limit ourselves to unfo ld i n g the i de a that " pure fa c t s " and "an o bj e c t i ve analysis of a situation" ( s h ou l d they exist altogether) can i n no way present a balanced appraisal w h i c h could function as the uneq u i v o ca b l e guide to re s p o n s i b l e a c t i o n . We can illustrate this idea with an example from clinical g e n e t ic s where fu t u re parents sometimes seek t o d i s c over t h e r i s k s t h ey run of h a v i n g a child with a part i c u l a r disorder. N o-o n e will doubt that i g n oran ce on such q ue s t io n s is a great d i s a dv an t age . B ut the conscious o r un co n sc i o u s a p p re hens i o n s which people nurt ure conc e r n i n g p rec i se fig­ ures or a p rec i se des c r i p t i o n of the p oten t ial disorder are fre q u en t l y e x a gg era t ed . M a n y ,

-

.

.

.

-

.

-

.

.

.

,

20

1

The Evaluation of Technology as an Interactive Commitment-Building Process

secretly hope that they will ultimately know what to do when the objective figures are available, but these people tend to be cheated in their expectations. For example, there is absolutely no such objective guideline encom­ passed in the knowledge that there is a 25% risk of having a child with a given heart disor­ der, if there is no means of tracing or prevent­ ing this disorder before the birth. Should a couple give up a planned marriage in such a case ? Should all plans to have children be abandoned? Should the couple use one of the technologically aided forms of reproduction? Knowledge of obj ective figures and data gives no answer to these and other questions. Peo­ ple then usually want to hear more from the counsellor than statistics and objective prog­ noses. They hope the counsellor can also give them objective information about the best course of action left open to them at that point. They try to find out what the counsel­ lor would do in their situation. Counsellors are well-trained, however, not to answer these questions. They realize that any answer that they would give would go beyond the limits of the solid information they can pro­ vide and would simply be an expression of their subjective evaluation of the situation. They even know that their evaluation would be somewhat unrealistic and beside the point, because they are not in the exact same situa­ tion as their counsellees. The counsellors' subjective evaluation cannot take into ac­ count the complex mix of feelings they cannot possibly share with the counsellees. Counsel­ lors realize that even exact figures, trends and facts do not give us a complete picture of their acceptability or desirability. Having a balanced assessment of a situation is always something more than knowing and accepting the generally recognized facts about the situa­ tion. Facilities for genetic counseling have de­ veloped strategies for dealing with those un­ certainties. These strategies reflect the belief of these facilities that the information they can provide is of utmost importance as well as their understanding that this information has only a limited value. They know that they cannot provide a balanced appraisal of the situation of the counsellee and they are not in the position to tell them what their responsi­ ble decision should be.

The situation of policy-makers who deal with technological projects, is quite similar to the situation of parents. B oth have to make appropriate choices among different alterna­ tive actions with far-reaching consequences. Both try to gain a better understanding of their situation by obtaining scientific informa­ tion. In neither case, however, can a detailed report full of figures and data replace the bal­ anced appraisal of the decision-makers in­ volved. A major difference between the par­ ents and the policy-makers is that the institu­ tions which are created to help parents are well-aware of the difficult and complex na­ ture of the decisions to be made, while the of­ ficial ambition of OT A, as created by the US Congress, was to produce scientific informa­ tion which provides a balanced appraisal of the situation. It should have become obvious by now that "assessment" of, and " responsi­ ble decision-making" in a complex situation simply does not work this way.

5 . 3 . 2 Subj ective Overall Assessment

While absolute obedience to scientific ob­ jectivity is given lipservice in the official de­ scription of TA, experienced policy-makers like the members of the US Congress have al­ ways known better. In reality, they never be­ lieved that someone else could come up with a balanced appraisal of a situation where po­ litical decisions have to be made. It would have been consistent with the general ap­ proach of scientific neutrality to appoint a small group of authoritative, skilled research­ ers as staff members and to give them the re­ sponsibility for setting up the Congressional TA activity. This scientific group should then assume the responsibility of identifying the assessment studies to be done, for selecting, hiring and firing the scientific collaborators, for carrying out the research and for publish­ ing the policy-preparing TA reports which would contain the overall balanced apprais­ al. In practice, the members of Congress tried to be more closely involved in pulling the strings of OT A. In each and every step they

5 The End

embodied the idea that p o l icy- m a k i n g tran­ scends scientific a n a l ys i s . (a) Fi rs t of all, Cong r e ss u nd e n i ab l y con­ sidered the task of choosing the issues to be studied as a pol it i cal and not a scientific mat­ ter. Me m be r s of C o n gre s s wanted to retain the exclusive right to i ni ti at e T A s t u d i es . OT A could o n l y carry out those studies w h ic h were e x pl icit l y requested by t h e Congression­ al commi t te es and su bc om m i tt e e s. In t h e o ry . the director and the M a n age me nt Board of OT A (officially n a m e d the TAB or Te c h n olo­ gy Assessment Board ) . could also initiate studies. I n pra c t i c e . OT A m a de l ittle or no use of this p oss i bility . Be s i de s , i t would not really make much of a d i ffe re n c e if it did. EM I LI O D A D D A R IO . OT A's fi rs t director, was a former Congressman and could h ardly be c ons i d ered a n independent scientist. Fur­ thermore . the charter of OTA required that the twelve me m b er s of t h e Manage ment Board we re a l l e lected me mbers of Co ngre ss . six fro m e a c h po l i tic a l party. (b) Seco n d l y . Congress did not o n l y want to d e c i d e what was to be s t ud i ed . it al s o wanted to monitor the work of the sci e n ti s ts who were act u a l l y c a r ry i n g out the re se a rc h . So. it proved to be usual in D A D D A R I 'j "2;.? " J

A n i ma l s

0

20 4 0

60

0

80 I 0 0

H u m a n cel l s

Plant cells

Plants

Microbes

Microbes

A n i ma l s

Anim als

Plant cel l s M i c robes A n i mals

0

2 0 40 60 80 I 00

J a pa n e s e s c i e n t i s t s :

be ne fits

20 40

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New Z e a l a n d p u b l i c : r i s k

H u m a n cells

Human cel l s

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Japanese p u bl i c : risk

0

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New Zea l a n d s c i e n t i st s : r i s k

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H u m a n cells

Human cells

Plant cells

Plants

M ic r o bes

Microbes

A n i ma l s

A n i mals

0

2 0 4 0 6 0 80 1 00

2 0 4 0 60 80 I 00

0

20 4 0

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Fig. 3 . Comparative perceptions o f the benefits a n d risks o f genetic manipulation i n Japan and N e w Zea­

land by public and scientists. Results from Japan are from Q7 of MACER (1992a), and New Zealand results are from the survey of COUCHMAN and FINK-JENSEN (1990).

The major reasons cited for the unaccepta­ bility of genetic manipulation (Tab. 2) can be grouped into categories:

1. 2.

Unnatural, playing God, unethical, feeling Disaster, fear of unknown, ecological and environmental effects

3. 4. 5.

Human misuse, insufficient controls, eugenics, cloning, humanity changed Health effects, mutations Not stated.

Group 1 concerns may persist with devel­ opment of the technology, but group 2 and 4

4

131

Perceptions of Ethical Biotechnology

Tab. 3. Benefits n f Genetic Ma nipulation Cited b y Respondents Japan Orga nism

% who

saw a

be nefit

New Zealand M p

Group

H

p

M

A

H

p

37.7 5 3 .5

78. 9 86.8

6 8.5 80. 5

53 . 1 7 1 .0 74.3

48.4 59.8 55.0

87.5 96.6 94.2

0.2 0.5

10.6 29.9 20.9

0 0

T

60.8

88.0

p

8.3

T s

24.4

0.4 0

24. 1

0

0.2 0 0

s

86.5

62 . 7 8 1 .2

8 1 .9

A 66.4 8 1 .6

8 1 .6

Reasons c ited as b e ndits ( % total respond e n t s ) :

Cure or p revent g•: n e t i c disease

0

1 .6

0

Disease con trol

p T s

5 .-t 10.0 1 1 .8

2.7 5.2 6.4

2.3

1 .2

3.6

4 2 .5

2.7

1 5 .0 7.2 1 1 .0

35.8

1 6.9 13.8 7.4

Medical a d v a nce . cancer cure

1 .8 1 .9

p T s

5.4 9. 1 7.0

1 .9 2.2 1 .7

1 0. 1 10.9

2.7 5 .9 4 .4

1 .7 19.3 2.8

3.2 1 8 .8

Make medicines

p

() 0.5

0.2 0 0.6

8.7 1 6. 7 31 .9

p T s

0.2 0 0.6

1 .3 2.2

p

0.6 3.2 3.1

Make use ful subst :mces. industry

Scien tific knowledge

T s

T

s

Agricultural adva nce

T

() 0

p

0.4

p

s

Increased yield.

to

m a k e m o r e food

Different varieties

T

0

0

s

0

p

0

T

0

s

Incre ased q ualit�

0.2

0

7. 1

4.4

23 . 1

9.3

2.3

14.8

()

0.8

20.5

0.2 3.0 3.3

1 .4 4.5 4.6

1 .8 6.8 8. 1

2.0

1 .0

0.4

6.7 3.8

3.1

4.5 2.7

1 9.2 23.2 20.7

16.9 1 8 .8 23.0

4.7 7.2

8.0 1 1 .8 1 3 .5

0

1 1 .5 27 . 6 22.4

20. 1 40 .6 4 4 .3

1 .9 3. 6 5.8

6.8 1 9. 9 1 6.4

1 7 .5 29.0 22 .6

0

2 .5

5.0 6. 7 3. 5

33.2 2 1 .3 24.5

4.3

1 .6 9. 1

1 .9 0

s

0.8

Exports increase . ..:conomics

3.8 3.5

p T s

0.5 0.9

0.4 3.8

Env i ronmental advan tage

p T s

0

3.6 1 .5 5.3

4.9

Ul

0.5

5.4

1 .0

p

5.1

T

1 .8

8.0 4.2

6.6 7.2 6.0

()

H u m a nity benefi t� - whole world be nefits

Doubtful benefit

B.:ncfit

not

stakd

0

9.7

3.5

0 1.7

3.7 0.5

4.6

s

5 .4

6. 1

7.4 6.8 6.9

p T s

0. 4 0.9 0.8

0.6 0.7 0.8

0.4 0.9 0.8

p

1 2.8 8.6 1 4. 1

30. 1 1 5 .0 26.3

25.8 1 7. 2 26. 1

T s

2.0 6.5 4.9

2.0

1 .8 5.2

p

0

8.2

10.6

26.9 22.0

0.5 1 .9

T

2.3

1.7

0 0

3.5

0.5 2.9

47 . 1 37.7 3.4

0.6 1.1

1 .9 0 1 .1

1 .4

3.9

1 .9

7. 9 2.9 1 0 .4

6.3 0.8 6.6

4.0 1.6 2.4

8.2 20 . 3

6.6 1 1 .4 8.2

24.6

1 0.6 3 1 .8 3 1 .0 12.2 1 0 .6

3 2. 5

32.6 36.7

1 .3

7.3 4. 1

7.3

7.3

1 1 .4

6.9

1 0.6 2.4 6 .0

2.6 0

5.6 0 4. 9

4.0 0

9.7

7.0

1 8.8

9.3

1 .6

3.8

4.9

2.4

0.9

1 .6

0.5 0.6 1 9. 4

20.5 22.0

The v a l u e s a r e expressed as % of t h e total respondents w h o an swere d Q7: in Japan, p ub li c N = 485 , teachers N = 2 2 1 . scientists N = 5 1 8 ( MA C E R . 1 992a ) ; and New Zealand. p u b l ic N = 2034, teachers N = 2 77 , sc ie n t ists !\' = 2 5 8 ( Co u cH '-l A r>; and FINK-JENSEN. 1 990) . Organism: H. human cells; P. plants; M. microbes; A, animals. Group: P . public : T . high school biology teacher; S. scientist . The absence of data is indicated by ·-·

132

4 Biotechnology and Bioethics: What is Ethical Biotechnology?

Tab. 4. Risks of Genetic Manipulation Cited by Respondents

Organism % total who saw risk

Japan M

Group

H

p

p

83.3 85.6 70.8

39.5 54.7 42.9

3.9 10.4 7.1 7.2

0 0

T

s

A

H

53.6 69.6 5 1 .7

6 1 .3 68.7 54.3

74.4 43. 9 56.7

0 0 0.4 3.1 0.9 1 .5 3.7 7.7 3.3 7.8 9.0

1 .0 1 .4 2.3 4.9 2.2 2.7 3.7 5.0 3.9 8.5 9.5 7.9 12.1 1 5.4 10.6 1 .5 1 2.7 2.5 4.9 6.4 1 1 .0 0.4 0.9 0.6 0 0 0 0.4 0 1 .2 2.1 5.0 2.1 3.3 3. 1 6.2 1 .0 0.5 1 .2 24.7

3.7 12.3

New Zealand p A M 42.4 25.6 38.9

67.4 57.5 56.1

58.4 25.0

0 0.5 5.5 4. 1

0 0 4.7 2.3 1.7 16.8 25.3 26 . 9

4.5 3.5 5.3 3.8

43.3

Reasons cited as risks (% total respondents): Unethical, ethical abuse

p T s

Playing God, unnatural

p T

Disaster, out of control

p T

s

s

Fear of unknown

p T

s

Ecological effects

p T

s

Biohazard, spread of genes

p T

s

Danger o f human misuse, biowarfare

p T

s

Eugenics

p T

s

Cloning, human reproduction abused

p T

Humanity changed

p

s

T s

Deformities, mutations

p

T s

Insufficient controls, need public discussion

p

T

s

Economic corruption of safety standards

p T

Not stated

p T

s

s

2.5 4.1 0.9 17 2.7 5.3 2.3 2.7 5.9 4.2 2.5 9.7 6.8 10.4 8.2 10.2 7.5 7.9 8.9 9.1 7.4 5.4 14.5 1 4.0 7.3 3.4 10.0 1.9 0.6 2.9 9.5 1 .8 5.9 3.3 3.7 1 .7 4.1 6.6 8.4 1 1 .7 5.5 9.5 15.8 9.9 1 1 .8 0 3.5 0 8.2 0 0 5.0 0 0 2.2 0 0 0 0 3.2 1.9 0 0 0 5.2 0 2.7 0 0 0.6 6.8 0.8 1 .5 0.4 4.9 2.3 10.0 2.7 1 .5 4.2 1 .7 2.2 4.5 2.2 3.6 3.2 3.2 5.6 7.0 5.6 1 .0 0.8 0.8 0 0.4 0.5 1 .2 1.1 1.2 33.2 13.8 1 9.8 23.6 13.6 15.8 22.0 12.1 1 5 . 2 .

13.6

6.0 3.5 1.1

5.1

18.6

1 0.6

6.6

4.6 1 1 .3 5.1 3. 1 9.3 5.1 10.2 5. 1

12.5 9.7 4.4

10.2 0 0

7.4 4 .6

8.0 3 .4 6. 3 7.4

5.1

1.8 8.2 7.5 9.1

0.5

1 8.4

4.6

3.4 2.3 5.7

5.1 6.7 2.9 7.4

0 0

0.6 0

3.5

4.3

1 2 .3

5.0 1 1 .7 7.6 2.0 9.5 6.4 45 .

6.9 3.5 1 .3

5 .3

3.0 4.8

7.0 3.5

2.8 17.1 4.8 1.1

8.2 4.4 1 0.8

0 0 6.4 3.8

0 0 15.5

10.8

10.4

0.8 0.9 6.4 2.0 0.4 7.0

4.6

4.0

9.1

8.7

1 4.8

10.5

2.3

2.6

16.7

17.4

5.1

3.1

The values are expressed as % of the total respondents who answered 07; in Japan, public N = 485, teachers N = 221, scientists N = 518 (MACER, 1992a); and New Zealand, public N = 2034, teachers N = 277, scientists N = 258 (CouCHMAN and FINK-JENSEN, 1 990). Organism: H, human cells; P, plants; M, microbes; A, animals. Group: P, public; T, high school biology teacher; S, scientist. The absence of data is indicated by '-'

4

concerns may he le sse ned by develop m e n t of technology. G roup 3 concerns can be les­ se n e d by regulations. as will discussed in Se ct . 8. People who d id not cite a reason may feel less strongly about the issue. but there is no real indication of what concerns they had. We should also note that many people expressed r e asoni ng across several of these types of con­ cern. The most common response in both coun­ tries for a ben t.: fit from ge netic m anipu l a t i on of human cells were medical reasons, as from microbes w he r e the benefit of making useful substances was also often cited ( Ta b . 3 ) . E co ­ nomic benefits were not cit e d much. with more re spondents in New Zealand listing these benefits, pe r ha p s because the economy is so de p e n de n t upo n b io te c h n o l o gy . in te rm s of agriculture . and the economic recession has been much harder there. In the reasons cited for gen e ti c manipulation of a n i mals. many more New Zealanders cited disease control of animals. as a reason. I n both coun­ tries sim i lar p rop o r t i o ns cited ··new varieties'' or "increased p r odu c tio n and food'' as the main benefits of ge netic manipulation of plants and an i m als. with a trend for more New Ze alander� to cite the latter. There was a lso a w i de diversity of re­ sponses to the reasons why people pe rc eiv ed risks from ge n e t ic manipulation (Tab. 4). The frequency of the common responses to Q7d did n ot differ greatly from those given to Q7b. tho u g h many respondents listed differ­ e n t reasons in response to th e se two ques­ tions. The risks were in general m ore involv­ ing h uman misuse . and activity. rather than abstract concerns such as ·· inter fering with nature". They were also more specific. so that more responde nts listed deformities and mu­ t a t io ns as a problem. In addition to ecological and environme n tal concerns. t h e r e were also substantial numbers who cited a risk con­ nected with the sp re a d of genes. vi ruses. and genetica l l y modi fied o r g a n i s m s (GMOs). ge n­ e rally labelled · · biohazard " in the categories in Tab . 4 . A fe w said that sci e n c e was always assoc i a t e d with danger. In a recent E u ro pean p u b lic opinion poll in t h e U.K . . France . Italy and Germany (per­ formed in 1 990 by G a l l u p for Eli L i ly . N = 3 l 56 . DIX O N. 199 1 ) . the respondents

Perceptions of Ethical Biotechnology

133

were asked to choose the largest benefit that they saw coming from biotechnology, be­ tween one of four possible be n efits from bio­ technology. Over half rated cures for serious diseases as the most important benefit. An­ other option was reducing our dependence upon pesticides and chemical fertilizers, which 26% of Italians, 24 % of Fre n ch , 22% of British and 1 6% of Germans, chose as the largest benefi t . The European re s p o n dents were asked a similar q u e st i on about their largest concern. Potential health hazards from laboratory ge­ netic research were named by 29% i n Italy. 1 7 % in France, 1 1 % in Britain and 10% in Germany. 40% of French, 35% of Germans, and 25% of B r it i sh and Italian respondents chose e ugenics , and slightly l owe r propor­ tions overall chose environmental harm, 34% in Britain, 33% in France, 22% in Italy and 2 1 % in Ge r m any . In the European survey, overall one third of respondents feel that biotechnology is ethi­ cal. and one third feel that it is unethical, and one t h ird think i t is i n be tw e e n, "neither". This compares to a more favorable accepta­ b i l it y of ge ne t ic manipulation in Japan and New Zealand, especially for n on - hu m an ap­ plications ( Tab . 2). In the USA w h e n people (N 1 273) were asked whether they thought that human gene t h e r apy was morally wrong, 42% said it was. and 52% said it was not, with 6% unsure (OTA , 1 987). However, o n l y 24% of the USA sample said t h at cr e a ti ng hybrid plants or animals by genetic manipul ation was morally wrong. but 68% said it w as not, 4% said it depends, and 4% said they were un­ sure. The peop le who found it morally unac­ ceptable were asked for reasons, and t h es e reasons can be compared to those given i n Tab. 2 from Japan and N e w Zealand. The US r esu l t s , expressed as % of the total sample. were that 3.1 % said that it was interfering with nature. 2.8% said it was playing God, and about 1% said they were afraid of u n ­ known results, 0.6% said it was mo rally wrong and d i d not cite a reason, and another 2-3 % had other reasons. It does re i nfo rc e the idea that abstract reasons are a major conce rn about genetic manipulation . but further data are needed. In the European survey, e u ge n i cs was the =

134

4

Biotechnology and Bioethics: What is Ethical Biotechnology?

major concern (DIXON, 1991). However, in the Japanese survey and in the New Zealand survey, the proportion of people who cited eugenic concerns from genetic manipulation of humans was equivalent to about 4% of the total respondents, half of the proportion who expressed concern because of environmental reasons, and much lower than the number of respondents who cited reasons related to per­ ceived interference with nature, playing God, ethics, or fear of the unknown (Tabs. 2 and 4). In 1993 surveys in response to the above question Q5d (Sect. 4.2) people were asked to give their reason for concern about "genetic engineering". In New Zealand and Australia 7% of the total expressed eugenic concerns, while only 0.6% of Japanese did (MACER, 1 994 ) . Because free response questionnaire data are unavailable from Europe, we cannot directly compare the apparently higher con­ cern about eugenics in Europe as opposed to New Zealand or Japan. One could speculate that it may be related to self-acknowledge­ ment of t he past e uge ni c abuses in Europe, and due to media coverage of the eugenic concerns raised by organized feminist and Green groups in Europe. Free response ques­ tions may provide a better estimate of peo­ ple's opinions and provide a better picture of actual perceptions than agreement with sug­ gestive concerns. Another feature of the free response sur­ veys was the low proportion of respondents

who cited environmental benefits (Tab. 3). In the European survey, discussed above, the choice of the benefit of reduced pesticide use and environmental benefits was popular. In Japan and New Zealand further questions concerning science were included in 016. Q16. To what extent do you agree or di sagree with the follow i ng statements that other people have

made? 1 strongly disagree 3 neither agree nor disagree

2 disagree

4 agree

5 agree

stron g ly

Q16f. Gen e t i cally modified plants and animals will

help Japanese agriculture become less dependent on chemical pesticides.

The response to Q16f, which asked if peo­ ple thought GMOs would have an environ­ mental advantage, was quite supportive (Fig. 4 ). The 1993 survey found the same values in New Zealand and Japanese public as 1991 , with similar values in Australia (MACER, 1994). The free response questions (Q7c, Tab. 3), however, suggest that it may not actually be a common feeling. Environmental benefits of biotechnology may be very unfamiliar, de­ spite the high level of concern expressed in Q5 about pesticides (Figs. 1 and 2). In both New Zealand and Japan, there should be more publicity associated with this environ­ mental benefit, though the chemical compa­ nies who make pesticides may have different

Public J • S t ro n g l y d1sag ree • 0 1 s a g ree

NZ

Teachers J

• Neither 0 A g re e

NZ

D S t r o n g l y a g re e

Scient i sts J

0

20

40

60

80

1 00

% of re sponde nts Fig. 4. Pe rce p tion of environmental benefits from applications of genetic e n gineering in agriculture in Japan (J) and New Zealand (NZ). Results from Japan are from Q16f of MACER (1992a), and New Zealand results are from the survey of CoucHMAN and FINK-JENSEN (1990).

5 Past and Present "Bioethica/ " Conflicts in Biotechnology

priorities ( see Sect. 7 ). As in the risk of euge­ nics discussed above, we see clearly the lack of reliable dat a about public perceptions. at least. among what has been published.

4.4 Concerns about Consuming Products of GMOs Products produced by genetically engi­ neered microorganisms, such as human in­ sulin or growth hormone . have been ap­ proved for medical use for over a decade . The first food products for human consumption have been approved for consumption. and it i s expected th at v e g e t a b l e products derived from G M Os will be approved in 1 994. We can expect many products t o be approved as safe for human con sumption in the next few years. so a pressing q uestion is what concerns the public has that could result i n conflict. The views o n t h e safety of products made by genetic manipulation were examined by Q8b (MACER. 1 992a) . as had also been used by COUCH M A t\ and FIN K-JENSEN ( 1 990). 75% of the J apanese public said that they were aware that G M Os could be used to pro­ duce food and medicines. similar to 73% of the public in .1\ew Zeal a n d . and in both coun­ tries. 97 % of s.cie ntists said that they were aware of t h i s Free response was requested of the concerns people had:

135

l ogy teachers. which are very concerned in Ja­ pan. Scientists in Japan are also more con­ cerned than their peers in New Zealand. though many Japanese company scientists showed less concern t h a n government scien­ tists (MACER. 1 992a). The concerns included significant numbers who saw the products as unnatural (see Sect. 5 . 1 ), and who had health concerns. Similar reasons were cited in the 1 993 International B ioethics Survey (MACER, 1 994 ). There appears to be joint perception of benefits and risks as for genetic manipulation. In a European-wide survey (N 1 2 800. MACKENZI E. 1 99 1 ) . 65% of people approved of genetic engineering to i mprove food and drink quality. but 72% said that it was "ris­ ky In an earlier US survey (OTA, 1 987) , 80% had not heard o f risks associated with genetically engineered products while only 1 9% had. However. since the time of that sur­ vey . we can expect that many people have heard of concerns about consuming products of genetic engineering. A related issue has been continued controversy about the use of genetically engineered bovine somatotropin, despite evidence that it is safe for human con­ sumption. These concerns will be considered in Sect. 7. =

".

.

Q8b. [f any of the following w e r e t o be produced from ge n e t ically modified orga nisms . would y o u

have any concern' a bout using them ? 1 No concern 2 Conce rn For each product that you are concerned about. what concerns wuuld vou have about u s i n -g i t ? Vegetables Dairy prod ucts Medicines M eat

The results a re l i sted in Tab. 5. Vegetables were of less concern . especially among the p u blic. and meat was the product with the highest concern. Dairy products were of inter­ medi ate conce rn. Medicines were still of con­ siderable concern. New Zealanders appear to be somewhat le-;s concerned about consuming products containing GMOs or made from them. than are the Japanese . The biggest dif­ ference is in the opinions of high school bio-

5 Past and Present

" B i oethical " Conflicts in

B iotechnology From the results of the above public opin­ ion surveys. and other data, we can see which issues among the variety that have been ex­ pressed by academics and protest groups in the decades of debate on biotechnology, are common and which are not. In this section we will consider the m ajor reasons cited for re­ jection of genetic manipulation research . The emotions concerning these technologies are complex, and we should avoid using simplistic public opinion data as measures of public per­ ceptions, rather we need to address the ex­ pressed concerns and apply policy measures

1 36

4

Biotechnology and Bioethics: What is Ethical Biotechnology?

Tab. 5. Concerns about Consuming Products Made from GMOs Product % total with concern

Group

Dairy

Japan Veget. Meat

p

5 1 .6 34.9 36.1

41.0 3 1 .5 32.3

T

s

Med.

Dairy

New Zealand Veget . Meat

55.4 36. 1 38.0

50.5 35.5 28.8

42.8 1 3.0 24.0

38.4 9.7 21.7

48.3 13.7 24.4

34. 1

7.2

Med.

9.7 19.8

Concerns cited about consuming such products (% total): Unnatural, will taste bad

p

T

s Don't know what we are consuming Unknown health effect

p

T

s

p

T

s

Long-term risk

p

T

s

New disease

Side effects

Because it is food, daily use

12.3 1 .5 2.8

7.8 1.1 2.7

2.0

0.4 1.4 0

0.6 1 .3 0

0.7 1 .4 0

0.4 1.4 0

6.0 1 .0 0.7

4.6 0.7 0.9

7.2 0.7 0.7

3 .4 0.4 0.4

8.9 7.2 5.5

7.4 6.3 5.5

9.5 7.7 5.7

7.8 7.7 5.2

9.4 4.0 4.3

7.7 2.9 3.5

10.1 4.7 5.1

7.8 0.4 4.0

2.3 0.9 2.0

2.4 0.4 2.2

2.6 1 .4 2.2

1.9 0.9 1 .8

1.5

1 .1

1 .3

0.8

1 .4

s

0.3 0.4

3.3

p

2.1 1 .8 0.7

0.6 1.3 0.6

1.9 3.2 0.8

5.9 5.5 1.3

3.0 3.2 3.6

2.5 3.0

1.9

2.4 3.4 3.4

4.1 3.6 3.2

6.1 9.5 9.4

5.3

9.1

9.6

5.9 9.0 9.9

5.5 9.5 8.5

5.1 1.8 8.7

3.8 1.9 7.8

4.3 1 .8 7.1

5.1 1 .5 8. 1

0.7 1 .8 1.1

0.6 0.9 0.9

0.7 0.9 1.1

1 .0 0.9 1 .0

1 .7 0.8 1.2

1 .5 0.7 1.1

1.9 0.7 1.2

1 .7 0.7 0.4

1 .3 1 .8 4.6

1.3 2.2 3.3

1.1

1 .3 2.3 3.3

1 .3

1.5

1 .9

0.3

2.3 4.6

1 .5 0 0.2

1 .5 0.4 0.2

1 .9 0.4 0.2

1.1 0 0

0.7 1 .4 0.7

0.7 1.8 0.7

0.7 2.3 0.7

0.8 0.9 0.6

0.9 0.9 0

0 0 0

0 0 0

0.4 0.5 0. 1

3.2 1 .8

3.4 1 .8 1 .9

2.9 1 .4 1.7

4.7 0.8 0.7

3.8 0.7 0.9

4.3 1.1

1 .8

3.0 1.8 1.8

0.7

4.1 0.7

0.4

0.7 1 .4 0.7

0.7 1.3 0.7

0.9 1.4 0.7

1.1 1.4 0.7

17.7 8.6 8.8

12.1 7.7 9.6

19.6 9.0 9.7

15.9 8. 1

4.7 0.8 2.6

4.2 0.4 2.8

5.8 0.4 3 .2

4.8 0.4 1.6

T p

T

p

T p

T

s

p

T p

T

s

p

s

Lack information, information is hidden

T

T p s

Not stated

1 .4 2.4

2. 1 2.3 1 .7

Other reasons: Medicines patients are weak; dairy - given to children

Economic corruption of safety standards, ethical concerns

1 1 .1

1 .8 1 .4 3.3

s Environmental effects

5.7 3.1 3.0

0.6 1.3 2.2

s No guarantee of purity or quality

8.5 4.5 4.2

1 .8

p

s Unknown research area

6.1 4.5 3.7

T

s Safety doubts, need to test properly

6.8 5.0 4. 1

p

T

s

p

T s

7.2

The values are expressed as % o f t h e total respondents who answered Q 8 ; i n Japan , public N = 527, teachers N = 22 1 , scientists N = 543 (MA CER, 1 992a); and New Zealand, public N = 2034, teachers N = 277, scientists N = 258 ( CoucHMAN and FINK-JENSEN , 1 990) . Group: P. public; T, high school biology teacher; S, scientist. Absence of data is indicated by '-'

5 Past and

Present " Bioethica/" Conflicts in Biotechnology

to lesse n the conflict that people find with biotechnology. Because be neficence is a basic ethical principle, we can assume that there are important grounds for pursuing research and apply i n g t echnology. providing we are consistent in re-;pecting the other ethical prin­ ciples. s uc h as 10 do no harm.

5 . 1 I n terfe re nce with Nature or

"Playing God"

There were also significant proportions of respondents who thought that genetic manip­ ulation was ink rferi n g with nature . or that it was p rofa ni ty to God . or said that t h e y had a bad feeling about it. Also many saw genetic manipulation. e spe c i ally of humans and ani­ mals, as unet hical (Tab. 2 . Sect. 4.3). These respondents m ay see these techniques as unacceptable . regardless of the state of tech­ nology and regulation. In the US survey. 46% said that we have no business med d l i ng with nature . while 52% disa g reed ( OTA. 1 987 ) . Although many scientists react t o people with these views as i rrationaL it is noteworthy that about 1 6% of the scientists and teachers in New Zealand and Japan who found these techniques u nacceptable also shared these views, and these reasons were also cited re­ garding genetic m anipul a tion of microbes. The questions about food also illustrate this con ce r n . I n J apan 12-1 6% of the public who were concerned about consuming prod­ ucts made from GMOs, said that such food­ stuffs or medici nes would be unnatural . while in N e w Zealand the values were much higher (Tab. 5 ) . These results were confirmed in the 1 993 International Bioethics Survey (MACER. 1 994). Australians were similar to New Zea­ landers. with other Asians expressing this idea less. like .J apanese. While rationally we can say such foods are j ust as natural as foods made from a n y modern crop or animal breed, I 0- 1 2 % of scie n t i s t s also said this. In a 1 988 public o p i n io n survey in B r itai n . 70% agreed that "natural vitamins are better for us than l ab o rat ory - ma de ones··. while only 1 8% disa­ greed ( D U R A ' S. lividans

w - z_w - 1

Klebsiella sp . .... Klebsiella sp. thuringiensis .... B. thuringiensis

B.

B. thuringiensis ....

S. violaceolatus •

w -s

->

Soil bacteria

S. lividans

pe r donor cell. or transconj ugant per recipient ce ll ( R )

w - 6- 1 0° w-

'

1 64

5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products

ment cannot be excluded and, therefore, should form part of the risk assessment. Mat­ ing in the environment outside the produc­ tion facilities can be excluded, because in the environment the concentrations of wild-type and rDNA microorganisms of the opposite mating type will be very low. Besides the horizontal flow of genetic ma­ terial between microorganisms and in rare cases between microorganisms and plants, this flow also exists between plants by pollen exchange. Whereas new traits of commercial crops introduced via classical breeding are often not of any use for their wild relatives, transgenic plants will often be equipped with new properties like salt and drought tolerance and herbicide or insecticide resistance, and these properties may be beneficial to the wild relatives as well. ELLSTRAND (1 988) has sum­ marized the probability of horizontal flow of genes via either wind or insect transferred pollen as a function of the distance between the donor and recipient plant (see Tab. 2). These data clearly show that a horizontal flow of genes (also rDNA) can occur with a rather high probability when wild relatives are present within 1000 meters, and therefore this should be included in risk assessment of transgenic plants, in particular if the foreign gene codes for properties that provide the re­ cipient with a clear ecological advantage. Tab. 2. Gene Flow by Pollen

Species

Isolation

Gene Flow

100-1000 m 8 km 5{}-100 m

>1

(% )

Herbs

Raphanus sativus Agrostis tenuis Phlox drummondii

4.5-18.0 8

Trees

Gleditsia triacanthos Pinus taeda Pseudotsuga menziesii

200 m

1 22 m 161 m

5.8 36 20.4-26.6

The available data demonstrate that pollen can act as a vehicle for the transfer of engineered genes from crops to their wild relatives. The spread of these genes into natural populations will probably be rapid even if the wild relatives occur 1000 m from the crop and if the engineered gene confers an advantage to the wild species.

In the event that by one of the above de­ scribed mechanisms for horizontal flow of genes, genes have been transferred, this does not mean that the gene will be expressed in the recipient cell. Even between relatively closely related species as E. coli and Pseudo­ monas aeruginosa many genes are not tran­ scribed because of inefficient promoters. It is important to keep this in mind when reading publications on horizontal flows of genes based on the PCR methodology, as this meth­ odology does not give any indication of gene expression. Fig. 2 summarizes experimental evidence of transfer of genetic information between unrelated species. The barrier between var­ ious species is clearly not as absolute as was thought in the early seventies, and the argu­ ment that rDNA technology is hazardous only because it surpasses natural barriers is at least disputable.

2.3 RNA Splicing and mRNAs Derived from Synthetic Genes

RNA splicing can be considered as a com­ mon process in eukaryotes and soon after the discovery of this phenomenon, DARNELL and DOOLITTLE (1986) proposed that RNA splic­ ing has played an important role in evolution. The nucleotide sequences of 5 1 and 3 I splice sites are well known and reasonably con­ served, although differences in nucleotide are permitted. Even taking into account that the sequences are not conserved absolutely, it is not too difficult to scan foreign genes for the potential that they may contain RNA splice sites that may result in a completely different­ ly processed mRNA and consequently in a completely different protein. Especially if chimeric genes are constructed and these con­ structs are transferred to eukaryotic hosts, it is essential to check for the creation of splice sites to eliminate unintended splicing as a hazard. For prokaryotes splicing is not a fac­ tor of the hazard analysis. To improve the translation rate of foreign genes they are quite often synthesized chemi­ cally in the codons preferred by the new host (ANDERSON and KURLAND, 1990). Also

2 Introduction into Some Technical Aspects of rDNA

1 65

Archaea

6

: Euryarchaeota

2

Fig. 2. Transfer of genetic information between unrelated species. Bacteria: 1. Thermotogales; 2, flavobac­ teria and relatives; 3. cyanobacteria; 4, purple bacteria; 5. Gram-positive bacteria; 6, green nonsulfur bac­ teria. Arcbea: kingdom Crenarchaeota: 7, genus Pyrodictium ; 8, genus Thermoproteus; and kingdom Eu­ ryarchaeota: 9. Thermococca les; 10, Methanococcales: 11. Methanobacteriales; 12, Methanomicrobiales; 13, extreme halophiles. Eucarya: 14, animals; 15, ciliates; 16, gree n plants: 17, fungi; 18, flagellates; 19, microsporidia (from D A V I ES. 1 990; WOESE et al.. 1 990).

genes coding f or enzymes that have to be modified to improve their usefulness in cer­ tain application (e.g .. detergents) are often synthesized as a modular system containing different DNA cassettes. Normally each cas­ sette is flanked by a unique restriction site enabling the r apid exchange of such a cassette by another carrying the modified genetic code. The introduction of restriction sites quite often requires silent mutations. Finally genes are often ( partly) synthesized chemical­ ly to improve the stability of the mRNA or their rate of translation. although general models that describe the stability of mRNA hardly e x i s t (BAlM and SHERMAN, 1 988). Synthetic genes that have new nucleotide se­ quences should be screened for frameshift mutations, splicing and premature termina­ tion as all these p roc e ss e s may result in the synthesis of unknown proteins. Consequently they can contribute to the intrinsic hazard of rONA products. Careful analysis of the tran­ scription products of the foreign (synthetic) gene can reduce largely the above mentioned phenomena as a source of hazard related to the rONA technology.

2.4 Reliability of Translation

Processes and Post-Translational Modifications

Although gene expression is mainly regul­ ated at the transcriptional level, there are a number of ingenious regulation mechanisms that have been developed on a translational level. Some of these mechanisms involve frameshifting or initiation of the translation at a site different from the normal start codon. These frameshifts result in proteins that differ from the protein derived from the nucleotide sequence, and therefore this phenomenon is important in the discussion on the intrinsic hazard of foreign genes. Various mechanisms of recoding the message of an mRNA have been discovered: 1. Plus-one frameshifts. One of the best studied e x am p le s of + 1 frameshifts is the release factor 2 (RF2). In RF2 a stop co­ don (UGA) is located in position 26 (CRAIGEN et al., 1 985). However, with a probability of about 50% a + 1 frameshift

1 66

2.

3.

4.

5.

5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products

(UGA --+ G AC) occurs resulting in the biosynthesis of RS2 (CRAIGEN and CAs­ KEY, 1 986). This type of frameshifts is only possible, if a certain sequence in the mRNA, called stimulator, is present to which the 16S RNA of the ribosome can bind. Recently also for the eukaryotic chromosomal gene involved in the post­ translational modification of ornithine de­ carboxylase, a + 1 frameshifting has been discovered (GESTELAND et al., 1992). Minus-one frameshifts occur quite fre­ quently in the translation of retroviruses. The stimulator is a stem-loop structure lo­ cated downstream of the place of frame­ shift (BRIERLEY et al., 1989). Minus-one frameshifts are not restricted to retrovi­ ruses, but occur also in E. coli (TsuCHI­ HASHI and KORNBERG, 1990). Hopping is another translation phenome­ non that can cause the synthesis of a pro­ tein different from the protein expected on the basis of the nucleotide sequence of the gene. This phenomenon is quite well documented for bacteriophage T4. At a certain sequence the ribosome leaves the mRNA molecule and rejoins it about 50 bases later (HUANG et al., 1 988). In the genetic information of certain re­ troviruses and some plant and bacterial viruses, codons are encoding amino acids differently from the codon table as estab­ lished by NIRENBERG and others. For in­ stance, in certain mRNAs that contain particular sequences (ZINONI et al. , 1 990), the stop codon UGA encodes selenocys­ teine (HILL et al., 1 991). Although in higher eukaryotes also UGA is used to incorporate selenocysteine in proteins, the mechanism in these cells is less well known, but it is likely that again down­ stream sequences play an important role (BERRY et al., 1 991). Normally translation starts at the triplet ATG. However, at a low probability translation starts at GUG (8% ) and even more rarely at UUG or CUG (KOZAK, 1983). This may occur also in the transla­ tion of an rDNA gene encoded product.

Although recoding of the genetic informa­ tion is a rare event and mainly restricted to

viruses and bacteriophages, it has been de­ tected in normal mRNAs of bacteria, lower and higher eukaryotes and, therefore, it is es­ sential that for each gene transferred into a new host at least a theoretical evaluation is made whether recoding can occur. This is of particular relevance, if the transferred gene is chemically synthesized to adapt the codons or to design a gene that is very suitable for pro­ tein engineering, as there is a small probabili­ ty that a stimulator sequence has been intro­ duced. On top of theoretical analysis, careful inspection of the proteins produced by the rDNA strain by 2D electrophoresis and West­ ern blotting and in cases of any doubt deter­ mination of the C- and N-terminal amino acids can eliminate recoding as a hazard. Besides recoding of the mRNA, foreign genes may be translated into a protein differ­ ent from the protein in the original host by differences in post-translational modification. The best studied difference in post-transla­ tional modification is glycosylation. A euka­ ryotic gene carrying the amino acid sequences Asn X Thr or Ser that serve as a recognition site for glycosylation in the endoplasmic reti­ culum and Golgi apparatus, will when trans­ ferred into a prokaryotic host not be glycosy­ lated. Alternatively, if the gene is transferred from one eukaryote to another, e.g., from a plant to a yeast or mold, the N-glycosylation site will be recognized by the new host, but the type of glycosylation will be different. Be­ sides N-glycosylation also 0-glycosylation ex­ ists, but the exact mechanism by which 0-gly­ cosylation takes place is not fully known and is consequently an uncertainty in rONA tech­ nology. Moreover, in addition to glycosyla­ tion, other hardly known post-translational modifications, such as N- or C-terminal pro­ cessing resulting in smaller proteins, phos­ phorylation, farnesylation, etc. can occur. All these changes will be noticed already in the initial research phase and when observed, the choice of host should be reconsidered (with the exception of differences in N-glycosyla­ tion) to eliminate the biosynthesis of a pro­ tein of which the intrinsic property is un­ known. With respect to N-glycosylation the situation is different. Firstly, the degree of glycosylation is not constant but seems to vary with cultivation conditions. Secondly,

2 Introduction into Some

quite a number of pro tein s have been made via rONA techn ology that have the same am­ ino acid sequence b u t d i ffe rent g ly c osylation The e nz ymic pr op e r t ies of t h ese enzymes are very similar as. e.g has been p rov en for the tt-galactosidase fr o m Cyam opsis tetragonolo­ ba when ex p re s sed in various hosts (OvER­ BEEKE et aL 1 990 ) . A l tho u gh any change in N-glycosylation ma y in pr i n c iple create an in­ trinsic hazardous p r o t ein the absence of any indication for this until n ow proves that it is e x t re mely unlikdy that this will really occur. However. the a llergic pro pertie s of an en­ zyme produced i n a new host may differ from those of the original enzyme. In most decision schemes for the appr ov a l of rONA produ c ts for food applications. the pro t ein will be tested in fe eding trials. If the results of these tests are sim i l a r to those for t h e natural pro­ tein, no hazard has been introduced by the transfer of the gene from the original source to the new host. .

..

.

2.5 Random and Site-Directed

Technical Aspects of rDNA

1 67

In most of the decision trees for approval of new food products no attention is paid to genes that have been modified in a well known way and on applying the schemes very s t r i ctly modified genes have to be rejected or will at least require much more testing as they a re not originating from, or are not (yet) found in a naturaL appro ve d source. Provided t hat all the test procedures for the wild typ e gene product have been carried out and the gene pr odu ct has been app r oved a si m ple scheme to cope with this p r ob l em for en­ zymes used in food or chemical processes, o r i n food s or in personal car e or detergen t products is proposed (Fig. 3, Tab. 3). This scheme takes into account the possibility that the modified gene product will have different immunological or enzymi c prope rties If the modified gene product deviates in significant aspects from the wild-type gene product then a completely new approval procedure has to be followed. On the other hand, if in all but a few. from a safety point of view secondary as­ pects, the modified g en e product is equal to the wild-type gene product a more simple ap­ p ro v al procedure is proposed. .

-

,

.

,

,

Mutated Genes

One of the great prom is es of rONA tech­ n ology is t ha t enzymes can be obtained that

can c a ta lyze reactions under non-physiologi­ cal c o ndi t i ons This is of particular relevance to the chemical indu s try with respect to the de ve lopment of processes in which e nzymes are used as catalysts. T h ese processes are more e nvironmentally friendly than most of the pre se n tly used processes in the c he mic al i n du s try Also for t he development of en­ zymes for cleaning products random or site­ d ir ec t ed mut a ge nesis is very important ( WELLS and E"TELL. 1 988). Bot h random and site-directed mutagenesis w i l l create en­ zymes that most pr o bably do not exist in na­ ture. Arguments t h a t nature has had four bil­ lion years to t ry out all possible combinations are n o t v a l i d be c a use firstly it h a s been c al c u l ated that by far not all poss i b le combinations h ave bee n made ( MANFRED EIGEN , personal communication ) and secondly. there has not been any e nvironmental pressure in nature to select those enz ymes the chemical or deter­ gent industry i s interested in. .

2.6 Protein Foldin g I n most cases the transcription and transla­ tion of the rONA gene will be performed without any fa i l ure Still this does not guaran.

.

.

­

Fig.

3. Decision scheme to evaluate the hazard of

proteins derived from site-directed or randomly mutagen ized ge n e s .

5

1 68

Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products

Tab. 3. Proposed Approval Scheme for Mutagen­

ized Proteins

2.7 Choice of Host Strain/Variety for Foreign DNA

Entry, Actions and Results

A.

B.

C. D.

Mutagenized gene Start complete approval procedure Determine nucleotide sequence of the gene(s) Gene(s) or gene product(s) do (does) not pose a hazard

Questions

Q 1. Q 2.

Q 3.

Q 4.

Q 5.

Has the non-modified gene product been ap­ proved by an official body? Has the modification been done using site­ directed mutagenesis? Has (have) the gene(s) due to the modifica­ tion any new sequence that may result in re­ coding phenomena or has (have) the modif­ ied gene product(s) a new stretch of at least 6 amino acids identical to another class of proteins? Has (have) the gene product(s) encoded by the modified gene(s) essentially the same im­ munological, physical and enzymic proper­ ties? Has (have) the nucleotide sequence(s) of the modified gene(s) been determined?

tee that the rONA product will be folded cor­ rectly. Intrinsically protein folding is a very complex phenomenon, moreover, it depends among other things on the translocation pro­ cesses and the redox potential in various cell compartments or organelles (HwANG et al. , 1992) and with a relative low probability this may result in (partially) improperly folded proteins. Sometimes very specific helper pro­ teins are required for the correct folding. If this helper protein is absent, improper folding occurs (e.g. , FRENKEN et al., 1993a, b). Al­ though our understanding of protein folding is rapidly increasing, it is still impossible to predict folding of rONA proteins in new hosts. For enzymes the specific activity (kcat per mass, determined by enzymic and immu­ nological methods) is a very accurate meas­ urement of proper folding. For non-enzymic proteins it is more difficult to determine whether the protein is folded correctly, but a combination of physical and immunological measurements can reduce this probability of an unexpected hazard due to improper fold­ ing considerably.

Directly after the discovery that between evolutionary unrelated species genetic mate­ rial could be transferred, the discussion about the safety of the host strain started. This was mainly due to the fact that the gut bacterium E. coli had become the work horse of the mo­ lecular biologists. To decrease the probability of a pathogenic strain being used as host in rONA technology, the strain E. coli K12 has been selected. This strain, originally isolated in 1 922, has lost during the many generations of cultivation on rich laboratory media four of the five essential properties to be a patho­ genic bacterium, notably the property of ad­ hesion in the gut, the production of entero­ toxins, its resistance against phagocytosis. Moreover, E. coli K12 became sensitive to the human immune system and lost its property to penetrate through the epithelial wall of the gut. The production of endotoxin was re­ duced largely but not completely lost (BERG­ MANS et al., 1 992). An important lesson can be learned from this. Microorganisms maintained for a large number of generations on rich laboratory me­ dia will with a high probability lose some of the capabilities they have acquired during evolution. This is not only valid for E. coli K12, but for many other strains selected on their performance in this type of media. Con­ sequently this means that strains, optimized to perform under standard conditions in a fer­ mentation process will have a largely reduced capability to survive under the severe condi­ tions outside the fermentation process. The other lesson E. coli K12 taught us is that pathogenicity is quite a complex proper­ ty. Experiments of GurNEE ( 1 977) to recon­ struct the pathogenicity of E. coli K12 by transferring the genetic material coding for the adhesion factor and the enterotoxin pro­ duction failed. Similar results were obtained by ISBERG and FALKOW (1985) who trans­ ferred the adhesion factors back into E. coli K12. When microorganisms used as host for rONA technology are functional microorgan­ isms in fermented food products (Tab. 4) and

2 Introduction into Some Technical Aspects of rDNA

169

Tab. 4. Main Functional Microorga nisms in E uropean Fe rmented Foods Microorganisms

Foods

Baked G oods

Lactobacillus

Molds

Ye asts

Bacteria

farciminus

p lan tarum

acidophilus

l ru eck ii

de h

Saccharomyces

cere�·isiae

xi

ri

Pich ia

e gu e s inusitus saitoi

Candida

vini

bre�·is buchneri

fe rmen tu m san

Wine and B randy

Leuconostoc

francisco

gracile venos

Hanseniaspora u varum

casei

Saccharomyces cerevisiae

t ru m

p la n a

fructiocrans

Kluyveromyces apicu/ata

rosei uvarum oviformis

des idiosus hilgardii

·

brevis Pediococcus

cerevisiae

Beer

Saccharomyces cerevisiae �� �·arum

Cheese a nd Dairy Products

Brevibacterium lin en s

Lacrococcus

Klu.v�·eromvces lactis

/actis c

.

rem o ris

fragilis

casei helveticus

bulgaricus

Leuconostoc

reuteri plantarum

cremoris

Pediococcus

acidilactici

Streptococcus

pentosaceum e rm op il

th

faecum Cabbage and

Cucumbers

Olives

Lactobacillus

h us

breds

plantarum

Pediococcus

meretoroides cerevisiae

L.. a ctobacil/us

p lama ru m

Sacch a ro my ces sp.

delbrueckii

Ha nsen u la sp.

Leu conostoc

hre�·is

Streptococcus sp. Pe diu cocc us sp. Leuconostoc sp. Meat

Laccobacillus Pediococcus A1icrococcus

Kluyveromyces sp.

De ba ryomyces sp.

plallfamm

Debaryomyces hansenii

lactis

Saccharomyces cannosus

acidilactici

pentosaceum caseo/yticus va rians

De ducted from Biotechnology 1 st Ed. Vol. 5 Chapters 1-8

Penicillum camemberti caseicolum roqu efo rtii

170

5

Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products

have a long safety record, the probability that such a strain becomes pathogenic through the transfer of one or a few well defined genes that code(s) for intrinsically safe proteins is extremely small. To put it in perspective, this risk is consid­ erably lower than the famous 12 D concept (the probability that less than one tin can in 10 12 will be contaminated with Clostridium botulinum and that this will result in the for­ mation of a detectable amount of toxin) which is used successfully in the food industry to ensure the safety of canned foods (SMELT, 1980).

Moreover, the probability that strains se­ lected for their performance in a fermenta­ tion process will survive in the environment will be very small. 2.8 Plasmid Stability and Stability of Integrated Foreign DNA

Stability of the plasmids or transposons carrying the foreign gene was a matter of great concern in the early days of rONA tech­ nology, and this concern is depicted in Fig. 4 (SAYRE and MILLER, 1991 ).

Concerns

Concern due to mobility

Concern for inserted structural genes

I

Transponson

------

.. � Frequency of insertionA·� etc. in host DNA .,.. _

•

-

-

'

Site-specific insertion

Concern for MGE genes not involved i n transfer

-

.

� _

_ _ _ _

_

'

- - Plasmid

-

--------

--

Transfer rate of transposon to plasmid

•

'

Non site-specific insertion

Rate of loss of MGE from cell and rate of uptake by. . . . .

•

Same species

�

i tor'""""""'

' '"'"'

Dlffe"'

Conjugation I Transduction I Transformation ami ,...,.

Medi u m : soi l , sediment, water, waste water, ground water

Frequency of phenotypic alteration in original host

''----

+

Frequency of phenotypic alteration in new host

___.

... ... •Adverse effect ..,. ,... ___

Fig. 4. Concerns about plasmid and transposon carrying rDNA genes.

2

Introduction

The s t abi l i ty of plasmi d s derived from pBR322 i n E. coli o r A RS - o r 2 ILm derived vectors in Saccha romyces cerevisiae h as been described in numerous papers. However. the reason for concern in relation to risk assess­ ment of rONA was not very clear. It can be argued that if a p lasmi d is unstabl e , m a n y pe­ digrees of the transformed c e l l will not carry the foreign ge ne(s ) and. therefore. the s e pedi­ grees are of n o con c er n in th e risk assess­ ment. Nearly al w a y s selection pressure is re­ quired for good stabi l i t y of vectors. Often a n ­ tibiotics are used for the selection pressure . A n tibiotics will not be p re sent in the e n vi r on­ ment in sufficient quantities . and c o n seq u e n t­ ly t h e fate of the plasmid in the transformed host in the environment will be even worse than t h e fate o f p l asmid s unde r sele c tion p ressure . w h ich alre ady is not very good (e.g., s e e for yeast vectors M u RRAY and SzosTAK. 1 983). This diminishes the p r ob a bility of transfer of the pl asm i d to unknown recipie nts considerably.

M ore recently, so-cal led food

into

Some

Technical

Aspects of rDNA

171

host. These i nte g r at ion vectors are very stable (stability most often identical to that of the chromosome ) . but the draw backs are that the vector is not always integrated at the selected site ( i lle gi timate in t e g ration ) and t h e number of gene copie s is qu i te low. R ecently these disadvantages have been overcome in an ele­ gant way by constructing an inte g ratio n vec­ tor that contains upstream of a gene ( encod­ ing an enzyme essential for the anabolism of t h e host) a defective promoter and part of the genes coding for ribosomal RNA ( UNILEV­ ER, pate n t

application, 1 989).

In

this way the

vector is inte g r ated in a multimeric form p re­ ci s ely at a prede fin e d locus in the chromo­ some of the host. The advantage of inte gra­ tion vectors is that the probability of horizon­ tal flow is extremely low an d may be ne­ glected in risk assessments. Vectors used to tra n sform plants are nearly all based on the tumor-induci n g plas m i d of Agrobacterium tumefaciens

(SCHELL, 1 987) .

From these vectors onl y that p a rt is main­ tained which i s esse n tial for integ r a t ion into the chromosome of the host plant. The disad­ vantage of this procedure is that the site of inte gration is not known beforehand and is difficult to determine. This means that a cer­ tain met a bol ic function can be da m aged in the host cell and that is a h azard. T h e a tt rac­ tive ness of u sing Ti- p lasm i d to transform p lants is that the forei g n gene is st a b ly inte­ grated in the chromosome of the host and that the probability of horizontal flux of the foreign gene is ex t re m ely low. More rece n tly other vectors and methods to transform p lan ts have been developed, but all res u lt in stab l e, site -unspecific inte gration, although

grade vectors ( fully c h a rac t eri ze d vectors that contain, wit h the ex ce p ti o n of the fore ign gene , on ly homologous seque nces and these sequences should only code for normal ana­ bolic fu n ctions in the h ost cell) have been de­ veloped both for proka ryotes and eukaryotes. These vectors are maintained in t h e host, be­ c ause they cont a i n a gen e e ncodi n g an essen­ tial enzyme of t he an abolism of the host, e.g. , an en zyme of the biosynthesis of an amino acid. In principle this sele ction pre ssure will be mai n t ai n ed i n the enviro n m e n t. however. these host cells are in general quite fast i dious. Therefore, the host cells will not survive very well in the e n v i ronment, and this will red uce very rece ntly i ndications have been obtained the risk of horizontal flow of g ene to un­ that site -s pecifi c integration in plants is possi ­ known recipients. M oreov e r. the recipient ble (P. HooiJKAAS, personal communica­ will have i ts own gen e for that anabolic func­ tion). Transformation of plants always me ans in­ tion which most likely is more effective in the te gratio n of rON A into the ch romosom e of recipie n t than in the foreign gene. In fermentation processes stability of vec­ the pla n t. This is also the ca se in t h e often tors c on t aining t h e gene of in terest is of major used anti-sense technology to repress the i mportance . as t he y i e l d of the g e n e product translation of m RNA. During the anti-sense i s often dire c t ly related to the number of gene studies quite often effects o f the posit i on of copies. E ve n ve ctors t h at are maintained by integration are observed as well as the rather se lection press ure are not c o m pletely stable. surpri s i ng result that also sense genes can re­ and therefore ,·ectors h ave been developed press translation (GRIERSON e t al. , 1 991 ) . which integrate into the c h r o m osom e of the These unexpected results sh ow o n ce m or e

172

5

Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products

that it is important to determine the place of integration and the effects on the metabolism of the host cell that integration can have.

2.9 Reprogramming of Metabolic

Pathways in Cells Hosting Foreign DNA

One of the targets for rONA technology will be the reprogramming of the metabolic pathway of the host cell. Intended reprogram­ ming of metabolic fluxes can be illustrated with four examples: (1) Anti-sense polygalacturonase (PG) in to­ matoes. In these tomatoes a gene coding for the endogenous PG gene is introduced but in the anti-sense direction ( S M ITH et al., 1 988). Although the anti-sense mechanism is not completely understood (GRIERSON et al., 1991 ) , one explanation is that the sense and anti-sense mRNAs "coding" for PG recognize each other and form a complex that cannot be transcribed. In this way the amount of PG is reduced, and this will decrease the cell wall degradation, and consequently the shelf life of the tomato is extended. (2) Using the same principles Calgene Inc. has developed rapeseeds in which the conver­ sion of stearic acid into oleic acid by a desatu­ rase is blocked by anti-sense 8-C9-stearoyl­ desaturase. This results in a higher level of stearic acid in rapeseeds, which is of advan­ tage for certain industrial applications ( CA L­ GENE, 1 991). (3) To improve the gassing power of baker's yeasts, GIST-BROCADES has developed a yeast strain in which maltose permease and maltase are expressed constitutively, thereby avoiding glucose repression of the endoge­ nous genes. Indeed this resulted in an in­ crease in the gassing power of about 25% (GIST-BROCADES, 1 987). (4) To improve the ethanol production rate of yeasts all genes of the glycolysis have been cloned and over-expressed. However, due to extensive feedback control mechanisms the ethanol production rate increased only by about 5% (SCHAAFF et al., 1 989). Whereas in the first example only a minor pathway in the metabolism was reprogram-

med, the rapeseed and baker's yeast exam­ ples are examples of a change of one particu­ lar step in a main metabolic route. Both ap­ proaches were very successful. However, the reprogramming of a whole main metabolic route in brewer's yeast was unsuccessful, be­ cause cells have many feedback inhibitions and other control mechanisms of main meta­ bolic routes. The above examples deal with intended reprogramming of the metabolism, thereby creating cells that may differ consid­ erably from the original host and should therefore be tested according to the full safety scheme. In most rONA projects metabolic repro­ gramming is not planned, but may be caused by intended or illegitimate integration (Sect. 2.8) . Moreover, change in metabolism can be caused by the intrinsic property of the intro­ duced foreign gene or by a helper gene, if the maintenance of the vector is based on the anabolic function of the helper gene product. Therefore, in the hazard analysis the possibil­ ity that the normal fluxes of metabolites in the host strain will be changed by the intro­ duction of foreign genes encoding enzymes should be considered. Using molecular bio­ logical techniques the occurrence of meta­ bolic reprogramming could be determined. Using Southern blotting coupled with RFLP/ RAPID analysis the site of integration could be determined, and if this integration resulted in disruption of a structural gene, the function of this gene should be determined. Alterna­ tively, by very sensitive analysis differences in the mRNA, profiles between wild-type and transformed cells can be determined (LIANG and PARDEE, 1992) . Also with enzymic or im­ munological methods the translation products of these mRNAs can be determined. Know­ ing or calculating the levels of enzymes it is possible to estimate the difference in fluxes of substrate conversions due to these changed levels (PosTMA, 1 990) and therefore the im­ portance of unexpected aspects of metabolic reprogramming.

3 Various

Stages in the Development of an rDNA Process

3 Va rious Stages in t he Development of an rONA Process or Product Soon after the Asilomar Conference in a number of countries committees were estab­ lished to develop guid e lines to evaluate the s afety of rON A experiments in the l aborato­ ries. These committees focused their effort on cre a ting frameworks for the catego r izati on of rONA experi m e nt s on the basis of intrinsic h azard of the foreign gene. nat ure of the vec­ tor u sed in the transfor m ation p r ocedures , pe rc ei v ed hazard based on the o r i gin of the fore ign gene, possib l e errors in the cloning proce dures and the intrinsic hazard of the host cell. I n i tially there were man y differences in the views of these committees, but after a number of years in nearly all Western cou n t rie s and Japan more or less the s ame rules for the evaluation of the sa fet y of l aboratory exper i ­ m e n ts were ap p l i e d . At the end of t h e se venties the fi rs t gu i de lines for exper i m e nts exce eding the 10 l i t er scale were e s ta b l i s h e d , and again these rules were quite similar in various countries. Early 1 980 r ules for pilot-plant and large-scale pro­ duction were for m u lated . I n mo st countries for e ac h containment level general approval for the facilities can be obtained, however, for each new type of process or product approval of the used strain. equipment and proces s ing are n ecessar y. The volume of I 0 liters for which an addi­ tional approval p roced ur e must be started is qui te arbitrary . Additional approval for pilot­ pla n t or large-scale production does in gener­ al not pose a problem to manufacturers, as transfer from lab-scale to pilot plant and from pilot pla n t to la rg e scal e i s always a point of careful evaluation of all a s pec t s of any new process/product. Although ofte n the ap p roval of p i lo t and production facilitie s and the pro­ cess has been rather t im e -co nsum i ng with a few ex cepti on s. e.g . . of the rONA pr od u ction of human insulin by Hoechst in Germany, ap­ prov al w as obtained. However, app r ov a l to produce an rONA product does not mean ­

or

Product

173

that a new product can be market e d . For pha rmaceutical products the procedures for approval of new p roducts , including rO N A products are quite clear. For rONA products in food proc e ssing or for their use in food or dete rgent prod ucts or in other consumer products. unclear procedures varying from country to co u ntry exist or even no proce­ dures are in place at aiL The absence of clear and uniform guidelines in Western Europe ( EE C ) , USA and Japan has c lear l y contrib­ uted to a considerable delay in the introduc­ tion of rONA products and resulted in cer t a i n companies reducing or even losing their inter­ est in rONA tech n ology . For companies it is e x treme l y i mportant that it is clear alr e ady at the start of a n e w research and development program what the approval procedures for the e n d product will be. I f a company knows the approval proce­ dure s , a sche m e for the development of an r O N A process/product, i nc l u d i ng the approv­ al procedures and an estimated time scale, can be set up. A typ i cal exam pl e of such a sch e me is g i ven in Fig . 5 . In sp i te of the many approval procedures, the de v e lopment of rONA processes and products by a co m pa n y that uses such an integrated development/ap­ proval scheme will in general not be slowed down by these procedures. Many of the q uestions of the decision sche­ mes can already be answered at the moment the project reaches the state of transfer from shaking flask to fermentation or small-scale gl ass ho u se exper i ment s . Approval of the fa­ cilities can be obtained, even if the project is still i n it s research phase , altho u gh in mos t countries approval for pilot-plant and large ­ scale production per project is necessary. However, this approval is normally not a problem. If necessary, the feeding and toxico­ l ogical studies can start as soon as the outline of the process on p i lot - plant scale has been e s tabl i shed . The e x tens i ve trials to get ap­ proval for pharmace utical products will take more time: however, also for new pharmaceu­ ticals produced via conventional techniques these tri a l s determine largely the ti me of in­ troduction. Such an app r oach also implies that d u ring the actua l research s t age of the development of a new rONA product the various steps in

174

5

Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products

Phase in project:

Idea Start

p roject 1 -2 year

Completion of molecular biology in lab. strain/variety

,,

1 -2 year

Decision point to

,

go from lab to pilot p la nt scale; Fillin g patents;

Dec isi on po i nts! actions

Checks

Completion of

of opti mization of production system

2 ye ar

,

Transfer to

pro ducti o n ,

,

Decision point to transfer proj ect from R&D to com pany

I

Start ( inte rnal) clearance procedure

I

discusion retailers and consumer

Start

organizations

Start consumer 1 trials 1 I I

Approvals

Laboratory facilities;

New project

lab scale

Process/Product

Pilot plant facilities; Ne w project pilot plant scale

clearance by authorities

Acceptance consumers

by

Fig. S. Different phases in the development of an rDNA product.

the construction of the new gene and its ex­ pression are carried out in such a way that the probability that approval will be obtained is optimal. In Sect. 2 the possible sources or er­ rors in the rONA technology that can render an intrinsically safe gene or gene product present in an intrinsically safe host organism into an intrinsically hazardous product have been discussed. Most of these sources can be detected during the research stage, and their absence should be checked by independent external experts. Spontaneous mutations can occur after completion of the laboratory ex­ periments and even during actual use of the transgenic organism in production processes or in agriculture. By applying common quali­ ty assurance/control protocols spontaneous mutations of the gene resulting in a change of catalytic or antigenic properties or molecular mass or physical characteristics or in a differ­ ent restriction pattern of the foreign gene and its flanking regions can be detected. Sponta­ neous mutations that are silent in all these as­ pects can be considered as safe (as the expres-

sion products are identical to the original products) . Larger rearrangements at DNA level will be detected by Southern blotting of microorganisms or RFLP or RAPID analysis of plant DNA. Both sets of techniques are (should be) standard procedures in fermenta­ tion or seed breeding industries, respectively, as such rearrangements may have an in­ fluence on other quality traits of the organ­ isms as well. Consequently there is no techni­ cal reason not to know for certain whether a transgenic organism carries a hazard. An im­ portant feature of the proposed scheme is (Fig. 5) that discussions with consumer organ­ izations and others start soon after filing pa­ tents bu t certainly long before the new pro­ cess is transferred to a production facility. In this way sufficient time is created to discuss the risk/benefit ratio of the new rONA prod­ uct with consumer organizations and others, and this may increase significantly the proba­ bility of acceptance of the rONA product by consumers.

4 Decision Schemes for Various Types of rDNA Products and Various Applications

4 De c is i o n Schemes for Various Types of rDNA Products and Various Applications of These Products 4 . 1 General

A number of committees ( have ) develop­ for t h e approval of be a p p l ied in various types of products. e.g .. pharmaceutical. per­ sonal care products. cleaning products. and in the food and process industry. This section will focus on decision schemes for food prod­ ucts. As no uniform gui d el i nes for these deci­ sion schemes exist worldwide ( KoK et a!.. 1993), it was necessary to start with different schemes devel op e d by universities or govern­ mental institutes, several national or intern a­ tional g uidelines and to develop these schemes. In Tab. 5 a number of guidelines and their main characteristics are summar­ ized. (ed) decision �chemes rONA p r od u c ts that will

In this section the guidelines proposed by the Department of Health of the U.K. for novel foods serve as a starting point. This choice was made because t he scheme includes all types of novel foods i nc l u d i n g foods de­ rived from biological species obtained via classical breeding and chem i ca l ly or enzyma­ tically m o d i fi e d foods or food ingredients. Moreover. the proposed decision scheme could be connected easily to the schemes pro­ posed in the Statement of Policy of the FDA on ··foods Derived From New Plant Varie­ ties'' and to recent proposals of t he GEZOND­ H EIDSRAAD ( 1 992) and the VOEDINGSRAAD ( 1 993) to t h e Dutch government which fit quite well within the EEC directives and may together with the U .K. guidelines serve as a framework for E E C decision schemes. 4.2 Decision Tree D erived from ' ' G uidelines on the Assessment of

Novel Foods and Processes"

In 1 99 1 the Department of Health in the issued a report in which the Advisory Committee on Novel Foods and Processes gives " G uidelines on the Assessment of Nov­ el Foods and Processes" (ACNFP, 1 991). In this report a decision tree for all novel foods is gi v e n and this tree includes also foods de­ rived from genetically modified organisms. Although it is called a decision tree, it does not end in qualifications like "approved" or "not allowed", but in a large number of ac­ tions. Unfortunately, the necessary act i on s to ob­ ta i n approval are not always clearly defined in this report. However, as the decision tree includes all foods, it is a good scheme to start with. Fig. 6 and Tab. 6 show t h a t part of the decisio n tree for novel foods derived from ge­ neti c ally modified organisms which is rele­ vant in the framework of this chapte r . U.K.

.

Tab. S. Comparison Between M ajor Characterist ics of Various G uide l i n e s for Food Products Made by. or Containing rDN A Material ( KoK e t al.. 1 993) Reference

A

B

IFB C ( 1 990) NNT (1991 )

+

+ +

-

ACNFP ( 1 99 1 ) WHO/FAO ( 1 99 1 )

Voedingsra ad

( 1 993 )

EEC ( 1 990 a. h ) OECD ( 1 99 1 ) FDA ( 1 992)

A,

uses

+

-

+

) +

'

+

+

+ +

+ +

c

D

'? -

+

E

F

-

+ -

+I-

+

+ + +

•)

•)

-

+

+

-

-

decision trees

B, case -by-case approach

+

'?

C. new regulation necessary D. risk assessm ent i n v olves animal fee ding trials E, allergy is co n s id e r e d as a n i m p o r t a n t factor F. m a nufacture r i s fully responsible + I - in certain but not all cases required

?

+

175

176

5

Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products NOVEL FOODS

Tab. 6. (Continued) Questions 1. Novel material? 2.

3. 4.

5. 6.

7. 8. 10. 11.

12. 13. 14. 15. 16.

Naturally occurring strain? Genetic change? Classical breeding? Significant change in genetic material? Human exposure? GMO? GMO? Does the food product contain genetic material? Human exposure? Human exposure? GMO? GMO a seed? GMO? GMO a seed?

The numbers I-XV above refer to the information requirements listed below I. II. III. IV. V. VI.

Fig. 6. Guidelines on the assessment of novel foods and processes. Truncated decision tree.

VII. VIII. IX. X.

Tab. 6. Guidelines on the Assessment of Novel Foods and Processes (Truncated Decision Tree)

Entry, Actions and Results

A.

This is not a novel food Exit point: Information requirements:

G. H.

I, II, III, V, VI, VII

I.

J. K. L. M. N. 0. P.

Q.

R.

Z.

I, II, III, IV, V, VI, VII I, III, V, VI, VII , VIII, IX I , III, IV, V, VI, VII, VIII, IX I , II, III, IV, V, VI,

VII,

VIII, X, XII

XI.

XII. XIII. XIV. XV.

Instructions for use Evidence of previous human exposure Intake/extent of use Technical details of processing and product specifications Nutritional studies History of organism Characterization of derived strain Toxicological assessment Human studies Assessment of a genetic modification proce­ dure Effect of a genetic modification procedure on the known properties of the parent organ­ ism Genetic stability of a modified organism Si te of expression of any novel gene t ic mate­ rial Transfer of the novel genetic material Assessment of a modified organism for survi­ vability, colonization and replication/amplifi­ cation in the human gut

I , III, IV, V, VI, VII, VIII , IX, X, XII I , III, V, VI, VII, VIII, X, XI, XII, XIII

I,

I I I , V, VI, VII, VIII, X, XI, XII, XIII,

XIV I , III, VI, VII, VIII, X, XI, XII, XIII, XIV,

XV l , III, V, VI, VII, VIII, IX, X, XI, XII, XII I

I , III, V, VI, VII, VIII, IX, X, XI, XII, XIII,

XIV I , III, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV

The food material must be genetically modi­

fied

4.3 Decision Scheme for "Foods Derived from New Plant Varieties " as Applied by the FDA

The FDA issued a Statement of Policy on foods derived from new plant varieties (FDA, 1992). The various decision schemes given in this statement have been integrated into one

4

Decision Schemes for Various Types of rDNA Products and Various Applications

1 77

Fig. 7. FDA Statement of Policy on "Foods derived from new plant varieties" . Integration of their decision schemes into one decision tree.

scheme (Fig. 7, Tab. 7). This scheme can quite easily be connected to the general scheme that covers all types of novel foods. Com­ pared with the scheme proposed in the U.K. (see Sect. 4 .2) and the Dutch schemes (see Sect. 4.4) it is remarkable that the FDA schemes include a number of questions on the (expected) allergic properties of the new vari­ eties. This is in contrast with the two Euro­ pean schemes. On the other hand, the FDA schemes do not ask many details on DNA constructions. This is consistent with their view that it is not the way by which the intrin­ sic properties of a product are obtained, but the intrinsic properties as such that matter.

4.4 Decision Schemes Developed

for the D utch Government for Foods Containing rDNA-Encoded Materials

The guidelines produced in The Nether­ lands are largely based on the rules proposed initially by PARIZA and FOSTER (1983) . Dif­ ferent decision schemes have been developed for four food product categories (G EZO ND ­ HEIDSRAAD , 1992; VOEDINGSRAAD , 1 993):

a ) Single chemicals or well defined mixtures of chemicals produced by biological sys­ tems modified by rDNA technology (deci­ sion scheme given in Fig. 8, questions in Tab. 8) b) Foods derived from transgenic plants (Fig. 9, Tab. 9) c) Foods derived from transgenic animals (Fig. 10, Tab. 10) d) Foods or food ingredients made by rDNA-modified microorganisms (Fig. 1 1 , Tab. 1 1 ) .

The Dutch schemes are the outcome o f a number of discussions between consumer or­ ganizations, governmental and academic ex­ perts on rDNA technology, toxicology and communication and industry and cover the whole range of food products. During the dis­ cussions it became clear that the traditional 90 days feeding trials are not (always) appro­ priate for the evaluation of food products made by rDNA technology. Therefore, much attention has been paid to find molecular bio­ logical approaches to guarantee the safety of these products. As not very much experience in this area exists, it was decided to use the traditional feeding trials and the molecular approaches simultaneously and to decide aft­ er a period of at least three years whether in-

5 Structured Risk

1 78

A ssessment of rDNA Products and Consumer Acceptance of These Products

Tab. 7. Foods Derived fro m New Plant V a r ie t i e s Decision Tree B ased on FDA S t a t e m e n t o f P o licy . M a y 1 992 Entry, Actions and Results Food derived fr o m a new (via rON A technology modified) p l ant variety? A. B.

Assess th e s a fe t y of t h e host pla nt and the donor of th e D N A (gene)

v a rie t y is

C.

New

E. F.

Consuh F D A

n o t a c c e pt ab

le

D.

No concern

G.

The p ro d uc t does n o t fit i n t h i s d e c isi o n s c he m e

Cons u h

FDA

for

a dd i t i o na l

or alternative test ing

Questions 0 1 . Will the modification re s ul t i n nu tritional e ffects ? 0 2. Does the host s pec i e s have a hist o ry of safe use ? 0 3. Do characterist ics of t h e host species. related spe cies 0 4.

c o l og i ca l tests? Do

.

or p r oge n i to r l i nes

w a r ren t

an alyti ca l

or

toxi­

test result p rovide e v i d e nce that tox ica nt l ev el s in the new pla n t v a ri e ty do not prese nt a safet y

conce r n ?

0 8.

Is t h e conce ntration and bio-availability of i m portant n u t rie n t s in the new var i e t y within the r a n ge in t h e host sp e c ies? Is food from the donor c om m o n ly a ller ge n ic ? Can i t b e d e monstrated t h a t the a l l e rg e n i c determinant has n o t b e e n transferre d to the n e w v a r i e t y of host'' Do c h a r ac t e r i st i c s of t h e donor species. re l at e d species. or p r oge n i t or lines warrent analytical or

0 9.

Will the

0 5. 0 6. 0 7.

ord ina ri l y observed

toxicological tests''

modification result in

the e xp re s s i o n of

pro t e in (s ) in

t he

new variety?

0 1 0. Is t h e newly introduced pr ot e i n prese nt i n food de ri v ed from the p l a n t ?

0 1 1 . Is the protein derived from a food so urc e sub sta n ti a ll y. or simi l ar to an edible pr ote i n ?

0 1 2. Is food from t he donor co m m o nl y a l l e rge n i c? 0 1 3. Is the i ntrod uce d p rot e i n re por t e d to be toxic?

0 14. Can it be d e mon st r a t e d that t h e a l l e rge n ic determinant has n ot been transfe rred to the new variety

of

host ?

0 1 5. Does

the biological funct i on of the i ntro d uce d pro te i n raise any safety co nc e r n ,

protein r e p o rted

or i s

the introduced

to be tox i c?

0 1 6. I s the i n tro d u c e d prote i n li ke l y to be a m acr oco n s t i t u e n t of the human or animal diet? 1 7 . Will the i nta k e of t h e donor prot e i n i n the n e w va rie t y be ge ner a l ly c o m p a ra bl e to the intake o f the

0

s am e or s i m i l a r pr o t e i n in t he donor or other fo o d ? 0 1 8 . Will the mo d i f ica t i on res u l t in the bi o sy nt hes i s of new or modified carbohydrates i n the n e w varie­

ty?

0 1 9. Has t h e re been a n intent ional alteration in the struc t u re . composit ion or level of ca rbohydrates in ,

the

new variety?

Q 20.

Have any structural fe a t u re s or function a l groups been i n t roduced i nt o t h e carbo h y d r a t e that do n ot

021.

Have t here been any a l t e rations that c o u ld a ffe ct d ige stibi li ty or n u t r i ti on al quality in a

normally occur i n food c a r b o hydrates? t h a t is l i k e l y to be a macroconstituent

of

ca r boh ydrate

the d i e t ?

0 22. 0 23.

Will the m od i fi c a t i o n r e s u l t i n the biosynthesis of

0 24.

Have the intentional alte rations b e e n i n a fat or o i l that w i l l be a

new o r modified fats or o i l s in the new va ri e t y ? structure, or co mposi t io n of fats or oils in the

Has t h e r e hee n an inte n tional altera t ion in the i d e nt i ty ,

ne w varie t y ?

0 25 . A re any unusual or toxic fa t t y a c i d s produ ced in the new va ri e t y?

m ac roc o ns ti tue nt

of the

diet?

4

Decision Schemes for Various Types of rDNA Products and Various Applications

179

Ftg. 8. Decision tree for well-defined s i n gle food components.

Tab. 8. Decision Tree for Well Defined Single Food Components Entry, Actions and Results A. Carry out evaluation studies to determine the safety of the product and make specifications C. Make new specifications D. Apply a process to reduce t he l e v e l of undesirable components E. Carry out a 90-day feeding trial X. It is not allowed to bring the component on the market Z. The component is a ppr o v e d for use in foods Questions

1 . Is the use of the component in foods allowed at this moment? 2. Does the component comply with e x is t ing specifications on ide n t it y and puri t y? 3. Are the existing specifications sufficient to control the presence of undesirable site components or too high levels of the i n te nde d component? 4. Are the levels of known components w ithi n the safety specifications? 5 . Is it possible t o reduce the level of undesirable components during processing in order to comply with the existing specifications? 6. Is it possible that the product con t a i n s unknown components? 7 . If the intended or assumed consumption of the component results in a change in eating habits will the new habit still be considered as safe? B . Does the eval uation show that the component is safe? F. Does the 90-day fe e d ing trial show that the component is safe?

Note: Q uestions B and F are not (yet) included in the Dutch decision trees as separate questions but form part of action A and question 5. respectively

deed the molecular biological methods are better than the traditional methods (see Fig. 8). Chymosin is most probably the first and most widely applied rONA enzyme in the foods area. The gene coding for preprochy­ mosin has been cloned (UNILEVER, 1981 ) and

expressed in the GRAS yeast Kluyveromyces lactis (GIST-B ROCADES, 1 982). Many publica­ tions on the properties, safety evaluation and production of chymosin have been issued, and therefore chymosin can serve as a mod­ el.

180

5 Structured Risk Assessment of rDNA Products and Consumer A cceptance of These Products

Fig. 9. Decision tree for foods de­ rived from transgenic plants.

Tab. 9. Foods Derived from Transgenic Plants

Entry, Actions and Results

A. Start a procedure for novel foods

B. Carry out evaluation studies and determine the safety of the product

C. Do these evaluation studies show that the expression product(s) is (are) safe? D. Apply a process to reduce the endogenous or new components to an acceptable level E. Carry out a 90-day feeding trial X. It is not allowed to bring products derived from this plant on the market Z. Products derived from this plant are approved for use in foods Questions

1. Is there sufficient know-how on host organism and donor DNA to start the approval procedure? 2. Are the components of the food only of an endogenous nature? 3 . (Are) is the expression product(s) of the donor DNA an endogenous expression product(s) of a/ another food? 4. Is there a possibility that consumption of the new component in the intended or assumed quantities will affect the health of the consumer negatively? 5 . Is it possible to reduce the (active) components to the allowed level during processing? 6. Is (are) the site(s) of integration of the donor DNA on the plant chromosome(s) exactly known? 7. Is that knowledge sufficient to conclude that the metabolism of the plant is not changed or are the changes within the naturally occurring variations? 8. Does the 90-day feeding trial show that the component is safe?

Fig. 12 shows a flowsheet of the rDNA chy­ mosin production process developed by GIST­ BROCADES. The flowsheet demonstrates clearly that the probability that genetically modified organisms (GMOs) that have pro­ duced chymosin will be present in the end product is practically zero. Firstly, the fermen­ tation liquid is filtered twice to separate the

GMOs from the enzyme, secondly, the liquid containing the enzyme is acidified with a solu­ tion containing about 200 mglkg benzoic acid (pH 2). The latter is necessary to transform prochymosin into the active enzyme chymosin and provides an additional guarantee that the end product is free of GMOs. Finally, in a lat­ er stage of the process an ultrafiltration step

4

Decision Schemes for Various Types of rDNA Products and Various Applications

181

Fig. 10. D eci s i o n tret! for foods d e ­ rived from animals t re at e d with prod ­ ucts made by modern biotech nology or obtained from transgenic animals.

Tab. 10. Foods Dt!rivt� d from Animals Treated with Products Obtained by Means of Modern B iotechnol­ ogy or from Transgenic Animals Actions and Results A. Start a procedure for B. Evaluate tht! prod u c t C.

D.

E. F.

G.

X. Z.

novel food s

in accordance with the national/international legislation for veterinary p ro d ucts This p rod uct should be analyzed as a no vel food Evaluate the safety of the new com ponents Does the e v a l uat i o n of the new component show its safety? Develop a procedure/process to reduce the level of the endogenous or new component Does the evaluation of t he p roce dure or proce ss to reduce the level of the e ndoge nous or new compo­ nent show that the level is acce p tah le ? It is not allov.:ed to bring p roducts derived from this animal on t h e market Products derived from this animal a re approved for use in foods

Questions 1.

2. 3.

4. 5. 6.

Is the food or food prod u c t derived from a transgenic animal? Is the food or food pr od u c t derived from an an imal treated or fed with a product made via rON A tech n ology ? Has the a n i m a l been treated w i t h a veterinary p roduct? Is there sufficient k n owl e dge and docu menta t ion about the host animal and the gene t ic donor material to start t he a pprov al p roced ures ? Are the components of the food or food product de ri ved from the tr an s ge n ic animal e nd oge no us? Is ( are ) the expression p roduct(s) encoded by the genetic donor material endogenous in other foods·�·

a possib i l i t y that consumption of the endogenous or new components in the inte nded or as­ quan ti ties will affect the health of the consumer negat ively? R. Is it possible to redu c e the endogenous or new components to an acce p t ab le level'?

7.

Is there

su m e d

1 82

5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products (ingredients) produced by GMO

Food

5

>--TN'--_.� y

y

N

N

y

Fig. 11. Decision tree for foods or food ingredients derived from GMO.

1

INOCULUM CULTURE

8

STERILE FILTRATE TANK

Fig.

2

INOCULUM FERMENTOR

9

3

FERMENTOR

ULTRA·FILTER FEED TANK

4

5

FILTER PRESS

MASH TREATMENT TANK

10

ULTRA· FILTER

12. Production of chymosin by rDNA

11

UF.CONCEN· TRATETANK

12

FORMULATION BLENDING TANK

Kluyveromyces.

6

FILTRATE

7

STERILE FILTER PRESS

13 STERILE FILTER PRESS

14 STERILE TANK

15

PACKAGING

4 Decision Schemes for Various Types of rDNA Products and

Va rio us Applications

1 83

Foods or Food Ingredients Produced with the Aid of Genetically Modified Microorganisms ( see also Fig. 1 1 )

Tab. ll.

Actions and Results

C. X.

Thi s product should be analyzed as a novel food It is not allowed to bring food products containing i ngredie n ts produced with this GMO on the mar­

Z.

Food product� co n t a i n i n g ingred ien t s produce d with this GMO are ap p roved

ket

Questions

unmodified mic roo rga n i sm have a record of safe use in food p roducts? Can on the basis of feeding and/or toxicological studies t he unmodified microorganism be considered as safe in food products? Is there sufficient k now ledge and documentation that the new gen e ti c material codes for (a) pr od uct(s) that is (are) acce pt a bl e in food prod ucts ? Does the G M O or an inherent part of it or the product(s) encoded by the new genetic material remain in the food product? It is intended that t h e modified microorganism fulfills a fu nctio n al role in the gastrointestinal tract of the consumer'' Has t he intended functionality been demonstrated? Is the modified microorganism free of genes encoding antibiotic resistance ? May the consumption of the food, in particular t he GMO or an inherent part of it, or the product(s) encoded by the new genetic material in the intended or expected consumed qu a nti tie s result in any n ega tive aspect on the health of the consumer? Is it possibl e to reduce the quantity of the GMO or an inherent part of it or the product(s) encoded by the ne w genetic m a teri al to an a cce pt a b le level? Is the p hysic a l state or the i nte gr ation into the chromosome of the host of the new genetic m at e ria l fully known? Does the integration of the new genetic material d i st u rb the metabolism of the ho st in such a way that hazardous p roducts may be formed? Does a 90-day feeding trial with the food product con t a in i n g the GMO or an inherent part of it show that the introduction of the new ge n et ic material into the host does not have an effect on the metabol­ ism of the host cell resulting in (a) hazardous compou nd( s ) ?

1 . Does the

2.

3.

4.

5. 6. 7.

8. 9.

10. 11. 12.

is

included to concentrate the chymosin. The

probability that a GMO will escape from the

process upstream of the first filtration unit is low, but certainly not zero. Naturally the fer­ mentation unit h as been designed to exclude the possibility that microorganisms from out­ side will penetrate the fermentation un it . However, the equipment is not aseptic and due to the high number of yeast cells in the fermentation unit . there is a probability that from time to time the rONA yeasts will es­ cape and enter the environment. However, as explained in Sect. 2.7, the probab i li ty that the _production microor_ganism. in this case Kluy­ veromyces lactis, will survive the conditions present in the environment is extremely low. TEUBER ( 1 990) described the safety evalua­ tion of chymosi n process and product. In this paper the chymos in gene is still assumed to be

located on a plasmid containing an antibiotic resistance marker. When a pplying the scheme of Fig. 8 for approval of this product, this is not allowed. At present, the construct carry­ ing the chymosin gene is integrated into the chromosome and does not carry an antibiotic resistance marker (GIST-BROCADES, person­ al communication).

4.5 Decision Scheme for the Approval of the Release of GMOs

It is likely that foods c o nt a ini n g pl an ts or microorganisms derived from genetic a lly modified organisms will be the first GMOs that will enter the market. Normally foods de­ rived from plant material will not be used to

184

5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products

(re)generate plants; however, food products like bread or yoghurt may contain rONA mi­ croorganisms that are still alive and are able to grow out. It is the release of this category of rONA organisms that is still a matter of much debate. Although certainly more com­ plex than dead material derived from GMOs there is no fundamental difference between

the approaches to assess the risk of these products. In Figs. 13 and 14 and in Tab. 12, a rational approach to assess the risk of living lactic acid bacteria in a dairy product is giv­ en. An important question in this type of risk assessment is whether one should stop with the transfer of genetic material from the host

Fig. 13. Decision tree for the risk assessment of the release of genetically modified microorganisms present

in food products for human consumption.

Fig. 14. Decision tree for

the risk assessment of the release of genetically modified microorganisms present in food products into the environment.

4 Decision Schemes for

Various Types of rDNA Products and Various Applications

185

Tab.

U. A Proposal for a Structured Assessment of the Risk Related to th e Introduction of Genetically Modified Micro o r ga n i s m s (GMOs) in (or as) Food Products

Entry, Questions, Actions and Results Food Products 1 (E). 2 (Q). 3 (R). 4 (0). 5 (A).

Genetical ly modified microorganism ( GMO) Has the product containing the GMO formal clearance based on animal feeding trials? The release of this GMO cannot be evaluated before it has this formal clearance Is this GMO produced as a mixed culture? Determine the probabilit y P (a) that the genetic information will be transferred to (one of) the other microorganisms present in the mixed culture

6 (0). ls P (a) > a'? (Note : in the research phase attention should have been pa id to minimizing the probability of such a transfer) 7 (A). This secondary transformed microorganism (STO) should be cleared in the same way as the GMO (compare qu estion 2 ) 8 (0). Official clearance obtained? 9 (A ) . Go to action 1 0 1 0 (A). Determine the amount of product that comes into the environment ( into the sewage system e ith er from factorie� or households or directly in the soil) before consumption ( = spilled product) 1 1 (0). Is V (spilled) > b V ( p ro d uc ed )? 1 2 (A). Go to action 40 to evaluate the behavior of GMO (and if appropriate the STO) in spilled products and continue with question 13 for consumed product 13 (Q). Will the product containing the GMO receive a physical/chemical treatment before consumption and will that treatment result in an inactivation of GMO by a factor > c? 14 (A). Determine the distribution of the residence times of GMO in the gastro/intestinal (gli) tract of the consumers. Take the time corresponding w i th 95% of this distribution curve as t (r) 15 {Q). Will the GMO lyse with a probability > d i n the gli tract? 16 (A). Although the correct procedure will be the determination where lysis will occur and the determi­ nation of the distribution of the time of intact cells in the gli tract, a worst-case scenario is used assuming the concentration of intact cells is not changed by the lysis and that the intact cells can transfer their genetic information during t (r) to other microorganisms in the gli tract 17 (A). De t erm i n e the probability P (e) that intact cells of the GMO transfer genetic information to nor­ mal inhabitants of the g/i tract. Use in these studies t (r) as contact time and the conditions of the gli tract. Determine also the probability P (f) that the GMO w i ll be transformed by genetic mate­ rial originating from the common gli tract microorganisms ( = modified GMO) 1 8 (Q). ls P (e) > e? 1 9 (A). D e t erm i n e whether the transformed inhabitants (or STO) obta in an advantage over untrans­ formed inhabitants in the g/i tra ct : A (i) Define A (i) in either faster growth rates t' (g); better adhesion h ' ; or higher production of certain metabolites {p (x) x = 1, } 20 (A). Determine the p robabi li t y P (g) that any of the events described under action 19 will result in the formation of a h a zar d ous microorganism (producing toxins) or that the STO will replace benefi­ cial microorganisms in the g/i tract) microorganisms 2 1 (Q). I s {P (e) + P (l)} · P (g) > g or P (m ) · P (g) > g? 22 (A). This risk is unacceptable and the GMO should not be released 23 (Q). Is the number of STOs larger than h per volume unit gli tract (compare action 19)? 24 (A). Determine the proba bi l i ty P ( i), that the STO can transfer that part of its genetic content that contains the genetic i nformati o n from the GMO to another microorganism of the g/i tract result­ ing in a tertiary transformed microorganism (ITO) 25 (0). I s {P (e) + P (i)} · P (i) > i or P ( m ) · P ( i) > i'? 26 (A) . Determin� whether the TIOs have an ad v antage over untransformed cells in the gli tra ct (com­ pare action /9) 2 7 (A). Determine the probability P (j) that any event described in action 2 6 will result in a hazardous microorganism 28 (Q). Is P (e ) ·P ( i) · P (j) > j or P (m) · P (i) · P (i ) >j? 29 (0). Is P (f) > f'! ' ,

. . .

1 86

5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products

Tab. U. (Continued)

30 (A). Determine whether the modified GMO gains an advantage over untransformed GMOs: B (i). De­ fine B ( i) in either faster growth rates t" (g); better adhesion h ; or higher production of certain metabolites {p (x) " , x = l , . . . } 31 (A). Determine the probability P (k) that any of the events described under action 30 will result in the formation of an hazardous GMO 32 (Q). Is P (fl P (k) > k? 33 ( A ) . · As described in action 16 a worst-case scenario is used to determine the probability that DNA of lysed GMO cells transforms other microorganisms of the gli tract. (Use for these studies t (r) as contact time and the gli tract conditions) 34 (A). Determine the probability P (l) that DNA originating from lysed GMO transforms normal inhabi­ tants of the gli tract (resulting in STO) 35 (Q). Is P (/) > 1? 36 (A). Determine the probability P (m) that DNA originating from the inactivated GMOs transforms normal inhabitants of the gli tract (resulting in STO). (Use for these studies t (r) as contact time and the gli tract conditions) 37 (Q). Is P (m) > m? "

·

38 (R). The GMO

can be released This is the end of the risk assessment in the g1i tract. The next phase will be the risk assessment of GMOs, modified GMOs and STOs in the en'rironment ("Sewage System").

39.

"Sewage System" (This scheme products) 40

(A).

41 (Q). 42 (Q). 43 (A).

44 (0). 45 (A).

46 (A). 47 (Q). 48 (A).

49 (Q). 50 (Q). 51 ( A ) . 52 (Q). 53 (A ) .

can

also be used for the release of microorganisms in the environment for non-foods

This decision tree deals with genetically modified microorganisms (GMOs), or modified GMOs and secondary transformed microorganisms (STOs) Determine the average residence times of the GMOs or modified GMOs and STOs in sewage (t (r2), t (r3) and t (r4), respectively) Is the microorganism considered STO? Will the GMO or modified GMO lyse with a probability of > n in the "sewage system" ( s­ system)? Determine the probability P (o ) that the GMO or modified GMO will transfer its genetic informa­ tion to other inhabitants of the s-system. Use in these studies t (r2) and t (r3), respectively, as contact time and the various s-system conditions to determine P (o) ls P (o) > o? Determine whether the transformed inhabitants gain an advantage (or new property) over un­ transformed inhabitants of the s-system: C (i) Define C (i) in either faster growth rates t"' (g); better survival s "' or higher production of certain metabolites {p (x) "' , x = 1, . . . } Determine the probability P (p) that any of the events described under action 45 will result in the formation of a hazardous microorganism Is {P(o) + P (u)} · P (p) >p? Determine the probability P (q) that a transformed hazardous microorganism in the s-system (STO) will enter the food chain Is {P (o) + P (u)} · P (p) · P (q) > q? Will the STO change the ecosystem considerably, e.g., replace the natural microflora? Determine the probability P (r) that the GMO will be transformed by DNA of the normal inhabi­ tants of the s-system Is P (r) > r? Determine whether the transformed GMO gains an advantage or new property over untrans­ formed GMO in the s-system: D (i) Define D (i) in either faster growth rates: t " " (g), better survival: s " " , or higher production of certain metabolites {p (x) " , x = l , . . .} Determine the probability P (s) that any of the events described under action 53 will result in the formation of a hazardous modified GMO Is P (r) · P (s) > s? "

54 (A). 55 (Q).

4 Decision Schemes for Various Types of rDNA Products and Various Applications

187

Tab. 12. ( Continue d )

56 (A). Determine the possibilit y P (t) that the modified GMO will e n t e r the food chain 57 (Q). Is P (r) P (s) P (t) > t? 58 (A). D e t e rm i n e the poss i b i lity P (u ) that the DNA origi na t i n g from the GMO transforms the normal inhabitants of the s-system 59 (Q). Is P (u) > u? 60 (Q). Will the STO lyse w i t h a probability > v in the s s y st e m ? 61 (A). Determine the probability P ( w ) that the STO wi l l transfer its genetic information to the normal inhabitants of the s-svstem 62 (Q). Is { P ( o ) + P (u)} · P ( �) > w? 63 (R). The GMO can be released if the "right band tree" starting with question 42 leads to result 72 64 (A). Determine whether the transformed inhabitants (TfO) gain an advantage (or new property ) over the normal i nhabitants of the s-system: E (i) Define E (i) i n either fas t er growth rat e s : t " " ' (g); better survival s ' " " or higher p ro d uc tio n of ce rtain metabolites ( P " " ' (x), x = l , . . . ) 65 (A). Determine the pro b ab i l i t y P (y) that any of the events described under action 64 w il l result in the formation of a hazardous TIO 66 (Q). I s {P(o) + P ( u)} · P ( w ) P (y ) > y or {P (o) + P (u)} · v · P (a ) P (y ) > y? 67 (A). Determine the probability P ( z ) that the hazardous TIO will enter the food chain 68 ( Q ). Is {P(o) + P ( u)} · P ( w) P (y) P ( z ) > z or {P (o) + P (u)} · v · P (a) · P (y) P(z) > z? 69 (Q) . Will the te rtiary t r a n s forme d microorganism (TIO) change the ecosystem considerably? 70 (A). Determine the pos si b ili t y P ( a ) that the DNA originating from the GMO via STO transforms the normal inhabitants of the s-system 7 1 (Q) . Is {P (o) + P ( u )} · v · P (a) > a? ·

·

-

·

·

·

·

·

72 (R). Provided that the new genetic information of the (surviving) GMO still has its original configura­ tion, the

GMO can be released

strain to the pri mary recipient, or eve n whether it should include the proba b i lity that the primary r e cipi e nt will pass its n e wly ac­ quire d genetic i n form at ion to a se con da ry re­ c ip i ent Other im po rtant but difficult ques­ tions to be answered are the accep ta bl e prob­ abilities of the transfer of this genetic mate ri al and how to e v a luat e these criteria. In t he ad­ ditional Tab. 13 very pre l im i n a ry proposals for the various criteria are give n Many of the p rob a b i lit i e s and numbers p r opos e d in Ta b 1 3 are not based on experimental data. It i s obvious that before GMOs in food products can be int roduced these proposed p rob a b i li ties and numbers should be confirmed and, whenever the proposals are not correct, be re­ placed. However. in an attempt to s t ru c ture the re­ search in this area and to avoid "political" in­ te rpr e tat i on s of the research data ob t ai ne d this scheme and the corresponding prob a bili­ ties a nd numbers are proposed. .

.

.

.

­

,

4.6 Integrated Scheme to Evaluate Any rDNA Product

Based on the various d e ci s ion schemes giv­ e n above, a general ize d decision scheme for all rONA prod uc ts has b e en d e ve loped (Fig. 1 5 , Tab. 14). This scheme divides the va rious types of products into groups, and for each group one of the previously discussed schemes can be followed. A lt hough this scheme has not been aut h or­ ized, it is useful d uring the d e v e l o pme n t phase of an rON A product as it po i nts out q uest ions t ha t m os t prob ab l y will have to be answered to obtain the approval of official bodies. This will guid e the research work in such a way that most of the questions c an be answered straight away.

Events Result

Probability Function

Probability

Donor

Recipient

P (a) > a P ( e} > e P (f) >f {P (e) + P (l)} · P (g) > g or P (m ) · P (g) > g {P ( e ) + P (/)} · P (i) > i or P (m) · P (i) > i P ( e) · P (i) · P (j) >j or P (m) · P (i) · P (j) >j P (f) · P (k) > k P (l) > l P (m ) > m P (o ) > o {P (o) + P (u)} · P (p) >p {P ( o) + P (u)} · P (p) · P (q) > q P (r) > r P (r) · P (s) > s P (r) · P (s) P (t) > t

a e f g i j

= 1 0 - 16 = 1 0 - 16 = 10 - 10 = 10 - 23 = 10 - 1 9 = 10 - 23 k = 10 - 19 l = 10 - 16 m = 1 0 - 16 - 16 0 = 10 9 p = 10 - 1 2 q = 1Q - 3 r = 10 - 10 s = 1Q - 19 t = 10 - 23 u = 1 0 - 16 w = 10 - 1 1

GMO GMO G/i tract cell

Co-ferment cell G/i tract cell GMO

P (u) > u

·

{P (o) + P (u)} · P (w) > w {P (o) + P (u)} · P (w) · P (y) > y or {P (o) + P (u)} · v · P (a) · P (y) > y {P (o) + P (u)} · P ( w) · P (y) P (z) > z or {P (o) + P (u)} · v P (a) · P (y) P (z ) > z {P (o ) + P (u)} · v · P (a) > a ·

·

·

STO STO Modified GMO STO Hazardous STO TTO TTO ---> Hazardous ITO Mod. GMO Hazardous GMO STO STO STO STO --> Hazardous STO Haz. STO Food chain Mod. GMO Mod. GMO --> Hazardous GMO Haz. mod. GMO --+ Food chain STO TTO --->

STO

G/i tract cell

--->

Lysed GMO Inactivated GMO GMO

G/i

Sewage cell

GMO

tract cell G/i tract cell Sewage cell

-->

Lysed GMO STO

Sewage cell

Sewage cell

y = 1 Q - 19

TTO

z = 10 -23 11 a = 10 b = 10 -2 d = 10 - 1 n = 10 - 1

Others

Lysed STO 11 c = 10 h = 1 0 - 14 1 v = 10 -

Sewage cell

Haz. TTO TTO

--+

Hazardous ITO

--+

Food chain

...,

� I: "'

!: �

$;:>,.

:::tl !;j ·

;.;-

). 1:! ., 1:! ::! ., :a.

�

t,

� '""c

�

$;:>,. I: "'

!;;'

1:1 ;::s $;:>,.

� ;:s '"' I:

::! ., .., ). R

5 Some Ethical Aspects and Acceptance of rDNA Products by Consumers

Fig. 15. Decision scheme

any rDNA product .

to ev aluate

5 Some Ethical Aspects

and Acceptance of r DNA Products by Consumers

One cannot d i scuss accep tan ce of rONA prod u cts without taking moral or ethical as­ pects into acc o u nt . In contrast to moral con­ siderations which are often based on emo­ tions, ethicists try to a na lyz e in a sc i en ti fic way the moral questions in detail and to for­ mulate standards for societies to re gula te their be h a vior . In a recent report for ICI STRAUGHAN ( 1 992) divided ethical concern towards 1 992 rONA technology in three groups: Modern biotechnology is blasp h e ­ mous, unnatural and di sre s p ectfu l . The b l asp h e m ou s arguments are based on the view ·'God has created a perfect, natural order: for mankind to impro v e that orde r by manipulating DNA, the basic in gredi e n t of all

189

co life, t hereb y cro s sing species boundaries insti­ tu t ed by God, is not merel y presumptuous but sinful " . An a l yzing rONA t e ch nol ogy it is d iffi c ult to conclude that rDNA technology is b l asp h emou s as it is a careful and very limited imitation of what has been used by Nature to deve lop the richness of biological diversity we know at prese nt. Applying th e laws of ther­ m o d yn ami cs t o the tot a lity of living systems on ear t h , it can be forecasted that at l e ast as long as the so l a r energy s uppl y exceeds the energy necessary for maintenance of t h e t o ­ t a l ity of living systems, new (higher) ordered structures will be created (MOROWITZ, 1 978) . Moreover , the horizontal and vertical fluxes of genes have created and will continue to c re a te novel forms of life. The most st ri k i n g ex a mple of a h o ri zon t a l gene flux in evol ut i o n is w it ho ut any doubt the transfer of gene t i c systems of archaebacteria i nto sp i ro c haete t h ere by formin g primitive e uk ary oti c cells having organelles like mitochondria (Fig. 1 6).

5 Structured Risk Assessment of rDNA Products and Consumer Accep tance of These Products

1 90

Tab. 14. Integrated Scheme to Evaluate Any rDNA Product

Entry, Actions and Results

A Not relevant to this scheme B. Evaluate the safety of the non-modified product

C. Stop evaluation procedure because evidence is insufficient D. Use approval systems for traditionally modified products E. Use adapted form of the scheme for newly defined chemicals (Fig. 8) F. Use normal approval systems for new pharmaceuticals G. Follow scheme for newly defined chemicals and the normal procedures for the approval of personal care products H. Use scheme for newly defined single food component (Fig. 8) J. Not relevant to this scheme K. Use scheme for products derived from animals (Fig. 9) L. Use one of the schemes for products derived from plants (Fig. 10) M. Use scheme for microbial products (Fig. 1 1 ) Questions

1. Is the product new or modified or does it contain a new or modified compound?

2. Is the product derived from a source (strain, variety, cultivar) or bred from an approved source?

3. Does the source contain a new trait ( = well defined genetic property/properties) obtained by rDNA

techniques?

4. Has the product or the new or modified compound been produced by a process that involves products 5.

6.

7.

8.

9.

10. 11.

produced by rDNA techniques? Is the product used as a pharmaceutical? Is the product used as a food? Is the product used for personal care? Is the product a single well defined compound? Is the product derived from animals? Is the product derived from plants? Has the non-modified product been approved?

�

Horizontal flux of genes --.

�

Protists

/

Primitive

t

Vertical flux of genes (genomes)

Fungi

Animals

Plants

Cyanobacteria

�

Spirochaete

Archaebacteria

Eubacteria

Fig. 16. Fluxes of genes and genomes during the evolution of Nature (L. MARGULIS, personal com­ munication).

Also external factors have influenced the creation of the present living systems as do

boundaries between species is weak. Al­ though the exact processes that resulted in

rONA technology in living systems, enzyme

most probably will remain obscure, circum­ stantial evidence is available that "natural

external

factors

at

present.

Without

any

systems have been created to adapt these cells

to the xenobiotics introduced by mankind (ALEXANDER, 198 1 ) . Finally the argument of

the formation of eukaryotes and eubacteria

boundaries" are rather a kinetic than a ther­ modynamic barrier. S ince evolution has been

5 Some Ethical

Aspects and Acceptance of rDNA Products by Consumers

going on for billions of years under quite varying conditions. even slow processes of transfer of genetic material from unrelated species will have occurred (see Figs. 2 and 16). Therefore. so-called natural boundaries can be considered more as an invention of biologists to divide the present biological world into often quite arbitrary groups. The second concern in ethical discussions is the "unnaturalness" of rONA technology. However, rONA technology is just applying enzymes deve loped during evolution for the purpose of changing DNA. The immune sys­ tem in mammals would not have been able to cope with the enormous number of foreign molecules, if it had not been based on cutting, joining and mutation of DNA sequences, in a superior but in principle similar way as mo­ lecular biologists do. It is very likely that in the near future it will be found that the im­ mune system is not the only system using in vivo methods similar to rONA technology. A candidate is the olfactory receptor system (R. AXEL, personal communication). In discussions rONA technology is often called disrespectfuL because it is perceived as "not to abide by the law as set (or perhaps as seen to be used) by Nature itself" . Another aspect of disrespect is that ··even if no rules as set by Nature are violated, it cannot be de­ nied that Nature has never been in the posi­ tion to organize itself against the interests of mankind on purpose and consciously, rONA technology enables man to do just that" . As such the argument that "Nature has never been in the position to organize itself on pur­ pose" is correct. However, it is not correct to introduce in the discussion on rONA technol­ ogy the argument that this technology will be used against the interests of mankind on pur­ pose and consciously. What is in the interest of mankind is a different discussion. The concern that rONA technology as such is "disrespectful"' cannot be counteracted by straight scientific arguments. STRAUGHAN ( 1 992) quoted the German philosopher KANT, who argued that "respect required treating others as ends, never only as means " . Accepting this view opens a rational way to discuss rONA t echnology. Applying rONA technology to c o r r ec t genetic diseases falls certainly within the category "ends"; howev-

191

er, using animals j ust as a means to produce rONA products is in KANT's view "disres­ pectful" . Until recently there has been no de­ bate on "ends" and "means" for plants and microorganisms. In fact, in ancient times the precursor form of our present civilization started with the cul­ tivation of plants and the use of microorgan­ isms to ferment many of these agricultural products to prolong the shelf life of these products. Since that time plant varieties have been selected and crossed to improve yield, to become resistant to certain harsh environ­ mental conditions, etc. Similar procedures have been followed to select the most appro­ priate microbial strains for fermentation pro­ cesses. Never in human history these proce­ dures (changes of the genetic makeup of these organisms) have been a subject of ethi­ cal discussions. Also in more recent times the work of MENDEL and PASTEUR on these pro­ cedures have in spite of tremendous influence on human life not been regarded by the pub­ lic as disrespectful. Of course they did not have any idea that in principle their work was based on manipulation of DNA. According to the criteria of KANT, the re­ sults of classical breeding can be seen as "end" and in line with that view no debates on the ethical aspects of traditional breeding have been held and traditional breeding is widely accepted in all societies. It is very diffi­ cult to understand that traditional breeding techniques are accepted as "respectful" and the much more precise rONA technology is considered as disrespectful. Having been in­ volved in various aspects of rONA technolo­ gy for nearly 20 years, I have noticed that mo­ lecular biologists are deeply impressed by the elegance of the solutions Nature has found to solve problems, and the vast majority of mo­ lecular biologists are very respectful to living systems. This respect is the driving force of numerous molecular biologists to unravel the way Nature works and to use this knowledge to find very specific and effective medicines, to ensure that agriculture will provide safe, nutritious and affordable food supplies for the ever growing population of this world and to ensure that the environmental problems created by this increase in population and the desire for a higher quality of life for the pop-

192

5

Structured

Risk

Assessment of rDNA Products and Consumer Acceptance of These Products

ulation of the developing countries can be met. Respect also means that certain types of rDNA experiments with animals and certain­ ly with humans will not be carried out. Often discussions on the ethical aspects of rDNA technology are blurred by risk aspects. As explained in the previous sections, this should be discussed separately. Provided that the necessary control experiments are done carefully (which should be checked by inde­ pendent bodies ) for nearly all approved ap­ plications of rDNA technology, it can be proved that the hazard is so small that it can be considered as zero as can the risk. For the average consumer to accept modern biotech­ nology it is very important that the risk is very low. In a recent survey in the U.K. the influence of the risk on the public acceptance of rDNA technology has been meas ured (Tab. 15). Tab. 15. Public Acceptability of Risks from the Re­ lease into the Environment of Genetically Engi­ neered Organisms

Risk Level Unknown 1:100 Unknown, but very remote 1:1000 1:10000

1: 100000 1:1000000

Approve (%)

Do Not Approve (%)

31

65

40

51

45

46

55 65 71

37 27 21 18

74

The prosperity of the present societies of Western Europe, USA, Canada and Japan are mainly based on the exploitation of scien­ tific discoveries and technological break­ throughs. However, besides these positive as­ pects the consumers in these societies have been confronted with a large number of un­ foreseen or neglected negative consequences of the application of these developments. Any discussion about the public acceptance of rDNA technology should take these posi­ tive and negative feelings of consumers into account. Therefore, it is essential that manu­ facturers estimate the benefits ve rs us ri sks for

new technologies or even for new products. In the case of rDNA products, it is obvious that the benefit of this technology for the de­ velopment of a new generation of very effec­ tive, precise medicines with minimal side ef­ fects is enormous. Nevertheless, the applica­ tion of rDNA technology for the develop­ ment of new medicines has not been accep t e d in all its aspects (e.g., gene therapy) , mainly because the communication with the consum­ ers has been insufficient and inadequate. The author is not aware of any systematic nation­ wide education program to teach students or consumers the benefits and risks of the var­ ious aspects of the application of rDNA tech­ nology. In an extensive analysis of the Dutch Institute for Consumer Research (HAMSTRA and FEENSTRA, 1989) only 57% of 1729 inter­ viewed persons knew the word "biotechnolo­ gy", and even of this 57% only 45% knew that insulin was made via biotechnology, whereas fewer than 10% of all interviewed persons knew that experiments are in pro­ gress on rDNA cells modified in such a way that they can inhibit certain forms of cancer. In a recent analysis done by the University of Strathclyde (U.K.) the p ublic was divided into seven specifically targeted subgroups. The attitude of the various subgroups towards biotechnology is extremely variable. As could be expected, certain applications of rDNA technology are not or hardly acceptable for the public: biological warfare (95% ) , chang­ ing the human physical appearance (84% ), cloning prize cattle (72% ), using viruses to at­ tack crop pests ( 49% ) and improving milk yield (47% ) . Medical applications are consid­ ered by most of the groups as acceptable (Tab. 16). Similar results were obtained in a Dutch investigation, although the acceptance of products made via rDNA te chn o l ogy that can contribute to an improvement of the envi­ ronment scores higher (HEIJS and MIDDEN, 1993). Labeling of products is only relevant if consumers are able to understand the infor­ mation on the label. According to the view of the FDA, labeling should not be based on the way a certain product is obtained. This is or should be part of normal approval for agricul­ tural practice or industrial processes, and if approved then labelin g is unnecessary. This is

6 Conclusions

193

Tab.l6. Attitudes to Applications of Genetic Manipulation Adapted from (A) MARTIN and TAIT (1992) and (B) HE!JS and MIDDEN (1993) Comfortable

Neutral

Uncomfortable

Microbial production of bio-plastics

(B)

91

6

3

Cell fusion to improve crops

Curing diseases such as cancer

(B)

81

10

10

(A)

71

17

Extension shelf life tomatoes

(B)

71

11

19

Cleaning up oil slicks

(A)

65

20

13

Detoxifying industrial waste

(A)

65

20

Anti blood clotting enzymes produced by rats

(B)

65

13 22

9.5

Medical research

(A)

59

14 23

Making medicines

(A)

57

26

(A)

54

25

13 19

Mastitis-resistant cows by genetic modification of cows

(B)

52

Producing disease-resistant crops

(A)

46

16 29

23

Chymosin production by yeast

(B)

43

30

27

39

31

29

(A)

23

26

49

Improving milk yields

(A)

22

Cloning prize cattle

(A)

30 18

47 72

(A)

4.5

(A)

1.9

9.5 12 2.7

84

Producing hybrid animals

Making crops to grow in the Third World

( A)

Improving crop yields

Using viruses to a\tack crop pests Changing human physical appearance

( A)

Biological warfare

common practice for near ly all food products, e.g., the label on a can of meat or fish never mentions that the

product

has received a heat

treatment equivalent to Fn of at least 5 (to en­ sure 12 decima l reduction of the risk of botu­

lism), but the consumers trust the government to check the manufacturer of these cans. An argument against the view of t he FDA is that certain consumers are in

princi ple

against

a

certain technique and these consumers have the ri ght to know which technology has been

applied gy, but

a product. However, this is not restricted to rONA technolo­

to produce

argument

applies to all types of technologies.

Without any doubt the label should contain

information on the contents of the produc t in order to inform the consumer. Therefore. it seems l ogica l that if a product still contains a foreign gene or gene product, it should be la­ beled. Accepting this view it is clear that also products derived from plants obtained via classical b re edi n g or products containing mu­ tated organ i s ms should be labeled. However. in view of the general ignorance of the public about biotechnology it is dangerous to label products containing rONA-derived products. Such labeling can repel consumers unneces-

7.2 4.5

sarily and can

15

31

82

95

therefore slow down considera­

bly the introduction of this technology even for applications that

are

considered by the

public as desirable, such as reduction of the amount of chemicals used to protect crops.

6 Conclusions It is v ery

likely

the

most

become

that rONA technology will

important

technology

in the

first part of the 21st century, because this

technology will help us to unravel the secrets of Nature, and by doing so we can learn from Nature how to cope with diseases and large ecological problems, for Nature has frequent­ ly faced these problems and found magnifi­ cent solutions. Also for food products rONA wil l become an i mportant tool to reduce the use of chemicals in agriculture and energy and production of waste during processing. Moreover. rONA

will provide techniques

to

opt i m ize the quality of food products and in­ crease the naturalness of food products (VER­ RIPS, 1991 ) .

194

5

Structured

Risk

Assessment of rDNA Products and Consumer Acceptance of These Products

The risk related to the introduction of new rONA products should be assessed carefully. Always two aspects should be assessed sepa­ rately. Firstly, the intrinsic toxicological or eco-toxicological hazard of the foreign gene( s) and the construction methods should be determined. If the foreign gene codes for a harmless protein and the host organism is safe (recognized as functional organism in fermented food; see , e.g., Tab. 4 of DFG Mit­ teilung XI, 1 987) and all the aspects men­ tioned in Sects. 2.3, 2.4, 2.6-2.9 are carefully analyzed and no mistakes or unexpected events have been found, then the hazard of this transgenic organism can be considered as zero. In that case an assessment of the proba­ bility that the foreign gene present in the transgenic organism will be transferred into a wild organism is not necessary because what­ ever that probability is the hazard is zero, so the product of hazard· probability (=risk) is zero. Nevertheless, a risk assessment for the eco-toxicological consequence will have to be made. If the hazard analysis shows that the haz­ ard is not zero, e.g., in case of a pharmaceuti­ cal product that encodes for an inhibitor of an enzymic reaction in malignant cells of a cer­ tain tissue but this inhibitor will also be able to block this reaction in healthy cells of other tissues or even other species, a full risk assess­ ment should be carried out. The open ques­ tion is then what will be an acceptable risk. No definitive answers to this question can be given. In the food industry the acceptable risk of microbial spoila�e (in the order of one product unit in 10- ) is much larger than the acceptable risk of microbial poisoning (rang­ ing between about 10-6 for relative innocent poisonings to 10 -Iz for poisoning by botulin­ um toxin). Also the kind of hazard related to rONA products and the acceptable risk will be related to each other. Moreover, as was explained earlier in this chapter, the risk as­ sessment of GMOs will be more complicated than that of cell-free rDNA products, but the approaches are not fundamentally different. For medicines made via rDNA technology, even a third factor will become important in this risk assessment, notably the benefit of the rDNA product to cure severely ill people.

The most important aspect of legislation of new scientific developments is clarity. Only if clear legislation is in place, will the manufac­ turers or seed companies know exactly under which conditions a new discovery can be com­ mercialized and can they calculate whether their benefit versus cost ratio will be positive. Although improvements of the present legis­ lation are certainly possible and harmoniza­ tion of the legislation between the various countries is of great importance, in most countries there is legislation of sufficient clar­ ity to enable introduction of this technology. However, nearly all these legislations are based on the assumption that rDNA technol­ ogy is an intrinsically hazardous technology and, as described above, this cannot be justi­ fied by scientific data. Governments should educate their citizens (especially pupils at schools) to ensure that they really understand this new technology and are. able to make real choices. This is im­ portant for all new technologies but especially for rONA technology, as this technology is closely related to the most fundamental pro­ cesses of life. A better understanding of biol­ ogy will certainly result in a better acceptance by the consumers. Acknowledgement The author is grateful for the contribution of ESTHER KoK (Rijks-Kwaliteitsinstituut voor Land- en Tuinbouwprodukten (RI­ KILT-DLO), Wageningen, The Netherlands) for preparation of Table 8 and W. HoEKSTRA (Rijksuniversiteit Utrecht, The Netherlands), E . KoK (RIKILT-DLO), 0 . K O RVE R , W. MusTERS (Unilever Research, Vlaardingen), D. ToET (Gist-Brocades; at present Hercules, Rijswijk, The Netherlands), B. DE VET (Uni­ lever, Rotterdam) and A. WEERKAMP (NIZO, Ede) for the valuable comments on the manuscript.

7

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Biotecllllology

Edited by ,H.-J. Rehm and G. Reed i n cooperation w ith A. Pu hle r and P. S tadler Copyright © VCH Verlagsgesellschatt m b H , 1 995

6 Strategic Regulations for Safe Development of Transgenic Plants

L. MEDLEY SALLY L. McCAMMON TERRY

Washington, DC 20090-6464, USA

I

Introduction I 98 Ch allenge 198 3 Identifiable Science-B ased Triggers 199 3.1 Policy 199 3.2 Science 200 3.3 Transparent Triggers 201 4 Effective and Responsive Regulations 203 5 Meeting Domestic and International Needs 207 5.1 Domestic Needs 207 5.2 International N eeds 207 6 Conclusion 209 7 References 210

2 The

1 98

6

Strategic Regulations for Safe Development of Transgenic Plants

1 Introduction In business, a strategic plan determines where an organization should be going. It is also used to assure that all organizational ef­ forts are pointed in that same direction. There is an old saying that "if you don't know where you are going, any road will take you there" (BELOW, 1 987}. For agricultural bio­ technology, strategic regulations are regula­ tions which provide a framework or process for actions that lead to consistent and plan­ ned results. Therefore, they are regulations that are developed and applied in a strategic manner. Strategic regulations are developed and applied in a comprehensive manner to avoid being one-dimensional or limited to a single issue focus. Although consideration of risk versus safety is of paramount importance, the regulations should also consider their im­ pact on other concerns such as product verifi­ cation/utilization, safe technology transfer, economic competitiveness, international har­ monization, and global needs/acceptance. Consequently, strategic regulations have a multi-dimensional focus. In our opinion, to ensure the best likelihood of success, strategic regulations should: (1) have identifiable science-based triggers that are consistent, eas­ ily understood, and transparent; (2} be effec­ tive and responsive as well as flexible and dy­ namic; and (3) meet domestic and interna­ tional needs.

2 The Challenge Biotechnology is an enabling technology with broad application to many different ar­ eas of industry and commerce. A recent re­ port by the Committee on Life Sciences and Health of the Federal Coordinating Council for Science, Engineering, and Technology, Biotechnology for the 21st Century: Realizing the Promise, Washington, DC., June 30, 1992, broadly defines biotechnology to "include any technique that uses living organisms (or parts of organisms) to make or modify prod­ ucts to improve plants or animals or to devel-

·

op microorganisms for specific use." The re­ port further predicts that, "by the year 2000, the biotechnology industry is projected to have sales reaching$ 50 billion in the United States." For American agriculture, biotechnology has the potential to increase productivity, en­ hance the environment, improve food safety and quality, and bolster US agricultural com­ petitiveness (OTA, 1 992}. However, if bio­ technology's vast potential, which is an out­ growth of substantial public and private in­ vestment, is to be of the greatest benefit, the development of appropriate and effective reg­ ulatory structures is a necessity. The 1970s and 1 980s in the United States have come to be associated with certain regu­ latory policy milestones for the development of modern biotechnology. The 1970s were as­ sociated with the concern over the safety of conducting experiments with recombinant DNA under conditions of adequate laborato­ ry containment. This led to issuance of the National Institutes' of Health guidelines for research involving recombinant molecules (NIH, 1976). The 1980s have been associated with concern over the safety of conducting ex­ periments using genetically modified organ­ isms outside of a laboratory in the environ­ ment. This led to issuance of the Federal Coordinated Framework for the Regulation of Biotechnology (OSTP, 1 986}. If the first three years are any kind of indi­ cator, the 1990s promise to be no less signifi­ cant in terms of their association with bio­ technology regulatory policy milestones. At the United States Department of Agriculture (USDA), a petition process has been final­ ized for removing transgenic plants from fur­ ther regulation (USDA/APHIS, 1 993}. The Food and Drug Administration (FDA) pub­ lished its policy statement on food derived from transgenic plants (FDA, 1992). The En­ vironmental Protection Agency (EPA} held an open meeting of the agency's Scientific Advisory Panel to assist in developing regula­ tory policy for plants genetically engineered to express pesticides (EPA, 1 992). Many of these new plant varieties will be available in the 1 990s. But their introductions will be un­ der circumstances unlike any met by other new plant varieties because of the technology

3

used to develop them. "Uncertainties over these new technologies raise questions of po­ tential impacts on food safety and the envi­ ronment, and possible economic and social costs. Nevertheless. there will be a push for . . . biotechnology .. . to be used commercially, adopted by industry. and accepted by the public .... The challenge. however, will be whether government, industry, and the public can strike the proper balance of direction, oversight and allow these technologies to flourish." (OT A. 1992. emphasis added). In ou r opinion. strategic regulations have the greatest potential for creating a frame­ work or process to meet this challenge. The following is a discussion of the Animal and Plant Health Inspection Service (APHIS), USDA. regulations for transgenic plants in such a strategic context.

3 Identifiable Science-Based Triggers One of the most critical and controversial decisions associated with the development of regulations is identification of scope. In other words, what organisms will be covered or what are the •·triggers·· for inclusion. We must guard against di fferent approaches to this is­ sue being inaccurately characterized as a con­ tinuation of the process-versus-product de­ bate. It is more appropriately characterized as a commitment by regulatory officials to the development of regulations that neither over­ regulate nor under-regulate. In the United States we do not know of any Federal agency which seeks to regulate based upon process only, independent of risk or uncertainty (MEDLEY, 1990). For biotechnology in the United States. this issue is best demonstrated by the publication of a proposed scope docu­ ment for regulation of biotechnology in 1990 and a very different final scope policy docu­ ment in 1992. (OSTP, 1 990. 1992). These two documents were very different and did little to resolve the scope debate or determine nec­ essary triggers for inclusion. Regulations which are strategic in their development can avoid this initial barrier by using triggers for

Identifiable Science-Based Triggers

1 99

inclusion that are consistent with adopted regulatory policies, based on sound science, and in themselves transparent.

3.1 Policy Industry analysts as well as academic scien­ tists have stressed the importance of US Fed­ eral programs and policies for the future of US biotechnology. particularly US Federal support for basic and applied research funda­ mental to the biotechnology industry (O L ­ SON. 1986; ERNST & YOUNG, 1 992). The US Federal investment in biotechnology research for Fiscal Year 1994 is approximately 4.3 bil­ lion US dollars. An adjunct to the US Federal investment in biotechnology is the Federal commitment to promote the safe develop­ ment of products of biotechnology. Such a commitment requires that each Federal agen­ cy with authority to regulate such organisms and products implement risk-based regulato­ ry requirements. These regulatory require­ ments should assure safety and facilitate tech­ nology development and utilization by re­ moving regulatory uncertainty. The Federal policy for the regulation of biotechnology was proposed on December 3 1 ,1984 (OSTP, 1 984), and published in final form on June 26, 1986 by the US Office of Science and Technology Policy (OSTP 1986) . The Federal policy is referred to as the "Coordinated Framework for Regulation of Biotechnology." The OSTP concluded that products of recombinant DNA technology will not differ fundamentally from unmodif­ ied organisms or from conventional products. Therefore, existing laws and programs are considered adequate for regulating the organ­ isms and products developed by biotechnolo­ gy. The USDA policy on biotechnology was consistent with the policy established by the OSTP. USDA's policy document of Decem­ ber 1 984 stated that existing statutes were ad­ equate for regulating the products of agricul­ tural biotechnology, and further, that USDA did not anticipate that such products would differ fundamentally from those produced by conventional techniques (OSTP, 1 984, p. 50896). This position was reaffirmed in the fi,

200

6 Strategic Regulations for Safe Development of Transgenic Plants

nal policy document of June 26, 1986 (OSTP, 1 986, p. 23345). The current Administration has framed its policy objectives in President CLINTON's and Vice President GoRE's initiative, Technology for America's Economic Growth, A New Di­ rection to Build Economic Strength, February 22, 1993, White House, Washington, DC. In this document, the Administration stated, in relevant part, the following objectives: ( 1 ) We must ... turn . . . to a regulatory policy that encourages innovation and achieves so­ cial objectives efficiently; (2) We can promote technology as a catalyst for economic growth by . . . directly support­ ing the development, commercialization, and deployment of new technology; [and] (3) To improve the environment for private sector investment and create jobs, we will: en­ sure that Federal regulatory policy encour­ ages investment in innovation and technology development that achieve the purposes of the regulation at the lowest possible cost. These policy objectives are reinforced by Executive Order 12866 (Fed. Reg. 58, 5173551744, October 4, 1993) which states, in rele­ vant part: (4) In setting regulatory priorities, each agen­ cy shall consider to the extent reasonable, the degree and nature of the risks posed by var­ ious substances or activities within its jurisdic­ tion. (10) Each agency shall avoid regulations that are inconsistent, incompatible, or duplicative with its other regulations or those of other Federal agencies. ( 1 1 ) Each agency shall tailor its regulations to impose the least burden on society, includ­ ing individuals, businesses of differing size, and other entities (including small communi­ ties and governmental entities), consistent with obtaining the regulatory objectives, tak­ ing into account, among other things, and to the extent practicable, the cost of cumulative regulations. However, one of the most prominent and essential aspects of the Clinton Administra­ tion's biotechnology policy is the requirement that there be more public access to the Feder­ al decision-making process or as GREG SI­ MON, Domestic Policy Advisor to Vice Presi­ dent GORE, states "the importance of a regul-

atory system for biotechnology that operates in an open and fair way" (BROWNING, 1 993) .

3.2

Science

Strategic regulations for biotechnology should be developed and applied using sound science as a cornerstone. However, moving genes across natural barriers creates uncer­ tainty for some scientists as well as for society in general. A major question is: what consti­ tutes an "unreasonable" risk? Such risks nor­ mally fall into categories of risks to the food supply, human health, and the environment. Plant and animal pathogens are included as well as carcinogens. Thus, uncertainty is created in new cases or situations in which pa­ thogens are used as part of the process of de­ velopment and genes for pathogenesis are in­ serted into an organism. The scientific community itself does not appear to be of a single mind as to the rami­ fications to the environment of moving genes from non-sexually compatible species and from pathogens into plants. In particular, the scientific establishment does not agree on the types of risk and what is low risk. For exam­ ple, in 1 989, the report by the National Re­ search Council, Field Testing Genetically Modified Organisms: Framework for Deci­ sions, emphasized familiarity with the "prop­ erties of the organism and the environment" in order to make a determination of risk (NRC, 1989). The Council stated that "(f]a­ miliar does not necessarily mean safe. Rather, to be familiar with the elements of an intro­ duction means to have enough information to be able to judge the introduction's safety or risk." Enhanced weediness was cited as the major environmental issue with plants. With the addition of traits for herbicide tolerance or pest resistance, it was felt that crop plants would be unlikely to become weedy. Howev­ er, the report also stated that "genetic modifi­ cations of only a few genes can produce a modified plant with significant, ecologically important alterations". They stated that, for initial tests, confinement was the "key to min­ imizing the environmental impact to nontar­ get species" (NRC, 1989).

3 Identifiable Science-Based Triggers

In the same year. the Ecolog i c al S ociet y o f A me rica publish ed a p aper entitled ·The Planned I ntrod uct ion of G ene t i cally E ngi ­ ne e red Or ganisms: E colo gical Considerations and Recommendations"' in which several fac­

tors were rated for t heir level of concern in a risk evaluation (TIEDJE et al.. 1989). These included factors r e l a t ing to the ge n e tic altera­ tion. the p are ntal organism . and the p heno­ type of the altered organism. Factors such as a new gene function b e i ng introduced to the parent o rg a nis m . the source of the gene being from an un rela te d organ­ ism, the vector being fro m an unrelated spe­ cies or pathogen, and the p are n t be ing self­ propagating all wa rran ted scientific evalua­ tion. Other s c i e ntis t s have ra is ed concerns over the effects of i n troduc ing genes from plant path ogens into the plants themselves; espe ci ally . concerns about viral coat protein gene s and vi ra l nucleic acid recombination have been discussed (HULL, 1990; DE ZoET­ EN, 1991). It a l so appears to us t ha t the view that one ge ne change cannot cause a change in pa thogen e sis is an oversimplification. g iven reports in the literature (PAYNE et al . . 1987; WHEELER,

1975).

Therefore. strategic regul ations for bio­ technology biosafety reviews sh o u ld focus o n the scientific ques tions and the most efficient way of doi ng the re v ie w in the context of fa­ cilitating the safe application of t he biotech­ nologies. Thus. a cer t ifica t i on system for eval­ uating any safety issues wh ile the v a rie t y is being developed, preferably at the initial field te sting stage. is most appropriate (CooK. 1993). Science must be the basis of the decisions th a t address the concerns asso cia te d wit h t h e application of b i ot e ch n o lo gy to agri c u lture . A n e cess a ry role for re gu l a to ry officials is to frame the qu es tio n s and issues t h at science must answer. Science is t h e base by which regul a tory officials can as s u re and build upon cre d i bi l ity , remain cu r re n t . and assure a ra­ tional ba s is for decision-making. Science and process are in ext rica bly linked for stra te gic r e g ula tio ns that evaluate bi o l o gic al programs and p rod ucts . In the area of b i o tech n o l o gy re gu l a tio n. science without the process to frame the is­ sues becomes ov e rwh e l m i n g and m i s le adi n g .

201

while process w i th ou t science is r educed to being bureauc ra tic , self-serving, and ineffec­ tive . Neither science nor regul ation can afford to be in an all or none category. To a d apt to new i nfo rm at ion and new needs, both types of systems need t o work together to fr am e and address the c o n cerns and requirements of the many co m po ne nts of our society.

3.3

Transparent Triggers

It is not e no u g h that the triggers for stra­ tegic r e g ulat i ons be co n s istent with na t i onal bio tech nolog y po licies and are science-based, they m us t also be e asy to understand and id enti fy (transparent). S uch transparency is necessary to enable those r e gul a ted to clearly understand the r e gula tory requirements. Tra nspa rent regulations should remove re gul­ atory u n ce rtain t y , e s ta b lish p r edictable stand­ ards and a l l o w sa fe tech n o l ogy utilization and expanded development. For those that have concerns about the biotechnology activities b e i n g re g u la te d , it should provide a clear or t ranspa re n t window to observe and evaluate gove rnmen t a l o v e r si ght . A PH I S re gulations , which were promul­ gated pursuant to authority g rant e d by the Federal Plant Pest Act (FPPA), (7 U . S . C. 150aa-150jj) as amended, a n d the Plant Qua­ rant i ne Act (PQA), (7 U.S.C. 151-164a, 166167) as a mende d , re gula te the introduction (impo rt a tion , interstate movement, or release i nt o th e en vironment) of certain g ene ti cal ly e ngi nee re d organisms and products. A geneti­ cally e ngine e re d organism is deemed a regul­ ated article if eith e r t he don or or ganis m, re c i pi e n t o r ga nism, vector or vector agent used in e ngine ering the o r g anis m be lo ngs to one of the taxa listed in se c t io n 340.2 of the regula­ tions a nd is also a pl an t pest; if it is unclassif­ ie d ; or. if APHIS has reason to believe that th e gen e tic a l l y e nginee re d o r ga nism p re se n ts a plant pest risk . (7 CFR par t 340; see a l s o McCAMMON and MEDLEY, 1990). Prior to the introduction of a regu l ated ar­ ticle, a person is require d under section 340.1 of the re gula tion s to either (I) notify APHIS in accordance with se ct i on 340.3 or (2) ob tain a pe rm i t in accordance with section 340.4. Under sec tio n 340.4, a p e rm it is g ra n ted for a

202

6

Strategic Regulations for Safe Development of Transgenic Plants

field trial when APHIS has determined that the conduct of the field trial, under the condi­ tions specified by the applicant or stipulated by APHIS, does not pose a plant pest risk. The FPPA gives USDA authority to regul­ ate plant pests and other articles to prevent direct or indirect injury, disease, or damage to plants, plant products, and crops. The PQA provides an additional level of protection by enabling USDA to regulate the importation and movement of nursery stock and other plants which may harbor inj urious pests or diseases, and requires that they be grown un­ der certain conditions after importation. For certain genetically engineered organisms, field testing may be required to verify that they exhibit the expected biological proper­ ties, and to demonstrate that although de­ rived using components from plant pests, they do not possess plant pest characteristics. An organism is not subject to the regulato­ ry requirements of 7 CFR part 340 when it is demonstrated not to present a plant pest risk (SCHECHTMAN, 1 994). A plant developed from a plant pest, using genetic engineering, is not called a plant pest, but rather a "regulated article". There has been misunderstanding as to the basic as­ sumption of APHIS regulations. The regula­ tions do not imply that part of a plant pest makes a plant pest or that plants or genes are pathogenic. The regulations instead have as a trigger that when plants are developed using biological vectors from pathogenic sources, use material from pathogenic sources, or pa­ thogens are used as vector agents, that they should be evaluated to assure that there is not a plant pest risk. For example, APHIS does accept that Ti plasmids used to transform plants have been disarmed. APHIS does a re­ view that allows a verification of the biology and procedures used; assesses the degree of uncertainty and familiarity, and allows the identification of any risks, should they be present and predictable. Vectors are evaluated because plant pa­ thogens are used to move genetic material into the plant (genetic materials from viruses and pathogens are used as promoters, termi­ nators, polyadenylation signals, and enhanc­ ers; and genes from plant pathogens are in­ serted to obtain resistance to these patho-

gens). Evaluation includes the verification of the removal of plant pathogenic potential of biological vectors so that pathogenic proper­ ties do not become part of the heritable char­ acteristics of new crop varieties. Strictly inter­ preted, concern is not over the use of viral promoters or disarmed Ti plasmids but over the elimination of genes for pathogenesis or unknown/non-characterized DNA. APHIS regulations do not assert that genetic traits would cause a plant to exhibit plant pest char­ acteristics unless the plant itself was already a pest to other plants. However, they do allow verification that (1) a disarmed plasmid was used, (2) genes implicated in plant pathogen­ esis did not become part of the heritable char­ acteristics of the plant, and (3) the introduced genetic material is inherited as a single Men­ delian trait, or lack of genetic stability of the new plant variety is not expressed by the plants in the field. APHIS has issued permits for field tests for plants containing various genes for insect to­ lerance, virus tolerance, fungal tolerance, her­ bicide tolerance, nutritional and value factors, heavy metal sequestration, pharmaceutical products, and selective markers. There are di­ rect implications of genetic factors on plant health and the effects of toxicants on benefi­ cial insect populations that are important to consider in evaluating impact on plants and the environment. The regulations would not be based on sound science if assertions rather than evi­ dence, or laboratory data alone, without field confirmation were used as the sole basis of decisions under the regulations. Molecular se­ quence information does not preclude the need for appropriate scientific evaluation and data collection in various environments in the field. The use of the technology itself poses no unique hazards, i.e., genetic material inserted into a plant via this technology will behave no differently than genetic material inserted via any other technology. The risks in the envi­ ronment will be the same; there is no evi­ dence that unique hazards in the use of rDNA techniques are present. The risk is in the genes interacting in a new genetic back­ ground and with an organism in a new envi­ ronment. In the case of the use of pathogenic

4

material that has been reviewed under the FPPA and the PQA. pathogenic genes could not be introduced into the heritable charac­ teristics of the plant without the use of the technique. Th e plant pest source of the genetic

material, not the techn ique. is the major basis for regulation .

4 Effective and Responsive Regulations The baseline for strategic regulations, simi­ lar to the baseline for a ny business. is whether the system is productive. i.e . . does it work. When applied. regulations should not only address any safety concerns raised about the use of the tech nology but also meet the needs of those being regulated. Some members of the academic research community had the following to say to fellow researchers about the effectiveness of the APHIS biotechnology regulations: .. our experiences with the permit process have been positive . We are all in agreement that the existent system is fast, friendly. and efficient. allowing us to concen­ trate our energy on experimentation rather than paperwork" (SHAW. 1 992 ) . I n addition t o being effective a n d respon­ sive, oversight in an area such as biotechnolo­ gy must be dynamic. flexible . and constantly evolving. Th is flexible and dynamic focus is needed because the technologies and their applications are rapidly evolving. The struc­ ture of regulations should assure safety and facilitate technology development and utiliza­ tion. Although regulations should be risk­ based, the purpose of regulation itself can be multifold and include: ( 1 ) safety: (2) product verification ; and ( 3 ) quality assurance. Regul­ ation is at the intersection of scientific risk as­ sessment and product evaluation and, in a new area like biotechnology. necessarily has to adjust and change rapidly with advances in both. AP H I S . like other U S Federal agencies . regulates the products of biotechnology un­ der i ts existing statutory authority. APHIS' broad historic authority to protect plant

Effective

and Responsive Regulations

203

health is applicable to the regulation of cer­ tain plants as well as microorganisms devel­ oped through biotechnological processes. Equally as important is the statutory and leg­ islative intent to empower APHIS (via the Secretary of Agriculture) to be the first line of defense in protecting US plant health. Hence , the statutes have built in flexibility to take those measures necessary to prevent di­ rect or indirect risks to plants (7 U.S.C. 150aa-jj ) . Almost s i x years have elapsed since APHIS first established regulations for cer­ tain transgenic plants. We are committed to assuring that our regulations are flexible and modified when appropriate to remove unne­ cessary restrictions or. if necessary, to add ad­ ditional ones. Flexibility of the system to ad­ apt based upon experience is essential for strategic regulations that enable the structure/ operation of the regulations to be most effec­ tive and responsive. Such regulatory systems should evolve and be well-designed. Thereby, strategic regula­ tions stimulate rather than frustrate or inhibit innovation. Strategic regulations provide op­ tions for the safe introduction and commer­ cialization of products of new technologies. They can stimulate private sector investment and innovation, while at the same time, re­ ducing regulatory costs and complying with environmental/safety concerns and man­ dates. APH IS, through strategic regulations, has attempted to develop a flexible regulatory structure that ( 1 ) evaluates on the basis of risk; (2) provides a means of specifying per­ formance standards as far as criteria for ex­ emption; (3) defines and documents risk or lack of risk; and (4) exempts regulated mate­ rial from oversight efficiently once evidence of lack of risk is presented. All procedures followed depend upon the i ndividual propo­ sal itself which the applicant submits and APHIS reviews. Therefore , this regulatory structure is applicant-driven which assures that design standards (rigid protocols) are avoided and performance standards empha­ sized. Our responsibility is to identify the risks and to make a decision as to their signifi­ cance. We have attempted to design a system

204

6 Strategic Regulations for Safe Development of Transgenic Plants

that evaluates the molecular biology and practices and knowledge from traditional ag­ riculture in order to document conclusions of safety or acceptable uncertainty. Under the APHIS regulations, our analysis compares the new plant line with previous varieties and crops in evaluating hazards. The initial stage of testing gives the most valuable information on the interaction of a gene in a new organism. The plant itself is the most sensitive test for the effects of a new gene in a new organism (e.g., assessing the in­ teraction of the trait, the plant, and the envi­ ronment). From 1 987 to 1 992, the primary regulatory option for the planned introduction of a transgenic plant was the permit. The regula­ tions stipulate that, once a complete permit request has been submitted, APHIS has 120 days in which to reach a decision whether to issue or deny a permit. The five major steps APHIS takes in this process are to: ( 1 ) evalu­ ate relevant information (both that submitted by the permit applicant and that gathered by APHIS from other primary and secondary sources); (2) notify and consult with regulato­ ry officials in States where the applicant pro­ poses to field test; (3) provide, through a gen­ eral announcement, an opportunity for public comment; (4) prepare a site-specific environ­ mental assessment; and (5) reach a decision as to whether to issue or deny the permit (McCAMMON and MEDLEY, 1 992). APHIS considers a broad range of infor­ mation for an environmental assessment, in­ cluding details of the biology and characteris­ tics of both the parent organism and the or­ ganism that provides the exogenous genetic material; factors associated with the modifica­ tion itself, such as whether or not gene se­ quences from a plant pest are used, and if so, how they have been modified to ensure they pose no risk of plant disease; the expected characteristics and behavior of the modified organism; and data concerning the environ­ ment in which it would be field-tested. Such information includes, for example, the loca­ tion and size of test plots, numbers of test or­ ganisms, nature of the nearby environment including the presence or absence of sexually compatible relatives, or the presence in the same county of threatened or endangered

species that could be impacted. On the basis of this analysis, APHIS decides whether or not to issue a Finding of No Significant Im­ pact (FONSI). If a FONSI is reached, a per­ mit is issued. If a FONSI is not reached, then the permit is denied, or issuance would be de­ ferred pending results of a more extensive analysis, known as an Environmental Impact Statement (EIS). APHIS has not yet declined to issue a permit for a field test because of failure to reach a FONSI. However, we have had applicants to either withdraw a submis­ sion for a permit based upon initial review by APHIS or not submit a permit request based upon pre-submission discussions with the APHIS scientific reviewers. After almost six years evaluating permits and considering the results of field trials un­ der permit, experience demonstrated that ca­ tegories could be defined for certain field tests that do not present plant pest risks, un­ certainty or significant agricultural safety is­ sues. Therefore, the type of regulatory analy­ sis described above for the issuance of a per­ mit was demonstrated to be unnecessary for such categories. General procedures already existed for ex­ emption of broad categories of organisms from regulation based upon scientific data, consistent with the internationally accepted definition for "case-by-case". That definition was adopted by the United States and other members of the Organization for Economic Cooperation and Development (OECD), and explicitly allows for exemptions based upon scientific data. "Case-by-case means an indi­ vidual review of a proposal against assess­ ment criteria which are relevant to the parti­ cular proposal; this is not intended to imply that every case will require review by a na­ tional or other authority since various classes of proposals may be excluded" (OECD, 1986). Many cases reviewed by APHIS are categorically excluded from coverage by the regulations. Some field tests are not reviewed or are reviewed only upon request. The increase in field trials in the United States of transgenic plants or plant-associated microbes in recent years has been explosive. In anticipation of dramatic increases, on March 31, 1 993, APHIS put in place two addi­ tional regulatory options, notification and pe-

4

became e ffectiv e on April 30. 1993. APHIS now has four options to facili­ tate the safe introduction of trans ge nic plants du ring research, development. and commer­ cialization : the organism is not a regulated ar­ ticle, a permit for movement or re lease, notif­ ication for mo vem e n t or release. and petition for removal from further regulation (USDA/ APHIS. 1 993). "Notification " and p e t i t io n o p tions pro­ vide for what a m o unts to s t rea m l ined re v iew o r e xe m pt i on from fu r th e r regu l ato ry review by APHIS. respectively. A field test con­ ducted under notification allows the appli­ cant. with A P H I S acknowledgement, to com­ mence a fi e l d trial wit h i n thirt y days instead of the 1 20 days re q u i re d under permit. Intro­ duction under notification ( section 340.3) re­ qui res that the introduction meets spec i fied eligi bi l i t y criteria and pe rfo rmance standards. The eligibility cr it e ri a impose limitations on the types of ge netic m od i fi c a t i on that qu a l ify for not i fi ca t i o n . and the p erfo rm an ce stand­ ards impose li m i t a t i ons on how the introduc­ tion may be c o nduc t ed The notification op­ tion is p re sen t l y restricted to fiel d tests of new varieties of six c ro ps : corn . potato. cotton . to­ mato, soy be a n and tobacco. A lthou g h it is expected that other crops will become e ligib l e for field tes t in g under the no tifi c a t ion option in the future, at the t ime t h is o p tion was ini­ tially ado pted these six crops captured ap­ proximately 85% of the field test permits be­ ing issue d The n otification o ption is further limited by p r e c l udin g certain ty p e s of modifi­ cations (e.g., those enc oding genes for phar­ maceutical co m po u n ds or from human or ani­ mal pathoge n s ) a n d re quiri ng field tests un­ der notification to be co nd u c t e d under speci-

tltJOn . which

"

··

.

.

.

.

Effective

and Responsive Regulations

205

fi e d p e rfo rm a n c e standards that am o un t to g eneti c containment (MEDLEY, 1 993) . Field tests not falli ng within these constraints may still be conducted under permit, as before. The petition option . for which the full term of art is "petition for determination of non­ re g ulat e d status.·· allows an applicant to re­ quest that APHIS decides whether a given transgenic plant or microbe should no longer be considered a regulated article. The dete r ­ mination is, as with a permit, based on infor­ mation provided by the app l ica n t which is considered with other information collected by APHIS. Once a p e ti t ion is ap p rove d by APHIS there is no lon ger any need for APHIS review or approval for in t roduct ion of the article into American a gricu l t ure or com­ merce (MEDLEY, 1 993). If food safety, pesti­ cide or other regulatory questions remain, however, the man d a to ry requirements of rel­ evant regulatory agencies, such as the FDA, EPA. and USDA's Food Safe t y a n d I nsp e c ­ tion Service, must be met. From 1 987 through 1 993, there h ave been 674 field tests of tra n s geni c plants or plant­ associated microbes approved by APHIS in the United States. Of these field tests 47 1 were conducted under permit, and 203 under n oti fication at 1 739 sites. These sites have been located in 42 of the 50 States (most oft­ en in California, Illinois, and Iowa) , and Puerto Rico. These n umbers reveal a substantial amount of research and de ve l opm e n t activity. The vast majority (85% ) of activities are being carried out by commercial entities Academia ranks second, with 1 1 % and the Agricultural Research Service (ARS) of the USDA third with 4% (see Fi g. 1 ) . ,

.

,

= 27 (4. 0%) ,- LJinfvl!rs/,Ues = 72 ( 1 0. 7%)

' "'""' ' u"''-'"'

Fig. 1. Source of applicants for biotechnology re lease permits 1 987- 1 943.

Commercial

=

575

206

6 Strategic Regulations for Safe Development of Transgenic Plants

Of the 34 crops or plant-associated mi­ crobes that have been field tested, by far the largest category has been new varieties of maize (corn), at 1 67. Soybeans and tomatoes are second and third, with about one hundred each, followed by the other crops presently eligible for field tests under notification, to­ bacco being lowest, at 35. The next two crops most often field-tested in the United States are cucurbits (melons or squash) and rape­ seed, at 28 and 20, respectively (see Fig. 2).

The largest category is for crops with im­ proved weed management qualities based on herbicide tolerance, comprising 32% of all field tests. This is followed by crops variously mod­ ified to resist losses to insect pests (most often by addition of the gene encoding the insectici­ dal protein derived from Bacillus thuringien­ sis), a category that embraces 21% of crops field tested. Modifications for resistance to vi­ ral diseases follow at 19% , and improvements to product quality at 16 percent (see Fig. 3).

Com Soybean Tomato Potato Cotton Tobacco

Melon & Squash

==-79 0

Rapeseed

Alfalfa

8

5

Clavlbacter

Rice

Pseudomonas Cucumber Xanthomonas Walnut Sunflower

F"iJ:. 2. l " y p l' ' ol p l a n t s a n d

Lettuce Sugarbeet

m i noorga n i s m s a n d n u m b e r

Apple

Poplar

o l p � r m i l s i " u l' d a n d o f no ­

0

Herbicide Tolerance = 1 7&

50

100

150

200

t i fi c a t ions a .: k nowll'dgcd l lJl\7 - l lJlJ_� _

(32.5�

*

Fig. 3. Gene-phenotype summary of permits issued and notifications acknowledged 1 987-1993. *

**

Metabolic characteristics, modified ripening, oil modification, seed protein starch/solid increase, wheat germ aggl utinate. Markers, male sterility, chiA, chicken lysozyme, DHDPAS, Rhyzobium R and C1 transcript activator (courtesy), tn5 (marker), tmr, transposable elements, pharmaceutical products, plant stress tolerance.

5

5 Meeting Domestic and International Needs Strategic regulations should provide a pro­ cess by which domestic and international needs are met. A coordinated procedural and scientific review of field testing and develop­ ment assures that plant products are develop­ ed, commercialized, and accepted. Regula­ tions must not only assure safety, they also must provide a framework for evaluation and technology transfer. This framework includes the initial phases of testing, the developmen­ tal phases, commercialization, and interna­ tional harmonization of evaluation. This will contribute to flourishing industries, global ac­ ceptance and use, and creation of jobs.

5 . 1 Domestic Needs To meet the domestic challenge, regula­ tions must take into account needs of the States, other Federal agencies such as the EPA and the FDA, as well as those of the public, including academic, consumer, envi­ ronmental, and industry groups. The regula­ tions must remove uncertainty and allow de­ velopment and utilization through document­ ing informed decisions and evolution based upon experience. The notification and peti­ tion regulations evolved because of docu­ mented experience with the field testing of certain crops. Domestic needs have been served through several avenues. USDA has developed a user-friendly system through publishing a User's Guide (USDA/APHIS, 1991), giving examples of applications for importation, movement, and release. Applications can now be submitted as well as processed, and per­ mits issued, via computer technology. Deci­ sions for release are based on information from workshops bringing together experts from various fields and affiliations (McCAM­ MON and DWYER, 1990; KEYSTONE, 1990). Federal Register notices alert the public to op­ portunities to comment on specific decisions. For example, prior to the decision to propose the notification and petition amendments to

Meeting Domestic and International Needs

207

the APHIS regulations, the Agricultural Bio­ technology Research Advisory Committee (ABRAC), in an open forum, reviewed the scientific basis for proceeding with a notifica­ tion and petition process based upon docu­ mented experience with traditional and gene­ tically engineered crops. Additionally, prior to the adoption of the rule amendments, com­ ments were solicited from the general public (FDA, 1992). Coordination across agencies is a necessity as agricultural, environmental, and food safe­ ty issues arise and as products develop. The decisions by one agency should support and build upon the decisions required by other agencies. The decisions required by the im­ plementation of these biotechnologies cut across the traditional responsibilities of sev­ eral regulatory jurisdictions. This requires an unprecedented integration of the entire deci­ sion-making process in order to assure that safety is assured, duplication is avoided, and the entire infrastructure is effective. In a democracy, multipartisan support must be achieved in order to proceed wisely. Thus, industry, the scientific community, domestic regulatory groups, non-governmen­ tal organizations and other public interest groups, all need to be involved as systems and policies evolve (OTA, 1 992). Regulations should allow decisions to be made in a trans­ parent manner and these decisions must be informed. Data and input must come from many perspectives. The questions do not eas­ ily distill into "either/or", "right/wrong", "yes/ no". Decisions of safety will not necessarily be the final answer, but these informed choices will be made on the basis of the best science available, and the process will be car­ ried out in the open.

5.2 International Needs The types of domestic concerns associated with the development of transgenic plants will most likely be the same types of concerns identified internationally. Due to the univer­ sal nature of such questions and concerns, products approved under strategic regulations should be generally accepted internationally. International harmonization will occur

208

6 Strategic Regulations for Safe Development of Transgenic Plants

through compatible regulatory systems that allow reciprocity of evaluations of safety. In­ ternational harmonization of approaches to commercialization means that ''equivalent"" approaches will be use d i n different countries. In this context . equivalent means "equal"' . not "the same ··. Facilitation of international trade , the prevention of trade barriers, and harmonization of international systems are all important results of a coordinated agreement as to approaches to review. Therefore . the strategic application of our USDA regula­ tions has required that we focus on ( 1 ) inte­ gration of compatible national approaches; (2) coordination of national approaches; and (3) assurance that scientific principles are used for evaluation of organisms (MEDLEY. 1 99 1 ) . A general process that can cover the needs of all countries for the use and regulation of biotechnologies ba se d upon the technique or the final product alone is unlikely. The infra­ structure . legal systems, types of products and testing, and other specific issues will be differ­ ent for each country and region. The biotech­ nologies will i m ple m e n t already e x i s t i n g needs, conventional goals, and production re­ quirements. The biotechnologies will affect agriculture in various ways through plant products that enter or are tested i n develop­ ing countries; through technologies that are used to develop products and commodities for local consumption or export: through ex­ port of products and commodities from the country; and through using the technologies to identify genetic resources and understand biological and ecological systems. The appro­ priate application of the biotechnologies will vary from country to country. Thus . internationally it would be difficult to develop a general document addressing procedures for e v a l u a ting the se products. Such a document would most likely result in the least common denominator being accept­ ed and would be the most restrictive. Thus. international agreement on the general issues for prod ucts has been and will continue to be the most useful approach. International agreement on consistent and compatible approaches for review should fo­ cus on the scientific questions and the most efficient way of doing the review. I nternation-

al agreement on the general issues for evalua­ tion is essential for transfer of the technology to developing countries and for acceptance of commodities and products in international trade. In the Americas. the I n ter-American I nstitute for Cooperation in Agriculture and the North American Plant Protection Organi­ zation have been forums for discussion of a wide range of issues relating to biotechnolo­ gy. The United Nations Organizations have also hosted many discussions. Recently, the scientific approaches to the evaluation of plants. and especially transgenic plants, have been developed internationally in the Organi­ zation for Economic Cooperation and Devel­ opment (OEC D ) I nternationally, several different venues h ave looked at and coordinated the ap­ proaches developed in each country based on scientifically identified issues. The United States frequently meets in bila teral discus­ sions with its t r ad i n g partners, Canada and Mexico, as well as with the European Com­ munity ( n o w : European Union, E U ) The de­ cisions and experience developed by one country should support and build upon the decisions required by other countries. Re­ cently, the USDA published its notification and petition procedures (USDA/APHIS, 1 993). This was followed soon after by the EU Simplified Procedures (EEC, 1 993) and the U nited Kingdom's " Fast Track Guide­ lines" (DOE/ACRE, 1 994). Each of these documents uses information that builds upon both local and international experience. These procedures will facilitate international harmonization based upon experience. Within the OECD, several documents re­ lating to the scientific principles underlying the safe use of genetically modified organisms have been developed. These have included documents on en vironmental testing of plants and microorganisms, the industrial use of mi­ croorganisms, food safety, and monitoring of these organisms in the environment. The process of developing these documents re­ quires the consensus of the member govern­ ments at each stage in the development of a document. Evaluation of initial field tests of transgen­ ic plants was treated by the O ECD in "Good Developmental Pr inci ples (GOP): Guidance .

.

6

for the Design of Small-Scale Field Research with Genetically Modified Plants and Micro­ organisms" (OECD, 1 992). GDP showed the rationale by which initial field tests could be evaluated and carried out safely. This deter­ mination is based on evaluating the plant, the site , and the agricultural practices. The next document, treating the develop­ mental testing of a potential new plant varie­ ty, is called "Scientific Considerations Per­ taining to the Environmental Safety of the Scale-up of Crop Plants Developed by Bio­ technology" (OECD, 1 993a). Scale-up in­ cludes performance trials, advanced tests, demonstration trials, yield trials, and seed in­ crease. The "scale-up" document shows how an evaluation is made to move from small­ scale tests to developmental-scale tests for crop plants for traditional uses such as food, feed, fiber and flowers. The emphasis shifts from containment to identification of envi­ ronmental issues. The environmental issues for crop plants can be framed, defined, and analyzed using the combined expertise and approaches of breeders, agricultural scien­ tists, and regulatory scientists. These environ­ mental issues are relevant at any scale. The issues will be the same no matter what the stage of the planting, whether initial tests, de­ velopmental tests, or commercial plantings. However, their probability of occurrence in­ creases with increasing scale. Familiarity with the host plant, the environment, and the trait is the basis for this analysis. When transgenic plants were first being reviewed, they were being defined as exotic organisms in some countries. This document provides the basis for viewing transgenic plants as familiar or­ ganisms with a new trait. Essentially, the basic premise of the "scale­ up" document is that plant breeders have a tremendous amount of knowledge about how crop plants behave in the environments in which they are grown and also can identify is­ sues of concern to agriculture, the agricultural environment, and the surrounding environ­ ments. However, plant breeders have not documented this knowledge previously in terms of safety. The "scale-up" document and the companion document "Traditional Crop Breeding Practices: A Historical Review to Serve as a Baseline for Assessing the Role of

Conclusion

209

Modern Biotechnology" (OECD, 1993b), which describes the characteristics of and ag­ ricultural practices used with 17 agricultural crop plants, treats the issues of safety on the basis of our familiarity with these crop plants. The commercialization phase of transgenic plants is now occurring. To assist in address­ ing commercialization issues, the USDA has funded a position for a consultant to work with the Environment and Agriculture Direc­ torates in OECD. The consultant is working on a project which will compare the different policies of the OECD member countries to­ wards development and commercialization of transgenic plants. The project will also ex­ plore ways that these new varieties will move into the traditional systems of seed certifica­ tion and variety registration. The point at which food safety issues are evaluated will also be compared.

6 Conclusion President CLINTON's technology initiative, articulated in the February 22, 1 993, Report Technology for America's Economic Growth, A New Direction to Build Economic Strength stated that investing in technology was neces­ sary for progress into the future and that this investment would require several compo­ nents. The report emphasized that although the transitional Federal role in technology de­ velopment has been limited to research initia­ tives, Government can play a key role in helping private firms. This can be accom­ plished while assuring a Government that is more productive and more responsive to the needs of its citizens. The report further stated that "regulatory policy can have a significant impact on the rate of technology develop­ ment in energy, biotechnology . . . regulatory agencies can affect the international competi­ tiveness of the industries they oversee . . . skillful support of new technologies can help businesses reduce costs while complying with ambitious environmental regulations". After the seemingly endless debates of the 80s, the Clinton Administration hopes to use

210

6 Strategic Reg u la tio ns for Safe

De�·elopment of Tran sgenic

the 90s to deve lop a regime for commercializ­ ing biotechnology products. a regime that is reassuring to the public. predictable and ex­ peditious for industry and free of unnecessary political h u rdles (SIMON . 1 993). Strategic reg­ ulations can assist i n achieving these goals by (1) having identifiable science-based triggers that are consiste nt, e asily understood. and transparent: (2) being effective and respon­ sive as well as flexible and dynamic: and (3) meeting domestic and international needs. Ack nowled gements

To Dr. VAL GIDDINGS for analysis of data on field tests. and Mr. CLAYTON G I V E N S for preparation of charts. Disclaimer

93/584/EEC. Commission Decision of 22 Octo­ ber 1 993 establishing the criteria for simpli fied procedures concerning the deliberate release into the environment for genetically modified plants pursuant to Article 6(5) of Co u ncil Direc­ tive 901220/EEC, Off 1. Eur. Commun. L279, 42-43.

( 1 992), Su bpan el on Plant Pesticides. Fed. Reg. 57, 55531 . E R N ST & YouNG. San Francisco ( 1 992), Biotech

EPA ( Environmental Protection Agency)

FJFRA Scientific

Admi nistrator

a nd Science Advisor. respec­ tively. APHIS. USDA. The views expressed in this chapter are those of the authors and do not necessarily represe n t those of the Uni ted States Government.

A dvisory Panel -

'93: A ccelerating Commercializ ation , September

1 992: and Biotech tember 1 99 1 .

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(1 990), Workshop on Safeguards for the Planned Intro­ duction of Oilseed Cru cifers , Proceedings, Cor­ n e l l U niversity, I t haca, NY, 33 pp. McCAMMON, S . L., MED LEY T. L. (1 990), C e r t ifi­ cation for the planned introduction of transgenic plants into the environment, in: The Molecular and Cellular Biology of the Potato (VAYDA, M . E . . PA R K W . D . • Eds . ) , p p . 233-250, Walling­ ford, UK: CAB I nternat ional.

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BioteclltloloKJ'

Ed ited by .H. -J. Rehm and G. Reed i n coop eration wit h A. P u h l e r and P. Stad ler Copyri�ht © VCH Verla�s�esellschatt m b H , 1 995

7 Biomedicinical Product Development

}ENS-PETER GREGERSEN Marburg, Federal Republic of Germany

General and Commercial Aspects of Biomedicinal Product Development 2 1 4 1 . 1 Product Development Follows Different Rules than Research 2 1 4 1 . 2 Commercial Chances a n d Risks of Pharmaceutical Development 2 1 4 2 Market Research 2 1 6 2 . 1 Creative Market Research and Other Valuable B ackground Information 2 1 6 2.2 The Product Profile 2 1 8 3 Registration Requirements 221 3.1 Three B asic Elements 221 3 . 1 . 1 Quality 222 3 . 1 . 2 Safety 222 3 . 1 .3 Efficacy 223 4 Tech nical Aspects of Product Development 224 4.1 Process Dev e lo p me nt and M an ufacturi ng 224 4.2 Analytical Development and Quality Assurance 226 5 Planning and Managing Product Development 228 5 . 1 Risk-Oriented Planning 229 5 . 2 Product Development Phases 230 5 . 3 Decision Making 232 5.4 The Project Manager 234 5.5 Organizational Structures and Motivation 235 6 References 236

214

7 Biomedicinical Product Development

1 General and Commercial Aspects of B iomedicinal Product D evelopment 1.1

Product D evelopment Follows

Different Rules than Research

Product development for biological phar­ maceuticals might appear as a simple contin­ uation of a research project after a sufficiently effective compound has been identified. From a scientific point of view there is no clear dis­ tinction between research and development. Until the clinical phase, product development utilizes the same basic skills and methods and - to a great extent - the experience of the same people who did the research. However, the rules change considerably as soon as in­ novative research turns into conservative test­ ing of quality, safety, efficacy and into analyti­ cal and process development. The decision to develop a pharmaceutical product transfers an active principle or com­ pound from the resource-limited research la­ boratory into a new environment, the stage of development. In a multi-disciplinary ap­ proach the compound is subject to a variety of analytical, pharmacological, toxicological, and clinical tests and trials. From now on methods, results, documentation and the ma­ terials created are under strict scrutiny ex­ erted by the developing organization itself and finally by several authorities. Research activities are hardly ever subject to such sur­ veillance and control concerning, for exam­ ple, the precision and consistency of methods and results. It usually takes time for a re­ searcher to fully acknowlewdge and accept this fact. Since there is no clear distinction between the research and development phase, projects frequently move into development while the people involved are unaware of the changed rules. This may result in neglecting essential aspects, in extra cost for the repetition of crit­ ical studies and in a considerable loss of time.

In larger organizations research and prod­ uct development are usually separated in dif­ ferent units because of the fundamental dif­ ferences between creative research and syste­ matic, goal-oriented development and be­ cause development requires special knowl­ edge and experience. In the field of biological pharmaceuticals, however, most companies and organizations are relatively small, since they traditionally operate on a national scale. They do not have several products under de­ velopment which are subject to a similar de­ velopment scheme. The methods are more complex, and the materials created in the re­ search phase are directly passed on for devel­ opment. Furthermore , biotechnological prod­ ucts are still in their infancy, and pharmaceu­ ticals from biotechnological processes are not yet routine products. Thus, there are many reasons why researchers in these areas in in­ dustrial and non-industrial research organiza­ tions contribute to or perform product devel­ opment. These scientists need to know more than j ust their science to understand their new task. The general aspects of biomedicinal prod­ uct development presented in this chapter are meant for researchers and scientists who are less experienced in product development. This chapter is also meant to prevent the oft­ en observed overly ambitious ideas about the commercialization of research results. Un­ realistic expectations about the simplicity and duration of development may lead to inap­ propriate management decisions, which may even endanger the future of research­ oriented enterprises. The success of biotech­ nology ventures does not only depend on good research but also on a realistic assess­ ment of the potential products and on the ability to adopt the required skills to effec­ tively develop research results into commer­ cial products.

1 .2 Commercial Chances and Risks of Pharmaceutical Development

Pharmaceutical development is expensive , and the risk that the project fails during this

1 General and Commercial A spects of Biomedicinal Product Development

process i s high . T h e following facts a n d fig­ ures may illustrate the costs and risks that may be expected. Although these figures do not differentiate between research and devel­ opment and are not specific for biological pharmaceuticals (they represent mainly chemical entities for human drugs ) , the gener­ al picture is similar for all types of pharma­ ceuticals, and the i mplications for product de­ velopment are essentially the same. The average capitalized cost to develop a human pharmaceutical product in the USA amount to US $ 231 million ( D I M A S I et al., 1 99 1 ) . Comparable figures for 1 982 are US $ 9 1 million (LANGLE and 0CCELL I , 1 983) and for the time between 1 963 and 1 975 US $ 54 million (HAN S E N , 1 979). On one hand, these considerable increases in cost, which tended to double within ten years, reflect the increas­ ing difficulties to find new and commercially attractive drugs, since these figures include the cost of aborted projects. On the other hand, a substantial part of the rising cost is due to the increasing regulatory demands which must be met to achieve marketing ap­ proval. The average time to develop a newly dis­ covered compound i ncreased continuously over the past decades from less than 4 years in 1 960 to more than 1 0 years in 1 989 (KARIA et al . , 1 992). A s a consequence, the average effective patent protection for human and an­ imal health products approved i n the USA between 1 984 and 1 989 was only 10 years and 7 months, including the possibility of restora­ tion of patent terms for medicinal products of up to 5 years (V A N G ELOS, 1 99 1 ) . Longer de­ velopment times automatically reduce the ef­ fective patent protection period and thus sig­ nificantly influence the revenue expectations. Despite the sharp increase i n development cost, the number of new products launched and their sales expectations remained fairly constant (LU MLEY and W A L K E R , 1 992). It has been calculated that i n the UK even the best selling 1 0% new drugs require longer than the effective life-span of their patents to recover the research and development cost; the majority of new pharmaceuticals cannot recoup these cost even after more than 20 years (PRENTIS et al., 1 988) .

215

Comparable figures with reasonable validi­ ty for animal health products are not availa­ ble. Veterinary product development cost are definitely lower, but the revenues are also much lower. Due to rising registration de­ mands, influenced by both the pharmaceuti­ cal and the agricultural sector, veterinary product development cost follow the same trend as human health products. In general the animal health market has stagnated since 1 980. The international com­ petition has increased, and the more produc­ ers of biologicals and vacci nes try to interna­ tionalize their products and sales in order to outbalance the price erosions by growth in sales volume. Whereas vaccine producers in the USA have been rather successful to pene­ trate European markets, European vaccines were prevented from access to the lucrative US market due to concerns about potential adventitious agents i n these vaccines (e.g., FMD , BSE). At the same time European vet­ erinary vaccines have to comply with increas­ ing regulatory demands and the introduction of GMP (Good Manufacturing Practice) standards. Relatively few really new and attractive products have been introduced in the animal health care market. The recently developed new and expensive human therapeutics do not play a major role in animal health care. Prophylactic vaccines against the major en­ demic diseases are already avai lable and are difficult to improve for a competitive price . Several other interesting vaccine candidates are stuck in the research phase due to unsur­ passable difficulties to achieve sufficient effi­ cacy. The contin uing high interest and invest­ ment in pharmaceutical research cannot be attributed to guaranteed high revenues. Re­ turn on assets - a commonly used measure of industrial profitability - for the eight most successful health care companies in the USA in 1989 was approximately 16% , or 1 1 % if re­ search and development expenditures are in­ cluded as gross assets for better comparability with other, less research-intensive industries ( V A N G ELOS, 1 991 ) . It seems that the general perception of high profits is strongly influenced by the com­ mercial success of a few ''blockbuster" prod-

216

7

Biomedicinica/ Product Development

ucts such as the H2-receptor antagonists, iver­ mectin or the recently launched erythropoei­ tin. These are the exceptions, whereas ex­ tremely hopeful candidates, rendering very moderate success, seem to be more the rule. The pharmaceutical industry is much more research-oriented than other industries and has to cope with higher risks. Due to the high development cost and long development times, risks must be eliminated as early and consequently as possible. Risk elimination must already start in the research phase and before the expensive industrial development commences. High-risk research projects need much time, thus they must be kept small and have to focus only on the major risk factors. Research projects should be clearly separated - if not physically, at least in mind - from the more rigid and much more expensive devel­ opment. Once an attractive product has been iden­ tified, the time factor becomes extremely im­ portant; risk and cost are no longer the only relevant criteria. From now on speed and effi­ ciency are of paramount importance. A minor planning error which results in a delay of a task on the critical path for only one month can delay the entire project by one month. Almost inevitably it also adds 1/12 of the an­ nual budget to the development cost. Thus, in a project with an average annual budget of $ 2.5 million, a delay like this can cost more than $ 200 000. Apart from these direct cost, later access to the market can cause much higher losses.

2 Market Research 2.1 Creative Market Research and Other Valuable Background Information

According to a study Management of New Products by Booz, ALLEN and HAMILTON conducted in 1 968, on average about 70-90% of the money spent in research and develop­ ment of new products is used for products which are failures. No industrial organization

would commit itself to an applied research or development project without investigating the general and market situation to reduce this failure rate. There is no reason why publicly funded research projects should not do the same. Starting a project without such an as­ sessment means being more concerned about doing the project right than doing the right project. Researchers (in academic institutes as well as in industry) tend to view market research in a very narrow sense. They do not perceive the potential of the approach, thus missing in­ novative ideas. Market research may, in fact, bring research ideas back to the earth and help avoid major mistakes. If used with a wider perspective and by a creative mind, it can help identify interesting options. Market research should add information and use it for a better assessment of chances, risks and options. It should not be used to reduce the project idea to a few simple figures. The use­ fulness of market research depends a good deal on intensive interaction between re­ search and marketing and information ex­ change in both directions. A basic assessment of important market and other environmental factors does not neccessarily require marketing experts. But if their advice is sought, it should be by an inter­ active process, not by presenting the idea for a verdict. During this process the marketing expert will probably identify the weak spots of the researcher's proposal. With reasonable background information the researcher (who else?) should also be able to recognize and understand the subjective assumptions (i.e., weaknesses) of the marketing expert's assess­ ment and to challenge them where adequate. The problem is that the additional informa­ tion usually requires changes of the direction or the priorities of the project. Unless there are very convincing arguments, a researcher who is convinced of an idea is unlikely to con­ sider such changes. The most convincing ar­ guments are those which are developed from one's own considerations. Thus, researchers should do their own market assessment to de­ velop an opinion about the chances, risks and best applications of their approach. (If they don't like the term market assessment, they

2 Mark et Research

may call it "SPA for "strategic project as­ sessment'' if this sounds more rep � table . ) One needs n o special skills t o identify the ma­ jor threats to and opportunities for a project. These are usually rather obvious. if some ba­ sic i nformation is available and i s considered critically. At the beginning it must be kept in mind that it is very easy to define an "ideal prod­ uct" . B ut this ideal product is probably the most difficult one to develop or may be an unrealistic development target. Sooner or lat­ er it pays off to have identified all the options, including the lesser ones with a higher proba­ bility of success. Of course , the optimal prod­ uct may be chosen as the aim of the project, but minor options should be included in the planning as a fall back position. The more detailed the collected informa­ tion is, the better it serves its purpose. Ac­ quitting oneself of the task by only quoting a figure about the (ill-defined) "market poten­ tial" of a product (usually followed by a sum of some hundred millions or even some bil­ lions) obscures the matter rather than illumi­ nating it. In many cases this figure i s so mean­ ingless that it would not result in any conse­ quences for the proj ect, if somebody simply changes the currency unit from B ritish Pounds to Italian Lira. Creative market research should initially collect a few basic figures on the occurrence of the disease or condition to be treated. Scientific review articles and epidemiological investigations as well as disease statistics may serve to provide these. As a next step infor­ mation should be collected about current methods to diagnose and treat the disease or condition. This includes the products or com­ pounds used, the frequency of their applica­ tion, cost of the products used and the overall cost of the treatment. Most of this informa­ tion can be obtained by a specific l iterature search i n the medicinal field or from physi­ cians and clinicians. Clinicians should also be asked for deficiencies in the current products or treatment schemes, such as side-reactions, lack of efficacy (in general or under certain conditions) and for other medicinal treat­ ments (e.g., prevention or surgical tech­ niques) which have an impact on pharmaceu­ tical products in this area. ..

2I7

This background information should be used to ide ntify the needs of the "market " . i . e . . o f patients a n d physici ans. o f veterinar­ ians and their clients or of diagnostic labora­ tories. I t also serves the purpose of checking whether the proj ect in mind has the required potential to i mprove the existing situation. A simple assessment of the likely cost of the new or improved product, compared to the benefits that it provides. can be very illu­ minating, even if the figures are only rough estimates. Acceptable costs for the new prod­ uct may be ded uced from prices of compara­ ble product classes or from specific products which are currently used to treat the disease in question. These prices are likely to give a reasonable estimate. Depending upon the es­ timated value of additional benefits of the new product, a premium can be added to the basic figure. This sort of simple calculation and estimate is particularly warranted for vet­ erinary products and for products which will compete with already existing and established products. If the existing products or prophy­ lactic treatment schemes cost only a few dol­ lars, the active ingredient is only worth a few cents. To get a rough idea about the upper limit for the cost of the active component in these cases, the market price of the existing product may be split up by the following "rule of thumb calculation": about 40-50% for cost of sales and a profit margin (before tax), 2030% for quality control, packaging and label­ ing and 10% for formulation. For lower priced products in a competitive environment the active ingredient may account for only about 1 0-30% of the market price. If it is believed that the proposed new product can compete in terms of cost of man­ ufacturing despite a more demanding process, or that the product offers significant advan­ tages which j ustify a higher price , it will be necessary to present evidence for a high-yield system or to focus on a proof of the claimed advantages. Live and vector vaccine approaches should take into account the epidemiological situa­ tion and health care schemes in the target countries. The efficacy of live vaccines and vectors may be affected by a pre-existing im­ munity in the population. Live vaccines can also interfere with screening tests, e . g . , for sal-

218

7 Biomedicinical Product Development

monellosis in people who handle food or for bovine leukosis in eradication schemes. Diagnostic tests may be rather useless, if the test result does not lead to any conse­ quences, for example, when no effective treatment is available or because the test pro­ cedure takes too long to influence the choice of therapeutic options. In the latter case a much faster and simpler "bed-side test" (or cow-side test for veterinarians) may be the better solution. The use of medicinal products and thera­ pies in man is more driven by ethical and less by economic considerations. Direct commer­ cial aspects such as cost of the product may be less critical. Instead, the assessment should concentrate more on safety and quality as­ pects and their scientific and economic ramifi­ cations. Which safety standards must be met by the product? Does it contain components with an unknown safety profile or a poor tol­ erance at the application site? What are the chances of replacing these and getting access to better components? Are adequate safety tests for attenuated or genetically modified microorganisms available or must/can these be established and will these tests give suffi­ cient confidence in the safety of the product to justify later trials in human beings? Who would be interested and could contribute to address the safety issues, e.g., by characteriza­ tion of the strain of microorganism used, by developing adequate models and tests? How early should these activities start or how long should the project proceed without address­ ing these very critical issues? Not only live vaccines, but also therapeutic polypeptides and subunit vaccines have to meet very demanding safety requirements, before they can be tested in humans. As soon as a protein with potential as a vaccine com­ ponent or a therapeutic drug has been identif­ ied, the questions arise of which systems and methods should be used to produce the active component, how to separate it from potential­ ly harmful components and how to purify it to the required degree. Assuming that a purity of at least 95% and only a very limited num­ ber of known and defined impurities will be allowed for a human medicinal product, the expression and purification systems and yields warrant some careful considerations at

a very early stage. The wrong choice or taking what is readily available, instead of using the best option, can result in a loss of time, im­ practical patent applications and a loss of the competitive edge of one's research. A list of aspects to be examined as part of a creative market research and far-sighted pro­ ject planning is given in Tab. 1 . Depending on the maturity of the project, it may not be nec­ essary or possible to cover all aspects. How­ ever, the attitude should prevail that it is bet­ ter to gather as much information as possible and then decide whether a specific piece of information is useful or not. Information nev­ er comes too early, but frequently too late ! Based upon this background information a thorough market assessment for a product to be developed identifies the potential strength and weaknesses of a new product as well as those of competitive programs or therapeutic schemes. This assessment should include the patent situation and the competitiveness of the organization in terms of the skills and re­ sources to develop, manufacture and sell the product when assessing the chances and risks of the intended development product. From this information one or a series of potential products can be identified, defined by their key characteristics (their product profile) and can be compared.

2.2 The Product Profile A product profile should be established for each development product or candidate . The product profile describes essential product qualities such as the indication, form of pre­ sentation, intended application and use pat­ tern, efficacy, safety, and other critical as­ pects, e.g., patent restrictions and cost limita­ tions for the compound or for the formulated product. The expected date of product launch and sales expectations as well as the expected development cost are important elements of the product profile. Tab. 2 summarizes and explains the aspects which should be covered by a product profile. Based on the product profile a cost-benefit analysis can be calculated. Such an analysis helps in deciding whether, under the given circumstances, a potential product is suffi-

2 Market Research

21 9

Tab. l. Points to Consider in Stra tegic a n d M arket-Orie nt e d P l a n n i n g of Research and Deve lopment for Bio l o gical M e d i ci n a l P rod ucts

General Aspects Occurrence of the d isease or c ond i t ion : ge og ra ph ic d ist ri but ion a nd fre q uenc y Curre nt d i a g n ost ic and th e r ape u t ic measures De ficiencies of current treat m e n t : effic acy . side-effects. cost. practicability

Potential im p ro ve m e nt s of existing met hods Acce p t a nce of p o t e nti a l i m p rove m e nt s: safety . cost . practicabi lity

I n ter a ct io n with health care and e radication schemes

Efficacy Aspects Potential indications. sci e ntifi c feasibility and risks

De gre e of e fficacy req u ired Systems a n d models to demonst rate e fficacy

Safety Aspects Pott:ntially harmful e ffects of the p ro p ose d p rodu c t

Safety requirements: s i m i l a r or better than existing p rod uct s Systems and m ode l s to assess safety

Commercial Aspects

Product p r i ce s and cost of current t reat m e nt

Fre q ue ncy of

a p pl ic a t i on

of existing p rod u c ts

Likely cost of the p ropose d new p rod u c t and treatment Cost/be nefit re lationship

Patent Aspects

Existing pate n t s and appl ications in the fi e ld Gaps and ch a nce s for an own patent app li c ati o n Availability a nd costs of patent support Cost/benefit of patenting

Project-Related Aspects

O t h e r research and d ev e l o p m e nt projects in this area: scientific competitiveness of t he own p roje c t S pec i fi c skills and methods re qu i red

Collaborators for specific proble ms ot to extend the scope of the proj ect

Who would be interested in the project/product and p ro v i de pract i ca l or financial

s upport ?

Funding organizations to be approached: interest and u se r groups. government and speci a l res ea rch funds. supranat ional fu ndin g org a nizations. industry

ci e nt ly at t ract i ve to d e v e l o p and w h ich indica­ tio n for the new co m pou nd is m o re or less at­ t ract ive . It is m ai n l y a m e a n s to p rioritize and to compare the par t ic ular develop m e n t prod ­ uct with other products under dev e l op men t

or under consi deration. This may be neces­

sary

since

seve ral

development ca nd i da te s may compete fo r the same resources such as perso n n e l . d evel op m e n t bu dge t capital in­ vestment, and prod uc t io n cap a ci t y It should be noted that c o st b e n e fit calcu­ l ations for the same d e velop m e n t p r oduc t may vary conside rably b e tw e e n different or.

.

-

ganizations ( H ODDER and RIGGS, 1 991). First. t h e calculation methods m a y b e differ­ ent. Second. the assu m ptio n s that go into these calculations. e.g., t h e expect ed sales of a certa i n product. may vary considerably.

These figures depend on company-specific factors such as avai lable sales force a n d pres­

e nce on relevant markets, as well as on cer­ tain personal o p i n ion s and other s ubj ective j udgeme nts. Apart from this. it is obvious that already e x i s ti n g man ufactu ring facilities with­ out the need for a maj or i n ve s t me n t can sig­ nificantly influence the result of a cost-bene-

220 Tab. 2.

7

Biomedicinical Product Development

Contents of a Development Product Profile •

I. Essential Product Characteristics

Indication Presentation

Application/use pattern Efficacy Safety/tolerability

Condition or disease to be treated. Target species for veterinary products Type of product and formulation, e.g., live or inactivated vaccine, vector vac­ cine, type of vector, liquid or lyophilized product, adjuvant, special formula­ tions Mode and frequency of application, e.g., route of application, single or re­ peated use, duration of use, booster intervals Specified or in comparison to other products or treatment schemes Specific demands, e.g., standards set by other products or treatments

II. Commercial Aspects

Cost of development Cost of product Investment costs Sales expectations Expected date of launch Patent protection Major product advantages Major development risks Cost-benefit

analysis

Per year until product launch, updated during development Active ingredient, formulation and packaging, cost limitations Manufacturing plant and equipment Differentiated by medicinal indications, by major countries Month and year for major countries Duration in major countries, quality of patent protection Major selling arguments, strategic importance Reasons for failure, e.g., efficacy, safety, regulatory risks, competing prod­ ucts or developments With annotations on critical limitations and including the important assump­ tions upon which the analysis is based

• The product profile should address all essential aspects of the product and the development. It describes the agreed development task and assists in management decisions.

fit analysis. Thus, a cost-benefit analysis is a scenario and the assumptions that formed the basis of the described situation should be specified and carefully taken into account, be­ fore general conclusions are drawn. Besides the aspect of providing informa­ tion to assist in decision making, a precise product profile has several other benefits. It creates a common vision about the direction of the development by defining the aim un­ mistakably to all people involved, thus assist­ ing in tight proj ect planning without the need for endless discussions about the goals. (About the importance of a common vision

for projects see also HARDAKER and WARD,

1 991 . ) Critical aspects of the project are ex­ posed at the beginning, and measures to solve these problems can be included in the devel­ opment plan at the best, most convenient and cost-effective time. Defining the product pro­ file helps to recognize changes in critical pa­ rameters (e.g., in efficacy) and deviation from

the decided development route earlier, so that counter-measures can be initiated before these become too costly. The later changes are initiated, the more expensive they are. Product profiles frequently tend to de­ scribe an ideal or almost ideal product be­ cause this is much easier and less controver­ sial to define. In order to become a meaning­ ful base for planning and decision making, the essential product characteristics in a prod­ uct profile should be described as minimum criteria which define what must be achieved and where the product must not fall short. Only minimum criteria are useful to define pote n ti al milestones for the development plan which in turn are used as an objective guide for decisions to continue a project or to abandon it, if the milestones cannot be achieved. Desirable goals for further improvements can be added where appro­ priate.

3

Of co u rs e a p r od u ct p r o fil e is not a one­ sided instruction. It re q uires input from re­ se arch , p re c l ini c a l a n d c l i ni c al d e v elopme n t m ar k e t in g a nd s ale s dep a r t m e nts and is de­ vel ope d by an iterative. st t:pwi se p roce d u re .

Registration Requirements

221

W h a t i s p oss i ble and achievable soon be­ comes a standard by which sub se q ue nt p ro d ucts w i l l be measured. This leads t o contin­ uous a nd des irab l e i m p rove m e n t s and re­ q ui re s continuous attention of those who de­ velop and r e g i st e r pr oduc ts Since there is no limit. very c os t l y and u ndes ir ab l e extremes may be anot h e r con seque n ce A ccord i ng to today·s standards . the most successful a n d b ene fic ia l p h arm aceu t ic a l prod uct s such as the vaccinia virus vaccine, live po lio vi ru s vac­ c i n e and other live vaccines, wo ul d pr ob a bly not be r e gi s t rabl e for a wide-spread use in hu­ mans. The fo l l ow i n g section gives on ly a basic u n ­ ders t a n d i n g of regu la tory re q uirements by p o i n t i n g out the common and e sse n t i a l ele­ ments whi c h a r e ap p li c able to most produ c ts For a more p rofo und but r e a son ab l y short overview wit h s p ec i a l emph asi s on th e techni­ cal rather than the formal requirements and for information about the spec ifi c g ui d e l ine s cove rin g biomedicines. t h e i n t e r e ste d reader is re fe r re d to G R EGE RSEN ( 1 994) . ­

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.

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3 Registration Requirements

,

R e g i s tr a t i on regu la t i o n s for medicinal product s d e sc r i b e th e q u al i ty safety. e fficacy and formal req u i rements for m a r k et approv ­ al. D u r i ng the last few decades p ha rma ce u t i c a l re g u l ati o n s i n the w e st e r n world have be­ c ome so c om p le x a n d s p e c i fi c t ha t t he tas k o f ob s ervi ng them cannot s imp l y b e d e le gated t o re gi s tra t i on s p ecia l i s ts Registration sp e c ia l ­ ists should be consulted alre a d y d u r ing t he p la n n i n g phase of a d e v el op m en t p roj e ct and should be able to give advice which laws. di­ rectives and gui d e l ines ap p ly in a s peci fic c ase an d t o wh a t de gree guidelines must be ad­ hered to. Everybody involved i n pro d uc t de­ velopment who develops a n a l y ti ca l m e th o d s a n d p ro c e sse s or c o n t ri but e s data on the q ual ­ ity. safety and e ffi c a c y of the pr od u c t candi­ date needs to know the sp e c i fi c directives a n d g ui d e li n e s c o ncer n i n g her or h i s field of ex­ pertise. For effective d e v e l opme n t one has to consider the details of reg i st r a ti o n r e q ui r e ­ me n t s al re ad y du r i n g th e p la nnin g of all ma­ jor ta sk s Otherwise months and years can be lost b ec au s e t ri al s a n d e x p eri m e n ts have to be a dd ed or r e p e ated after the d e v elop m e n t has a l ready been fi n i s h e d and the re g i st ratio n dossiers were handed i n . The re g istra t ion of m e d ici n a l products is governed by relative values which cannot be c le a rl y d e fi n ed or l i m i te d . for e x a mpl e by e t h i c a l con siderations and the e ndeavor to ensure t h e best poss i b l e quality and s a fe ty of pharmaceut icals. As a consequence. one can­ not expect that r e g is t ra t i on g u id e li nes give definite s pe c i fi ca t i o n s for all m aj o r p roduc t characteristics and define exactly what must be d o ne or - which is p ro bab l y m o r e impo r tant needs not to be done. R e g i st rati o n re­ quirements are flexible and ch a nge wi t h t i me .

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3 . 1 Three Basic Elements Market app r ov a l or re gistrati on of a p h ar m ace u t i cal p ro d uct depends on the fu lfill­ ment of three main requi rem e n t s:

­

•

•

•

Q ua l i t y S a fet y E ffi c a c y

This sounds fa i r l y simple. but these three basic terms must be i n te rp r e t ed in a very wide sense; every s i ng l e aspect within these catego­ ries must be sub sta n t i a ted and proven under p ract i cal conditions. The scope and defini­ tio ns c h a nge with time and wi th scientific, pharmaceutical , and m e th o d o l og i cal progress. The d e fi n i t i o n s fo r qua li t y sa fe t y and efficacy vary between product g rou ps countries, au­ thorities and between people within a u t ho ri­ ties. In fact. there are no e x a c t definitions at all. Q ua l ity - as far as it can be j udg e d inde­ pendently of sa fe t y and efficacy - is in p rin ci ­ ple assessed by a comparison w i t h the state of ,

,

222

7

Biomedicinical Product Development

the art, i.e., with similar products. Products with inferior quality than other products may need improvements before they can be regis­ tered; products which surpass current stand­ ards will raise the general standards. Safety and efficacy, too, are no absolute values which can be easily defined. Market approval depends on a reasonable relationship be­ tween safety and efficacy, between risks and benefits. Quality, safety and efficacy are no indepen­ dent criteria. The quality can significantly af­ fect the safety and efficacy. A highly effica­ cious and beneficial product may be accepta­ ble, even if it has serious side-effects. Keeping these interdependencies in mind, product de­ velopment must address and emphasize the three basic registration requirements in the same order as listed above, starting with the product quality, although project risks suggest a different strategy which concentrates more on efficacy. Without a defined quality, all safety and efficacy tests may be irrelevant, and without an adequate safety, efficacy trials under natural conditions cannot be carried out. 3 . 1 . 1 Quality

Quality does not only comprise the final product itself and its attributes that can be tested. The high variability, in particular of biological products, demands that all varia­ bles of the manufacturing process are evalu­ ated. Product quality commences with the starting materials and their attributes, runs through the entire manufacturing process and extends to the manufacturing facility and its infrastructure. Everything that can affect the product quality must be assessed, tested and documented. For example, if one intends to harvest a product continuously from a cul­ ture, it must be specified what "continuously" means. If it is intended to harvest a hundred times over a hundred days, one has to prove that the product is still the same after the hundredth harvest - and probably even beyond that limit - to add some safety mar­ gin. Of course, it is necessary to validate all in­ process control and product quality control

tests, i.e., to substantiate that the tests really measure what they are supposed to do and within which limits. All claims on product safety and efficacy depend on the specified quality; if the quality is not consistent, safety and efficacy may not be the same. Safety and efficacy data for the product are only valid if they were estab­ lished with material of the specified quality. The practical implications are that test mate­ rial must meet the relevant specifications of the final product before safety and efficacy data can be generated. For biological prod­ ucts, this means that the test substances have to be made by a process which must not de­ viate from the final manufacturing process in essential elements. If the manufacturing pro­ cess is changed during the development, all previous data with earlier material may be worthless, unless bioequivalence can be prov­ en. 3 . 1 .2 Safety

Safety of a product comprises any aspect of its production, use and disposal. This includes the manufacturing premises and their envi­ ronments, starting materials (especially cells and microorganisms), the active component of the product as well as metabolites, impuri­ ties and the excipients. Excipients are compo­ nents which are added to the product, for ex­ ample, preservatives, vaccine adjuvants, sta­ bilizers, emulsifiers and release controlling substances. Safety of the manufacturing process and the facilities is covered by a variety of regula­ tions concerning the layout of facilities, work organization, procedures and related controls and inspections. General national regulations on work safety and biohazard control meas­ ures, specific regulations for manufacturing pharmaceutical products and quasi-legal GMP requirements have to be applied. These are an inherent part of the registration dos­ sier and market approval to ensure consistent quality and safety of the product and its man­ ufacturing. Safety of the product itself for the target organism, the user (who applies it) or the en­ vironment is addressed by a range of preclini-

3 Registration Requirements

cal and clinical assessments which depend on the product and its use p at t e rn . The range of sa fe t y fe a t u res t o be a ss e s se d includes local and systemic tolerance . acute and chronic t o x ­ icity, im m uno t oxic i t y and. for vet e ri n a r y me­ dicinal prod uc t s . also the e cot o x i c i ty . Tests for m u t age n i city . tu mor ige ni city and repro­ duc ti ve t ox ici ty may also be requ ire d for ce r­ t a in pro d ucts or indications. For s afe ty a sse s sm e nt of a pharmaceutical produ c t i n the ta rge t organi s m it is necessary to know the action and fate o f t h e pr o du c t and its compone nts within the body. after it has been ad m i n i s t ered . This knowledge de­ rives from pharmacodynamic and pharmaco­ ki n etic studies. the re su l ts of w h i c h will in­ fluence the c h o i ce and s e t u p of sa fety tests to be conducted. Pharmacodynamic studies in­ vestigate the in fl u e nce of p harm a ce ut ica l sub­ stances on the human or animal organism.

such as their mode of a c ti o n and mechanism of side e ffe ct s a l o n g w ith d os e - e ffe c t re la t i on ­ s h ip s . Pharmacokinetic studies address the influe nce of the o rg a n i sm on absorption. distribution , metabol ism. and elimination (A DM£) of pharmaceutical pr oduc t s in ade­ quate models and in the target spe ci es . Phar­ maco ki net i c studies for biomedicines ( espe­ c ial l y metabolism and e l i m i nation st ud i e s ) are usual l y less intensive than fo r chemical drugs. For b i o log i cal p ro duc t s the ( c h e m i c a l ) e x ­ c i p i e nt s are often o v e r l oo ke d . T hey . too. may have effects or side-effects a n d can leave resi­ dues in animals tha t e n d up in human food. Their choice for a d e v e lo pme n t p rod u c t must be considered c ar e fu l l y . Eit h e r one uses in­ gredients with a well established quality and safety profi le or a v a ri e t y of a n al y t i cal and safety data have to be e st ab l i sh ed for these excipients. Safety studies fo r n e w e x c i p i e n ts may cost more than the safety assessment of the biological p ro du ct i t se l f . It is e s sent i al to d e m on st r a t e that p ha rma­ ceuticals for food - p ro d u c i n g animals do not have harmful effects on humans. pa rti c ul arl y if residues of the active co m p o n e nt or of exci­ pi en t s and of their metabolites may occu r in m e a t . milk or eggs. Th is means that e x t e nsi v e studies regarding the safety for humans and res id ue depletion s tudi e s m ust be p erform ed with t hese p rodu ct s .

223

As a ge nera l rule , p r od u c t s that are used once or a fe w times have to u n d e rgo few­ er safety tests than products which will ad­ mi nistered regularly or over a longer time. Less - if any - side-reactions are tolerated for p rod u c ts intended to be used in hea l thy indi­ viduals (e.g.. v ac c i ne s ) than for p rod uc t s which are used in diseased individuals. In any case t he benefits must c learl y outre ach any po tent i al si de - e ffe c t s. on l y

3.1 .3

Efficacy

A p h a r ma c eu t i c al product m u s t fulfill its p u rp o s e under all recommended conditions and it m ust do so reproducibly. E xpe r i en c e shows that efficacy in controlled e x pe ri m e nt s does not guarantee that the product does the same and t o the sa me degree u nd e r p rac t ica l conditions. Pharmaceuticals for h u m a ns must be te s ted i n human beings for their pharma­ codynamic and pharmacokinetic characteris­ tics to prove their effectiveness and safety . These clinical trials are normally carri ed out i n t hree stages. each p h ase invol v i ng an i n ­ creased number of patients (see Tab. 4 be­ l ow ) . Clinical trials in humans are u s u ally the most critical, most e xp e n s ive , and mo st time­ co nsu m ing developmental step and can ac­ count for more than o n e half of the deve l op­ ment costs. Concerning the proof of e fficacy fo r animal health p rod u ct s . there is o fte n the misconcep­ tion that controlled e x p e r ime n t s in the target spe c i e s (pen tr i a l s o r a challenge e x peri m en t under controlled c o nd i t ion s ) which show that the product is efficacious. are sufficient to register a product. Animal health products also have to undergo cli nical or fi e l d trials to prove their efficacy and s a fe ty u n der p ract ic al conditions. Quite often, these trials reveal several hitherto unrecognized we akn e s s e s of t h e product. However. c l i n ical trials for vete r­ in ary med ici nal p roducts are much less c ri t ­ i ca l. le ss e x p ens iv e , and usually less t i m e - co n­ su m i n g than hu m an clinical trials. Due to the p re cli n ical pharmacological, efficacy and safe­ ty tests p e r for med in the target species, the cli nical trials are mainly designed to confirm p re clinical e fficacy data and to provide a b roa d e r basis for the safety evaluation.

224

7 Biomedicinical Product Development

Clinical trials are an important base of effi­ cacy claims for the product. As a logical con­ sequence, all indications for which the prod­ uct is recommended, all proposed routes of application, treatment schemes, doses, rele­ vant age groups and, in the case of veterinary products, all recommended species must be tested. For an effective development it is of­ ten better to initially concentrate on only one or a few of the potential indications to reduce the risk and to get the product on the market earlier, than to follow up all variants at the same time.

4 Technical Aspects of Product D evelopment Medicinal products must have a consistent quality in order to be reliably effective and safe. Achieving consistency in all aspects is a cumbersome technical and analytical task which takes much time and which is usually not the main virtue of research work. Scien­ tists without experience in product develop­ ment tend to neglect the technical aspects which lead to a consistent product quality. Increasing registration requirements for the product and the production process as well as environmental issues also add a signif­ icant technical and analytical dimension to the development. This particularly applies to products derived from biotechnology. Com­ pared to conventional biological products, the final product is usually much better defined and its manufacturing process can be better controlled. But it requires the application of a variety of quite sophisticated techniques to do so.

For most new biotechnological products, processes and analytical methods have to be newly established. This represents a major and costly part of product development. In newly founded biotechnology firms pertinent technical experience and practical knowledge about the application of regulatory require­ ments is usually missing and must be develop­ ed. Early information and consideration of these aspects may considerably shorten this learning process.

4 . 1 Process Development and Manufacturing

The active ingredient of a potential prod­ uct, as it was identified in research, is initially produced in minute amounts and by a process which in most cases is not acceptable for a pharmaceutical product or for large-scale pro­ duction. Process development represents a link between research and manufacturing and adapts the research methods to the needs of production or develops new methods where necessary. Process developers must take mul­ tiple aspects into consideration (Tab. 3). Their task would be much easier, if research­ ers were aware of these aspects. In the worst case process development can imply that an entirely new procedure to ob­ tain the active ingredient must be found and established. Frequently master seed stocks (cells, viruses, bacteria) must be newly gener­ ated and tested, since those from research are not suitable because of their quality (contami­ nants, inhomogeneity) or unclear history and documentation. Unacceptable starting materials used in re­ search must be replaced by those which meet the regulatory quality and safety criteria. Ref­ erence to standard volumes of pharmaceutical ingredients and excipients should be made to decide whether a certain ingredient can be used. Standards are described in the pharma­ copoeias of relevant countries, in The Extra Pharmacopoeia ( MARTINDALE, 1993) and in the Handbook of Pharmaceutical Excipients (AMERICAN PHARMACEUTICAL ASSOCI A­ TI O N/THE PHARMACEUTICAL SOCIETY OF GREAT BRITAIN, 1986). The German Lexi­ kon der Hi/fsstoffe ( FIEDLER, 1989) also pro­ vides many useful informations about accept­ able excipients and about their applications and safety. Components used and approved for human food may also be considered as po­ tential ingredients for certain applications. Hazardous components cannot be used at all or have to be removed during the process. Special conditions apply to the use of starting material of human or animal origin to avoid the presence of adventitious agents in the fi­ nal product.

4 Technical

Aspects of Prod11ct Development

225

3. Process Deve lopment for B iological Pharmaceuticals: Major Points to Conside r in Process Development

Tab.

I. Starting Materials and Excipients

Availability: appropriate quantities. regular supply Quality: specifications and consistency (compliance with pharmacopoeia speci­ ficat ions if these exist ) Safety acceptable for a pharmaceutical product and freedom of adventitious agents. e.g human serum components. bovine serum! Masters seed cultures: quality. documentation. suitability ..

II. Safety and Environmental Aspects

Work safety. e .g .. organic solvents, aerosols containing microorganisms Contamination from the e nvironment Contamination of the environment Cross-con tamination and separation of activities Waste material decontamination and disposal Ill. Legal and Regulatory Aspects

Registration requirements for product and process Lice ncing of facilities Good Manufact uring Practice ( G M P ) I nfri ngement o f existing patents? IV. Economical Aspects

Cost of goods Y ie lds

Recovery rates I nvest ment into equipment/facility

Process developers should check existing patents and patent applications in order to avoid patent infri ngement with any use or process patent. On the other hand. there may be possibilities t o pate nt the particular pro­ cess newly developed or critical elements of it. Economic aspects such as yields from cell culture or fermentation. product recovery af­ ter purification and cost of materials and equipment need constant attention. Produc­ tion cost forecasts should be calculated and updated regularly. A variety of product safe t y . work safety. environmental safety aspects and other legal aspects m ust be taken into consideration when a process is designed. Good Manufac­ turing P ractice standards for facilities, equip­ ment. and working procedures must be met. GMP approval is subject to inspection a nd re­ quires constant attention and updating. Ex­ tensive documentation must be provided to comply with these requirements.

Manufacturing facilities are approved for their specific purpose , e.g., for the manufac­ turing of one particular product. If it is in­ tended to manufacture another product in the same facilities, this must also be approved and requires very strict measures to avoid any cross-contamination and mix-ups. Either the facilities have to be separated, or production runs for different products have to be per­ formed at different times with intensive cleaning and decontamination in between. The preferred option is of course to devel­ op a manufacturing process for an already ex­ isting manufacturing plant. If adequate and approved facilities are not available , the pos­ sibility should be considered to develop the product in cooperation with somebody who has free capacities in a suitable plant. ( Many conventional vaccine producers have more capacities than they need.) If this alternative is unacceptable, considerable investment and time will be required to establish manufactur­ ing facilities. They have to be planned, built,

226

7

Biomedicinical Product Development

equipped and approved first, and it will be necessary to gain sufficient experience with the new plant and the manufacturing process in these facilities. The use of existing manufacturing facilities also overcomes another common limiting fac­ tor in product development: the availability of product for test purposes and clinical trials. All critical tests must be done with a product which is essentially the same as the final prod­ uct, if the data from these tests are to be used for the registration application. Research ma­ terial of d ubious quality is definitely not ap­ propriate. It may take months or years to develop a controlled process which reproducibly gives a product with adequate quality. As a conse­ quence, process development must start very early in the development phase. The product specifications should not simply evolve from the process; the main parameters should be fixed beforehand. This does not only provide clear objectives for process development, it also makes sure that no time is wasted .by test­ ing products of inadequate quality which may render the data obtained useless for registra­ tion purposes. In some cases it may be unavoidable to change relevant product specifications. If ma­ jor pharmacological and safety tests have al­ ready been done, it may not be necessary to repeat all of these. Comparative tests (bio­ equivalence studies) with the earlier and the new product should be performed to check whether both are equivalent in all critical as­ pects. In the case of higher standatds, (e.g., for purity) this may be relatively simple, low­ ering these standards, however, will be diffi­ cult to justify and requires thorough studies about the nature and the effect of the addi­ tional impurities.

4.2 Analytical Development and Quality Assurance

Quality assurance schemes for medicinal products have evolved mainly from experi­ ence. Whereas initial quality controls were carried out only with the final product - with elimination of batches which did not pass the

test - nowadays quality assurance covers the entire manufacturing process and continuous­ ly develops towards a more holistic system. Presently quality standards cover everything that goes into the product (starting materials, excipients, the active ingredient and its by­ products) , everything that could come into contact with the product (e.g., air, water to clean vessels, packaging materials) or has the potential to influence product quality without being noticed by the usual checks (e.g., per­ sonal qualification, management responsibili­ ties, the validity of methods, documentation). The given examples may illustrate the general scope of modern quality assurance for phar­ maceutical products. Analytical procedures have to be develop­ ed for the active ingredient as well as for starting materials and the excipients used in the final formulation. These tests should be able to specify and confirm the identity, puri­ ty, potency, stability and consistency of these materials. If significant impurities, degrada­ tion products or critical metabolites occur, analytical methods for these will also be re­ quired. In-process control methods must be de­ vised and developed to observe all relevant steps of the manufacturing process in order to have adequate control over the inherent var­ iants and to detect potentially harmful con­ taminants at a stl\ge where they may be easier to trace. The spectrum of tests to be employed com­ prises methods from microbiology, immunol­ ogy, protein and peptide biochemistry, ge­ netic engineering and physico-chemical meth­ ods as well as animal experimentation. If these exist, for example, in pharmacopoeias, standard method descriptions have to be fol­ lowed. Critical steps of the manufacturing process and analytical methods have to be validated carefully. Process validation will be required, for example, for the inactivation or elimina­ tion of potentially pathogenic microorganisms (e.g., viruses in transformed cell cultures) from the product. This can be done by run­ ning spiked samples through the process or through a smaller laboratory version of the process which exactly mimics all relevant pa­ rameters. Volumes, tests, and test sensitivity

4 Technical Aspects of Product Development

must be considered carefully and statistically for such experiments. Analytical methods a re validated by inves­ tigating specificity . sensitivity, detection lim­ its. quantification limits. accuracy (of the indi­ vidual r e sult) precision ( variation between different tests ) . applicability and practicability under laboratory conditions and the robust­ ness (susceptibility to interference) of the method. This enables t h e organization itself to employ these tests much more consciously and with bet t e r res ult s . but it also serves the purpose of enabling the registration authori­ ties to use these tests for the regular batch control tests. Official guidelines by the regulatory au­ thorities for the validation of analytical meth­ ods and processes are available for consulta­ tion. Good Manufacturing Practice ( G M P ) standards arc a further step towards the con­ cept of "total quality". Implementing and maintaining a G M P status requires commit­ ment of the e n t i re organization and special and constant attention by those who are in charge of qualit y assurance. Because of the complexity and wide scope of the subject and the amount of paperwork (some translate GMP as "Give M e Paper " ) extra personnel or external consultants will most likely be required. GMP includes for example: .

·

•

•

•

• •

The organization . management struc­ ture. personal qualifications and train­ mg Standard Operating Procedures (SOPs) with appropriate documentation and implementation systems ensuring their effective application Production. packagi ng. labeling. han­ dling. testing and approval of starting materials. i n te r m ed i a t e and final prod­ uct

Construction. infrastructure and main­ tenance of buildings and equipment Regular inspections and self-inspections and many more details.

Whereas GMP

as well as GLP (Good La­

bora tory Practice ) and GCP (Good Clinical Practice ) arc m a in ly acti ng on the operational

227

or technical level. other quality assurance standards have been established by the Inter­ national Organization of Standardization ( ISO) to assure quality at the organizational level. I nadequate organizations with unclear tasks and responsibilities can severely in­ fluence the quality of products and services. In the near future further quality assurance elements as recommended by the quality guidelines ISO 9000- 9004 will certainly also be applied to pharmaceutical developers. manufacturers and to sales organizations. A formal accreditation of compliance with these standards requires the implementation of quality assurance schemes covering. for ex­ ample, the following aspects of a business: • • •

• •

•

Management responsibility and com­ mitment Organizational structures with explicitly defined and delegated responsibilities Quality assurance systems covering all functions in procurement, production, control of production, handling, stor­ age . product identification, packaging, delivery . marketing, afte r-sales servic­ ing. product supervision and "design " (design res ea rch and development) Identification of non-conformity and corrective actions Means to ensure product traceability, facilitating recall and planned investiga­ tion of products or services suspected of having unsafe features U se of statistical methods to enhance and maintain quality at all stages and of all activities in the product cycle. =

It is to be expected that by the year 2000 or earlier compliance with ISO quality manage­ ment standards will be obligatory for staying in business. The personnel cost of implement­ ing and maintaining these q uality assurance systems should not be underestimated.

228

7

Biomedicinical Product Development

5 Planning and Managing Product D evelopment The development of a modern pharmaceu­ tical product is a complex task which is fur­ ther complicated for biological or biotechno­ logical products by the potential variabilities of the biological production system and the resulting consequences. Therefore, apart from considerations of adequate skills and re­ sources, careful and very detailed planning and controlling is imperative for the success of development. Those who are unexperienced with the tools of project planning and managing may refer to one of the numerous books about project managing. Although these books are usually aiming at more technical applications, the basic techniques do not differ and are of course also applicable to other areas. Alter­ natively one can buy a project management software package and learn the application of these tools directly by using it in the planning process. Knowledge of the essential registration re­ quirements is mandatory for the planning of a pharmaceutical development project. If these are neglected, the development process will be like navigation in unknown waters without a compass or a map. The risk of a shipwreck is high, in any case the j ourney will take much longer and will cost more. Provided that a reasonable and useful product profile (see Tab. 2) has been estab­ lished, the general aim of the project and the most relevant objectives have already been decided. The objectives which serve as orien­ tation points in the project will most likely address the exact indication, efficacy, the type of product, its formulation and application scheme. Another important general objective in the product profile may be the expected price limit for the production of the active in­ gredient or the formulated product. Specific tasks and measurable success criteria for process development and manufacturing, e.g. , in terms of yields and recovery after purifica­ tion, can be deduced from this price limit. Other very specific objectives and the majori­ ty of project tasks relate to specific registra­ tion requirements.

It may take several months to establish a workable development plan, and most of this time will be required to collect the neccessary information. At the beginning the project plan will probably be a rather simple outline which then grows continuously while the pro­ j ect progresses. A project master plan which covers the major sections, milestones and de­ cision points can be established far ahead and - if prepared thoroughly - will remain essen­ tially unchanged from then on. More specific and detailed planning and updating is done in subordinated plans for the individual sections and must be performed continuously. Development plans must be much more detailed than research plans. The simple rea­ son for this is that the commercial environ­ ment in which development takes place re­ quires a much stricter planning, use and con­ trol of time, budgets, and manpower. Significant time savings can, for example, be achieved by preparing tasks and trials ear­ ly and by careful and extensive evaluation of trials. Often time is lost, since in negligent project plans resources for the planning and evaluation phase of larger studies as well as certain aspects, which can be tested simulta­ neously and do not require separate experi­ ments, are ignored. This applies especially to clinical trials which need considerable time to get started and where it is possible to collect data on efficacy, pharmacology, safety and tolerability aspects at the same time. Many tasks have to be performed accord­ ing to very detailed legal and quasi-legal standards which may differ from country to country. Relevant countries' guidelines must be checked and considered in planning the in­ dividual tasks. Studies performed according to GLP standards, animal trials and clinical studies can only be performed, after internal or external examinations of protocols or ap­ proval procedures have been passed. In this situation it is essential that all people in­ volved start their activities with precise and detailed instruction and are given sufficient time for a careful preparation of their tasks. Good project plans include the preparation of relevant studies and trials as specific tasks in order to avoid delays. Effective project controlling also needs de­ tailed planning. Under normal circumstances

5

Planning and Managing Product Development

the p l a n s must be exact e n ou gh to allow p r o­ gress to be m on i t ore d a t i n t e rv a l s of 2--4 weeks. ( Some industries and c o m p a ni e s have much t i gh t er sche mes! ) I n cr i tica l situations or for activities on the c ri t i c al pa th (if de­ laye d, activi ties on the cri t i cal path de l a y the entire p roj e c t ) . more frequent ch e c ks and cor­ rections may be necessary. Where possible, progress should be m oni t o red before a task is finished. Requesting i n fo rm a t i o n abou t the pr ogres s halfway t h ro ugh a j ob can also create a better a w are n e ss for time limits a n d ta rg e t dates. If p ro b l e m s are li kely. m e a n s to solve them can be pl an ne d a nd i m p le m e n t e d before these problems cause m aj or co ncer n .

5. 1 Risk-Oriented Planning The most di fficult a n d controversial part in planning and m anagi n g of a de v e l op m ent process is to k ee p t h e r i g h t balance between the t h ree cor n e rst ones cost . r i s k . and time. Using more time r e d u c e s the risk b u t i n ­ creases the cost and d elay s t h e p rod uc t launch. Con troller and m a rk e t i n g manager will raise t h e i r pro t e st . Taki n g more ris k s in­ cr e a se s the po ssi b i l i t y o f n o t m e e t i ng the mi­ lestones. and eve ry body is concer ne d . There is no way to do it r i g ht fo r e v e ryo ne ! The willingness to t a k e risks can be a key element for a r ap id and cost-effective devel­ op m e nt prog r a m . M a k ing a ssum p t ion s about the likely outcome of a piece of work and commencing the next step w h i c h depends on a particular resu l t be fo re i t is av a i l able . does increase the risk, but it also permits to short­ en the d e ve l op m e n t time considerably . The most rele v a n t risk to be co nsi d e re d during the d ev el o p m e n t of a b i ol ogical phar­ maceutical is the efficac y and sa fe t y in t h e tar­ get organism. De s p it e exte n s i ve p re c l i n i c a l tests, m a n y product c a ndi dates are aban­ doned after first tests i n h u ma n s . Th e p rob lems e nc o un te re d at this stage a re o fte n due to pharmacological or immunological d i ffer ­ e n ce s he tween t h e model used in the preclini­ cal tests and humans. T h us . it is ne ce ssary to plan P h a se I c l i n i c a l trials as e arly as possible. S i m i l a rly m o s t ve t e r i n a ry development pro­ jects fai l due t o a lack of efficacy and unex­ pected <Jdverse e ffects w hich remain unno­

229

ticed until the p rod u c t is tested in the target species. Ve t e r i n a ry p rodu c ts should be tested i n t h e t a r get s pe c i es as soon as sufficient p rod uc t is a v a ilab l e . Tests under p r act i c a l conditions s h ou l d follow as soon as possible. Quite often m ajor progress, but also unex­ pected n eg a t i ve results. come from experi­ me nts in humans (or pr im a tes) or in target animal sp e cies . Besides the al r eady emphasized i mpo r ­ tance of tests in the target or ga nism , the im­ portance of animal and in vitro models for pharmace u tical pro d u c t development h a ve to be p oin ted out. In most cases the available range of models a n d in vitro t e st s needs to be extended for t h e d e v el opm en t phase , because the models used in research are not adequate n or sufficie n t . Considering the fact that all p o t e n ti a l facets and variations of a new act ive co m pone n t (different conformations, concen­ t rati o ns . formulations the mode of action, im­ m u n o l o gy , p h a r m aco k i n e ti c a n d s a fety a n d e ffi c acy under various conditions) should b e studied , the availability of models can be an im porta n t asset for a fast and cost-effective prod uc t deve l opme n t . Models allow certain aspects to be investi­ gat e d i n m ore d ep th , but t h e y r e fle ct o n ly a part of the entire situation. The refore, they need to be v a l i d a t e d by c o m pa r i n g their re­ sults with t h o se in the t a rget o rg a ni sm . Mod­ els should be considered as a v al ua ble addi­ t ion. not as a replacement fo r tests in t h e tar­

ge t organism. The eco n o m i c feasibility of a p r oduct ca n be a n othe r m ajor risk which n e ed s contin­ uous attention dur i n g t he d ev el o p m en t . This is e sp eci a l ly true for animal health projects a n d for all the products which will compete with simpl e and effective alternative treat­ me nts. for example, with e x i s tin g vaccines. Fa c t o r s d i re c t l y affe c ting the economic assess­ ment a r e t hose l isted i n the prod u c t pr ofi l e u nd e r " co m mercial aspe c ts " (cf. Tab. 2). A p roj e ct manager will have to control t he de­ velopment cost a n d pa y spe c i a l attention to details like yields and recovery rates d uring t h e proce s s de v e lop m e n t . Critical l i mi ts fo r t he m a n u fa ctu r in g should be addressed by s e t ting s p e cific objectives. One should not forge t that the economic

aspects of a project depend on the underlying

7

230

Biomedicinical Product Development

assumptions about the product's characteris­ tics. Less efficacy than assumed or a slightly compromised tolerability may seriously affect a product's performance and viability on the market. 5 .2 Product Development Phases

As a starting point for the planning of a de­ velopment project, Tabs. 4 and 5 propose and summarize a phased scheme of a risk­ oriented development plan. Several impor­ tant milestones and decision points have al­ ready been included. Each phase must fulfill certain criteria in order to be accomplished before the next phase may start. Management decides whether a project is advanced enough Tab. 4.

to proceed to the next phase, since this deci­ sion is usually associated with the involve­ ment of more people in different departments or of external participants and has significant financial implications. The data and informa­ tion needed for an assessment of progress and criteria for the decision should be known be­ forehand. Most of these criteria, which are in­ cluded in Tab. 5 as proposed milestones (which need to be specified in detail for a giv­ en project), address the critical aspects of the project and the question what should be done to reduce these risks and to allow the project to enter the next phase. The first management decision will be to forward a research proposal and component to development. This decision should not be made if the active principle (substance) is not

Product Development Phases, Main Risks and Tasks

Project Phase

Main Risks

Main Project Tasks

Research

Scientific feasibility, efficacy

Proof of a reproducible active principle Achievement of sufficient efficacy

Pre­ development

Efficacy, safety, economic feasibility

Confirmation of efficacy in best available models or in tar­ get species Limited, orientating safety studies Establishment of a small-scale process, scaleable and with acceptable quality Calculation of economic parameters

Preclinical development

Efficaccy, safety

Evaluation of efficacy for all indications Full pharmacological, immunological and safety evaluation Process development and validation Analytical development and validation

Clinical development

Efficacy, safety and tolerability

Registration

Formalities, safety, quality

Updating/improvement of dossier Additional safety studies Additional quality assurance tests of validations

Postmarketing development

Safety, acceptance and practicability

Drug monitoringlpharmacovigilance Further safety assessment Postmarketing trials

•

Phase 1: Dose-finding, pharmacologic action, metabolism, side-effects: Intensive studies in patients or healthy individu­ als, usually 20--80 subjects • Phase II: Controlled studies on effectiveness and on side-ef­ fects: usually no more than several hundred subjects• Phase III: Expanded, controlled and uncontrolled trials on efficacy, safety, risk-benefit relationship, practicability: usually several hundred to several thousand subjects•

Numbers quoted from 21 CFR 312.21 {USA)

5 Planning and Managing Product

Tab. 5.

Development

231

Prod uct Developm e n t Phases, Milestones and Decisions

Milestones

M ajor Decisions

Research

Active component characterized

Effi cacy

pr ove n

;&>

Decision to enter pre-developme n t Decision on indications

Pre-development Effi c a cy confirmed in re l i able m od e l ( s ) or in the target species for veterinary products No s afet v risk i d e n t i fied Scal e a b l � process av a i l able: yields. cost and quality acceptable Favorab l e economic fe asibility s t u d y

;&>

Decision to enter preclinical development Decision on t a rget countries Decision on ( preliminary) product specifications Decision on man ufacturing site and method

Preclinical development

Proven

effi c ac y for all i ndications

Acceptable safe t y/tolerability for all i ndica­

tions/condition�

Process d et a i ls according to plan : scale. y i e l ds . cos t . product specifications

;&>

Decision on p roduct specifications Decision on fi nal production process

Decision o n i n dications t o be pursued

Decision to enter clinical development Preliccncing serials passed quality cont rols; trial material a v a i l a b l e

;&>

Decision to s t a rt clinical trials

;&>

Decision to file registration

;&>

Decision

Clinical development Successful co m p l e t io n of Phase I S ucce s sfu l completion of Phase I I Successful

completion of

Phase I I I

Registration

Obtain market approv a l

Decisions afte r completion of a phase should not exclude

to

m a r k e t product

that preparations

for later activities can be made

before that decision . The act u a l ac ti v i ty i n question (e.g . . clinical trials. p roduct sales), may only start with full approv a l .

or insufficiently d e fine d. A re­ combinant antigen which is incompletely characterized most likely needs much more research before it can be considered a devel­ opme n t candidate. I t should stay in the less costly research l a bor a t o ry until sufficient effi­ cacy wit h a clearly cha r a ct erize d antigen is

yet av a i la b l e

achieved. There would be no point in testing s afety features or to develop a process for a component if its essential fe a t u re s are still u n ­ known. The ability to complete the product profile to a reasonable degree could serve as a pre re qui s ite for a decision to enter develop­ ment.

232

7 Biomedicinical Product Development

An important element, which is frequently used in drug development, is the introduction of a pre-development phase which serves the purpose of reducing major project risks be­ fore the full development commences and be­ fore extensive resources are allocated to the project. It can also serve as a time buffer to complete missing points of the product pro­ file. In order not to delay the project too much, this project phase must have a limited duration of usually one year, but not more than two years. As far as possible, the crucial risk factors efficacy, safety, and economical risks should be investigated, e.g., by perform­ ing efficacy trials under the best available conditions. These could be target species ex­ periments for veterinary indications and a range of animal model studies or perhaps even a small study in primates for human in­ dications. Short-term safety tests can be per­ formed to indicate where potential problems may be and which range of toxicity tests will address them. Most likely the methods used in research to generate the active component are unsuitable for later production, and the pre-development phase may be used to iden­ tify, investigate, and calculate better options. The introduction of defined project phases and management decisions before each new phase mainly intends to create a clear basis and an overall agreement before major new activities are initiated. These management tools should be h andled pragmatically in or­ der not to cause unnecessary complications and time delays. For example, it could be nec­ essary to approve preparations for clinical trials months before the preclinical develop­ ment has been finished and before the formal decision to enter clinical trials is envisaged. The planning of such trials and the recruit­ ment of trial cooperators and trial subjects can take a long time, which would be lost if decision procedures were not flexible enough. 5 . 3 Decision Making

Decisions are only the visible result of a process which is preceded by the generation of data, writing of reports and statements, ex­ change of information, meetings, and discus-

sions. For larger development projects, in which many people are involved and deci­ sions imply significant expenses and invest­ ment, this process can take a considerable time. If decisions are well planned and pre­ pared, they represent an important element of stability and support. If applied in the wrong way, they may severely hamper the progress of a project. A well-founded decision to enter the devel­ opment phase of a product usually takes sev­ eral months. Often delays occur because the decision is not anticipated and the necessary facts, figures, and reports are not collected in advance. But also if the decision-making indi­ viduals are not prepared and do not indicate early enough what kind of information and prerequisites they need to make the decision, months could be lost. For example, the exis­ tence of an acceptable product profile ( cf. Tab. 2) including the required information and evaluations may be used as a basis for a development decision. Major decisions can and must be antici­ pated and prepared by both the decision makers and by those who's further work de­ pends on the decision. The major decisions for a development project, as proposed in Tab. 5, should be integrated in the project plan along with the necessary tasks for their preparation. Management should provide guidance on the information needed for such decisions. Most larger companies have estab­ lished routine schemes for the major project decisions and for the necessary documenta­ tion. If applied pragmatically, such schemes can shorten decision procedures considera­ bly. Minor decisions should not be made by the top management. Considering the number of people who are directly or indirectly in­ volved, the time spent and the cost of this time at work, a decision can be more expen­ sive than the expenditure for the object of the decision (WITIE, 1 969). If the suspicion arises that this could be the case, the project organi­ zation is probably top-heavy, and delegation is done without giving appropriate authority. Delegating responsibility to a proj ect man­ ager and to project team members also in­ cludes the delegation of decisions to them. Extent and limits of the delegated responsi-

5 Planning and Managing

bility and authority should be defined in the job descriptions. Only if there is trust and confidence in their capabilities. responsibility and decision making can be delegated. Unless there are important and very con­ vincing arguments which have not been taken into account. the subordinate's decision should be respected. Accepting a subordi­ nate 's decision can sometimes be very diffi­ cult for the superior manager, particularly if (s)he would have decided differently and the decision is cri ticized and must be defended. Overruling decisions of subordinates or fac­ ing them with already made decisions which would have fallen into their direct responsi­ bility can seriously affect the working rela­ tionship. Approval of a project requires the consent of many people, but a single "no" can cause the project to collapse. This mechanism has the potential of being misused by individuals to undermine projects they personally do not like. Risky projects (projects are by definition risky) are frequently surrounded by people who question the entire project by emphasiz­ ing one or the other inherent risk. If their concern has bee n recognized before and was considered during previous decisions, such criticism seems inappropriate and the critics should be requested to provide more con­ structive proposals. Decisions to s t o p a project are the most difficult decisions. Although perseverance and full support by everybod y are essential for the success of any project. there is a point where "the plug must be pulled''. A feeling of personal failure if the proj ect fails. selective perception and reporting of information , ma­ jor setbacks being considered as temporary problems and the hope to recoup at least part of the investment are strong forces which hinder a reasonable decision at the right time. STAW and Ross ( 1 99 1 ) have discussed the personal intere sts of people involved in such situations in more detail. Simple recipes do not exist to prevent the project dragging on in a hopeless situation. But things can be done to make decisions to stop a project more rationally and less pain­ fully for those affected by it. First . the fee ling of personal failure must be eliminated. Many organizations still con,

Product Development

233

sider the fear of failure and direct or indirect punishment (status, sala ry no further promo­ tion) as an important driving force - accord­ ing to the "carrot and stick" method to keep a donkey moving. This method seems hardly adequate for the needs of project work with responsible and highly skilled individuals. Proj ect groups and their managers need recognition of their work and praise if they did a good job. This also applies to a project group which could not solve the scientific or economic problems of the proj ect despite all reasonable efforts. The only reason to blame somebody personally would be if she or he refused to do what could have been done. In this case the person needs to be retrained to solve the problem. Second, honest reporting also of negative results must be encouraged. The best encour­ agement is a modest, rational response and the offer of active help if unexpected prob­ lems arise . Finally, one must not accept the argument that too much money and effort already went into the project and that it needs only some further investment to rescue it. Decisions must be based on the future perspective of the project. The past, including all money spent, does not count. The project should be evaluated in exactly the same way as a new project proposal and using the same kind of information. I f in the new scenario, chances and risks, cost and time to develop the prod­ uct do not justify the continuation of the pro­ ject it should be stopped based upon objec­ tive and rational arguments, but not because someone failed. Project decisions tend to take a long time and even proj ects which eventually finish up successfully are sometimes subject to several critical decisions during their life-span. In these times the individuals in the project group may frequently ask themselves, wheth­ er their efforts are worth it. The rule should be that as long as there is no official decision to discontinue a project, everyone should continue unharmed by the ongoi ng discus­ sion. ,

.

,

7

234

Biomedicinical Product Development

5 .4 The Proj ect Manager

The success of any larger and complex pro­ ject depends to a great extent upon an effec­ tive project management. Development pro­ jects for medicinal products need project managers with a variety of skills and personal qualities to cope with the very demanding job (see Tab. 6). A good working knowledge in different scientific fields (e.g. , medicine, mi­ crobiology, immunology, protein biochemis­ try, pharmacology, toxicology) as well as in technical subjects (e.g., biotechnology, pro­ cess development, analytical methods, formu­ lation, manufacturing) are valuable assets for the planning and management of a project. Project managers must be prepared to contin­ uously learn about these aspects. It is not sufTab. 6.

Responsibilities of a Project Manager

Planning

Development of a project concept Definition of objectives, milestones, and deci­ sion points Definition of project tasks Scheduling of project tasks Planning of resources Replanning and updating of plans Coordination

Identification of shortages Reallocation of resources Negotiation of use of resources versus time performance Preparation and initiation of major decisions Organization and chairing of project meetings Special tasks as required ("putting out fires") Development and provision of missing skills Controlling

Cost monitoring Compliance with time frames (milestones) Compliance with quality criteria (objectives) Effective use of resources Adequacy of documentation Information

Effective communication among project group members Initiation of scientific and technical reports and documentation Progress reports Project presentation and justification to the management

ficient to rely entirely on the specialists, since good decisions and judgement need overview. Furthermore, it could be helpful to know the subject in detail, if resources and time per­ formances have to be negotiated. Management skills, certain personal char­ acteristics and psychological knowledge are required to coordinate and control the project and to maintain progress despite the unevita­ ble setbacks. Project managers must always think ahead, sense potential problems before they actually appear and devise measure to avoid them. Nevertheless, they must be pre­ pared to spend much of their time by solving unexpected problems and conf!icts and de­ fending their project against criticism which is raised from various sides as soon as a proj ect does not proceed smoothly. Project managers are always in the most prominent position when problems are tackled. They are the scapegoat and need a high level of resistance against frustration. Success will be claimed by everyone. Project managers need clear and adequate organizational structures with delegation of defined duties and authority. Delegating the responsibility for a project to the project manager means that the "ability to respond" (in French: responsabilite) must be given. Re­ sources and authority should be at the project manager's disposition to react according to the needs of a situation. For the benefit of the project, this must include the full authority to use the planned and agreed resources plus a certain degree of flexibility in special cases without the need for extensive discussions, negotiation, and approval procedures. The assistance and support of all proj ect group members is essential for a project man­ ager. Considering the fact that project manag­ ers have to impose very unpopular time, cost and quality control measures on their work, some individuals in the group may have diffi­ culties with accepting this. Project managers can fulfill their task only by delegating work to other members of the project group. (There will always be enough left for them to do. ) The presence of unqual­ ified or less agile project team members re­ veals itself by the repeated inability of certain individuals to achieve agreed objectives and milestones or much earlier by the fact that

5 Planning and Managing Product Development

others ( usually the p roj e c t managers) have to do essential parts of t h eir job. Another indi­ cation for weak s po t s in the project group a re peo p le w h o ' s p l a n n i ng an d re p o rti n g needs constant assistance and who do not actively and in time collect the information w hich they need for t he i r work. If pe r m anen t pressure mu s t be applied to ensure that o bj ec t i v es are met completely and in time . this c ou l d either indicate that neces­ s ary skills are missing or that the p roj e c t p la n was too ambitious and u na ch ie v a b le . Since the individuals should know best what they can or cannot achieve in a certain time. this can be av oid e d by a delegation of the pl a n ­ ning of details ( and provi si o n of assistance where necessary ) to the funct i o n a l groups and to the individual project members. If the problems remain the same . the project man­ ager faces the very difficult task of c h a n gi n g the g ene r al attit ude and mo t i va t io n of the proj e c t g roup . B ut who motivates th e p roj e ct manager? For further re ad i n g about this su bjec t the classic a rt i c le The Project Manager by PAUL GADDIS ( 1 991 ) as well as the Harvard Busi ­ ness Review. v o l u me Motivation a re recom­ mended (see References) .

5 . 5 Organizational Structures and Motivation An organization w h ich focuses enti rely on only one project should not h ave m aj o r i nter­ nal co nfl i c ts aoout resou rces. Such a '·task force " represents a largel y i nd e pe nden t group

within an organization with far-reaching com­ peten ce s . which is created tem p orarily and in e xcep t ional situations to solve a critical p rob ­ lem or for v e r y large proj ects. Under normal circumstances different de­ partments

or groups

with d i fferen t

skills

con ­

trib u t e to one or several p r oj ect s besides their o w n r o ut i n e work, e.g.. in research. Some­ bod y within these departments is nom ina t ed as p roj e c t leader a n d continues to report to the head of his department. Qu i te often the differe n t leaders of these functional de p ar t ­ m e n t s a c t u a lly lead the p r oje c t , each of them with a particular personal o p i ni on a n d p refe r -

235

ence . An overall responsibility and a coordi­ nating pe rson with a d equa t e a u t h ori ty is miss­ ing. A common solution to accomodate the needs of de v elo p m e nt projects is the creation of a matrix management structure. In a matrix orga nization a project ma n a ger is appointed, who reports d i rect l y to the h i g h e r manage­ ment and. as far as it concerns the p roject , is usually on an equal le ve l with the functional managers who control t h e resources. The au­ t ho r i t y of the p roj e ct manager reaches across the functional dep a r t me n t s . A matrix organization cle a rl y puts more emphasis on project work. Since in a commer­ cia l ly oriente d organiz at ion research p roj ects

with a higher p riori ty than develop ment pro­ j ec t s rare ly exist. it also stre n gt h e n s de velop ­

ment activities. In other words, if the func­ tion al d e par t m e nts conduct research and de­ v e l opment , conflicts between t h e se two activi­ ties are usually re so l v ed by giving the higher prior i ty to the d evelo p ment proj e ct . The matrix orga n izatio n does not abolish resource a n d p r iority conflicts between differ­ ent

projects

t h e se

and their managers. If

necessary,

conflicts have to be resolved on a higher level, either b y t he upper management or by a project s t ee ri n g committee. This s teeri n g committee acts as project mandator . ap p roves p roje ct plans . decides in case of conflicts and has the overall responsibility for product de­ v elo p ment . Th e p r oject managers should be members of the s t ee r i n g comm i t tee .

Matrix organ izations p rovide for an effi­ c ien t use of resources and a better coordina­

tion across the functional departments (BARTLElT and G HOSHAL, 1 990). However, much t ime must be sp e n t on proper pl a nnin g, coord inat i on , ne go ti a tion a n d fi nd i n g agree­ ments about details. Pr oj e c t team members report at least to two bosses and have t o or­ ganize, n egoti a te and pri or i t i ze their work be­ tween their functional manager and one or several p roj e c t managers. The individual i n a matrix organization can be caught in a difficult situation and bears the u n p le as an t consequences if the structure does not function properly. This, as well as the in­ heren t ins tabil i ty of the system, may result in a situation where the individuals d i sre ga rd proj e c ts and set their own p rioritie s .

236

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Biomedicinical Product Development

Tab. 7.

Main Motivation and Dissatisfaction Fac­ tors on the Job " Motivation results from: 1. Achievement

2.

Recognition 3 . Work itself 4. Responsibility 5. Advancement � Motivation is achieved on the individual level! Dissatisfaction results from:

1 . Company policy and administration 2. Supervision 3. Relationship with supervisor 4. Work conditions 5. Salary � Dissatisfaction must be avoided on the organi­ zational level !

The five most important factors on the job which motivate or lead to dissatisfaction, ranked accord­ ing to their importance. •

Organizational structures and administra­ tion have a significant potential for dissatis­ faction among the staff and thus may severely influence the overall performance of the or­ ganization. Tab. 7 lists the five major factors which can result in positive motivation or dis­ satisfaction at work. It was summarized from 1 2 different investigations and covers all hier­ archical levels and jobs in various organiza­ tions (HERZBERG, 1 986) . The message given by this table is rather clear: Dissatisfaction seems to be caused mainly by internal struc­ tures, supervisors, and general work condi­ tions. Discontent about the salary ranks rela­ tively low on this negative side of the list (and does not appear among the motivating fac­ tors ! ) . Changing the dissatisfaction factors which are criticized only by an individual per­ son seems difficult because this would in most cases affect the entire organization. If, howev­ er, the majority of staff complains about such aspects, changes must be considered serious­ ly. Motivation can quite simply and effectively be created by the delegation of recognizable sections of work or independent parts of a project along with adequate authority to make own decisions concerning these parts. This allows the individual to assume responsi­ bility, creates more interest in a given job and

makes sure that the individual 's achievements become visible and are recognized. Motivation appears to resemble biotechno­ logical products: they both have a tremen­ dous potential and are inexpensive and highly effective. In practice, however, their availa­ blility is rather limited because their applica­ tion is more difficult than expected. Acknowledgements I owe special thanks to GARY COBON and

JIM HUNGERFORD who critically reviewed

draft versions of this chapter and made many important suggestions for its improvement. My colleagues at Behringwerke AG, Bio­ tech Australia Pty. Ltd., and Hoechst AG contributed greatly to this work by providing good practical examples and competent ad­ vice at many occasions. At this place I wish to thank all those who shared their experience with me and who's cooperation I enjoyed during the past decade as an i mportant source of learning and motivation. The responsibility for the content of this chapter lies entirely with the author. The views and opinions expressed are those of the author and are not necessarily those of the persons and companies mentioned above.

6 References AMERICAN PHARMACEUTICAL ASSOCIATION/THE PHARMACEUTICAL SOCIETY OF GREAT

B RIT­

(1986), Handbook of Pharmaceutical Exci­ pients, Washington, DC-London. AIN

BARTLETT,

C.A.,

GHOSHAL,

Management: Not a Structure,

S. (1990), a

Matrix

Frame in Mind,

HBR 90401, Boston: Harvard Business School Press. DIMASI, J.A., HANSEN, R.W., GRABOWSKI, H . G . , LASAGNA, L. (1991 ), The cost of innovation in pharmaceutical industry: new drug R&D cost es­ timates, J. Health Econ. 10, 107-142.

(1989), Lexikon der Hilfsstoffe fUr Pharmazie, Kosmetik und angrenzende Gebiete.

FiEDLER, H.P.

(Lexicon of Excipients for Pharmaceuticals, Cos­ metics and Related Areas), Aulendorf/Germa­ ny: Editio Cantor.

6 Referen ces The p r oj e c t m anager, i n : Pro­ ject Management, HB R 90053, pp. 29-37 . Bos­

G A D D I S , P . O . ( 1 99 1 ) ,

ton: H a rv ar d B usiness School Press.

GREGERSEN, J.P. ( 1 994), Research and De v elop ­

ment of Vaccines and Pharmaceuticals from Bio­ tech n o logy: A Guide for Effective Project Man­ agement, Patenting and Registration, W e i n h e i m -

New

York

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B a se l

V CH .

-

C a m b r i d ge

-

Tokyo:

HANSEN, R.W. ( 1 979), The pharmaceutical devel­ opment process: Estimates of d e v e l op me nt costs

and times and the effect of proposed regu latory

changes, in: Issues in Pharmaceutical Economics ( C H I EN , R. 1 . , Ed. ) , pp. 1 5 1 - 1 86, Cambridge, MA: Le x i n gt o n Books. HA RDAKER, M., W A R D , B . K . ( 1 99 1 ) , How to make a team work , i n : Project Management, HBR 90053 ,

pp. 39-44 , Boston:

Harvard

Business

School Press.

Harvard Business Review, ( 1 991 or l ate st editions), Article Collecti o n N o. 9001 0: Motivation, B os­

ton: H arva r d B u siness School HERZBERG, F.

P re ss . ( 1 986), One More Time: How Do

You Motivate Employees? H B R 6 8 1 08, J a n . ­ Febr. 1 986. Bost o n :

Harvard

Press.

B us i ne ss School

H O D D E R , J . E . , R I G G S , H.E. ( 1 99 1 ), P i t falls i n

uating

eval­

risky projects, in: Project Management,

HBR 90053 , pp. 9-28, Boston: School Press.

Harvard

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KARI A , R., LIS, Y., WALKER, S . R . ( 1 992) , The e ro­ sion of e ffective pa t e n t life - a n i nte r na ti on a l co m p a rison , in: Medicines, Regulation and Risk ( G R I FFIN, J.

P.

Ed.),

2nd Ed.,

pp. 287-302, B el­

fast : T he Queen ' s Unive rsity of Be lfast .

L A N G L E , L . , 0CCE LLI, R. ( 1 983 ) , T h e COSt of drug, J . d 'Economie Medicate l, 77-106. LU MLEY, C . E . , WALKER, S . R. ( 1 992),

ris k

of pharmaceutical

rese arc h ,

a

new

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and

i n : Medicines,

Regulation and Risk ( G R IFFI N , J. P . , Ed. ) , 2nd

Ed., pp. 303-3 1 8, Belfast: The

Queen's Univer­

si t y of Belfast.

MARTINDALE ( 1 993), The Extra Pharmacopoeia, 30th E d . , London: The Pharmaceutical P r ess .

E., W I RTZ, T. ( 1 992), Effizientes Pro­ jektmanagement. D Ussel dorf: ECON V er l a g .

MEHRMANN, PRENT I S ,

R.A.,

WALK E R ,

TuCKER, A . M .

( 1 988 ),

S.R.,

HEA R D,

D.D.,

R & D investment a n d

p har m ace u t i ca l i n novation in t h e U K , Manageri­ al and Decision Economics 9, 1 97-203 . STAW, B . M . , Ross, J. ( 1 9 9 1 ) , K no w i n g when to pull the plug, in: Project Management, H B R 90053 , p p . 57-6 3 , Boston: H arvard B usiness School Press.

P . R . ( 1 991 ) , Are prescription drug high? Science 252, t 080-1 084. WITTE, E. ( 1969), Mikroskopie einer unternehme­ rischen Entscheidung, I B M 1 9 ( 1 93 ) , 490 (quoted

VANG ELOS,

p r ice s

a ft e r MEHRMANN and WIRTZ ) .

Bioteclrtwlog}'

E d i ted by , H . -J . Rehm a nd G. Reed in coop eration wit h A. Puhler and P. S tadler Co p yright © VCH Verlagsgesellschatt m b H , 1 995

Regulations for Recombinant DNA Research, Product D evelopment and Production in the US, Japan and Europe

8

- Analogies, Disparities, Competitiveness -

D IETER B RAUER Fran k furt a m Main , Fe deral R e pu b l i c

of

Germany

HORST DIETER SCHLUMBERGER Wuppe rtal .

I Introduction

2

USA

242

2 . 1 The N I H

Fed e ral Re public

of

G e rm a n y

24 1 G u id e l i n e s

242

R e v i ew Processes 243 D i re ct o r of the N I H . Recom b i n a n t DNA Advisory Committee O ffice of Re com b i n a n t DNA Activities ( ORDA) 243

2 . 2 Committees a nd Offices I nvolved i n 2.2. 1

2 . 2 . 2 I n stitutional Biosafety Committee ( I B C )

( RA C )

244

2.3 B i osafety L e v e l s . Cl assification and Re v i ew of Ex p e rime n t s

2 . 4 Large - Scale Uses of O rganisms C o n ta i n i n g

a n d Prod uction )

2.5 Construction

246

of B u i l d i n gs

2 44 Recombinant DNA Molecules ( Res e a rch

for Recombinant DNA Operations

248

2.6 P ro d uc t Approval and Production Facility 248 2 . 7 Sh i p me n t and T r an sp o rt o f Or ga n i sm s Con t a i n i n g rONA M a t e r i a l s 2.8 Field Test ing of Recombinant Organisms

and NIH

250

249

240

8

Regulations for Recombinant DNA Research, Product Development and Production

3 Japan 253 3.1 Introduction 253 3.2 Recombinant DNA Technology in Research, Product Development and Production 255 3.2.1 Containment Categories, Classification and Assessment of Experiments 256 3.2.2 Construction of Facilities for Research (STA and MHW Guidelines) 259 3.2.3 Construction of Facilities for Production (MHW and MITI Guidelines) 259 3.2.4 Field Trials (MAFF Guidelines) 260 4 European Union 264 4.1 Directive 90/219/EEC on the "Contained Use of Genetically Modified Microorganisms" 266 4. 1 . 1 Scope of the Directive 266 4.1.2 Classification of Microorganisms and Operations 267 4. 1 .3 Procedures and Duration of Obtaining a Permit 267 4.2 Directive 90/220 EEC on the "Deliberate Release into the Environment of Genetically Modified Organisms" 269 4.2. 1 Procedures and Duration of Obtaining a Permit for the 'Deliberate Release ' of GMOs 269 4.2.2 Procedure and Duration of 'Placing on the Market' of Products Containing or Consisting of GMOs 270 4.3 Directive 90/679/EEC on the "Protection of Workers from Risks Related to Exposure to Biological Agents at Work" 271 5 Concluding Remarks 271 6 References 276 ·

I Introduction

1 Introduction Th i s

ch apte r

compares

reg ul ation s of re­

ope ra t i ons i n re­ p rod uct development and prod u ct ion of th e United States of America and of J a p an with t h ose of t h e E u r ope a n U nion. The Euro­ pean regulations are enacted in two rONA­ spe c i fi c EC Council D ire ct i ve s. 90/2 1 9/EEC and 90/220/E EC ( E E C . 1 990a . b ) . The de­ sc r i p t i o n of the U S a n d Ja pan e s e r e gul a ti o n s are base d on t h e respective g u i d e l ines , i n t e r vie w s a n d mat e ri al p r o vid e d by v ar io u s insti­ tutions such as u n i v ers i ti e s . government agen­ cies and i n d ust ry . The obj e ct i ve of this report is to p o i n t to the differe nces in re g u l a tion s for recombinant D N A ( rONA ) o pe r a t ions with respect to research. large-scale research. d e­ v e l op m e n t . p rod u ct ion and to t he deliberate release of re co m b i n a nt organisms. Proce­ dures for the approval of products and l ic ens ­ ing ( e . g . . fo r drugs. d i ag n os tic s . foo d s an d seed s ) are not considere d . T h e United States did not adopt any specif­ ic l eg i sl atio n to r e g u late genetically modified o r ga n i s m s ( G M O ) or t h e i r prod uct s . The ha n dli n g o f G M Os is cont rol l e d by guidelines issued by the N ational Institutes of Health ( N I H ) w h i c h have be e n continuously ad­ juste d to scienti fic exp er ie nc e and progress. The government p o l i c y to s u p e rv i s e rONA activities and t h e i r prod u ct s applies existing l e gis la t i o n t h r o ugh three government agen­ cies: the Food a n d D r u g Admin istration (FDA ) . the A nimal and Plant Health I n s p ec­ tion Service (APH I S ) of the U S Department o f Agriculture ( C SD A ) a n d t h e E n v ir o n me n ­ tal Protection Age n cy ( EPA ) . I n recent meas­ ures to furt h e r simplify the a pp l ica tio n of bio­ technology. t h e US government has d eci ded to a dh e re to a r i s k- ba s ed a p p r o a ch to guide review . This risk-based a pp ro a c h o f re g ul a to­ ry con t r ol i s scie n t i fica l l y sound an d pro pe r ly protects p u b l i c health and the e n v iro n m e n t a ga i n s t p o t e n t i a l h azards. and moreover. it avoids obstruc t i n g safe in n ov atio n s . Japan has extensive e x pe r i en ce in handl i n g micr o or g a n is m s i n biotechnological proce­ d u re s a s w e l l as i n m o n i tor i n g biot e ch n o logi­ c al production processe s. In th i s conte xt, the long-standing p r actic e has proven the value of combinant DNA ( r ON A ) search.

­

241

e m p loy i ng flexib le gui del ines i nstead of ri g i d l aws w h i ch - as a rule - are difficult to adapt to scientific progress. Japan has developed a review sy st e m for recombinant DNA technol­ ogy w h i c h can be eas i l y h andled and which is h ighly flex i b le. I t i s based on guideli ne s and has been si m pli fie d d u r in g the past years. Ja­ pan very c l o s e ly follows th e OECD recom­ m e n da t i on s. The OECD emp h as i ze d as early as 1 986 . on the basis of worldwide e x p e ri e nce . that novel risks are not i n vo l ved in experi­ ments a n d op e r at i o n s with ge netically modif­ ied organisms. D ep e nding on the na t u r e of t he recombinant DNA experimentation a n d the p r ope rties of the product. a v a ri e ty of g u i d e l i ne s issued by different ministries are to be considered. In the core areas - i.e., with r e ga rd to c las s ifi c a tio n and e va l u a tion of re­ combinant DNA o p e r a t ion s. as well as to the r esu ltin g conta inment leve l s - the diffe r ent guidelines are i de ntica l . De s pite the worldwide sa fe t y record of re­ c o mb i nant DNA t e ch n o lo gy , i.e., no rONA­ s pe c i fi c accidents have been rep or te d al­ though many t h ous a nd s of experiments have be e n carried out in thousands of l abor a t o ries and p ro d u ct i on p l a n t s , the Eu ropean Unio n ( E U ) has chosen a technology-specific ap­ pr oa c h for the regulation of recombi nant DNA t e c h n ol o gy . In co ntr a s t to the U nited States and Japan. it i s not the product and its application . that is primarily reg a r de d as a risk. but the methods by which p ro ducts are derived. This legal approach i s t e ch ni cally de­ s c r ibe d as "horizontal " as opposed to a "ver­ t ical ' ' . pro duc t -oriented re g u lato ry system. This leads to an o v e r l ap of s ev eral a pp r ov a l procedures for any biotechnological p r o d u ct; it is t i m e - co n s um i n g and expensive and hampe rs Eu rope a n competitiveness. The Eu­ ro pea n regulations a r e also extremely un­ usual i n that they a re de s igne d to re g u l a te i m a gin e d rather tha n real risks. At the time o f generat i on of th e r es p e ctive EC C ou n c i l Di­ rectives in 1 98 7 . the responsibility for the reg­ ulation o f b i ote ch no l o gy shifted from the ex­ perienced Di rec t o r at e General XII (Re­ search) and D ir e c tora t e General I I I (Econo­ my and Dr u g Approva l ) to the D i rectorat e General XI (Environment). In E u ro p e , the Directives disregarded the int e rn at i o n a l e x­ pe r i e nc e which h a d led 1 986 to the statement

242

8 Regulations for Recombinant DNA Research, Product Development and Production

of the OECD that "it is expected that any risk associated with the application of rONA or­ ganisms may be assessed in generally the same way as those with non-rONA modified organisms." In Europe, universities, research institutions as well as industry repeatedly ar­ gued in vain that there is no scientific evi­ dence that recombinant DNA technology would pose unique risks to human health or to the environment.

2 USA Biotechnology consists o f a set o f different processes and methods of which the most powerful tool is gene technology. The pro­ duction of organisms with new molecular techniques may or may not pose risks, de­ pending on the characteristics of the modified organism and the type of application. The Na­ tional Research Council (NRC, 1 989; OSTP, 1992a) has extensively reviewed the potential risks of introducing genetically modified or­ ganisms into the environment. The Council reached the general conclusion that organ­ isms, that have been genetically modified, are not per se of inherently greater risk than un­ modified organisms. In August 1 990, President BusH approved 'Four Principles of Regulatory Review for Biotechnology' (OSTP, 1 992b) which can be applied as general rule of regulatory review, as follows: 1. Federal government regulatory oversight

should focus on the characteristics and risks of the biotechnology product - not the process by which it is created. 2. For biotechnology products that require review, regulatory review should be de­ signed to minimize regulatory burden while assuring protection of public health and welfare. 3. Regulatory programs should be designed to accommodate the rapid advances in bio­ technology. Performance-based standards are , therefore, generally preferred over de­ sign standards.

A "performance-based standard" sets the ends or goals to be achieved, rather than specifying the means to achieve it, e.g., through a design standard. For example, a performance-based standard for contain­ ment would permit alternative biological approaches for assuring containment in place of a design-based standard requiring specific physical barriers. 4. In order to create opportunities for the ap­ plication of innovative new biotechnology products, all regulations in environmental and health areas - whether or not they ad­ dress biotechnology - should use perform­ ance standards rather than specifying rigid controls or specific designs for com­ pliance.

"Design-based" requirement may preclude use of biotechnology products even when such approaches may be less costly or more effective. For example, a require­ ment to employ specific pollution control equipment would prevent the use of inno­ vative biotechnology pollution remedia­ tion or control techniques. The new administration is continuing this policy. According to a policy statement by President CLINTON and Vice-President GoRE (1 993), "regulatory policy can have a signifi­ cant impact on the rate of technology devel­ opment in energy, biotechnology, pharmaceu­ ticals, telecommunications, and many other areas. " Therefore, the US regulatory policy will be reviewed in order to "ensure, that un­ necessary obstacles to technical innovation are removed and that priorities are attached to programs introducing technology to help reduce the cost of regulatory compliance. " 2 . 1 The NIH Guidelines

After the moratorium of Asilomar in 1 975, the "Guidelines for Research Involving Re­ combinant DNA Molecules" were promul­ gated by the National Institutes of Health (NIH) in June 1 976. These guidelines were revised several times whereby some relaxa­ tion of primarily restrictive provisions were achieved according to the state of science and

2

technology. The latest complete version of the NIH Guidelines was published on May 7 . 1 986 (NIH, 1 986a). On J uly 1 8, 1 99 1 t h e ap­ pendix K of the NIH Guidelines was intro­ duced addressing " Physical Containment for Large-Scale Uses of O rgan i sms Containing Recombinant DNA Molecules'' (N I H . 1 99 1 ) . Based o n the Biological Control Act ( 1 902), the original Food and Drugs Act ( 1 906) and the Federal Food, Drug and Cos­ metic A ct (F D CA) ( 1 938) , the Food and Drug Administration (FDA) is the regulatory agency which approves rO NA products. ex­ cept recombinant pesticides plants and ani­ mals. The NIH Guidelines apply to all rONA re­ search conducted at or sponsored by any in­ stitution recei v ing financial support from the Federal government. Alth o ugh the NIH Guidel ines are not binding for private compa­ nies, they have created a mechanism of com­ pliance for the private industrial sector. Fur­ thermore. indus try is required to comply with gener al safe ty standards issued by the Occu ­ pational Safety and Health A dministra tion (OSHA) of the US D epart me n t of Labor. Appendix K of the N IH Guidelines which concerns the large-scale use of rONA organ­ ism s is particularly relevant to the private sector (NIH, 1 99 1 ) . Some cities such as Cam­ bridge and Worcester, Massachusetts. and Berkeley, California, have introduced local ordinances that require universities and in­ dustry to ob s erve the N I H Guidelines. There is no evidence that private companies in the United States did not follow and comply wi th the NIH Guidelines.

USA

243

B. Experiments which require I B C approval before initiation of the experiment C. Ex perimen ts which require IBC notifica­ tion at the time of i nitiation of the experi­ ment D. Expe riments which are exempt from the procedure of the NIH Guidelines .

To determine the different types of rONA experiments with respect to safety classifica­ tion and safety measures, different commit­ tees, offices and serv ices are a s signed for re­ view.

.

,

2.2 Committees and Offices

Involved in Review Processes A ccording to the NIH Guide l ines rONA experiments are divided into four classes: ,

A . E xperime nts

w h i ch re q ui r e specific " Re­ combinant DNA A dviso ry Committee (RAC)" review and app ro val by the "In­ stitutional Bi osafety Committee (IBC)" and the Director, NIH. before initiation of the experi m e n t

2.2. 1 Director of the NIH,

Recombinant DNA Advisory Committee ( RAC ) and NIH Office of Recombinant DNA Activities ( ORDA ) U nder the N I H Guidelines, the D irector is the final decision maker. He can over­ rule the advice of the RAC, as was th e case with the first somatic gene the rapy expe ri ments. Every action t a k en by the Director must meet the goal of achieving "no signifi­ cant ris k to health or the environment" by any rONA experiment. The Recombinant DNA Advisory Com­ mittee ( RA C) advises the Directo r NIH, concerning rONA research and meets three to four times a year. The committee consists of 25 members appointed by the Secretary, Health and Human Serv ices including the chair. At least 14 members are selected from auth o ri ti es knowledgeable in the fields of mo­ lecular biology or rONA or other scientific fields. At least six members shall be knowl­ edgeable in applicable law, standards of pro­ fessional conduct, the environment, public and occupational health or related fields. Representatives of Federal agenci e s shall serve as non-voting members. The chairman can install subcommittees w ith additional ex­ perts in order to investigate issues further. RAC meetings, including the agenda, are an­ nounced in the Federal Register and are open to public comment. The meetings are open to the public. The specific funct i on s and opera,

NIH,

­

,

,

244

8 Regulations for Recombinant DNA Research, Product Development and

tion procedures of the RAC are defined in the NIH Guidelines. The Office of Recombinant DNA Activi­ ties (ORDA) serves as a focal point for infor­ mation on rDNA activities and provides ad­ vice to all within or outside NIH including scientific and industrial institutions, Biosafety Officers, Principal Investigators, Federal agencies, State and local governments and the private sector. In the case of experiments that require both IBC approval and RAC review, the IBC has to submit the necessary informa­ tion to the ORDA which decides, whether RAC review is to be initiated or not. ORDA is responsible for reviewing and approving IBC membership. The Federal Interagency Advisory Com­ mittee on Recombinant DNA Research (In­ teragency Committee) is composed of repre­ sentatives from approximately 20 agencies, provides additional oversight and coordinates all federal rDNA activities. Its members are non-voting members of the RAC.

2.2.2 Institutional Biosafety Committee

( IBC)

The IBC supervises all rDNA work of an individual institution that is involved in rDNA research, development or production and often also assumes the function as a gen­ eral safety committee including general occu­ pational safety and health, and environmental protection. The IBC shall comprise no fewer than five members, so selected that they col­ lectively have experience and expertise to as­ sess the safety of rDNA experiments and any potential risk to public health or the environ­ ment. Large organizations usually establish an IBC with more than five members. The biological safety officer (BSO) is mandatory when research is conducted at the Biosafety level 3 (BL3), Biosafety level 4 (BL4), and at all large-scale operations. The BSO serves as a member of the IBC. For institutions that have to comply with the NIH Guidelines, two members shall represent interests of the com­ munity with respect to health and protection of the environment and shall not be affiliated with the institution. At federally funded insti-

Production

tutions, these non-affiliated members are usually appointed by the local Board of Health. Commonly, private companies have established an IBC and usually appoint two additional members from the community or experts from other public non-affiliated or­ ganizations (e.g. , universities). In the few sites with specific city ordinances (i.e., Cambridge, Worcester, Berkeley) and/or State laws that regulate rDNA operation, private companies are obliged to establish an IBC as requested by the NIH Guidelines. Except for experiments which require re­ view by the Federal Recombinant DNA Ad­ visory Committee, only the IBC reviews and approves experiments or must be notified of rDNA projects. The IBC has the competence to deal with all safety issues under the NIH Guidelines. The IBC meets regularly and has to submit an annual report to ORDA con­ taining a list of the IBC members and back­ ground information of each member on the request of ORDA. The registration docu­ ments submitted to the IBC for review are, however, not communicated to ORDA and, thus, remain confidential. Upon request, only those documents on research projects must be released under the Freedom of Information Act which are submitted to or received from Federal funding agencies. On request of the applicant, data involving important intellec­ tual property rights or production know-how are kept confidential.

2.3 Biosafety Levels, Classification and Review of Experiments

The NIH Guidelines introduced four biosa­ fety levels (BL1-BL4) which consist of com­ binations of laboratory techniques and prac­ tices and safety equipment appropriate to the potential hazards derived from the organisms used. Based on the "Classification of Etiolog­ ical Agents on the Basis of Hazard" pub­ lished by the Center for Disease Control (CDC) in 1974, a list of classified microorgan­ isms is included in the NIH Guidelines. These organisms are divided into five classes where­ by non-pathogenic organisms are in Class 1 and pathogenic agents are in Classes 2, 3, and 4. Class 5 agents comprise disease agents

2 USA

which are forbidden entry into the US by law. by US Department of Agriculture policy or which may not be studied in the US except at specified facilities ( N I H Guidelines Appendix B-III - Classification of Microorganisms on the Basis of Hazard ) . e.g .. the WHO Collabo­ rating Center for Smallpox Research in At­ lanta. It must be emphasized that the N I H Guidelines are based on existing experie nce and established approaches to the contain­ ment of pathogenic organisms. In addition. two levels of biological containment were in­ troduced which limit the survival of a host­ vector system and its dissemination in the en­ vironment. Recombinant DNA experiments are classified into four categories initially as­ sessed, judged and based on the experience obtained with similar non-modified organ­ isms. Meanwhile. a substantial amount of ex­ perience with organisms containing rONA molecules has accumulated. In addition to the NIH Guidelines. the National Cancer I nsti­ tutes recommend three safety levels for re­ search with oncogenic viruses which corre­ spond to the categories B L2 . BL3 and B L4. A

Experime nts that require review of the Recombinant DNA Advisory Committee. approval hy the IBC and the Director . N I H . before initiation are: A-1 Deliberate formation of recombinant DNAs containing genes for the biosyn­ thesis of toxic molecules.

A-3 Deliberate transfer of a drug-resistance trait to microorganisms that are not known to acquire it naturally, if such ac­ quisition could compromise the use of the drug to control disease agents in hu­ man or veterinary medicine or agricul­ ture. A-4 Deliberate transfer of recombinant DNA or DNA or RNA derived from re­ combinant DNA into human subjects. The requirement for RAC review should not be considered to preempt any other review of experiments with human sub­ jects. I nstitutional Review Board (IRB) review of the proposal should be com­ pleted before submission to NIH. This approval procedure of the RAC thus applies only to new types and certain speci­ fied experiments, e.g., with highly toxic mole­ cules or the deliberate transfer of recombi­ nant molecules into h uman subj ects (e.g., so­ matic gene therapy). Such experiments may only be initiated after review by the RAC and approval of both the Director, NIH. and the I B C.

B

Le t h a l it y for ve rtebr a t e s a t an LD;o o f less 100 na n o g r a m s pe r ki logra m body weight. e . g .. microb i a l toxins such as the bot u­ l i n u m toxin. t e t a n u s t ox i n . Shigella dysenter­ iae ne urotox i n . Specific approval has b e e n g i v e n for t he c l o n i n g i n E. coli K 1 2 D N A s con taining ge nes coding for the biosynt hesis of t oxic molecules w h i c h a re lethal to verte­ brates at 1 00 n a nograms to 100 m i c rogr a m s p e r kilogram body weigh t . Con t a i n m e n t lev­ els for t hese e x perime nts are also sp e c i fi e d in Appendix F of t h e NIH Guidelines (NIH. than

1 986h ).

A-2

Deliberate release into the environment any orga nism containing recombinant DN A . except certain plants, as specified i n Appendix L of the N I H Guidelines

of

( N I H . 1 986b ) .

245

C

Experiments that require IBC approval before initiation For experiments that require IBC ap­ proval before initiation, a short registra­ tion document must be submitted to the IBC which contains a description of: (i) the source (s) of DNA (ii) the nature of the inserted DNA; (iii) the hosts and vectors to be used; (iv) w hether a delib­ erate attempt will be made to obtain ex­ pression of a gene, and what protein will be produced; and (v) the containment conditions specified in the NIH Guide­ lines. The I B C has to review and ap­ prove the proposal before the experi­ ment is initiated. Experiments which fall under this procedure can be carried out at B L2 , B L3 and B L4 containment. For work with Class 5 agents an additional permit must be obtai ned from the US Department of Agriculture (USDA). Experiments that require I B C notifica­ tion simultaneously with the initiation of experiments

246

D

8

Regulations for Recombinant DNA Research, Product Development and Production

A registration document containing the information listed under B must be sub­ mitted to the IBC, which in turn shall re­ view the proposal. However, review pri­ or to initiation is not needed. The ex­ periments which fall into this category can be carried out at containment level BLl and comprise those in which all components derive from non-pathogenic prokaryotes and non-pathogenic lower eukaryotes. Exempt experiments Certain rONA molecules are exempt from registration and approval by the IBC. Examples are listed in the NIH Guidelines, e.g., DNA molecules which consist entirely of DNA segments from different species that exchange DNA by known physiological processes or DNA from a prokaryotic host when propa­ gated only in the same host organism (self-cloning).

It is estimated that approximately 80% of experiments reviewed by the RAC are de­ voted to the application of rONA technology to humans, e.g., by gene transfer protocols and somatic gene therapy. More than 99% of the experiments are classified into categories B, C and D. While experiments falling into category C can be initiated at the time of fil­ ing the notification, experiments classified into category B usually can be initiated within a few days after filing the registration form to the IBC. IBCs from universities and private companies are not required to send copies of the registration documents to ORDA, thus rONA experiments classified into the catego­ ries B, C and D are not published, as is often assumed and incorrectly stated by European regulatory authorities and politicians. Experiments that require BL4 containment can be reviewed and approved by the IBC. Such experiments are - unique in the United States - prohibited by ordinance in the city of Cambridge, MA. It is probably noteworthy that the NIH Guidelines reflect the "state of the art" and can be rapidly adapted to scientific progress and are considered "never (to) be complete or final, since all conceivable experiments in­ volving recombinant DNA cannot be fore-

seen. Therefore, it is the responsibility of the institution and those associated with it to ad­ here to the intent of the NIH Guidelines as well as to their specifics".

2 . 4 Large-Scale Uses of Organisms Containing Recombinant D NA Molecules (Research and Production)

Appendix K of the NIH Guidelines (NIH, 1991) specifies physical containment guidance for large-scale research or production involv­ ing viable organisms containing DNA mole­ cules ( > 10 liters of culture fluid). This ap­ plies to both large-scale research and produc­ tion activities, and addresses potential haz­ ards that may be associated with rONA or­ ganisms. Other potential hazards accompany­ ing large-scale cultivation of genetically mod­ ified organisms such as toxic properties of the products, physical, mechanical or chemical as­ pects of downstream processing must be con­ sidered separately. For large-scale operations, the NIH Guidelines apply with the following minor additions: •

•

The institution shall appoint a Biologi­ cal Safety Officer (BSO) with duties specified in the NIH Guidelin es (sec­ tion IV-B-4). The institution shall establish and main­ tain a health surveillance program for personnel engaged in activities that re­ quire BL2 and BL3 containment.

For large-scale operations four physical containment levels are established which are referred to as Good Large Scale Practice {GLSP) , BLl -LS, BL2-LS and BL3-LS. No provisions are made for large-scale research or production requiring BL4 containment. If necessary, the requirements will be estab­ lished by the NIH on an individual basis. Depending on the containment level •

discharges containing viable recombi­ nant organisms may be handled accord­ ing to governmental environmental reg-

247

2 USA

Organizational and technical safety specifi­ cations are provided in the N I H Guidelines and are summarized in Ta b 1 . To qualify for GLSP, an organism must meet certain criteria such as non-pathogenici­ ty and built-in environmental limitations, and must have an extended history of safe large­ scale use (OECD, 1 986) . With respect to

ulations (GLSP) or need to be inacti­ vated by a validated inactivation proce ­ d u re (BL I -LS to BL3-LS). containment e q u ipment has t o reduce the potential for escape of viable or­ ganisms (BL I -LS) or to prevent the es­ cape of viable organisms ( B L2-LS and BU-LS).

•

.

Tab. 1. C.omparison of Te ch n ic a l and Organizational Measures of D i ffe re nt B iosafety Levels a t Large­ Scale Pract ices ( a dapted from NIH Guideline s • according to M E AGHER, 1 992)

Criterion

GLSP

B L l -LS

B L2-LS

B L3-LS

duce exposure to biological. chemical, or physical agents

•

•

•

•

clothing

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

Provide written i nst ruction and training of personnel to re ­ Provid e changing and h andwashing facili t ies and protec t ive Prohibit eati ng. drink ing. smoking, mouth pipet t i ng and ap­ plying cosmetics in the facility Develop e m e rgency pla ns for handling large spills Inactivate waste solut ions and m a terial in accordance with their biohazard pote n t i a l Use

a

validated prot ocol to ste r i l i ze closed vessels

•

Operate i n closed systems

Control aerosols by e ngineering or p roced u ral controls to prevent or minimize re lease of organisms during sampling, addition of materials. transfer of c u l tured cells, and remov ­

•

•

•

•

•

•

al of materials. products. and effluents from system to

•

•

Ensure med ica l surve i l l ance

•

•

Treat exhaust gases from a closed syste m c

Rotate seals and other penetrations into a closed syste m

•

•

desig ne d to prev e n t or m i n i m i ze leakage

•

•

tegrity of containment

•

•

Ensure permanent identification of closed systems

•

•

Incorporate monitoring or se nsing devices to mon i to r in­ Validate i ntegrity t e s t i ng of closed systems Post

a

•

universal biohazard sign on e ach closed syste m

Require controlled access t o facility ( double doo rs , a i r

•

• •

lock)

•

ensure in tegrity of con t a i n m e n t fe atures

•

and decontam i n a t i o n

•

Maintain closed syst e m at as low a pressure as possible to Design walls. cei l i ng. and floors to permit re ady cleaning

Protect u t il i t i e s and services against contamination

•

into the e nvi ron ment in the event of an accident

•

Design controlled area to precl ude release of culture fluid

d

Appe ndix K-1 - V, N I H G ui d e l ines ,

" In

,-

Fed. Reg.

56, 33. 1 78 ( 1 99 1 )

GLSP, m i n i m ize b y procedure ; i n B L l -LS, minimize b y engineering

In B L t - L S . m i n i m ize

248

8 Regulations for Recombinant DNA Research, Product Development and Production

practical applications of large-scale opera­ tions, this means that the construction of fa­ cilities is conducted according to the permit system outlined in Sect. 2.6 and that the IBC assesses the potential risks and determines the measures necessary to ensure occupation­ al and public safety. It is the IBC that deter­ mines the procedures to be followed in the case of an accident, e.g., containment and measures to handle a large spill. At the few city sites (Cambridge and Wor­ cester, Massachusetts) where local ordinances are in place, additional permits for rDNA large-scale operations must be obtained. The permit requires compliance with the NIH Guidelines and is issued commonly on an an­ nual basis and, usually, is renewed automati­ cally. In an amendment of the Municipal Code of the City of Cambridge such permits can since February 22, 1993 be obtained with­ out a public hearing.

2.5 Construction of Buildings for Recombinant DNA Operations

There are no regulations specific for this rDNA technology at Federal and State level with regard to construction of buildings, i.e., laboratories, pilot (up-scaling) and produc­ tion plants, to conduct research, product de­ velopment and production. In general, any building owner has to acquire a variety of permits from the competent State or city au­ thorities according to respective Federal and State laws and city ordinances. These permits include safety issues with regard to construc­ tion, fire prevention, electricity, waste and waste water management. At this level, there are no specific requirements for technical construction of laboratories or other facilities, e.g., specific containment requirements, equipment or even specific demands for the intended use of the building. It is, however, required that the characteristics and the ex­ pected amount of waste water are outlined in order to obtain the necessary permit for the connection to public waste water processing plants. A certified architect, the construction com­ pany and representatives of the owner submit

a construction plan of the building, and plans for technical installations, i.e., electricity, plumbing etc., to the competent city depart­ ment in order to obtain the permits. The building permit is usually granted within 1 to 3 weeks so that construction work can start immediately. For obtaining other permits at State or Federal level, e.g., FDA approval for experimental animal facilities, more time may be needed. However, these permits are usual­ ly obtained at the time when the construction work is concluded. Partial permits can be ob­ tained for construction work, electrical instal­ lations, plumbing, etc. This speeds up con­ struction work and helps to reduce costs. During the different stages of construction the progress of construction is supervised by inspectors from the respective State or city authorities. After completion of the building, the occupation and the use of the building is granted by issue of the "Certificate of Occu­ pancy". There are no differences in the administra­ tive approval procedures for setting up facili­ ties for chemical, bacteriological, immunolog­ ical or recombinant DNA operations, in al­ most all locations in the US. Cities like Cam­ bridge and Worcester (Massachusetts), and Berkeley (California), require an additional permit for working with recombinant DNA methods. The permits have to be obtained from the respective Boards of Health accord­ ing to local rDNA-specific ordinances. The ordinances obligate the applicant to meet the provisions of the NIH Guidelines on recombi­ nant DNA technology. This permit is closely linked with the operation and the obligations of the Institutional Biosafety Committee and is usually obtained within 30 days. It is valid for a whole building and is not temporally re­ stricted or restricted to certain specified rooms or floors. It may even be effective for a large organization such as a university.

2.6 Product Approval and Production Facility

In the United States, approval of products by the responsible agency (e.g., FDA, APHIS) is necessary for the marketing of

2

products and is based on s afety inves t igat i on s of t h e product. There is no permit r equired with regard to spe c ifi c demands for t he ap p l i­ cation of rONA methods. O n ly the general building pe r mits for t h e p ro d u c t i o n fa c i li t y are require d . It needs t o be e m p ha s i zed that the FDA is not involved at the stage of t h e construction of experi mental or large -scale produ c tion fa­ cilities. FDA in s p e c ts p rodu c tion faci l ities when products are to be approved for a P rod ­ uct License A pp l i c a t i on (PLA ) to p lac e a p rodu ct onto the market. e.g . . drug s . diagnos ­ tics, food additives and ce rtain foods. A t this stage, performance-based reg u l at i ons that are not s pe cifi c for the p rod u ction me thod. such as valid a t ion of downstream process i ng . good man ufacturi n g pr a c t ice fo r produc t i on of clin­ ical t rial s u pp lies , virus inactivation. and other rec omme n dations that may be laid down in a variety of " Points to consider . . . " . a re em ­ p loy ed . The s e inves t i gations and measures are based on a de c ision of the C o ngre ss t o prov ide FDA under the Food. D rug and Cos­ metic A ct (FDCA) with the authority n eces­ sary to regulate foods. d r ugs . diagno s t ic kits. addition, under the provisions of the Public Health Service Act . FDA also regu l ates and approves biological

devices a n d cosm etics. I n

products . Biological products for

use in humans are .

p rovisions of the FDCA and. thus. under t he responsibility of FDA's Center for Biolog i cs Evaluation and Research (CB E R ) . Biological dr u gs for ani­ mals are regu l at e d under the Virus. Serum and Toxin Act (VST A). T h e s e p rod u cts are therefore . subject to the

administered by the U S D e p artmen t of Agri­ culture and the FDA Center for Food S afe ty and requ i re reviews for food additives at the pre - ma r keting level . Genetically m o d ifie d crops. esp e c i al l y the e x pr e s s i on p roduct s of in trod uced genes are define d as an "additive " a n d . therefore . ne e d regulat i on . When a production faci lity is larger t h a n 2 1 0 000 sq . ft (ca. 1000 m ) . the gen e ral lice ns­ ing and ap p r ov a l r egulation s requ i r e that FDA considers t he gene r al e nvironmental i mpact of applications before taking any final action. F o r this. FDA demands the m anu fac ­ turer to sub m i t an Environme n tal Assess­ ment Certificate ( EAC) under the N at iona l

USA

249

Environmental Policy Act (NEP A) of 1 969 w h ich must include a descri p tion of the con­ tai n me n t p roce dures used to protect the workers. the environment and the p roduct , and the system used for solid. liquid and ga­ seous waste disposa l . This is a general re ­ q u irement for all p roduct io n facilities and is not s p e cifi c for pro d uctio ns us i ng G MOs. S imilarly , a p etit i on m ust be filed and a p ­ proved by USD A/APHIS p r i or to the mar­ ke t in g of recombinant crops which d emon ­ strates that the respective crop possesses p ro p er t ies that do not jeo p ardize the environ­ ment and can s afely be released and mar­ keted. A review of the procedures fo r produc t ap­ p roval is not w it h i n the scope of this chapter and will not be further di scussed .

2.7 Shipment and Transport of

Organisms Containing rDNA Materials The NIH Guidelines curre n tly r equire that molecules" shall not be transferred to other i n v e s t igators or i nstitutions unless their facili t ies and t e chn i ques have been assured to be adequate by their local IBC. To comply with this requirem e nt , the fol lowing proce­ dures must be followed: " rO N A

• Befo r e rece i v i ng rON A mater i als or other p otent i al l y hazardous agents, the i n vest i ga t or must have a pproval from the I B C that allows the use of the host­ vect or-dono r recombinant system in question unles s s uch s ys t ems are ex ­ em p t . • B ecause the labeling requirements for cargo tra n s p ort change frequ e ntly , the i n v esti gator should contact the IBC regular l y b e fore ship p ing p otent i ally hazardous and, therefore, regulated agents i nc l ud i ng r O N A m aterial . • When t r ans p orting rONA material lo­

cally, it must be packaged under the of the NIH Guidelines. Inte r s tate transport of recomb i nan t pla n ts , soil ba c teria , p lan t and animal p athoge n s requires a p erm i t issued by p rovis i on s

250

8 Regulations for Recombinant DNA Research, Product Development and Production

USDA/APHIS. Such a permit is usually obtained within 10 days and can also be used for multiple shipments. When plants or plant materials are shipped, they must be shipped in such a way that the viable plant material is unlikely to be disseminated while in transit and must be maintained at the destination faciFty in such a way that there is no release into the environment.

2.8 Field Testing of Recombinant Organisms

Field testing of recombinant organisms re­ quires the permission of the Animal and Plant Health Service (APHIS) of the US De­ partment of Agriculture (USDA) or the En­ vironmental Protection Agency (EPA) when recombinant microorganisms are to be re­ leased. The application for the field test must contain the data about the applicant, in the case of a foreign applicant also the US-based cooperator. APHIS works out a document in which risks are assessed and which serves as the basis for the permit. Permits for field trials are regularly published in the Federal Register. The published lists of permits con­ tain the registration number, the receiving date and the date of issue, the applicant, the recipient organism, the coding gene and the state of the release. APHIS also informs the state of the in­ tended field trial and coordinates possible modifications of the trial. In some states, e.g., North Carolina, that have further regulations on rDNA, a State permit is required. The State regulatory system must parallel the Fed­ eral regulations. In other states, a specific no­ tification is necessary (e.g., Wisconsin, Ha­ waii) and in Minnesota, West Virginia and Oklahoma the Federal permit is necessary to comply with State regulations. Plants that contain recombinant genes from the same species, in the sense of "self­ cloning", are not under regulation. However, a researcher informs APHIS through a letter that the intended release does not fall under the regulations, and APHIS returns a "letter of agreement" usually within 10 days. This is

a voluntary procedure that has become a common custom. New options for field trials with recombi­ nant crop plants were established by USDA/ APHIS (1993). These new provisions amend the existing regulations executed by APHIS through a notification procedure for the in­ troduction of certain plants and furthermore provides a petition process allowing the de­ termination that plants are no longer regul­ ated articles. The US Department of Agricul­ ture has, based upon experience, adjusted and supplemented its system for regulating the field testing of new plants, and thus en­ courages further progress and innovation in this area of new biotechnology (PAYNE, 1992). The new rules are based on the fact that the number of documented field trials with genetically engineered organisms approved by regulatory agencies of the US greatly ex­ ceed approvals of any other country and, par­ ticularly, that ample experience has accumu­ lated. The experience with field releases veri­ fies that these trials have proved to be safe and did not give rise to plant pests or environ­ mental risks. In particular, the data show that there are the same kinds of ecological con­ cerns with genetically engineered crops as are associated with other non-modified plants (i.e., weediness, competitiveness, toxicity) . Up to September 1 993, 465 permits for field trials on 1208 different sites had been issued. During the time period between March and September 1 993, when the notification proce­ dure was enacted, 105 notifications at 276 sites were received (MEDLEY, 1 993; Figs. 1 and 2). Comparable to the categories A-D defined by the NIH Guidelines, there are four different procedures for the use of recombi­ nant plants outside greenhouses regulated by USDA/APHIS: A.

Field tests which need a permit

To obtain a permit, the applicant has to comply with the user guides and in particular has to file the necessary forms and its appen­ dices (usually approximately 15 to 20 pages). APHIS assesses the environmental impact from the data obtained. The issue of a permit

2 USA

251

600 500 400 300 200 1 00 0

88

89

Fig. l. Release pe rm i t s and re lease sites in the US 1 988-1993 (Source : MEDLEY, 1 993).

90

CJ

91

92

F i s c a l Ye a r

Pe r m i t s

93

N o t i fc

- S i te s

Org a n i s m s re l e a s e d Corn To m a to S oy b e a n Po t a t o C o t to n To b a c c o M elon & Squash Rapeseed Al falfa Clavi bacter Rice Pseudomonas Cucumber Xanthamonas Wal n u t S u n f l ow e r L e t t uc e Apple Sugar beet Po p l a r A g ro s l l a a l u a t r l a Allegheny Sucberry Papaya Pea n u t Pet u n i a Plum Sorbua ap S q u a s h , M e l & Tm to TMV

� II

2&�2£ 41

27

0

20

72

120

.,

40

60

60

1 00

N o of p e r m i t s and n ot i f i c at i o n s fig. 2 . Number and kind o f crops released i n the U S 1 988- 1 993 (Source : MEDLEY, 1 993) .

1 20

1 40

252

8

Regulations for Recombinant DNA Research, Product Development and Production

is published in the Federal Register and infor­ mation on the permit must be released upon request under the Freedom of Information Act. If the necessary criteria are met by the applicant, the permit has to be issued within 1 20 days; the average time of approval is usually 90 days. Only North Carolina requires a separate permit by State law whereby no additional data are requested, but a public hearing may be carried out. Only if scientific questions are raised by the public, will a hear­ ing take place. To our knowledge, this has happened only two or three times. This law may, however, expire in September 1995. With the permit issued by APHIS, field trials can be conducted in all states of the U nited States. For field tests on more than 10 acres with transgenic plants expressing a pesticide phe­ notype (e.g. , BT cotton) , a voluntary experi­ mental use permit issued by the Environmen­ tal Protection Agency is recommended in ad­ dition to the APHIS permit. EPA is responsi­ ble for regulating the application of pesticides and for issuing permits for field trials with re­ combinant microorganisms (not vaccines). Regulatory procedures of EPA are not re­ viewed in this chapter. After the termination of a field test a "ter­ mination report" has to be filed with APHIS.

The notification 30 days prior to the field test must include the name, address, trade names of the plant, etc. and has to be filed with the Director, BBEP of APHIS. The reg­ ulated articles eligible for introduction into the environment under the notification proce­ dure must meet the following requirements and performance standards: 1.

2. 3.

4.

5.

Field tests which need only notification B.

This applies to formerly regulated articles for introduction under the notification proce­ dure without a permit. A regulated article is an organism that has been genetically engi­ neered - via recombinant DNA techniques ­ from a donor organism, recipient organism, vector or vector agent, any of which is a plant pest, or contains plant pest components. Oth­ er genetically engineered organisms may be regulated articles, if they have been genetical­ ly engineered using an unclassified organism or if the Director, Biotechnology, Biologics, and Environmental Protection (BBEP), de­ termines that the genetically engineered or­ ganism meets the definition of a regulated ar­ ticle because of plant pest potential.

6.

The regulated article is one of the fol­ lowing plant species: corn, cotton, pota­ to, soybean, tobacco, tomato and cer­ tain additional plant species to be de­ termined by the Director, BBEP. The introduced genetic material is sta­ bly integrated in the plant genome. The function of the introduced genetic material is known and its expression in the regulated article does not result in a plant disease. The introduced material does not (i) cause the production of an infectious entity, or (ii) encode substances that are known or likely to be toxic to non­ target organisms known or likely to feed or live on the plant species, or (iii) encode products intended for pharma­ ceutical use. To ensure that introduced genetic se­ quences do not pose a significant risk of the creation of any new plant virus, they must be (i) non-coding regulatory sequences of known function, (ii) sense or antisense genetic constructs derived from viral coat protein genes from plant viruses that are prevalent and en­ demic in the area where the introduc­ tion will occur and that infect plants of the same host species, or (iii) antisense genetic constructs from non-capsid viral genes from plant viruses that are pre­ valent and endemic in the area where the introduction will occur and that in­ fect plants of the same host species. The plant has not been modified to contain the following genetic material from animal or human pathogens: (i) any nucleic acid sequence derived from animal or human virus, or (ii) coding sequences whose products are known or likely causal agents of disease in an­ imals or humans.

3 Japan

C.

Field tests which are exempt

from regulations This applies to "self-cloning" of plant genes, but i t is recommended, and is a prac­ tised custom, to consult APHIS on a volunta­ ry basis. In such cases APHIS recognizes the "non-regulated" status in written form in a "letter of agreement" usually within ten days.

253

the relevant city and/or State officials before receiving the permit by APH IS. Only for first field tri als, the public is extensively informed by the applicants. Except for the first field testing of geneti­ cally engineered microorganisms (i.e. , "ice­ minus" Pseudomonas syringae in California) and unlike the responses from opponents of releases in the Netherlands and in Germany, no vandalism occurred at any of the sites where releases of GMOs were conducted.

D . Marketing of recombinant

plants For this purpose , a petition for determina­ tion of the non-regulated status for an article has to be filed with the D irector, BBEP. This petition can be filed already at early stages when the breeding program is started in ac­ cordance w ith procedures and formats speci­ fied. The required information comprises bio­ logical data of the narrowest taxonomic groupings applicable, experi mental data, de­ tails of the inserted genetic material and a de­ scription, why the article in question is unlike­ ly to pose a greater plant pest risk than the unmodified organism from which it was de­ rived. After the filling of a completed petition, APHIS published a notice in the Federal Reg­ ister allowing public comment within a 60 day period and consults with other Federal agen­ cies. Within 1 80 days after receiving the peti­ tion, the Director, B B EP , furnishes either an approval or a denial in written form. The first petition granted concerned the "Flavr Savr TM , tomato developed by Calgene Inc. , California. APHIS assures that State authorities are kept informed about pending applications which may involve the field testing and/or in­ troduction of genetically engineered plants within the State by using the existing working relationship with the Department of Agricul­ ture of the State. The provision for notifica­ tion by APHIS of the State officials is written into USDA's regulation. Companies applying for . field testin g of ge­ netically engineered organisms usually inform

3 J apan 3 . 1 Introduction

Japan regulates recombinant DNA tech­ nology ( r DN A ) by a variety of guidelines which places the properties of genetically modified organisms (GMO} to the fore (Fig. 3 } and follows very closely the OECD recom­ mendations (OECD, 1 986} and the N IH Guidelines. The OECD recommendations state that "there is no scientific basis for spe­ cific regulation of the use of recombinant DN A organisms " . Apart from the Ministry of the Environment, all the ministries involved have enacted guidelines to supervise recombi­ nant DNA operations: 1.

Science and Technology Agency (ST A ) : Guideline for rDNA Experi­ ments (first version 1 979) 2. Ministry of Education ( MoEd}: Guide­ line for rDNA Experiments in U niver­ sities and other related Research Insti­ tutes (first version 1 979) 3 . Ministry of International Trade and In­ dustry (MITT): Guideline for Industrial Application of rONA Technology ( firs t version 1 986} 4. Ministry of Health and Welfare (MHW}: Guideline for Manufacturing D rugs etc. by Application of rDNA Technology (first version 1 986} 5. Ministry of Health and Welfare: Guide­ line for manufacturing Foods and Food Additives by application of rDNA

8 Regulations for Recombinant DNA Research, Product D evelopment and Production

254

E X P E R I M EN TA L : SCIENCE & TECHNOL AGENCY

M I N I STRY OF E D U C AT I O N

UNIVERSITI E S

M I C R O - R G AN I SM S

I

]\_

P R I V A T E A N D N AT I O N A L R E S EA R C H I N S T I T U T I O N S P LANT C E L L S

I

I I

I I

P LA N T S

L A RG E - S C A L E F E RM E NTATI O N

INDUSTRI A L :

M I C RO - O RGAN I SMS C L O S E D P RO D U C T I O N P R O C E S S P HARMAC EUTI CALS , COSMETI C S ,

Foo o

E N Z YM E S FINE CHEMCALS

PESTICI DES , F E RT I L I Z E R S FEED ADDITIVES ,

CONTROLLED MOD E L ENV I RO N M E N T

I

I

O P EN EN V I RONMENT

ANIMAL D RUGS

t

I

M I N I S TRY O F l N T E R N ' L TRAD E & I N D USTRY

MI N I STRY O F H EA LT H

t

t

I

t

M I N I STRY O F A G R I C U L TU R E , F O R E S T R Y & F I S H E RY

Fig. 3 . Framework o f

ENVI RONMENTAL AGENCY

Techniques (first version 1 99 1 ) Ministry of Health and Welfare: Guide­ line for Safety Assessment of Foods and Food Additives produced by rDNA Techniques (first version 1 991 ) 7. Ministry of Health and Welfare and Ministry of Education: J apanese Guide­ lines for Gene Therapy Clinical Re­ search (first version February 1 994) 8. Ministry of Agriculture, Forestry and Fisheries (MAFF) : Guideline for Appli­ cation of rDNA organisms i n Agricul­ ture, Forestry, Fisheries and other re­ lated Industries (first version 1 989).

6.

Product authorizations are effected i n ac­ cordance with the relevant guidelines of the

guideli n es for re gulation of recombinant DNA

technology i n Japa n .

responsible mm1stries. The different guide­ lines contain identical criteria for classifying genetically modified organisms and for con­ tainment conditions, and have been revised and continuously simplified since their intro­ duction. In 1 990, the Ministry of the Environ­ ment (MoE) proposed legislation for regulat­ ing field trials with GMO. This suggestion was, however, not pursued as a result of the negative responses of other ministries, univer­ sities (Tab. 2), the Japan Health Foundation and the Federation of Economic Organiza­ tions (Keidandren). At present, the Ministry of the Environment considers to issue a guideline for the use of recombinant organ­ isms in 'bioremediation' , 'leaching' or 'bio­ mining'. The policy of the Japanese govern-

3 Japan

Appeal of 45 Professors Regarding Safety rONA Technology (September 1 990, Science Council of JBA )

Tab. 2.

of

1. rONA technology was developed in 1 974 and is presently an essential technology for health, food and environment. 2. During the past 16 years, a lot of scientific knowledge has been accumulated, where no risk was observed. 3. Scientists have come to common agreement that "there is no particular risk in rONA tech­ nology". 4. The Guideline of NIH as well as other coun­ tries has been relaxed greatly as a result of confirmation of the safety of the technology. 5. In Japan, scientists followed the guidelines of the Japanese government and more than 30 000 experiments were carried out. Not even the smallest risk was observed. 6. The initial guidelines of the Japanese govern­ ment for rONA experiments and industrial ap­ plication were relaxed. Moreover, we request further relaxation of the guidelines and the is­ suance of guidelines for large-scale experi­ ments. 7. In Japan there are moves to submit a "genetic engineering bill" to the diet. We are very con­ cerned that the movement might be based not only on the scientific knowledge accumulated for the past 16 years but also on the product basis and might adversely affect the develop­ ment of rONA technology.

ment towards biotechnology and recombinant DNA technology has been outlined in an "Environment White Paper" (MINISTRY OF THE ENVIRONMENT, 1 991 ). This document clearly states that there are no particular envi­ ronmental risks associated with the develop­ ment and exploitation of biotechnology and recombinant DNA technology. As an interesting fact and unlike customs in other countries, it is necessary to obtain consensus with all parties concerned before legislation may be enacted; decisions based on a majority are evidently not sufficient in Japan. The achievement of a consensus is usually more time-consuming than attaining decisions in the US or in Europe. Decisions that are supported by all participants are usually funded on higher investment levels and are difficult to be overruled by changing

255

majorities. This may also explain that the Ja­ pan Bioindustry Association (JBA), sup­ ported by MITI and about 200 enterprises, started a rather costly nation-wide 1 0-year program to achieve understanding and ac­ ceptance of the use of biotechnology and re­ combinant DNA technology on a broad scale in 1991 . At the end of 1 992, the Japanese market for products produced by recombinant DNA technology amounted to over 5 billion DM. By the end of 1990, 76 products from 31 com­ panies had been approved under the jurisdic­ tion of the Ministry of Health and Welfare. Of these, 72 obtained "Good Industrial Large Scale Practice (GILSP)" status, and the re­ mainder were classified as containment level 1. At present, more than 60 recombinant pharmaceuticals are in clinical trials, and in 1 993 about 40 different products were at the stage of approval (Tab. 3). As in the USA, re­ search and development in Japan is carried out in numerous areas of business including many small enterprises. At present, there is a lack of experience in Japan with regard to field trials of recombi­ nant organisms. To date, only one field trial has been carried out with a TMV -resistant to­ mato variety. However, four further permits for field trials for rice, melon and petunia were granted in February 1993, and about �0 further projects have by now reached the stage of experiments in "open" greenhouses. Japan strictly follows the OECD recommen­ dations and strives to reach the same high lev­ el in field trials as the United States.

3.2 Recombinant DNA Technology in Research, Product Development and Production In contrast to the USA and European states, different State authorities are responsi­ ble for research in Japan: the Science and Technology Agency (STA) for application­ oriented research, and the Ministry of Educa­ tion for research at universities. About 67% of rONA research is carried out by the indus­ try, approximately 18% at universities · and 13% in independent research institutions.

256

8

Regulations for Recombinant

DNA

Research. Product

Tab. 3. A c t u a l Cases of I n d us t r i a l izat ion of rONA Technology

1 . I ndustrial Application M i nistry

P rodu c t

M i n i s t r y of International T r a d e and Industry

Chemical

(Tot a l

and Experimental Applications (as of Se p t e m b e r 1991) Cases 110

agents

62

15

A m i no acids

Others

M inis t ry of H e a l t h and W e l fare

3

D i a gn osis . observation

(Total 80)

Agric u l t u re . F o re s t r y a n d

and Production

Enzvmes

1 90)

Minist ry of (Total 5 )

Development

25 47

Medical t rea t m e n t F i sh e r y

V acc i ne

8

Amino acids

3 1

Medical treatment

A pp l i c a t i o n in the simulated mode l environme nt

2 . Experimental A pplicat ion Ministry and Age n c y

Science and Tech nology Agency

M i n istry of Educa t i on

1 275

Total

(as of

M a rch

1 442

Outside the st a n d a rd " Within t h e stan d a rd h O utside the standard" W it h i n the standard b

1990) Cases 10 526

about

2 000 21 06 1

" Cases for which individual examination is necessarv h Cases for w h i c h the standard is stipulated i n t he g u i deli n e

The Science and Technology Agency (Tab. 4), which acts under the responsibility of the Prime Minister, plays a special role in coordi­ nating and supporting science and technolo­ gy .

T h e s h a r e of the Science and Technology Agency of t h e budget of '" Science and Tech­ nology by Ministries and Agencies" which amounted to about 33 billion OM in 1 992 . is correspondingly high ( see Tab. 5). The tasks and the importance of the Science and Technology Agency must princi­ p ally be assessed in association with the com­ plementing tasks of M ITI. and with the coor­ dination of activities of these two governmen­ tal institutions. The guideli nes of the Science and Technol­ ogy Agency and the Ministry of Education are exclusively used for work with recombi­ nant microorganisms. plants and animals in laboratories or closed greenhouses in re­ search and development. The guidelines of M ITL MAFF and MHW are used for com­ mercial work and for field trials.

Containment Categories, Classification and Assessment of Experiments

3.2.1

The Science and Technology Agency's '"Guidelines for Recombinant DNA Experi­ ments" were enacted by the Prime Minister on August 27, 1 979 and have been simplified nine times since then. The core of the guide­ lines is the differentiation of recombinant DNA work into "standard experiments" and '"non-standard experiments". A standard ex­ periment includes experiments w ith volumes up to 20 liters in the containment levels P l to P4. Large-scale experiments in the contain­ ment levels LS-C, LS-1 and LS-2 are non­ standard experiments (Tab. 6). It is intended to give up the differentiation of rONA work by volume at the text guideline update. In ad­ dition. biological safety measures B 1 and B2 have been defined (Tab. 7 ) . For categorizing rONA operations, the organisms a r e listed into four risk categories, and the resulting

3 Tab. 4.

The Role of the Science and Technology Agency (STA)

Examples of Main Activities

1 . Exploratory Research for Advanced Technolo­

gy - Precursory research for embryonic science and technology system - Frontier research program - Development of new technology transfer 2. Promotion of Science and Technology Aiming at More Affluent Life Styles - Promotion of human genome analysis - Solution of problems closely related to living 3. Playing Active Roles in International Society through Science and Technology - The human frontier science program - International thermonuclear experimental reactor project - Space station program 4. Promotion of Science and Technology Admin­ istration - Planning and formulation of science and technology policy - Overall coordination functions in science and technology administration - Promoting science and technology policy re­ search 5. Promoting Research and Development in Ad­ vanced Fields of Science and Technology - Nuclear energy, nuclear safety - Ocean development, aeronautical technology - Earth science and technology - Disaster prevention - Materials science and technology - Life sciences Functions of the STA

Operation/Coordinating/Monitoring of: Science and Technology Policy Bureau Science and Technology Promotion Bureau Research and Development Bureau Atomic Bureau, Nuclear Safety Bureau Advisory bodies Institutes Public corporations Research and development activities in major countries Administrative structure and technology in Japan

containment levels are described in detail in the guidelines. The guidelines describe the criteria which define the classification of a "non-standard" experiment:

•

• •

•

•

Japan

257

Work with non-characterized microor­ ganisms, if their non-pathogenicity has not yet been proven, work with genes which code for pro­ teins that are toxic for vertebrates, work with host organisms or vectors and certain work with DNA sequences which correspond to Risk groups 3 and 4 or DNA sequences from these organ­ isms (described in appendices 1-(1 ) , 2(4) and 3-(4) of the guidelines), field trials, large-scale experiments which corre­ spond to biosafety levels P3 or P4 and which do not satisfy certain criteria de­ fined by the guidelines. The preparation of characterized proteins having "useful functions", coded for by host-vector systems d e ­ fined in the STA guidelines corre­ sponding to a containment level of Pl or P2, is categorized as a "standard ex­ periment" and, thus, does not require any further approval by the Science and Technology Agency.

All other operations are classified as "standard experiments". Comparable with the mode of operation of the "Institutional Biosafety Committees" in the USA, "stand­ ard experiments" in Japan either are commu­ nicated to the Biosafety Committee of the in­ stitution by the scientist at the beginning of the project or may be started only after ap­ proval by this Biosafety Committee of the re­ spective institution. "Non-standard experi­ ments" can be started after the approval of both, the research institution and the Science and Technology Agency (Fig. 4) . Prior to ap­ proval, the Science and Technology Agency arranges a review by the "Recombinant DNA Advisory Committee" in the "Council for Science and Technology". This committee consists of 14 scientists and meets at intervals of six weeks. The containment criteria summarized in Tabs. 8 and 9 permit the categorization of the above-described experiments (notification or approval for Pl, P2, P3 level and non-stand­ ard experiments) with microorganisms or mammalian cells for laboratory and large­ scale work. The containment conditions for

8

258

Regulations for Recombinant DNA Research, Product Development and Production

Tab. 5. S h are

of

the B u dge t of Science and Technology by Ministers and Agencies Budget

Authorities

46.5

Mi n i s t ry of Education

25.8 12.1 5.9

Science and Technology Age ncy Mi n is try of International Trade and I n d u st r y

Defense Agency

M i n is t ry of Agricultun:, Forestry and Fisheries Mi n is t ry of H e alt h and Welfare Ministry

Others

of Post

Share ( % )

3.6

2.9 1 .5

and Te lecom m u n ication

1.7

100.0

Tab. 6. Levels of Physical C on t a i nme n t i n Large -Scale Fe rme ntation Mechanisms of Exh a ust from Fe rment-

Fermen t e rs

Struct u re

e rs

Accommodation of Installation for Tre atment of R e comb i nant O rg an is m s (Centrifuge etc . )

LS-C

Faci lity havi n g we ll -

Designed to minimize

Well-maintained

m a i nt ai ne d la rge - sca le

release of recombi-

fe rme nters or e q u i v a l -

nant o rg an i sms

ent faci l i ties

LS- 1

We l l - e q u ippe d expe ri m e n ta l fa c i lit i es u s i n g

various tightly con-

t a i ning apparatuses

such as la rge -s cale ferme n t e rs LS - 2

The same

as

a bo v e

None

Designed to prevent

Steri lizing filter or

S afe t y cabinet or equi-

release of recombin a n t orga n i s m s and to

o the r st eri lizin g m e an s

valent means

Microbe -removing p e rfo r m a n ce better or

Class-II safety cabinet or equivalent means

facilitate i nte rio r s te r il ization without ope ni ng the vessel The same as above. and especially parts subjected to direct contact with fermen t er. s u c h as revolving

seal or t ubi ngs. must

be designed with adeq uate precaution to prevent leaks of recombinant orga nis m s

recombinant DNA work with viruses are re­ corded in Tab . 10. Similar tables for projects with animals. plants and parasites are also part of the guidelines. The operator who is re­ sponsible for installations and work subject of the Science and Technology Agency guide­ li nes reports to the Science and Technology Agency annually on all R & D work. These re ports are kept confidential by the Science

eq u iv a l e n t to HEPA fi l te r , or other s ter i l i z ing means

Means to monitor air-tightness of the appara-

t u s d u r i ng l a rge - sc a l e culture experiments

and Technology Agency and are not available

for inspection by third parties.

In practice, the Japanese guideline system ensures that the research and development projects can either be started immediately or within a few days or, if the Science and Tech­ nology Agency has to review a project, within a few weeks after notification.

3 Tab. 7. B l and B2 Le v e l Host-Vector Sys te m s 81 Lel'el Host-Vector System

-

a. EK1 . The h o s t v e c tor system composed of Esche­

richia coli K 1 2 strain. wh i ch is ge netically and physiologically well understood . n ontoxic. and poorly viable under natural conditions, and its i nduced strain as host. and plasmid or bacterio­ p ha ge as vector that are i nconj uga t a b l e and not transfe rable to other hacte ria. The host must not have conj ugatable plasmids or conventionally i n ­ t r o du ce d hacteriophages

b. SC l . The host-ve ctor system composed of a lab­

c.

oratory-maintained s t r a i n of yeast . Saccharo­ myces cerevisiae. as host , and pla s m i d or mini­ c hro m os o m e as v ec t or

BS l . The host-vector system compose d of an in­ duced s t r a i n of Bacillus .subtilis M a rburg 1 68 w h i c h has m u t a t i o n of multinut ritional require­ ment for ami n o acids or nucleic acid bases as host, and pl a smi d or bacte riophage that is i ncon­ jugatable and not transferable to other bacteria

d. The host-vector

s y s t e m composed of animal or plant cells (excluding those for diffe re n tiation ) as host ( e x c l u d i ng those cases to p rod uc e infec­ tious viruses)

82 Level Host-Vector System

a. EK2. Those s y s t e m s belonging to EK l , and co m posed of a ge n e t ic a lly defective host , which h as very low via bi l i t y except under s p e c ia l i ncu­ bating con d i t i o n s and a highly host-depende nt vector. which has ve ry low transferability to oth­ er cells. The system must have a survival ratio for recombinant cells of 10 parts per billion aft e r 2 4 h of incubation except for spe c i a l conditions.

3.2.2 Construction of Facilities for

Research (STA and MHW Guidelines )

As in the U S A . building permits for facili­ ties to carry out general research including re­ combinant D N A experiments are issued by local governments. These permits are based on the " Construction Standard Law" . Within the scope of the authorization process, the general and local regulations are taken into consideration, and competent authorities are involved. e.g .. e nvironmental, health and wa­ ter authorities. The owner is obliged to post a sign at the building site outlining and de-

Japan

259

scribing the construction plans and, if appro­ priate. the construction authority can order a local hearing for the installation which to date has rarely occurred. Close cooperation be­ tween the central and prefectural authorities is traditional in Japan. Documents relating to the authorization procedure are forwarded to the responsible ministry (Science and Tech­ nology Agency, M ITI or MHW) on a volun­ tary basis for inspection and examination, e.g. , of the con tainment level and safety measures. The central authority notifies the local authority promptly of its position, so that construction permits for rONA research facilities can be, as a rule, obtained within 3-4 weeks. Since this procedure has proven to func­ tion well, 45 of the 47 prefectures have de­ cided not to introduce any provisions for au­ thorizing facilities to carry out recombinant DNA technology. Exceptions are the prefec­ tures of Aichi (since June 1 , 1 990) and Kana­ gawa (since September 1, 1 993) in which rONA operation permits are required for rONA production facilities. However, these are not required if the internal Safety Com­ mittee or the Science and Technology Agency approval procedures are applied.

3.2.3 Construction of Facilities for

Production (MHW and Guidelines )

MITI

The administrative procedure for the in­ stallation of production facilities is similar to that of installing research and experimental facilities by local building permits. The com­ petent ministries are responsible for licensing products, using the respective guidelines (Fig. 3): MHW for recombinant pharmaceuticals and foodstuff additives by consulting the "Pharmaceutical Affairs B ureau" or the "Food and Sanitation Investigation Coun cil". Other industrial products are subject to MITI guidelines. Since there are not yet any mar­ ketable products of recombinant organisms, i.e foods such as the "Flavr Savr ™ " tomato in the USA, the implementation of respective guidelines has not been considered to be nec­ essary. .•

260

8 Regulations for Recombinant DNA Research, Product Development and Production

Institutional Safety Committee

•

• • • • •

Heads < of < • • •

Institution

•

• •

•

• • •

•

Laboratory

• • •


2 Biotechnology in

:-! P r im e

�

�_j

Japan

379

,

--

Minister

�I I

ro-n

-

__

r C.�ounci l

j j1

Science a n d ••.•ec h no I ogy

L ____ . __ __j � -- -

Scien..:c and

1,.I !

Tech nology

-----1

' ·----------'

•

New Energy & I n d ustrial

,__

:

'

j

.--- ·

Development

i

M n i s t ry of · Post a nd Teleco mmu-

!---j

I

Organization

i

LJ i j ·

I'

IHl

i·

M inist rv of Agricu it u re . Forestry and Fishl:· r ie s

Institutes

I r ;

Center

Bio-re l a ted

1------1 Research

Advancement Institution

Health Science

l� ry �f

d

Counci l

Hea l t h a n d

A vers e Drug Relief &

! Welfare 1------1 Research : - - ---· ---- · ----J Promotion 1

Fund

, Scie nce a n d

__

lr-----l 1

_j

Fig. 2. St ructure of S&T in Japan. w i t h

Research Compan ies Research Projects

National Hospitals National Research C e n te rs Research Com p anies

Research

Science

un cil l _M_i_ni�t -f'i-.(�� I Co � Education.

l_Cull�r_e

Research Companies

Tsukuba Institutes

Research Council

'

Research Companies

Research Projects

Agncul t ural

_____, _-

Mi n

Tsukuba R e se arch

Japan KeyTec

nicatio n

I '--·------'

.

Frontier Research Programm

Scie nce and T e c h n o l ogy

Trad..: and l ndust ry

i

Japan

A gen cy of I n d u st r i a l

ci

of

I ntern ational

1

!

I n d u st r i al Technology Co un l

;

- -�

Minist ry

!

1�

R I KEN ERA TO Projects

f-------; Corporation of

' Agency

�:--

Research Deve lopment

i

e mp h a s s on

life sciences.

Proj ects

Universities Research Institutes Cooperative Research Centers

380

13

Biotechnology in the Asian-Pacific Region

Life Science-Related Budgets of Major Japanes Ministries, and Major Programs Relating to B iotechnology

Tab. 6.

Ministry or Agency

Budget, FY 1 993 (Billion Yen)

Science and Technology Agency (STA) Ministry of International Trade and Industry (MITI)

28.5

Ministry of Health and Welfare (MHW)

50.5

Ministry of Agriculture, Forestry and Fisheries (MAFF)

10.1

Ministry of Science and Education (Monbusho) Environmental Agency (EA)

20.7

Other ministries Total budget

8.4

2.0

Major Institutes Working on Biotechnology

Major Programs in Biotechnology

RIKEN (main institute and Tsukuba branch) National Institute of Bioscience and HumanTechnology National Institute for Advanced Interdisciplinary Science National Institute of Health National Institute of Hygienic Sciences National Cancer Center National Hospitals Food Research Institute National Institute of Agrobiological Resources National Institute of Agro-Environmental Sciences

Human genome analysis ERATO projects Frontier research programs Biochips, micromachine technology, glycotechnology, marine biotechnology, genome analysis, biological C02 fixation Bioremediation

National Universities, Cooperative Research Centers Environmental Research Institute

Genome projects relating to gerontology Anticancer project Gene therapy projects AIDS prevention Food safety Rice genome project Genome studies in agricultural animals Tissue culture for plant and tree propagation Embryo transfer project B iosensors for the food industry Genome projects Cancer-related projects Joint research with industry Environmental impact of biotechnology Release of recombinant organisms B ioremediation

0.5 1 20.8

Universities The Ministry of Science and Culture (Mon­ busho) is in charge of 97 national universities, with 78 attached research institutes. It also controls the curricula of the 41 1 private and public universities of Japan. Monbusho with­ out doubt is a strong player in Japanese S&T, but its simultaneous responsibility for the Ja­ panese school system, which in the opinion of

experts waits for urgent reforms, seems to re­ duce its manoeuvrability in science affairs. Thus, other ministries such as STA and MITI have taken on much of the initiative to im­ prove the conditions for basic research. Ex­ amples are: STA's "Frontier Research Pro­ gram" and ERATO projects; ST A's and MITI's "Human Frontier Science Program"; the foundation of a basic research-oriented MITI institute "National Institute for Ad-

2

vanced Interdisciplinary Science" in its re­ search complex in Tsukuba; and the defini­ tion of "Centers of Excellence" among na­ tional research centers. The number of scientists leaving their uni­ versity with a Ph.D. degree is small, in the or­ der of 20% . A science master course is com­ pleted, as a rule, at the age of 22, and most graduates at this age enter a company where they are further trained. In special cases, they later return to a university for a doctoral course, financed by their company, in order to learn special techniques and foster the company's relations to a university. The major national universities are those of Tokyo, Osaka, Kyoto and Fukuoka (Kyu­ shu), which contribute about 50% of all scien­ tific publications originating from Japan. However, biotechnology is a popular research target in many universities, and some have in­ troduced curricula specializing in biotech­ nology. Recently, 23 "Cooperative Research Centers" have been established throughout Japan, where cooperative projects with local industry are being carried out. However, the politically most important mission of academ­ ia in Japan is to provide advice to the govern­ ment, through the countless committees un­ der the "Science Council" (see Fig. 3). An­ other key function for information exchange resides in the learned societies, of which there are over 500 in the science field. The largest and most influential society for the biotech­ nologies is the "Japan Society for Bioscience, Biotechnology and Agrochemistry" (formerly "Society for Agricultural Chemistry"), with a membership of over 1 1 000 (655 member companies), but numerous others, e.g., the "Japanese Biochemical Society" (over 1 0 000 members), the "Society of Fermentation Technology" (2500 members), the "Protein Engineering Society" (500 members), contri­ bute to form consensus about the positioning of Japan in S&T. Associations, research associations and re­ search companies A unique feature of S&T in Japan is the importance of industrial research consortia. In fact, opinion polls among industry leaders

Biotechnology in Japan

381

repeatedly showed that the organization of collective development of enabling technolo­ gies was considered one of the pre-eminent responsibilites of the government - more im­ portant than even tax deductions. This atti­ tude contrasts sharply to the Western busi­ ness community where individual approaches to competitiveness are clearly favored. Associations. In the field of biotechnology, MITI, later also the MHW and MAFF, started to organize associations as early as 1 980. Their function is similar to the US lob­ bies. They become involved in initiating and harmonizing regulations and standards, pro­ viding training, disseminating information and acting on needs as diverse as organizing exhibitions at home and abroad, or enhancing public perception. The major biotechnology associations are indicated in Tab. 7. Research associations. The function of a re­ search association is to introduce or jointly develop new industrial methods through a temporary industrial consortium. As in 1 993 more than 100 research associations had been formed in Japan, it can thus be claimed that RAs have played an important role in gov­ ernment-organized technology changes. Es­ tablished by MITI in 1968, and emulated by other ministries later, these research consor­ tia have covered fields as diverse as improved jet engine construction, deep-sea manganese nodule mining, 5th generation computers or biosensors for the food industry. A selection of research associations important for the field of biotechnology and their industrial participants is summarized in Tab. 8. While these and other research associa­ tions generated a wealth of information, and certainly helped to rapidly disseminate new methods throughout the industrial research community, there were drawbacks such as the question of intellectual property rights (usual­ ly the rights belong to the government - thus JITA, the pertinent body of MITI, owns more than 20 000 patents). Recently, a new format of industrial R&D consortia was organized. Research companies. Organized again by the "guiding" ministry, but heavily co-fi­ nanced by a consortium of at least 3, some­ times over 100 firms, these companies are typically founded for a lifespan of 7 to 1 0

13

382

Biotechnology in the Asian-Pacific Region

Tab. 7. Major B i ot ech n o l o gy Associations in Japan A b bre v iatio n

N ame of A ssoc i a t ion

G ui di ng

Type of I n d ustry

Number of

Participating

Ministry

C omp a nie s

( for m e r ly

Association ( formerly

Heavy i n d ust ry ,

M ITI

JBA

Japan B ioindustry

about 230

chemicals.

fe rmentation, energy,

B IDE C )

pharmaceuticals

B ioechnology Develop m e n t Center) J ap a n Hea l t h Scie nce

JHSF

MHW

Socie ty

for

Tec h n o ­

I nnovation of

STAFF

M AFF

1 80

Ph armaceuticals, food

about

Food, agriculture,

about 1 60

Foundation fisheries

A gricult u r e , Forestrv

Fisheri e �

and

Tab. 8. Some Japanese Research Associations Relating to Biotechnology Name of Research

Main Target

Assoc i a tion ( RA )

Orga n izing

Number of

Ministry

Participating

Duration

Compan ies

Fi n a n c i a l Syste m RA for biotechnology

B io re acto r s .

1 980-90

MIT!

14

M ITI

21

1984--90

EA

13, p l us 7 foreign

1 990-99

large-scale cell

t e c h no l og y . gene tic

engineering F un ct i o n al

1 988-98

p ro t e in complexes Bioreactor and

Aqua

R e n aissance ' 90

biose nsor

technology for compact sewage plants .. Bioremed i a t ion

E x -situ

Ne twork L aboratory"

microbial

treat ment of

com p a n i e s

polluted soil

from industri al sites

R A for food

V a l u e -added

bioreactor

ca rbohydrates. proteins and l i p ids t h rough

l

immobilized

bi oc a t a ys t s

EA

== E nv i ron m e n t a l

Age ncy

MAFF

55

1 982--88

2

years. They are usually located in a building specially constructed for this purpose. Finan­ cial support is not limited to one ministry, but includes various national and local bodies, e.g., the Japan Development Bank or the Hokkaido Development Board. Intellectual property is shared among member compa­ nies. Some examples are indicated in Tab. 9. The project management and capitalization of research companies and research associa­ tions in the field of biotechnology is carried out by the following organizations: STA: MITI:

Tab. 9.

a) Research Development Corpora­ tion of Japan (RDCJ) b) Frontier Research Program a) New Energy and Industrial Tech­ nology Development Organiza­ tion (NEDO) b) Japan Key-Tee Center (jointly with Ministry of Post and Tele­ communication)

Biotechnology in Japan

383

MHW: Adverse Drug Sufferings Relief and Fund Promotion Research (ADSRRPF) MAFF: Bio-oriented Technology Research Advancement Institution (BRAIN) A typical financial scheme, for BRAIN, is shown in Fig. 3. Nearly the same systems ap­ ply for the project management bodies of the other ministries. While most of the research associations and research companies are focused on indus­ trial targets, there is an increasing number of cooperative projects in the basic sciences. The STA has taken an early lead in this area, through its ERATO and Frontier Science Projects. ERA TO projects. Started as a program in 1981, the format of these projects relies on a project coordinator of high scientific reputa­ tion, who obtains laboratories and generous financial support for a limited period (usually

Japanese Research Companies Active in the Field of Biotechnology

Name of Company

Participating Industry

Main Target

Duration (years )

Guiding Ministry

Protein Engineering Research Institute, Osaka Research Institute for Environmental Technology for the Earth ( RITE ) , Kyoto Marine Biotechnology Institute, 3 locations Drug Delivery Systems Institute Institute for Advanced Skin Research Biosensor Laboratories Co., Ltd. Seatechs Co.

13 companies

Establishment of protein engineering techniques

10

MITI, through Japan Key-Tee Center

60 companies

Global C02 reduction, bioreactor technology, biodegradable polymers etc.

10

MITI , thorugh NEDO

24 companies

Biochemicals of marine origin

10

MITI, through NEDO

7 companies

Targeted drug delivery systems Artificial skin systems

7

MHW, through ADSRRPF MHW, through ADSRRPF

Turf Grass Co.

3

companies

4

companies

Optoelectronic sensors for in-vivo monitoring

7

MHW, through ADSRRPF

3

companies

Aquaculture or large fish

5

4

companies

Recombinant herbicideresistant turf grass

7

MAFF, through BRAIN MAFF, through BRAIN

7

384

/3

Biotechnology in the Asian-Pacific Region

Priv a t e ·

E n ter­

: prises : anJ

Investment �-------.ooo+-- Capital

Associ­

a t ions

Ca p it a l I nvestment

Loan Service

Mediation i n A rra n ging Joint Research Mediation i n A rra nging the A c q u isit i on of Genetic Res ou rces Research I nformation Service M is ce l l a n e ous

Fig. 3. Fina ncial sch e m e of B R A I N ( M i n i s t r y of Agriculture . Fo re st ry and Fisheries).

5 years ) to investigate basic questions. H is group is composed of usually about 30 scien­ tists, with delegates from universities. re­ search centers and companies. At present, there are 18 E RATO projects. and 15 m o re have been completed. The annual budget is arou nd 3 b i l l ion ye n. Projects relating to bio­ tech nology are : Fuse tani B i o loul i ng Project Okayama Ce l l

Switching Project � agaya ma Protein A rray Proj ect

bioadhesives

mechanism of cel l gr ow t h a n d d i v i sio n 20 p r o t e i n c rys ta l s

Project

i m p a ct of n u t r it i o n o n be h a v ior and bra in in trons i n the h uma n

Project

genome

Tori i N ut r i e n t -Stasis

I keda GenoSphere

\1 izutani Plant Ecoche m i c a l s Project Hot a n i M o l e c ular A sse mbly Project

ecologically active plant metabolites

Frontier Research Program. Established in 1 986 at the RIKEN research institute of the ST A in new laboratories built for this pur­ pose, this program is internationally open and includes foreign project leaders. The annual budget is about 2 billion yen. The program presently comprises

Plant homeostasis res e a rc h

G lycob io logy res e a rch

molecular biology, glyco te c hnology Frontier materials research

Brain mechani sms of

mind and behavior

bacterial flage lla aggre ·

lnaba B i o p hoton Project ( c o m p leted )

gati o n mechanisms

Horikoshi S u pcrbugs Project (completed)

extremophilic micro­ o rga n isms

photoreception, signa l t ra ns du ct i on , p l a n t h o rm o nes glyc o cell biology, glyc o

n a no-elect ronics materials, nano­ p h o t o n ic s materials, ex o tic nanomateria l s neu r al information processing, n e ural networks, n eural systems

ult rawe a k l ight

Photodynam ics

sub-millimeter wave s ,

e m issions in biology

res e a r ch (Sendai)

photophysics, orga­ nometallic

p h o tody n ami cs , photobiology

2 Biotechnology in Japan

Contextual measures. R e g u la tio n s Japan is a nation with a pa t r i a rc hica l histo­ ry. Thus. Japan has evolved into a s t rongly reg ul a t ed country. but at the same time citiz­ ens' and consumers ' protection are vital is­ sues. Co n s e n s us building among fractions is. on the ot h e r hand, a time-consuming and oft­ en difficult routine of J a pa n ese life . In the field of gen e t ic e n g i n e e ri n g . the US lead, as is sued 1 983 i n the fo r m of the NIH gu ide l i ne s , was closely followed, but the rivalries among ministries. who exerted " g ui dan ce " for their ind us tri es or universities proper, has l e d to a number of diverse ministerial g u i d e l i ne s con­ ce rnin g ge n e t i c engineering, w h ic h only in 1 991 were unified to a national g u i de l i ne (is­ sued by the ST A). This guideline is very simi­ lar to the pe rt in e nt US gu ide l ine s . Attempts of the Environmental Age n c y , in 1 991 , to is­ sue genetic en gi ne ering l e g i sl a t io n were re­ j e ct ed. Patents J apa n is o n e of the c o n stit u t i n g p a r t i e s of t he "Budapest Co n ve n tion " w h ic h r e gul a tes the deposit of microorganisms and other forms of life in the fra me work of patent applications. Depositories The main de pos i to ry for m icroor ganisms (over 8000 st ra i n s ) is the Japan Co l l e ction of Microorganisms (JCM). located at STA's RIKEN research i nst i tu te , which also serves as th e world data center for the World Feder­ ation for Culture Collections (WFCC). There are se parat e de posit orie s for pa te n t strains at the MITI National Institute of B ioscience and Human Technology in Tsukuba, for cell lines at t he Monbusho National Institute of Ge­ netics in Mi shi m a , and for germ plasm at MAFF's gene bank at the National Institute of Agrobiological Resources in Tsukuba. In addition . t here are se ve ral pr i v ate l y orga nized d e p o s i tories , the largest (over 8000 strains) being the Ins ti t u te of Fer me nta tion in Osaka (IFO), originally fo un d e d by the Takeda Company.

385

I n fo rmatio n n e twork s For gen e ra l S&T i nform a t ion , the most im­

por t a nt

system is J I CST (Japan Information Center for Science and Te ch n o l o gy ) , a n o r g aniza ti on under the ST A which, t hro ugh a national network connected t o overseas hosts in Europe and the USA, p rov ide s about 8 million documents on-line. JICST is also pre­ paring to become the national host for ge­ nome sequence data from national research centers and com p a n ies . ­

Present tendencies. Genome sequencing C o mp are d to the USA, Japan had a late entry into genome sequencing. A maj o r pro­ ject was carried out at STA's Tsukuba Life Science Center of RIKEN, where several comp a nie s such as H itachi, Seiko and Mitsui K now l ed ge I nd u st ry collaborated in the de­ velopment of h i g h - spe e d robots for gene se­ que nc i n g . Since 1 993, governmental activities for genome sequencing have been greatly en­ hanced. M aj o r p roj e cts are summarized in Tab. 10. Global en vironment projects. As J a p a n is located in the windfall of emerging Asian in­ d u stri a l ize d nations such as Korea and China, acid rain and o t he r forms of air pollution have become a major concern to t he nation. During recent years, Japan has taken a range of steps to co un ter ba l a n ce these effects by po­ litical and technological measures.

Tab. 10. Major Seq ue nc i ng

Japanese Projects in Genome

M i n ist ry

P roje ct

STA

Human

Monbusho

P rogr a m , JICST Database Research p rojects at university level

MITI

Center of DNA Analysis at Yokoha­

Genome

Genome

MAFF MHW

ma: Genome of i nd ustri a lly relevant microorganisms Rice genome p rog ra m , A rabidopsis ge n o me , various vegetables and fruits Human ge nom e s with relevance to an a geing population (e.g., Alzheimer)

386

13 Biotechnology in the Asian-Pacific Region

Documentation. The National Institute of Science Policy, an organization under the STA, continuously collects data on SOx, NOx and C02 in Asia. The National Aeronautics and Space Development Agency (NASDA), also under STA, will launch its first ADEOS satellite in 1 995 , with the goal to carry out continuous surveillance of environmental pa­ rameters in Asia from space. "New Earth '21 " Program. Based on a re­ port of the Environmental Agency in May 1992, the program focuses on a range of measures to promote environmentally friend­ ly technologies and to absorb environmental C02• The central facility for this program is the Research Institute for Environmental Technology for the Earth (RITE), located in Kansai Science City near Kyoto, where a con­ sortium composed of a large number of in­ dustries, under MITI guidance, carries out re­ search on biodegradable polymers, improved bioreactor technology, and enhanced chemi­ cal or biological COz assimilation. International Center for Environmental Technology Transfer (ICETT). Founded in 1 990 through an initiative of Yokkaichi city and MITI, and strongly supported by ODA funds, this institute has the goal to train 10000 engineers and technicians from devel­ oping nations in environmental technology. So far, workshops and training courses abroad have reached about 1000 engineers and technicians, mainly from and in the de­ veloping Asian nations. International Tropical Resource Institute. The main target of this project is the conser­ vation of biological diversity through the es­ tablishment of regina) centers for tropical re­ sources, with a strong financial commitment from Japan.

twelve hundred years to keep her indepen­ dence, except for brief interruptions during the height of the first Mongol empire in the 1 3th century and the annexation by Japan in the 20th century. While Korea is part of a broader East Asian culture centered on Chi­ na, she has managed to keep her national identity and has made significant contribu­ tions to the culture of mankind, e.g., through the invention of printing technology with movable metal types in the 1 2th century. Af­ ter half a century of extreme disarray, follow­ ing the annexation through Japan in 1910 and the Korean war of 1 950-53 which split the country in two nations, the Republic of Korea (ROK, "Korea") entered a period of rapid economic growth. Today, the Korean econo­ my is larger than that of all but eight OECD countries, and is the thirteenth largest export nation in the world. Some pertinent statistical data are summarized in Tab. 1 1 . During its post-war growth, the Korean economy has become a manufacturing and service-oriented economy in 1 990, only 18.3% of the GNP was achieved by agriculture, 27.3% by the manufacturing industries and 54.4% by the service sector. Whereas the four leading export items in 1 961 were iron ore, tungsten, raw silk and anthracite ( 40% of to­ tal export), these were, in 1991 , electronic products, textiles/garments, steel products and ships (60% of total exports). Whereas un­ til 1990 the USA was the major export mar­ ket, followed by Japan and the EEC, the ex­ ports to other Asian nations have sharply ris­ en since 1990, and in 1 992 contributed about 113 to the overall value. Korea's period of rapid economic growth started with a population that was well-edu­ cated by the standards of most developing countries. As early as 1 960, primary school at­ tendance was almost universal (95% ) By 1 990, 35% of the population had received a high school education. The number of stu­ dents in four-year colleges and universities nearly doubled during the 1980s. By 1 990, the share of college graduates in the adult popu­ lation had doubled from 6 to 12% compared to 1 980. Standardized international tests sug­ gest that the quality of education in Korea is high, even in comparison to OECD countries. The Korean government is further emphasiz.

3 Biotechnology in the Republic of Korea Bong-Hyun Chung and Rolf D. Schmid Located between two powerful neighbors, China and Japan, Korea has managed over

3

Biotechnology in the Republic of Korea

387

Tab. 11. Demographic and Economic Data of Some Northern Asian Countries

So u t h

Nort h

Korea

Kore a

( RO K ) Popula tion

( 1000 , 1 990)

42.9

Area (1000

km2)

99

Inhabitants

per k m 1

GNP

( b i l l i on

432 242

US-$. 1 990)

GNP per capita ( U S-$, 1 990)

5659

J ap an

China

( D PR K ) 1 23.6

1 156.0

1 20.5

378

9597

181

327

120

2940

373

2 1 .8

23.2

1 064

4 23800

323

1

9.7

Average annual volume growt h over previous 5 years

- 0.5%

9

6.8

3.5

9.8

2 1 .6

27.9

40. 2

3.0

39.8

Total fertility rate (births per woma n )

1 .8

2.3

1 .7

2.5

ing the role of higher education, e.g. , through offering free middle and high school educa­ tion, and through changing school curricula in favor of science and mathematics. At the uni­ versity level, subsidies will be provided to the private sector colleges (which account for 75 percent of total enrolment) as a means to raise the proportion of science and engineer­ ing graduates to 55% of the total ( 1 992: 40% ). Another form of government interven­ tion in the labor market is the requirement that private enterprises with more than 1 50 employees either train their own employees or pay a levy (0.67% of their payroll on aver­ age) to the government. When the system was introduced in 1977. 33% of the firms opted for the levy - in 1 992, this figure had in­ creased to 80% . Out of 2700 companies. 500 train their own employees. while 2200 firms, mainly smaller ones, have opted for the train­ ing levy. The Korean government spends an additional W 1 70 billion (about 0. 1 % of the GDP) for this purpose.

firms, chaebols, were created as an i nstrument to allow an economy of scale and in turn to develop "strategic industries" as leaders for export and the economy in general. The gov­ ernment helped strongly in the capitalization as well as in subsequent diversification of these trusts, but, in contrast to other countries who also promote big businesses, exercised strict discipline over these chaebols by penal­ izing poor performers and rewarding only good ones. Thus, the government repeatedly refused to bail out large-scale, badly man­ aged, bankrupt firms in otherwise healthy in­ dustries, and instead selected better managed chaebols to take them over. After maturation of the Korean economy, however, the govern­ ment now follows a policy of "economic de­ mocratization" , promoting small and me­ dium-sized industries, in particular technolo­ gy-based firms. By this move, it is intended to remedy the imbalance between large and small enterprises. However, the combined sales of the five largest chaebols (Lucky­ Goldstar, Hyundai , Daewoo, Samsung and Sunkyung) increased from 1 2.8% of GNP ( 1 975) to 52.4% ( 1 984). A number of these trusts became involved in the fermentation business, which started by producing fermented foods and drinks such as soy sauce, beer and rice wine, and later ad­ vanced to the production of amino acids, en­ zymes and antibiotics. The products of tradi-

Exports as % GDP ( 1 990 ) Rural popul ation

( % of

po p u l a t i o n .

1 990)

The industry In the period after the Korean war. the government started industrialization based on proven technologies at their mature stage, taking advantage of a well-trained but low­ waged labor market. At this point, large

26.6

13

388 Tab.

Biotechnology in the Asian-Pacific Region

12. B iotechnological Products of Korea, 1980

Product Alcoholic beverages Fe rment e d soy b ean prod u cts Kim chi Dairy products -

Amino acids Antibiotics Mushrooms Starch sugars Enzymes Biological products Vitamins and organic acids Total

Value 1980 (1000 US-$)

Major Producer

1 286 000 32 800

Oriental Brewery Co . , Jin Ro Ltd., Chosun Brewery Co. Samyang Rood Co., Whayoung Co.

34 300 168 500 77 100 167 700 57 100 51 400 1 4 300 1 8 600 700

Doosan Farmland Co. Hank uk Yakult Milk Products, Bing-grae Co., Seoul Dairy Cooperative Miwon Co. , Cheil Sugar Inc. Cong Kun Dang Corp., Dongmyong Industries, Yuhan Chemicals Sun Hill Glucose Co. Pacific Chemical Industrial Co., Dong-A Pharmaceutical Co. Shinhand Milling Co.

1 906 500

tiona! biotechnology in 1980, before the ad­ vent of genetic engineering in Korea, are summarized in Tab. 1 2. In 1982, after the successful operation of genetic engineering-based venture companies in the USA, 19 companies joined to form KOGERA, the Korea Genetic Engineering Research Association. The member compa­ nies and their interests in the area of biotech­ nology are summarized in Tab. 13. The professional manpower of KOGERA increased from 64 (7 PhDs) in 1 982 to 415 (48 PhDs) in 1990, and investments rose from about 5 billion to 54 billion Won (about 80 million US-$) in the same period. Simultaneously, Korean companies in­ vested in US ventures or produced and/or sold biotechnological products under license from US companies. Tab. 14 gives some ex­ amples. The value of imported recombinant phar­ maceuticals was 16.6 billion Won (about 23 million US-$) in 1991, as compared to sales of 34.7 billion Won (about 47 million US-$) on domestic fermentation products, mostly of non-recombinant origin.

The government The Korean government is interventionist by nature and only recently has liberalized to some extent. The Presidential Council for Science and Technology is the supreme advi­ sory body to the president. It has 11 mem­ bers, including representatives of universities, government research institutes, and private industry. The present chairman is SHANGHI RHEE, former minister of science and tech­ nology. The council meets every other week and its chairman reports to the president on a monthly basis. The General Committee of Science and Technology, which coordinates activities of the various ministries, is chaired by the prime minister. The vice chairman is the minister of the Economic Planning Board. A total of 14 ministries are represented in the committee. The structure of S&T, pertinent to biotechnology, in the Korean government is summarized in Fig. 4. The Science and Technology Policy Insti­ tute (STEP/), affiliated to KIST under the Ministry of Science and Technology, has re­ cently been strengthened and in the Korean language is now called the Science and Tech­ nology Policy and Management Institute. STEPI is responsible for managing the Highly Advanced National Project (HAN), an inter-

3

Biotechnology

in the

Republic of Korea

389

Tab. 1 3. Member Co m p a n i e s of the Korea G e n e t i c E n gin ee ri ng Association (KOGERA) Com pa n y

Sales ( Won

No. of E m p loyees

Major

Prod uc t Lines

Focus in B i o t ec h n ol ogy R&D

Bill.

1 992 )

Cheil Foods & 1 264.8 C h e m i c al s ( S ams ung g ro u p ) Chong K u n g Dang 1 0 1 .2

5 5306

1 459

Cungs 's Foods Dong-A

1 88 . 3

2049

38.5

576

Pharm a ·

ceutical Shin

Dong

Pharmaceutical

H a n gk uk Yagurt

II Dong P ha r m a ce utica l KOH A P

34.9 660.4

Kolon Industries

775 .6

987

1 97 1 5476

Korea Explosives

Korea Green

M i w on Oriental B rewery ( Doosan

Pharmace uticals

Antibiotics, EPO, cyclodextrin Functional foods. bioconversion

Chemotherape utic agents,

H e p a t i t i s B v acci n e s, di a gn os t ic kits. CSF, glu t a t h i o n e

P l a s m a f ra c tio n s .

Vaccines, TNF

fe r m e n te d food

ant icancer age nts

Soy m i l k . barley fl a k e s . j uice enzymes. d i a gn os t i cs . an t i b i o t i cs a n t i b i o ti cs .

Pharmaceuticals.

vi t a mi ns . i n t e rme d i a te s Nylon yarn. p o l ye st e r

1 27.9

1 1 96

2096.0

1 1 718

4 15.2

3647

460.2

1 969

45 1 . 0

5 1 90

Y u ha n

1 27.7

1 5 39

Yung Jin Pharmaceutical I ndustries

98. 1

5838

1 238

giensis toxin,

thurin-

lact i c a ci d

Biopolymers, EPO, fermenters Cancer diagnostics, steroids, biopo-

fil m s

lyme rs

A ntibiotics, B. thuringiensis toxin H e p a t i t i s B vaccine, di a gno s t i c kits, EPO

M i cro b i a l p rodu ct s .

p l as m a fr ac t io n s .

d i a g nost i cs

Plastics. pe t roc h e m i c a l s , s pe c i a l t y chemicals,

p h a r m ac e u t i cal s C on di m e n t s , am i n o p o l ye s t e r res i ns

a ci ds .

Beer. wine. food

Interfe ron, C S D , human g r ow t h h o rm on e

A m i n o a c id s , re c o m b i n a n t p h enyl a la n i n e , sweeteners, pigments Y e as t i mpro ve m e n t , embryo transfer. virus-free hop

Cosmetics , food. e nzymes Pharmace uticals. vete rinary

47 1 0.9

Humanized, monoclonal a n tibo d -

ies, anticancer a ge n ts , B.

Nylon textures. p o l ye s ter

process ing

Pacific Ch e m i c al

Lactic acid fermentation, r e n ni n g ,

v a rn

Explosives. fine

group)

Yukong

v a cc i n e s . m i lk . i n st a n t

che m icals

Cross Lucky

Interfe ron, EPO, h e pa t i t is B vaccine, oligosaccharides

S u g a r . co nd im e n t .

pharmace uticals

drugs.

cosm e ti cs Pe t ro l e u m . pe t roc h e m i c al p rod uc ts

Antibiotics, cosmetics. drinks

E nzymes, h y al u ro n ic acid, collagen,

c yc lo d e x t r i n

Co l l a gen , human gon a do t r opi n ,

prot e ases

B i o p o ly m e rs , a m i n o a cid s, w astewa te r t re a t m e n t M i c r o b i a l p ro d u c t s

390 Tab.

13

Biotechnology in the Asian-Pacific Region

14. Korean-USA Ties in the Field of Biotechnology (Selection )

Korean Company

US Partner or Licenser

Venture/Product

Year of Start/Sale

Lucky Ltd.

Chiron Corp.

Lucky Biotech Corp.

1 984

Cheil Food & Chemcials Korean Green Cross Miwon, Inc.

Eugenetech International Alpha Omega Labs. Princeton Biomeditech. Corp. Eli Lilly

Daewong Lilly Ph arm. Korea Essex Korea Green Cross Cilag Korea

Schering Plough Serono Cilag International

Dong-A Pharm Korea Abbott

Merck Abbott

Dong Shin Pharmaceuticals Kolon Pharmaceuticals Lucky Ltd.

Abbott Centocor

Kang Nam Industries

Ecostar International

Quidel

ministry project (see below), and other na­ tional projects, and has a direct reporting channel to the Ministry of Science and Tech­ nology. The funding of biotechnology has grown strongly in the past 10 years, as summarized in Tab. 15. The most comprehensive program for S&T, including biotechnology, is with the Ministry of Science and Technology (MOST). It was established in 1967 with the objective to drive scientific research programs in gov­ ernment research institutes, support univer­ sity research, and assist commercial R&D in industries. It is maintained, however, that MOST's long-term science and technology policies were largely ignored by the ministries shaping industrial policies, and were not inte­ grated into national development plans. Due to government priorities and an industry structure focused on the cost-efficient produc­ tion of mature products invented abroad, in

1 984 1 987 1 988

Insulin, human growth hormone a - I nterfero n �-Interferon Immune repressor, EPO Hepatitis B vaccine Diagnostic kits for hepatitis B, various cancers Pregnancy test kit Diagnostics for colon cancer Ovulation/pregnancy test Biodegradable plastics

1987, 1 989 1 987 1 991 1 988, 1 990 1 990 1 988-90

1 988 1 988 1 989 1992

turn-key plants engineered and imported from the industrialized nations, there was lit­ tle demand for Korean efforts in R&D (in 1970, there was just one corporate R&D cen­ ter in Korea). Aggressive recruitment of over­ seas-trained Korean scientists and engineers, or tax incentives and preferential financing for corporate R&D activities faltered due to the easy means of acquiring and assimilating foreign technologies then available from many sources. In spite of these drawbacks, MOST managed to set up 21 research insti­ tutes; its most important research facility in biotechnology is the Genetic Engineering Re­ search Institute (GERI) (see below). When the economic environment changed in the 1980s, through protectionism in Western ex­ port markets, rapid wage rises and competi­ tion from lower wage neighbors, the time be­ came ripe for a major shift in technology pol­ icy. In 1 987, MOST adopted a "Long-term Science and Technology Development Plan

3 Biotechnology in the

,-

Pla n ning Board

Ministrv of

; Presidential

I 1--

Policy I n stit u t e ( STEPI)

J

I

Korea Institute of Tech nology ( KIST)

Institute (GERI)

Korea Advanced Institute of S c ie n ce and Tec h n o logy (KAIST)

I

Korea Rese a rch

I nstitute of Chemical

Technology

: on S c ien ce a n d

Korea Institute of Ene rgy Research

! Technologv �I

Ko rea

G i nse n g and Tobacco

Rese arch

I n s ti tu te

Prime Minister

General Committee

I

The Science and Technology

Genetic Engineering Research

! Council

, ;

391

I . I Econom1c

r-- Sc i e n c e. and Te c hno logy r-

Republic of Korea

of S c ience and

Technology

�

r--

M i n ist ry of Ed uc a t ion

1--

103 U niversities and Colleges

1--

Agricultural Science Institute Horticultural Expe rime nt Station

I

I

r--

Mi n i st ry of Agriculture a nd

Livestock Experiment Station

Fisheries

Korea Food Research Institute

Ministry of r--

1--

Health a nd Social

National Health Institute Health Safety

Institute for

Research

We lfare

r---

M i n i st ry of Trade .

1-- Kore a Ac a d emy

of Industrial Technology

Industry and E n e rgy

�

Ministry of Fi n a n ce

1--

Korea G inse ng and Tobacco Research Institute

Fig. 4. St ruct u re of S&T in Kore a . with e m p h asis on l ife sciences.

392

13

Biotechnology in the Asian-Pacific Region

Tab. 15. R&D Investments in Biotechnology by the Korean Government and Industry, 1 982-1 990

(Million Won) 1 982 Ministry of Science and Technology (MOST) Ministry of Agriculture and Fisheries (MAF) Ministry of Education (ME) Ministry of Health and Social Welfare (MHSW) Total Government Korean Traders Association (KTA) Private Industry Grand Total

•

•

1 986

1988

1 990

70

860

1660

2420

7370

0

480

520

890

1 170

0 0

50 20

600 110

930 120

1 290 1 20

70 0

1410 0

2890 20

4360 30

9950 0

3150

12 130

16 400

25 630

35 690

3220

13 540

19310

30 020

45 640

Toward the Year 2000", defining biotechnol­ ogy as one of the priority areas. Launched in 1 992, the Highly Advanced National Project (HAN) aims at the development of competi­ tive R&D capabilities in eleven critical tech­ nologies, one of which is for new functional biomaterials (biotechnology). The program has been dubbed " G-7 project", because its goal is to 'catch up with the advanced technol­ ogy of Japan and leading Western nations by 2001 . The Korean government and industry plan to spend more than 6000 million US-$ on the project over the next ten years. This plan also sets the goal for Korea to share 2% of the global biotechnology markets by 2001 . Within the biotechnology sector of the HAN, MOST adopted the following R&D pro­ grams: •

1984

Screening technologies for biomaterials (cell regulating factors, bioactive lead structures) Renovating technologies for biomater­ ials (protein engineering, transgenic ani­ mals and plants, new enzyme technolo­ gy) Process technology for biomaterials (biodegradable polymers, recombinant proteins, new sweeteners and lipid food, cell culture and bioreactor technology)

The supervising institutions are: Cell Regulating Factors Bioactive Lead Compounds Protein Engineering Transgenic Plants and Animals New Enzyme Technology Biodegradable Polymers Recombinant Proteins New Sweeteners and Lipid Food Cell Culture and Bioreactor

Genetic Engineering Research Institute (GERI) GERI GERI GERI GERI Korean Institute of Science and Tech­ nology (KIST) GERI Korea Food Research Institute (KFRI) The Korean Genetic Engineering Research Association Technology (KOGERA )

The budget proposed for these targets is provided jointly by the government and by in­ dustry, as shown in Tab. 1 6. MOST is an important funding agency for the universities as well, through its Korea Science and Engineering Foundation (KO­ SEF). In 1 99 1 , KOSEF supported 7 biotech­ nology-related Science and 3 Engineering Re­ search Centers in the universities (total fund­ ing: 5.95 million US-$), and 55 biotechnology­ related research projects (0.46 million US-$) . The Ministry of Agriculture and Fishery (MAF) is focused on the support of agricul­ ture and the food industry. The Office of Ru-

3 Biotechnology in the Republic of Korea

393

Tab. 16. R&D Investment for Biotechnology within the H A N Project (Million Won)

1 99 2

1 993

1 994-1 997

Government (MO S T) Industry

3840 2326

5001 3074

1 1 1 000 366 000

260 000 790 000

790 000 1 650000

Total

6166

8075

477 000

1 050000

2 440 000

1 998-2002

2003-2007

1 US-$ = 800 Won

ral Development in the MAF maintains 1 0 re­ search institutes, with a biotechnology budget of about Won 50 000 million (about U S-$ 62.5 million) for biotechnology-related R&D in 1 993. The Ministry of Education (ME) is in charge of the 103 Korean universi ties, and re­ sponsible for basic research and manpower training. It is also a major funding source for the universities, th rough the Korea Research Foundation and the Korea Higher Education Foundation. The Ministry of Health and Social Welfare (MHSW) has two research institutes under its jurisdiction and provides grants for basic re­ search in the universities. Whereas the Ministry of Trade, Industry and Energy (M TIE) was not yet directly in­ volved in governmental S&T policy, due to the functions of MOST, it successfully estab­ lished, in 1989, its Korea A cademy of Indus­ trial Technology and, concomitantly with in­ dustry's growing emphasis on S&T, is begin­ ning to take a more active role in future tech­ nology policies. National Research Institutes. Under the ad­ ministration of the Ministry of Science and Technology (MOST) , the leading national re­ search institution is the Korea Institute of Science and Technology (KIS T) . In 1 985, the Genetic Engineering Promotion Law pro­ vided the basis to establish at KIST the Ge­ netic Engineering Research Institute (G ERI),

located since 1 991 at Daeduk Science Town, Taejon. GERI's staff is over 300 (about 90 Ph.D.s), and the budget for 1 993 was US-$ 20.4 million. I n its 9 divisions, all fields of mo­ lecular genetics, protein chemistry, protein engineering, microbial genetics and ecology, enzyme engineering and fermentation are be­ ing addressed. It also functions as the official culture collection laboratory of Korea.

Further institutes of MOST involved in some areas of biotechnology R&D are: Korea A dvanced Institute of Science and

Founded in 1 97 1 by the Ministry of Science and Technology (MOST) as a graduate university, this is one of the most prestigious graduate schools in Korea and considered to be Korea's "Center of Ex­ cellence", especially in the area of science and engineering. It is the only university in Korea that is not under the control of the Ministry of Education. Its total staff are 3 1 8 professors, 203 1 Ph . D . students and 1223 M.S. students, who are well funded: research contracts in 1 992 totaled Won 22 billion (about US-$ 30 million, or on average just under US-$ 1 00 000 for each faculty member). In its three depart­ ments related to biotechnology (Dept. of B io­ technology, Dept. of Life Science and Dept. of Chemical Engineering), there are 24 pro­ fessors who are focused on biotechnology. KAIST runs a B io-Process Engineering Re­ search Center (BPERC) , supported by KO­ SEF. Technology (KA IS T) .

Korea Research Institute of Chemical Tech ­

It had an applied biology division fo­ cused on the development of new bioproducts and materials. Recently, it became a part of GERL

nology.

Korea A tomic Energy Research Institute (KA ERI) at Daeduk Science Town. This was

founded in 1 973 as the principal research in­ stitute of atomic energy, and runs a Radiation Biology Department Engineering Laboratory with 7 staff members. The Korea Institute of Energy Research at Daeduk Science Town has a biomass research division with 6 staff m embers. The Korea Ginseng and To bacco Research Institute at Daeduk Science Town carries out several projects in genetic engineeri ng. It is managed by the Ministry of Finance.

394

13 Biotechnology in the A sian-Pacific Region

The Ministry of Agriculture and Fisheries (MAF) operates two institutes in Suwon which carry out major projects in biotechnol­ ogy: the Agricultural Science Institute has a staff of 200 ( 50 Ph.D.s), and the Horticultural Experiment Station totals 1 39 coworkers, in­ cluding 20 Ph.D.s. Nine other research organizations under the MAF are also involved in some form or other of biotechnology-related R&D, e.g., the Livestock Experiment Station in Suwon (total 335 employees, 3 1 Ph.D.s). Under the Ministry of Health and Social Welfare (MHSW), the major research insti­ tute in the life sciences is the National Health Institute in Seoul. In its wide range of pro­ grams, about 20 are related to biotechnology, ranging from AIDS to the development of monoclonal antibodies. The Institute for Health Safety Research in Seoul specializes in testing new medical and pharmaceutical prod­ ucts, including drugs developed by recombi­ nant technology. Universities The Republic of Korea has 103 universities and colleges, most of which have some de­ partments related to biotechnology, e.g., bio­ logy, biochemistry, food science or agricultur­ al chemistry. In addition, 24 universities have recently added new biotechnology-related de­ partments such as Departments of Genetic Engineering etc. Seoul National University (SNU) is considered the best university in Korea. An extremely small number of stu­ dents gain admission to SNU every year after fierce competition. In the three science and engineering-related colleges of SNU (engi-

neering, natural science and agricultural and life science), 49 out of the 449 professors, and 135 out of the 1 098 Ph.D. students are fo­ cused on biotechnology. Recently, SNU re­ named its Department of Zoology into De­ partment of Molecular Biology. Currently, 1 8 universities maintain genetic engineering re­ search centers, which are usually staffed by members from several departments. They re­ ceived total government grants of 1 .37 million US-$ in 1 990. Lately, some universities have created inter-university research centers in order to promote collaborative research in this area on the regional and n ational level. The number of scientists and engineers in the life sciences, employed at Korean universi­ ties, is summarized in Tab . 1 7 . Associations KOGERA, the Korean Genetic Engineer­ ing Research Association founded in 1 982, was mentioned already. I n 199 1 , under the guidance of the Ministry of Science and Tech­ nology (MOST) , 50 companies from the phar­ maceutical, chemical, food and environmental business plus 5 government research centers, includi ng the Genetic Engineering Research Institute (GERI), formed the Bioindustry As­ sociation of Korea (BA K). The mission of BAK is to promote the development and in­ dustrialization of biotechnology, to partici­ pate in the foundation of i ndustry, to collect and disseminate information, and to improve international cooperation. The companies as­ sociated within BAK are indicated in Tab. 18. Plant Biotechnology. Korea has established several projects in the field of plant biotech-

Tab. 17.

Number of Scientists and Engineers in the Life Science, Genetic Engineering and Biotechnology at Korean Universities Field

1 987

1 988

1 989

1 990

1 991

1992

Science Medical Science Agriculture and Fishery

295 1 72 227 1 25

398 1 98 235 130

420 230 266 1 44

41 1 238 268 1 60

425 223 246 1 50

438 280 280 1 47

Tota l

819

961

1050

1 077

1 034

1 1 45

Engine ering

3 Tab. 18.

Biotechnology in the Republic of Korea

395

Member Companies and Institutes of the Bioindustry Association of Korea (BAK) ( 1 992)

B. Braun Korea Boryung Pharmaceutical Co. Cheil Sugar Inc. Cheil Synthetic Textiles Co. Cho Seon Pharmaceutical and Trading Co. Choung Kun Dang Corp. Coong Ang Chemical Co. Dae Woo Engineering Co. Dae Woong Pharmaceutical Dong Bank Corp. Dong Shin Pharmaceutical Co. Dong Suh Foods Corp. Dong-A Pharmaceutical Co. Doo San Technical Center Dr. Chung's Food Co. Genetic Engineering Research Institute Green Cross Medical Equipment Corp. Han Kuk Yakult Milk Products Han Mi Pharmaceutical Ind. Honam Oil Refinery Co. Hoong A Engineering Co. II Dong Pharmaceutica Co. Jindo Industries, Inc. Jindo Ltd. Julia Ltd. Kohap Ltd. Kolon Industries, Inc. Korea Explosive Co. Korea Fermentor Co.

Korea Green Cross Corp. Korea Green Pharmaceutical Korea Institute of Industry and Technology Infor­ mation Korea Research Institute of Chemical Technology Korea Zinc Co. Kwang Dong Pharmaceutical Lucky Ltd. Miwon Co., Ltd. Miwon Foods Co. Nhong Shim Co., Ltd. Oriental Chemical Industry Ottugi Foods Co. Pacific Chemical Co. Pohang Iron and Steel Co. Pulmoun Foods Co. Sam Yang Co. Sampyo Foods Co. Shinhan Scientific Co. Soo Do Chemical Co. Sun Hill Glucose Co. Tainan Sugar Industiral Co. Tong Yang Nylon Co. Woo Sung Co. Yu Kong Ltd. Yhuan Chemical Co. Yuhan Corp. Yungjin Pharmaceutical Ind.

nology. Clonal propagation methods were in­ troduced as early as the mid-1960s, and re­ combinant DNA technology in plants was studied since the mid-1980s. Ornamental crops constitute a major field of industrial ap­ plication, and at present 1-2 million flowers (mainly Gerbera, carnations and Gypsophila ) are commercially produced per year via mi­ cropropagation. Vegetables such as potatoes and green onions constitute another field of industrial application, and it is estimated that over 15 million potato microtubers are pres­ ently produced. Transgenic rice, bermuda grass, hot pepper, potatoes and many other vegetables, e.g., watermelon, Chinese cab­ bage and Ginseng, have been studied. Lead­ ing research centers in this area are (a) the Plant Molecular Biology and Biotechnology Research Center at Gyeongsang National Uni­ versity, (b) the Agricultural Biotechnology In­ stitute at the Rural Development Administra-

tion of MAF, and (c) the Bioresources Re­ search Group at GERI. Contextual measures. Patents Korea introduced a patent system in 1946, and joined the Budapest convention in 1 988. The national depository for microorganisms, plasmids etc. is the Korean Collection for Type Cultures (KCfC) at GERI, Taeduk Science Town. In addition, there are two ma­ jor depositories, namely the Korean Culture Center of Microorganisms (KCCM) and the Korean Cell Line Research Foundation (KCLRF), both in Seoul. The number of bio­ technology-related patents (ICP classification C12) issued in Korea increased from 1 1 1 (1 984-1986) to 267 in 1 992; about half of this number was filed by foreign companies or their subsidiaries. About half of all Korean

3%

13

Biotechnology in the Asian-Pacific Region

Te c hno l ogy I nformation (KINITI) in Seoul, which is m a n a ge d by the M i n i s t ry of Trade, I n d u s t ry and Ene rgy and s erv ice s m a inly the i nfo r m a tion on t r a d e an d i n d ustry The other is the K o re a Research and Development In­ fo rm a tion Center (KORDIC) at Daeduk Science Town s u pp o r ted by the MOST, which services the i n formation on th e scientific R&D.

patents o n b i ot e c hn o l o gy were filed by j ust 5 comp a n i e s and institutes: L u ck y Ltd . (33 ap­ pli c at io n s i n 1 992 ) . Cheil S u ga r Inc. a nd G E R I ( 1 1 each ) , Miwon Co. and Pacific Chemical Co. Genetic e n g i n e e ring

.

r egu l a ti o n s

So far. there are no re g u l a t i ons such as re­ DNA guideli nes for t h e biotech­ nology in d u s t ry However, the Ministry of Health and Social Welfare is p rep a ri n g a draft of such regula tion which will soon be is­ combinant

.

4 Biotechnology in the

sued.

Research i n form a t i o n

People ' s Republic of China

networks

Jane H.

A t Daeduk

Science Town and at Seoul , two major scientific information centers have been installed and linked to other national a n d international services through K R E O N e t . O n e is the Korea I n stitute of I n d ust ry

J . Tsai

Mainland China (Fig. 5) has an area of 9.6 m illi o n km 2 and 1 .2 b i l li o n i n h abitants. Due to the large number of people , the Chinese government has always been under p re ssure

­

e

Yumen e

CHINA

e

�he hot C�en gde

Jiuquan

•

Yimhuan

e l an z h o u

X i n in g e

X i " an Chengdu

e

Kunming •

Fig. 5. Map of the People's Repub l ic of China.

•

•

•

e T ai y u a n

e Z engzho

Hefel e eW •

uhan

Changsha

?U

�

uindao

Nan�n

•

( h angc h u n

Shen yan("

y �

e B eoJing

C h ongquin •

Uiqihar

4 Biotechnology in the People 's Republic of China

397

Tab. 19. H istory of B iotechnology R&D i n China

Stagt::

Period

M ajor Targets and Products

2

be fore 1 950 1 950- 1 978

Tradit ional fe rmentation product s such as soy sauce . sake etc. Ant ibiotics. vitamins, amino acids. e nzymes, plant t issue cult ure

3

1 978- 1 990

•

•

4

1 990-

•

establ ish new biotechnological techniques t h rough joint ventures with foreign insti tutes t ra i n scie ntists abroad establish CNCB D ( 1 983 )

Focus on

•

ge netic engineering

•

modern fermentation procedures

•

cell biology

to organize food supplies and medical care . Since the ··open door"- and the "market economy " policies were proclaimed in 1 987 and 1 993. respectively. C hina's economical growt h rate has increased several fold and ranked top of the glo b al list last year. At p res­ ent. the Chinese government is increasingly combining its efforts to commercialize results of b iotechnology R&D with its "open door" policy towards fo re ign inv e stors. Historically. biotechnology in China can be grouped into four major stages. as illustrated in Ta b . 1 9 . Based on a report of the State S cience and Tech n ol ogy Commission (SSTC), the market for biotechnological p rodu c ts in 1 990 i s sum­ marized in Tab. 20. China is the world's largest producer of an­ tibiotics with an annual output of over I 0 000 ton s . There are over 40 e nzyme manufactur­ ing factories wi t h an annual output of over 2000 tons. I n 1 986. R & D on biotechnology gained of­ ficial priority status in China's government planning . Scientists. local and international

entrepreneurs looking for bu si n ess in the bio­ technology field are presently backed up by a new fund i ng system and by e xten si ve support for technology transfer. China's huge domes­ tic market attracts worldwide attention. De­ spite difficulties imminent in its socialist polit­ ical s y s tem . C h i n a's g enet ic e n gineers have recently managed to ach i eve the following re­ sults: • Genetically engineered wheat was p l ant­ ed on 65 000 ha of land. • F rom 1 986 to 1 992, the cultivated area of hybrid rice species occupied about 1 27 million ha, resulting in a harvest of 200 billion kilogram rice, which represented an increase of 5-1 0% in yield. • A genet i cal l y engineered strain of Alfal­ fa grew on 1 0 000 ha of land, with a har­ vest i ncrease of 1 620 tons. • TMV-resistant tobacco, cultivated in an area of 1 3 000 ha, provided the govern­ ment with RMB 400 m ill ion in income tax. e q uivalent to 9-1 0% of the total na­ tional income tax.

Tab. 20. Market o f Biotechnological Products i n China, Product

Tra d i t ional biotechnologica l products A n t i biotics Amino acids E n zymes

1 990

Annual Production

Sales Value

(Tons)

( M i l l ion RMB ) 6600

1 0 000 75 000 2000

R M B = Ren - M ing- B i . eq uivale n t to Chi nese Yuan

300

398 •

•

13

Biotechnology in the Asian-Pacific Region

Transgenic calves and fish were success­ fully bred. Recombinant vaccines for hepatitis-B and hemorrhage fever, and a-interferon and interleukin-2 were commercialized.

The government Starting from 1 980, biotechnology was identified to be one of the top high-tech pri­ orities in China, and any business associated with biotechnology was entitled to a number of government incentives. Major government programs include •

•

•

incentives on reduced income tax (re­ duction to 15% in certain economic zones and coastal cities, in comparison to 24% elsewhere), exemption of income taxes for the first three years of produc­ tion, the establishment of a patent system ("intellectual property protection law") , and the foundation of "science-based eco­ nomic zones" (SEZ).

Moreover, the government has permitted foreign companies to hold between 25% and 1 00% of equity in Chinese companies. China has devoted considerable capital investments for the development of biotechnology. Gov­ ernment funds are available in three forms: grants, loans and equity, for financing both domestic and foreign investments. Funding for R&D in this particular field has increased by a factor of 25 during the past ten years. The attempts to liberalize the national market led to an enhanced dependency of China's new biotechnology start-ups on the industrialized countries. Most orginal re­ search still remains in agriculture, but biome­ dical research and protein engineering have been defined as new targets in the govern­ ment research policy. In March 1985, the government announced several programs to improve R&D. These were: • •

"7.5 Plan" (1 985-1990) "8.5 Plan" (1 990-1 995 )

• • •

"863 Plan" (since 1986) "Spark Plan" (since 1 985) "Torch Plan" (1988--1 990).

Among these plans, the "863 Plan", also known as the "High Technology, Research and Development Program", has medium­ and long-term goals, aiming at the frontiers of global high-tech development and adapting the principle of "limited target but strong fo­ cus" in selected subjects. About 3000 Chinese scientists and technicians, and more than 200 institutions with about 200 projects, were in­ volved in the programs and plans mentioned above. In addition, the National Science Fund provided RMB 100 million for scientific re­ search, of which 30% is used for innovations in biotechnology. The funding of the "Torch Plan" is either derived from banks, or is pro­ vided through grants from CNCBD, resulting in a budget of RMB 300-500 million annual­ ly. In the framework of this program, the fol­ lowing institutions were established: China National Center for Biotechnology (CNCBD) in Beijing, established in 1 983. The center is not only China's top maker of bio­ technology policy, but also the authority in reviewing research grants. China-EC Biotechnology Center (CEBC) in Beijing, founded in 1 991 ; it is organized in a similar way, and acts as the link between China and EU countries, being jointly man­ aged by CNCBD and the DG-XII of the Eu­ ropean Commission. It is responsible for the co-operation and implementation of all bio­ technology-related international scientific co­ operation activities. China New-Investment Enterprise Compa­ ny (CIEC), established by the government in 1 987, and affiliated to the State Science and Technology Commission (SSTC) and the People's B ank of China. CIEC is one of the very few companies which will grant loans in foreign currency and provide equity for new businesses. Shanghai Research Center of Biotechnolo­ gy, Chinese Academy of Science (CAS), was founded in 1 991 by the government. The gov­ ernment investment for the center and its pi­ lot plant, affiliated to the Institute of Micro­ biology of the CAS in Beijing, was about US-

4 Biotechnology in the People's Republic of China

$ 15 m i ll i o n The c en ter g iv e s p riorities to ge­ netic e ngin e er i ng of m ic roorgan isms and cell biology, as we l l as e nzym e engine e ring The center has established a gene bank. China United Biotechnology Corporation (CUBC) was approved in 1992 and is admin­ istered by the State Science and Technology Commission (SSTC). It is an ind e pendent en­ t e r pri se for b i ological science a n d technol ogy de vel o pm ent and is regi st e red at the China Industrial Commercial Administration B ur­ eau. Its role is to l i n k scie ntific research and i n dustr i a l applicati on s CUBC collaborates extensively wi th bioindustries at home and abroad. Its maj o r business is to a) handl e bi o t ech n ol ogy trade. b) establish biote ch nol o gi ­ cal and related in d u s t ri e s by joi n t ventures, c) organize ex ch ange and coop e ra t i o n in the field of bi o tech no l ogy d) engage in indenture a n d co n signmen t of domestic and overseas bi op roduc ts e) act as an agent of overseas manufacture rs. and f) p r o v i d e consul tan cy and services re lati n g to b i o produc t s and bio­ tech nology tradin g The economic development of China is central ly controlled by the po l itic a l system. If one wishes to e n ter into an a c ade m i c or c om ­ merci al r e lat io nshi p in China, it is thus h i g h l y i mport a nt to find the app ropri a t e Ch i n ese partner i n t h e per tin e n t administration unit. This is not always si m ple due to the de c en­ tral i ze d o rgan iz ati o n of the State Council. The relationship between gov e r n m e nt au­ thorities and research institutions relevant to b i ot ec hnology is sche m a t i c ally illustrated in Fig. 6. On the n a t ion a l level. top researchers are presen t ly enco u rag e d to se rv e as employ e es or c onsult an t s to enterprises. Top re se a rchers now o fte n offer their expertise to foreign companies. which results in an i ncr ea sed in­ fluence of top-class scientists. .

.

.

­

.

.

-

.

National

State

Key

Laboratories

and

Science Economic Zones. As a measure to i m ­ prove on bi o t e c hno log ic a l research, the so­

called State Key Laboratories were re c ent l y established (Tab. 21 ). In order to p rov i de an ap p ropriat e infra­ structure for both national and forei gn invest­ ments. central and local governments have created several s o called Science Econ omic Zones (SEZ) or High-Tech Sci en ce Parks -

399

( HTSP), which have a semi-autonomous po­ litical and economical status. The best-known SEZ or HTSP are listed in Tab. 22.

Industrial a ctiv i t ie s : joint ventures and newly established b i otechno logic a l c om p a n ies

Joint ventures wi th fore i gn partners are en­ c o uraged by the gov e r n m en t . Rep r e se ntative join t projects are shown in Tab. 23. In orde r to promote commercialization of biote chnology in China, the CNCBD, several research institutes and universities have joint l y set up several high-tech enterpri ses which are listed in Tab 24. ­

.

Regulations The Chinese Patent Office was established in 1984 and came into function in 1985. Safety protocols for genetic engineering and bio­ technology R&D were prepared by the SSTC and came into effect in December 1993. These regula t i ons es t ablish g u ide l i ne s for safe pi lot p l an t and labora t ory research work, and for the safe manufacture and field release of GMOs. They also cover th e t r ansport a tion de s t r uc tion a n d disposa l of GMOs and all re­ lated materials. In order to i m pl em ent t h e se bios a fe t y regulatio n s the Chi n a National Bio­ s a fet y Commission ( CNBC) was established, and fu n ctions under the direct l eadershi p of the Chinese State Council. The secretariat of the CNB C. which deals with the daily admin istration of the Commission, is l ocat e d in the National Center for Biotechnology Develop­ ment (CNCBD). The rules stip u late that any living GMO w aste must be treated or des t royed prior to its entering the e nv i ron me nt and that all ex­ peri m ental records must be readily available for a period of t en years. Regulations cover all genetically engineered, or DNA manipu­ lated plants animals and m ic ro organi sm s Traditional methods of hybrid b reedi n g chemical fertilization and tissue culture are not included in these guidelines. ,

,

­

,

,

.

,

400

13 Biotechnology in the Asian-Pacific Region State Council of People's Republic of China

I China National Center for Biotechnology (CNCBD)

State Educational Commission of P.R.C. (SECC)

r--

f--

r--

Ministry of Agriculture of P.R.C.

r--

f--

-

Ministry of Light Industry of P.R.C.

Fig. 6.

f--

-

State Science and Technolgy Commission of P.R.C. (SSTCC)

f--

Institutes

Universities and Colleges

Universities

f--

China-E.C. Biotechnology Center (CEBC)

Chinese Academy of Sciences (CAS) f-(Academia Sinica f-of P.R.c.) f--

Chinese Academy of Medical Sciences f-(CAMS)

Chinese Academy of Agricultural Sciences (CAAS)

Chinese Academy of Preventive f-Medical Sciences (CAPMS)

Universities and Colleges

Universitites and Colleges

Institutes

Institutes

Universities and Colleges

Universities and Colleges

Ministry of Public Health of P.R.C. (MPH)

f--

i-

i-

-

State Bureau of Medicines Administration of P. R.C.

-

Structure of S&T in China, with emphasis on life sciences.

Environmental Protection Law China is planning to spend 0.7% of its an­ nual GNP in order to improve the environ­ ment. In fact, the Chinese people have paid very little attention to this problem so far. Conclusion Although the "open-door" policy is an im­ portant step to stimulate biotechnology R&D in China, there are also serious drawbacks for the industrialization of results, e.g., there is a

·

danger of unnecessary and overlapping in­ vestments in new areas of biotechnology R&D despite the limited national market. Moreover, the strong links between the Chi­ nese political system and economical devel­ opment could hamper the commercialization of biotechnology. Problems such as the lack of financial resources, the slow transfer of technology at the national level, and the lack of well-trained researchers must be taken into serious consideration.

4

Biotechnology in

the

People's Republic of China

Tab. 21. "National State Key Laboratories'" Related to Biotechnology

National State Key Laboratory

Plant Molecular Biology and Ge ne tic s La b or a torY Division of Fish Genetics and Bree ding Plant Cell and Chromosome

Laboratory Biochemical Engineering Laborato rY National Laboratorv of Protein and Plant Genetic Engineering Laboratory of Genetic Engineering Laboratory of Enzymology Bi omembrane and Memb rane Biotechnology Laboratory Laboratory for Bi o l ogical Safety Medical and Pharmaceutical Biotech Laboratory Laboratory for Agricultural

E colo gy Laboratory for Biosensor Rese arch Laboratory of Fermentation Technology Laboratorv of Viral Genetic Engineering Laboratory of Natural Pharmacopoeia Laboratory for Cancer Genetics Molecular Oncology Research Laboratory Laboratory t'or Experimental Hema t ology

National Major Laboratory of Medical Genetics Laborator y of Molecular Biology Laboratory of Medical Neurology Laboratory for Nuclear Medicine Laboratory of Agricultural Biotechnology La boratory for Crop Genetics Laboratory for Plant Insects Pathol o gy State Key Biotech Laboratory for Tropical Crops Nati ona l Ve ter i nary Biotechnology Laboratory The National Laboratory of Fish Sperm Resources and Biotechnology CAS

SEC MPH MA

Chinese Academv of Science State Educational Committee MinistrY of Public Health Min ist r�' of Agriculture

Affiliate d Institutions

L oc ati on

Shanghai Plant Physiology Instit ute

Shangha i

401

G over n ment Authori ty CAS

Institute of Hydrobiology

Hube i

CAS

Institute of Genetics

Beijing

CAS

Institute of Chemical Meta ll urgy Peking University

Beijin g

CAS

B e ij ing

SEC

Fud an Uni versity J ilin U niversitv Institute of Zoology: Peking University: Q inghua University Zhongshan Un ivers i t y Nanjing University

Shanghai C hangch un Beijing

SEC SEC CAS/SEC

Guango n g Nanj ing

SEC SEC

La n zhou U nive rs ity

Lanz h ou

SEC

Sh a n ghai

SEC

Jinan

SEC

B eij ing

MPH

Beijing

MPH

Shangh ai

MPH

B e iji n g

MPH

Tianjin

MPH

Changsha

MPH

Institute for Basic Me dical Rese arc h .

B eij in g

MPH

Shangh ai M edi ca l U ni versity Jiangsu Provincial Institute for N uclear Med ic i n e Beijing Universi t y of Agriculture

Shanghai Wuxi

M PH M PH

B eijin g

MA

East China University of Che mical Techno l ogy Shandong University Institute of Virology. Chinese Academy of Preventive Me dic ine Beijing Medical University Shanghai Cancer Research Institute Institute of Oncology. Chinese Ac ademy of Medical Sciences Institute of Hemat ol ogy . Chinese Academy of Medical Science Hunan Medical University

Ch i nese Academy of Science

Hu azhong Unive rsity of Agriculture Institute of the Chine se Academy

of Science

Wuhan B eij ing

MA MA

Institute of H uanan Tropic Crops

H ainan

Harbin Veterinarv Rese arch Institute. Chinese' Academy of Agricultural Science Chinese Academy of Fishery Science: Changjian Fishe ry Research Ins t itute

H arbi n

MA

Shashi

MA

402 Tab. 22.

13 Biotechnology

in

the Asian-Pacific Region

Science Economic Zones/High-Tech Science Parks (Selection)

Beijing High-Tech Wuxi High-Tech Nanking High-Tech Shenyang Dalain Tienjin Chengdu Chonggin Weihai Torch Park Qindu Jinan Zhongshan Torch Guanshou Shenzhen Zhuhai Changchuan Harbin

Beijing Jiangsu Nanjing Liaonin Liaonin Hebei Sichuan Sichuan Shan dong Shandong Shandong Guandong Guandong Guandong Guandong Jilin Heilongjiang

Dachin Changsha Fuzhou Xiamen Torch Hefei Hangzhou

Heilongjiang Hunan Fujan Fujan Anhui Zhejiang

Tab. 23.

Nanin Zhenghou Shijiazhuang Lanzhou Pudong Caoheijing Hainan Qanming Taiyuan Ulumugi Baotou

Guangxi Hen en Hebei Gansu Shanghai Shanghai Guandong Yuannan Shaanxi Xinjiang Inner Mongolia

Joint Venture Projects and Their Partners

Project

Foreign Partner

Subject/Chinese Partner

Hepatitis-B vaccine Rice genome project

Pharmacia (Sweden) Rockefeller Foundation (USA)

ELISA test kit

Biochemical Systems (Austria) Merck, Sharp & Dohme (USA)

Large-scale preparation of HB vaccine 16 projects within "863 plan". US- $ 1.5 million per year support, plus training of young Chinese scientists abroad Atomic Energy Institute

Hepatitis-B vaccine B lood substitute (hemoglobin) Various Chinese drugs (Hismanal, Vermos, Motillium etc.) Pharmaceuticals

International Hemoglobin Technology Division (Canada) Johnson Pharmaceutical Comp. (Belgium) Abbott Co. (USA)

Recombinant HB vaccine, with Beijing Institute of Biological Products and Kang-Xin Biotechnol­ ogy Corporation, Shenzhen Shanghai Research Center of Biotechnology, Shanghai Proxince Shanxi Pharmaceutical Co., Xian Ninbo Abbott Biotechnology

5 Biotechnologv in the Republic of China (Taiwan)

403

Tab. 24. China ' s New Bio t echnol og y C o m pani e s Company

Locat ion

China United B io t e chnolo gy Corp. K e xi ng B io l ogical Products Corp. Sino-Tech Products Corp. New-Life Pharmaceutical C o r p. K angta i B i o l ogica l P roducts Natural I n st ant Health Products Co.

Shenzhen, Shenzhen, Shenzhen, Shenzhen. Shenzhen, Shenzhen, Shenzhen,

B.S.

M edical and Biochemical Co. Weko Bio-tech Ltd. Membrane Separation & Biotechnology Co. Tian Wang Intern. Pharmaceutical Co. North China Pharmaceutical Corp. Changchung Institute of B i ologi cal Products Wuxi Enzyme Factory

Sino-American Biotechnology Co. East China B iot ech no logy Engineering Co. Yuan Dong Biotechnology Co.

Huxain Biotechnology Co.

Be ij ing B i otec h no l o gy Co.

Hubei Institute

of Biotechnology

5 B iotechnology in the Republic of China (Taiwan) Jane

H. J.

Tsai

I ntrodu c tion

The Republic of China in Taiwan has an area of 36000 km 2 and twenty mil lion inhabi­ tants. With an average growth rate of 9% since 1952, the island has been very prospe­ rous and has accumulated foreign reserves of US-$ 980 billion. Most companies in Taiwan are small to medium size in comparison to the industrialized nations. Expansion of research and development has therefore become one of the main responsibilities of the govern­ ment: undertaking joint ventures with foreign companies and research institutions were the main aims of the government at an early stage. However. recent rise in labor costs, shortage of available industrial land, substan­ tial appreciation of curre ncy and strong pres­ sure for environmental protection are render-

CJuandong CJuandong CJuandong CJuan don g CJuandong CJuandong CJuandong Shenzhen, CJuandong Shenzhen, CJ uandong Hainan. Hainan Hebei

Chan gc hun Jilin Wuxi. J iangsu Loyang. H e nan Shanghai S h a nghai Shanghai .

Beijing

Wuhan, Hubei

ing the traditional manufacturing business no longer competitive. Development of high technology has therefore raised the hope for the nation to maintain the rapid economic growth and to become one of the industrial­ ized nations by the year 2000. High-tech oriented biotechnology has been identified by the government and the business sector since 1982 as one of eight strategic areas of S&T. Biotechnology business opportunities are entitled to a number of incentive programs created by the government: they include tax exemptions for up to five years, government loans to subsidize 50% of the cost of the de­ velopment for industrial products, duty ex­ emption on imported machinery and materi­ als for the purpose of manufacturing, and market information service. Consequently, the government has created several institu­ tions to handle R&D and to work with the industrial sector in order to promote bioin­ dustry. Among these institutions are the Biomedical Institute and the Molecu la r Biolo­ gy Institute at Nankang which were estab­ lished for basic research and for training; both are fully supported by government funds. The development of industrial processes is carried out mainly at the Development Center of Bio-

404

13

Biotechnology in the Asian-Pacific Region

technology (D CB) in Taipei, and by the Uni­ on Chemical Laboratories (UCL) of the In ­ dustrial Technology Research Institute (ITRI) at Hsinchu. Both institutions are non-profit organizations and are operated semi-private­ ly. Their funding sources can be either ob­ tained from government agencies or from the private sector. In addition, the Food Industry Research and Development Institute (FIRDI) at Hsinchu has been developed into an excel­ lent R&D center and the major depository for microorganisms and plasmids. There are at least twenty academic labora­ tories, medical schools or agricultural re­ search centers which are involved in biotech­ nological research. All national universities and their research centers are fully supported by the government. Among them, Academia Sinica leads the field. In 1 994, Nobel Laur­ eate Professor Y. C. LEE returned from the USA and became head of the institute. Other universities such as National Taiwan Univer­ sity at Taipei, the National Tsing-Hua Univer­ sity at Hsingchu, the National Chung-Hsing University at Taichung and the National Cheng-Kung University at Tainan also play an active part in biotechnogical research. In 1 980, the Science-based Industrial Park (SIP) was established in Hsinchu by the Na­ tional Science Council (NSC) . By 1 992, nearly one hundred high-tech companies had been set up within SIP benefiting from various in­ centive packages for S&T-related invest­ ments. In addition to these efforts of the govern­ ment, the private sector has established thir­ teen biotechnology-related venture capital firms since 1 986. The cumulative initial equity of these funds meanwhile exceeds US-$ 250 million. In 1990, the government announced that private companies may apply for public R&D funding on a competitive basis. Such policy has resulted in many new research la­ boratories and investments in private compa­ nies. Since 1 992, the output of the "bioindus­ try" has been US-$ 27 billion p.a., 17% of to­ tal industries. This production figure com­ prises traditional industries of agriculture, food, pharmaceutical and specialty products. Industrial biotechnology R&D efforts in government-supported institutions have been organized into six major programs, namely

• • • • • •

pharmaceutical products agricultural products specialty chemicals biological agents used in pollution con­ trol biosensors, and strain collection and improvement.

Combined R&D expenditures of industry and the government in the agricultural and medical sciences were in excess of US-$ 300 million in the FY 1989-90. 33% of this budget went to the "upstream" research bodies, mainly the universities and Academica Sinica; 50% went to government and quasi-govern­ ment laboratories ("midstream"); and 17% went to "downstream" institutions, predomi­ nantly private and public enterprises. The government funded 86% , and industry 14% of R&D. The industry Taiwan is a leading manufacturer of fer­ mentation products such as glutamate and an­ tibiotics. The combined annual sales of fer­ mentation products and biological products was estimated to be US-$ 2500 million and 100 million, respectively (1992) . Monosodium glutamate alone accounts for US-$ 300 mil­ lion per year in sales, generated by 4 produc­ tion plants of 3 companies. The brewing and sugar industry, a major driving force for new biotech investments, amounts to over 80% of the total sales. Sales figures are summarized in Tab. 25. The most important companies related to biotechnology are those based on traditional fermentation technologies, as outlined in Tab. 26. The total market value of biotechnological products was estimated by the National Science Council to be in the order of US-$ 46 million in 1 987, with an increase to US-$ 1 86 million in 1990 and US-$ 807 million in 1 996. Recently, several companies focused on the "new biotechnologies" were set up. They are listed in Tab. 27.

5 Biotechnology in the Republic of China (Taiwan)

405

Tab. 25. Sales Figure s of Fermented Products and B i ologica l Products. 1988-90 Type of Product

1988

Agricultura l products

336

Food and related goods Speciality chemicals

Sales

313.5

( Bi l lion

198 9 329 352

33.5

31

1990

Number of

314

70 084

371

3101

NT-$)

36.3

Manufacturers

45 4

Tab. 26. Taiwanese Companies Selling Biological or Fermentation Products Sales (U S - $ Million) 1989 and Products

Company China New Pharmaceutical Co. Kaohsiung Chemical Co.

Pan Lab. Inc.

Polyamine Corp. President Enterprise San-Fu Chemical Co. Ta-Tung Enterprise Tai-Tung Enterprise

Tai wan Cyan amid

Gluconic acid, clinical enzymes

20

3 13

10

Animal vaccines Strain improvement service Urokinase, bromelain, selenium yeast

613

Soy sauce. yoghurt

33

Citric acid

1151

Cyclodextrin, enzymes

6 20

U rokina se

Tetracyclines

Taiwan Green Cross

3

lmmunoglobins. factor VIII

Taiwan

4

Animal vaccines

Serum Co.

Taiwan Sugar Co.

Taiwan Tobacco and Wine

685 291 5

Monopoly Bureau

Ly sin e , Torula yeast, ethanol

Beer. rice wine, distilled sp irits

Ve-Dan Corp.

176

Glutamate. Chlore/la, blue-green algae

Ve Wong

173

Glutamate, soy sauce, cephalosporin

288

Milk products, glutamate, soy sauce, yoghurt

Wei-Chuan Food

Tab. 27. Taiwanese New Biotechnology Companies Company

Year

Number of

Value of Assets

R&D Budget

Founded

Researchers

(US-$ Million,

(NT-$ Million)

1989)

Tai-Fu Pharmaceutical Co.

Tai-Da Pharmaceutical Co. General Biologicals Corp.

BGH Biochemi cal Co.

Life Guard Pharmaceutical Inc. Ever New Biotech Co.

1982

6

6.0

4--5

1982

4

1. 5

4

1984

10

12.0

10

1984

3

0.5

3

5

28.0

10

8.0 1.5

1 984 1984

Search Bioi. Technology Group King Car Biotech Co.

1988

Ming-Sheng

1988

Pharm.

1987

3

5

1.5

7

1.5

5

3.0

3-5

Technology Inc. Taiwan Biotech Inc.

1989

Hwa-Yang Pharm.

1989

3

1989

2

Technology Inc. Grand Biotech. Corp. Total

1 .5

5.0 70.0

10 10-20 10

406 Tab. 28.

13

Biotechnology in the Asian-Pacific Region

Member Companies of BIDEA

USI Far East Corp. Eternal Chemical Co., Ltd. Y. F. Chemical Corp. Taiwan Pharmaceutical Industry Association King Car Biotechnology Industrial Co., Ltd. Taitung Enterprise Corp. Tung Hai Fermentation Industrial Corp. Industrial Technology Research Institute Shinung Corp. President Enterprise Corp. Lifeguard Pharmaceutical Inc. Taiwan Monosodium Glutamate Manufacturers

Yung Shin Pharmaceutical Ind. Co., Ltd. Development Center for B iotechnology Ve Wong Corp. Wei Chuan Foods Corp. Chui Shui Che Foods Mfg. Co., Ltd. China Chemical Synthesis Industrial Co., Ltd. Food Industry R&D Institute Cyanamid Taiwan Corp. Crossbond Corp. Hanaqua International Corp. Polyamine (Taiwan) Corp. Standard Chern. & Pharm. Co., Ltd.

However, exports of high-tech biotechno­ logical products at present play only a minor role in Taiwan's trade. In 1989, the Taiwan Bioindustry Develop­ ment Association (BIDEA) was formed for the promotion of Taiwanese bioindustry. The 26 member companies of BIDEA are sum­ marized in Tab. 28. BIDEA includes several public research institutions and some 200 individual mem­ bers. The main task of BIDEA is to carry out research and investigations into biotechnolo­ gy and bioindustry, to gather information on a national and international scale, to partici­ pate in educational measures, hold symposia, to plan and promote large-scale projects, through interaction with policy-makers, and to enhance international cooperation. BI­ DEA has close contacts to JBA in Japan.

foremost university. It occupies a total space of about 10000 m2, including a pilot plant of 700m2 which is among the most advanced pi­ lot plants in the world. DCB is operated by 300 employees, of whom 15% hold Ph.D. de­ grees, 70% M.S. degrees, and 12% with B.S. degrees. The research areas of DCB are sum­ marized in Tab. 31. In addition to funding R&D at universities and research centers, Taiwan's government has initiated a range of measures for the pro­ motion of technology-based industries.

The government The government's role in promoting the development of biotechnology is illustrated in Tab. 29. The government has strongly stimulated R&D in the field of biotechnology. The perti­ nent budgets for the period of 1988-1992 are indicated in Tab. 30. The largest part of the budget has been spent through the Development Center of Biotechnology (DCB), the major governmen­ tal research institute for R&D in biotechnolo­ gy. DCB is located on the campus of the Na­ tional Taiwan University in Taipei, Taiwan's

•

In 1983, the

Industrial Development Bu­

a body under the Ministry of Economic Affairs, began a subsidiary program for new products and processes. Government funds were made available to cover the cost of development as well as the interests on capital borrowed to fi­ nance a project; such funds are provided by the Executive Yuan (Cabinet), pri­ vate industry and royalties from success­ ful projects, ranging from 1% to 4% of the profits. In addition, a technology­ oriented company may claim for tax ex­ emption on production equipment, which usually accounts for up to 10-20% of the total investment. Once production of a high-technology product has begun, the company can claim exemption from any tax payment on this product for five consecutive years. As a result of these measures, the maximum rate of taxation for a technology-based company can be as low as 22% , as compared to 33% for other types of business. reau (/DB),

5

Tab. 29. The

Biotechnology in the Republic of China (Taiwan)

Framework for the Promotion of Biotechnology in Taiwan Basic Research

Promotion

Execution

407

Government

Universities, research institutes

Applied Research

Technology Development

Commer­ cialization

Academia Sinica, Science Council (NSC) National Council of Agriculture Department of Health

Academia Sinica

Agriculture Experimental Research Institute University institutes Non-profit organizations Industry Hsinchu Science Park

DCB ITRI, FIRDI Public and private industries

NSC National Science Council MOEA Ministry of Economic Affairs MND Ministry of National Defense MOC Ministry of Communication Development Center for Biotechnology DCB Industry Technology Research Institute ITRI FIRDI Food Industry Research and Development Institute

Tab. 30.

Budget for Governmental R&D in Biotechnology (NT-$ Million)

Organization Academia Sinica National Science Council Council of Agriculture Ministry of Health Development Center for Biotechnology (DCB) Total (NT $) Total (US-$) -

1 989

1990

1 99 1

1 99 2

20 4 2. 5 40 20 270

22 4 2. 5 42 20 280

24 55 44 25 2 90

26 60 46 35 290

92 200 172 100 1 1 36

39 2. 5 1 2.7

506. 5 16. 3

1 988

538.0 1 7.4

557 0. 1 8.0

2000 64. 5

1 US-$=30.77 NT-$

•

•

•

The Bank of Communication, Taiwan's official development bank, provides up to 70% on loans in order to finance high­ tech investments in the medium- and long term. The China Development Corporation is a privately run organization and also of­ fers low-interest loans. The government further assists new high-tech companies by providing up to

49% of equity and granting up to

•

•

25%

ownership to its founders for the use of new technology. The statute of investments by foreign na­ tionals permits the repatriation of profits from approved investments. Capital can be repatriated at a rate of 20% per year after the start-up. Venture capital organizations have re­ cently been admitted to Taiwan. They

13 Biotechnology in the Asian-Pacific Region

408

Tab. 31. Research

A r e a s of

the

D e velo pment Center of B i otec h no l o gy (DCB), Taipei

Division

Area of R&D

Molecular biol ogy

Gene cloning, gene expression on large scale. st r ucture of nucleic acids

Microbiology

b ioreactor d e sig n ,

Current Projects

Industrial microbiology , cont in uous environmental mi­

Cell biology and immuno log y Biochemistry

crobiology, bioremediation A ntigen- specific T-cell clones, human T-T hy bri cl o nes and lymphokines. hu­ manized antibodies P rot ei n e nginee ring , enzyme immobi­ lization, enzy me reactor design , bio­ sensor techno logy , amino acid de riva ­ tives and peptide products

Agricu l tur al

Plant tissue culture technology. bio­

biochemistry

Process development

logical con t rol of plant diseases a n d pests, new pesti cide technology. diag­ nosis of agricu l tura l pollutants Large-scale cell cul t ure technology. process design and economic evalua­ tion. pilot and prod uction plant engi­ neering

Information services

U pd a ted information about biotech­ nology

dustry Pharmaceutical

R&D

R&D for the Taiwanese bioin ­

New chemical

lead structures for

p ha rmaceutica l s , bulk and gene ric drugs R&D

can invest abroad. under the condition that they m u st transfer the technology back to Taiwan. R e g u lat i ons

In 1987, th e government i n trodu ced a ma­ jor revision of t he patent law. Under this reg­ ulation. foreign firms are able to file suits against patent infringements and re q ue s t pen­ alties for the violation of patent laws. Genetic engineering regulations date back to Se p te m­ ber, 1989. They are very similar to the p erti­ nent r e g ulati o ns of the USA. In order to re­ duce env i r o n mental pollu tio n , the cabinet in 1987 established the Environment Protection Administration (EPA) directly under the cab­ inet. The EPA is responsible for introducing

HBV recomb i nan t vaccines, animal diagn os tic k its , hepati­ tis C diagnostic kits, DNA probes Strain improvement, microbial insec­ ticides, industrial enzymes, solid-state bioremediat ion T - ce ll culture and cloning, mouse­ mou se - B - ce ll h y b ri domas , bispecifi c vaccines, NPC

humanized antibodies Aspartam p roduction by enzymatic synthes is , amino acids via e nzymic con ve rsio n , d esig n and synthesis of growth hormones, piezoelect r i c bio­ sensors

Evaluation and deve lo pment of mi­ pesticides , transgen ic plants, d i agnosti c systems for plant diseases crob ial

Recombinant hepati t is B

vaccine,

bioinsecticide and b iope st icide

pro­ duction process, mammalian cell and hybridoma prod u c t i on on large scale, pilot p l an t services Market anal ysi s , st ra te gic a naly sis for pro duct develo pm ent , databases.

technology transfer Antibiotics, anticancer, anti-viral and anti-hypertensive agents, drug s afety and metabolism, formulation

le g islative prop osals and implementing na­ tional laws designed to protect the environ­ ment and natural reso u rce s . R&D of the EPA has b ee n conducted t h ro ugh grants, coopera­ ti v e agreements and research contracts with universities and o t her p ri vate institutes. The total bud get (including govern ment protec­ tion plans) was NT-$ 61.5 billion ( app rox . US-$ 2.46 billion) in 1990. The estimated in­ vestments for the environment from FY 1991-1997 will be U.S. $ 37 billion, acco rdi n g to the six-year National Develo pme n t Plan.

6 Biotechnology in the

6 Biotechnology in the Member States of ASEAN

I m port s :

Member

States

of ASEAN

409

raw materials, capital goods , and consumer goods (fr o m J a p a n , the USA. Singapore and Germany)

Indonesia wel c o m es foreign investment, p art icu larl y in ex port - o rien ted industries. 6.1 Indonesia Foreign companies norm al ly establish joint ventures, but may take 100% e q u ity in pro ­ Susono S aon o jects worth at least US$ 50 million or in those located in remote areas. Investments are ap­ General proved by the Investment Coordinating Indonesia is a tropical cou ntry with a t otal Board, which provides specialist help to for­ area of 9819317 km 2• which compri ses eign companies in taking advantage of incen­ 1919317 km 2 of land consisting of 667 isl a n ds tives such as duty-free allowances. The direct and 7900000 km2 of sea (including the Exclu­ investment data reveal a rapidly expanding sive Economic Zone). It has a wet season I ndonesian economy, if still c oncent rating on with an average temperature of 22 to 28 oc, low-technology industries. Total foreign in­ and a mean annual rainfall of 700 mm. Indon­ vestment in 1992 was US-$ 10.3 billion, an in­ esia has a rich flora and fauna - about 1 0% of crease from US-$ 8.8 b i lli on in 1991. Lea di n g all living sp ec ies in the world are represen ted sources of foreign investment are Taiwan, Ja­ pan. Bri tai n , and Hong Kong, while leading in Indonesia. W i th a total pop ul a ti o n of 183 million. it is targets of foreign investment are chemicals, the fourth largest country in the world i n m in in g , and hotels. D urin g the last few years, terms of p o p u l a t i o n . Its pop ulati o n growth tourism has become another im po rta nt indus­ rate p re s e n tl y is 1.8%, with a life expectancy t ry . In 1992, 3 m i l l i o n tourists generated re­ of 55 years for males and 58 years for females. c ei pt s of US-$ 3.2 billion. Ei gh t y percent of the Indonesians are mus­ lim, but c hristi ani ty . hinduism and buddhism Research and Development are also present. Economy Indonesia's economy has grown dramati­ cally d uri n g the l a s t 25 years. The nation's gross domestic product (GOP) reached a lev­ el of Rp 273 trillion i n 191)3, and growth in GOP averaged 7% in real te rms over a 25year period. Inflation r a t e is between 6.0 and 7.0%. The agricultural sector tends to de­ crease, e.g., from 19.5% of G O P i n 1991 to 18.5% in 1992. Ov e r the last five years, pro­ d u c t i v i ty in manufacturing increased in real terms by 18%. Exports in 1993 were US-$ 38.4 billion. and imp ort s US-$ 34.9 billion. leading to a trade su rp l us of US-$ 3.5 b i l l i o n . The leading items are: Exports:

gas. textiles/garments. and p l ywo od (to Japan. the EU and t h e

oil &

USA)

The basic policy of the government on R&D is to use them as a means to improve planning and to accelerate national develop­ ment. There are two categories of R&D pro­ grams: "short-term" and "long-term" pro­ grams. In the "short-term" programs, priority is given to R&D activities in the fields of agri­ culture, industry, energy, and mineral re­ s ou rces , with emphasis on labor a bsor p tio n , the use of local materials. and the balance of payments. In the "long-term" programs, em­ p ha sis is on human and natural resources a nd the environment. The implementation of this policy is carried out by research institutes and universities, whose research acti vit i es are coordinated by the State Minister for Re­ search and Technology. As most of R&D ac­ ti vit ie s are conducted by government institu­ tions and universities, the govern m en t is still the biggest source of funding (Tab. 32). Indonesia's spending on R&D in 1991 was Rp 500 billion, equivalent to 0.2% of the

410

13 Biotechnology in the Asian-Pacific Region

Tab. 32.

Sources of Funding and Performers of

R&D

Source (%) Performer (%)

Government

Industry

Others

80 62

19 33

1 5

country's GDP. The breakdown of R&D ex­ penditure is summarized in Tab. 33. Within the non-ministerial research insti­ tutes (LPND), R&D accounted for about 25% of the total budget. The most important of the LPNDs, the Agency for National Atomic Energy (BATAN), had the largest R&D budget, with 35% of the LPND total. The high level of R&D support for BATAN reflects the government's policy aimed at de-

Tab. 33.

veloping an indigenous nuclear energy capa­ bility. In 1991, about one half of the nonsalary R&D funds of public universities was di­ rected toward engineering or agricultural sciences (80% ) and to the medical and physi­ cal sciences (20% ) The R&D workforce of Indonesia is sum­ marized in Tab. 34. .

The industry The participation of the private sector in R&D, and in the business of biotechnology, is still insignificant. A limited number of large companies, mostly joint venture companies, are active in the production of flavoring sub­ stances such as soy sauce and monosodium glutamate (MSG), beer, and lactic acid bever-

Use of R&D Expenditure Budget 1 99 3/94 (Billion Rp) Development b Routine•

Institution Performing R&D No-Department/Ministerial Institutions

(LPND)

National Aerospace Agency (LAPAN) Indonesian Institute of Sciences (LIPI) National Atomic Energy Agency (BATAN) Agency for Technology Assessment and Application (BPPT) National Survey and Mapping Coordinative Agency (BAKOSURTANAL) Central Bureau of Statistics (BPS) National Archives National Library Environmental Control Agency (BAPEDAL) Others Sub-total

0 16.967 29.7 53 3.8 71 0 0 0 0 2.667 0. 38 2 53.640

6.8 28 26.66 3 22. 211 21 .468 16.948

Total 6.8 28 4 3.6 30 51 .964 25. 339 16. 94 8

15.4 20 0. 351 2. 307 4.4 54 21. 376 138.0 26

1 5.4 20 0. 351 2.307 7.1 21 21 .7 58 191.666

55. 644 1 2. 584 6.817 1 1 6. 301 36. 216 7. 341 128. 238 36 3.141 501.1 67

82.6 98 23.1 64 41 .259 1 16. 301 36. 216 1 1. 28 2 142. 709 453.6 29 645. 29 5

DepartmentaVMinisterial Institutions

Ministry Ministry Ministry Ministry Ministry Ministry Others

of Agriculture of Industry of Mining and Energy of Education and Culture of Health of Forestry Sub-total Grand total

• excluding budget for training and services b excluding capital (building and equipment)

27.0 54 10. 580 34.44 2 0 0 3.941 14.471 90.488 144.1 28

6 Biotechnology in the Member States

of ASEA N

41 1

Tab. 34. R&D Workforce in I ndonesi a . 1 993 Training Level

Indust ry

U n iv e r s it y

99055 80 945 4360 32 1 5

1 5 375

1 7 620 425 230

75 1 5 250 2400 775

1 87 575

33 650

1 8 500

Government

Diploma (D3 ) Bachelor ( S 1 ) Masters (S2) Ph.D. ( S3 ) Total

Total

11 4 505

1 1 3 81 5 7 1 85 4220

239 725

Tab. 35. Companies Active in B iotechnology C om pa ny

Location

O w ne rs h i p

P ro du cts

Perum Bio Farma P. T. Kalbe Fa rm a

Ba n du n g Ja k a rt a

S ta te ent e r p r i se

P. T. M e ij i I ndonesia

J a k a rt a

J apanese

Vaccines, sera, diagnostics Pharmaceuticals, di agn os t ics

J a karta

Fre nch

Pharmaceut icals, vaccines

J a k a rt a

S w i ss

Antibiotics

Surabaya

State e nte rprise

Probolinggo M oj o k e rto G resik Sura kart a Su rab aya

Indonesian J apa n e s e K o re a n Indonesian State e nt e rpr i se Indonesian

V acc i nes , a ntig e n s G l utamic acid

Pharmaceutical I ndustries

P. T. Rhone-Poulenc Indonesia

Pharma P. T. Sandoz B ioc h e mi c Farma I n do ne s ia Pusat Ve t e ri n a r i a Farma

P. T. S a s a Inti P. T. Ajino m ot o

P. T. Miwon Indonesi a

P. T. Indo Acidatama

Perusahaan Daerah Aneka K i mia Rhizogin Indonesia

J a k a rta/Bogor

ages. Others have started with the production of h uman and animal vaccines, sera, and diag­ nostic kits for a number of diseases. Most of the R&D is carried out by their overseas partners. Many medium and small companies are active in the prod u ct io n of traditional fer­ mented foods and beverages such as tempe . None of them, however. is conducting R&D to improve their products. Major companies active in biotechnology are listed in Ta b 35.

Indonesian

•

•

•

The government

·

Gl utamic

acid

G lutamic acid Ethanol E t ha n ol

Rhizobium starter cultures

velopment of Biotechnology (NCDB) was es­ tablished by the MSST. The Committee has the following functions:

.

The m a i n body responsible for S&T is the Mini stry of State for Science and Technology ( M SST) . Biotechnology has received a high priority in the national S&T development program. To that end, a National Committee on the De-

Antibiotics

•

to prepare and formulate a national bio­ technology policy and development pro­ gram to assist national development, to give guidance and encouragement in the development of bioindustry and its supporting R&D and human resources, to give directions for the establishment of national, regional, as well as an inter­ national network of cooperation on bio­ technology, and to mon i to r the implementation of the national policy.

To implement this policy, a program has been formulated in 1 990, with the following priorities

412

13

Biotechnology i n the Asian-Pacific Region

(1) production of fine chemicals and phar­ maceuticals such as antibiotics, amino acids, vitamins, (2) mass production through micropropa­ gation of industrial, horticultural, and forestry plant species, (3) improvement of food crops quality, in particular rice and soybean, (4) improvement of beef and dairy cattle quality through embryo transfer, and (5) production of various diagnostics and vaccines for human and animal dis­ eases. The program is implemented by several "Centers of Excellence": •

•

•

Centers of Excellence on Agricultural Biotechnology I and II, coordinated by the Central Research Institute for Food Crops (CRIFC) and the R&D Center for Biotechnology (LIP/), respectively, both in Bogor Center of Excellence on Health Biotech­ nology, coordinated by the Medical Fac­ ulty of the University of Indonesia in Ja­ karta, Center of Excellence on Industrial Bio­ technology, coordinated by the Agency for Technology Assessment and Applica­ tion (BPPT) in Jakarta.

Universites The main task of the universities is in edu­ cation and training. Research is only con­ ducted in laboratories and institutes attached to different faculties of the universities. Some universities, however, have specific research institutes which operate independently of the faculties. Administratively, state universities are under the jurisdiction of the Ministry of Education and Culture (see Fig. 7), but in their activities, including research, they enjoy a considerably high degree of autonomy. There are over 15 000 Science and Engineer­ ing faculties in Indonesia's public universities: about 20% of the 1 .5 million students at pub­ lic and private universities are enrolled in the natural sciences and engineering. The public universities play an important role in S&E education, enrolling nearly 1/2 of all students in this field. Public universities on Java con­ tinue to enroll more S&E students than do those on the other islands, but the enrollment rates on the other islands are increasing faster than on Java. The number of S&E degrees awarded to the 22-year-old population in In­ donesia was about 4 per 1000 . Major univer­ sity faculties active in biotechnology R&D are summarized in Tab. 37. Contextural measures

Each of these centers has the task to set up a network of institutions active in its particu­ lar field. Besides the NCDB , there is also a National Commission for the Preservation of Plant and Animal Genetic Resources, which was set up by the Minister of Agriculture. Although there is no formal working arrangement with the NCDB, a close cooperation exists at the operational level because a number of R&D institutes are represented in both. Research institutes There is a considerable number of research institutes concerned with studies relating to biotechnology. They are summarized in Tab. 36.

Indonesia has recognized the value of mi­ crobial and cell culture collections. At least 6 culture collections provide reliable services: 1. the Veterinary Research Institute's (Balitvet) culture collection for animal pathogenic microorganisms, 2. the Bandung Institute of Technology's (ITB) culture collection for industrial microorganisms, 3. the Medical Faculty of the University of Indonesia's culture collection for human pathogenic microorganisms, 4. the Agricultural Faculty of Gaj ah Mada University's culture collection for soil microorganisms, 5. the Faculty of Science of the University of Indonesia's culture collection for in­ dustrial molds, and

6 Tab. 36.

Biotechnology in the Member States of ASEA N

413

Research I nstitutes Concerned with R&D in Biotechnology

Institute

Location

Supervision

Targets

Indonesian Sugar Research I nstitute (ISRI)

Pasuruan

MA

Central Research Institute for Food Crops (CRIFC), Laboratory of Plant B iotechnology Marihat Research Center

Bogor

MA

Dextranase, xanthan gum, sugarcane breeding, wastewater treatment, genetic engineering techniques Molecular genetics of rice diseases, cell and tissue culture, nitrogen fixation, bio-fertilizers, bioconversion

Pematang Sian tar CiawiBogor Bogor

MA MA

Bogor

MI

Jakarta

BPPT

Bandung

LIPI

CibinongBogor

LIPI

Jakarta

MSRT

Research Institute for Animal Production Research Institute for Veterinary Science Institute for R&D of Agro-based Industry (IRDABI) Center for the Assessment and Application of Technology (BPPT) R&D Center for Applied Chemistry {RDCAC), Indonesian Institute of Sciences (LIP!) R&D Center for B iotechnology (RDCB) , Indonesian Institute of Sciences (LIP!) Eijkman Institute for Molecular B iology

Tissue culture on cocoa, tobacco, rattan, vanilIa, oil palm etc. Feed improvement using ferme ntation, mannanase, embryo transfer, phytase, cassava-protein Cloning of veterinary toxins, veterinary immunology, monoclonal antibodies Industrial biotechnology, fermentation of soybean curd whey, food quality control Antibiotics production; plant, fish and livestock production; vitamin, enzyme and amino acid production Bioconversion of solasodine, waste water treatment, fermentation, tempe

MA

6. the R&D Center for Biotechnology's culture collection for economically im­ portant microorganisms. In 1 989, a patent law was passed which provides patent protection for 14 years. With respect to biotechnological invention, howev­ er, the law is not too supportive because no patent will be granted to (a) any process for the production of foods and drinks for human and animal consumption, (b) foods and drinks for human and animal consumption, (c) new plant varieties and animals, (d) any process for the production of new plants and animals or their products. Although no special regulation on the re­ lease of genetically modified organisms (GMOs) has been drafted, there are several laws which could be used to safeguard the en-

Fermentation and enzyme technology, SCP, plant biotechnology for tropical fruits, embryo transfer technology Mitochondrial DNA mutations in human diseases, ageing process, energy-transducing systerns, thalassemia, diagnostic kit for Dengue hemorrhagic fever

vironment and society against possible haz­ ards due to the release of GMOs. Recently, in August 1993, a Guideline on Genetic Engi­ neering Research has been released by the State Ministry on Research and Technology. While the emphasis of this guideline is on the requirements for and control of research on genetic engineering, it provides to some ex­ tent additional protection against possible hazards of GMOs release.

6.2 Philippines Jeannie Scriven The Philippines, made up of more than

7000 islands, has a population of 67 million (1994) which is expected to grow to 75 million

13 Biotechno/ogv in the Asian-Pacific Region

414

r-1'--1

MA

�

RD R C__. F_ __I_ __�t--------1'---C _A -�_A ---�-r -

___

MF

>- -

-

-

A FRO

--'------�

Pre side n t

tI I

Direct MA MF

ME Ml

MSRT MSEnv LIP I BPPT

ma nage me nt

-

- - --'------'

line

Coo rdin ative scienti fic m a nageme nt li ne Ministry of A griculture Mimstrv of Forestrv

Mi nistr

y

of

Education and

Ministry of I n d u s t ry

Culture

State Minister for Research and Technology

State Minister for the E n v i ronm e nt and Population I ndonesian I nstit ute of Sciences

Agency for the Development and App l i c a t i o n of Technology

BAT AN

National Atomic Energy Agency

AFRO

Age ncy for Forestry R ese a rch and Development

AARD Univ

Agency for Agricultural Research and Developme nt U n ive rsi ty

CRIFC

Centra l Research Institute for Food Crops

IRDABI

Institute for R & D on Agrobased Industry

I UCB

RDCB

I n t e r U niversity Cente r on Biotechnology R&D Center for Biotechnology

Fig. 7. Struct ure of S&T in Indonesia. w ith emphasis on life sciences.

6 Tab. 37.

Biotechnology in the Member States of ASEA N

415

University Faculties with Major Activities i n Biotechnology

University

Location

Field of Study

Faculty of Pharmacy, University of Airlangga Food and Nutrition Development and Research Center (FANDARC), Gadjah Mada University (UGM) Inter University Center for Biotechnology, Gajah Mada University

Surabaya

Plant cell cultures, biotransformation with plant cells, rat hepatocyte cultures Biopreservation, lactic acid bacteria, cell fu­ sion among Aspergillus strains, monoclonal antibodies for aflatoxin

Yogyakarta

Yogyakarta

Inter University Center on Biotechnology, Institut Teknologi Bandung School of Medicine, University of Airlangga

Bandung

Department of Microbiology, University of Indonesia Faculty of Agriculture, Gaj ah Mada University

Jakarta

Inter University Center on Biotechnology, Institut Pertanian Bogor

Bogor

Surabaya

Yogyakarta

by the year 2000. In the fifties, the Philippines was the second richest country in Asia, be­ hind Japan. During the eighties, the economy grew by an average of 1 .5% but the popula­ tion grew by 2.5% per annum. Currently, more than 40% of the population live below the poverty line. Foreign debts - incurred un­ der MARCOS are in the region of US-$ 34 thousand million. 40% of the state budget is used to finance these debt repayments. Gross domestic product ( GOP) quarterly growth in mid 1994 was 3.8% compared to stagnation in GOP growth between 1991192 and 2.3% in 1 993. This is due to two factors - political sta­ bility under General RAMOS and better elec­ trical power supplies. During 1993 in Manila, there were "brown-outs", which meant that there was no electricity for 10-12 hours daily. However, a bright spot on the economic front is electronics, instrumentation and control in­ dustries, which generated more than a third of total exports in 1 994. Expenditure for

Genetic analysis of Waardenburg syndrome, Thalassemia, Dengue viral antigens, diagnostic tools based on PCR, erythromycin and BT toxin production Microbial fermentation, enzyme technology, genetic engineering, biological waste-water treatment Reproductive health, infectious diseases, can­ cer and degenerative diseases, forensic serolo­ gy Dengue virus diagnostics, Salmonella diagno­ sis, hepatitis C research Baculo virus detection, CVPD-free citrus see­ dlings, PCR technology, SMZ coat protein ge­ netics for virus-free soybean stocks, food bio­ technology Improvement of plant productivity by tissue culture, embryo transfer, microbial biotechnology, waste treatment, culture collec­ tion

R&D is 0.12% of GDP, below the UNESCO recommendation of 1% for developing coun­ tries. The Philippines has an agricultural-based economy. However, it is blessed with a diver­ sity of organisms available, which may be pos­ sible sources for natural products in the fu­ ture. The country produces some 30 million metric tons of organic waste per year, includ­ ing corn stalks, rice straw, coconut husks and shells. However, transport costs may limit commercial exploitation of these raw materi­ als. Annual production of bagasses is esti­ mated to be about 6.4 million metric tons while that of coconut shells and husks is 7.5 million tons. There is urgent need for the pro­ duction of planting materials by means of tis­ sue culture techniques to help speed up the country's coconut replanting program. There is no home Philippines pharmaceuti­ cal industry; it is entirely dependent on im­ ports. There is a limited volume of anti-diph-

416

1 3 Biotechnology in the

Asian-Pacific Region

theria, and anti-tetanus vaccines produced by the Department of Health. As far as biotech­ nology activities in the private sector are con­ cerned, there is some production of animal vaccines at commercial level by Biologics Corporation, Riverdale Tryco and the B ureau of Animal I ndustry. Haemorrhagic septicemia vaccines are produced and it is planned to commercialize swine plague and hog cholera vaccines. Current research includes DNA probes for hepatitis B virus, pregnancy testing kits. a monoclon al antibody against Schisto­ somia j aponicum. experimental production of penicillin and antifungals and rifamycin. Bio­ technological products include Zymax, a pro­ biotic and poultry additive using yeast and bacteria. a Bacillus th uringiensis powder to control vegetable pests and malaria. a my­ corrhizal inoculant for pine seedlings. and nata de coco. As far as the agrochemical and food sec­ tors are concerned, there is little R&D in bio­ technology. which is characterized by such firms as the San Miguel Corporation. a multi­ national in the food and beverage trade. The U FC company recently built a ten thousand liter fermentor for its vi negar production. Scie nce and technology (S&T) activities are monitored by the D epartm en t of Science and Technology (DOST) . The DOST in turn guides five councils: Agriculture and Forest­ ry, Health, Advanced S&T ( PCASTRD). In­ dustry and Energy. and Aquatic Manage­ ment. DOST also directs the following re­ search institutes: Industrial Technology De­ velopment Institute . Food and Nutrition Re­ search Institute . Forest Product Research and Development Institute . Philippine Nuclear Research I nstitute. The bulk of S&T man­ power is to be found in academic institu­ tions: S&T Manpowe r State colleges and universities Department of Agriculture Department of Environment and Natural Resources Department of Scie nce and Technology Other commodity research institutes M iscellaneous

% of Total 47 27

5.7 2

13 5

In 1 990, the country had some 58 doctoral degree holde rs and 1 50 personnel with master degrees engaged in biotechnology research and development. In 1 990, the government drew up a M aster Science plan through DOST: it identified biotechnology as a prior­ ity area. The Philippine Council for A dvanced Science and Technology Research and Devel­

(PCASTRD) prepared a strategy, which was to develop agriculture, aquacul­ ture , health, industry and the environment. In agriculture . fertilizer substitutes, tissue cul­ ture . biological control agents, animal pro­ duction and improvement, and tissue culture for secondary metabolites were to be given attention . Diagnostics and vaccines, coconut tissue culture , tailored fats from coconut oil and the application of biotechnology in refor­ estation were to support productivity in agri­ culture. Six projects are to be implemented between 1 991 and 1 996 including penicillin production. A major center of R&D activity is at the University of Los Banos, at the National Insti­

opment

tutes of Biotechnology and Applied Micro­ b iology (BIO TECH).

The siting of the Inter­ national Rice Research Institute (IRRI) near­ by provides scientific impetus and technologi­ cal resources in the Los Banos region. In late 1994. IRRI produced a "superrice" hybrid, which could improve yields by 25 % . The fol­ lowing are areas of expertise at B IOTECH: molecular biology (isozyme markers for gene mapping in mungbean, high insecticidal activ­ ity against rice pests in Bacillus thuringiensis) , micropropagation ( tissue culture studies of crops) . microbial control of pests and dis­ eases, microbial fertilizerlbiofertilizer, and legume-specific inoculants, and food/feed fer­ mentation bioconversion. B IOTECH is also developing alternatives to conventional prod­ ucts and processes, such as mycorrhizal ta­ blets for reforestation, cell and protoplast cul­ ture of orchids. lysine production, inoculants, pasteurella vaccine, and mushrooms. Re­ search on medicinal plants under the "herbal medicine program" is being carried out. B IO­ TECH maintains a culture collection for safe­ keeping and research uses. The Philippines Coconut Authority has a gene bank for coco­ nuts and IRRI maintains rice plant cultures. The University of the Philippines at Diliman

6

Biotechnology in the Member

concentrates on medical and i ndustrial re­ search, such as economically important plant and fish species. Regarding financing biotech nology devel­ opment, there are soft loans available to the private sector to commercialize products through the Development Bank of the Philip­ pines, with the endorsement of DOST. Re­ search funding comes mostly from interna­ tional sources. such as the the Japan Society for the Promotion of Science. which provides exchange scientist programs. The Philippines is currently debating a change in its patent laws. Patents may be granted by the Bureau of Patents. However. the critical evaluation of patent applications is limited since the exper­ tise to assess is lack ing. T he r e are regulations governing the traffic of microorganisms and biotechnology experime ntation formulated by DOST. based on U S and Australian guide­ lines.

6.3 Malaysia Jeannie Scriven Average economic growth over the period 1 970-1 990 was a steady 6.7% and currently the Malaysian economy is growing by over 8% per annum. Gross domestic product (GOP) per capita lies in the region of US-$ 2570 with a population of approximately 20 millions. However. factory owners are com­ plaining of labor shortages. and other Asian countries, (including Vietnam. Indonesia and India), can supply cheaper workers. There is a danger that Mal aysia may soon become too rich to qualify for tariff exemption under GATI. The problem facing Malaysia now is to keep its cost-base low enough to compete with other countri es. There is an inflation rate of 3.7% ( 1 993). The economic indicators dur­ ing July 1 994 were an increase of 8.4% in GOP. and growth of 10.6% in industrial pro­ duction when compared with the previous year. GOP is projected to grow at 7-8% per annum into the next century. Malaysia's in­ vestment in R& D . at present below 1 % of GOP. is expected to reach 1 .6% by 1 995. The economy i s changing from being pre­ dominantly agriculturally based - rubber,

States

of ASEAN

41 7

palm oil, cocoa and forestry represented 18.7% of GOP in 1990 - to being manufactur­ ing and service based (for example, semicon­ ductors) . It is hoped that manufactured goods will make up 80% of exports by the year 2000 . One example of successful industrializa­ tion is that Malaysia has launched its own mo­ tor industry with penetration of 60% of total automobile sales. M alaysia has declared that it wishes to achieve the status of an industrial nation by the year 2020 (Vision 2020 strategic plan). In 1 987, a National Biotechnology Com­ mittee was established and a B iotechnology Program coordinated under the auspices of the Malaysian National Council for Scientific Research and Development (MPKSN) . The MPKSN reported in 1 993 that, when com­ pared with European universities, about 1-2 researchers comprise the biotechnology re­ search base in a Malaysian university, as against 8- 1 2 at a European university. A peer review system was also absent. As a result of the findings. the MPKSN decided to establish a National Biotechnology Center, and to set up a Bioprocessing-Prototype Manufacturing Facility (BPM). This is intended to provide large-scale process facilities. Five priority in­ vestment areas for the center were identified: diagnostics. plant tissue culture scale-up, bio­ technology of oleochemicals , natural products screening and development, and environmen­ tal biotechnology. The MPKSN commissioned a study to evaluate current biotechnology activities and their potential for commercialization. It came to the conclusion that Malaysian industry and the private sector do not generally use bio­ technology, but that certain sectors could cer­ tainly benefit. including pharmaceuticals, vac­ cines, diagnostics, food, novel plants etc. As for industrial biotechnology, there was a very low level of activity. Few i ndustries existed for pharmaceuticals, diagnostics and ad­ vanced food production; industry was not in­ volved in publicly funded grant schemes and biotechnology needed to be promoted. The study also found that there was lack of aware­ ness in industry as to opportunities available and there was inadequate organization/struc­ ture . It also found that research was "iso­ lated", there was little contact between uni-

418

13

Biotechnology in the Asian-Pacific Region

versities and industry, there was an inade­ quate base of science students and lack of knowledge about patents and rights. It was felt that R&D funding was not operating effi­ ciently. AU research programs undertaken by the 24 research institutes and eight universities are overseen by the MPKSN. For the current Five Year Plan (1991-95) RM 600 million has been provided. Two important government departments with regard to biotechnology are the Malaysian Technology Development Cor­ poration and the Malaysian Industrial Devel­ opment Authority. A Technology park is be­ ing set up adjacent to the main North-South Highway linking 5 universities and 8 insti­ tutes, including the Palm Oil and Standard and Industrial Research Institutes. There is some success in transferring insti­ tutional research into private sector manufac­ turing practice. A food-based Newcastle Dis­ ease vaccine, developed by Universiti Pertan­ ian Malaysia, and the production of diagnos­ tic kits for Dengue fever and Japanese ence­ phalitis by Universiti Sains Malaysia, have found partners in the private sector. Also the technology to deal with mill effluents in the palm-oil agroindustry using a bioreactor will be commercialized. Large plantation compa­ nies, such as Guthrie Chemara, have small R&D sections, made up in this instance by one senior scientist and assistant. Their role is micropropagation or cloning of palm-oil seed­ lings. Such private sector activity is often to meet in-house needs. However, the palm-oil industry has been set back in the field of clon­ ing oil-palm seedlings, because of the abnor­ malities in the fruits of tissue culture-derived oil palms Areas of relevance to biotechnology in the private sector are food processing, agricul­ ture, aquaculture, pharmaceuticals and waste utilization. Fermentation technologies are used in tapioca and sago palm starch and veg­ etable oil processing, while enzymatic pro­ cesses are used in the production of fruit juices, lipases and fats. International compa­ nies, relying heavily on foreign technology, characterize the food sector. Research for the rubber industry is carried out at the Rubber Research Institute of Malaysia (RRIM) and has focused on genetic diversity. Because of

the waste generated by rubber, coconut, co­ coa and palm-oil estates, the government has introduced discharge regulations. There is in­ terest in producing biofertilizers and in using microorganisms to deal with the waste slurry. The medical and veteri nary pharmaceutical market is growing by 10% annually; products include diagnostic kits, vaccines, antibiotics and hormones. There are some government fiscal indus­ trial incentives including building allowances, plant and machinery capital allowances and tax relief for R&D companies. It is intended to implement biosafety guidelines in 1994 which deal with the release of genetically modified organisms (GMOs) into the envi­ ronment.

6.4 Singapore Jeannie Scriven With a population of almost 3 million, Sin­ gapore's economic base consists of electronic manufacturing (mainly discdrives), communi­ cations, financial and banking services, trans­ portation and petro-chemical refineries. Be­ tween 1 988 and 1 992, the economy grew on average at 8.2% . Gross domestic product (GDP) per capita for 1992 was S-$ 26 604 ( = US-$ 16627 equivalent) . Gross expendi­ ture on R&D was 1 .27% of GOP in 1 992. The government is highly interventionist in its economic policy; a strategic business unit for the National Biotechnology Program was established in 1 988, with the aim of founding a technology base for biotechnology. It was also to develop manpower. Singapore Bio-la­ novations was founded by the Economic De­ velopment Board (EDB) in 1990 to encourage industrial biotechnology activities in Singa­ pore. Four categories of projects are targeted: early startup, existing biotechnology compa­ nies, overseas promising biotechnology pro­ jects and new foreign biotechnology projects which are to be established in Singapore. During 1992, Research and Development (R&D) spending was as follows:

6

Biotechnology in the Member States of A SEA N

S$ millions % of total Private sector biotechnology firms Higher education sector Public research institutes Government sector

577.6

61

1 56

16

1 10 1 05

12

11

There is assistance from the National Science and Technology Board (NS TB) to help promote R&D in the private sector. with finan cial grants and project costs. Private companies can also take advantage of other business development i ncentives including pioneer status (exemption of corporate tax). In the Singapore Biotechnology Directory published in 1 994. the private sector is repre­ sented by 26 firm s with more than 50 em­ ployees. However. the directory did not list any maj or Japanese firms. subsidiaries or trading supplies or even Beechams (pharma­ ceutica l s ) The N STB is responsi b le for R&D promotion. but is not involved in medical re­ search. Its R&D r es earch budget for 1 993 was S$ 350 million I t fu nds 5 research institutes and 4 research centers. whose recurrent an­ nual budgets are given i n parentheses: .

.

GIMT G I NTIC I ns t i t ut e of Manufact u ring Technology (S$ 6 million) IMCB Institute of Molecular and Cell Biolo­ gy (S$ 25 million ) Institute of Microelectronics (S$ 17 IME million ) ISS Institute of System Science { S$ 18 million) ITI Information Technology Institute {S$ 16 m i ll ion ) CRISP Ce nter for Re mote Imaging and S e nsing Processsing CWC Center for Wireless Com munication MTC Magne tic s Technology Center MSRC National Supercomputing Research C e n ter The NSTB formulated a National Technol­ ogy Plan. which has two targets to be reached b y 1 995: nat i o na l expenditure on R&D should reach 2% of G OP and the ratio of re­ search scientists and engineers should be 40

419

for every ten thousand workers. A S$ 2 b il­ lion fund was provided to support R&D, to fund research, to develop manpower and to build a suitable infrastructure. Biotechnology is one of the areas targeted. Much of the R&D in the higher education sector takes place at the National University of Singapore (NUS) . The chemical engineer­ ing department at the NUS is the only dep art ment graduating chemical engineers a n d re­ searching in large-scale production and purifi­ cation techniques I n order to meet manpow­ er training needs as well as development in the field of fermentation technology, the Rio ­ processing Technology Unit (B TU) of the NUS was established in 1 990. It was equipped to the tune of S$ 26 million, with much of the fermentation apparatus coming from B . Braun B iotech (Germany). Its aim i s to "facil­ itate the application of research in bio­ technology and to meet the process develop­ ment needs of the local biotech industries". The unit is funded ultimately by the EDB . It seeks to promote multidisciplinary collabora­ tive research between university and indus­ try. As far as manpower training is concerned, a Massachusetts Institute of Technology­ NUS international workshop on "Fermenta­ tion and Bioprocess Technology" has been held. BTU was also joint organi zer of the 3rd Asia-Pacific Biochemical Engineering Con­ ference during 1 994. The technical sessions included topics such as Bioproducts from Pro­ karyotes. and from Eukaryotes, Biocatalysis/ Protein Engineering, B ioprocess Monitoring, Modelling and Control , and Bioremediation and Decontamination. Current activities in­ clude protein/peptide and DNA/oligonucleo­ t ide sequencing and synthesis. The unit is pre­ pared to take on contract jobs for industry in fermentation, cell culture and product purifi­ cation. The BTU will provide custom-made peptides in immunological assays, DNA and peptide sequencing, and synthetic oligonu­ cleotide primers and probes. The Institute of Molecular and Cell Bio logy ( IMCB) was inaugurated in 1 987, with the aims of developing a modern research culture for biological and biomedical sciences and to train scientists. The research topics are as fol­ lows: Cell Regulation. Molecular Genetics/ ­

.

420

13

Biotechnology in the Asian-Pacific Region

Protein Engineering, Plant Molecular Biolo­ gy, Molecular Neurobiology, Tumor Immu­ nology/Virology, and Microsequencing and Peptide Synthesis service. The institute has 1 60 scientists, half of whom have Ph.D. de­ grees. The institute has research ventures with the following biotechnology companies: Glaxo UK (brain research) , Amylin Corp. USA (diabetes research) Glead USA (anti­ sense technology) Genzyme USA (TNF-{3), Millipore (protein microsequencinglpeptide synthesis), Bayer AG Germany (mosquitoci­ dal toxin) and Singapore Bio-Innovations. During 1 994, the IMCB officially opened a Center for Natural Product Research, in or­ der to discover novel lead compounds for the development of new drugs. The funding for the center is staged over 10 years; Glaxo will contribute S$ 30 million, the EDB S$ 10 mil­ lion and the IMCB (through the NSTB) will contribute S$ 20 million in infrastructure and research support. The staffing will rise from 1 5 scientists to 30 by 1 995. There are two government departments which are important for biotechnology devel­ opment - the Primary Production Depart­ ment (PPD) and the Singapore Institute of Standards and Industrial Research (SISIR). The former (PPD) is affiliated to the Ministry of National Development and its terms of ref­ erence are to supply safe, wholesome and quality foods, the safeguarding of the health of animals, fish and plants, and as a center of excellence for tropical agrotechnology ser­ vices and to support trade in primary produc­ tion. To this end, it is involved in projects such as hydroponic farming technology, soil­ borne diseases of trees, poultry disease and integrated pest management strategies. It has an R&D staff of 50, five of whom have docto­ rates. Its total budget is S$ 35.3 million. SISIR is affiliated to the Ministry of Trade and Industry, and is involved in standardiza­ tion, certification, quality systems, quality promotion, Consultancy and training activi­ ties. It is also responsible for measurement standards, technology transfer, materials technology, patent and technical information. It has a staff of 570, and a total budget of S$ 46 million. Singapore adheres to the Interna­ tional Standards Organization 9000 regula­ tions. There is no official culture collection in Singapore.

As part of the Information Technology 2000 masterplan, a science and technology network called Technet was founded to pro­ vide computing support. The NSTB helps with the expenses incurred in applying for pa­ tents and encourages the commercialization of technology developed overseas. Financial assistance is available; up to 50% of costs to a limit of S$ 30000. There is also funding avail­ able for patent applications in the US.

6.5 Thailand Jeannie Scriven Thailand has a population of 58.6 million

( 1993) with modest population growth pros­ pects. Its annual gross domestic product (GDP) per capita is US-$ 1402 ( 1991 ) with a real annual growth rate from 1987 to 1 991 of 1 1 .2% . Compared to its neighbors, Thailand is ahead of Indonesia and the Philippines but behind Malaysia and Singapore. GDP quar­ terly growth in mid 1 994 was up 7.5% on 1993, and industrial production increased by 10.7% , while consumer prices increased by 5.4% Agro-industry is the economic base of the country (tapioca, rubber, fruits, rice , su­ gar-cane, fish and poultry) while manufactur­ ing exports (food and beverages, tobacco, tex­ tiles, computing components, construction materials and transport equipment) increased by 12% . Tourism provides a steady inflow into the balance of payments. The inflation rate for 1 994 was 4% . Thailand made a commitment to biotech­ nology in 1 983 with the establishment of the National Center for Genetic Engineering and Biotechnology (NCGEB) formed under the Ministry of Science, Technology and the En­ vironment (MOSTE). Between 1 984 and 1 987, the budget increased from 7 million Baht (approx. US-$ 300 thousand) to 29 mil­ lion Baht (approx. US-$ 1 .2 million). In 1 985, supported by US-Thai cooperation, the Science and Technology Development Board was founded, with the task of underpinning development in priority areas, including bio­ technology. This Board was merged with the NCGEB and two other national centers to form the National Science and Technology

6

Biotechnology in the Member States of ASEA N

Development Agency (NSTDA) in 1 992. The current budget { 1 994) for NSTDA is 490 mil­ lion Baht (approx. US-$ 19 million) with 1 32 million Baht (approx . US-$ 5 million) ear­ marked for NCGEB . The National Research Council of Thai­ land is responsible for the formulation of R&D policy and supports research funding i n science a n d technology. Most research is car­ ried out in the universities. Current R&D ex­ penditure by the Thai Government is about 0.25 % of its GNP, equivalent to US-$ 1 00 million. About 20% o f this amount i s spent on biosciences and biotechnology. The NCGEB has initiated national projects including the Biotechnology Information Net­ work and a pilot plant for biochemical engi­ neering, situated at Mahidol University. The King Mongkut's Institute of Technology at Thonburi also has a pilot plant up to the 1 000 liter-scale at its disposal. Major research di­ rections are presently: - the improvements of crops, in particular rice , - the development of biological fertilizers and pesticides, - products related to human and animal health (vaccines, therapeutics), - energy-related targets (e.g., recycling of biomass, methane generation), - environmental R&D. In the private sector, Thailand has Asia's largest beef and dairy cattle ranches and is its largest producer of poultry. Under the Five Year Development Plan { 1 992-1 996) , the government hopes to increase agriculture tech nology investments in the private sector. Thailand's pharmaceutical industry has a yearly turnover of more than US-$ 1 .2 billion, mostly in packaging and the formulation of imported products. For the future, there are business chances in the development of spe­ ciality chemicals, diagnostics, vaccines, anti­ biotics, amino acids and other food-related biotechnical products. Unfortunately, the pri­ vate sector has not yet taken advantage of new biotechnological techniques such as ge­ netic engineering or hybridoma. Also, the re­ latively weak infrastructure (difficulties in transport and communications) and occasion-

421

a] water shortages do not encourage develop­ ments in the private sector. Most R&D work in biotechnology in the public sector is carried out in some 20 institu­ tions with almost 500 scientists. Four universi­ ties produce between 50-100 graduates in biotechnology per annum. There is some bio­ technology activity at Chiang Mai U niversity in the north of the country and at the Prince of Songkla University at Hat Yai, close to the Malaysian border. As far as contextual measures are con­ cerned, the government introduced tax ex­ emptions for R&D expenditure in order to encourage biotechnology. In 1 979, a patent system and standards were established. Cur­ rently there are no guidelines as to the pro­ duction of biochemicals. The Thai Industrial Standards Institute issues specifications for i ndustrial products, including biotechnology. The Government's Department of Medical Science monitors standards and quality con­ trol for biological products, including vac­ cines. The NCGEB has commissioned a study to consider what steps to take with regard to laboratory safety, field trials and environmen­ tal release. Patent law is particularly weak, since the Government fears that foreign firms will be the first to corner the market in local genetic resources if rigorous laws are intro­ d uced. A culture collection is available at the Thailand I nstitute of Scientific and Tech­ nological Research (TISTR) with its Micro­ biological Resources Center. As an example of a biotechnology-transfer project for the benefit of the private sector, the Carl D uisberg Gesellschaft financed a soy sauce quality control center for Thai produc­ ers: this is augmented by an executive club. It is hoped that the manufacturers will carry the costs of the quality control center. However, the difficulties of financing such a venture illustrate how fragile biotechnology develop­ ment is when the manufacturing base is lim­ ited. In the field of international cooperation, NSTDA cooperates with many countries, for example, the USA, Japan, Australia, Britain, Holland and the ASEAN countries. In 1990, the EC began joint EC/ ASEAN projects; in this framework, a group at Mahidol Univer­ sity is collaborating in the protein engineering

422

13 Biotechnology in the A sian-Pacific Region

of Pseudomonas lipase with Novo in Den­ mark, the University of Milan and the GBF, Braunschweig in Germany.

7 B iotechnology

sector. Biotechnology, with its various appli­ cations in the medical , agricultural and min­ ing markets , is considered a key technology to support such goals. However, while some im­ pressive results have been achieved, the "crit­ ical mass" of the internal markets may still be too small to support significant industrial de­ velopments on an international scale.

1n

Australia

The industry

Alan J. Jones and Rolf D. Schmid

The Australian and New Zealand Biotech­ nology Directory, in its latest version of 1 993, lists 1 78 Australian companies active in bio­ technology, of which 1 02 are manufacturers (Tab. 38).

Australia, one of the few OECD members in the Asian-pacific trading zone, is hampered by a sparce population ( 1 7 million) on a vast territory, similar in size to the USA or China. As a consequence, it suffers from small, high­ ly competitive national markets, from long continental and intercontinental distances, and from severe competition by its Pacific neighbors. Its advantages reside in a wealth of resources, mainly in agriculture and mining, and in a well-trained population whose edu­ cation is mostly based on B ritish traditions. After its ties to the United Kingdom were reduced as a consequence of the formation of the European Community, A ustralia has con­ tinuously strengthened the trade with her Asian-Pacific neighbors. In 1 990/9 1 , only 12% of its trade was with the EEC, but 28% was with Japan, 30% other Asian nations, and 1 1 % with the USA. The Australian economy is largely based on services ( > 60% of its GDP) and primary industries (agriculture and mining, 20% of GDP), whereas its manufacturing industries are of only modest but growing magnitude ( 1 5 % of GDP). As a result, industrial R&D is limited and accounts for only 40% of n ational R&D , which in turn is among the lowest of the OECD countries ( 1 .2% of GDP). Howev­ er, the country has developed excellent capa­ cities for S&T in the public domain, as indi­ cated by, e.g., overproportional international citation rates in areas such as chemistry, biol­ ogy or the earth sciences. In its brief post-colonial history, Austra­ lia's governments have invested considerable efforts to create a national manufacturing in­ dustry, by taking advantage of the public S&T

Tab. 38. Australian Biotechnology Companies:

Areas of B iotechnology B usiness

Major Focus on Manufacturing of

Number of Companies

Biologicals Pharmaceuticals Diagnostics Vaccines Food and beverages Plant agriculture Aquaculture Environment Medical devices Animal biotechnology

21 19 17 5 10 9 3 7 2 9

Concomitant to Australia's population dis­ tribution, 3 out of 4 companies are located in New South Wales or Victoria, i.e., in the met­ ropolitan areas of Sydney and Melbourne. Most of the companies are medium or small enterprises, and only 1 0 employ more than 60 people. Others are subsidiaries of large inter­ national firms. In many instances , biotechnol­ ogy is j ust one area of interest for such com­ panies, and the number of " dedicated bio­ technology companies", by the US definition , is 27. The total industrial workforce of profes­ sionally qualified staff in this field is esti­ mated to be around 1 400. Tab. 39 gives a list of those companies with > 40 professionals in biotechnology R&D.

7 Tab. 39.

Biotechnology in A ustralia

423

Major Companies in Australian Biotechnology

Company

Main Business

Burns Philp & Co.

Food, yeast and retailer company V accin es antibio tics , ph armaceuticals

Commonwealth Serum Laboratories Biotech Australia

Institute of D rug Technology Australia AGEN B iomedical

Arthur Webster South Australian Brewing

,

Vaccines, veterinary products, diagnostics Pharmaceuticals, diagnostics D iagnosti cs Veterinary vaccines Alcoholic beverages

In view of this limited capacity, and of the high standard of public research, the Govern­ ment has established several incentives for the creation of R&D-driven companies. Apart from a 150% tax concession for R&D, used by about 1 600 companies since its initia­ tion in 1985, there are Grant Schemes, includ­ ing a focus on strategic technologies as in the former Biotechnology Gene ric Grant Sch e m e, now operated under Auslndustry. In 1987, the "Factor (F) Scheme" was inaugurated as a tool to develop a pharmaceutical industry in Australia. In a country with strong traditions in social security and healthcare, but also with a time-consuming drug approval system and harsh price regulations, the program refers to the sixth (factor f) out of eight factors to be considered by the Pharmaceutical Benefits Pricing Authority when negotiating prices paid to manufacturers of pharmaceuticals, predominantly of ethical drugs. It allows for higher notional prices to be paid to a compa­ ny in return for approved programs of devel­ opment and a significant commitment to pro­ duction, research and development inside Australia. Apart from these subsidies, more direct attempts have been made to capitalize on Australian public R&D. Some examples are: Biotech Australia Pty Ltd. was founded in 1 979 and acquired, first in 1 981 by the mining company CRA as a strategic investment, sec-

Australian (A)/ Foreign (F)

Tu rnov er (Million $A, 1992)

Professionals in R&D

A

2500

1 80

A

1 52

17 5

F

85

(Hoechst AG) A

60

A A A

47 45

some 10

40

ond in 1989 Hoechst AG took a 50% interest, and in 1993 Hoechst acquired full ownership. Hoechst prides itself with the philosophy that Biotech Australia will maintain its own iden­ tity. Product developments have occurred wi th assistance from Government grant sche­ mes including numerous collaborations with Australia's premier research institutions. Bio­ tech Australia has specialized in animal health products and food diagnostics , but has an increasing commitment in the human health area. The recent establishment of a new plasminogen PAI-2 pilot plant and a sub­ stantial increase in R&D expenditure attests to this. The company also holds key patents in inhibin biochemistry. BRESA TEC Ltd. started in 1 982 from the Biochemistry Department of the University of Adelaide and became a world leader on porcine growth hormone. Recently, the com­ pany focused on transgenic animals and bio­ chemical reagents. The company became public in 1 987, and American Cyanamid and others took over the majority of shares. Turn­ over at present is aro un d $A 2 million. BIO TA Scientific Management (BSM) Pty Ltd. was founded 1 985 by CSIRO with a fo ­ cus on a molecular designed inhibitor to viral neuraminidase (influenza cure) Glaxo re­ cently invested $A 4 million in the company. AMRAD Co. Ltd. was established in 1 986 by a $A 50 million investment of the Victo.

424

13 Biotechnology in the Asian-Pacific Region

rian government as the commercial arm of Australia's leading biomedical research insti­ tutes. Due to licensing agreements and inter­ national alliances based on the products of its institutes, pharm aceutical sales topped $A 30

1 992. Gene Shears Ptv Ltd. was founded in 1 989 jointly by CSIRO and Groupe Limagrain, a million in

French-based seed company, in order to com­

mercially exploit a CSIRO pate nt on ribo­ zymes. In 1 99 1 . Johnson & Johnson joined the group.

Source funding

of R & D

The government The S&T policy of Australia is shaped by

many bodies, and the funding is appropriated mainly by the central gov e rn ment and indus­ try, as schematically shown in Fi g.

8.

The country's history was shaped by a co­

lonial government which, though liberal, still

largely displays interve ntionist behavior. This

is in particular true for economic affairs. As

S&T

in industrialized nations is a major fac­

tor for building the economy, the develop-

S e c t o r of R per formance

&0

Commonweal th government S 1 8 8 8 mil l ion

Business e n t e r p r i s e

S 1726 m i l l i o n

Overseas

S 54 m il l ion

P r i v a t e n o n - pr o f i t

S 57 m i l l i o n

Fig. 8. Flow of funding for Australian R&D

(1 988-1989).

7 Biotechnology in Australia

ment of the S&T policy of Australia is the re­ sponsibility of the Minister for Industry. Science and Technology , whose budget is lo­ cated in the Industrv. Science and Technolo­ gy portfolio. Goven 1 ment support for indus­ trial R&D. the budgets for the major govern­ ment research agencies. e. g . . of the CS IRO. AIMS, ANSTO and the Co-operative Re­ search Centres (CRC, see below), are also lo­ ca t e d in this portfolio. In 1 989. a Prime Min i s ­ ter ' s Science and Engineering Council, and a Coordination Committee on Science and Technology were established as discussion and evaluation panels. The latter is headed by the Chief Scientist. an institution borrowed from the British S&T system. Since the Chief Scientist is also the CEO of the Council, his function is pivotal in science policy coordina­ tion and development. A S TEC, the A ustralian Science and Tech ­ nology Council. is interlinked with the Science and Engi neering Council, but forms an independent source of advice, since its members are leading academics and business executives. The

A ustralian Research Council (A RC)

under the Ministry for Employment, Educa­ tion and Training. and the National Health and Medical Research Council (NH & M R C ) are the major bodies for university research grants.

Tab. 40.

425

National research centers/CSIRO Among the national research centers, the Industrial R e ­ search Organization (CSIRO) is by far the largest (followed by the Defence Science and Technology Organization, D ST O ). It is struc­ tured into 6 institutes and 35 divisions, which cover all major economic activities in the country. This includes several divisions re­ lated to biotechnology, as outlined in Tab. 40. Total CSIRO staff in 1 992 was about 7300, and total expenditure was about $A 650 mil­ lion. with about 25% coming from industry and competitive government funding. In its 5 years' strategic plans, the development of manufacturing industries, animal and plant production, and R&D programs on health and the environment take a lead position. Ac­ cordingly. CSIRO spends about 17% of Aus­ tralia's R&D budget on plant production, and 26% on animal production. It shares large parts ( > 30% ) of the national R & D budget in rural-based manufacturing (food, beverages, fi bers a n d textiles, wood prod ucts) and in e n­ vironmental research. CSIRO has established a wide range of co­ operative R & D programs with industry and with universities, notably through the Coop­ erative Research Centres (CRC's, see below). In Sydney. the Biomolecular Research Insti­ tute was jointly founded in 1 990 by the CSICommonweal th Scien tific and

Biotechnology-related Divisions of CSIRO and Their Major Targets (Examples)

Major Areas

CSIRO Institute

Di vision

Location

Institute of Industria l

Biomolecular E n g i n e ering

Protein X-ray crystallography, protein engineering, gene therapy, virus biology, receptors a n d cytokines, vascular cell technology. biomaterials. recombinant

lnstit ute of Animal

Animal

North R y de Laboratory. Parkville Laboratory ( 1 80 staff)

Health

(200 staff)

eases, vaccine development

Plant I ndustry

Canberra (400 staff)

Breeding programs includ i n g transgenic plants, with emphasis on wheat, barley, rice , cotton, oilseed, potato and tomato, pasture, sugar cane, eucalyptus, and soil improvem e n t

Technologies

Production and Processing I nstitute of P la n t Product ion and Processing

G e e long

vaccines

Diagnostic center for veterinary dis­

426

13

Biotechnology in the Asian-Pacific Region

RO, next to its Parkville Laboratories of Bio­ molecular Engineering, and by the Strategic Research Foundation of the Victorian Gov­ ernment, as a specialist facility for molecular imaging and rational drug design. The staff is around 60, with sophisticated equipment in X-ray crystallography, NMR and biocomput­ ing. The aim of the institute is to discover, synthesize and develop novel therapeutic compounds of commercial value in the treat­ ment of important diseases such as HIV, he­ patitis B and C, influenza and cancer. Some of the institutes are linked to the local univer­ sities. CSIRO also provides a range of education­ al programs relating to biotechnology and other science areas, e.g. •

•

•

•

•

•

the CSIRO Double Helix Science Club (for elementary schools) the CSIRO Science Education Centers (for school children) the CSIRO Women in Science Project (for school girls) the CSIRO Student Research Scheme (for secondary students) the BHP Science Awards (for school teachers), and the CSIRO Scholarships.

Several research centers outside the CSI­ RO, with significant acitivities in various ar­ eas of biotechnology, should also be men­ tioned. The Australian Institute of Marine Sciences in Townsville is located close to the Great Barrier Reef. Its 106 professional staff is fo­ cused on marine biotechnology, environmen­ tal studies, mariculture, genetic studies of wild and cultured stocks and bioactive meta­ bolites. The Australian Wine Research Insti­ tute in Adelaide is financed by the wine-mak­ ing industry of Australia, through a subsidy of $A 6 per ton of pressed grapes. Major activi­ ties include grape flavor, selection and im­ provement of oenological significance by ap­ plication of molecular biology, and optimiza­ tion of malolactic fermentation in wine. At the Sugar Research Institute in Brisbane, the capital of the sugar belt of Australia, various aspects of sugar biotechnology and biological treatment of wastes from sugar refineries are

studied. A range of outstanding biomedical research institutes is located along the "Park­ ville Strip", near Melbourne. Examples are the Baker Medical Research Institute, and the Ludwig Institute for Cancer Research, which has a strong focus on IL-6, EGF and GM­ CSF-receptor research. The Peter MacCallum Cancer Institute is targeting R&D at haemo­ poiesis, stem cell and tumor biology, whereas the Macfarlane Burnet Centre for Medical Re­ search has a strong emphasis on virology re­ search including HIV, HTLV-1 , hepatitis vi­ ruses, rubella, herpes viruses, respiratory vi­ ruses, and papilloma viruses. The St. Vincent 's Institute of Medical Research is specialized in bone cell biology, protein chemistry, includ­ ing protein crystallography, hypertension re­ search, and peptide hormone design. The Ho­ ward Florey Institute of Experimental Physiol­ ogy and Medicine has its main activities in the molecular biology of peptide and protein hor­ mones, whereas the Murdoch Institute for Re­ search into Birth Defects emphasizes genetic services and human genetics research; and the Walter and Eliza Hall Institute of Medical Re­ search, with its professional staff of about 80, is a major research center for genetic, molec­ ular and cellular aspects of immunity and can­ cer, including diabetes and other auto-im­ mune diseases. Sydney also offers strong sup­ port to the biomedical area, through, e.g., the Garvan Institute of Medical Research, with its emphasis on cancer, metabolic diseases, bone and neurological disorders, and the Heart Re­ search Institute, strongly focused on molecular biology (mammalian cell cultures, cytokines, antioxidants), whereas the leading institution in Brisbane is the Queensland Institute of Medical Research, with its Sir A lbert Sakzews­ ki Virus Research Laboratory. Universities In 1 992, Australia counted 32 national uni­ versities. About 5% of an age group entered university, and the total number of students was 560 000 . About 5% of these were foreign students who paid education fees, half of them from Indonesia, Malaysia and Singa­ pore. About 2/3 of all students went to the 1 6 universities located i n populous New South

7 Biotechnology in

•

• •

•

the U niversity the University (Sydney ) the University the University bane ). and the University

of Melbourne of New South Wales of Sydney of Queensland (Bris­ of Adelaide

Monash University in Melbourne is consid­ ered a further top place in science and engi­ neering education. Science and engineering are preferred fields of studies: at present they receive about 80% of all competititve grants from the Aus­ tralian Research Council (ARC). the major funding agency for academic research. and the biological sciences take the lead. Biotech­ nology-related training and research plays an important role in many faculties. and repre­ sentative examples are shown in Tab. 41 . In an attempt to commercialize results of academic R&D. the government has initiated several plans: •

•

•

•

Since 1 989, several hundred "research centres" have been formed at the 32 uni­ versities, to enhance collaborative links within the university and to commercial partners. Many universities participate in the Co­ operative Research Centres' program. initiated in 1 990 (see below). Most universities have also established commercial arms. These are all members of ATICCA. the Australian Tertiary In­ stitutions Commercial Companies Asso­ ciation. As an example. ANUTECH Pty Ltd . . the commercial transfer point of the Australian National University ( ANU) in Canberra. markets about 70 inventions of ANU personnel, and has grown to a turnover of about $ A 40 mil­ lion per annum. In 1 992, the formation of the Australian Technology Group (ATG ) was an­ nounced. built on the model of the Brit­ ish Technology Group in the U K , a body

427

for the commercialization of public sec­ tor R&D. The initial investment by the government was A$ 300 000 .

Wales. Victoria and Canberra. While there is no formal ranking of the universities, > 50% of all competitive grants were won by just 5 universities, namely •

A ustralia

Cooperative research centers In 1 990, the Australian government intro­ duced a new scheme to develop core capacity in areas of joint strategic research. A limited number of participant institutions (5-10) from industry, research centers and universi­ ties coordinate to form a "Co-operative Re­ search Centre" (CRC), managed by a project leader, but not centralized as a single working unit. Since indigenous industrial R&D in Australia is relatively weak, transnational corporations are also accepted as participants in the scheme. but the percentage of public R&D in the CRCs is high. At present, 52 CRCs have been established; the central gov­ ernment contributes up to 50% of the total cost, the remaining funds come from the par­ ticipating organizations. The 52 CRCs will re­ ceive over $A 870 million from the Govern­ ment over the initial contract period of 7 years, or about 3% of Australia's national S&T budget. 10 new CRCs will be announced in the next and final round. CRCs have been formed in six broad fields of research, namely manufacturing technology, information and communications technology, mining and en­ ergy, agriculture and rural-based manufactur­ ing, environment, and medical science and technology. The following CRCs include as­ pects of biotechnology: •

• • •

• • • • • • •

•

CRC for Molecular Engineering and Technology CRC for Industrial Plant Biopolymers CRC for Plant Science CRC for Waste Management and Pollution Control CRC for Tissue Growth and Repair CRC for Cellular Growth Factors CRC for Biopharmaceutical Research CRC for Eye Research and Technology CRC for Cardiac Technology CRC for Premium Quality Wool CRC for the Cattle and Beef Industry (Meat Quality) CRC for Aquaculture

13 Biotechnology in the Asian-Pacific Region

428 Tab. 41.

Biotechnology-related R&D Activities at Australian Universities ( Samples )

University

Institute/Center

Research Targe ts

University of Queensland, Brisbane

Centre for Molecular Biology and Biotechnology Centre for Drug Design and Development Dept. of Chemical Engineering Dept. of Medical Laboratory Science Dept . of B iotech nology Research School of Biological Sciences Centre for Protein and Enzyme Technology Centre for Bioprocess Te chnology Dept. of Microbiology Plant Cell Biology Research Centre Dept. of Biochemistry and Microb io log:,v Dept. of Applied Biology and Chemical Engineering Wa i te Agricult ural Research Institute School of B iological Sciences

Gene regulation and expressio n in pathogenesis and emb ryogenesis

Queensland Institute of Technology, Brisbane University of New South Wales Australian National University, Canberra La Trobe University, Me lbourne Monash University, Melbourne

University of Melbourne

Royal Melbourne Institute of Technology, Melbourne University of Adelaide Flinders University of So u th Australia, Adelaide Murdoch University, Perth

• • • • •

CRC CRC CRC CRC CRC

for for for for for

Dept .of Biochemistry

Sustainable Cotton Production International Floriculture Food Industry Innovation Vaccine Technology Viticulture

As an example, the CRC for Molecular En­ gineering and Technology in Sydney aims to develop new sensing and diagnostic tech­ niques for healthcare, therapeutics, process

Computer-assisted design of enzyme inhibitors Fermentation, down-stream processing, genetic engi­ neering DNA-based diagnostics Microbial and animal cell fermentation, downstream processing, enzyme reactors, genetic enginee r ing Plant molecular biology, crop biotechnology, hos t­ pat hogen interaction s Enzyme technology, downst ream processing , protein design Design of downstream processing steps Metabolic design for bioremediation Molecular biology of plants, transgenic plants Microbial transformations , vaccines Biosensors

Molecular plant biotech nology Biotechnology for coal liquefaction, genome sequencing M ass product ion of algae

control and environmental monitoring m ar­ kets. Research programs are focusing on making sensors which are more sensitive, reli­ able and selective than those currently availa­ ble. There are three research programs cover­ ing the development of molecular sensing de­ vices: molecular recognition, molecular switching and studies of cellular biochemistry. Center partners are the School of Chemistry and Department of Biochemistry at Sydney

7

U n iversity , the D e p ar t ment of Cl i n i c a l Bio­ chemistry at t h e R o y al Prince Alfred Hospi­ tal; CS I R O ' s D i vis i o n s of Biomolecular E n g i ­ n e e r i ng , Applied P hy s i c s a n d Foo d P ro ce ssi n g ; and the AMBRI consortium. com­ pri s in g A WA Ltd., Bioclone A u s tra l i a Pty Ltd . , CSI RO. M e m tec Ltd. and Nucleus Ltd. The center p l a n s to p ro v i d e sp e c i a l i s t grad ­ uate and p os tgr ad u at e tra i n i n g . It has federal fu n di ng of A$ 2.2 m i l l i o n a ye a r. ­

P at e nt i ng and genetic e n gin e e r i n g re gul atio n s

a m e m be r of the B u d a p e s t deposit of p a ten te d forms of life . The national d e po s i t o ry is the National B u r e a u of Standards L a b o r a t o ry (NSBL) in Sydney. I n 1 987, the v a li d i t y of patents for pharmaceuticals was e x t e n d e d from 1 6 to 20 years. in o rd e r to c o mp e n s at e for a slow d r u g registration syste m . A s evident from t h e p u bl i c a t i on p ro fi l e in Asia (Tab. 2), Australia 's activities i n ge n e t i c e ngi n e e ri n g a re h i g h . A s u rv ey on genetic ex­ p e r i me n t s and rele ases of ge n et i c a ll y mod i f­ ied plants and microorganisms is gi v e n in Ta b . 42 . Three m aj o r r e g u l at ions co n c e r n i ng ge­ netic e n g i n e e r i n g were issued by t he Genetic Manipulation A dv i so r y Committee ( GM A C ) , a part-time body e s t a bl i s h e d in 1 988 and pre­ do mi n a ntly c o n s isting of scientific experts. Guideline 1 covers smal l - scale ge n e t ic ma­ n ip u l ati o n work ( < 10 L, c on t a in ed animals; 1 98 1 -90: 1 755 cases). There is an exe mp t i o n fo r ge neti c work on d e b ili t a t e d E. coli Kl2, and for se lf-clon ing e x pe r i m e n ts. Guideline 2 cove rs l a rge - sca l e work with recombinant DNA ( > l O L; 1 98 1 -90: 1 5 Australia is

Treaty

Tab. 42.

on the

Genetic

Experiments a nd

Re le as e

Large -scale

( > 10 liters) e x pe r i ment s

Releases of genet ical ly modified org a nis m s

A ustralia

429

c a ses ) . It contains a G ILSP category for work within t h e g ui d e l i n es but of negl igible risk. Su c h work requires only G I L S P standard procedures. Guideline 3 c ov e rs the pl an n e d release of re c omb i n a n t DNA organisms. A fourth guideline c o n c e r n i ng tr an sg e n i c animals was recently issued by a joint work­ i n g party. Deliberate release of t r a n s ge n ic an­ imals and pl a nt s exceeds 16 a n d includes to­ matoes, cotton and alfalfa. Over 82 institutional b io s afe ty committees watch over the co r rect ap plicati o n s and ad­ herence t o t hese g u i de li n e s, which form a vol­ unt ary code . There can be s a nc t io n s , which are mo re p u ni t i v e for p u b li cl y funded i n s tit u ­ tions than fo r p ri v ate ly fu nded research bod­ ies. C on t i n u i n g breaches of su b s t a n t i v e requi­ rements could result in an enquiry under pu b­ lic health a nd o c cu p a t io n a l health and safety l e g i s l a ti o n .

Acknowledge ments

G e ne ro u s fi na n c i al s up p or t for c o ll ec t i n g and compiling the i n fo r m a t i o n used in t h is survey has been p ro v i d e d by the B undesmi­

n i st e r i u m fiir Forsc h u n g und Te ch n o l ogi c ( B MFT) in Bonn, t h roug h its Proj ect G r o up BEO in Jiilich, Germany. R. D. SCHMID wish e s to e xpress h is si n ce r e g r a tit ude to Prof em. S AB U RO FUKU I , Kyoto University, to Prof. ISAO KARUBE, RCAST, The U n i ve r s i t y of Tokyo, and to Mr. a n d Mrs. M. K A wA S H I M A , Kurihashi, for i n v al u able support and help i n assessing the s i t u a t i on of b i o tec h n o l o g y i n J a pa n . B . H. CHUNG w a n t s to express his appre­ ciation to Mr. Ho M I N CHANG in GERI for advice a n d s u p p o r t .

of G e n e t ically Modified Org a nis m s in Australia Proposals

Sma l l -scale recom h i n a n t experiments

Biotechnology in

29

39

Approvals

Current

3394 24 27

1 974 24

( A ug. 5 ,

1 994)

27

430

13

Biotechnology in the Asian-Pacific Region

JEANNIE SCRIVEN wishes to thank leading ASEAN scientists for their help - Dr. YoNG­ YUTH (Thailand), Dr. PHAN (Philippines) and Alumni of the GBF's International Training Programme in ASEAN countries for their invaluable support. JANE H. J . TsAI wants to express her sin­ cere thanks to Dr. DING YONG (NCBD), Prof. Ao SHI-ZHou and Prof. LIANG-wAN YONG (AS) and to Prof. H siN TSAI (DCB) for continuing support.

Personal Remark: The Authors ROLF D. SCHMID holds a Dr. degree in Chemistry and is Professor of Technical Bio­ chemistry at the Center for Bioprocess Engi­ neering , University of Stutt gart, G erma n y . JANE H. J. Ts A I holds a Ph.D. degree in Biochemistry and is President of the Chinese­ German Professional Association at Gottin­ gen, Germany. JEANNIE ScRIVEN holds a B. A. degree in political science and is the Chief Organizer of the International Training Programme in Bio­ technology of the Gesellschaft fiir Biotechno­ logische Forschung (GBF) in Braunschweig, Germany. SvsoNo SAONO holds a Ph. D . degree in Microbiology and is Senior Research Staff of the R&D Center for Biotechnology at the In­ donesian Institute of Sciences (LIPI) at Bo­ gor, Indonesia. BONG HYUN CHUNG holds a Ph.D. degree in Biochemical Engineering and is a Senior Research Scientist in the bioprocess engineer­ ing group at the Genetic Engineering Re­ search Institute of KIST at Taeduk Science Town in Taejon, South Korea. ALAN J. JONES hol ds a Ph. D . degree in Chemistry and a B . A. degree in Economics, and is currently Counsellor of Industry, Science and Technology at the Australian Embassy in Bonn, Germany.

8 References Bibliography to Section

1

ABSTRACTS SERVICE ( 1 994) , CA SEARCH, Columbus, OH: American Chemical Society . FAO (Food, Agriculture Organization of the Uni­ ted N atio ns) ( 1991 ) , FA O Yearbook Production 1 991 , Vol. 45, Statistics Series No. 104, Rome. KEIZAI KOHO CENTER ( 1 994 ) , Japan 1 994, An In­ ternational Comparison, Tokyo: Taiheisha Ltd. ISBN 4-87605-025-2. OECD (Organization for Economic Co - operation , Development) ( 1 994 ) , Main Science and Tech­ nology Indicators 1 994/1, Paris: OECD Publica­ tions Service. I S B N 0-8213-1977-9. SCIENCE AND TECHNOLOGY AG E N CY ( 1994 ) , In­ dicators of Science and Technology, 1 994, T o k yo : Science and Technology Statistics Office. ISBN 4-17-152269-2. THE WORLD BANK ( 1991 ) , The World Bank Atlas 1 991, Wash i ngton DC. I S B N 1 -08213-1977-9. CHEMICAL

Bibliography to Section

2

(Japan)

( 1 990 ) , Action Pro­ gram to Arrest Global Warming. KEIZAI KOHO CENTER ( 1 994 ) , Japan 1 994, An In­ ternational Comparison, Tokyo: Taiheisha Ltd. I S B N 4-87605-025-2. MIYATA, M. ( 1 994 ) , Toward a new era in biotech­ nology, Sci. Techno[. Jpn., 10-1 1 . NI KKEI B IOTECH ( 1994 ) , Nikkei Baionenkan 94 (Bio Yearbook), Tokyo. ISBN 4-8222-0822-2. SCHMID, R. D. (1988), Tsukuba, K a n s a i Science City und 26 mal Technopolis : Wissenschafts­ stadte in Japan, Chern. Uns. Zeit, 149. SCHMID, R. D . (1991), Biotechnology in Japan, Heidelberg: Springer Verlag. I S B N 3-540-535543. SCHMID, R. D. (1991 ), Verbundforschung in Japan. Nachr. Chern. Tech. Lab. , 39. SCHMID, R. D. ( 1 993 ) , Globale Umweltp rojek te in Japan, Nachr. Chern. Lab. 41, 428-434. S C IEN CE AND TECHNOLO GY AGENCY ( 1991 ) , White Paper on Science and Technology 1 991 .

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ISBN 4-88890-21 3-5.

INC. ( 1994 ) , Japan Company Hand­ book, First Section, Autumn 1994, Tokyo. ISSN

TOYO KEIZAI 0288-9307.

Bibliography to Section 3 (Korea)

M. J. ( 1 990 ) , Present status of genetic engi­ neering and biotechnology in South Korea, Crit. Rev. Biotechnol. 10, 47-67.

CHo,

8 References G W Y N N E . P. D i r e ct ing techno logy in As i a ' s ' D ra ­ gons ' ,

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384 .

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Concise Hand­

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di

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(Ed.): ATAS

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S.

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pp.

Application and

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13

Biotechnology in the Asian-Pacific Region

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Biotecllllology

Ed ited by , H . - J . Rehm and G . Reed i n cooperat ion with A. Puhle r an d P . S ta d l e r C o pyright © VCH Verlagsgesellschatt m b H , 1 995

17

Press Coverage of Genetic Engineering in Germany: Facts, Faults and Causes

HANS MATHIAS KEPPLINGER SIMONE CHRISTINE EHMIG Mainz, Federal Republic of Germany

1 2 3 4

I n t rod u ction 496 Representation of Genetic Engineering 496 Causes for the Way of Representation 501 References 504

496

J 7 Press Co verage of Genetic Engineering in Germany: Facts, Faults and Causes

1 Introduction Genetic one of the

Tod a y , ge netic engineering in G e r m a ny is at a cross-road . Its rapid development seems

is

quite possible. but it may also be blocked in widely known as

the foreseeable future . With this as a ba c k ­

b r a n c h e s of science w i t h the most

gro u n d . the i n v e s ti g ation prese n ted i n this chapter intends to describe the represe ntation

e ngi n ee r i ng

promis i n g fu t u re . This c o n c e r n s its contr ibu­

t i o n to the di agnosis and cure of heridi tary defect!- a n d serious d is e a s e s . to the pro d uc ­

tion of vaccines a n d drugs. to growi n g pl a n t s and bree d i n g a nim al s as well as to i t s applica­ tion i n the area of e nvironmental p ro t e c ti o n .

of g e n e tic e ngineering i n the mass media and to a n a l yz e some essen tial reasons for its criti­ cism and acceptance by the mass media (for

d eta i l s see K E PPLI N G E R et a l . . 1 99 1 b ) . There­ fo re . we have q u a nt i t a t i ve l y an aly ze d the ex­

Gen etic e ngi n ee r i n g is at t h e same time . how­

t e n t and the manner i n w h i ch ge n e t i c e ngi ­

e x p ose d to ma s sive c r it ic i sm . A l te r a t i o ns

newspapers. four reg io n a l daily newspapers ,

ever.

are

one

of th o s e branches of sc i e n ce . which

to t h e ge n e t ic make-up of m icr o or g a n is m s . p l a n t s . a n i m a l s and h u man s make g e n e t ic

gineering

appear to b e

an

en­

especially s e r io us

i n t e rfe rence i n i ntact nature. since the

t ions

seem

a l ter a ­ t h e i r c on s e q ue nce s to a fte ct the wh ole population. P e o pl e ' s are

i n v i s i ble

and

fears ran g e . there fore . from b i olog ic al risks

such

as

the uncontrolled spread of c h a n g e s

o rga n is ms caused

in

by g e n e t i c engi neering t o

social risks such as de c re as i n g acceptance of

handicapped e n ce

people. Here particular r e fe r ­

i� made to l o n g -ter m conseq u e nces. u n ­

k n o w n co n s e q u e nces and ir r e v e rs i bl e conse­

quences.

The o p pone n t s of ge n e t i c e n g i n e eri ng in

G e rma n y grou p themselves i n or g an izat i o n s as G e n - e t h i s che s Ne t z wer k ( ge n e t ic ­

s uch

ethical n etw o r k ) . B e r li n . O k o - l ns ti t u t ( e c o ­ l ogical i n s t i tute ) . F r e i b u r g . and Komitee ftir

portrayed

ne e ring is

i n s i x national daily

two w e e k ly papers. two w e e k ly ma g a z i n e s

and four p op u la r science m a g a zi n e s . As

a

rule . the basis of the a n aly s i s is a random sample from one si x t h of al l editions in t h e ye ars 1 987 to 1 989. The popular science m a ­ g a zi n e s are a n exc e p t i o n - from these we took account of half of all e d i t i o ns . In addition , we

i nvestigated

30

ists and 30

pol i t i c a l editors, res p e c t i v e ly . In

experts.

30

scientific j o urn al­

the case of the experts, we were d e al i n g with

persons i n leading pos i t i o n s a t research insti­ t u t i o n s i n universities, Max-Planck i n s tit u t e s as well as research e n terpri ses. They may be

regarded as distinguished specialists, j udgement possesses considerable

w hose s i g n ifi­

cance. This is also true in a similar way for the

scien tific

j our n alis ts

we

i n t e rviewed ,

who

G r u n d re ch t c und Demokratie (committee for

w e re among the most respected i n their field. The r e l ev a n c e of the a nswers is, therefore,

consti t utio n a l r i g ht s and democracy ) . Sens­

competence of those interviewed . In the case

bachtal. w h \) claim to re pre se n t public wel­

of the political edi tors, we were concerned

They appe a l to the p u b li c with n u mer o u s publ ications a n d sometimes al so offe r ser­

a re not re p r es e n tativ e , st a ti s t i c al l y s peak i n g ,

fare. or

rather the natural order of t h i ng s .

v i c e s s uc h

as

with the e mployees of daily newspapers. They n or do they have specialist know l ed ge .

s up plyi n g speakers for the f i g h t

aga i nst ge n e tic e n g i n e e ri n g .

The

magazi ne

natur prov i d e s t h e m with a forum which re­

ceives c o n si d e rabl e attention. Examples for t h e i r acti vities a re the years of st ruggle

a ga i n s t t h e

based not on t he number but o n the s p e c i a l

manufacture

o f human insulin us­

ing ge ne tic e n g i n e e rin g by t he Hoechst AG

com pany and against an outdoor e x p e r i m e n t

w i t h pdun i as changed by g e n et i c engineering

2 Representation of Genetic Engineering I n the e d i t i o n s i n v esti g ate d from 1 987 t o 1 989, t h e 18 newspapers and m a g a z i ne s p ub­

hy t h e M a x - Planck-l nstitut ftir Ziich t u ngs fo r ­

lished a total of 524 articles with 4494 evaluat­

i n Cologne .

ing state m e n ts on genetic e n g i n e e r i n g. Pro­ j e c te d to all e d iti o n s in the p er i o d of i nvesti-

�ch u n g

( i n � t i t ut e

for

plan t

b re e d i ng researc h )

2 Representation of Genetic Engineering

to 2688 articles with We took into consideration here t h e varying publication frequency of the pape rs. Most of the articles and statements appeared i n the national dailies. Th e y con-

gation,

t h b co r r e s p o nd s

22 024 stateme n t s.

497

tained a total of 302 articles with 2294 state­ ments. Thus. it can be established that the journalistic discussion of genetic e ngineering in the period of investigation took place chiefly in the national dailies ( Tab. 1 ) .

Tab. I. N u m be r of Articles and Statements from 1 987 to 1 989. editions of t h e popular science magazines

Basis:

One sixth of all editions; half of all

A rticles

Statements

Proj ection: Articles Statements

1'1

n

n

Coded :

n

National dailies

Frankfurter

Rundschuu

Siiddewsche Zeinmg

Frankfurter A llg. Die Welt

Zeitrmg

die ruges::.eitung

Handelsb latt

To t a l Average

61

59

366

366

2 1 96

477

354

2 862

41

5 16 298

47

543

83

11

302

94

498

3 096

282 66

3 258

246

Tot a l

Average

Weekly papers

Die Zeit

Rheinischer Merkur

1 812

1 3 764

302

2 294

6

33

36

2 31 II

35

12

50.33

50

1 2 .5

24 17

Tot a l

41

Average

20.5

Magazines

Der Spiegel Stern

Tot a l

A" crage

Popular science magazines namr

.)pektrum

cler Wissenschaft P. AI. Maga::.in /Jild dr:r wissemcltafi

382.33

1 08

1 86

1 98 210

79

66

474

300

1 530

255

63 .75

308 1 73

481

240.5

1 44 1 02

246

1 23

382.5

1 848

1 038

2 886

1 443

1 67

62

30

372

17

229

1 02 51

1 374

53 9

1 02

1 078

1 87 370

16

5

8.5 51 17 8 38

1 1 4.5

1 39

1 14 28.5

1 235 308.75

Al l pape rs

524 29. 1 1

4 494

Average

75

648

12

Tot a l

An:rag.c

564

2 2 94

Regional dailies

Westdemsche A llgemeine Kieler Nachriduen Miinchner Merk u r Rhein;: eiumg Koblen::.

1 788

249.67

72

34

76

1 002

687

278 374

7 40

228 57

2 470

2 688

22 024

1 49.33

6 1 7 .5

1 223.56

498 Tab. 2.

1 7 Press Coverage of Genetic Engineering in Germany: Facts, Faults and Causes

Authors of the Articles on Genetic Engineering National Daily Newspapers (n = 302) %

Scientific journalists Other journalists News agencies Other identifiable authors Non-identifiable sources No information Total

Regional Daily Weekly Newspapers Newspapers (n = 50) (n = 41 ) %

%

20 20

12 14

22 7

18 2 38 3

16 2 28 28

4 66

101

1 00

99

By far most articles on genetic engineering were not written by scientific journalists. Only 17% of the articles analyzed were written by authors who were clearly proven to be scien­ tific journalists or who were identifiable as such. The source of a large number of articles could not be identified. Even if one supposed that half of these articles were written by scientific journalists - which is very improba­ ble -, it can be established that the image of genetic engineering in the press is determined mainly by journalists . without specific expert knowledge. Here the significant role of the news agencies is remarkable, above all for news coverage in the daily newspapers (Tab. 2). In contrast to popular science magazines, daily newspapers, weekly papers and weekly magazines have clearly defined editorial sec­ tions, which generally include a special scien­ tific section. However, most statements on ge­ netic engineering do not appear - contrary to the widespread assumption - in the scientific sections of the daily and weekly papers, but in their political sections. The scientific sections took only second place here. All the other sections played no great part. In the political sections, genetic engineering was character­ ized on the whole rather negatively, in the scientific sections in contrast definitely posi­ tively. (The tendency of the statements was assessed on a scale of - 3 to + 3.) It should be remembered that the political sections are given attention by many more readers than the scientific sections. Thus, a central prob-

Magazines

Popular Science Magazines

Total

(n = 17) %

(n = 1 1 4) %

(n = 524) %

6 6

13 3

29 59

5 72 7

17 15 12 3 47 8

1 00

100

1 02

lem has been identified: genetic engineering is given press coverage particularly in those places where its presentation rather tends to be negative and where it is widely read (Fig. 1 ) . The articles concerning genetic engineering dealt with a wide range of topics, which can only briefly be summarized here. General

3. Statements Concerning Various Areas of Application of Genetic Engineering in Newspapers and Magazines• Tab.

Genetic engineering in general Human genetics Human health Animal production Plant production Environmental protection Other areas of application Total •

b

Number of Statements

Tendency of Statements

(n = 4.494) %

X

41 22 12

(n = 4.01 4 ) b

12

- 0. 1 8 - 0. 1 7 + 0.89 - 0.26

11

+ 0. 5 1

2

- 0.20 + 0.49

101

+ 0.03

6 national dailies, 4 regional dailies, 2 weekly pa­ pers, 2 magazines, 4 popular science magazines Mean values ( + / - 3). Without statements on the general political, economic and legal frame­ work of genetic engineering

2

Representation of Genetic Engineering

499

St atements: Tendency Number + +

3 -"I 1 -1300 : 1200 1 1 00 1 000 900 800

• .5 0

0

Political sections

700 600

500

400 300 200 100 - o +------'-_.l •

Fig. 1 . M a k i n g genetic engi­ neering a subject o f discus­ sion and the tendency of its

tions).

n -1 -3

'

__j

quest i o ns concerning genetic engineering were definitely the center of interest. Human genetics was also reported relatively freque n t­ ly. Both topics on the whole revealed a slight­ ly ne ga tive tende ncy. This was also true for the application of genetic engineering in ani­ mal production. In cont rast, the significance of genetic en g in e er i ng for human health and for pla n t p rodu ct ion was given definitely posi­ tive coverage (despite the discussion of an outdoor e x per i m e nt with petunias in the pe ri ­ od of t he investigation) . These two topics were o n l y touc h e d on in one t hi rd of all state­ ments. Th us, a s eco n d pro blem has been identified: topics given a negative coverage were dealt with frequently, whereas topics given a positive coverage were discussed rare­

ly (Tab. 3 ) .

Edit orial sections

•

- 0.5

representation i n va rious

edito rial sections. Number of statements and mean val­ ues ( + I - 3 ; without state­ ments concerning condi­

__L........J.__...J__..J__.1._ ...l L-_,

_

e

• Number of s t a t e m e n t s T e n d e n c y of r e p r e s e n t a t i o n

The papers investigated reported the opi n ­ ions of various prominent persons concerning

genetic engineering . Some of these persons belong to org a n ization s which develop and apply genetic engi n e e ring, others belong to organizations which criticize both. A mong the first-named organizations are academic re­ search institutions and ind u strial c omp an i e s , among the last-named organizations are the alternative research institutions, citizens' ac­ tion groups and . for example, the Greens (the German ecological party). In the political sec­ tions of t h e daily and weekly papers especial­ ly those members of the latter org anizations had a say, whose opinion of ge netic engineer­ ing was very negative. In the scientific sec­ tions, especially those members of the first­ mentione d or ganizations had a say, whose at-

500

17

Press Coverage of Genetic Engineering in Germany: Facts, Faults and Causes

titude was relatively positive. Thus, a third problem has been identified: Those who de­ velop and make use of genetic engineering have no sufficient say in the places where the readers obtain their information (Tab. 4). In theory, the tendency of the news cover­ age in the news items should be independent of the tendency of the opinions exp re sse d in Tab. 4.

the comments. In reality, however, in most papers there was a clear connection between the tendency of the statements in the com­ ments and the tendency of the statements in the news. Thus, a fourth problem has been identified: The journalists' views in the var­ ious editorial departments, expressed in the comme n ts , had an influence on the tendency

Statements by Various Authors in the Political and Scientific Sections of Newspapers and Magazines •

Academic research institutions, industry Alternative research institutes, interest groups, churches, The Greens •

Political Sections Number of Tendency of Statements Statements b n

Number of

Statements n

Tendency of

1 40

+ 0.90

1 84

+ 0.56

189

- 1 .64

28

- 1 .86

Scientific Sections

Statements b

n ational dailies, 4 regional dailies, 2 weekly papers, 2 magazines Mean va l ues ( + / - 3). Without statements on the general political, economic and legal framework of genetic engineering 6

b

Tend e n c y

of the

news items

T •3 ' • 1.5

Westdeutsche

• Allge m eine +1

Fr ankl.

•

e P.M.

M a g a zin

b i l d der

• wissenschaft

A l l g . Ztg.

Munchner

e Welt

Merkur •

F r ankl. Rundschau e Hande l s b l a t t e z e it • S ud d z t g • R h ein Mer k ur of 1--------+------__._+:..·...:=-------+_...;__._...;._____f----� · · · -l Tendency • 1.5 • 3 t he c o m m en ts •1 -3 -2 - 1 Rheinz tg.

Koblenz

• Spie gel e

natur

:

-1

.l _ 3 Fig. 2. Tendency of the representation of genetic engineering in comments and news items in individual newspapers and magazines. Basis: Evaluating statements in all editorial sections: mean values ( + / - 3); without statements concerning conditions. Abbreviations stand for: Frankfurter Allgemeine Zeitung, Frankfurter Rundschau, Suddeutsche Zeitung, bild der wissenschaft, Rheinischer Merkur, Rheinzeitung Koblenz.

3 Causes for the Way of Representation

501

T e n d e n c y of s t a t e ­

m e n t s by e x p e r t s

T

•3

: + 1. 5 • Mi.i nc h n er Merkur

F r a nk f urter Rundschau

Stern

+1

bild d . wiss.

Zeit e

..

Spiegel

•

•

•

Spektrum der Wissenschaft

Welt

e S i.i d d . Z t g .

Frankl. A l l gem. e

e R h ein. Merkur

. p . . . __, T e n�ency of statements -- . M . M a ga z 1 n _ 31-- -..l.r-S---_....,--------t---- ---+-----4 b y j o urn a l i s t s + 1.5 + 3 +1 t a g e s z eitung • Z eitung

Rhein z t g . •

natur e

Koblenz

_1

1 _3

Fig. 3. " l nstrum �ntalization .. of experts. Basis: Statements by journalists and scientists: mean values ( + 1 - 3 ): wi t hout 'tatements concerning conditions. Abbreviations see Fig. 2. of the

represe ntation of genetic engineering in the news and re ports. Thus. the news and reports on curre nt events seemed to confirm the views of the comme ntators (Fig. 2 ) . ( I n

German newspape rs, usually both t h e com ­

ments and the news are written by the same j o urn al i s t ) In many instances. experts diffe r in their opin ions. I n m o st cases. howeve r. there is a clear m aj o r ity for one point of view. In the .

prese nt study, all or almost all of the experts

in te rv i ewed judged genetic engineering posi­ tively . They assessed i t as being very useful and con sidered i t s potential for doing h arm quite low (cf. K E PPU N G E R et a J . . 1 99 1 b . p p . 3 1 -35 ) . Most n e wspa pe rs and magazines l e t those e x pe rb have their say. who ch arac­

terized

thus conveyed

of the

e

ge netic

e xp

opposite

a

n g in ee r ing

e x p e r ts have a say ,

who

gave genetic

and

thus

portrayed a misleading picture of actu al views among the experts. Thus, we can identify a

fifth

problem: The j ournalists' views have a decisive influe nce on the public vi s ibility of experts ( Fig. 3 ) .

3 Causes for the Way of Representation T h e represe ntation of ge netic engineering

in

the papers investigated can be attributed

mainly

to

six causes:

thoroughly adequate picture

e rts views. '

positively. They

those

e ngineering negative news coverage

S ome papers used the

techn ique . They let - corresponding

to the tenor o f the j ournalists' attitudes -

l . A considerable number of journal ists h ave

a negative attitude towards genetic engi­ neering ( K EPPLI N G E R e t

al.,

1 99 1 b. pp.

28-

502

17 Press Coverage of Genetic Engineering in Germany: Facts, Faults and Causes

30). This is especially true for political edi­ tors, but also for part of the scientific jour­ nalists. The journalists' attitudes were evi­ dent both in their general opinions con­ cerning genetic engineering as well as in their views concerning its risks (Tab. 5). 2. A considerable number of journalists mis­ trust scientists, especially political editors; but this is also true, with reservations, for scientific journalists. The journalists' mis­ trust is shown both in their judgements concerning the credibility of the employees of the industrial companies (see KEPPLIN­ GER et al. , 1 991b, pp. 61-65), as well as in

judgements about the trustworthiness of employees in academic research institu­ tions (Tab. 6). 3. The shortcomings in the representation of genetic engineering in the press to a con­ siderable extent are due to flaws in the or­ ganization of the editorial departments: those who have specialist knowledge are often not responsible, and those who are responsible frequently do not have special­ ist knowledge. Specialist knowledge availa­ ble is not used adequately. Scientific jour­ nalists competent in their special fields sel­ dom write articles on genetic engineering.

Tab. 5.

Opinions of Journalists and Scientists Concerning the Risks of Genetic Engineering. Question: "Various risks are being discussed in connection with genetic engineering. Please go through the following list: which of these risks are, in your estimation, to be taken very seriously, quite seriously, less seriously, or can be ignored completely?" Number of people questioned who were of the opinion that a risk was "to be taken very seriously" or was "to be taken quite seriously"

"Discrimination of individuals with unusual genetic features on the job market" "Decreasing willingness to accept the life of handicapped peopie" "Military use of organisms altered by genetic engineering" "No clear-cut transitions from the correction of defective genes to optimization of human hereditary factors" "State-enforced abortion of unborn babies with genetic defects" "Uncontrolled spread of manipulated organisms in outdoor experiments" " Increased use of chemical pesticides as a result of the development of herbicide-resistant plants" "Pressure for rationalization and accelerated structural change in agriculture" "State-enforced information on genetically caused risks to one's own health" " Impairment of health in laboratory staff through contacts with new combinations of organisms" "Unintended creation of new pathogenic organisms from originally non-pathogenic material" "Systematic 'breeding of humans' by private or state organizations" " Environmental pollution due to accidents due to new combinations of organisms" Total

Scientists

Scientific Journalists

Political Journalists

(n=30) n

(n=30) n

(n=30) n

15

23

18

12

21

19

12

20

26

11

19

26

11

11

8

10

22

27

10

19

20

10

18

16

10

16

18

5

18

21

3

23

28

3

13

16

2

18

27

114

241

270

3

503

Causes for the Way of Representation

Tab. 6.

Confidence in Scientists in the Case of Controversial Science Projects. Question: "Please imagine case: Scientists at a u niversity institute are planning to test plants altered by genetic engineer­ ing in an outdoor experiment. Scientists from an alternative scientific institution claim that there is danger of an uncontrolkd spread of these plants. The scientists concerned dispute this and refer to appropriate preliminary investigations. Which si d e would you rather trust?" the following

·The scientists concerned'' 'The scientists of the alternative institution··

Scientific

Political

Scientists

Journalists

Journalists

II

n

n

24

12

4

3

6

7 7 l

10 10

Other

3 1 2

Total

30

30

30

·'Both to the

same

extent''

"Neither ..

Tab. 7.

Presumed Causes

of Shortcomings in Press Coverage . Question: "The mass media's representa­ technology is often criticized as being inaccurate. Regarding this I would like to read you an o pi n i on . Please tell me whether you think that this opinion is correct, partly correct or incorrect. The opinion is as fo l l ows : The shortcomings in the representation of science and technology are not based so much on the fact that the scientific journalists have had poor training and are badly informed. It is due much more to the fact that their articles hardly get a chance in day-to-day press coverage, because the po litical editors take every topic of general interest out of their hands."

tion of science and

.. , agree

.. 1 agree

completely with this opinion" in part with this opinion"

.. I do not agree with this opinion"

.. , don't know'' No definite answer Total

4.

Moreover, they have no influence on the articles of their non-specialist colleagues in the poli t ical department (Tab. 7). The attitudes of (German) journalists to the subjects of their news coverage have an effect on the way they represent them. A great m a ny journalists approve of the con­ scious playing up of information which supports their own views. These views sig­ nificantly i n fl ue n c e the choice of news (see KEPPLINGER et al., 1 989, 1 9 9 1 a ). We call this "instrumental actualization'' of infor­ mation: information is instrumentally se­ lected and published.

Scientific

Political

Scientists

Journalists

Journalists

n

n

n

6 12 8

4 14 8

1 11 17

3

4

1

30

30

30

1

5.

Numerous scientists recognize the necessi­ ty of actively informing the public about their own work. Only a few, however, take the initiative and publish articles about their activities in the press. Thus, for exam­ ple, two thirds of the scientists interviewed were of the opinion that scientists " (must) on their own initiative inform (journalists) about the background knowledge which is vital for understanding (their research)". Only seven, however, had published an ar­ ticle in a daily or weekly newspaper. In do­ ing so t h e y have - to a large extent - left the field to the opponents of genetic engi-

504

17 Press Coverage of Genetic Engineering in Germany: Facts, Faults and Causes Tendency of the statements

1.5

1.0 Fig. 4. Representation of genetic engineering seen in the long term. Basis: Statements concerning genetic engineering in the political sections of the Frankfurter Rundschau, Siiddeutsche Zeitung, Frankfurter Allge­ meine Zeitung, Welt, Zeit, Spiegel and Stern from 1%5 to 1989 as well as statements concerning technology as a whole in the named sources from 1 965 to 1986 (without statements on conditions) . From KEPPLINGER (1989)

neering (see

6.

KEPPLINGER et al., 1991b,

pp. 90-93). Journalists' attitudes to genetic engineer­ ing, and linked to this the characterization of genetic engineering in the press, are the expression of a general "Zeitgeist", which the mass media were involved in bringing

about {for details see KEPPLINGER, 1989, pp. 157-164). This is demonstrated by comparing the representation of genetic engineering with that of other technologies (energy, chemical industry, transport, etc.). Data from the recent past indicate that here a change in trend is taking place or has already taken place (Fig.

4).

4 References (1 989), Kiinstliche Horiwnte. Folgen, Darstellung und Akzeptanz von Technik

KEPPLINGER, H. M.

in der Bundesrepublik,

Frankfurt am Main/New

York: Campus. KEPPLINGER, H. M., BROSIUS, H.-B.,

STAAB, J. F., G. ( 1 989), Instrumentelle Aktualisie­ rung. Grundlagen einer Theorie publizistischer Konflikte, in: Massenkommunikation. Theorien, Methoden, Befunde ( KAASE, M., SCHULZ, W., Eds. ) , pp. 199-220, Op laden : Westdeutscher Verlag. KEPPLINGER, H. M., BROSIUS, H.-B., STAAB, J. F. (1991a), Instrumental actualization: A theory of mediated conflicts, Eur. J. Commun. 6, 263290. KEPPLINGER, H. M., EHMIG, S. C., AHLHEIM, C. (1991b), Gentechnik im Widerstreit. Zum Ver­ LINKE,

hiiltnis

von

Wissenschaft

und

Journalismus,

Frankfurt am Main/New York: Campus.

Biotecllllology Edited by ,H.-J. Rehm and G. Reed in cooperation with A. Puhler and P. Stadler Copyright© VCH Verlagsgesellschatt mbH, 1995

18 The Regulation of Modem Biotechnology: A Historical and European Perspective A Case Study in How Societies Cope with New Knowledge in the Last Quarter of the Twentieth Century

MARK F. CANTLEY Paris, France

Introduction 1

2

508

Origi ns and Beginnings: from Avery to Asilomar, and Capitol Hill 509 1.1 Slow Progre s s : The Decades Before Asilomar 509 1.2 The G endic Revolution: Acceleration. and Irreversible Knowledge 510 1.3 As ilo m ar 511 1.4 From Asilomar to Capito l Hill: A Dialogue of Scientist, Public and Regulator

1.5 Observations 515 B eg i nni n gs in Europe: From ··GMAG" to the EC's 1982 Council Recommendation 2.1 The 2.2 The

2.3

2.4 The

2.5

51 6 UK Working Parties, Health and Safety Legislation, and "GMAG" 5 1 6 European Commission . DG XII: Towards the First Biotech Research Programme,

"BEP" The The

2.6 The

513

518

1978 Proposal for a Council Directive on rONA Work 518 CREST Paper 5 1 9 Economic a n d Social Co mmit t e e 520 European Science Foundation Adds I ts Voice: ··No Significant Novel

Biohazards''

521

2.7 Report of the N or t h

Atlantic Assembly 524 Council of Europe 525 Division of Opinion in the European Parliament; Council Recommendation Adopted 525

2.H Report of the 2.9

82/472

506

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

3 From Research to Strategy, Co-ordination and Concertation, by Commission and Industry 526 3.1 Calm Before the Storms: The Early 1980s and the International Scientific Networks 526 3.2 Scientists Redeploy Effort, from Regulation to Research, Forecasting and Strategies 528 3.3 The Framework Programme for R & D, and the 1983 Communications: A First Community Strategy for Biotechnology 529 3.4 "A European Approach to Regulations Affecting Biotechnology", 1983 532 3.5 The Co-ordination Problem 533 3.6 The B iotechnology Steering Committee and Its Secretariat, "CUBE"; the Implementa­ tion of the 1983 Strategy, and the Different Interests of the Commission Services 534 3.7 Should European Rio-Industries Create a Lobby? The Davignon Meeting of December 1 984 535 3.8 The European Biotechnology Co-ordination Group, EBCG; ECRAB ; and Their Extended Family 536 4 1 985-1 990: From Strategy to Legislation 537 4.1 Research and Concertation as Elements of a Strategy: The Biotechnology Action Programme, "BAP", 1985-1989 537 4.2 The European Parliament Reviews Strategy: The Viehoff Hearings and Report 540 4.3 BSC Creates B RIC, Debates Strategy, and Fades 543 4.4 1986: The "Hinge" Year: ( 1 ) BRIC Starts Work: The Background of Sectoral and Chemicals Legislation 546 4.5 1986: The "Hinge" Year: (2) National and International Developments 549 4.6 1986: The "Hinge" Year: (3) European Responses by Industry, Member States and the Commission 550 4.7 The Preparation of the 1 988 Legislative Proposals, and Their Adoption 553 4.8 Horizontal or Sectoral Regulation, Process or Product? A Continuing Conflict 561 5 Policy Evolution at National Level, in Different Continents, Countries and Cultures 565 5.1 USA: NIH RAC, Existing Agencies, and the Co-ordinated Framework 566 5.2 UK: From GMAG to ACGM and ACRE; Statutory Developments in 1990-1 992; the House of Lords Report and Government Response 573 5.3 Germany: The Catenhusen Enquiry, the 1990 Gentechnikgesetz, and the 1993 Revision 580 5.4 France: The Two Commissions, Gallic Pragmatism 587 5.5 Japan: The Attentive Spectator 592 5.6 Other Countries 597 5.6.1 The Netherlands 597 5.6.2 The Scandinavians 602 5.7 Generalizations: From Concrete to Abstract, from National to Global 605 6 International Actors: European, the OECD, the UN Agencies and Rio 607 6.1 Other Europes, Scientific {ESF, EMBO, EFB) and Political {EC/U, CoE, ECE) 608 6.2 The OECD Role in Biotechnology and Safety 6 1 1 6.3 The UN Agencies (1): WHO, FAO, ILO, IPCS, UNIDO, the World Bank and CGIAR, ICGEB, UNESCO and ICSU 618 6.4 The UN Agencies (2): UNEP, Rio, Agenda 2 1 , CSD , and the Convention on Biological Diversity 627 7 Re-thinking and Review: 1 990-1995 633 7.1 The Rio-Industries in Europe Find Their Voice 633 7.2 The Birth of the BCC, and the April 1991 Communication 636 7.3 Implementing the 1 990 Directives: DG XI, the Committee of Competent Authorities, and National Developments 642

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

7 .4 The White Paper and the Next Stage: From Corfu to Essen, 7.5 Puhlic Opinion: The Joker in the Pack - or the King? 656 8 Synthesis and Conclusions: Learning from History 667 Personal Statement 672 9 References

673

and the

1 995

Review

507

647

508

18 The Regulation of Modern Biotechnology:

Introduction The events described below occurred over a period of two decades, from the mid-1 970s, covering the birth and early years of modern biotechnology and the first practical and com­ mercial applications of genetic engineering. The story is a complex one, for the several reasons discussed below; a story of many strands, but also of many interlinkages, many interactions, between the various strands. The danger for any narrator of such a story is that the more comprehensively and thoroughly he presents the complexity, and the mass of de­ tail, the greater is the risk of concealing the salient lessons; and there are important les­ sons to be learned, by all the different players concerned, but especially for public policy in Europe. Therefore, selectivity, omission and compression have had to be applied, in the in­ terest of greater significance and transparen­ cy. The "story" is about how different societies have coped, are coping, with a sudden surge of knowledge and understanding about the basic structures and mechanisms of living things. In focusing on public policy and regul­ ations, the intention is less to tell the story of the remarkable scientific discoveries and technological developments and inventions, well described elsewhere, than to study how societies learn to digest the new knowledge, and to manage its consequences; in the hope of showing how they may learn faster and manage better. The various strands of the story are spun and interwoven through time, so time will serve as a common base and organizing prin­ ciple; although various countries are at differ­ ent points on their respective "learning curves" of experience, and the curves are not identical. The learning process which can be per­ ceived across the various strands is a multidi­ mensional one, in several distinct respects: -

multi-disciplinarity of the scientific base multi-sectoral applications multi-constituency multi-national multi-international-institutional.

A

Historical and European Perspective

Each of these facets is here briefly intro­ duced, and recurs in the narrative that fol­ lows. The scientific base of biotechnology is mul­ ti-disciplinary, drawing upon elements from biochemistry, microbiology, molecular biolo­ gy, genetics, process engineering (including especially, but not restricted to, fermenta­ tion); and no area of the life sciences and technologies has remained unaffected by the surge in knowledge and technique, particular­ ly at the molecular level. A similar multiplicity characterizes the sec­ tors of application. In every area of human in­ teraction with living entities and systems, there is scope for the application of greater knowledge, and consequently greater subtlety and efficacy of intervention - in agriculture and food production, in health care, and in the recycling of organic wastes, water purifi­ cation, and protection and management of the natural environment. More "bio-rational" approaches may be seen as good in them­ selves, for values aesthetic, ecological or eco­ nomic; or as essential responses to competi­ tive pressures, from competitors to whom the global knowledge base is no less accessible; or as essential tools for maintaining (or achiev­ ing) decent standards of health and nutrition, for a human population approaching and passing ten billion, and while reversing the current degradation of the planet. As issues relating to biotechnology and ge­ netic engineering came into greater promi­ nence, the number of interested "constituen­ cies" increased. The scientists themselves, at Asilomar, initiated through systematic en­ gagement with journalists, a wider debate en­ gaging the political leaders and their staff, and the general public. The previous para­ graph refers to the various economic sectors, agricultural, industrial and other, who were progressively drawn into the debate. The cir­ cle of debate was further widened by ethical considerations, to draw in philosophers and theologians. Within government, ripples spread from Research Ministries, concerned with both basic and applied science, to appli­ cations involving Ministries of Industry and Trade, Agriculture, Health, Environment, Education and others; and issues involving regulatory and legal aspects, engaging Patent

1 Origins and Beginnings: From A very to Asilomar, and Capitol

and M i ni st ries of Justice. The se­ which they awoke or reacted varied from country to country, although within the European Community the processes of Com­ m u nity legislation tended t o bring similar Ministries into synchrony in their preoccupa­ t ion s , with biotechnology as with othe r to­ pics. The debates about biotechnology have from the start been international. because of the natural internationalism of science. As the techn ologi es moved into application, this internationalism was doubly reinforced: by the continuing p ro gre ss towards an open world economy: and by the increasing signifi­ cance within that economy of k nowledge- i n­ tensive sectors (such a s biotechnology), and consequently of intellectual proper ty. The former de velo pm e nt could be underlined by r e fere n c e to the 7-year, "Uruguay Round" of GAIT negotiations, culminating in the signa­ t u re of the agreement at Marrakesh in April 1994: the latter aspect, by the significant at­ tention and controversy which biotechnology attracted within the trade-related intel lectual property element of the GAIT agreement. The multi-national policy implications and multiplicity of a spects mentioned above had their institutional counterparts, epitomi zed by the presence of biotechnology on the agenda of practically every agency of the Uni ted Na­ tions. UNIDO, U N E P . WHO and FAO colla­ borated in the development of biotechnology guidelines. Common biotechnology-related policy questions face international agricultur­ al research center s. or intern a t i ona l confer­ ences on harm o n i zation of authorization/reg­ istration procedures for pharmaceuticals. At the "Earth Summit" in Rio de Janeiro, June 1992, bi ote chn ology figured signifi cantly in the debates on biodive rsity, and in the articles of the resulti ng con v ention ; within the "Agenda 21" deve lopment plans for the 2 1 st century. there are many references to bio­ technology. including the whol e of Chapter Offices

quence in

16.

This multidimensional character will be brough t out in what follows. drawing particu­ larly on developments within the European Community or U nion; whose own constitu­ tion and institutional structures were un­ dergoing rapid evolution during the same de-

Hill

509

cades. This aspect int er acted significantly, and sometimes adversely, with the process whose description is the central aim of this essay: how soci e ti es digest and learn to manage the surge of new knowledge and methods sum­ marized by the word "biotechnology". Some points are commented on in the nar rative ; a final section draws together a s ynthesis and conclusions.

1 Origins and Beginnings: From A very to Asilomar, and Capitol Hill 1.1 Slow Progress: The Decades

Before Asilomar

1 994 saw the 50th anniversary of the classic paper by OSWALD AvERY and colleagues (A VERY et aL 1 944) , in which they identified DNA as the molecule uniquely associated with the storage and transfer of genetic infor­ mation betwe e n different strains of bacteria. His work on Pneumococcus, the bacterium responsible for pneumonia, had started three decades e ar l ier during World War I . A de­ cade after AvERY's paper, WATSON and CRICK used crystallographic data and bio­ chemical reasoning to elucidate the structu re of DNA, i n the U K MRC's ( Medical Re­ search Council) Laboratory of Molecular Biology, Cambridge. In the same year and la­ boratory, SANGER published the amino-acid sequence of the protein insulin. X-ray crystal­ lographic methods - developed in Cam­ bri dge 's Cavendish Laboratory by the BRAGGS, fath er and son , in the 1 920s - had there first bee n applied to biological mole­ cules by BERNAL and PERUTZ in the 1 930s; an init i ati ve which led, two decades lat er , to the double h elix . Following the double helix discovery, t he gen e tic code was elucidated; following AVE­ RY. and through the work of LEDERBERG and others, the field of bacterial genetics was progressively developed. But more decades of work and progress elapsed before COHEN

510

18

The Regulation of Modern Biotechnology:

and BoYER at Stanford could (in 1 974) pub­ lish (and subsequently patent) their use of re­ striction enzymes with bacterial plasmids for the fundamental "cut and stitch" activities which became known as genetic engineering. Also in the mid-seventies, SANGER, and GIL­ BERT and MAXAM at Harvard, published their methods of reading, nucleotide-by-nu­ cleotide, genetic sequences. This history of some of the most significant discoveries of twentieth-century science has been often and more fully described, for their significance attracts the historians of science, and will long and rightly continue to do so (see, for example, the review by WITKOWSKI, 1988). As background to the policy and regul­ atory debates which developed around bio­ technology, the purpose of recalling the histo­ ry is to identify the salient factors which lead many observers to speak of the "Genetic Revolution" (e.g. , DAVIS, 1991 ). A useful chronology of the two latest decades was as­ sembled by RYSER and WEBER (1990).

1 .2 The Genetic Revolution: Acceleration, and Irreversible Knowledge

As is indicated by the dates quoted, the gestation periods for these major scientific discoveries and developments were measured in decades, rather than years. But from these slow beginnings, a steep acceleration has fol­ lowed. Understanding of the molecular mech­ anisms of all living systems was a progressive, interactive process. The interactions stimu­ lated further insights, hypotheses, experi­ ments and discoveries; the process was car­ ried forward in an increasing number of cen­ ters around the developed world; the knowl­ edge thus gained was cumulative, irreversible, and globally available. Subversive and perva­ sive, the discoveries could not be reversed, nor the powerful but simple techniques and methods disinvented. Could they, should they, be controlled and regulated? That was the original question at Asilomar; and was re­ current through the years that followed. The subsequent developments in the life sciences and technologies, over the decades

A

Historical and European Pe rspective

from the mid-70s, interacted increasingly with the "Information Revolution" of data stor­ age, software sophistication, computing pow­ er, and global electronic networking. By the early '90s, DNA sequence data read by auto­ mated machinery was pouring into the 2 or 3 global databanks at a rate of millions of nu­ cleotides per month. This flood of new knowl­ edge, of which DNA sequence remains mere­ ly one aspect, albeit the most fundamental, has been generated and driven by massive in­ creases in the financial, human and technical resources devoted to the R & D effort, by both governments and private sector. The technical resources themselves have become enormously more efficient and productive, both within the biology laboratory (e.g. , in se­ quencing technology), and in the information handling within and beyond the laboratory: at all levels of scientific data, extending also to clinical, and bibliographic, and beyond science to the provision and use of commer­ cial and legal information, including a related massive growth of patent applications and in­ tellectual property rights. This quantitative surge of knowledge, and the acceleration of its rate of further expan­ sion, have had, and continue to produce, shock waves: qualitative effects rippling across scientific disciplines, government and international institutions and policies. The shock waves extend through agriculture and food production, health care, and environ­ mental management, reaching into philoso­ phy, theology and ethics. UNESCO in 1993 created an International Committee on Bio­ ethics; over the previous two decades every UN agency had found itself involved in the implications of the new knowledge. An OECD study of long-term economic impacts of biotechnology in the mid-1 980s, was obliged to appear with a modified title: "Eco­ nomic and Wider Impacts of Biotechnology"; for the "Wider" impacts would be noticed first (OECD, 1 989). The changes within the life sciences are profound, as the traditional disciplines are flooded with illumination from the molecular level, from scientists who know not the name of LINNAEUS. Virologists who have split over the years into sub-groups focused on bacteri­ al, insect, plant, animal, clinical or other viral

1 Origins

and Beginnings: From A very to Asilomar, and Capitol Hill

sub-disciplines, now find a re-emergence of in projects such as the World Virus D a t abank . Molecular evolution re-examines and illu m i nat es the legacy of DARWIN; taxonomy. s y stematics and nomen ­ clature are re invi gor ated and (particularly in the context of d e clin i ng biodiversity) recog­ nized as essential to the rational st r u c tu ri n g and m an a geme nt of the new knowledge . The i mp lic a tio ns for publi c po l i c y o f the b i olo gica l revolmion did not strike all depart­ m e n ts of gove r n men t simultaneously, nor s i mi l a rly . If on e uses an orchestral metaphor, the violins of Science had the privilege of ini­ t i a tin g the new theme; other sections of gov­ ernment res pon ded as in a fugue , with answ­ ers or variations on the theme; and with the increase in the number of se c tions of govern­ ment pa rtici pa t i n g . the need for a conductor of the orchestra became ever more apparent. There were to be many orchestras, and many cond uc tors ; h arm o n y, and h arm on izat i on be­ tween traditions and places . proved elusive.

common i nte r e sts.

1.3 Asilomar In agricultural o r medical research , in p l an t or animal bre e d i ng , and in the p roductio n of

5 11

the conference, MAXINE SINGER and DIETER SoLL. drafted a letter addressed to the Na­ tional Academy of Sciences and the Institute of Medicine , re q u es t i ng the formation of a st udy committee. to assess the biohazards posed by recombinant DNA research, and recommend appropriate action. The letter was pu blis h ed in Science (SIN GER and SoLL, 1973). As a result the N ational Ac ade m y of Sciences announced in February 1974, that PAUL BERG w ou ld chair the study commit­ tee. The 11 members, all active i n recombi­ nant DNA research, were conscious of th e quickening pace of research, and appre h e n ­ sive about p ossible accidents. Their report was also published in Science, on 26 July 1974 (B E R G et al., 1 974), and almost sim u ltaneo us ­ l y (sl ightly abridged) in Nature. The text of the "Berg letter" is reproduced below: "Potential Biohazards of Recombinant DNA Mole­ cules Recent advances in techniques for the isolation and rejoining of segments of DNA now permit con­ struction of biologically active recombinant DNA molecules in vitro. For example, DNA restriction endonucleases, which generate DNA fragments containing cohesive ends especially suitable for re­ joining have been used to create new types of bio­ logically functional bacterial plasmids carrying anti­ biotic resistance markers and to link Xenopus /aevis ribosomal DNA to DNA from a bacterial plasmid. This latter recombinant plasmid has been shown to replicate stably in Escherichia coli where it synthe· sizes RNA that is complementary to X. laevis ribos· omal DNA. Similarly, segments of Drosophila chromosomal DNA have been incorporated into both plasmid and bacteriophage DNAs to yield hy­ brid molecules that can infect and replicate in E.

fermentation antibiotics, the c ontin ui n g de ­ v e l opm e nt and application of the life sciences during the early post-war decades were rou­ tinely pursued. in fa mi liar compartments with relatively little inter-sectoral interaction . b e y ond a pe rfun c t or y acknowledgement of common roots in biology. Basic science , the dramatic discoveries referred to above. were saluted with Nobel prizes. but impi nged only sporadically or slowly on practical concerns. coli. That h a s c han ge d since the mid-70s. Several groups of scientists are now planning to It has become a convenience or a c l ic h e to use this technology to create recombinant DNAs date histories of biotechnology from a confer­ from a variety of other viral, animal, and bacterial e nce held at Asilomar. California, in Febr u a ­ sources. Although such experiments are likely to facilitate the solution of important theoretical and ry 1975: whose origins were somewhat earlier. practical biological problems, they would also re­ ln February 1973. a c on fe rence on biohazards sult in the creation of novel types of infectious was held at Asilomar, Cal i fornia . It attracted little attention, but stimulated further DNA elements whose biological properties cannot be completely predicted in advance. thought . In June 1973. the annual session of There is serious concern that some of these artif­ the Gordon C on ference on Nucle ic Acids was icial recombinant DNA molecules could prove bio­ held in New Hampton, New Hampshire, and logically hazardous. One potential hazard in cur­ was devoted to the problem of hazards in r e ­ rent experiments derives from the need to use a combinant DNA research. The co-chairs of bacterium like E. coli to clone the recombinant

512

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

DNA molecules and to amplify their number. Strains of E. coli commonly reside in the human in­ testinal tract, and they are capable of exchanging genetic information with other types of bacteria, some of which are pathogenic to man. Thus, new DNA elements introduced into E. coli might possi­ bly become widely disseminated among human, bacterial, plant, or animal populations with unpre­ dictable effects. Concern for these emerging capabilities was raised by scientists attending the 1973 Gordon Re­ search Conference on Nucleic Acids, who re­ quested that the National Academy of Sciences give consideration to these matters. The under­ signed members of a committee, acting on behalf of and with the endorsement of the Assembly of Life Sciences of the National Research Council on this matter, propose the following recommendations. First, and most important, that until the poten­ tial hazards of such recombinant DNA molecules have been better evaluated or until adequate meth­ ods are developed for preventing their spread, scientists throughout the world join with the mem­ bers of this committee in voluntarily deferring the following types of experiments. Type 1: Construction of new, autonomously re­ plicating bacterial plasmids that might result in the introduction of genetic determinants for antibiotic resistance or bacterial toxin formation into bacteri­ al strains that do not at present carry such determi­ nants; or construction of new bacterial plasmids containing combinations of resistance to clinically useful antibiotics unless plasmids containing such combinations of antibiotic resistance determinants already exist in nature. Type 2: Linkage of all or segments of the DNAs from oncogenic [cancer-inducing] or other animal viruses to autonomously replicating DNA elements such as bacterial plasmids or other viral DNAs. Such recombinant DNA molecules might be more easily disseminated to bacterial populations in hu­ mans and other species, and thus possibly increase the incidence of cancer or other diseases. Second, plans to link fragments of animal DNAs to bacterial plasmid DNA or bacteriophage DNA should be carefully weighed in light of the fact that many types of animal cell DNAs contain sequences common to RNA tumour viruses. Since joining of any foreign DNA to a DNA replication system creates new recombinant DNA molecules whose biological properties cannot be predicted with cer­ tainty, such experiments should not be undertaken lightly. Third, the director of the National Institutes of Health is requested to give immediate considera­ tion to establishing an advisory committee charged with (i) overseeing an experimental program to

evaluate the potential biological and ecological haz­ ards of the above types of recombinant DNA mole­ cules; (ii) developing procedures which will minim­ ize the spread of such molecules within human and other populations; and (iii) devising guidelines to be followed by investigators working with poten­ tially hazardous recombinant DNA molecules. Fourth, an international meeting of involved scientists from all over the world should be con­ vened early in the coming year to review scientific progress in this area and to further discuss appro­ priate ways to deal with the potential biohazards of recombinant DNA molecules. The above recommendations are made with the realization (i) that our concern is based on judge­ ments of potential rather than demonstrated risk since there are few available experimental data on the hazards of such DNA molecules and (ii) that adherence to our major recommendations will en­ tail postponement or possibly abandonment of cer­ tain types of scientifically worthwhile experiments. Moreover, we are aware of many theoretical and practical difficulties involved in evaluating the hu­ man hazards of such recombinant DNA molecules. Nonetheless, our concern for the possible unfortu­ nate consequences of indiscriminate application of these techniques motivates us to urge all scientists working in this area to join us in agreeing not to initiate experiments of types 1 and 2 above until at­ tempts have been made to evaluate the hazards and some resolution of the outstanding questions has been achieved. Paul Berg, Chairman David Baltimore Herbert W. Boyer Stanley N. Cohen Ronald W. Davis David S. Rogness Daniel Nathans Richard Roblin James D. Watson Sherman Weissman Norton D. Zinder Committee on Recombinant DNA Molecules Assembly of Life Sciences, National Research Council, National Academy of Sciences, Washington, DC 20418"

The Asilomar conference was widely dis­ cussed in advance, and received worldwide press coverage. The many subsequently pub­ lished descriptions and interpretations bring out several facets of what the conference was and what it achieved.

1

Origins and Beginnings: From A very to Asilomar, and Capitol Hill

A t the most factual level . the occasion was in v i t ation -onl y scientific meeting in which eminent specialists discussed the possible risks which migh t be associated with recombi ­ nant DNA techniques or experiments: and means for managing or reducing these conjec­ tural risks. The re was discussion o f various levels of risk for classifying experiments; and co rresponding levels of physical containment. Among the more constructive ideas . which British pa rtic i pa n t s such as BRENNER empha­ sized at the conference. was the concept of biological containment: the use of strains of microorganism disabled in ways which would limit their ability to survive or reproduce out­ side the contained vessel and special condi ­ tions provided in the e x periment . This area of the Asilomar debate was the sta r ting-point for a great deal of risk assessment research over the following years - practically all of it reassuring, but always limited b y the logical impossibility of ·· p rovi ng '' a negative . As an innovation in scientific communica­ tion, Asilomar could be seen both at the time and subseq uently in various lights. Many commentators are inclined to congratulate the organizers on the integrity and transpar­ ency with which they were prepared to com­ municate the ir concerns to a broader public. Press representat ives were invited to the con­ ference, with the understanding that they would listen to the whole four-day conference b e fore reporting. The resulting reportage was serious and competent. and generally ac­ knowledged the obvious sincerity of the scientists themselves. Some commentators nonetheless set Asilo­ mar in the context of tradition they would de­ scribe as "elitist". characterized by the arro­ gant assumption that on complex matte rs . only those who understand the complexities sh ou ld be involved in making decisions. Against such elitism it is argued that demo­ cratic procedures require the involvement of representatives of a broader constituency - of the taxpayers who have paid for publicly funded research. of the workers who might be the most immediate victims of a laboratory ac cid e nt or i nfection, and by the same logic. of the general public who, on various conjec­ tures. might also be victims either of an acci­ dent (such as an epi de m ic initiated by a rean

513

combinant organism) , or be exposed to risks associated with products placed on the mar­ ket. The developments in genetic engineering to which Asilomar drew attention catalyzed a fundamental debate about the control of science and technology; or, insofar as such a debate was already in progress, extended and amplified it to all areas of the life sciences and technologies, their applications, and implica­ tions. 1.4 From Asilomar to Capitol Hill:

A Dialogue of Scientist, Public

and Regulator The debate triggered by Asilomar was in­ tense and widespread. The temptation to ex­ aggerate and simplify, for journalists, car­ toonists, or politicians, local and national , was great: and was not resisted. Scientists were often angered by the misrepresentations, and by the strident and hostile tone of the attacks they encountered - in some notable cases from major environmental movements . B ut a few eminent scientists supported the critics, in their calls for intense security provisions or a total moratorium on all rONA research. The result was a high profile, sometimes heated, public debate . with scientists often facing the ill-informed hostility of "public in­ terest groups" or local politicians. The con­ struction at Harvard University of a high se­ curity ("P3") laboratory for recombinant DNA research led to one such battle, in sum­ mer 1 976. which was widely reported. This featured the colorful language of the local mayor of Cambridge , Massachusetts, ALFRED YELUCCI:

"'It's about time the scientists began to throw

all

their god-damned shit right out on the table so that

we can discuss it .. .. Who the hell do the scientists think they are that they can take federal tax dollars

that are coming out of our tax returns and do re­ search work that we then cannot come in and ques­ tion?"

The period of angry debate lasted several a period summed up a decade later by NORTON ZINDER (1 986) as "[divisible) into three periods : years;

514

18

The Regulation of Modem Biotechnology: A Historical and European Perspective

Asilomar (1974-76) , the 'recombinant DNA wars' ( 1976--78), and detente". The American experience during 19741 978 offered points of comparison for Eu­ rope, facing the same issues at approximately the same time; and for both the US and Eu­ rope during the second wave of concerns which arose during the latter half of the 1 980s. Essentially similar issues were involved in each case. Public concerns in the United States rose to a peak during 1 976--1 977, with the corre­ sponding introduction in Congress (both House of Representatives and Senate) of bills to regulate recombinant DNA research. At the same time, following the Asilomar confer­ ence, the National Institutes of Health (NIH) , under Director D ONALD FREDRICKSON, had been active in developing guidelines for the conduct of such research, through the NIH Recombinant DNA Advisory Committee (NIH RAC). The first version of these guide­ lines was released by NIH on 23 June 1 976, and published in the Federal Register on 7 July. A major feature of the debates in the US was the progressive development of a well-or­ ganized, articulate and balanced response by the scientific community. The leading role was played by the American Society of Mi­ crobiology (ASM), but many other profes­ sional associations of biological and medical sciences joined with ASM in a broad alliance, through semiformal linkages via their execu­ tive officers, and widespread networks capa­ ble of providing rapid responses. The recommendations of the ASM were summarized in a nine-point statement, ap­ proved in May 1977, and widely reported: "1.

That all responsibility for regulating action re­ lative to the production and use of recombinant DNA molecules should be vested in HEW (the Department of Health, Education and Wel­ fare). 2. That to advise and assist the Secretary of HEW, an Advisory Committee should be es­ tablished whose membership in addition to lay people should include representatives with ap­ propriate technical expertise in this field. 3. That institutions and not individuals should be licensed.

That in each institution engaged in DNA re­ combinant activities, to the maximum extent possible, direct regulatory responsibility should be delegated to a local biohazard committee. These committees should include both mem­ bers with appropriate expertise conducted at that institution, and representatives of the pub­ lic. 5 . That experiments requiring Pl [the lowest cate­ gory of physical containment in the NIHRAC guidelines] requirements should be exempt from these regulations. 6 . That license removal is an effective and suffi­ cient deterrent to obtain compliance. Further, that ASM is opposed to the bonding of scien­ tists or to the establishing of strict individual liability clauses in the conduct of DNA recom­ binant activities. 7. That ASM goes on record favoring uniform na­ tional standards governing DNA recombinant activities. 8. That the Secretary of HEW should have the flexibility to modify the regulations as further information becomes available. Further, we support the inclusion of a sunset clause in the legislation, i.e., that legislation will be re-evalu­ ated after a fixed period of time. 9. That ASM expresses its concern that in estab­ lishing such important legislation governing re­ search, and that this proceed only after due and careful deliberation." (From HALVORSON, 1986) 4.

The ASM nine points emphasize relevant competence and technical expertise; delega­ tion of responsibility to local committees, ap­ plying uniform national standards; the ex­ emption from regulation of low-risk experi­ ments (requiring Pl containment); and flexi­ bility to adapt and re-evaluate legislation in the light of experience. All these points re­ mained valid and important in the discussions during subsequent years and in other coun­ tries and legislatures. During 1 977, the scientific concerns were effectively communicated both in public, and to the staff of interested Congressmen. Amendments to earlier bills were prepared, progressively incorporating the scientific ad­ vice; informed scientists communicated their personal views on pending legislation to their respective senators or representatives. The in­ formation indicating the absence of harmful spread or effects of recombinant organisms was influential. By September, Senator AD-

I Origins and Beginnings: From A 1•ery

( i n a letter to the Pres­ ident's Science Advisor FRAN K PRESS) that most of the l egi s. l a ti o n being considered was ill -designe d for a c h i e ving its stated o bject i ve namely. p rotect i on of the p u bli c without im­ peding re s e arch. He indicated his inten ti on to e xplore the use of e x ist i n g statutes to regulate recombinant DNA research. At hearings in N ov e m b er 1 977, the ASM ex p r e ss ed their concerns about "the apparent i n te mp erat e rush to establish legislation to regul a te recombinant r e s earc h without first con s ul t i n g with t h e a p p ro p riate ly qualified scie nti fic and medical experts, the n e ed to un­ derstand that early a llegat i ons concerning re­ combinant DNA research were characterized by uncontrolled i m a g i n a ti o n and excessive claims by i n d ivi d u al s who lacked kn ow ledge of i nfectious disease . and the need for mini­ mal interi m legislation to ex t e nd appropriate g u i deli ne s to all re com b i na n t DNA activities reg a rdl e s s of funding source During t h e fal l of 1 977 and in 1 978, the ASM cont in ue d to work closely with Con­ gressional committees, a n d the prospect of federal legislation declined. LAI ST E V E N SON w rote

,

. ..

US ex p e r i e n ce i n the post-Asilomar period was of s ig n i ficance as a successful ex­ a m p le of open di a l o gue between the scie n tifi c .

co m mu ni t ie s The successes can .

be related to the flawless safety record of ge­ ing

engineering in t h e

US

over the follow­

years: and to the p o s iti o n of scientific and

economic leadership in biotechnology which the US m a i nta i n e d . More generally and im­ p o rt antly the U S expe rience provided, for sc ie n t ist s in all fields and legislatures every­ w he re an object l e ss o n in how to manage the i nterface betwe e n sc i ence and society in a way t h a t was d e m oc r a t ic and transparent; and that i n conseq u e nce . was ge nerally accepted .

,

and e ffective.

ex p e ri e n ce was n o t inevita­ national conference in O ct o ber l lJ80, on "recombinant DNA and the Federal G over n m e n t ' " , prese n tations were made by Federal officials resp o n s ib le for agency con­ c e r n s o n the subject ( 1 7 Federal agencies parThis su ccessful

ble.

At

a

5 15

t i c i pa t e d ) by former Cong re s smen and their key aides re sponsib l e for l egislat i ve activ i ty in the field, and by Washingt o n lawyers special­ izing in s uch issues. Lawyer STEPHAN LAw­ TON had been involved in drafting one of the main House Bills (for Co n gre s sm a n ROGERS) on regulating DNA re s ea rch Having nar­ rated in detail the events during March 1 977 to mid-1 978. he concludes: ,

.

··Here ends the story. but not necessarily the les­ be l i e ve that all of us can Jearn from this ex­ per i en ce with the reco mb i na n t DNA resea rch legis­ lation that did not pass. Lesson number one is that Congre ss is very wilJ­ ing and quite able to act ve ry q ui c k l y when the pub­ lic health is at stake. Lesson number two is that whoever dre amed up t he l e gis l ativ e process was a geni us to the extent that t he legislative process is slo w e n ough to pre­ vent a stampede of unwise legi sl a tion Lesson number three is th at Co n gress in my j udgement had and continues to have an extremely hea lth y opinion of the scientific community. Con­ gress is w i l l ing to listen to well-reasoned ar gu m en t s and. believe it or not, Congressmen have the capac­ ity to change their minds when confronted with new and we ll-reasoned a rg u men t s . sons. I

.

,

,

"

,

The

netic

A.�ilomar, and Capitol Hill

P re scie n t ly he went on to ask:

1 .5 Observations

and political

ru

" Is t he l e g is l ati o n dead? Yes, for the time being. Is it dead forever ? Maybe and m aybe not. The issue i t se l f will not be dead in W as hi ngton for a long time. It will be kept alive for several reasons. First, t here are several committees of Congress that con­ t i nue to hold hear i ngs on the activities of the NIH and on re combi nant D N A ge n e r ally , princ i pa l l y the two science comm i t t e e s which don ' t have legislati ve j u r isdic t i on over the recombi n an t DNA iss ue s but continue in a very pos i ti ve way to expose them­ selves and the public to the issue. Second, there is a very interested, s op h i sticated medical press in W a sh ing to n who will follow the issue. T h i r d I think the sheer e xcit e m ent of t he issue will keep the qu e s t i on of whether or not there should be gov­ e rnm e nta l involvement with respect to recombinant DNA research a l ive These t hree facto rs - the science committees' interest and the ir oversight hearings. the press. and the sheer exc i te m en t of the issues - w i ll ke ep Congre ss interested in the issue . " ( LAWTON. 1 98 1 ) ,

,

.

He concluded with the "old adage in Wa s hingt o n (of Bismarckian vintage and origi n ) . t h at ''if you wa n t to respect your laws "

516

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

like you love your sausage, do not watch too closely the process by which either is made".

2 Beginnings in Europe: From " GMAG" to the EC's 1 982 Council

Recommendation 2.1 The UK Working Parties, Health and Safety Legislation, and " GMAG"

When concern about the conjectural haz­ ards of recombinant DNA research was ex­ pressed in 1 974 (by the Berg letter), United Kingdom scientists were among those most affected in Europe, in view of the number of programmes and centers concerned. Such re­ search was all funded through universities or research councils, and it was therefore straightforward for the Department of Educa­ tion and Science to institute suspension of all work involving the recombinant DNA tech­ nique until government guidelines had been promulgated. A committee - the Ashby Working Party - was set up in July 1974 to advise on whether such work should proceed in the UK. Its report was published in De­ cember 1 974, and recommended that such work should go ahead provided adequate sa­ feguards were established (HMSO, 1974). The Ashby report especially focused upon the concept of "biological containment", by crippling the plasmid vector and its bacterial host. By reporting so promptly, the concepts developed by the Ashby Working Party could be used by UK or other scientists in the Fe­ bruary 1975 Asilomar conference. The government responded by setting up under Sir ROBERT WILLIAMS another work­ ing party in August 1 975, to prepare a code of practice for work involving genetic manipula­ tion. This reported promptly, in August 1 976 (HMSO, 1 976), like Ashby's working party completing its report within 12 months; but

the scientific community was frustrated by the two-year delay in its work. The Williams Working Party also recom­ mended the establishment of an advisory body to maintain surveillance of work involv­ ing genetic manipulation, and advocated that statutory regulations be developed. As a re­ sult, the Genetic Manipulation Advisory Group (GMAG) was set up by the Depart­ ment of Education and Science, and held its first meeting in January 1 977. Its membership comprised eight scientific and medical ex­ perts; four "public interest" representatives; four trade union representatives, for worker interests; and two representatives of manage­ ment, one nominated by the Confederation of British Industry, the other by the Committee of University Vice-Chancellors and Princi­ pals. The concept of "public interest" represent­ atives was an innovation in opening up the committee proceedings and allowed a greater flow of information to the public; although the GMAG meetings, unlike those of the NIH Recombinant DNA Advisory Commit­ tee, were held in private. GMAG initially followed the advice of the Williams report regarding guidelines for the review of proposals for recombinant DNA work. The Williams guidelines emphasized good working practices, and four physical containment levels ranging from least to most stringent. GIBSON ( 1 986) summarizes the dif­ ferences from NIH as follows: "Category I equated approximately to the NIH P2 facility requirements and Category IV is more demanding than the NIH require­ ments for its highest containment category. The categorization of experiments outlined in the Williams report is based on a scheme re­ flecting evolutionary relatedness, that is, the closer the animal source of the DNA insert was to that of man the higher the contain­ ment requirement would be for that particu­ lar experiment. This scheme was abandoned in 1979 in favor of a risk assessment scheme." Publication of the Williams report and the creation of GMAG enabled scientific work to resume in the UK, where some ten Category III containment facilities were constructed. At GMAG's request, the Medical Research Council also sponsored training courses for

2 Beginnings in Europe: From

"GMA G " ro the ECs 1 982

biological safe ty officers at the government's Microbiological Research Establishment at Parton Down - now the Centre for Applied Microbiology and Research. Following the in­ troduction in 1 979 o f the GMAG assessment scheme. most experiments were recategorized to the lower. "Category 1 ·· . containment level. where the req uirements were simply those of ··good microbiological practice ''. The 1 970s saw a growing demand in many countries for i mproved health and safety at work, and the rising consciousness of risks in­ fluenced the rONA debate. The UK had in 1 974 adopted a comprehensive statute , the Health and Safety at Work Act. which gave wide-ranging powers to the government's Health and Safety Commission, implemented through t he Health and Safety Executive (HSE) and the Factory Inspectorate . Under this Act. there followed more specific statuto­ ry regulations requiring all establishments (including ministries and research institutes) to set up loca l safety committees. " Regula­ tions on Genetic Manipulation" (SI 1 978 No. 752) were also i ntroduced, operative from 1 A ug u st 1 978 . These provided that ''persons should not carry on genetic manipulation un­ less they have previously notified the Health and Safety Executive and the Genetic Manip­ ulation Advisory G roup". Although local bio­ logical safety committees were not a statutory requirement. GMAG would only give its ad­ vice when proposals had been discussed with the local biological safety committee. The UK genetic manipulation regulations introduced a defi nition that was used in sub­ sequent European and many national legisla­ t i ve proposals: "'genetic manipulation ' means the forma­ tion of new combinations of heritable materi­ al by the insertion of nucleic acid molecules. produced by whatever means outside the cell, into any virus, bacterial plasm id. or othe r vec­ tor system so as to allow their incorporation into a host organism in which they do not nat­ urally occur but in which they are capable of continued propagation". G M A G 's development of a risk assessment scheme in 1 979. implemented from January 1 980 onwards, diminished scientific concerns abou t overzealous safety committees, unne­ cessary delays. and excess disclosure of ideas

Council Recommendation

517

to competitors. Some rONA work was ex­ empted from regulations, and almost all work could be done at Category I level. As the U K lacked a definitive description of ··good microbiological practice" , a guid­ ance note on ""Guidelines for Microbiological Safety" was developed by scientists in a ''Joint Coordinating Committee for the Im­ plementation of Safe Practices in Microbiolo­ gy" , and this was accepted by GMAG in July 1 980. G I B S O N ( 1 986) d escribes the Joint Coordi­ nating Committee's action, by the scientific com munity, as ''almost exceptional in the rDNA debate in the United Kingdom"; and emphasizes the role of individual scientific contributions. In particular, ""SY DNEY BREN­ NER (of the Medical Research Council's La­ boratory of Molecular Biology ) first gave, in July 1 978, the GMAG the initial concept for the risk assessment scheme that proved so successful. It was introduced in March 1 979, and revised in January 1980. Local biological safety committees were able to operate with ease the risk assessment scheme, which was sufficiently flexible to allow scientific or med­ ical information to be introduced when reach­ ing a decision. The scheme resulted in most work being recategorized to either Category I or GMP. it was also Dr. B RENNER's develop­ ment of the disabled Medical Research Coun­ cil ( M RC) E. coli strains (MRC 8 in particu­ lar) which allowed GMAG to incorporate the concept of biological containment in its risk assessment scheme with greater confidence." Categorization of experiments was carried out by the local biological safety committee. From 1 980 onwards, it was only in cases of uncertainty, or where work in Categories I I , I I I or I V was envisaged, that GMAG was asked to advise on a case-by-case basis. The UK Williams report and the GMAG Code of Practice appeared before the p ubli­ cation (June 1 976) of the NIH guidelines, with the result that countries elsewhere in Eu­ rope involved in rONA work i nitially decided to adopt the GMAG guidelines. In general, the absence of framework legislation such as the U K's Health and Safety at Work Act made it more difficult to introduce legislation to cover genetic engineering. As a result, when the N I H guidelines were introduced,

518

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

with less demanding containment require­ ments and with a comprehensive and codified system for categorization of experiments, al­ most all mainland European countries de­ cided to adopt these. Implementation meth­ ods and standards varied widely, and this was the background to the first legislative initia­ tive by the European Commission, described below.

2.2 The European Commission, DG XII: Towards the First

Biotech Research Programme, " B EP "

The European Commission's Directorate­ General for Science, Research and Develop­ ment ("DG XII") had since the mid-1 970s ad­ vocated a Community R & D programme to address on a Europe-wide basis the chal­ lenges and opportunities of the advances in molecular biology. Study reports were com­ missioned from eminent academics to but­ tress the case: from DANIEL THOMAS of Uni­ versity of Compiegne, on enzymology (THo ­ MAS, 1 978); from ARTHUR R6RSCH, then of University of Leiden, on genetic engineering (Rorsch, 1 978); and from CHRISTIAN DE DuvE, of the International Institute of Cellu­ lar and Molecular Pathology, Brussels ( DE DUVE, 1 979). At that time, and up to the implementation (in 1 989) of the Single European Act, there was no specific legal basis under the founding treaties of the European Communities for R & D programmes (other than a reference to co-ordination of agricultural research in Article 41 of the Treaty of Rome, founding the European Economic Community; and the research aims pervading the Euratom Trea­ ty). The R & D programmes proposed by the Commission during the 1970s and 1 980s therefore had to use as their legal basis the very general provisions of Article 235: "If any action by the Community appears necessary to achieve, in the functioning of the Common Market, one of the aims of the Community in cases where this Treaty has not provided for the requisite powers of action,

the Council, acting by means of an unanimous vote on a proposal of the Commission and after the Assembly has been consulted, shall enact the appropriate provisions." This had the drawback of requiring a unan­ imous vote of the Member States. It was therefore considered politically essential to include in the proposed programme provision for research and development of risk assess­ ment methods for rDNA work. A back­ ground study on risk and safety aspects was commissioned ( SARGEANT and EVANS, 1 979). The Biomolecular Engineering Pro­ gramme, or "BEP", was finally adopted by Council on 7 December 1 981 , with a budget of 15 million ECU, to run from 1 982 to 1 986. Of its 1 03 projects, in fact only two addressed risk issues; but this aspect was in principle in­ itiated by BEP, and expanded substantially in later programmes. Expertise on genetic engineering matters within the Commission services was located in DG XII, the Directorate-General for Science, Research and Development; indeed, it was only by the chance presence of staff re­ cruited for biological safety-related work un­ der the Euratom Treaty that there was within the Commission a small but alert nucleus of staff cognizant of the subject, and capable of identifying, and interacting with, competent external scientific advisers such as the authors of the study reports cited above. 2.3 The 1 978 Proposal for a

Council Directive on rDNA Work

The DG XII biology staff, in consultation with the Scientific and Technical Research Committee (CREST), the European Science Foundation (see below), and other external sources of scientific advice, formulated in 1978 a "Proposal for a Council Directive es­ tablishing safety measures against the conjec­ tural risks associated with recombinant DNA work" ( EUROPEAN COMMISSION, 1 978a). As for the research programme proposals, the le­ gal basis was Article 235 (see above). This proposal was submitted by the Com­ mission to the Council on 5 December 1978. At all the ten places where it referred to "haz-

2 Begmnings in Europe: From "GMA G " to the EC 's 1 982 Cou n cil Recommendation

ards·· o r "risks " . t h e word was preceded by t h e adjective "conjectural". The preamble re­ ferred in positi ve terms to the value of basic and applied science. and the need to combine protection of man. his food supply and envi­ ronment with the development of recombi­ nant DNA wor k . I t stressed the international and e pid e m i ol o gical character of the conjec­ tural risks: and the risk that differing provi­ sions in force o r in preparation in Member States would affect their scientific and tech­ nological competitiveness. The rapid evolu­ tion of understa nding . the need to consider local circumsta nces. and the need to safeg­ uard scientific and i ndustrial secrecy and in­ tellectual property. were similarly acknowl­ edged. The definition of " recombinant DNA work " was identical to that of "ge netic manip­ ulation" in the U K regulations. q uoted abov e . The substance of the proposed Directive was to req uire prior notification to, and au­ thorization by. national authorities, prior to all research or other work involving recombi­ nant DNA. National authorities would devel­ op categorization systems for rONA work. keeping the Commission informed; and the Commission would publish them. Member States would s u b m it to the Commission at the end of each \ e ar the list of authorizations during that y e a r . and a general report on their experience and problems. Of lasting significance was the final Art i c le . No. 5 . which read: "Because of the unceasing progress of knowledge and techniques in the field of hasic and applied biology, this Direc­ tive and its continued applicability to produc­ tion activities of industries shall be thorough­ ly reviewed . and revised if necessary. at regul­ ar i n terval s not exceeding two years.'' A s this proposed Directive moved into de­ bate in the E u ropean Parliament. the Com­ mission' s staff. the scientists and administra­ tors in D G X I I . were alert to the evolution of opinion in t h e U S during 1 978. towards non­ legislatio n . The experience of the NIH RAC, a n d o f the U K G M A G . was accumulating: the scient ific debat e w a s progressing: and a con­ sensus was deve loping that some of the initial e xprc:ssions of scientific ( and ot her) concern had been exaggerated. NIH Director D o N

519

FRE DRICKSON visited DG XII Director-Gen­ eral G u NTHER ScH USTER in 1 978, to convey to him the lessons of the U S experience; and emphasized the desirability of avoiding fixed statutory controls. The Parliament had commenced its scruti­ ny. and was adding amendments more rigidly specifying containment requirements; but in­ s pired by the US and UK experience, the Commission on the advice of ScHUSTER de­ cided in 1 980 to withdraw their proposed Di­ rective, and replace it by a proposal for a Council Recommendation ( E URO PE A N CoM­ M I S S I O N , 1 980) . This ( non-binding) proposed Recommendation was that Member States adopt laws, regulations and administrative provisions requiring notification - not author­ ization - of recombinant DNA work.

2.4 The CREST Paper At a meeting with CREST (the European Committee - of Member State officials - ad­ vising on matters of research, science and technology) in September 1 978, the Commis­ sion already acknowledged (EUROPEAN COMM ISSION , 1 978b) that rONA technology opened up new avenues for fundamen tal and applied work, which would lead to '"an enor­ mom improvement in our knowledge of ge­ netic structures and genetic functions", which, ''in the long run , could completely revolution­ ize certain production methods in agriculture and industry". The risks associated to rONA work. deliberate malice apart, were "at the moment conjectural and, to a very large ex­ tent. controllable". Reference was made to experiments and other considerations leading to the view that "man and his environment, since they survived the continuous flow of in­ formation between species, may possibly be considered as relatively tolerant to any new form of recombinant DNA". The NIH detailed guidelines for classifica­ tion were cited, but with the comment that "At the moment only the laboratories spon­ sored by the NIH are compelled to follow these guidelines which are presently under re­ vision and will probably be made less strin­ gent". Regarding the (mid- 1 978) E C situa­ tion,

520

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

"Within the European Community, the United Kingdom has rendered compulsory advance notifi­ cation of genetic manipulation work by all those who intend to carry out such work on the national territory. A code of practice, which differs from that of the NIH on essential points dealing with classification procedures and containment methods, is at the moment operated on a voluntary basis but with the understanding that the inspectors of the Health and Safety executive have extensive powers to enforce duties as well as precautions recom­ mended by the British Advisory Group. The other Member States have also prepared or adopted guidelines for research with recombinant DNA which in some cases adhere to either the B ritish or the American system and in others represent a compromise between the two sets of guidelines. I n France, the Netherlands, Denmark a n d Belgium, the National Advisory Committees have been as­ signed the task to register the work at hand and to review research proposals. While a declaration of agreement has been drafted in France under which governmental, academic and industrial laboratories will submit to review and approval any project for recombinant DNA work, only o n e Member State (the Netherlands} has, in addition to the United Kingdom, clearly indicated an intention to intro­ duce legislation for recombinant DNA research. "

The Commission note acknowledged that the elaboration or adoption of guidelines in the Member States and in other European countries had been greatly facilitated by the critical reviews and recommendations issued by the Ad Hoc Committee on rONA research of the European Science Foundation (ESF; see below), and by a Standing Committee on recombinant DNA of the European Molecu­ lar Biology Organisation (EMBO). In spite of the declining assessment of the seriousness of the conjectural risks, the Com­ mission put forward six reasons for national legislation:

( i ) gravity of the hazards - "conjectural" did

not mean benign, and it was because of these heavy potential consequences that containment methods (physical and bio­ logical) had been developed; (ii) expansion of rONA work - as rONA use was becoming widespread, then the risk, if any, was "increasing with time in pro­ portion with the total number of sites"; (iii) transnational nature of the risks - as vi­ ruses and bacteria do not respect fron-

tiers, this "reduces the liberty of individ­ ual nations to define and to follow inde­ pendent policies in the field of genetic manipulations". Agreements and gua­ rantees on the objectives and scale of protection systems in neighbouring coun­ tries could "best be generated through legal dispositions, taken in each country, which are based upon a core of princi­ ples adopted in common"; (iv) research in laboratories from private en­ terprises - publicly funded rDNA might allow effective control over research ac­ tivities in universities and public research institutes, but in the absence of legal dis­ positions it was difficult to envisage the laboratories of private industry following the same rules; (v) harmony between Member States - to avoid large variations in research poten­ tialities and "the development of differ­ ing conditions of safety, work and access between Member States, and, subse­ quently, to the concentration of research activities at the most permissive sites"; (vi) the exemplary value of legislation on re­ combinant DNA technology - the inter­ esting argument was advanced of using rONA as a prototype, "a choice material for establishing compatibilities between legislation and the development of mod­ ern technologies and for preparing a first basis to the dispositions which will un­ doubtedly have to be taken in the future to protect man against his own achieve­ ments. Provided that the legislation is to­ lerant, flexible, and associated to a stim­ ulation of research through funding, the opportunity should not be missed". The self-interest in the last sentence may be noted - DG XII had to argue for another three years and more before their research programme was adopted.

2.5 The Economic and Social Committee

The proposal for a Community Directive went forward to Council in December 1 978,

2 Beginnings in Europe: From " GMA G " to the ECs 1 982 Council Recommendation

but the fi rst o ffi c i a l response was that of the Econom ic and Social Committee (ESC), a consultative body stat utorily in v olved in all C om munity legi slation, and represen t i ng the ''social p a r tner s ·· - business. consumers, trade un i on s . Their report, d e l i v er e d in J uly 1 979. r ev iew e d t he h i story of the p re vi o us y e a rs , i n ­ c l u d i n g US experience . I t emphasized the de­ clining assessments of risk , the absence of sp ec i fi c proble ms. and noted that the pr ov i sion of costly safety measures was not in itself evidence of danger. Industry and agriculture wo u l d benefit from ap pli cati o ns of the new knowledge . and in ge nera l . th ey q ue st ione d the urgency of a Directive if one considere d only conjectural risks. H ow e v e r , t h i s assessment depended upon cont i nued self-d iscipline by the scie nt i fic co m ­ m u n i ty , which could not be a ss ured : and som e countries - Ne therlands was mentioned - fe lt that legislation would help to reduce the la­ tent mistrust among th e g e nera l po p ula t io n . They noted that if l egi s l a t io n were adopted . it w ou ld need to be ada p tab l e to rapid scie ntific c h ange . The ESC re port on balance su ppor ted the Commission proposal for a D i rect i v e : but proposed also t h a t the ESC itself held a p u b lic h e a r i ng, jointly with the Commission , in view of the differences of scie n ti fi c opinion, and in order to bring togeth e r op inio n also of unions , industr} . a g ri c u lt ure and p ub l ic inter­ est groups . The Comm i ssion respon ded to the chang­ ing climate of o p i nio n by w it h draw i n g its pro­ posal for a D i rect i ve . and p u tti ng forward in J une 1 980 the p r op o sa l for a Council Recom­ m e ndat i o n cited above ( E UROPE A N CoMMIS­ SION , 1 980) . I t s ope ni n g sentence summarized the reason for the change : "An a n a l ys i s of the cu rr e n t situation in the course of the l ast two years. in the U ni t e d S tat es as w e l l as in Europe . to evaluate the importance ot t he dangers result i ng from ge­ netic engineering. h a s shown that the conjec tural risks associated with the work involving the pr od uc t i o n or utilization of r eco m b i na n t D N A are probably n o n - e xi st e nt or small . " ­

­

­

521

2.6 The European Science Foundation A dds Its Voice : " N o Significant Novel Biohazards " D ur i ng the po s t - Asi l o ma r yea rs , a n im p or tant role was p l a y ed by the European Science Fo un dation . This body was set up in 1974, as a m e e t i ng-p l ace for t he research councils of E u rop e ; with a m is s i o n for setting obj ectives and s tim u l ating basic research in E urope . By th e 1 990s, it had over fift y members, from some 20 countries. From the s tart , it also had a close re l at i on s hi p w i th t h e E uro p ean C om­ m uni t y . In addition to its various activities i n the fi e l d o f basic scie nce , it pl a y ed a sign i f­ icant and influential role in ar t ic ul a t i ng the voice of the European scientific co m mu n i t y concerning t h e regulation of recombinant DNA research a n d bi o technolo gy . Its annual assembly functions as a kind of " par l iament " of 70-80 scholars d e l egated by the member countries to r e v i ew its activities. The ESF had in 1 976 established a n "Ad Hoc Co mm i t t ee on Recombinant DNA Re­ sea rc h (G e n eti c Manipulation)". T h e y b ro ugh t together scientists i n v ol ved in rONA over­ sight and on national committees from many European countries, and one result of their w or k was to promote a pr ogre s si ve conver­ gence of scientific p rinci ple s for rONA safety. The evolution of t h eir views between 1976 and 1 98 1 a l so illustrates the rapid change of scientific op i n ion s regarding risks, w hi ch was e v ery w h e re a feature of those years, in the U S , in the European Commission , an d at na­ t io na l level in Eu rop e - cf. further e x ampl e s in S e ct . 5. Meet i n g in A m s te rdam on 1 0 Se pt e m b er 1 976. the Committee discussed both the re­ cently finalized firs t version of the NIH Guidelines; and the UK R epo r t of the Work­ ing Party on the Pract i ce of Genetic Ma n ipu lation (the ''Williams report " ) . They noted th e differences: the NIH system of safeguards re lied to a greater extent on biological c o n­ tainment. the U K on phy s i c a l . The American g u i de l i ne s were written down i n m ore detail tha n the UK recommendations and code of prac tice . The NIH administrative system was de sign ed to c ov er research funded by the NIH, the UK system would address all !abo­

­

522

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

ratories, under the aegis of a national central advisory committee. The ESF discussed the two systems, each coherent in itself, but decided against mixing them; and recommended the UK system. Its reasons mentioned the points above; and stressed also the importance of the statutory support under the British Health and Safety at Work Act. The Committee "emphasized strongly the importance of such legal support to ensure the effectiveness of an advisory ser­ vice", and "assumed that similar support ex­ isted in comparable legislation in other Euro­ pean countries, or could be provided". Flexi­ bility was also stressed, given the rapid devel­ opment of the field. EMBO's Advice

Sought

The European Molecular Biology Organi­ sation, EMB O , was also an active participant in the rONA debates of the 1 970s. It was founded informally by a group of molecular biologists meeting at Ravello, in Italy, in 1 963, and the following year acquired official status as a non-profit association under Swiss law. Under pressure from the scientific com­ munity, and recognizing the significance of the new discipline, a number of European governments agreed to set up an organiza­ tion, the European Molecular Biology Con­ ference, in 1 970. Among the activities of the EMB C was the donation of funds for fellow­ ships, courses and workshops, managed by EMBO. The inter-governmental agreement that led to the EMBC also paved the way for the creation of the European Molecular Bio­ logy Laboratory, EMBL, which came into ex­ istence in July 1974. EMBO, the original organization, acquired a high reputation for the quality of its activi­ ties - it also publishes the successful EMB O Journal. Commenting on EMBO on the occa­ sion of its silver jubilee, Nature remarked that "the keys to its success are the select commit­ tees and reviewers, who decide which applica­ tions to support, and JOHN ToozE, EMBO's executive secretary" (ANONYMOUS, 1 989). ToozE was an energetic participant in the rONA debate - see in Sect. 8 the reference to his "Documentary History of the DNA Sto-

ry" - and it was a natural step for the ESF to seek a second opinion from the body which in Europe effectively represented the scientific discipline most concerned. The ESF Committee sought further advice, inviting the EMBO Standing Advisory Com­ mittee on Recombinant DNA to compare the US and UK provisions. The EMBO commit­ tee's report was completed in October 1976, and circulated at the ESF Assembly meeting on the 26th of that month. The result, based on their Ad Hoc Committee's report, but in­ cluding amendments adopted at the Assem­ bly itself, was ESF's recommending that: subject to appropriate safeguards, research on Recombinant DNA molecules should be pro­ moted and further developed in Europe. 2. adequate measures be taken to ensure the pro­ tection of the public and its members as well as of animals, plants and the environment. These measures are set out in Recommendations 3 to 6 below. 3 . guidelines for such research, designating in suf­ ficient detail the appropriate safeguards for the different kinds of experiments with Recombi­ nant DNA, be rigorously followed by all re­ searchers and all laboratories carrying out such experiments. 4. in the first phase, the recommendations and code of practice in the United Kingdom Report of the Working Party on Genetic Manipulation be adopted as the guidelines for Recombinant DNA research in Europe, provided that the Eu­

"1.

ropean Committee which is referred to in Rec­ ommendation 9 below is set up immediately in order to ensure that the same levels of contain­ ment are used in the different European coun­ tries for the same categories of experiments. * 5. HWATSON and TOOZE. Few ofthosewho

for interpreting the recommendations and code of practice for Recombinant DNA research re­ ferred to above, for advising researchers in their use, and for supervising their implementa­ tion should be established forthwith in those European countries which have not already set up such a body. 6. in European countries national registers of la­ boratories carrying out Recombinant DNA re­ search be established and that all laboratories, whatever their source of financial support, be legally required to declare relevant aspects of their programmes of Recombinant DNA re­ search to a national register. We envisage such registers as being non-classified documents and we advise that they should be exchanged

2 Beginnings in Eu rop e: From "GMA G " to the ECs 1 982 Council Recommendation a mong t he n a t io n a l b o d i e s refe rred to i n Rec­ omme n d a t i o n 5. 7 . in each c o u n t ry the necessary administrative and supervis1•ry measures be de vise d i n con­ nect ion with a p p r op r i a t e e xs tin g national legis­ lation. to ensure that t he gu i d e l ine s a d opt e d be st rictly adhe re d t o by all l aboratories - gove rn­ ment al. industrial or p ri va t e - or in u n ive rs i t i e s or other re s e a r ch establishments. 8 . the n a ti on a l bodies in E urope r e fe rre d to i n Recommendation 5 should keep i n cl os e con­ t a c t with e a c h o t h e r , with the E M B O S t a n d i n g ,

Advisory Com m i t tee o n Recombinant DNA, with t h e appropriate c om m ittees of t h e N I H i n

c om m it t e e s for Recombin a n t DNA rese arch in other c oun t r i es We w i sh t o emphasize t h .: im p ort a n c e bot h f o r the safety of the public a n d for the development o f t h e science , of e nsuring t h a t the s a m e e xpe ri me nts are not cla�sified as diffe ri n g in level of ri s k and hence level of containment, i n the d ifferent America

and

with

.

.

.

countries. 9. to gi ve

e ffe c t to

R e c om m e n d ati o n 8

above . a

C o m m it tee of represe ntatives of t h ose national bodies for Recom b i n a n t D N A resea rch referred t o i n Recommendation 5 abo�·e. * of t h e E M B O Standing A dv iso ry Com­ mittee on Re c o m bi n a n t DNA r e se arch and of European

the Europe an M e d ic a l

Research Councils and

with represel! tation of Agriculwral research * sh ou l d be e s t ab l ished under the aegis of the E SF. It sho u l d c o m e together a t an e a r ly date a n d hold r e gula r m ee t i n gs at freq u e n t intervals i n t h e first p h ase . * * These mee t i n gs will p ro ­ .

vide

for m u t u a l i n formation . and advice o n ge n e r al po l icy for Re comb i n a n t DA r e s e ar c h and for the discus­ sion of dec i�i o ns on specific expe riments, in an oppo rtunity

consultation

particular concern ing biological containment. * This

process

should lead

to

the

building

up of

com mon bod y of experience in all quest ions co ncerning Recombinant D N A research. at E u­ rope an leve l . A further task of this Commi t tee will be to k e e p t he g uid e l i nes under continuous

and t o c onsi d e r whether and, if so, how they should be re v i se d in the l i gh t o f the deve l ­ opm e n t of t he scie nce and of safety m e a s ­ ures. revi e w

Foot notes to E S F recomm e n dations: *

The words in i t alics are amendments w h ic h were

proposed a nd agre ed **

It

is

iirst in

du r in g t h e A ssembly. proposed that t h is committee should

meet

J anuary 1 477 and at three -monthly i n t e rv a l s

during t h e

year.

The Assembly also agreed to maintain a ·· Liaison Committee on Recombinant DNA" ,

523

t o continue the work of keeping the situation under review . Four years later, by J anuary 1 98 1 , scientific opinion regarding DNA risks had considera­ bly evolved, and ESF's Liason Committee considered their work was done. They ex­ pressed this view vigorously in a brusque , one-page report, here reproduced in full: ··statement from the ESF Liaison Committee on Recombinant DNA Research The ESF Liaison Committee on Recombi­ nant DNA, at its meeting on 1 4- 1 5 th January. 1 98 1 . unanimously decided that its work of promoting the necessary harmonization of national recombinant DNA guidelines is now sufficiently complete for the Liaison Commit­ tee to be disbanded. Although the national guidelines of some countries are still evolving towards the position already reached by oth­ ers. the Committee believes that there is no further need for formal and regular liaison at the ESG between representatives of national recombinant DNA committees. Extensive information supports the view that recombinant DNA work per se entails no significant novel biohazards. This is already accepted by some national recombinant DNA committees and in those countries special sa­ fety precautions beyond good microbiological practise together with the use of appropriate host organisms are no longer required for re­ combinant DNA work except when known pathogens or toxin producing organisms are involved. It has been established that recom­ binant DNA techniques offer safer ways of studying and using pathogens and for the pro­ duction and study of toxins than conventional methods. The Liaison Committee endorses these national decisions. In several countries certain microorgan­ isms produced by recombinant DNA meth­ ods are now being grown on an industrial scale. Although some concern has been ex­ pressed about the biosafety of these large scale operations, the Liaison Committee points out that the fermentation industry al­ ready has long and extensive experience of large scale fermentation, i ncluding that of known natural and dangerous pathogens. Consistent with its statements in the preced-

524

18 The Regulation of Modern Biotechnology:

ing paragraph the Committee emphasizes that the large scale fermentation of microorgan­ isms produced by recombinant DNA meth­ ods does not pose novel or special problems. Finally, the Liaison Committee reaffirms its opinion that there is no scientific justifica­ tion whatsoever for new legislation specific for recombinant DNA research and more­ over, it sees no j ustification for further exten­ sive recombinant DNA risk assessment pro­ grammes." The report was approved by the assembly of ESF on 12th November 1 981 . Their view that the debate was virtually over was widely shared - see the quotation in Sect. 8 from the 1 981 "Documentary History" by WATSON and TOOZE. Few of those who participated in the ESF Assembly of Novem­ ber 1 981 could foresee that thirteen years lat­ er, they would again be called upon to reiter­ ate a similar message (see Sect. 7.4). This view expressed at the ESF Committee in January 1 981 , and endorsed by the Assem­ bly in November, was influential; many scien­ tists gave similar opinions at the Commission­ supported hearings in May 1 981 , held by the Economic and Social Committee. The ESC hearing focused more on social risks, such as the concentration of knowledge in the hands of industry, leading to commercial (or even military) applications not necessarily benefi­ cial. Nature's report (BECKER, 1981 a) sum­ marized views on safety and regulation as fol­ lows: "Although many of the speakers argued that the DNA guidelines were safety regula­ tions looking for a hazard, some members of ESC confirmed afterwards that they were in favour of legally enforced safety regulations, even if they needed to be frequently revised to take into account changes in risk assess­ ment. It was suggested that the Community was merely going through the same process that had taken place in the United States a few years ago, but a little later because of the several countries involved."

A

Historical and European Perspective

2.7 Report of the North Atlantic Assembly

In parallel with the ESF and ESC delibera­ tions, two Parliamentary bodies had also been considering the topic of rONA safety: the North Atlantic Assembly, an inter-parliamen­ tary assembly of the North Atlantic Alliance, which acts as a link between NATO authori­ ties and member parliamentarians; and the Parliamentary Assembly of the Council of Europe, which brings together the democra­ cies of Western Europe (and whose member­ ship in the 1 990s has expanded, almost pari passu with the democratization of Eastern Europe). The North Atlantic Assembly (NAA) es­ tablished in November 1 978 a sub-committee on genetic manipulation, which in eighteen months completed a study on "the potential benefits of recombinant DNA research, and the postulated risks; on whether there was a need for regulations or legislation; and on as­ pects of commercialization". The group was chaired by ROBERT McCRINDLE of the UK, and included French, German and US mem­ bers. The NAA group contacted many key scientists, including the ESF group, who drew to their attention the de facto emerging con­ sensus on good laboratory safety practices and the similarity of national guidelines, whether modelled on the US NIH RAC, the UK GMAG, or a combination. NAA's group noted the rapid adaptation of the guidelines under the NIH RAC, and commended its (January 1 979) expansion from 1 1 to 25 mem­ bers, to increase non-scientific representation - similarly to GMAG. NAA consulted also the World Health Or­ ganization in Geneva, in February 1980, on the question "whether, in the opinion of WHO, a universal set of guidelines regulating recombinant DNA research was necessary and if so, whether WHO could act as the reg­ ulatory body? In reply it was felt that precedents exist for international guidelines (e.g., in the world­ wide movements of biological and pharma­ ceutical products) and that WHO has the scientific and legal ability to draft such guide-

2 Beginnings in Europe: From " GMA G "' to the ECs 1 982 Council Recommendation

lines but that a n y action would of n ecess i t y have to e m a n a t e from national initiatives. Ciiven the general fe elin g that ris k s from re­ comb i n a n t DNA r e se a rc h had been e xa gg er ­ ated it w as con sidered that even if a res olu ­ tion w as pas s ed by the World Health Assem­ bly it would be difficult to e n visa ge member states t r e a ti n g i t a s binding. " The conclusions of the NAA s ub - co m mi t ­ tee, publ ished in March 1 98 1 (NORTH AT­ LA NTI C ASSEI\1 B L Y. 1 98 1 ) , w e re " t hat t he benefits of r ec o m bina nt DNA rese arch out­ we igh t h e risks and that m a x imu m encourage­ me n t should be g i ve n to de v el op this research for t he benefit of m a n k i nd . Nevertheless we fe lt that c o n t ro b are still adv i s a b le on cer ta in a s pe ct s of the research s u c h as experiments using h i g h l y d a n g e r ou s p a thoge n s or on the germ cells of human b e i n g s . We argue h o wev­ er for a flexi ble se t of control guidelines which both protect from any poss ibl e dangers that may arise - but at the same time - do not ham per research so t ha t the public may bene­ fit, as s o on as p o ss ib l e . from all the possibili­ ties offered by the implementation of this n e w tech nology . "

2.8 Report of the Council of

Europe A similar conse nsus seemed to develop i n the Co u n c i l of Europe, in a report prepared by Mr. ELMO \ J I ST and presented by t hei r Le­ gal A ffa i r s Committee . They had organized a P ar li am e n ta r y Public Hearing in Copenhagen in M ay 1 981 . under the title. ·· G e n et ic E n g i ­ n e eri ng: risks and chances for human r i g h t s " . The i r r e p ort w as b a s e d on that hearing. and took a c c ou nt of the work cited above - by the NAA, the European Commission. the Eco­ nom ic and Social Committee, and the ESF. It reviewed various models for regulation of ge­ n e t i c engi neering. acknowledging that differ­ ent countries would adopt different solutions: but foc u s e d pa rticularly u p o n the (then dis­ tant ) prospects for the e ng i n e er i n g of human gen e s . and re lated issues for human rights. The final Recommendation was adopted b y t he Parl iame n tary A s s e m b l y on 26 January I 982. It distinguished between concerns " a ris -

525

ing from uncertainty as to the health, safety and environmental i mp l ic ati o n s of e x p eri­ mental research ''; and "those a ri s i n g from t h e longer-term legal, social and ethical issues r a i sed by the prospect of kno wi n g and inter­ fering with a person's heritable ge net ic pat­ tern" (COUNCIL OF EUROPE, 1 982) . R e gardin g the fi rs t concern, the resolution e m p h a si zes the potential value of th e new techniques and of the advances in under­ s ta nd i n g ; refers to freedom of scientific enqui­ ry as a basic value. but one carrying duties and r e s po n s i b ili t i e s in regard to the h e al t h and safety of the public and the non-contami­ nation of the e n v i r o n me n t ; refers to e a rl i e r uncertainties. but notes that these "have in recent y e a rs bee n l arge l y resolved - to the point of allowing s u b s t a n t i al relaxation of the c on t ro l and containment me as u r es i n i t ially in­ stituted or e nvisaged"; and advocates that " s t r ict and comparable levels of prot e ct i on should be provided in all countries for the gene ral public and for l ab o ra t ory w o r ke r s aga i n s t risks involved in the ha n dli n g of pa­ thogenic m i c ro-o rga n i sm s in g e ne ral , irres­ pective of whether techniques of ge ne t i c engi­ neering are used". Regarding the l e gal , social and eth ical is­ sues, t h e Resolution refers to Articles 2 and 3 of the E u r o p ean Convention on Human Ri g ht s as imply ing "the right to i nherit a ge­ netic pattern whi ch has not been a rt i fici al l y changed"; but goes on to add that ''the expli­ c i t reco gni t i o n of this r ig h t must not imp e de d e v e l o pm ent of the t h erape u ti c applications of genetic e nginee r i n g ( ge n e t h er apy) , which holds great promise for the treatment and er­ adication of certain diseases which are gen e ti ­ cally transmitted" .

2.9 Division o f Opinion in the European Parliament; Council Recommendation 82/472 Adopted

During the debate on the Commission 's proposal for a Council Recommendation, rather than a Directive. on t h e control of rDNA work. opinion i n the E u ropea n Parlia­ ment became deeply divided. Fo l l ow i n g their May 1 98 1 hearing, the Economic and Social

526

18 The Regulation of Modern Biotechnology: A Historical and

Committee had disagreed with the Commis­ sion proposal, and advocated a Directive. In the European Parliament, the rapporteur was D oM E N I CO CERAVOLO, an Italian Commu­ nist. His report argued that even if a risk was only due to a hypothetical chain of events, this was not a justification for thinking it any less valid or significant. The conjectural risks could not be dismissed, because no suitable criteria were available for assessing them. However, the liberals and conservatives, at that time a majority in the Parliament, sup­ ported the Commission proposal, concerned that too much legislation would slow down the growth of Europe's biotechnology indus­ try ( B ECKER, 1 981b). The proposal for a Rec­ ommendation was approved by Parliament early in 1 982, and adopted by Council in June that year. In October 1984, the Committee of Minis­ ters of the Council of Europe adopted almost the same text as a recommendation for their (then) 21 Member States; with slightly greater flexibility for Member States, who were left free to decide on the categories of risks re­ quiring notification (because, it was said, the biological risks had previously been overesti­ mated). It was also indicated that work would continue on studying other, ethical, ques­ tions.

3 From Research to Strategy, Co-ordination and Concertation, by Commission and Industry 3 . 1 Calm B efore the Storms: The Early 1 980s and the International Scientific Networks

With the adoption of Council Recommen­ dation 82/472, recommending national sys­ tems of notification of recombinant DNA work, the regulatory debate in Europe

European Perspective

seemed to quieten for some years. The rec­ ommendation was a rational response to un­ certainties; it allowed the Member countries with significant research activities, and with correspondingly developed oversight struc­ tures, to develop further and to adapt these structures to evolving perceptions of need. Conscious of public sensitivities, the scientists involved co-operated readily with national authorities; international harmonization de­ veloped through the usual scientific networks, and through various international bodies, such as those referred to below. European Sdence Foundation

The European Science Foundation had been active in the early years, as mentioned above, and in the January 1981 report of its rONA group appeared to have concluded its work; but at the request of the Council of Eu­ rope, it conducted in 1982 a survey of nation­ al regulatory developments, referred to in Sect. 5 . 1 below. The European Federation of Biotechnolo­ gy was founded at Interlaken in 1 978, through an initiative led by D ECHEMA (the German Chemical Equipment Manufacturers Associa­ tion), the (UK) Society of Chemical Industry, and France's Societe de Chimie Industrielle. The Federation expanded through the 1980s to include over 60 learned societies; from the various disciplines of the life sciences and technologies, and from all parts of Europe (mainly, but not exclusively, Western). DECHEMA had since the early 1970s within Germany been a leading advocate and source of information in relation to biotechnology. The subject was seen at that time mainly as the modern development of the fermentation industry, requiring an inter-disciplinary syn­ thesis of biochemistry, microbiology and process engineering; and relatively slowly, D ECHEMA and the EFB extended their concept of biotechnology to include the new genetics. The EFB has various Working Parties, many of which interacted significantly with the European Commission, by conducting studies, organizing meetings, etc. Among the groups active in this way were and are those

3 From ReJearch

to

Strategy. Co-ordination and Concertation. by Commission and Industry

on Education . Environmental B iotechnology . and (during recent years ) . Public Perception: but of pa rt icu l a r significance to the regulatory debate was that on S afe ty . which published a series of influe ntial technical papers on var­ i ou s aspects o f safe concepts and practices in biotechnology ( K OENZI et at . . 1 985 . 1 987: FRO MM E R et al.. 1 989. 1 992. 1 993 ). As key members we re also active in national and O E C D group�. and (after 1 99 1 ) in CEN wor king groups (for European standards) . duplica t i o n of activity was avoided . and con­ sensus (e.g., on r i sk - base d categorization of microorganisms) was readily spread between the various in terested constituencies. Within the I CS U ( International Council of Scientific Unions) ''family" of world-wide scientific uni on s . COG E N E . the Scientific Committee on Genetic Experimentation , was established by the 1 6th General Assembly of ICSU i n O c t ob er 1 976. to serve as a source of advice concerning recombinant DNA activi­ ties. Its purposes were defined as follows:

(i)

t o revie w . e v a l u ate

and make available in fo r m at i o n on t he practical and scien­ tific benefits, safeguards, containment fa­ cilities and other technical matters; ( ii) to consider e nvironmental. health-re­ lated and other consequences of any dis­ posal of biological agents constructed by recombinant DNA techniques; ( iii) to foster opportunities for training and international exchange : and (iv) to provi de a forum through which inter­ ested national. regional and other inter­ national bodies may communicate . ( B E R N A R D I . 1 991 ) In

March 1 979. COGENE's Working Group on Recombinant D N A G uidelines prese nted a report. and the Committee organ­ ized the first COGENE S ym po si um . on Re­ c om b i n a n t D N A and Genetic Experimenta­ tion . in Wye . UK. B E R N A R D I ' s view is that ·'These actions played an i m portant role in downgrading the excessively stringent con­ tainme nt co n d i t i o n s which were imposed un­ til t hen . . . Certainly the timing of these actions - three month s a ft e r the Eu ro pean Commis­ sion had proposed its Directive (Dec. '78 see S e c t . 2.3 above) - and the international

527

character of I C S U , were favorable for in­ fluencing the E uropean authorities and th e ir advisers. COGENE continued to work for rat i ona l i ­ zation of condi t ions imposed on rONA work, t h eir Working Group on Risk Assessment publishing in July 1 99 1 a report which was cir­ culated to other international a g encie s . More widely influential may have been a three-page statement prepared at a joint w orkshop by COGENE and SCOPE, I C S U ' s S tand i n g Committee on Problems of the Environment, in 1 987 (published in MOONEY and B ERNAR­ D I , 1990 ) . For it addressed an issue which at that time was emerging into the political prominence it has since retained: the release of genetically engineered organisms into the environment. Again , the timing was signifi­ cant in relation to regulatory proposals of the European Commission (see Sect. 4), although the relative weight of scientific advice was by then dim i nishing in competition with the in­ fluence of other actors. B ut the core of the SCOPE/COGENE statement was a succinct and balanced summary of scientific views on the risks of field release, and the appropriate means to approach these. On

risks:

"In view of the gre at potential of new technolo­ gies for addressing e nvironmental and other prob­ lems, and because most introductions of modified organisms are likely to represen t low or negligible ecological risk . generic arguments against the use of new genetic m e thodologies m ust be rej ected. In­ deed, t he spectrum of available tools represents an evolving and expanding continuum, which includes conve ntional met hods, rONA tech niques, and oth­ ers. While much attent ion has been focused on the methods used to modify organisms, it is the prod­ ucts of these technologies and the uses to which they will be put that should be the obj ects of atte n ­ t i o n , rather t h a n t h e particula r techniques e m ­ ployed to achieve t hose ends. Similarly. one must reject generic safety argu­ m e n ts based on the asse rtion that all introductions must have occurred some time during the course of evolution . Therefore, each introduction of a n or­ ganism. whe t h e r modifie d or not, must be j udged

on its own merits. within the context of the sca le of the

appl ication

and the

possible

environ mental

costs and benefits. Size, geographical scal e , and frequency of intro­ duction a re among the factors that are important in

528

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

determining whether a particular introduction will become established or spread. Therefore, small­ scale field testing involves different considerations than does large-scale (e.g., commercial ) application . This does not suggest that small-scale testing should be exempt from examination for regulation, but simply that any risks are likely to be much smaller and more easily managed than those for large-scale applications. Nor does this suggest that all large-scale applications will be problematical, since we have many examples to the contrary, in­ cluding vaccines, biological control methods, and the use of rhizobia in agriculture."

On risk assessment: "The properties of the introduced organism and its target environment are the key features in the assessment of risk. Such factors as the demographic characterization of the introduced organisms; ge­ netic stability, including the potential for horizontal transfer or outcrossing with weedy species; and the fit of the species to the physical and biological envi­ ronment. The scale and frequency of the introduc­ tions are important related factors. These consider­ ations apply equally to both modified or unmodif­ ied organisms, and, in the case of modified organ­ isms, they apply independently of the techniques used to achieve modification; that is, it is the organ­ ism itself, and not how it was constructed, that is important. Each proposed introduction must be treated on its own merits, but this does not suggest that each needs to be considered de novo. As experience ac­ cumulates with particular kinds of introductions in particular environments, more generic approaches to these classes of introductions can be developed. The bases for classification should be refined con­ tinually, providing a set of criteria that will allow any proposed introductions judged to be innocuous to be carried out speedily and those judged to be problematic to be given the attention they de­ serve. "

Statements such as those of SCOPE/CO­ GENE quoted above , and similar opinions expressed by the EFB Working Group on Sa­ fety in Biotechnology, and the European Science Foundation, remained consistent and apparently valid throughout the 1 980s and later years. But the situations in which they competed for influence were changing in key respects. The continuing scientific successes, and the inescapably central role which the new knowledge and techniques had to play in any

research concerned with understanding bio­ logical structures and functioning, led inexor­ ably towards application. Application of the new biotechnology, in the production of mol­ ecules of interest by genetically modified host organisms, was normally in fermenters of large-scale, or at least, on a scale greater than laboratory. In agriculture, application would mean the release in progressively less con­ fined conditions (greenhouse, test plot, etc.) of genetically modified plants and microor­ ganisms. "Large-scale" and "Field Release" were terms that entered political discourse in the next round of legislative debate on bio­ technology regulation in Europe. But before describing this, the debate on regulation should be set in a wider context of the debate on strategy, which also developed from the early 1 980s.

3.2 Scientists Redeploy Effort, from Regulation to Research, Forecasting and Strategies

The Commission staff in Directorate-Gen­ eral XII (Science, Research and Develop­ ment) who had been active in the "post-Asi­ lomar" activities on regulation were in 1982 able to turn their energies to the management of the new research activity, the Biomolecular Engineering Programme ("BEP"; 15 million ECU, 1 982-86), for which they had argued and negotiated during some six years. The phrase "Biomolecular Engineering" com­ bined references to genetic engineering (re­ flecting the study by RoRSCH, 1978) and en­ zymology (reflecting the study by THOMAS, 1978), as well as risk assessment work (draw­ ing on the study by SARG EANT and EVANS, 1979). The significance of research and technolo­ gy for economic competitiveness acquired ever-increasing political visibility through the latter decades of the twentieth century; but apart from a reference to the co-ordination of agricultural research (Article 41 ), research did not feature in the original EEC Treaty of Rome (1957), founding the European Eco­ nomic Community. Separate Treaties in 1 95 1 and 1 957 had founded the Coal and Steel

3 From Research to Strategy. Co-ordination and Concertation, by Comm ission and Comm u n i t y , and Euratom for atomic energy research: but i t w a s only in 1 974. after much study and debate, that the situation started to change: and a further decade-and-a-half elapsed before research had an explicit legal basis, via the coming into force (in J uly 1 989) of the Single European Act. At a Counci l meeting in Paris on 1 4 J anuary 1 974, four Resolutions were adopted on the development of a common policy on science and technology. i ncluding the co-ordination of national policies and the joint i mplementation of projects of i n terest to the Community ( E u ­ ROPEAN COI\l M I SS J O N . 1 977a). RALF D A H ­ REN DORF of Germany was the first Commis­ sioner to have responsibility ( 1 973-76) for Community R & D policy. DAH R E N D O RF established in 1 974 a " Eu­ rope + 30" group of experts. under the chair­ manship of M EP W A Y L A N D YouNG (subse­ quently Lord K E N N E T ) . charged with consid­ ering how long-term ( i .e . . up to 30-year) fore­ casting could feed into the choice of Commu­ nity R & D obj ectives. At that time . long­ term studies and "futurism" tended to be dominated by US think-tanks - RAND Cor­ poration , Hudson I nstitute and others - and the Club of Rome , famous for its " Limits to G rowt h ( M E A DOWS et al. . 1 972) . was not as close to public policy as the US Congressional Office of Tech nology Assessment, founded in "

1 97'2. E u ro pe + 30"

report was ambitious ( KENNET, 1 976), proposing the creation of a new Community i nstitution for futures stud­ ies; the final implementation was modest, be­ ing the adoption (by a Council Decision in 1 978} of a Community programme of " Fore ­ casti n g and A ssessment in Science and Tech­ nology", or F A ST: with a budget of E CU 4.4 million . for the five vears 1 978-83. The new u nit was housed with in D G X I I : and was the origin of a n e w initiative on biotechnology. The mandate of FAST was broad . It in­ cluded " highl i ghting prospects. problems and pote n t i a l con fl i ct s l i kely to affect the long­ term development of the Community and defi ning alte r n ati v e courses of Community R & D action t o help solve or achieve them ur t\) render c o ncrete these possibilities'' ( E u ­ R O P E A "' CO L N CI L. 1 978). With six graduate staff. it divided its work into three strands: The

"

• • •

Industry

529

Technology. Work and Employment " Information Society" ''Bio-Socie ty".

The third strand comprised a series of stud­ ies. workshops and widespread network con­ sul tations, conducted with a long-term per­ spective, and assisted in particular by the Eu­ ropean Federation of B iotechnology. The re­ sults were used to assemble the "Bio-society" section of the first synthesis report of t he FAST programme, in September 1 982 ( FAST. EU ROPEAN COMMISSION , 1 982) . This became, with little adaptation, the first draft of a " Community strategy for biotechnology in Europe"; and reports with that title were published both by DECHEMA (on behalf of the E FB) in 1 983, and by the Commission as a "FAST Occasional Paper" in March 1983 ( FAST. EU ROPEAN COMMISS I O N , 1 983). The whole FAST report, i ncluding the "Bio-socie­ t y sections was subsequently published un­ der various titles ( FAST, CO M M I S S I ON DES ,

"

FA ST E U ROPEAN COM M I SSION,

1 983; 1 984; FA ST­

G R U PP E , K O M M I S S I O N D E R E G ,

1 987).

COMM U N A UTES

E U ROPEEN N ES ,

,

3.3 T h e Framework Programme fo r R & D, and the 1 983 Communications: A First Community Strategy for B i otechnology

From 1 981 to 1 984, the Commissioner re­ sponsible for both Research and Develop­ ment (mainly D G X I I ) and Industrial Affairs (half of DG I I I , the other half being Internal Market) was Vice-President E T I E NN E D A V ­ I G N O N . of Belgium. He had during 1 982 been politically responsible for the first "ESPRIT", a E uropean Strategic Programme of R & D in I n formation Technology: with a budget of 750 million ECU. at that time a massive pro­ gramme. It was, therefore, seen as significant G ASTON when President Commission T HO R N in his annual programme speech to Parliament in February 1 983, announced that for biotechnology , the Commission would "follow the same approach as for ES PRIT". ,

530

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

The absence until mid-1 974 of a formal commitment to Community level R & D poli­ cy has already been noted. Through the 1 970s and early 1980s, the policy objectives for R & D tended to be unsystematic and ad hoc. The integration of Euratom's research activi­ ties, including those conducted at the Joint Research Centre's various facilities, and the political aftermath of the 1974 oil-shock, led to an initial predominance of energy-related research. Similarly, environmental research was emphasized in the years following RA­ CHEL CARSON's "Silent Spring" ( 1 962), the Stockholm conference of 1 972, and in the context of the apocalyptic predictions of the Club of Rome's successive publications "Limits to Growth" (MEADOWS et al., 1 972), "Mankind at the Turning Point" (MESAROV­ IC and PESTEL, 1974), and others. By the ear­ ly 1980s, the relative weakness of European industrial performance vis-a-vis US and Ja­ pan was increasingly emphasized. As Commissioner responsible for Industry and Research, DAVIGNON reacted to the pre­ viously unsystematic approach to Community R & D priorities by proposing the institution of a comprehensive, systematic, multi-year "Framework Programme", with explicit ob­ jectives, to be pursued through specific R & D programmes. To the international eco­ nomic challenge, he responded by seeking to increase the share of expenditure devoted to industrial competitiveness, from under 10% in the early 1 980s, towards 50% or more by the end of the first Framework Programme, 1 983-86. This Framework Programme was prepared by a dozen background papers, each being a "Plan by Objective"; most of them written by outside experts, but that on bio­ technology by FAST staff (CANTLEY, 1983) . Like the FAST report, this paper followed the DAVIGNON philosophy of setting Com­ munity R & D activities in the context of a broader strategy and objectives. In a resolu­ tion of 25 July 1 983, the Council endorsed the concept of the Framework Programme; and approved the development of biotechnology as part of the objective, "promoting industrial competitiveness". President THORN's February 1983 speech was the Commission's first official mention of the word "biotechnology" , and reflected a

perspective much broader than just "rDNA research". Drawing upon the recommenda­ tions of the FAST report, and with some in­ put from DG III (particularly its Food and Pharmaceuticals divisions), the Commission presented a first communication to the Coun­ cil at the Stuttgart summit of June 1 983: "Bio­ technology: the Community's role" (EuRo­ PEAN COMMISSION, 1 983a). A parallel "Back­ ground note" (same reference) provided an overview of national initiatives for the sup­ port of biotechnology, including not only EC but US and Japanese details (EuROPEAN COMMISSION, 1 983b ) This communication, like the FAST report, emphasized the great progress in the life sciences in recent years; the broad range of application and likely scale of future markets; and the strengths of the US and Japan. This case was strengthened by selective quotation from contemporaneous US reports, by the Of­ fice of Technology Assessment and others (see Sect. 5.1 ) The relative weakness of biotechnol­ ogy in the Member States, in spite of consid­ erable scientific strengths, was attributed to "lack of coherence in R & D policies and the absence of structures on Community scale". Although BEP, the Biomolecular Engi­ neering Programme, had started only the pre­ vious year, it was said to be "regarded as a starting-point for the more ambitious action recommended by the 1984-86 framework programme for Community R & D . " There should be training and mobility of scientists and technicians; efforts to put biotechnology across to the general public; a strengthening of basic biotechnology through projects half­ way between research and applications; and improvement of the research context includ­ ing data banks and cell collections. Even with these support and training activ­ ities, biotechnology would be "unable to de­ velop in the Community unless a favorable context is provided to encourage it"; and the three "necessary factors" identified were: .

.

•

•

•

access to raw materials of agricultural ori­ gin, on the same conditions as competitors outside the Community adaption of industrial, commercial and in­ tellectual property systems rules and regulations.

3 From Rest'arch

to Strategy,

Co-ordination and Concertation,

On the last . the communication empha­ sized the need to harmonize the i nternal mar­ ket, particularly for the health industries, and above all to prevent the appearance of specif­ ic national standards. ··The advisability of in­ troducing ne\\ regulations should be exam­ ined from the outset at Community level, as far as possible using the various instruments already available to the Community". The commun ication was favorably received by Council. and the Commission was encouraged to develop ove r the following months a fuller action programme . The followi ng communication in October that year (CO M ( 83 )672, E U ROPEAN CoM­ M I SSION. 1 983 h ) noted US reports dismissive of Europe ·s competitive strength in biotech­ nology, and outlined six action priorities to meet the challenges and opportunities of bio­ technology: (i)

Research and train ing: horizontal actions ··focused upon the removal of bottle­ necks which prevent the application of modern genetic and biochemical meth­ ods to industry and agriculture " : and "in­ forma tion infrastructure and logistic sup­ port for the life sciences R & D through databanks. collections of biotic materials and related information/communication networks: and the sophisticated data capture technologies which are generat­ ing such i n formation in ever-increasing 4uantities": together with specific ac­ tions "intended to stimulate certain par­ ticular developments within well-defi ned sectors of biotechnology which can con­ tribute to t he solution of problems re­ lated to the common policy in agricul­ ture and i n the health care sector. (The Biotechnology Action Programme was proposed the following year - see E u Ro­ PEA N CO 'V1 M I S S J O N . 1 984. and further reference� below) . ( i i ) Concertation o f B iotechnology Policies: " a central activity of concertation: inter­ serv ice, international. and between Com­ munity and Member States··. with "ac­ tive mon it oring and assessment of strengths, weaknesses and emerging op­ port unities and challenges" : the principal tool to be "an expanded series of net-

by Com m iss ion

and Industry

531

works, established in cooperation with the Member States to provide an ad hoc system of collaboration between individ­ uals, specialized groups and institu­ tions", coupled with "an information base, regularly updated by scanning, se­ lecting, interpreting and sorting in an or­ ganized way the incoming flow of infor­ mation". (A decade later the B IODOC documentation center would have some 60000 documents in 2000 files, and a steady flow of visitors; providing the ba­ sis for regular press reviews, an internal News-Sheet, and the European B iotech­ nology Information Service, EBIS.) (iii) New Regimes on Agricultural Outputs for I ndustrial Use: the Commission an­ nounced its i ntention to propose to Council new regimes for sugar and starch for industrial use. (This was subse­ quently implemented, from 1 986 on­ wards.) (iv) A European Approach to Regulations affecting Biotechnology (discussed be­ low). (v) A European Approach to Intellectual Property Rights in Biotechnology: the communication noted that it was "in­ dispensable that the i ndustrial property laws and instruments available in the Common Market match the need of science and industry and of the Commu­ nity's goals"; and that "Failure to pro­ vide such protection for intellectual property will drive firms to protect them­ selves by commercial secrecy. Such se­ crecy will inhibit precisely the collabora­ tive patterns of activity which are n eeded in this complex i nter-disciplinary field.'' The major unresolved issues noted were: - "the patentability of biotechnological inventions as such; - the implications and conditions asso­ ciated with the rules of practical pro­ tection requirements and procedures (e.g. associated with the deposit of mi­ croorganisms and conditions for re­ lease to third parties); - the additions to the existing problems concerning plant and animal variety protection. of complex new reactions with patent law".

532

18

The Regulation of Modern Biotechnology:

It was suggested that Member States should be invited to share with the Com­ mission information about the aims and context of ongoing and planned work in this area (as they might have submitted to the OECD 1 982 survey - subsequent­ ly reported in BEIER et al., 1 985). Mem­ ber States were urged to ratify the Euro­ pean and Community Patent Conven­ tions. The Commission proposal for a Directive on the protection of biotech­ nological inventions followed four years later (EUROPEAN COMMISSION, 1 988) after extensive consultation. The final adoption became a matter for heated po­ litical debate and contentious amend­ ments, in 1 994; it was one of the first to­ pics to require the "conciliation proce­ dure" established by the Maastricht Treaty, for reconciling a deadlock be­ tween Council and Parliament, a dead­ lock still unresolved in December 1994. (vi) Demonstration Projects: "designed to fa­ cilitate the transition between research developments and full scale exploitation on a commercial basis". (The first such projects formed part of the specific agro­ industrial "RDD" - Research, Develop­ ment and Demonstration - during the 3rd Framework Programme, 19901 994.)

3 .4 " A European Approach to Regulations Affecting Biotechnology" , 1 983

The October 1983 Commission communi­ cation, under the above title, treated this top­ ic under three sub-headings: • • •

Biological Safety The Consumer and the bio-industry The Regulation of Products and their free circulation.

On the first topic, "Biological Safety", it noted that "Public and parliamentary opinion is divided between admiration of the new dis­ coveries in biotechnology, and concern about some of the possible implications or conjectu-

A

His to rica l and European Perspective

ral risks of their use. This concern is reflected in the extensive discussion, studies and re­ ports on the need for regulation and control of various aspects of the life sciences; a de­ bate vigorously pursued throughout the de­ veloped industrial world" . Noting this widespread concern, and the similarly persistent concern with "issues such as animal welfare and their use in tests, which also impinge on biotechnology", the commu­ nication argued that "it is clearly a normal role for the Commission to ensure regulatory provision to maintain rational standards of public safety; to this end, monitoring the so­ cial dimensions of biotechnology and their in­ terfaces with policy". Regarding action, "in order to maintain awareness of evolving pressures for new poli­ cies or regulations, a monitoring function is needed, to collate at Community level the evolving views of national regulatory bodies and interested international organizations (OECD, WHO, Council of Europe, etc.), and hence to advise the Community on regulatory initiatives or international negotiations. This function can be appropriately combined with the concertation role described in item (ii) above [i.e. of the 1983 communication], and provision for it is included in the budget esti­ mates". Under the second topic, "The Consumer and the bio-industry", the communication noted that the roles of the public authorities, at both Community and Member State level, impinged at several points upon the "bio-in­ dustries" (pharmaceuticals, agro-food, etc.) and the consumer. The Commission sought to "encourage innovation, harmonize regulatory regimes, create a genuine common market and ensure that regulations were based on ra­ tional assessment and well-informed debate; while seeking always to maintain high stand­ ards of nutrition and safety". But regarding action, as with the previous heading, "the need is to maintain in the Commission the ca­ pacity to monitor the situation, and hence to concert necessary policy discussions and ini­ tiatives across the services, with Member States, and with other relevant groups (e.g. consumer associations)". All these modest suggestions were in fact implemented over the following ten years,

3 From Research to Strategy. Co-ordination and Concertation. by Com m ission and Industry

through the co ncertation action. supported under the R & D programmes BAP ( 1 985-89, see below) and B RIDGE ( 1 990-93). includ­ ing the dialogue with consumer associations ( see RO B E RTS . 1 980. K ATZ and S A TT E L L E . 1 991 : ECAS . 1 992 ) . But the attitude towards biotechnology-specific regulatory initiatives implied by the 1 983 communication could be summarized as attentive inaction. Under the t h ird heading. "The Regulation of Products and their free circulation " . the Commission was addressing the central re­ sponsibility of DG I I I ( Internal Market and Industrial Affairs ) . While emphasizing that the hio-industrics. in view of their high entry costs and long time scales ( for both R & D work. and re gulatory approval) had great need of the fu l l dimensions of European and world markets. the communication was pru­ dent in this, its init ial assessment: ''From a first review of the situation . it would appear t hat the application of current Community regulations i n the various fields (pharmaceuticals . veterinary medicines. chemical substa nces. food additives. biopro­ tein feedstuffs ) will meet current regulatory needs, provided that there is close coopera­ tion between the competent authorities in the Member States and the Commission. Such co­ operation can be achieved by greater re­ course to the existing institutional or scientific committees and . as necessary, use of the new information procedure for technical standards and regulations adopted by Council in its di­ rective 83/ 1 89/EEC of 28th March 1 983". Regarding po-;sible future action. it contin­ ued: " on the basis of its e xperience deriving from the use of these various instruments. the Commission will put forward general or spe­ cific proposals appropriate to create a regula­ tory framework suitable for the development of the activities of the bio-industries and for t he free circulation of goods produced by bio­ t echnology ".

3 . 5 The Co-ordination Problem

The program me of activity which the Com­ mission had thus published in its October 1 983 communication reflected the multi-facet-

533

ted character of biotechnology's challenges to policy. Within the Commission structure, it was clear that the interests of several Directo­ rates-General would be involved. This was a basic problem of public policy for biotechnology, with which the Commis­ sion. and gove rnments, and international or­ ganizations, all had to wrestle increasingly over the following years: how to achieve a co­ ordinated. or integrated. response to the wide-ranging but inter-connected challenges of biotechnology . through administrative structures which were essentially vertically divided. The problem was explicitly ad­ dressed by an OECD study report, on "Bio­ technology and the Changi ng Role of Gov­ ernment" (OECD, 1 988) . An intense and continuous competition for attention charac­ terizes the top of any administrative hierarchy or government . just as the front page of a newspaper has only a fi nite amount of space for one or two lead stories on any given day. This theoretical demand for simultaneous at­ tention can be met only by chopping a prob­ lem into pieces treated in parallel by separate age ncies. But the continual demands for con­ flict resolution and co-ordination require de­ cisions to be pushed up to the higher levels. where they must compete for, or await, their turn for resolution. The Commission through the early decades of modern biotechnology comprised a grad­ ually increasing number of independently nominated Commissioners. two from each of the larger countries of the Community, one from each of the small; thus increasing from 9 at the start of the 1 970s. to 1 3 ( after U K , Dan­ ish and Irish accession in 1 973), to 1 7 with the accession of Greece ( 1 98 1 ) , Spain and Portu­ gal ( 1 986). and reaching 20 with the acces­ sions of Austria, Finland and Sweden in J an­ uary 1 995. Each Commissioner has responsi ­ bility. typically, for one or two D irectorates­ General . and is advised by a Cabinet selected for compatibility with his/her language, na­ tionality and political orientation. The result is a body which, although formally committed to Community goals, has a continuing tenden­ cy to reflect the European reality of distinct and conflicting interests: and the Commis­ sioners do not face the constraint of re-elec­ tion, either personally or as a political group.

534

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

The consequent differences of outlook, inter­ ests and objectives are conveyed to the Direc­ torates-General for which they are responsi­ ble. The main countervailing force to frag­ mentation is the strength of the center, i.e., the President and his staff, supported by the Secretary-General. These came significantly into play in biotechnology only from 1 990 on­ wards; see Sect. 7. The six-point strategy of October 1 983, laid down in communication COM(83)672, recog­ nized that several Directorates-General must be involved. Following an inter-service meet­ ing in December 1 983, and discussion at the level of several Commissioners' cabinets, DAVIGNON together with the Commissioners DALSAGER (for Agriculture, DG VI) and NARJES (for Internal Market, the other part of DG III) put forward to the Commission a paper on its internal co-ordination of policy for biotechnology. This was accepted on 2 Fe­ bruary 1 994.

3 .6 The Biotechnology Steering Committee and Its Secretariat, " CUB E " ; the Implementation of the 1 983 Strategy, and the Different Interests of the Commission Services

The Commission agreed on the Davignon proposal to create a "Biotechnology Steering Committee" (BSC), to be chaired by the Di­ rector-General of DG XII (Science, Research and Development), and open to other ser­ vices in function of their interests. A secre­ tariat, which became known as the Concerta­ tion Unit for Biotechnology in Europe, or "CUBE", was established by redeploying the biotechnology staff from the FAST pro­ gramme; with responsibilities focusing on monitoring developments in biotechnology, diffusing information about biotechnology to the services concerned, and supporting these services and the BSC in implementing the ac­ tion priorities laid down in the October 1 983 communication. The Biotechnology Steering Committee provided in principle a forum for discussing

biotechnology matters of common interest at a senior level - originally that of Directors­ General. But it was not a decision-making body; and the time pressures on senior staff in the Commission made them reluctant to de­ vote time to a mere "debating club". The con­ sequence was dilution of the participation to a more junior level as the years went by; and a declining frequency of meetings: the num­ bers of meetings in the five years 1 984 to 1 988 were: 3, 3, 2, 1 , 1 . The starting of the Biotechnology Steering Committee signalled a recognition by the Commission of the need for a co-ordinated strategic approach; the location of its Chair and Secretariat in DG XII was both a reflec­ tion of its background, and the seed of its sub­ sequent failure; issues further treated in the following section. The creation of the BSC was nonetheless a workable solution in the early 1 980s. The is­ sues seemed to be satisfactorily divisible; DG XII was promoting across the Commission a greater awareness of biotechnology, in parti­ cular drawing attention to the competitive challenge presented by the United States. DG XIII, responsible for Information Market De­ velopment, was in March 1 982 persuaded to establish with DG XII a Task Force for Bio­ technology Information - aided by the bless­ ing of (then) Director-General RAY AP­ PLEYARD, a Cambridge biologist by back­ ground. Reports by the US Congressional Of­ fice of Technology Assessment ( 1 98 1 ) and the Department of Commerce ( 1 982) were un­ derlining the commercial potential, and ex­ tensive publicity accompanied the creation and expansion of the early biotechnology spe­ cialist companies such as Cetus ( 1 97 1 ) , Gen­ entech (1 976) and Biogen ( 1 981 ). With simi­ lar perceptions growing in national adminis­ trations, the political will developed for a more substantial biotechnology R & D pro­ gramme; and after extensive consultations with Member State experts, DG XII prepared and the Commission put forward in April 1984 a proposal for a "Biotechnology Action Programme" (BAP; EUROPEAN COMMIS­ SION, 1 984), discussed in Sect. 4.1 below. Below the BSC, its Secretariat CUBE re­ mained active in monitoring and information­ diffusion activities; and acquired resources

3 From Research to Strategy. Co-ordination and Concertation, by Commission and Industry

and an additional mandate with the adoption in March 1 985 of the Bi o techn o logy Action Programme; see Sect . 4. 1 . Other parts of the 1 983 strategy pu r sue d a r elati v ely separ a t e devel op ment. For DG III, t h e main day-to-day business through the 1 980s conce rne d the pr o gressive deve l opment of harmonized C ommunity - w i d e legislation in various sectors . Two of these - pharmaceuti­ cals, and the food industry - might i n theory become fields of a p p l ication for the latest ad­ vances in the life-sciences; but the scientific discoveries. the technological in v en t i o ns and the j o u r nalisti c enthusiasm for the word "bio­ technology " , did not yet perturb these secto­ rally-channelled activities. They were typica l ­ ly conducted as an intense dialogue between t he Commission staff in th e DG I I I division concerned , and the corresponding industrial trade association or lobby; interacting with co rr e spo n ding debates at national level. The diffe rences to be resolved usu a lly centerd upon differen ce s of national interest, with comp romises being arrived at to offer some­ th i ng for all the maj o r players, and no coun­ try's national champion(s) unaccepta b l y pen­

535

Common Agric u ltural Policy - in practice, the Ministries of Agriculture rather than the Co mmissi o n staff in DG V I - were at best ambivalent about the innovations offered by biotec h no logy - be it isoglucose and peptide hormones in the 1 980s (increasing productivi­ ty in sectors plagued by prod uction surpluses, and troubling consumer lobbies) , or transgen­ ic animals in t he 1 990s (bringing the wrath of the animal welfare movement to bear o n the farmer ) .

,

alize d .

From t h e 1 Y60s to the 1 980s, extended de­ bate and negot iation at national, Community . and wider inte r n a ti o nal levels concerned the control of chemical p ro duct s . and involved DGs I I I and DG XI (Environment ) . This im­ pinged on bi o te c hn o logy regulation onl y i nd i ­ r ect ly , i n the late 1 980s; and is described in Sect. 4.3 below . A lo n g - r un n i n g argument required bilater­ al discussion between DGs I I I (Industry) and VI ( A gricult u re ) . con cer n i ng t he p ricing of the raw m aterials for the fe rmentation indus­ tries. The microbes needed a s o urce of carbon - fermentable sugars , or starches (which co ul d be e nzymatica lly hydrolyzed to sugar) . But whatever the raw material, it was agricul­ t u ral in o ri gi n . and its pricing and control were matters for the Common Agricultural Policy. By 1 9Hh, new price regi mes for non­ food uses of sugar and starch were adopted by t he Council of ( Ag r ic u l t ure ) Ministers, aft­ er long and cuntentious arguments. For in spite of a n o m i n al commitment (in Article 39 of t h e EC Treaty ) to t he encouragement of technical innm ation. the "managers" of the

3.7 Should European Bio-lndustries Create a Lobby? The D avignon Meeting of December 1 984

Such arguments in the mid-1 980s seemed to be a world away from the "gene wars" of 1 975--82. and from the controversies raging n o isil y in the United States between various fe dera l agencies claiming oversight, or facing court challenges from J EREMY RIFKIN. T o or­ ganize the defence and pursue the common int e rests of the nascent bio-industry in the USA, two industrial associa tions had been created. The Industrial B iotechnology Asso ­ ciation, IBA, was founde d in 1 981 , by a doze n or so large firm s for whom a $ 10 000/year s ubscri p tio n was negligible. For the more nu­ merous start-ups, typically based on acad emic science, venture capital and entrepreneurial flair, there was the Association of Biotechno­ logy Companies, su b scription $ 600, formed in 1 983; which by the end of the 1 980s had several hundred member comp an ies . IBA and ABC merged in 1 994, to form the "Bio­ Industry Organi z ation , 8 1 0 " . The FAST r e p ort and the 1 983 Co mm is­ sion communications had drawn atte ntion to the US situation, and as indicated, there was a theoretical assent at p o l i tical level by DAVIG­ NON and his cabinet, to the need for a " Com­ mu n ity strategy" . But the earnest arguments recorded in these communications received tolerant indifference at service level in the other DGs, w h o saw the mysteries of bio­ technology as st ill playthi n gs of D G XII and their scientific co mm u n i t y, or abstractions in

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The Regulation of Modern Biotechnology: A Historical and European Perspective

the unread scribblings of the FAST team. Real issues were matters such as the price of sugar. European industry was invited to meet the Commission in 1 984, to discuss the Commu­ nity actions in biotechnology, the nature and mechanisms of the liaison between industry and the Commission, and the question of pos­ sible need for a specific bio-industry associa­ tion. Key leaders were sought, from the sec­ tors most concerned. President that year of CEFIC, the Council of the European Chemi­ cal Industry, was JOHN HARVEY-JONES, Chairman and Chief Executive Officer of ICI. To find a date convenient for both D AVI G ­ NON and HARVEY-JONES was no easy matter, and it was finally on 12 December 1 984, in the last month of the 1 981-84 Commission, that the meeting took place. Some 1 7 industrialists were present, to meet with Vice-President DAVIGNON, and Directors-General FERNAND BRAUN of DG III and PAOLO FASELLA of DG XII, accom­ panied by supporting staff. In addition to HARVEY-JONES were JACQUES SOLVAY of Solvay; HANS-GEORG GAREIS, head of Re­ search at Hoechst; CALLEBAUT of Amylum, the starch refiners; A. LouDON of Akzo, and other senior men from major companies; for the middle ranks, HILMER NIELSEN of Novo; and for the smaller firms, A L EX AND E R STA­ VROPOULOS of Vioryl, Athens, and JOHN JACKSON of Celltech, ( DENIS CREGAN of Kerry Creameries was fog-bound at London airport). Not present, to their irritation, were Monsanto Europe; CEFIC were still reticent about their "European-ness". DIETER B EH­ RENS of DECHEMA was present, a salute to his leadership in the European Federation of Biotechnology, and their work with FAST; but was treated with indifference, as a general with no troops. The company was mixed, the agenda un­ certain, and DAVIGNON was called away with apologies - to a more demanding en­ gagement after the first hour. The price of su­ gar was a tangible ·problem: on that, there could be a demand for action, and (two years later), a concrete result. B ut on abstractions such as "biotechnology", "rDNA" and "regu­ lation", the discussion was desultory, the par­ ticipants too high-level to know the detail,

and the agenda too vague for them to have been briefed. A press release was issued next day, indi­ cating that broad consensus had been reached on a list of topics: the need to avoid compart­ mentalization of the market, the need to modify for industrial use the price of raw ma­ terials of agricultural origin, the need for leg­ islation at European level concerning patents, and a coherent action concerning the proce­ dure for placing on the market of new prod­ ucts. Most of the press release referred to R & D and training actions, and the establish­ ment of "centers of excellence" in biotechno­ logy R & D. Regarding the question of an industry as­ sociation, there was a conspicuous silence. HARVEY-JONES recognized the Commis­ sion's need for an industrial interlocutor to give hard answers, and CEFIC had set up a group which could help; but it could not speak for the other two associations men­ tioned, EFPIA (the European Federation of Pharmaceutical Industry Associations), or CIAA (the Confederation of the Agro-Food Industry). He referred to the possibility of a loose grouping of the three federations, with the secretariat provided by CEFIC; and this was what subsequently developed.

3.8 The European Biotechnology Co-ordination Group , EBCG; E CRAB ; and Their Extended Family

The European Biotechnology Co-ordina­ tion Group was established in June 1 985, in­ cluding the three Federations mentioned, to­ gether with GIFAP (the international associa­ tion of the agrichemical industry ) , and AM­ FEP (the Association of Microbial Food E n ­ zyme Producers) , which included among its principal members Gist-Brocades and Novo. There was considerable reluctance in some of the sectoral trade associations - particularly EFPIA - to go beyond the loose structure of EBCG, which had neither Chairman nor bud­ get, and simply met in rotation in the pre­ mises and under the chairmanship of its 5 founding associations.

4 1 985-/990: From Strategy to Legislation E B CG was created as part of a coherent struct ure . i n which a biotechnology R & D su b g r oup would be set up, under CEFIC l ead e r s hip as an elem e n t or extension of their qui t e acti ve R & D group; and on r e gul­ atory matters . E FPIA would lead via a body k nown as "'ECRA B " : European Comm i ttee on Regulatory Aspects of Biotechnology. On patent matte rs it was noted that UNICE . the gene ra l represe ntative body for i n d us t ry in the EC. a l re a d y had a working group on pa tenting which cou ld handle any need for action or response by in d ustry on that sub­ _j ect. D u ring the following years. additional Eu­ ropean sectoral associations j oined EBCG. FEDESA. for t he Animal Health Industry. w as created in March 1 987. to give stronger represen tation for a sector t roubled by the unhappy historv of their steroid hormone products or analogues. Although cleared by the relevant scientific a dvisory bodies, yield or growth-enhancing pro d ucts attracted p ub­ lic and poli t ic a l hostility and were little wel­ comed by the Community authorities at a time when the managers of the Common Ag ricultural Policy were wres t ling with growing problems of surpluses. The shadow of the ste­ roid hormone battles of the mid-eighties - in clud i n g a related trade dispute between the EC and the L S . who had authorized use of the products - fe ll heavi l y across the subse­ quent discussion of the pept i d e hormones. s tarti n g with hovine somatotropin ( B ST) in t h e late eigh ti e s and nineties. Bei n g p roduced by genetic e n g i n e e r ing, j ust as the analogous human growth hormone ( H G H ) had been one of earliest molecules targeted (successful­ ly) for industrial production by the bio-phar­ maceutical industry. BST became a fl agsh i p molecule for the bio indu s try. M a n y other ships i n tha t large and i l l -defined fleet would have preferred to salute other fl ags and not be d rawn into conflicts with agricultural poli­ cy or a n i mal welfare concerns remote from their own pre oc c upa t ions : but " misfortune ac­ qua i nt s a man with st r a n ge bedfe llows". The European Plant Breeders' Associa­ t io n COM A S S O . brou g h t another broad di­ mension to E B CG : correctly acknowledging that the scientific success in p lant cell genetic e ngi n e e ri n g a n d other breakthroughs would -

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inevitably bring them into increas i n g involve­ ment in biotechnology. Parallel with the extension of its fam ily in va rious sectoral directions. EBCG was faced with insistent requests for some form of mem­ bership. or associate relat i o n ship from na­ tional bio i ndustry ass o ciatio n s Amo n g these. most prominent and well - organized was the French association, Orga nibio (Or­ ganisat i on Nationale Inter-professionnelle des B i o-industri e s) Their foundi n g preside n t G E R A R D NoM I N E . subsequently described the alphabet soup of national associations and their aspirations, in an article in Biofutur (NOMINE. 1 987) . I n s p it e of this broade n ing o f interest, and the policy challenges e merging at Commu n ity level in the 1 980s; and in spite of various ef­ forts to d e s i g n and finance a more effective body: EBCG was finally abandoned by indus­ try as ineffectual. A meeting was p rop ose d for some date in 1 991 ; a convenient date was difficult to find; and the conclusion, "Why bother? " was the de facto d e mise the n u n c dimirtis, of EBCG. For by then, more effec­ tive industrial representation had emerged; lar gely in response to the failures of EBCG and ECRAB to anticipate or counter effec­ tively the challenges to industry on the regul atory front in the late 1 980s ,

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4 1 985-1 990: From Strategy to Legislation 4 . 1 Research and Concertation as Elements of a Strategy : The Biotechnology Action Programme, " B AP " , 1 985-1 989

The October 1 983 commun i c ati on on strat­ egy for biotechnology was favorably received at Council meetings of Ministers of Indust ry (November 1 983) and Research ( N ovembe r 1 983, February 1 984) . An ambitious propos a l was drafted, in consultation with national and industrial re p resent a ti ves thus enabling the .

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18 The Regulation of Modern Biotechnology:

content of the programme "to be better ad­ apted to medium and long-term requirements of European industry and agriculture, and to make it fully compatible with national activi­ ties". The Commission's " Industrial R & D Advisory Committee" (IR D A C), a group of industrial advisers, created by Commission decision in February 1 984, contributed their advice and opinion on the content of subse­ quent biotechnology R & D programmes. I R­ DAC held a Round Table meeting on bio­ technology in October 1985, and subsequent­ ly created a specific Working Party ("WP-5"), which met from June 1986 onwards under the chairmanship of HILMER NIELSEN of Novo lndustri. Its mandate being limited to "R & D " , it was constrained to commenting on broader issues of Community policy; although several of its active participants were subse­ quently instrumental in the launch of the SAGB (see Sect. 7. 1 ) . The proposal for the research action pro­ gramme in biotechnology was published in April 1 984 (EUROPEAN COMMISSION, 1984). It itemized the topics for a Research and Training Action in biotechnology, compris­ ing: •

•

•

Sub-programme 1: Contextual measures (bio-informatics, and collections of biotic materials) Sub-programme 2: Basic biotechnology: pre-competitive topics in the following ar­ eas: - technology of bioreactors - genetic engineering - physiology and genetics of species important to industry and agriculture - technology of cells and tissues cultivated in vitro - screening methods for the evaluation of the toxicological effects and of the bio­ logical activity of molecules - assessment of risks Training grants.

Although the research and training action was the core of the proposal, and accounted for the bulk of the ECU 88.5 million re­ quested, the April 1 984 communication was also the occasion for a full re-statement of the Commission's strategy for biotechnology. The

A

Historical and European Perspective

document opened with quotations from US reports dismissive of European capabilities, and re-stated the action priorities of the Octo­ ber 1 983 communication. The proposal fo­ cused on two of the priorities, Research (see above) and Concertation (see below), but it reviewed action also on the other four. On new regimes on agricultural outputs for industrial use, proposals for revisions to the sugar and starch regimes were announced as imminent for the former, and in preparation for the latter. On intellectual property rights in biotechnology, the Commission mentioned the establishment of an inter-service working group on biotechnology, identifying needs for improvement which could be used to prepare the Community position in the discussions and negotiations likely to follow the OECD enquiry, then in progress, on patenting in bio­ technology. On demonstration projects, pro­ posals would follow later, once R & D pro­ jects were in progress and targets could be better evaluated. On "A European approach to regulations affecting biotechnology", the communication presented the Commission's views in some detail. Monitoring" of questions of biological safety, in particular the regulation of recombi­ nant DNA ("genetic engineering") work and the "social dimensions" of biotechnology would be included in the "Concertation Ac­ tion" (see below). The document reiterated the general case for a common internal market, then referred to consultations the Commission had under­ taken with committees of government ex­ perts, with industry, and with its own expert scientific committees in various sectors touched by biotechnology such as pharma­ ceuticals, chemicals, human nutritions, animal feedstuffs etc." The conclusion from these consultations and review was stated: "it would appear that the application of current Community regulations in the various fields will meet current regulatory needs, provided that there is close cooperation between the competent authorities in the Member States and the Commission. Such cooperation can be achieved by greater recourse to the exist­ ing institutional or scientific committees and, as necessary, use of the new information pro­ cedure for technical standards and regula-

4

tions adopted by Council in its Directive 83/ 1 89fEEC of 28th March 1 983. On the basis of its experience derived from the use of these various instruments. the Commission will put forward general or specific proposals appro­ priate to create a regulatory framework suita­ ble for the devel opment of the activities of the bio-industries and for the free circulation of goods produced by biotechnology. " The document then discussed the pharma­ ceutical sector, a nd announced the Commis­ sion's intention , arising from consultations with industry and the Pharmaceutical Com­ mittee , to submit legislative proposals to Council in July I 984. These would have as ob­ jective the impleme ntation of concertation at Community level for " biotechnologically ori­ ginating medicaments''. and would include - a proposal for a framework of consultation at community level prior to national deci­ sions on the marketing of drugs produced by biotechnological or other high technolo­ gy processes ( this Jed in 1 987 to the Direc­ tive 87/22, establishing the "prior expert concertation .. procedure ) : - proposals t o facilitate the rapid adaptation to technical progress of the provisions of existing directives on proprietary medicinal products and veterinary medicinal prod­ ucts; - a proposal to control the admission to the market of copies of innovative products, "to protect the R & D investment of the re­ search-based manufacturer". On " Concertation" (in the broader sense, not to be confused with the 87/22 procedure referred to above). the communication elabo­ rated at length the logic of a network-based monitoring and information function, to be conducted in close liaison with "t hose respon­ sible for biotechnology-related policies in the Member States'', with industry (via industry associations) and other organized interests. and ·'in conj unction with the relevant services a t Communitv and Member State level". The following list of nine tasks was proposed, and subsequently adopted. as the mandate of the concertation action: the only material amend­ ment between the April 1 984 proposal and the March 1985 Council Decision being the

1 985- 1 990: From Strategy to Legislation

539

inclusion in item 8 (at the request of Parlia­ ment) of the words. "and risks". " Concertation activity will be implemented with the objectives of improving standards and capabilities in the life sciences, and en­ hancing the strategic effectiveness with which these are applied to the social and economic objectives of the Community and its Member States. In conjunction with the relevant services in the community and the Member States, the following tasks will be executed: 1. monitoring the strategic implications of de­

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velopments elsewhere in the world for bio­ technology-based industry in Europe, working with the services of the Commu­ nity, Member States and other interested parties to identify ways in which the con­ textual conditions of operations for bio­ technology in the Community may be fur­ ther improved, to promote its develop­ ment in all useful applications, and the supporting scientific capabilities, responding to the needs for research and information in support of the specific ac­ tions of other services of the Commission, identifying opportunities for enhancing through concertation and cooperation the effectiveness of biotechnology-related pro­ grammes in the Member States, and pro­ moting collaborative initiatives in biotech­ nology with and between industry and uni­ versities, consideration of how the safe and sustaina­ ble exploitation of the renewable natural resource systems in Europe may be en­ hanced by the application of biotechnolo­ gy, promoting in co-operation with developing countries and relevant i nstitutions the pur­ suit of the same task (see preceding para­ graph) within their respective regions, monitoring and assessing developments in biotechnology bearing on safety and other aspects of the 'social dimension'. disseminating knowledge and increasing public awareness of the nature and poten­ tial and risks of biotechnology and the life sciences, establishing an ad hoc system of collabora­ tion between groups and individuals with

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18 The Regulation of Modern Biotechnology: A Historical and European Perspective

interests and capabilities in the life sciences and biotechnology, so creating networks, as informal and flexible as possi­ ble, adapted to the particular problems un­ der study: the networks to have the triple function of providing an active input into the programme, encouraging coordination through the exchange of information be­ tween the participants, and assisting the broader diffusion of information envisaged in the preceding task." The "BAP" proposal was adopted by March 1 985 with relatively little controversy, albeit with the budget initially reduced to ECU 55 million. Following the review of the programme, this was increased by ECU 20 million, to cover the accession of Spanish and Portuguese laboratories, and the allocation of increased resources for bio-informatics and risk assessment studies. The programme supported the Commu­ nity's first substantial programme of risk as­ sessment research. More than ECU 6.0 mil­ lion was allocated, to support the research of 58 laboratories across the Member States, in 16 transnational projects, which could be grouped under 5 headings: 1 . Risk Assessment of Microorganisms under Physical Containment 2. Risk Assessment of Depollution Bacteria 3. Risk Assessment of Plant-interacting Bac­ teria 4. Risk Assessment of Transgenic Plants 5. Risk Assessment of Genetically Engi­ neered Viruses. This work contributed to the initial develop­ ment of a scientific base of relevance to regu­ latory needs, although inevitably many open­ ended questions remained. Further risk as­ sessment research was conducted in the suc­ cessor programme, B R IDGE ( 1990-93) , on activities seen as complementary to the pro­ jects in BAP: "Monitoring and control techniques: sampling and probes for engineered organisms and in­ troduced segments of DNA; methods and in­ strumentation for high resolution automated microbial identification and the establishment

of adequate data bases; creation of a bank of specific probes and chemical signatures for a large number of specific microorganisms; era­ dication methods. Assessment techniques: biological contain­ ment; gene stability and gene transfer; devel­ opment of microcosms and stimulating meth­ ods for impact analysis. Acquisition of fundamental kno wledge on gene behaviour (horizontal transfer between

species, rearrangement of introduced genes in the host organisms), and on the survival and adaptation of released organisms, in particu­ lar soil bacteria, and including modification of host range and tissue range for engineered vi­ ruses. No vel constructions: biologically contained organisms, suicide vectors or constructions which cannot develop outside the host organ­ isms, engineered organisms which can be de­ stroyed in the environment by known and specific techniques. 62 laboratories from the EC and EFTA coun­ tries are selected in B RIDGE to work in 1 4 projects aiming at t h e evaluation o f possible interactions between GMO's and related spe­ cies. In addition, a large, so-called' targeted', project involving 10 laboratories is also un­ derway for the development of methodolog­ ies rendering possible the automated identifi­ cation of microorganisms in the soil. Finally six laboratories are working in identifying the state of the art on the identification and mo­ lecular taxonomy of fungi in agricultural ap­ plications. " (VAN HOECK and DE NEITAN­ COURT, 1 990)

4.2 The European Parliament Reviews Strategy: The Viehoff Hearings and Report

The debate on the BAP proposal triggered in the European Parliament not only discus­ sion of the scope and content of the research programme, but a wider interest in the issues raised by biotechnology. The Parliament de­ cided to prepare an "own initiative" report ­ i.e., not merely the formal opinion on, and proposed amendments to a Commission pro-

4 / 985- 1 990: From Strateg_v

posal. but an in-depth investigation of a topic in itiated by the Parliament itself. The " rap­ porteur" nominated was Dutch Socialist MEP Ms PHIL! V t E H OFF. who was assisted by Ms ANNE M I F K E R( >O B E E K . of University of Am­ sterdam. The Parliam entary investigation started with a public hearing on 20-2 1 November 1 985. A background dossier was provided ( V I EHOFF. 1 985 ). with contributions from various invited experts. addressing a broad range of topics. I n her Foreword. the rappor­ teur highlighted "four issues that need more attention in the years to come ": First. the issue of access and distribution of biotechnology (the potential of biotechnology for the Third World. but their inability to get ac­ cess to the technology: the possible effects of the US export control policy on high technology ) - Second . the i s-;ues of regulation and risks ("a pit y . . . that the international efforts at OECD level to establish a common con­ cept for the attai nment of a harmonization system on in ternational guidelines have been delayed. because of the fact that the American delegation could not accept the proposed text" ) - Third. the restructuring of agriculture (" Biotechnology will enforce a restructur­ ing of agricult ural policy on a much broad­ er scale and perhaps at a much faster speed than acknowh!dged until now " ) - Fourth, the �timulation o f social ly useful products (malaria vaccine: orphan drugs: food pro­ duction in Third World: toxic waste treat­ ment local . small scale energy produc­ tion ). ·-

The Commission also submitted to the Hear­ ing a paper closely based on the April 1 985 BAP proposal: indicating that Commission services were ··active in monitoring the evolu­ tion of t he regulatory questions raised by de­ velopments in biotechnology . . . have partici­ pated in international discussions . . . A cen­ tral issue in these debates concerns the ade­ q uacy of exist ing regulatory regimes to cover the new challe nges posed by biotechnology.

to Legislation

541

I n some areas. it is likely that they are already adequate: e.g. the Directive 82/471 on novel protein feedstuffs . . . .. In other areas. the Commission indicated that it was currently assessing the position; and referred to the recently-created Biotech­ nology Regulation In ter-service Committee ( B R IC). Opinions and formal inputs to the Viehoff report over the following year ( 1986) involved no fewer than six of the Committees of the Parliament: covering Research and Technology, Agriculture and Food, Environ­ ment & Consumer Protection, Economic Af­ fairs and I ndustrial Policy, Social Affairs and Employment. Legal Affairs & Citizens' Rights. The fi nal report and resolution were adopted in Plenary Session of the Parliament in February 1 987. There had been widespread consultation. debate and argument. Controversy was not absent, for a parallel "own initiative " report on biotechnology and European agriculture was being conducted under a German, Green rapporteur, MEP FR I E D R I C H W I L H E LM G RA F ZU BARING­ DORF. His report and standpoint were se­ verely critical of the "industrialisation " of ag­ riculture in general , and of biotechnology and ge netic engineering in particular. Inevitably. the Part A of his report - the formal Resolu­ tion - was heavily amended to the point where the final resolution . as voted in the same (February 1 987) Plenary Session, large­ ly contradicted the Rapporteur's original in­ tentions. The Resolution on the Viehoff report (Eu­ ROPEAN PARLIAM ENT, 1 987) was entitled: "On biotechnology in Europe and the need for an integrated policy" , an expressive title , which summarized the comprehensive nature and central message of the report. The resolu­ tion opened with references to the review of the ongoing BAP research programme ; to a 1 986 Commission discussion paper on agro­ industrial development (which led later to the ECLA I R Programme of Agro- Industrial Re­ search) ; and to the opinions of the six Parlia­ mentary Committees mentioned above. Next, eleven recitals were incl uded, emphasizing the need to enlarge the research programme (not least, to enable the new Member States to participate) , but also stressing five negative views or reasons for prudence:

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The Regulation of Modern Biotechnology: A Historical and European Perspective

"- determined that the social, economic, eco­ logical, ethical, legal and health aspects of new developments in the field of biotech­ nology should be evaluated and assessed at the research and development stage, - recognizing that biotechnology has up to now researched only a few aspects of the way in which DNA works, and convinced that it would be extremely dangerous and irresponsible to rush to transform these processes into marketable products, in view of the complex structures of the or­ ganisms and ecosystems being interfered with, - aware of the predominantly negative ef­ fects of the use of biotechnology by the in­ dustrialized countries on the Third World countries, - whereas to date there are no reliable scientific methods for assessing the me­ dium and long-term effects of the irrever­ sible release of genetically manipulated organisms into the environment, - whereas the first experiments in release of genetically manipulated organisms are al­ ready underway and, for the first time in the Community, such an experiment was authorized and carried out this summer (i.e., 1 986) in the United Kingdom, de­ spite the fact that there are no compre­ hensive and binding provisions at national or Community level governing safety and liability in respect of such experiments." Within the body of the Parliamentary Re­ solution's 29 numbered statements or de­ mands, there was the usual mixture of posi­ tive statements (cf. item 1 below), and special interests; but also many cautious and risk-em­ phasizing statements and demands, such as those quoted below: " 1 . Asks the Commission to review its bio­ technology programme with a view to provid­ ing the Community with an effective strategic programme that affords Europe the means of increasing its competitiveness on world mar­ kets vis-a-vis Japan and the United States and enables the Community on the one hand to diversify its biotechnological research in such a way that resources are made available above all for basic research which takes a hol-

istic view of life and work, gears its objectives to regional needs, safeguards, the bases of life and promotes forward-looking ecological re­ search and, on the other hand, to investigate the medium and long-term effects of the use of genetic engineering in all its potential fields of application; ( .) 8. Considers that human medical research must exclude the manipulation of human genes, particularly human germ-cells, and that veterinary medical research must respect the integrity of individual animals and species and breeds of animals; 9. Stresses the importance of research in the areas of medical biotechnology and envi­ ronmental biotechnology (e.g. degradation of toxic substances), which are under-repre­ sented in the current programme, but at the same time warns against the dangerous illu­ sion that environmental protection can be re­ placed by 'biotechnological repairs' to the en­ vironment; 1 1 . Expects the Commission to give prior­ ity in future to projects studying the problems posed by the intentional release into the envi­ ronment of genetically engineered natural mi­ croorganisms ('deliberate release') and de­ mands that such releases be banned until binding Community safety directives have been drawn up, possibly on the basis of the relevant OECD recommendations; ( . . .) 12. Asks the Commission to be aware in a general sense of the repercussions of each re­ search project on the environment and sug­ gests that for each research project a sum yet to be determined should be set aside in the overall financial package for an environmen­ tal impact study; 13. Calls for an assessment of the political and ecological repercussions of possible risks of epidemics or any restriction of gene re­ sources and suggests a feasibility study for a European Institute for Ecology; 1 4. Demands that the principles and guide­ lines of good practice with regards to the safe­ ty of workers in laboratories, including uni­ versity and research institutes, be strictly re­ spected and broadened in scope in view of the special risks associated with genetic engineer­ ing methods; . 0

4 1 985-1 990: From Strategy to Legislation

1 5 . Welcome s the recent inventory by the Commission 's B iotechnology Regulation In­ terservice Committee as an important step to­ wards creat ing a European biotechnology regulation system and calls for harmonization of Memb e r States' provisions with regards to s a fety and the e n v i ronment to provide for common pr oce d ure s for risk assessment and imposition of c o nditions at each stage of the develo p m en t o f p roj ec t s involving microor­ ganisms carrying genetic material and sug­ gests a s t ep-by-step appro ac h for regulating the various phases of biotechnology processes ( laborato ry , tri als . limited product i on , mass producti o n) and a case - by - ca se approach for a pproaching ne\\ biotechnology products; (. . .) 1 7. Calls on t he Commi ssion to submit a safety study e x amining the present state of legislation and desirable standards as regards liability and ins u rance cover. disaster preven­ tion and protectio n against sabotage or ter­ rorist attacks both in respect of research es­ tablishments and of production plants; (. . .) 28. D eman d s that existing provision s re­ garding the d es ignation of prod u cts be ad­ apted to take into account both the genetic production p r o c e dure employed and the com­ position of the products"" . The Viehoff Resolution of February 1 987 aptly summed up the political situation for biotechnology at E uropean Community level . It showed a broad awareness of the potential of biotechnology . and the need for a cohere nt strategy. respo n ding to the need for interna­ tional competitiveness. But on regulation . it was une q u i v o c a l ly conservative . seeing " spe­ cial risks asso c i a t ed with genetic engineering method s " (para 1 4 ) . demandin g a complete ban on field releases ··until binding Commu­ nity safety dir e ctives have been drawn up" (para 1 1 ) . and with simila r ly restrictive views on gene therapy (somatic or germ - line) and animal t ra nsge n e s i s (para 8 ) . T h e re s eem e d to b e little evidence of U S influence. and of t he earlier US consensus o n the a bs e n ce o f n e ed for new. biotechnology­ specific legislation ; but that consensus related essentially to l a b oratory rD N A work . As large-scale fie ld p r o duction and then field re­ leases became current issues in the US, the

543

possibili ty of legislation remained very much alive . For example, a major conference - the .. Second Annual Brookings conference on Biotechnology" - was held at the B rookings Institution in Wash i ngton , DC, in February 1 986, and PHIL! V IEHOFF attended this . The background pape r ( MELLON, 1 986) reviewed the i ssues , defining the ·'elements of an ade­ quate regulatory regime " , and presenting the case for "A New I ntegrated Statute : A Hypo­ thetical Statute for the In terim Regulation of Releases of En g ineered Organisms". 4.3 B S C Creates B RIC, D ebates Strategy, and Fades

The Commission communications on bio­ technology. up to 1 985. although presenting a st r ategic approach, were in practice largely drafted by the research service , DG XII, with ma rginal additions by other services. These additions. so far as concerned regulations , had on regulatory q ue s tions generally de­ fended the adequacy of existing or planned sectoral measures. The services concerned were DG I I I ( I nternal Market and Industrial Affairs) . and DG VI ( A griculture) . The development of large-scale industrial p roduction . and sl ightly later, but foreseeably. the field re lease of genetically modified mi­ croorganisms and plants, fuelled increasin g debate about the adequacy of existing regula­ tory structures and approaches. These de­ bates took place in the US , in various Euro­ pean countries . in the OECD Group of Na­ tional Experts on Safety in B iotechnology. and within the Commission services . In all countries. such debates clearly re­ quired an inter-agency or i nter-min i sterial fo­ rum for policy debate; and in the Commission services. this was apparently provided by the Biotechnology Stee r i ng Committee. Howev­ er. DG X I I 's main interest was in w i nning the resources for larger R & D programmes, and managing them efficiently, within a process of developing the more systematic approach represented by the " Framework Pro­ gr amme " . Certainly the FAST programme had pro­ duced broad and generally competent strateg­ ic analyses; but the programme was located

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The Regulation of Modern Biotechnology: A Historical and European Perspective

within DG XII, not in an autonomous Com­ munity institution, as recommended by the "Europe + 30" group; and its prescriptions were therefore unlikely to be implemented unless they coincided with other powerful in­ terests, within the Commission services and beyond. The creation by the Commission President of a separate "Forward Studies Unit", and the creation by the European Par­ liament of a "Science and Technology Op­ tions Assessment" unit (sometimes described as the "poodle" of the Committee for Energy, Research & Technology Committee by MEPs active in other Committees) each underlined the non-centrality of FAST. None of these forecasting and policy assessment initiatives came close - at least, during the 1 980s and early 90s - to the authority and central posi­ tion of the US Congressional Office of Tech­ nology Assessment (OTA). The broad scien­ tific networks of DG XII, and of its Concerta­ tion Unit for Biotechnology in Europe, CUBE, had little political weight in the devel­ oping conflicts over regulation. The Directorate-General for the Environ­ ment, DG XI, started to attend the BSC from its 5th meeting (in July 1 985) , and were con­ scious of the discussions of regulation of field release, in which the US Environmental Pro­ tection Agency and Department of Agricul­ ture were engaged. Technical arguments about regulatory details were not appropriate for the Directors-General at BSC level. Con­ sequently in July 1 985, the BSC agreed to es­ tablish B RIC, the Biotechnology Regulation Inter-service Committee. The functions of BRIC were defined to be: "a) to review the regulations applied to com­ mercial applications of biotechnology; b) to identify existing laws and regulations that may govern commercial applications of biotechnology; c) to review the guidelines for rONA re­ search; d) to clarify the regulatory path that prod­ ucts must fol low; e) to determine whether current regulations adequately deal with the risks that may be introduced by biotechnology and to initiate specific actions where additional

regulatory measures are deemed to be necessary; f) to ensure the coherence of the scientific data which will form the basis of risk as­ sessment and in particular to avoid unne­ cessary duplication of testing between various sectors." The Chair was divided between DGs III and XI; the Secretariat would be provided by DG XU's CUBE. DG VI (Agriculture) indi­ cated that, while accepting this arrangement, they felt no less involved, having significant regulatory experience and responsibilities in fields which would surely be important areas of application for biotechnology. DG V (Em­ ployment and Social Affairs) , having respon­ sibilities for both worker safety and public health, were also active participants. BSC remained in theory the parent of BRIC, to resolve disputes arising; but in prac­ tice, this was unworkable , for two reasons. Firstly, B RIC met almost every month, hav­ ing 15 meetings from its first in September 1 985, to its 1 5th in October 1986; BSC met three times during this period. Secondly, any basic inter-DG dispute could not with certain­ ty be resolved at BSC, under its DG XII chairmanship; but might ultimately have to be resolved at Commissioner level between cabi­ nets, or in the Commission itself. Although the Commission met weekly, its ability to handle technical disputes would require care­ ful preparation and briefing, and could be used only infrequently, on major issues. In consequence, BRIC was the active cen­ ter within which the inter-service discussions on regulation of biotechnology were develop­ ed within the Commission, from 1 985 to 1 990. A first and useful initiative by B RIC was the preparation of an inventory of existing Community regulations relevant to biotech­ nology (EUROPEAN COMMISSION, 1 986a). The subsequent role and work of BRIC are presented in the following sections. The Biotechnology Steering Committee faded out, for the reasons indicated above; meeting only once in 1987, and one final time in 1 988. Yet its final meeting in July 1 988 was in many respects its most significant. Occur­ ring five years after the 1 983 strategy papers,

4 / 985- / 990: From Strategy to Legislation

and a few weeks aft e r publication ( M ay 1 988) of the Commissi on proposals on biotechnolo­ gy regulation ( Sect . 4.7 below ). the BSC meeting of J uly 1 9HX sought to launch a com­ prehensive review of strategy for biotechno­ logy. I t might t h us have developed and res­ tated the ·· need for an in tegrated approach '' ( to quote the title of the European Parlia­ ment's Viehoff Report ). and could have been a guiding influe n ce on the subsequent evolu­ t ion of the May 1 988 regulatory proposals. The basic papers for the July 1 988 BSC meeting itemized the many changes in the strategic environment for biotechnology. since 1 9H3: - the scientific progress. and (consequent) pervasive signi ficance of biotechnology: - the industrial development: - the GATT ( U ruguay Round) negotiations. which would liberalize agricultural trade . and alter the attitudes of Agricultural Min­ istries to S & T i n novation: - the competit ive challenge : -- the Single European Act , adopted July l 9X7. to become effective July 1 989: facili­ tat ing (by majority voting on Article 1 00A) the progress towards a common internal market by 1 992: and with an exte nsive new Section ( Titlt: VI ) devoted to Research and Technological Development, and starting with t he blunt language of Article 1 30F: "The Community's aim shall be to strengthen the scientific and technological basis of European industry and to encour­ age it to become more competitive at inter­ . national leve l . . The meeting was attended by an unpreced­ ented galaxy o f Directors-General or other senior staff. from Directorates-General I ( ( External Relations) . I I I ( I nternal Market and I ndustrial Affairs) . V ( Employment and Social Affairs ) . VI (Agriculture ) . V I I I ( De­ velopment) . X I ( Environment) . and XII ( Science . Rese arch and Development). The arguments for a strategic review were accept­ e d : hut as the background papers had not been widely r e ad or fully digested. it was agreed to invite all services to develop their views o n the papers. and/or the review of strategy for biotechnology.

545

These views were received and assembled, in an internal " Interim Document: Towards a Redefinition of Community Strategy for B io­ technology". But an institutional/practical question was now pressing. The final trimes­ ter of the 4-year Commission, 1 986--8 9, was approaching: and the thoughts of Commis­ sioners and their cabinets were preoccupied with their personal and political futures. Few could expect to be in the same posts in Janua­ ry 1 989 - if indeed they returned to the Com­ mission at all after Christmas. Why waste something as important as the re-statement of Community policy for biotechnology on the dying days of an outgoing Commission? Sure­ ly better to await the new year, and enlist the enthusiasm of the incoming team? In circulating the Interim Document in De­ cember 1 988, the B S C Chairman referred to some salient communications that had ap­ peared since J uly, such as the proposal ( Octo­ ber 1 988) for a Directive on the Protection of B iotechnological I nventions; to others in pre­ paration, such as the DG VI proposal for a Community system of plant variety rights , and DG XU's proposal, already circulated in draft, for the next biotechnology R & D pro­ gramme, BR I DGE ( ECU 100 million, 1 99094) : and to the outcome of the mid-term re­ view of progress on the U ruguay Round. Also mentioned were the recent " B io-Ethics" and "Bio-Safety" conferences (Mainz, 8-9 September 1 988, and Berlin, 27-30 November 1 988) . He indicated the intention to continue preparing a draft communication on biotech­ nology for consideration by the new Commis­ sion. taking into account the I nterim Docu­ ment and other matters referred to, with a view to integrating these in a draft document for consideration at the next meeting of the Biotechnology Steering Committee. But the BSC did not meet again . The new Commissioner responsible for research and technological development had other priori­ ties . particularly for institutional re-organiza­ tion of DGs X I I and XI I I, for implementing the second Framework Programme ( 1 987-9 1 ) and preparing the third ( 1 992-95), and for im­ proving the management procedures for re­ search contracts. Vice-President P A N D O L F I and his cabinet took no part in either the reg­ ulatory debate on the two biotechnology Di-

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The Regulation of Modern Biotechnology: A Historical and European Perspective

rectives being negotiated through Parliament and Council, or the broader strategic policy issues of biotechnology; beyond dismantling the unit of DG XII which had been principal­ ly concerned, and delaying the proposed EC Human Genome R & D Programme for fuller consideration of its ethical dimensions. 4.4 1 986: The " Hinge" Year: ( 1 ) B RIC Starts Work : The B ackground of Sectoral and Chemicals Legislation

After the first "Gene-Splicing Wars" of the post-Asilomar years, and the corresponding discussions in Europe which led to the 1 982 Council Recommendation, there followed some years of relative calm, so far as con­ cerned new initiatives for the regulation of biotechnology. As indicated in the preceding descriptions of Commission communications in 1 983, 1 984 and 1 985 , the general feeling in the Commission services responsible for var­ ious sectoral products was that the applica­ tions within these sectors of the new biotech­ nology would not pose insuperable problems, and could be handled within sectoral legisla­ tion. The research aspects had been ad­ dressed in the earlier debates, and resolved at Community level by the national notification requirements which followed (or, for the countries mainly concerned, preceded), the adoption of the 1 982 Council Recommenda­ tion. The situation was changing, as biotechno­ logy moved towards applications in large­ scale industrial production facilities, and field release of genetically modified organisms (GMOs) - microorganisms or plants. Public and political attention were being continually stimulated by high-profile press coverage, which could be summarized under three cate­ gories: (i) the scientific discoveries, and the related progress of techniques, were generating a flood of new insights; the correspond­ ing excitement diffused from the leading scientific journals into the popular press;

(ii) the economic potential and implications, although ultimately unquestionable, were often exaggerated by the promoters of new, start-up companies seeking to at­ tract risk capital, or to sell equity to large companies; again, such "hype" was prone to exaggeration and distortion in the popular press, and readily merged into science fiction; (iii) both in the US and in parts of Europe, opposition and hostility were continuing and in some areas increasing due to a mixture of motives, the mixture varying from country to country. There was a long-standing and justified concern by environmental groups that the track re­ cord of big industry and modern agricul­ ture included disruption, destruction and persistent pollution; and the scientists fi­ nancially linked to these interests had been as venal and prone to error and bias as any other human group. Anyth­ ing which industry promoted with enthu­ siasm was ipso facto suspect. Given that some of the technologies, and certainly the new knowledge, could be ap­ plied to matters involving life, reproduction and death, there was a sensitivity to ethical aspects which would be intensified by various current, or imminent and foreseeable, appli­ cations of the new knowledge. These would range from specific aspects such as genetic screening, or in vitro fertilization, to more generalized concerns about "interfering with nature", or "scientists playing God"; those who spoke, wrote and broadcast about such concerns did not lack an audience. The World Council of Churches prepared a rather hostile report (WCC, 1 989), containing serious inac­ curacies. The entry of environmental interests into the policy debates on biotechnology was thus an obvious development in the mid-eighties, as the public authorities at national and Com­ munity levels interpreted their general re­ sponsibilities for the protection of the envi­ ronment in relation to the challenges of the new processes and products resulting from biotechnology. DG XI, the Directorate-General responsi­ ble within the European Commission for mat-

4 / 985- 1 990: From Strategy to Legislation

ters of environmental policy. took up with characteristic energy the responsibility of co­ chairing the Biotechnology Regulation Inter­ service Committ e e . Th e y brought to the new issues their extensive regulatory experience of which two areas of safety l egis l ation were considered particularly relevant : ,

•

•

c h emica l s (see below the ··sixth Amend­ ment" DirectiYe ) : potentially hazardous industrial activities. .

Alt h o u gh each BRIC-participant service had its own interests and experience , the co­ c h airs DGs I I I and XI were p articularl y in­ fluential, being responsible for drafting the subsequent biotec h nology directives. The ex­ perience of DG XI w it h Chemicals legislation was of strong relevance as an influence on their thinking, and subsequently on their drafting, as a paradigm for regulating the products of biotechnology. The rules for the control of chemicals were one of th e first areas to receive e xtensiv e at­ tention and efforts for the development of har­ monized Comm unity-wide procedures. The history was l on g and complex. and many of the issues discussed and contested at length from the mid-sixties through to the mid-eighties and beyond were relevant to other areas of legisla­ tion, at l e a s t in gener al terms. The difficulties and disagreements would lie in the details. of how far rules and procedures developed in re­ lation to new (or existing) defined chemical entities could or should be applied to geneti­ cally modified organisms, in all their mystery and multi-molecular structural complexity. The central issue of principle was whether the fact of modification by certain t e c h niques of DNA re­ combination - ge n e tic engineering - defined an activity or a class of products ipso facto requir­ ing regulatory o v e rs igh t If this point was con­ ceded, whether for reasons of scientific uncer­ tainty, e x pe rt di s ag ree m e nt, public and poli t i­ cal concern, or some mixture of these (and in effect the 1 982 Council Recommendation ac­ knowledged the political legitimacy of focu sing upon recombinant DNA organisms), then a se­ ries of practical questions would follow. To these practica l questions. a collection of "off­ the-shelf" answers we r e potentially available from the chemicals experience. .

547

The early 1 980s saw the coming into force of the provisions of Council Directive 79/831 / E E C a directive "amending for the six th time Di r ective 67/568/EEC on the approxima­ tion of the laws, regulations and administra­ tive p rov isions relating to the classification, packing and labelling of dangerous sub­ stances"; known for brevity as t h e " Sixth Amendment". Although five amendments to the Annexes and Articles of the original 1 967 Directive were adopted b e twe e n 1 969 and 1 983. the Sixth Amendment rep laced the whole of the substantive parts of the parent Directive and the first five amending Direc­ tives, with the exception of the formal articles on the introduction of national laws, regula­ tion and administrative provisions. It re­ peated in expanded form the provisions of the parent Directive dealing with classifica­ tion, packaging and labelling of dangerous substances, and added a procedure for testing and notification of new chemicals. Certain product categories were excluded from the scope of the Directive - particularly medici­ nal products, foodstuffs and feedingstuffs; which in Commission terms were responsibili­ ties of DG I I I and DG VI. The Sixth Amendment defined or required discussion of many matters of subsequent rel­ evance to the biotechnology Directives: -

- Notification: Prior to being placed on the

market, substances would be notified to the competent a ut h ority (see below) of the Member State in which the substance was first manufactured or imported; subject to a range of exceptions for most polymers, sub­ stances test marketed for research and analysis, small quantities, and substances already on the market before 18 S e p tember 1 98 1 (an inventory of such would be pre­ pared subsequently by the Commission). The notification had to include a technical dossier containing a "base set" of informa­ tion and the resu lts of tests, a declaration on unfavorable effects in relation to envis­ aged uses, a proposed classification and la­ belling, and proposals for recommended precautions for safe use. Testing Requirements: Annex VII d e fined the "base set" of information required with notification, essent i a ll y i d e n t ical to t he

548

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-

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The Regulation of Modern Biotechnology: A Historical and European Perspective

"Minimum Pre-Market Set of Data" suffi­ cient for an initial hazard assessment, as set out in an OECD Council Decision of De­ cember 1 982 (see Sect. 6.2). Annex VIII defined additional test requirements ("step sequence testing") to be applied when suc­ cessive quantity thresholds were exceeded. These additional tests concerned mainly long-term health and environmental ef­ fects, including toxicity to aquatic species. Competent Authority: Me m b er States were required to appoint the competent author­ ity responsible for receiving the notifica­ tion, examining conformity with the Direc­ tive, possibly requesting further informa­ tion, and transmitting a copy of the dossier or a summary to the Commission, who would then forward it to other Member States. Confidentiality: The notifier could indicate the information he considered to be com­ m e rci ally sensitive : the competent authority would decide. Classification: The Directive set out 14 dan­ ger categories, including "dangerous for the environment"; and Annex V defined proce­ dures for determining the physico-chemical properties and toxicity and eco-toxicity of the substance. Annex VI set out the gener­ al pri nci ples of the classification require­ ments. Committee fo r Adaptation: A committee was established with power to adapt to technical progress the Directives concern­ ing elimination of technical barriers to trade; the committee could take decisions by qualified majority. A nnexes VI (Part 1 ) , VII and V I I I were excluded from this pro­ cedure.

The evolution of the Sixth Amendment was strongly influenced by the US legislative activity, and international discussions at OECD; particularly in the preparatory work for a 1 974 O ECD Council Recommendation on the Assessment of the Potential Environ­ mental Effects of Chemicals. In 1975, the Commission had established a working group which linked discussions ongoing in various Member States; and as a result of a French draft law and these consultations, the Com­ mission p u bl i s h e d a proposal for a Directive

in j ust 15 months. In 1 976, the USA adopted their "Toxic Substances Control Act" (TOS­ CA) , and from 1 977, the Environmental Pro­ tection Agency published implementing rules. Thereafter, the US legislation became an in­ creasingly important factor in the negotia­ tions in the Community. HAIGH (1 984) comments critically on the procedure through which the Sixth Amend­ ment proposal was developed between publi­ cation of the Commission 's proposal (Sep­ tember 1 976) and adoption of the Directive (October 1 979). Although the basic structure remained as in the proposal, there were "very numerous changes of detail", so that "the ulti­ mately adopted Directive must be considered as having been fundamentally changed". H A I G H remarks, with references to the UK situation, that: "In general, it must be said that both the Economic and Social Committee and the European Parliament failed to appreciate the significance of the draft Directive or even to reflect what were to become the ma­ jor issues of subsequent concern. In Britain only the House of Lords gave substantial at­ tention to the draft, and even so only cov­ ered part of the major problems. The Directive as finally adopted reflects very long, detailed and complex consideration in the Council working group. The nature of changes incorporated, sometimes involving subtle shifts from Article to Article, are a

clear indication of the difficulties which were encountered. It is consequently one of the most difficult of Directives to understand. The most important change after the Direc­ tive was proposed was the introduction of s t ep sequence testing at the initiative of the German government which was being prod­ ded by its chemical industry. In actual fact, no public allusion to step sequence testing let alone any text setting out its principles and provisions - can be found in any official document prior to publication of the Direc­ tive in the Official Journal. But quite apart from this major omission, by late 1977 it was already increasingly evident that the Direc­ tive as finally adopted would differ sign ifi· cantly from the proposal making the Sixth Amendment one of the most obvious cases where lack of intermediate public informa­ tion makes the Community legislative pro­ cess so difficult to reconstruct."

4

Both the content of the Sixth Amendment Directive. and the procedure leading to its ad­ o ption offer illu m i nating parallels to the sub­ sequent development of the biotechnology D i r ecti ves. Each service p a r ti C i pating in B RIC brought to it its own background. precedents. and perceptions of need shaped by their spe­ cific experience. Reference has been made to the sectoral interests of I ndustry ( D G I II ) and A gric ulture ( D G V I ) . The background of leg­ i s lation for worker safety was contributed by DG V; like DG xrs res p onsibility for envi­ ronmental protection . DG v · s was a ''hori­ zontal'' approach. applying across various sec­ tors. The scientific culture of DG X II was similarly cross cutting Finally. in the later meetings of BRIC. the r ecent l y established Consumer Policy Service started to pa rtici­ pate, having general interests in product safe­

TEN H U SEN . Although the Commission's re­

.

-

.

ty.

Such were the diverse strands within the Commission which were brought together in B RIC. 4.5 1 986: The " Hinge '' Year: (2) National and International Developme nts

The year 1 986 was the hinge , on which sub­ sequent develop m ents in biotechnology legis­ lation turned. It was marked by a number of events of national . Europe an and global s i g­ nificance, which c reated an insi s tently in­ fluential backg rou nd to the deliberations and activities of BRIC. Nati onal d e velopments in biotechnology regulation are further discussed in S ect. 5 . Three had parti c ula r in flue nce i n 1 986: ,

- Denmark bec a me the first European coun­ try - proba b ly the first country in the world - to adopt legislation specifically on b iot echnology. with the adoption in J u ne 1 986 of the Gene Technology Act. - G e rm any s B undestag had on 29 June 1 984 established a " Commission of Enquiry on Prospects and Risks of Genetic Engineer­ ing". under the C h air m a ns hip of Social De mocrat member Wo LF-M ICHAEL CA.

'

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1 985-1 990: From Strategy to Legislation

-

port was published in January 1 987, its exis­ tence and the probability of resulting na­ tional legislation in Germany were widely recognized in 1 986. T he Un i ted States through its Office of Science & Technology Policy (in the Exe­ cutive Office of the President) published in the Federal Register of 26 June 1 986, the announcement of the " Coordinated Frame­ work for the Regulation of Biotechnology", c omprizing : the policy of the Federal agen­ cies involved with the review of biotechno­ logy research and products"; and indicating that existing statutes provided "a basic net­ work of agency jurisd i ction over both re­ search and products" . .

Also in 1 986, the OECD published its re­ port. "Recombinant DNA Safety Considera­ tions " . including the Council Recommenda­ tion of 16 July 1 986 (further discussed in Sect. 6.2). Although published later in the year, the content of this was already known and agreed in government circles in the early months of 1 986. The OECD report was a maj or consid­ eration . as could be illustrated by the case of chemicals. The influence of the OECD on worldwide developments in this sector was underlined by the formal agreement, in 1 984, between the OECD and the International Programme on Chemical Safety (IPCS) , re­ garding reciprocal use of guidelines, method­ ologies and evaluations developed by the two organizations. (IPCS itself was established by a memorandum of understanding between WHO (the World Health Organiz ation) UNEP (the United Nations Environment Programme) and ILO (the Interna ti onal La­ bour O ffice) in April 1 980). Thus the O ECD work on the testing of chemical products and related concepts, such as Good Labo r atory Practice, would be used by these UN agencies as the basis for worldwide rules in these ar eas. The discussion above of the negotiation of the Sixth Amendment Directive indicates the influence of OECD on the content of the Community Directive; a similar influence was exerted on the data requirements referred to in the US Toxic Substances Control Act The Commission was thus faced with con­ flicting arguments. On the one hand, the US ,

­

.

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The Regulation of Modern Biotechnology: A Historical and European Perspective

administration, and the Commission services with sectoral responsibilities, were arguing for the adequacy of sectoral legislation for bio­ technology products. Regarding the oversight of research, the NIHRAC guidelines and var­ ious national provisions in Europe, coherent with Council Recommendation 82/472, ap­ peared to be meeting needs. The OECD re­ port and Council Recommendation had expli­ citly recognized that "there is no scientific ba­ sis for specific legislation to regulate the use of recombinant organisms". On the other hand, the Danish and German initiatives made clear the threat to a unified common market presented by divergent national legis­ lation; and the ongoing debates (on the Vie­ hoff report) in the Committees of the Euro­ pean Parliament made clear their developing wish for legislation specific to biotechnology.

4.6 1 986: The "Hinge" Year: (3) European Responses by Industry, Member States and the Commission

The Commission services through BRIC prepared and published in November 1986 a communication from the Commission to the Council, COM (86)573, entitled "A Commu­ nity Framework for the Regulation of Bio­ technology". This referred to a high-level meeting between Commission staff and Mem­ ber State officials, that had taken place in April 1 986; and a few days prior to that, ECRAB, industry's "European Committee on Regulatory Aspects of Biotechnology", had also met. ECRAB (see Sect. 3.8 above) had pre­ pared their position paper directly in re­ sponse to the request of the Commission. Their paper stated bluntly that, in the view of their five participating organizations (AM­ FEP, CEFIC, CIAA, EFPIA and GIFAP), it was "neither necessary nor desirable to for­ mulate a single set of guidelines and rules which cover every aspect of biotechnology". The paper quoted the OECD Report's state­ ment (quoted above); and added:

"The industry associations concur with the OECD view that no new legislation is needed for the industrial use of gene­ tically modified organisms for the man­ ufacture of new products . . . It is the in­ dustry view that any additional require­ ments for product specifications can be accommodated in the present legisla­ tion and that there is no basis for any discrimination against biotechnological products." Where the paper acknowledged a need for caution, risk assessment (although "the risks involved are . . . to a large extent conjectural") and further research was in the planned re­ lease of live GMOs : The paper reviewed the various beneficial applications in agriculture and the environment, again referring to the OECD report for further details; and put for­ ward a "Proposal for a risk assessment sche­ me". The recommendations here were for a stepwise development process, again quoting the OECD report: " in a stepwise fashion, moving from the laboratory to the growth chamber and greenhouse, to limited field test­ ing and finally to large-scale field testing". The language of the paper was careful in its vocabulary, speaking of guidelines and rules; but acknowledging the obligation to docu­ ment the risk assessments at each stage and the conclusions drawn, and to make this in­ formation available to the authorities in an agreed form. This should be on a commonly accepted basis in Europe, applying to all or­ ganizations whether industrial or non-indus­ trial, private or publicly owned, and with mu­ tual recognition by the various countries of evaluations and conclusions from the risk as­ sessments. The conclusion of the ECRAB paper was that the involvement of the authorities in the scale-up steps could be satisfied by a notifica­ tion procedure. Authorities should be advised by expert committees, comprising competent scientific technical and public representatives, from government, academia and industry. The ECRAB paper was clear and timely, delivered shortly before the meeting of 29-30 April between Commission staff and Member State officials, at which it was circulated.

4

The meeting

was co-chaired by Mr. TON Y

Deputy D i rector-General of DG XI, and Mr. ToM G A RV E Y , Director of FAI RCLOUG H ,

the

DG

III

D i rectorate

Pharmaceuticals. There

were

twen ty-six

Member State s :

6

( I I I-A)

Foods

and

including Chemicals.

partlctpants

from the

UK; 5

from

from Den­

mark ; 3 each from France . Germany. and

ly; 2 e ach from B e l g i u m

Ita­

and the N e t herlands;

from I re l a nd and Sp a in . Commission in att e n d ance from DGs I I I , V. VI . XI a n d X I I - the " B R I C-participant" ser­ 1

each

staff were vices.

A

··summary of

D i scussi o n " was subse­

quently prepared and circulated . and is the basis of the COM M I S S I O N .

quotations l 986b ).

be low

( E U ROPEAN

· · Extensive re fe rence was made to the re ­ cently-completed OECD report , " Recombi­ nant DN A Safety Considerations" (to be published later in 1 986 ) ; several of those present ( including rom mission sta ff) had participated in this expert group. and all ac­ cepted its work as a good starting-point. Specific refe re nce was made to its concept of ·'Good I ndustrial Large -Scale Practice " (GILSP). Also noted was its emphasis on the absence of rational basis for t reating the regulation of rDNA organisms separately from t he regu lation of other organisms. This ·'non-discrimination" point was stressed by seve ral participants - t he basis for regulation should be risks of toxicity. pathogen icity, ecotoxicity . etc. rather than the fact of re­ combination. Also referred to was a report produced a few days earlier by " E CRA B " (European Comm ittee o n Re gulatory As­ pects of B iotechnology ) , representing the five major European i ndustrial associat ions with biotechnology interests. [ see above ] On Indust r i a l containment: Many states fe lt that existing legislation was adequate , given notification. and observance of GI LSP. A conce rn expre ssed partic ularly in re l a t i o n to compulsory not ification of industrial recom­ bina nt activities was that this could raise p rob le m s of comme rci al con fiden t i a l i t y which might inhibit compliance . or make such proposed legislat ion unacceptable . On Field release: It was a cce p t ed that the scientific basis for prediction of effects was inadequate . and research for this purpose should be re i n forced: in t h e meantime, there

/ 985-/ 990:

From Strategy to Legislation

551

should be notification and case-by-case con­ sideration prior to approval. While the desirability of a Communi t y framework of regulation was generally agreed there was some reticence expressed. Some States, particularly the U.K., France and the Nethe rlands, seemed inclined to view existing legislation as a basic require­ ment to which countries might add further requirements relevant to their particular sit­ uation - geographical , climatic or regional; a l t ho ug h Commission staff s tat e d that such regional specificity could be and someti mes was included in Comm unity Directives. I n other Member States, le g i sl a t i o n specifi ­ cally relating to recombinant organisms was said to be imminent ( Denmark's parliament passed such an Act a few weeks after the meeting, on 30 May), or under review, as in Germany. Other points raised in the debate: - the problems of definition can be severe of biotechnology, or even of " recombi­ nant": is a gene deletion a recombination? Or should all " modifications" be consid­ ered? Definition would be important in determining the coverage of any legisla­ tion; - there was acknowledgement that pressure for regulation was motivated by public concern, and a spillover effect from other a reas of technology where accidents of un­ expected nature or scale have occurred; - one participant e mphasized the risks and loss of life resulting from delaying certain types of innovations ( e .g. vaccines, thera­ pies); - the speed of development of the science was so much gre ater than the speed of legislation t hat the latter should focus on principles and esse ntials, not on technical detai ls; - conformity to a common level of safety does not have to imply detailed technical stan dardiza tion;

- international harmonization with major trading partners should be sought, on ba­ sis of

OECD

guidelines;

- some speakers suggested an inventory - or at least an illustrative list of organisms; there was a feeling t hat there should be uniform containment standards through­ out the Community for any given organ­ ism.

Regarding possible systems for Co mm u n ity legislatio n , reference was made to two exist-

552

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

ing systems of potential relevance to biotech­ nology; that for pharmaceuticals , and that for chemical product s . Towards the end of the mee t ing , Mr. GAR­ VEY summarized the consensus as follows: 1. Agreement on the need for a Community approach to preserve a common market 2. Guidelines regarding ph ysical and biologi­ cal con t ai n ment at production level, in­ cluding waste management, could be a use­ ful initiative for the Commission to pro pose 3. Non-release - to be approached on the ba­ sis of existing legislation 4. The ECRAB report was a constru ctive contribution; it called for action only on deliberate release, and that action should be Community action 5. On deliberate release - for most people the top priority for action - there was need for very close collaboration between Mem­ ber States, based on a step-by-step process and notification, bearing in mind the need for flexibility to take account of special re­ gional or climatic needs. The German del­ egation had emphasi zed the need to define our terms precisely . ­

The key question was what should follow this meeting; possibilities mentioned included a forum for regular inform ation exchange on specific topics , particularl y on containment and on deliberate release, research questions , the role of the Commission, discussion with industrial representatives and other inter­ ested groups. Mr. GARVEY said that B RIC demon­ strated the interest of the Commission. Its di­ rection by the DGs for Environment and for Industry underlined the pe rvasi ve nature of biotechnology. This had been the first meet­ ing with Member States, to explain roughly where we had got to, and to obtain Member State reactions. The Commission's objective would be a Communication to Coun cil, outlining a strate­ gy and work programme in the area of bio­ technology, and focusing on health and envi­ ronmental protection, and on the internal market. This would be produced in the next month or two. "

BRIC now had the inputs from industry and Member States; in fact no further meet­ ings of such broad and general character as that of April '86 took place, and of the subse­ quent smaller consul t ative meetings, few if any records were kept or published. The promised communication to Council, "A Community Framework for the Regula­ tion of B iotechnology " , was published in No­ vember 1 986 (EUROPEAN COMMISSION, 1 986c ) ; it comprised just twelve paragraphs , summarized below : introduced the new t echniq ue s known as "genetic e ng inee ring " ; (ii) raised the question of risks, for con­ sumer/worker health and sa fe t y , or for the environment. More p rec i se modifi­ cation posed no a priori extra or new risks in enclosed manufacturing proc­ esses, although laboratory work had been subject to re g ula to ry oversight in both the EC and the US; the prospect of deliberate release in agricultural and environmental applica tio n s had sparked further debate; (iii) hence various national reports, and the OECD report - distinguishing enclosed use and planned release; (iv) OECD's GILSP - "no new or addi­ tional risks, either for the workers in­ volved, the environment, or in respect of the resultant p roduct s " ; (v) OECD report concludes on pl a nne d release, that "while risks exist, they can be assessed to some extent by ana­ logy with . . . existi ng organisms. How ­ ever, there is insufficient experience at this stage to lay down a coherent set of regulations. Instead t he report rec­ ommends a prior case-by-case evalua­ tion of all planned release applica­ tions"; (vi) reviewed Commission actions from the 1 982 Council Recommendation to d a te , including the creation of B RIC, the review of regulations, the A p r i l 1986 meeting w i t h Member States, and the ECRAB paper; and men t io n ed the Community and national risk assess­ ment research programmes; (vii) con cl uded that "the Commission be­ lieves the rapid elaboration of a Com­ munity framework for biotechnology regulation to be of crucial importance to the industrialization of t hi s new (i)

4 1 985-1990:

technology in the Community. Equal­ ly, citizens, industrial workers, and the environment, need to be provided with adequate protection throughout the Community from any potential haz­ ards arising from the applications of these technologies. The internal mar­ ket arguments for Community-wide regulation of biotechnology are clear. Microorganisms are no respecters of national frontiers, and nothing short of Community-wide regulation can offer the necessary consumer and environ­ mental protection"; (viii) announced the intention of the Com­ mission "to introduce proposals for Community regulation of biotechnolo­ gy by Summer 1 987 with a view to providing a high and common level of human and environmental protection throughout the Community, and so as to prevent market fragmentation by separate unilateral actions by Member States. The Commission's proposals will address two distinct aspects of the use of genetic engineering, viz: A. Levels of physical and biological containment, accident control and waste management in industrial ap­ plications, and, B . Authorization of planned release of genetically engineered organisms into the environment." (ix)

(x)

referred to the possibility that propo­ sal (A) might cover other biological agents used in industry; stated "Because international experi­ ence of risk assessment in the field of 'planned release' is still limited, it is not possible to propose any general guidelines or testing requirements for the time being. The Commission will be proposing a Community case-by­ case evaluation and authorization pro­ cedure based on mandatory phased notification by industry. This is in line with industry's own proposals and with the recommendation of the OECD re­ port. The stages at which Community notification would be mandatory, the procedures for dealing with agricultur­ al and environmental applications, and the general question of a priori ex­ emptions, have yet to be agreed and will be a matter for further discussion with experts and with Member States officials in the light of the re-evalua-

From Strategy to Legislation

553

tion of existing Community legislation referred to in par (vi)"; (xi) emphasized the international dimen­ sion and the need to maintain broad harmonization, in particular with prin­ cipal trade partners; (xii) announced that "The Commission is convinced that the development of a Community regulatory framework, which will both provide a clear, ration­ al and evolving basis for the develop­ ment of biotechnqlogy and also ensure adequate protection of human health and the environment is an urgent ne­ cessity. To this end the Commission services, working together in the framework of BRIC, are l a unching the necessary work to draft proposals for legislation on genetically engineered organisms to be presented to the Council by Summer 1 987. In the meantime, the Member States are re­ quested to inform the Commission of their activities and intentions in the field s of biotechnology regulation a n d risk assessment research".

The language of this communication clear­ ly went beyond the views and recommenda­ tion of the ECRAB paper, the Member State opinions of April '86, and the OECD report; it represented a determined thrust towards legislative proposals. At the same time, it may have anticipated accurately the probable pressure from the European Parliament - the views of the Viehoff report were noted in Sect. 4.2.

4.7 The Preparation of the 1 988 Legislative Proposals, and Their Adoption

The division of responsibilities within B RIC was not controversial. DG V were pre­ paring a specific "industrial Directive" (the seventh such) on worker safety vis-a-vis bio­ logical agents, within the context of a general Framework Directive on Worker Safety: ori­ ginally Council Directive 80/1 107/EEC on the protection of workers from the risks related to exposure to chemical, physical and biologi­ cal agents at work. This framework was su-

554

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

perseded by the ad option in J une 1 989 of Council Directive 89/39 1 "on the introduction of measures to encourage improvement in the safety and health of workers at work". The con tained use of gene t ica l ly modified micro­ organism s in in d ustrial processes would be a joint responsibility between DGs I I I and X I . O n the deliberate release t o the environment of GMOs. c hef- de - file would be DG XI. Through BRIC. mutual transparency, consist­ ency and co-ordination would be assured. in­ c luding scien t i fic inputs from DG XII . and ag­ ricultural views from DG VI. To services inexpe rience d in regulatory politics, this seemed a satisfacto ry arrange­ ment; and where a common base of scientifi ­ cally based risk assessment was present, s o it proved . The proposal for a Directive for the pro­ tection of workers against the risks of expo­ sure to biologic al agents was prepared by DG V staff, from the divis i on r esponsible for in­ dustrial medicine. Their networks included Member State authorities responsible for hos­ pital pathology laboratories, and pharmaceu­ t ical companie s familiar with handling dan­ gerous pathoge ns . e.g . . in connection with the development, testing a nd produc tion of vac­ c i ne s . The DG V Direct iv e addressed in p r inciple all biological agents, defined as "mi c roorgan­ i s ms. including those which have been geneti­ cally modified. all cult u res and h uman endo­ parasites, which may be able to provoke in­ fection, allergy or toxicity" and classified these into four risk groups, on the basis of the risks they presented, and the availability of prophylaxis and therapy: '" 1 . group I biological agent means one that is unlikely to c ause human disease; 2. g r oup 2 bio l ogical agent means one that can cause human disease and might be a hazard to workers: it is un l i k e l y to spread to the community; there is usuall y effec­ tive prophylaxis or treatment available; 3 . group 3 b i ologica l agent means one that can cause s �vere human disease and pres­ e nt a se r i ou s h azard to workers; it may present a risk of spreading to the commu­ nity, but there i s u sually e ffe ctive prop h y ­ laxis or treatment available;

4. group 4 biological agent means one that causes severe human dise ase and is a seri­ ous hazard to workers; it may present a high risk of spreading to the community; there is u s ually no effective proph y laxis or treatment available. " Similar classifications had been developed and discussed by various national bodies, in Europe and elsewhere; by the "Safety in Bio­ technology" working group of the European Federation of Biotechnology; and by the World Health Organization . The DG V pro­ posal envisaged that any genetically modified microorga n isms should for the purposes of the Worker Safety Directive be allocated to one of the four categories, depending on the characteristics of the host organism and genetic insert. The final Directive 90/679 (adopted in November 1 990), as it required assessment of biological agents and their classification into the above four categories, did not require any specific references to ge­ netic engineering (beyond a reference in Ar­ ticle 1 to the Directive's application being "without prej ud i ce to the provisions of the biotechnology Directives 90/21 9 and 90/220", which had been adopted se ven months pre­ v i ously ) . Progress of the DG V directive was at B R I C largely a matter for information and re­ port, and it provoked no significant conflict of views. It was valuable nonethe less to other services as an e x empla r in handling certain general issues, of which the risk-based classi­ fication of biologic al agents was the most sig­ nifica n t. Member States were require d to bring into force the laws, regulations and ad m inist rative provisions necessary to comply with the Di­ rective within three years, i.e. by 26 Novem­ ber 1 993; and by 26 May 1994, the Council was req uired to adopt a fi rst list of group 2, group 3 and group 4 biologica l agents (Direc­ tive 93/88, providing this, was adopted on 12 O c tober 1 993; initially omitting coverage of gene t ical ly modified microorganisms) . For ex­ posure to group 1 biol ogi cal agents, most of the Articles of the Directive (on ri s k reduc­ tion, information to competent authori t y and to workers, hygiene and individ u a l protec­ tion . health surveillance, etc. ) do not apply ;

4

but the principles of good occupational safety and hygiene should be observed. Technical adjustments to the Annexes in the light of technical progress . changes in in­ ternational regulations or specifications and new findings in the field of biological agents can be adopted by a standard procedure of the Framework Directive 89/39 1 . B RIC met ten times between the Novem­ ber 1 986 communication COM (86)573 (dis­ cussed in the preceding section), and the pub­ lication in May 1 988 of the communication COM (88) 1 60. comprising proposals for two Council Directives: one "on the contained use of genetically modified microorganisms "; and one ··on the deliberate release to the environ­ ment of genetically modified organisms". A number of significant points. some of them controversial. had to be resolved in the inter-service discussions. Scientific interests ( approximately represented by DG XI I , but as there are scientifically competent staff in all the services concerned . none could or did claim a monopoly on scientific expertise) were basically uneasy about the question of scope. and the stigmatization implied by fo­ cusing upon the rONA techniques. Yet it was the progress in these techniques which had been trumpeted in the media; highlighted at Asilomar; financed by industry; and specifica­ lly addressed by the 1 978-1 982 Community deliberations le a di n g to Council Recomme n­ dation 82/472. These techniques were the ob­ ject of the OECD report " Recombinant DNA Safety Considerations" (OECD, 1 986) , and the I CSU-COGENE "Committee o n Ge­ netic Experimentation" ( B ERNARDI, 1 991 ) . The OECD Counci l Recommendation had recognized that "there is no scientific basis for specific legislation to regulate the use of re­ combinant DNA organisms'', and this had e qually been emphasized by ECRAB. But the European Parliament's resolution of Februa­ ry 1 987 (on the Viehoff report) had called for a ban on deliberate release of GMOs until binding Directives were drawn up. The compromise adopted was to empha­ size , in the explanatory memoranda to each of the two proposed Directives, that some naturally occurring microorganisms might also be of concern . and that the Commission was "working towards the development of co-

/ 985-/ 990: From Strategy to Legislation

555

herent methods of risk assessment . . . and will on this basis examine if and how the accom­ panying proposal could be modified or ex­ tended to cover non-genetically modified or­ ganisms" . The field release proposed direc­ tive similarly referred to the rise of public concern as the reason for an approach "which focuses on the new techniques of genetic en­ gineering" as " the first and most urgent step in the regulatory process; however. this will not impede evolution towards a more organ­ ism-related approach. Thus, the Commission will. as experience and knowledge on the matter build-up, undertake to regulate the re­ lease of certain categories of naturally-occur­ ring organisms, such as known human, plant, or animal pathogens, and non-indigenous or­ ganisms. Moreover, different categories of or­ ganisms and/or techniques may be estab­ lished, allowing different requirements for or­ ganisms of different levels of risk ". The definition of "genetically modified or­ ganism" in the contained use proposal was es­ sentially still that of the 1 978 UK regulations and the 1 982 Council Recommendation; in the deliberate release proposal, the tech­ niques were briefly and vaguely defined in a separate Annex 1 , as "organisms which can be obtained by such techniques as recombi­ nant DNA. microinjection, macroinj ection microencapsulation . nuclear and organel transplantation or genetic manipulation of vi­ ruses." The proposal e nvisaged that the Com­ mission would adapt the annexes of the Di­ rective to technical progress, by amendments concerning "new techniques to be covered or deleted as appropriate" . There was disquiet at th e essentially politi­ cal reasoning for focusing on rONA organ­ isms, and DG XII continued to develop ideas for a " European Bio-Safety Science Board", similar in function to the US B iotechnology Science Coordinating Committee (see Sect. 5 . 1 ) . The need for an independent, high-level scientific review mechanism to advise upon and to review regulatory aspects of biotech­ nology in Europe was discussed at the March 1 985 meeting of the B iotechnology Steering Committee, and DG X I I was invited to draft and circulate a proposal. It was envisaged that the principal role of such a Board would be to consider and advise

556

18

The Regulation of Modern Biotechnology:

upon basic principles conducive to safe prac­ tice in biotechnology; and to promote ex­ change of information between regulatory au­ thorities and advisory bodies at Community level, in the Member States, in other coun­ tries, and in discussion at international bod­ ies. It would define needs for research, and provide a credible source of objective infor­ mation for all persons engaged in the field, and for the general public. Although such a mandate was drafted, there was indifference or outright opposition from other services in BRIC and BSC; and Vice-President NA RJES (the Commissioner responsible for Research, and Industrial Af­ fairs, 1 985-88) did not press the proposal at Commission level. The debate on the drafting of the contained use and field release Direc­ tives dominated the time and attention availa­ ble for inter-service attention to biotechnolo­ gy, and DG XII itself was preoccupied with the management of the current R & D pro­ grammes, and the preparation of their ever­ larger successors (at least, for biotechnology), in the following Framework Programme. (The BRIDGE programme proposal, re­ questing ECU 1 00 million, for 1 990-93, was prepared during 1 988; but published only fol­ lowing agreement at Council on the budget envelope for the third Framework Pro­ gramme.) Both proposals took as legal base Article 1 OOA, the customary basis for common inter­ nal market legislation. Paragraph 2 of this Ar­ ticle indicated that "a high standard of protec­ tion for human health and the environment" was to be incorporated in any common mar­ ket legislation; paragraph 4 correspondingly indicated a rather stringent opposition to na­ tional legislation with different standards. Particularly for the deliberate release Di­ rective, Article 130S, under the new Title VII ( "Environment") of the Single European Act, might have seemed the more appropriate le­ gal basis; but this had the tactical disadvan­ tage of requiring unanimity at Council. Arti­ cle 100A required only a qualified majority; and since the deliberate release Directive would contain a section relating to the placing on the (common internal) market of prod­ ucts, this could justify the corresponding legal basis.

A

Historical and European Perspective

The contained use Directive dealt with the safety in contained use of genetically modif­ ied microorganisms (GMMs), including ques­ tions of waste and accident prevention. Mi­ croorganisms were classified into Group I, on criteria basically identical to those of the OECD 1 986 report, for "GILSP" microor­ ganisms; Group II were "non-Group I". I t should be noted in passing that the criteria for definition of GILSP drew largely upon the experience and standards of the pharmaceuti­ cal industry, and were not necessarily ideal for the definition of good practice or low-risk microorganisms in other sectors, or in basic research. There was nonetheless a tendency to view "Group II" microorganisms as a "higher risk" category, since it included high­ er risk organisms; but the definition was not precisely risk-based, and would soon give rise to needs for review. The contained use Directive defined two categories of operation (we use here the lan­ guage of the Directive as finally adopted; in the case of this Directive, there was little change from the original proposal): Type A operation: "shall mean any op­ eration used for teaching, research, de­ velopment or non-industrial or non­ commercial purposes and which is of a small scale (e.g., 1 0 liters culture vol­ ume or less); Type B operation: "shall mean any op­ eration other than a Type A opera­ tion" . The activities covered b y the Directive could thus be summarized in a 2 x 2 ta­ ble, depending on the microorganisms (Group I or Group II) and type of op­ eration (Type A or Type B); see Fig. 1 . The Directive defines the role of the com­ petent authority or authorities (to be desig­ nated by Member States), the various infor­ mation requirements, and the role of the committee of representatives of Member States, defined by Article 21 . The Article 21 Committee procedure could also adapt An­ nexes II to V to technical progress. During the negotiations, the scope of both Directives was defined by Annex I, listing the techniques to be included in, or excluded

4 1 985-1 990:

From

Strategy

557

to Legislation

"Type

"Type

8 " Operation ( Art . 1 (e): Non-type A )

A " Operation (Art. 1 ( d ) : Teaching. R & D. or Non-industrial or Non -commercial and of Small Scale ) ( e .g. :s: 10 liters)

Art . 7 . 1 : Principles of G ood M icrobiological Practice and of Good Occupational Safety and H y gi e ne G roup I G M M s (Art . 4 )

II I

l g_

F i rst Use? Notification. of Annex VA Details

P l u s A n n e x V B Details

t_

I

I

9.2

J

Keep records. Subsequent operations: Notify, 60- Days Go Ahead

Available to NCA on Request

Art. 7.2: Principles of Good Microbiological Practice and of G ood Occupational Safety and Hygiene Plus: Annex IV Con tainment Me asures

I

G rou p II G M M s ( Ar t 4) .

I

I I

I

1 8. I JO.l l

First Use? Notification

of

I I

Plus Annex VC Details

l

Annex VA Details Plus Annex VD Details

Await NCA Conse nt

Subsequent Operations:

J

1 1 1 0.2

Subsequent Operations: N CA Consent Required

Notify.

60-Days Go Ahead 1 8. 1

Annual Summary Report by NCAS to the

Commission Fig. 1. Outline of Council Directive 90/2 1 9 on the Cont ained Use of Genet i cally Modified Microorgan­

isms.

from , the definition of "genetically modified microorganism" ( as envisaged in the original proposal for field release ) . But. also in both Directives. Annex I was during the negotia­ tions at Council removed from the scope for amendment by Committee procedure. As the techniques listed were defined in some detail, in terms of inclusions and exclusions seen as relevant at the time of drafting or negotiation . the effect of this was to ··freeze .. the scope definitions; which elsewhere - particularly in

the US context - were the most central topic for discussing the evolution of regulatory oversight requirements. At a late stage in the negotiations, the legal basis of the contained use Directive was switched to Article 1 30S, as unanimity among the Environment Ministers appeared attaina­ ble . and this title i ndicated that it was essen­ tially "floor" legislation, on top of which Member States might add national require­ ments (subject to a general requirement of

558

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

compatibility with the aims of the EC Trea­ ty) . The contained use and field release Direc­ tives were put forward in a single communica­ tion by the Commission, had a single rappor­ teur (Dr. GERHARD ScHMID, German Social­ ist) in the European Parliament, and general­ ly followed a closely parallel track through the negotiations, to their adoption simulta­ neously as EEC Directives 90/21 9 and 90/220 at the meeting of the Council of Ministers (Environment) on 23 April 1990. Implemen­ tation in national legislation similarly was set for 18 months later (23 October 1 99 1 ) for both Directives. The deliberate release Directive remained based, as proposed, on Article lOOA; and is summarized below in its form as adopted. The preamble emphasizes preventive ac­ tion; the self-reproducing character of organ­ isms, hence possibility of irreversible effects; the need to ensure the safe development of industrial products using GMOs (i.e., the in­ tent, however apparently restrictive in detail, is fundamentally positive); case-by-case eval­ uation; and a "step-by-step" approach from research to commercialization. The Directive is in 4 parts, plus corresponding annexes, and can be summarized as follows: Part A: General (Articles 1-4): defini­

tions, exclusions (Annex I), a general obligation laid on Member States (MS) to take "all appropriate measures to avoid adverse effects"; and the require­ ment to define a "national competent authority" (NCA). Part B: For R & D or other activities not involving placing on the market: (Articles 5-9): requires notification to NCA of details as specified in Annex II; NCA transfers to Commission with­ in 30 days, who transmit to other MS within a further 30 days; the original NCA has to respond to the notifier within 90 days. Where sufficient experience is judged to have accumulated, an NCA may pro­ pose to the Commission a simplified procedure. NCAs may also require public consultation. The notifier has to

submit a post-release report on health and environment risks. There will be developed a system for the exchange of summary information. Part C: For placing on the market of products comprising or containing GMOs (Articles 10-18): consent to marketing of such products is to be giv­ en only if the products comply with an environmental risk assessment as speci­ fied in Annexes II and III. For prod­ ucts covered by EC legislation provid­ ing for a specific environmental risk as­ sessment similar to the provisions laid down in this Directive, the remainder of Part C (Articles 1 1-1 8) need not ap­ ply. The Commission has to establish by 23 April 1 991 a list of such EC legis­ lation (by that date, there was none). Article 11 requires notification to NCA, which (Article 12) has within 90 days to provide a reasoned rejection, or for­ ward the application to the Commis­ sion, who transmit immediately to the other Member States. Absence of ob­ jection within 60 days leads to automat­ ic approval. If there are unresolved ob­ jections, there is a decision at Commis­ sion level in accordance with the Arti­ cle 21 procedure. Part D: Final provisions (Articles 1 924): defines the Commission-level com­ mittee decision procedure, and includes provision for adaptation to technical progress of the requirements specified in Annexes II and III. As was indicated in the previous section, the November 1986 Commission communica­ tion indicated a more restrictive approach than was advocated by the representatives of Member States with the greatest experience of biotechnology. Some concessions to scientific sensibilities were made in the preambulatory and expla­ natory sections of the May 1 988 proposal for the Directives, whose scope and content de­ parted further from scientific and industrial advice. As the Directives were discussed in the committees of the European Parliament, they acquired an increasing burden of more re-

4

strictive amendments. The rapporteur. Social Democrat Dr. G E R H ARD ScHM I D . had a Ph.D. in chemistry. and had worked at the In­ stitute for Biochemistry in Regensburg. But as a politici an he was conscious of the grow­ ing support for the "Greens . . ; and therefore . conscious of the acute sensitivity of public opinion to "gene technology'' issues. was in­ clined to a cautious and restrictive approach . These developments were watched with growing alarm by scientific and industrial cir­ cles, in Europe and elsewhere in the world. I n a n editorial in Gene ( Y o u N G a n d M I LL E R , 1 989) , the Commissioner of the US Food and Drug Association and his assistant had expli­ citly criticized the Commission 's proposed Di­ rective on field release . on three grounds:

1 985- 1 990: From

Strategy to Legislation

559

ence: and at odds with the published state­ ments of the OECD and with US policy. In a similar vein, the US Government through their Ambassador to the European Communities, made known their concerns about the Directives and the amendments ad­ opted by the European Parliament, in a state­ ment dated July 7, 1 989, on "International Harmonization in the B iotechnology Field", from which the following quotations are tak­ en:

"The directive is foc used on the regulation of "genetically modified organisms (GMOs)'", which are defined as those ma­ nipulated with only certain rece ntly develop­ ed techniques. including recombinant DNA. Thus the directive prefere ntially singles out for stringent regulation the newest tech­ niques of genetic manipulation that enable the most precise and predictable genetic changes. This is at odds with the broad con­ sensus that these newest techniques repre ­ sent a clear refinement, an improvement on conve ntional techniques of genetic manipu­ lation that enhances the precision and pre­ dictability of the effects of intervention. Such GMOs are clearly not a functional ca­ tegory, and most certainly not one corre­ lated to risk . "

··It is in the mutual interest of the EC and the U nited States to resolve differences in the ap­ proaches used for the ove rsight of B iotech nology. To minimize adverse impacts on research and de­ velopment, and to avoid the creation of barriers to inte rnational trade. I n the spirit of achieving inter­ national harmonization, we offer the following comments on the proposed EC Directive on delib­ e rate release of genetically modified organisms and the proposed amendments. The Directive is based on "genetically modified organisms .. (GMOs) that are defined by the meth­ od of modification. B y basing the Directive on the technique by which the organism is modified, the E C is regulating orga nisms produced by a given process. This is not a functional category directly correlated with the characteristics of the organism. As e xpressed in the U S coordinated framework for the regulation of biotechnology, the US generally regulates products rather than the process by which they are obtained. We are concerned whether dif­ fe rences in approaches and their implementation may lead to difficulties in our attempts to achieve inte rnational harmonization. It is important to em­ phasize that whether an organism is " unmodified" or "genetically modified" is, in itself, not a useful determinant of safety or risk. W e are concerned that the D irective may affect rese arch and development and would ask how those sections of the Directive dealing with re­ se a rch will be implemented. The USG attempts to make the degree of regulatory review commensu­ rate with the level of risk. Does the EC anticipate that it will provide guidance on the degree of re­ view for negligible or trivial risk experiments and provisions for exemption?"

O n the second point, they described such a regulatory focus as "likely to become either too burdensome to allow progress, or too su­ . perficial to protect abuse . : as a departure from good science and the lessons of experi-

There followed various detailed criticisms or questions about the scientific expertise of the Article 21 Committees; the handling of data developed outside the EC; the handling of confidential business information; and oth­ er matters.

•

•

•

the underlying premises on which it was based: the risk of a regulatory approach that would hinder research and development; the possible use of its provisions to erect non-tariff trade barriers to foreign prod­ ucts.

Developing the first point. they noted that:

560

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

On the subject of definitions and scope, al­ ready mentioned: "The definitions on "GMO" and "use" (Article 2) may present a trade barrier if companies do not have a clear understanding of the intended mean­ ings. The Directive does not appear to allow for the creation of exemptions as experience is acquired. This lack of flexibility in the regulatory structure may impede international harmonization with countries such as the United States where provision for exemption is made . "

Finally, the US note comments on the amendments passed at first reading in the Eu­ ropean Parliament: "Several of the amendments passed by the Euro­ pean Parliament appear to be based in part on pub­ lic concern and unsubstantiated fears about geneti­ cally modified organisms, rather than on accumu­ lated scientific knowledge and experience with test­ ing or organisms. If adopted, these amendments could have severe negative impact on research and development, innovation, product development and trade. We would, therefore, specifically urge the Council of Ministers to reject or modify the listed amendments for the following reasons. " (There follows a list of various amendments, and arguments against them.)

It was not only from the US that such criti­ cisms were received. A few months after the publication of the Commission's proposals, on 1 st October 1 988, at its 40th meeting, the Council of EMBO, the European Molecular Biology Organization discussed the regula­ tion of rONA research in Europe. Members of the EMBO Council explained the current situation in each of their countries. They were unanimously of the opinion that rONA was a technique, and that any legislation should fo­ cus not on the technique but on the safety or otherwise of the products generated with it. Those present drew up and unanimously agreed the following statement for the atten­ tion of the EMBO Conference: "Over the last 15 years, experience has shown that recombinant DNA methods, far from being inherently dangerous, are an im­ portant tool both for understanding proper­ ties of life and for developing applications valuable to humankind and the environment

(vaccines, diagnostics, pharmaceuticals etc. ) . E M B O strongly believes that there is no scientific justification for additional, special legislation regulating recombinant DNA re­ search per se. Any rules or legislation should only apply to the safety of products according to their properties, rather than ac­ cording to the methods used to generate them. Furthermore, EMBO believes that de­ cisions concerning such issues should be tak­ en at a European rather than a national lev­ el. At a time when European unification is accelerating, it would be incongruous for re­ search to be illegal in one country and per­ fectly acceptable in a neighbouring state."

This statement, with a covering letter, was transmitted to members of the European Par­ liament on 16 May 1 989, by Professors MAX BI RNSTIEL, Chairman of the EMBO Council, and LENN ART PHILI PSON , Director-General of EMBL, the European Molecular Biology Laboratory. On 18 May, an open letter was addressed to the Presidents of the European Parliament, the EC Council, and the Commis­ sion, by the European Nobel Laureates in Medicine and Chemistry (16 in all): "Dear Mr. President, In the fourth week of May the European Parliament will debate in Plenary Session a subject which is of vital importance for the future development of science in Europe, namely the three Commission proposals for Council Directives on biotechnology. The Council will decide on this matter at the be­ ginning of June. Recombinant DNA is a method in biology, without which modern research in this field is not possible. It allows small and well de­ fined changes to be introduced into the ge­ nomic set-up of an organism. More than 90% of research and production use non-pathogenic and safe organisms. There are well established and international­ ly accepted safety standards which have been followed by a community of about one hundred thousand researchers in the past 15 years. The EC Commission has proposed three Council Directives, based on this experience. In principle there is no scientific justification to single out a technique for regulation in­ stead of basing it on the properties of the generated organisms. Consequently, the pro­ posal on "Worker Protection" relates to

4 1 985-1990: " E x pos u r e to B io l ogi cal A ge n ts'' i rr e s p e c ti ve of th e method by w h i ch t hese agents may have obtained t h e i r charact e ristics. The proposals on " Contained Use" and " D e l i be rate Release " of ge netically modified o rg an ism s are i n line w i t h a l re a dy existing OECD recomme ndations a n d t h e guidelines of a numbe r of m aj or countries. such as the USA and Japan.

Amendments have been proposed which are based on u n founded fe a rs rather t h a n on sci e nt i fic ri�k ass essme n t . They a re both i m ­

pr a ct ic a l and w i de l y i n h ibitory t o the pro­ gress of k nowledge and its responsible b e n e ­ fi c ial a pp l i c at i o n s . We r e fe r in particular to those t abled by the rapporteurs for the E n ­ vironme n t , Public H e a l t h . a n d Consumer Protection Committee. as we l l as those ac­

From Strategy to Legislation

561

This letter may have contributed to the nar­ row defeat of an amendment proposing a five-year moratorium on field releases. It was during 1 988-1 989, in parallel with the debate on the Directives, that leading companies became convinced of the need to create a lobbying organization focused speci­ fically on biotechnology: the Senior Advisory Group for Biotechnology (SAGB) was created in mid-1 989. In spit e of rapid efforts, it was too late to pl ay a decisive role in the months leading up to adoption of the two Di­ rectives, on 23rd April 1 990. Its efforts none­ theless became increasi ngly influential from early 1 990 onwards, and are described in Sect. 7. 1 .

cept e d add i t ionally i n t h e same committe e . We would therefore appeal for your support for the Commission ' s p rop osals . unamended.

i n this important debat e . "

Regulation, Process or Product?

Following the adoption by Council of its ··common posi tion" in November 1 989 . the Directives returned to Parliame nt for second reading. On 8 February 1 990. the Nobel Laur­ eates wrote again to the three Presidents. shortly before the second reading in Plenary Session of the two proposed directives. Hav­ ing recalled their earlier letter of May 1 989. they continued: ''Now that the

two d i r ec t ives

4.8 H orizontal or Sectoral

"

c o n t a ine d

use ·· and "deliberate re lease " have been car­ ried by EC Council and reviewed by the E n ­ vironm e n t Com mittee of the E u ro pe a n Par­

liame n t . i t ap p e a r s t o us tha t t h ey contain a n um be r of provisions re la t i n g to research

which are bot h based on non-scientific cri t e ­ r i a and s o unduly b u rde nsome as to be dis­

couraging. Examples are. with regard to "contained use " measure s based on volume

use d , and w i t h regard to "deliberate re lease "

the requirement t h a t rese arch p roje c t s be submitted for e x am inat ion to a ut horit ies at t hree le v e l s : member State conce rned, Com­ munity. and all other m e mber S t ates If o t he r ame ndments pro pose d by the Envi­ ronment C o m m i ttee pass the E u ropean Par­ l iament a t the second re ading. t his hi g h ly .

worrying situation may become e v e n worse . We are t h e re fore cal l i n g your attention to t h i s prob lem in ge ne ra l . and we rely on your

help to e nsu re t h a t all due obj ec tivi t y and calmness will be u se d in dealing w i t h t hese two s u bjects . ..

A Conti nuing Conflict

"Horizontal" and sector-specific legislation are not necessarily conflicting alternatives. There are many topics on which it is evident that the same rules or standards have to be observed, whatever the sector: for example, rules on financial reporting and taxation, or animal welfare, or worker safety (as in the framework Directive 89/391 and the specific Directive concerning exposure to biological agents. 90/679). Similarly there may be uni­ form rules for handling or disposing of ra­ dioactive materials. However, the controversy arising in the context of biotechnology, or more specifical­ ly, relating to genetic engineering techniques, concerned whether these techniques posed or could - in some research activities or applica­ tions - pose risks of a character specifically attributable to these techniques; and if so, whether the assessment and management of those risks required expertise and regulatory oversight of a character essentially similar across diverse sectors. Scientific opinion, while admitting that genetic engineering could make possible gene transfers and fu nc­ tional consequences not otherwise attainable, held that the risk assessment which might in some sectoral applications be desirable or necessary did not differ in essentials from ex-

562

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

isting risk assessment requirements for the sector; e .g. , the assessment of a live recombi­ nant vaccine both for its safety and efficacy in intended use, and for side effects including environmental impacts, are not different in kind from the assessment of a non-recombi­ nant live vaccine. The assessments for a bio­ pesticide, a food product, and a vaccine are, however, very different, given the different circumstances of use and corresponding fac­ tors to be assessed. These general points were central to argu­ ments concerning, and leading to, the changes which occurred between the Commission's original proposal, and the version finally ad­ opted, of the Directive 90/220 on field release. Of these changes, the most significant con­ cerned the first Article of Part C: "Placing on the Market of Products Containing GMOs" [Article 8 in the COM(88) 1 60 proposal, Arti­ cle 10 in the Directive as finally adopted] . This issue is discussed in the following para­ graphs. Reference had been made repeatedly in the earlier Commission communications, and in the views expressed by industry, to the ability of existing or developing Community legislation specific to particular sectors to cope with products arising in these sectors that happened to have been made by biotech­ nology. This view was accepted by all Com­ mission services; and consequently Part C of the Directive, whose inclusion was strongly contested by some services, was defined as a "stop-gap" measure for what remained after the opening article defined the exclusions, as follows: "Articles 9 to 16 of this Directive, do not apply to: - medicinal products, - veterinary products, - foodstuffs, feedingstuffs and their additives, - plants and animals produced or used in agriculture, horticulture, forestry, husbandry and fisheries, the repro­ ductive material thereof and the products containing these organisms, - or to any products covered by Com­ munity legislation which includes a specific risk assessment. "

In the Council Working Party on the Envi­ ronment, and in the light of Parliamentary Amendments, this comprehensive exclusion from Part C was transformed into the version comprising Article 1 0: " 1 . Consent may only be given for the plac­ ing on the market of products containing, or consisting of, GMOs, provided that: - written consent has been given to a no­ tification under Part B or if a risk anal­ ysis has been carried out based on the elements outlined in that Part; - the products comply with the require­ ments of this Part of this Directive, concerning the environmental risk as­ sessment. 2. Articles 1 1 to 18 shall not apply to any products covered by Community legisla­ tion which provides for a specific environ­ mental risk assessment similar to that laid down in this Directive." This change reflected a concern that exist­ ing legislation - Community or national - for the sectors which the Commission had pro­ posed to exempt, did not in general contain explicit language specific to GMOs; still less the specific language in the Annexes of Direc­ tive 90/220. However, the clear preference of Commission and Council for sectoral legisla­ tion was expressed by the following declara­ tions, recorded in the minutes of the Council Meeting of 23 April 1990: Re Article 10 (2) "The Commission undertakes, when pre­ paring legislation on marketing authorization for products consisting of, containing or which could contain GMOs, to include in its proposals provisions for a specific environ­ mental risk assessment of the product similar to that provided in this D irective. The Com­ mission also undertakes, where appropriate, to propose modifications to existing product legislation in order to provide for such envi­ ronmental risk assessment." "The Council and the Commission agree that where any future legislation adopted by the Council provides for a specific environ­ mental risk assessment similar to that pro­ vided in this Directive for any product cov­ ered by this Directive it will be indicated that

4 1985-1990: From Strategy to Legislation

Articles 1 1 to 18 of this Directive shall cease to apply to that product. " This concession to sectoral legislation nonetheless implied a permanent connection, based on the Annexes of Directive 90/220, be­ tween that Directive and all future sectoral legislation for products containing or com­ prising living organisms. The assumption thus expressed contrasted with the "sunset clause" approach which was written into US legislative proposals at the same period, as a recognition of the conjectu­ ral nature of the risks addressed; and under­ lined strongly the special character of genetic engineering techniques, which by virtue of their use would impose upon any products concerned, whatever their nature and whatev­ er the genetic modification, a requirement for separate regulatory treatment. The Directive thus strongly contradicted the repeated de­ mands by industry to avoid discrimination against the products of biotechnology, and the statements by the Commission that this would be avoided. Plant Protection Products: A Test Case

A specific product category in which this issue arose soon after adoption of the Direc­ tives concerned plant protection products (i.e., pesticides or similar). DG VI (Agricul­ ture) had sought for many years to achieve agreement on a Directive concerning the placing on the market of these products. Bio­ pesticides, although a small part of the pesti­ cides market, were nonetheless seen as a sig­ nificant sector, not least because of their po­ tential "environmental-friendliness"; and it was not merely conceivable, but already clear, that improving the efficacy of bio-pesticides would be an early target of the genetic engi­ neer. The world's first (experimental) field release of a genetically modified organism, in 1 986, had been of a baculovirus used as a bio­ pesticide. DG XI made clear to DG VI, in September 1 990, that as a result of the adoption of 90/ 220, although the Directive on plant protec­ tion products could apply to GMOs, in prac­ tice a clearance regarding the environmental

563

impact of a GMO product, "because of its special characteristics", would be a necessary prerequisite for a marketing authorization under the Plant Protection Directive. It was pointed out by DG XI that all field tests of GMO products would permanently have to receive clearance under 90/220; and they ar­ gued that the reason for also including envi­ ronmental risk assessment for GMO products was to ensure continuity between the evalua­ tion at the field test stage and the product marketing stage, and "avoid the need to du­ plicate the highly expert Committees needed to review the particular environmental risks associated with GMOs". This argument did not find favor with the Ministers of Agriculture in Council, who ad­ opted the Plant Protection Products Directive 91/414/EEC on 26 June 1991 , with a clause re­ cognizing that for a transitional (three-year) period, recombinant bio-pesticides would be assessed under 90/220; but requiring the Commission to prepare for Council a propo­ sal then assimilating the assessment of such products within the procedures for pesti­ cides. Similar arguments developed elsewhere; for example, in regard to medicinal and veter­ inary products. The Commission in Novem­ ber 1990 put forward a series of proposals re­ lating to the future system for the free move­ ment of medicinal products in the European Community, in communication [COM(90)283] (EUROPEAN COMMISSION, 1990b). Regard­ ing environmental assessment, this stated: "in view of the increasing awareness of the effects of medicinal products on the environ­ ment, the Commission is proposing that in ap­ propriate cases an application for authoriza­ tion for a medicinal product for human use include an assessment of the potential risks presented by the product for the environ­ ment. The details of the information required will be specified in the Annex to Directive 75/ 318/EEC on the testing requirement for me­ dicinal products for human use. So far as veterinary medicinal products are concerned, similar provisions have already been proposed by the Commission and are currently under consideration by the Council [COM(88)779 final]." Thus the environmental risk assessment

564

1 8 The Regulation of Modern Biotechn ology: A Historical and European Perspective

would where appropriate form an integral element of the application for authorization for medicinal or veterinary medicinal prod­ ucts; a procedure consistent with the EC Treaty, and in particular Article 1 00A para­ graph 2 ("a high standard of protection of hu­ man health and the environment") and, in the Title V I I ( Environment) . Article 1 30R, paragraph 2 ( '"consideration of envi­ ronment shall be an integral element of the Community's other policies··. However, perhaps because the Pharmaceu­ ticals division of DG I l l had been too preoc­ cupied to follow the understandings, develop­ ed during the biotechnology debate. about the relation between the "horizontal" [90/220] and " vertical" ( sectoral ) legislation regarding GMOs. the communication continued: "so far as live vaccines containing geneti­ cally modified organisms are concerned. Council Directive 90/220/EEC of 23 April 1 990 shal l apply". This mistake wa o; n o t repeated when the Food Products division of D G I I I drafted the proposed Regulation on Novel Foods; but clearly the continuing influence of 90/220 could not be avoided. In the original proposal [COM(92)295 ] of July 1 992. the Article con­ cerned included the following language: 1 . Where the food or food ingredient falling under the scope of this Regulation con­ tains or consists of a genetically modified organism within the meaning of Article 2 paragraphs 1 and 2 of Council D irective 90/220/EEC( 1 0 ) on the deliberate release of genetically modified organisms. the in­ formation required in the request for au­ thorization mentioned in Article 6 shall be accompanied by: - a copy of the written consent. from the competent authority . to the deliberate release of the genetically modified or­ ganisms for research and development purposes provided for in A rticle 6( 4) of Directive 90/220/EEC, together with the results of the release(s) with respect to any risk to human health and the envi­ ronment; - the complete technical dossier supplying the information requested in Annexes I I and I I I o f Directive 90/220/EEC and the

2.

environmental risk assessment resulting from this information. Articles 1 1 to 18 of Directive 90/220/ EEC( 1 0) shall not apply to food or food ingredients falling under the scope of Arti­ cle 6 which contain or consist of a geneti­ cally modified organism. I n the case of food or food ingredients fall­ ing under the scope of this Regulation con­ taining or consisting of a genetically modif­ ied organism. the decision mentioned in Article 6 paragraph 2 shall take account of the environmental safety requirements laid down by Directive 90/220/EEC.

However, the European Parliament made clear in its opinion on the proposal at first reading, adopted 27 October 1 993, its con­ tinuing preoccupation with genetic e ngineer­ ing. Amendments were adopted demanding a separate authorization procedure under Part C of Directive 90/220 for foods or food ingre­ dients contai ning or consisting of genetically modified organisms. The Commission could not accept the obvious contradiction with both its declaration to Council of 23 April (see above), and its reiteration of the "si ngle procedure" policy in the April 1 991 commu­ nication (see Sect. 7.2); but revised the text in terms coming close to a de facto separate pro­ cedure. The inclusion of e nvironmental risk assess­ ments appropriate to a product category with­ in the corresponding sectoral legislation had been the understanding inscribed in the Council Minutes of 23 April (see above) , and was similarly understood by Member States. For example . a September 1 990 UK Govern­ ment list of "Priority tasks for the implemen­ tation of Directives 90/2 1 9/EEC and 90/220/ EEC" notes under Number 1 : "The establishment of a list of Community legis­ lation for the marketing of GMO products exempt from Part C of the Deliberate Release Directive, Article 10. The response of the Commission at the July meeting on this aspect was not helpful. The consen­ sus achieved in the negotiation and adoption of this Directive was, in part, depe ndent on rapid deve lop­ ment of adequate product based clearance sche mes. The U K believes that "dua l "' (i.e. both product and technology based) clearance systems shoul d be

5 Policy Ew>llllion at National Level. in Different Continents, Countries and Cultures avoided and that Part C of t h e D e l iberate Rele ase Directive should ope rate only as a safe t y net w h i l e product Directives a r e develope d . "

Thus by the end of 1 990. the new legisla­ tion at Community level had initiated two re­ sponses. On the one hand. the two new Direc­ tives would have to be transcribed into na­ tional legislation. Following this. there would be the corresponding establishment of nation­ al competent authorities. and the running in of their procedures: and. in parallel. the es­ tablishment of the necessary procedures at Community level. The whole process could be expected to take many years. On the other hand. it was already becom­ ing evident in 1 990 that. although scientific and industrial opinion had lost the political battle regarding legislation. regulation and control of genetic engineering and GMO products. the consequences of this defeat would not diminish or disappear. Rather, the progress of the technology world-wide. and the central role of the new knowledge in all advanced areas of application of the life sciences, would inevitably amplify and high­ light the consequences. There was no reason for the speed of ad­ vance of knowledge and world-wide diffusion of the technology to be adapted to the rhythm of the legislative and administrative processes within the Community and Member States: the divergence betwee n the two rapidly built up the pressure for review and adaptation. To this we return in Sect. 7. after reviewing some of the other actors and developments at glo­ bal and national levels which impi nged upon developments in Europe and at Comm unity level.

565

5 Policy Evolution at National Level, in Different Continents, Countries and Cultures Introduction

The story of modern biotechnology is one of the diffusion of new knowledge from an in­ itially small number of point sources: from in­ dividuals or laboratories, and from the key publications describing landmark experi­ ments (or experiments which in retrospect, after some delay - in the case of G REGOR MENDEL, several decades - come to be recog­ nized as such) . International scientific net­ works. and modern means of communication, broadcast and electronic, have in recent times shifted the shape of the diffusion process to­ wards worldwide simultaneous awareness; but operational awareness depends still upon there being in any given laboratory, or in any given country. individuals and groups capable of understanding, digesting, replicating and adapting to their local circumstances and in­ terests the new information and techniques. In the context of Third World development, the term currently in vogue is "capacity-build­ ing". In the following sections, some highlights and main trends or events are described. mainly under country headings. Such a seg­ mentation , natural enough in geographical or political terms, has defects for describing the diffusion of scientific knowledge. However, this chapter is not mainly about the diffusion of the scientific knowledge. but about the his­ tory of the regulatory response. Regulatory response has two contrasting characteristics. On the one hand, it has naturally to respond or react to the scientific developments, and its pattern in time and space must therefore re­ flect the characteristics of the scientific pro­ gress. ( Ambitiously, it may even attempt to anticipate, as in the case of biotechnology. ) On the other hand, regulatory processes are generally determined by national legislatures and executive authorities . driven by and re-

566

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

fleeti ng n ational and local sensitivities and

advanced country, but because it was in that

political p riorities When scientists or regulators, of similar background training and awareness, are faced

country that the debate about the regul ation of biotechnology was first played out i n depth and in breadth.

.

with sim ilar challenges, they react in similar ways - all the more so because they are close­ ly comm unicating with one another, and have

objective reasons and e ffective means for seeking harmonization and efficient s ha ring of effort. There are two fundamental common factors: a single gl ob a l scientific community, with a broadly shared understanding of a common scientific method ; and our common humanity, with some shared concerns and al­ most universally ackn owledged values, ex­ pressed through various solemn declarations, and given institutional form through bodies such as the agencies of the United Nations. Between these , or beyond them, lies every­ thing that makes for individual, local and na­ tional diversity.

It would be tediously repetitive to describe the essentially similar ways in which all the s ucce ss ive national authorities responded to the perceived needs for regulatory oversight of biotechnology. In the following sections, the approach is therefore selective , pe rh aps arbitrarily so, because of the limitations in the materials readily available to the a u th or The .

aim has been to focus upon countries which by their scientific scale and eminence, or their unusual transparency or originality of ap­

proach, or p arti cu l ar val ues and sensitivities, illuminate the range of responses, the main historical trends, and the interplay between the local and the general .

5 . 1 USA : NIH RAC, Existin g

A gencies, and the Co-ordinated Framework The dominance of America (i.e., the USA) in scientific, economic and lingu ist ic terms is both a fact and an expository conve­ nience , even when it bruises and irritates oth­ e r national sensitivities. Sect. 1 h as focused upon the first quinquennium after A si lomar and_was inevitably largely devoted to US de,

In depth, in that it was in America that the leading edge scientists, both American a n d

from other leading scientific countries, had first to p articipate in the debate, intensively, to the full limits of their abilities and under­ standing; in cl uding not only their scientific

understanding, but their ability to comm uni­ cate in various contexts and in unfamiliar ways. Their understanding and comm unica­ tion abilities had to address simultaneously multiple chal lenges: from scientific peers. from the general p ubl ic the media, and the activists. Science had to address the political ,

community on Capitol H i l l , and in State

and

even mu n icipal authorities. Hence the de bate

was also "in breadth"; although in those early years there were absentees who would later become sig nifi ca n t : the organized voices of in­ dustrial or agricul tu ra l interests were largely absent the debate would ultimately have to become broader still. But i n the early years, the absence of sectoral economic i n te rests may have contributed to the integrity of the US debate , and consequent international ac­ ceptability of its conclusions. It is easy in retrospect to select and ridicule some of the simplistic early fears and exagger­ ations; more constructive is to focus upon what emerged from the ea r ly American de­ bate, for America and for others. We have sought to emphasize the constructive nature of the messy but open communication process between the scientific an d po litica l communi­ ties, and would count as regrettable the rela­ tive failure of Europe in subsequent years to profit from that debate : "He who does not learn from history is condemned to repeat i t . " But Parliaments and Congresses a r e n o t e lec­ ted s i m pl y to endorse the lessons of history , or to import uncritically experience develop­ ed e lsewhere. As childre n growi ng up or as countries facing contemporary challenges, we demand the right even to make our ow n "'mis­ takes" for who has the right to say they are "mistakes"? With these caveats, we woul d sum marize as -

-

5

Policy Evolution at National Level, in Different Continents, Countries and Cultures

The early establishment by the Director of the National I nstitutes of Health of the N IH Recombinant DNA Advisory Committee (NIH RAC), its openness of debate, and the participation in its discussions of scientists, Federal officials from all the agencies con­ cerned, and activists, built credibility, and confidence in the integrity of the process. This focal point provided not only an excuse, but good reason, to delay the legislative delib­ erations while the smoke of scientific uncer­ tainties diminished. The subsequent adaptability of the N I H R A C was n o less important. As the successes of the basic science brought applications into prospect - large-scale industrial production, and field releases - the RAC initially ad­ dressed the challenges, creating appropriate advisory sub-groups, but then readily ceded oversight to the relevant regulatory agencies. As to which agencies were relevant, and as to whether existing statutes were adequate to the challenges posed by the new science and applications - that was the maj or U S lesson of the e arly and mid-1 980s, culminating in the "Co-ordinated Framework" of 1 986, and the steadily growing confidence there after that "no new legislation" was the right decision at least, for the U S , given its existing Federal agencies, and their rule-making (and unm ak­ ing) possibilities within existing statutory frameworks. The approach which thus evolved through the 1 980s laid a sound basis for continued US scientific advances, and for commercial growth and expansion through the 1 990s. There will as a result be progressive and rela­ tively unconstrained assimilation of the new knowledge into the established channels and networks, specific to human needs and activi­ ties, in food production, health care, and the relationship with the biosphere. NIH RAC

To underpin the above brief summary of the U S experience, some of the main events and reference materials should be noted. The NIH RAC itself greatly contributed not only to contemporary debate but to the historical record, by the publication of the Recombinant

567

DNA Technical Bulletin, from 1 978 to March

1 993; not only recording the formal business of the RAC, but serving as a focal point for much other information, debate and news rel­ evant to the progress of recombinant DNA research, development and applications. Formally, the RAC was ( and remains) ad­ visory to the Director of the National I nsti­ tutes of Health. Observance of the Guidelines was an explicit obligation only on institutions in receipt of N I H grants; but such was its per­ ceived authority in both scientific and regula­ tory circles that other parties conducting such research - in particular, industry - chose vol­ untarily to subj ect their proposed activities to RAC review. This may have been for various defensive motives, in the context of either the strategic threat of legislation, or the more specific threat of court action by activists crit­ icizing a company's experiment. The N I H , with t h e endorsement o f t h e Federal Intera­ gency Committee on Recombinant DNA Re­ search (through which the Federal agencies ensured mutual information and co-ordina­ tion of their relevant interests and actions), provided a mechanism for voluntary com­ pliance. From the start, it was recognized that the Guidelines m ust be dynamic. ELIZ A B ETH MI­ LEWSKI ( 1 98 1 ) published in the Bulletin a re­ view of the evolution of the guidelines. The original Guidelines were issued in 1 976. The first major revision took place in 1 978, after an extended process of public consultation; including the development of the adaptive mechanism itself, which M I LEWS K I describes as follows: "A proposal to modify any section or to introduce new provisions into the Guidelines must be published for public comment in the Federal Register at least 30 days prior to to a RAC meeting. The proposal and any public comments are then discussed by the RAC in open session. A final decision on the propo­ sal is rendered by the Director, NIH, after consideration of RAC recommen­ dations." Under these procedures, modifications were regularly made thereafter, typically ev-

568

18 The Regulation of Modem Biotechnology: A Historical and European Perspective

ery three months, with occasional re-publica­ tions of the Guideli nes to take account of the accumulated changes: most recently, in June 1 994. In July 1 98 1 , they were reissued to re­ flect a revision exempting from the Guide­ lines approximately eighty to ninety percent of all recombinant experiments. The details of the progressive adaptation over the next decade are recorded in the Bul­ letin and in the Federal Register. The N I H RAC, after significant involvement i n the first field release experiments and related contro­ versies, was able to withdraw from that area as the interests of the Federal agencies with statutory powers were defined and develop­ ed. These i nterests were codified as formal rules under the various relevant statutes through rule-making procedures and public consultation via the Federal Register similar to those used for adapting the NIH Guide­ lines. By 1 995 , practically the whole of the RAC activity had shifted to the consideration of gene therapy protocols (the Bulletin was discontinued in 1 993 as its functions could now be covered by the journal Human Gene Therapy ) . Other rONA research was by that time either exempt; or delegated to local I n­ stitutional Biosafety Committees operating under NIH RAC G uidelines; or covered by the rules and statutes of other Federal agen­ cies. As gene therapy developed, and the num­ ber of protocols submitted started to grow rapidly in 1 994, the N I H RAC changed gear again, withdrawing from the vetting of proto­ cols for routine experiments with human gene therapy (for whose approval the FDA would remain responsible). From October 1 994, only protocols raising novel scientific or ethi­ cal questions would be submitted to the Com­ mittee; which at the same time expanded its responsibility by acquiring an advisory role to the FD A. T h e Coordinated Framework

The inter-agency debates about scope and boundaries of regulatory authority them­ selves developed in the early 1 980s, increas­ ingly requiring central co-ordination. It was therefore from the Executive Office of the President, Office of Science and Technology

Policy (OSTP) , that proposals for co-ordina­ tion were put forward, and ultimately led to executive decisions. I n April 1 984, the Admin istration estab­ lished an interagency working group, under the Cabinet Council on Natural Resources and the Environment, with the charge to study and coordinate the government's regul­ atory policy for biotechnology products. Speci fically, the group was asked to: 1 . Review the regulatory requirements which have been applied to commercialized bio­ technologies. 2. Identify existing laws and regulations that may be applicable to biotechnology. 3. Review the function of the NIH Recombi­ nant DNA Advisory Committee and its role in biotechnology commercialization and safety regulation. 4. Clarify the regulatory path that a company with a new product would follow to meet Federal health and safety requirements. 5. Determine whether current regul atory re­ quirements and Federal review are ade­ quate for new products. 6. Develop specific recommendations for ad­ ministrative or legislative actions to pro­ vide additional regulatory review if war­ ranted, while maintaining flexibility to ac­ commodate new developments. 7. Review court rulings regarding the grant­ ing of patents for biotechnology. 8. Review other Federal actions such as sup­ port of basic research and training, US pa­ tents and trade laws, and other policy is­ sues which affect commercialization and US position vis-a-vis international firms. The results of the initial efforts by this in­ teragency group were reflected in the Federal Register of December 3 1 , 1 984, where the OSTP published its proposal for a "Coordi­ nated Framework for Regulation of Biotech­ nology", inviting comments by 1 April 1 985. The purpose of the proposal was summarized as being: "to provide a concise index of US Jaws related to biotechnology, to clarify the policies of the major regulatory agen­ cies that will be involved in reviewing

5 Polin· Evolution at National

Level. in Different

research and products of biotec h nology , to describe a scientific adviso ry mecha­ nism for a s s e ssment of biotechn o logy issues. and to explain how t he ac t ivities o f the Federal ag e n c ies in biotechnolo­ gy will be coordinated . . . These formal p ro posal s were taking place against a background of scientific advances. i ncreasing industrial investment activity and company start-ups. occasional high-profile Court disputes by activist groups chal lenging whether due process w as being fo ll o wed . and con t inuing Congressional i nterest . The Con­ gressional Office of Technology Asse ssment ( OTA ) was c o n tinuing to build a good repu­ t a tion for its comp e ten t and balanced reports. its D i rect o r J A C K G I B B O N S always prudently see kin g to ensure that each investigation was based on bipartisan interest expressed by both houses of Congress: the Senate and the H o us e of Representatives. OT A reports con­ tributing significantly to the public and politi­ cal debates at t h i s period i ncluded: •

•

1 981 : "The Impacts of A p plied Genetics Applicat io n s to M icroorgan isms. Animals and Plants" : 1 984 : "Commercial B i o technol o gy : An In­ ternational Analysis".

Mention should also be made of a report ( non-OTA) prepared for OSTP in 1 983: •

"Competitive and Tr a n sfer Aspects of Bio­ techn o logy : Co mmerc i al A spects of Bi o ­ te c hnol o gy : Po li c y Option Papers " . 27 May 1 983:

and of the Department of Commerce 's publi­ cation, July 1 984. of a report. " Biotechnolo­ gy" . in its se rie s . " High Technology Indus­ tries: Profiles and Outlooks " . These titles summarize th a t the balance of j udgement in o ffi cial circles a nd among i n­ fluential a d v is e r s was now decisively shifting from con cern s about r i s k s . towards concerns about ensuring the expl o itati o n of commer­ cial opportunities. and capitalizing upon US scientific leadership. Flattering references would be made to the strength of science else­ where. the l i g h t ne s s of the i r regulatory con-

Con tinentJ, Countries and

Cultures

569

straints. and the competitive capabilities of foreign companies, especially Japanese . ( The European policy proposals at the same period were making similar references to the U S sit­ uation - see Sect . 4. 1 : bu t were written in DG X I I . Science , Research and Development, read only in research Ministries and scientific circles if at all. and did not achieve compara­ ble political influence . ) The cited Department o f Commerce report gives "a summary of the issues which emerged as being of the most immediate con­ cern t o the successful development of bio­ technology pr o ducts and consequent US in­ ternational competitiveness''; the list com­ mences w i t h safety ove rsigh t , and a co mpli ­ ment to the N I H RAC: " I ndustry representat ives believe that the uncerta i nty over future ov e rs i ght of safety issues related to co mm e rci a l recombinant technology is creat i ng delays i n product test­ ing. appro val. realization of revenues, i nvest­ ment i n products and in companies whose product lines may become subject t o future regula t i on . I ndustry representatives would like to see the N ational I nstitutes of Health's Recombinant DNA Advisory Com­ mittee ( RAC) ex p a nd its role as overseer of recombinant DNA research protocols into all areas that may be i mpacted by recombi ­ n a n t DNA applications, i ncluding t h e testing and production of re co m bi n a nt DNA p r od­ ucts. Whether or not the RAC continues/ex­ pands its role , a consensus e merged that ad­ ditional regulatory committees should not be cre ated within the gove rnment."

In June 1 986, the OSTP announced again in the Federal Register (FR) the ''Coordinated Framework for Regulation of Biotechnolo­ gy " . as refined in the light of comments re­ ceived fo l l o wing the 1 984 publication; which had also contributed to refinement of the in­ teragency coordinating mechanism. The pub­ lication invited further public c o mment on certain new concepts which would be the sub­ ject of rule-making. Since the 1 984 publica­ tion, the interagency group under the former Cabinet Council on Natural Resources and the Environment had been succeeded by a " D ome s tic Policy Council Working Gro up on Biotechnology". This Working Group was re-

570

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

sponsible for the Coordinated Framework, and also considered policy matters related to agency jurisdiction, commercialization, and international biotechnology matters. The

BSCC, and

Interagency Coordination

At a more scientific level, there had been established in October 1 985, under FCCSET, a "Biotechnology Science Coordinating Com­ mittee (BSCC)", charged with an advisory and coordinating role across Federal agencies undertaking research in biotechnology. FCCSET, the Federal Coordinating Council for Science, Engineering and Technology, was a statutory interagency coordinating mechanism managed by the OSTP. Chaired by D AVID KINGSBURY of National Science Foundation, the BSCC brought together se­ nior staff from all the agencies principally concerned: the NIH, the FDA (Food and Drug Administration), the USDA (US De­ partment of Agriculture) and the EPA (Envi­ ronmental Protection Agency). One of the primary activities of the BSCC had been the development of definitions, be­ cause a common scientific approach was seen as a fundamental requirement for a coordi­ nated Federal regulatory framework. The June 1 986 FR publication invited public com­ ment upon BSCC-proposed definitions of "intergeneric organism", and "pathogen". These definitions would describe the combi­ nations of genetic material that would cause a modified organism to come under review. Among the proposed exemptions from re­ view, the BSCC proposed "genetically engi­ neered organisms developed by transferring a well-characterized, non-coding regulatory re­ gion from a pathogenic donor to a non-pa­ thogenic recipient". This particular point was a focus of later controversy, particularly in view of the importance to plant genetic engi­ neering of the Ti (tumor-inducing) plasmid from the plant pathogen Agrobacterium tume­ faciens.

The B SCC was also attempting to define what constituted "release into the environ­ ment", and was establishing a working group on greenhouse containment and small field trials in order to develop scientific recom-

mendations. It may be noted that, here as elsewhere, the work and preoccupations in the US regulatory debates interacted closely with the deliberations at the OECD (see Sect. 6.2); the key actors in the interagency debates in Washington also travelled regularly to Par­ is for meetings of the Group of National Ex­ perts on Safety in Biotechnology. The FR publication describing the Coordi­ nated Framework contained a section on "In­ ternational Aspects". This emphasized US in­ terest in the promotion of international scien­ tific cooperation and understanding of scien­ tific considerations in biotechnology; and in the reduction of barriers to international trade. It announced that the US was "seeking recognition among nations of the need to har­ monize, to the maximum extent possible, na­ tional regulatory oversight activities concern­ ing biotechnology". In this connection, the document referred to the OECD expert group responsible for the report, "Recombi­ nant DNA Safety Considerations for Indus­ trial, Agricultural and Environmental Appli­ cations of Organisms Derived by Recombi­ nant DNA Techniques" (OECD, 1 986); and quoted an extended summary of the main points of this report. The Coordinated Framework announce­ ment, a 93-page document (FR 5 1 /21302), in­ cluded policy statements from the Food and Drug Administration (FDA); the Environ­ mental Protection Agency (EPA) ; the US Department of Agriculture (USDA); the Oc­ cupational Safety and Health Administration (OSHA); and the National Institutes of Health (NIH). The 1 986 FR publication did not end pub­ lic or interagency controversy about the regu­ lation of biotechnology. The Reagan Admin­ istration had made a fundamental policy choice, in determining that biotechnology could be safely regulated under existing regu­ latory authorities; and the "Coordinated Framework" was the justification and exposi­ tion of that approach. SHAPIRO ( 1990) in an extended and scholarly review of biotechnol­ ogy regulation (including 420 references or footnotes in his 70-page study), summarizes as follows the potential problems of the Coor­ dinated Framework:

5 Policy Evolution at National Level, in Different Continents, Countries and Cultures

"This structure poses three challenges to ef­ fective regulation. First, different agencies may have concurren t j urisdiction over the same experiment or product. While this problem is not unique to biotechnology, it deserves attention here because research and development in the still-infant biotech­ nology industry may be discouraged by the costs of duplicative regulation. Second, re­ liance on existing statutes has left gaps in the regulatory coverage of biotechnology: some products or types of research are not regulated by any agency. Finally, EPA has been forced to regulate biotechnology under authority given to it by Congress to regulate chemical substances. For this reason, EPA may lack sufficient regulatory authority to regulate some aspects of biotechnology."

In spite of these criticisms, SHAPIRO writ­ ing four years later, or six years after the ori­ ginal (1984) publication, comments that "Most observers to-day give the Coordinated Framework generally good marks for the road map it provides to agency responsibility for regulating biotechnology"; a judgement which many would still support in the rnid­ '90s. On the first criticism, of regulatory re­ dundancy, agencies have through various pro­ cedures coordinated their interactions, and are meeting statutory deadlines for proc­ essing applications. Regarding regulatory gaps, there are some gaps over genetically en­ gineered animals; but not large, e.g., there would be relevant statutes if the animal is a plant pest, an agent for animal or human dis­ eases, or sold for food. On the third point, re­ garding adequacy of regulatory authority, EPA's use of TOSCA {Toxic Substances Control Act) to regulate microorganisms leaves on the agency the burden of proving that the "chemical" (for so microorganisms were defined, to allow the use of this Act) presents "an unreasonable risk of injury to health or the environment". The 1 986 Framework clarified many as­ pects of interagency coordination, but not all. The FDA had simply stated that they did not need to establish new procedures or require­ ments for the review of new biotechnology­ derived products. However, the two other major regulatory agencies - USDA and EPA - announced policies for developing addition­ al rules and guidelines.

571

In July 1 987, after public notice and com­ ment, USDA's Animal and Plant Health In­ spection Service (APHIS) published final reg­ ulations addressing "the introduction of or­ ganisms and products altered or produced through genetic engineering which are or which there is reason to believe are plant pests". These regulations required case-by­ case review of all organisms produced through recombinant-DNA techniques if the donor organism, recipient organism, or vector was listed by USDA. EPA had proposed (in the Coordinated Framework) to develop new regulations that would give " . . . particular attention, under both FIFRA (Federal Insecticide, Fungicide and Rodenticide Act) and TSCA (Toxic Substances Control Act), to mi­ croorganisms that (1) are used in the environment, (2) are pathogenic or con­ tain genetic material from pathogens, or (3) contain new combinations of traits." From its inception (in 1985), the BSCC had been troubled by disputes concerning the scope of regulation of biotechnology. One of the most controversial concerned BSCC's proposed exemption of the case referred to above - organisms created by the addition of well-characterized non-coding sequences from a pathogen. On this, EPA's proposed rule was in conflict with the opinions of sev­ eral other agencies at the BSCC; but in a court case brought against OSTP by the Foundation on Economic Trends, the BSCC had responded (in late 1 986) that the defini­ tions published in the Coordinated Frame­ work were "not binding". The BSCC's stand­ ing was further damaged when the Chairman, D AVID KINGSBURY, was charged in October 1 987 by a Congressional committee with a conflict of interest (having been a director of a biotechnology company at the time when he drafted the scope/exemption definitions), and subsequently resigned. In response to EPA's insistence on the above point in its TSCA rule, the following Chairman of the BSCC (JAMES WYN GAARD­ EN, ex-Director of NIH, then at OSTP) wrote

572

/8 The Regulation of Modern Biotechnology: A Historical and European Perspecti ve

to the Office of Management and Budget (OMB) requesting them to withhold authori­ zation of the EPA proposed rule . until the "other (BSCC) committee members could re­ view the proposed rule from a scientific per­ .. spective . EPA remained obdurate , claiming a division of sc i entific opinion on the issue: and WYNGAARDEN again wrote (August 1 988) to OMB. indicating that all other agen­ cies opposed the EPA proposal . as "i nconsis­ tent with the conceptual b asis of the Coordi­ nated Framework ". because th e y did not use scientifically de t erm i ned likelihood of risk bases for categories of regulated microorgan­ isms" . EPA refused to attend further meet­ ings of the BSCC. thus b loc king the achieve­ ment of consensus on the appropriate scope for Federal oversight. Through 1 989. the BSCC continued to wrestle with the scope issue, through a ··scope Subcommittee" chaired by the USDA Assistant Secretary for Science and Educa­ tion. C H A R L E S H E s s . Me anwhile, although i n d us t r y complain e d about the ongoing dis­ pute . and associated regul atory uncertainty the interagency bickerin g was becoming seen as esoteric, philosophical. and in fact not holding up s i g n i ficantly a growing flow of field release research applications to both EPA and USDA. EPA 's draft guidelines had been made public. and they continued to re­ view all field rel e ases of GMOs on a case-by­ case basis. The disagreement and polarization of opin­ ion at BSCC also limited its ability to function as an advisory body to the State Department in connection with international activities - in particular at OECD. in connection with the March 1 990 discussion document on "Good Developmental Practices ( GOP)" for small­ scale field trials (see Sect . 6.2). "

.

Separating Research an d Policy: The Council on Competitiveness

Analyzing the failure of BSCC, SH AP I RO ph a si z es the failure to distinguish science from policy issues: and in effect, the response of the Administration was to shift the policy r esponsibility to the White House Council on Co m petitivene ss leaving research coordinaem

.

tion to the Biotechnology Re search Subcom­ mittee of a reconstituted FCCSET Commit­ tee on Life Sciences and Health (CLSH). On the research side , the FCCSET CLSH pro­ duced in February 1 992 an impressive report, "Biotechnology for the 2 1 st Century", outlin­ ing how and why the US Federal Govern­ ment through its various agencies would spend $ 4.03 billion on biotechnology R & D in Fiscal Year 1 993. The preface, addressed to Members of Congress was signed by OSTP Director ALL A N B ROM L E Y . U nperturbed by the change of Administration, the same sub­ committee produced in June 1 993 a similarly handsome report, ''Biotechnology for the 2 1 st Century: Realizing the Promise" , with a bud­ get of $ 4 3 billion . the preface now signed by President CLINTON's Science Advisor, J A CK ,

.

G I B BONS.

To resolve the interagency regulatory di­ lemmas, the Bush Administration instituted in 1 990 a review of regulatory issues under the Council on Competitiveness. In August 1 990, four Principles of Regulatory Review of Biotechnology " were announced, as guid­ ance for Federal agencies: "

Federal government regulatory oversight should focus on the characteristics and risks of the biotechnology product - not the process by which it is created. 2. For biotechnology products that require review, regulatory review should be de­ signed to minimize regulatory burden while assur i ng protection of public health and welfare . 3. Regulatory programs should be designed to accommodate the rapid advances in biotechnology. Performance-based stand­ ards are , therefore, generally preferred over design standards. 4. In order to create opportunities for the application of innovative new biotechno­ logy products, all regulations in env i ron mental and health areas - whether or not they address biotechnology - should use performance standards rather than specif­ ying rigid controls or specific designs for compliance . "

"I.

­

;- PCJiicr Evolwion at National Le vel. in Differell/

Changt!

of

Administration, Continuity of

Policy

Republican to a Demo­ the CLI NTON victory in the N o w m b e r 1 9Y2 election did not alter ba­ sic US n a t i o n a l interests, nor the regulatory p h i l osop h y fm biotechnology whose evolu­ tion h a s been outlined above . A specific illus­ t r a t i o n \li a s p ro v i d e d by a U S D A proposal p ub l i s h e d in t h e Federal Register on 6th No­ T h e c h a n gt:

from

a

c r a t P rt: s i d e n t w i t h

vember 1 4lJ2.

preamble published with regulations, the 1 992 notice re ­ c a l k d t h a t " A PH I S stated its intention to m o d i fy or a m e n d the regulations to ensure t1 e x i b i l i t v and to remove restrictions when warra n t e d " . Thc m ai n point of the new notice was a p roposa l : R e fe r ri n g to the

t h e J l)8 7 fi n a l

notification process in troduction of certain transgen­ i c p l a n ts w i t h which the ( A PH I S ) has h a d cons iderable experience . . . . This d oc u m e n t also proposes to amend the re g u l a t i o n s to allow for a petition pro­ cess a l l o w i n g fo r a determination that ce r t a i n t ra n sge n i c plants are no longer co n s i d e r e d regulated articles. The pro­ posed amend ments would provide a prucedurc fo r fi ling a petition for deter­ m i n a t i o n of nonregulated status for t h ose orga n is m s which do not present a pl a n t pest r i s k and therefore should n o l o n ge r be r e g u la t ed articles."

··to

p r o v i d e fo r a

fo r t h e

S u bject

' a rious conditions concerning t h e n a t ure o f t h e introduced ge netic material . the n e w p roce d u re proposed to i n t roduce this s im p l i fi e d p ro c e d u re for six major crop spe­ cies. fo r which i t w a s felt that sufficient ex­ peri e n c e had a c c u m u l ated: corn, cotton, pota­ to. soybe a n . t o bacco . tomato. In March 1 993. t h e s e r u l e s w e r e published in fi nal form. with o n l y m i n or m o d i fications. in response to com­ m e n t s a n d the j udgement of the incoming A d m i n i s t r a t i o n ( some details were revised. e . g a 3 D - d a y n o tice period, rather than zero ) . I n fa c t s u c h a simplification o f procedure w a s beco m i n g i nescapable, given the acceler­ ation of r c q u e � t s for field trials and the hiring fre e ze o n a d d i t i o n a l staff at USDA. Release to

Continents,

Coun tries and

Cultures

573

pe rmits had roughly doubled every year from 1 987 onwards. reaching 5 1 in 1 990, 90 in 1 99 1 , 1 60 in 1 992. 306 in 1 993 , and 521 in 1 994 (to end-November) . With the new system in place. 1 89 of the 1 993 field trials and 454 of those in 1 994 were notifications; thus reduc­ ing the authorizations to 67 of the 521 total. G iven the multi-site nature of the requests. the 1 994 figures corresponded to releases at 1 7m� sites. 1 490 covered by notification. A paper on renewal of the American econ­ omy through technology was published by the President and Vice-President in February 1 993. This and subsequent speeches by G REG S I M O N . Domestic Policy Adviser to the Vice­ President ( and a former Congressional staffer who had worked intensely on drafting an "Omnibus Biotechnology Act" ) , made clear the conti nuing determination of the US under the new Administration to maintain leader­ ship in biotechnology. With the continued safe track record of the technology , the scale of Federal research expenditure, and the growing political perception in Congress of the significance of the technology for US in­ ternational competitiveness (there is a bi-par­ tisan biotechnology caucus of some one hundred Congressmen ) , the trend towards simplification and lightening of regulatory burden seems likely to persist.

5 .2 UK: From GMAG to A C G M and ACRE ; Statutory Developments in 1 990-1 992 ; the House of Lords Report and Government Response

The U nited Kingdom, birthplace of the double helix discovery and still a significant force in science , was a major player in the first decade of the biotechnology regulatory debate. Subsequently, its role had to be played in conformity with the rules of the Eu­ ropean legislative frameworks.

. .

GMAG: Creation, Mandate and Activities

Reference has been made in Sect. 1 to the establishment in December 1 976 of

574

18

The Regulation of Modern Biotechnology:

"GMAG", the "Genetic Manipulation Advi­ sory Group"; whose "advice " regarding the conduct of rONA research was in practice given statutory force by the requirement of the Health and Safety Executive (under the authority of the 1974 Act on Health and Safe­ ty in the Workplace) , that research conform to the GMAG Guidelines. GMAG itself was created by the Department of Education and Science, as the Ministry then responsible for funding university research and the activities of the Research Councils; its secretariat was provided by the Medical Research Council. Its membership comprised scientists, civil servants from potentially interested govern­ ment departments, and "public interest" rep­ resentatives, including trade union represen­ tation and lawyers; innovations in social poli­ cy for the oversight of science which attracted then and subsequently considerable academic interest, and general approval for its "trans­ parency". Its meetings were nonetheless con­ ducted in closed fashion, its participants re­ quired to sign the Official Secrets Act. The terms of reference were: ( 1 ) to advise a) those undertaking activities in genetic manipulation, including activi­ ties relating to animals and plants, and b) other concerned individuals and organi­ zations; (2) to undertake a continuing assessment of risks and precautions (particularly any new means of physical or biological con­ tainment) and of any newly developed techniques for genetic manipulation, and to advise on appropriate action; (3) to maintain contacts with relevant gov­ ernment departments, the Health and Safety Executive, and the Dangerous Pa­ thogens Advisory Group; (4) to maintain records of containment facili­ ties and the qualifications of Biological Safety Officers; and (5) to give advice on general matters con­ nected with the safety of genetic manipu­ lation, including health monitoring and the training of staff. GMAG's activities were similar to those of the US NIH Recombinant DNA Advisory Committee. It initially advised on individual

A

Historical and European Perspective

proposals, and on the establishment of guide­ lines for risk assessment of the conjectural hazards of genetic manipulation. It also pro­ vided guidance for the establishment of local Genetic Manipulation Safety Committees. GMAG developed guidelines regarding appropriate levels of physical and biological containment within laboratories, for different types of organisms and experiments; and as experience accumulated without adverse inci­ dents, the guidelines were progressively re­ laxed. There was close awareness of the evo­ lution of scientific progress worldwide, and of the regular adaptation of the NIH RAC Guidelines. However, with the successful progress of research and development, it was evident in the early 1980s that industry would wish to proceed to large-scale fermentation produc­ tion, and use, of genetically-manipulated mi­ croorganisms. Progress in the genetic engi­ neering of plants was similarly promising, raising the imminent prospect of field releases of genetically modified plants and microor­ ganisms. But as genetic engineering develop­ ed towards more routine acceptance and ap­ plications, the position of GMAG under the DES began to look anomalous. For example, by September 1 982, in GMAG's third report, the Secretary of State for Education and Science, Sir KEITH JoSEPH was writing in the Preface: "Since the Second Report [ of GMAG ] was published in December 1 979, much scientific information on the biological applications of recombinant DNA technology has accumu· lated. Because the original fears about the work have so far not been substantiated and because of the very responsible attitude of those who carry out the work, this Report explains that the group were able, in early 1 980, to introduce a risk assessment scheme for the categorization of experiments, and within a year to advise a further modifica­ tion of the procedures governing the notifi· cation of individual experiments . . . . The Group have also revised their proce­ dures for giving advice on the large scale use of genetically manipulated organisms. The Report records that the Group's advice on that area of work will in future be restricted to the biological properties of the organism being used; the Health and Safety Executive

5 Policr Evolution at National Ln·el, in Different Continents, Countries and Cultures w i l l . as pa n uf their responsibilities under the Health and Safety at Work Act 1 974. con t i n ue tn nt: concerned with t he physical aspe c t s of ,afe t y . "

taking activities relating to ge n et ic manipulation ( ii) the cat e gori z atio n of experiments (iii) exemptions from the Health and Safety (Genetic Manipulation) Regulations 1 978 (iv) the assessment of risks and precau­ tions (and in particular of any new methods of physical or biological containment) and of any newly de­ veloped techniques for genetic ma­ n ipulation (v) at the request of HSE, the specifi c precautions necessary in individual cases of experimental work (vi) at the request of HSE, the biologi cal aspects of individual cases of the non-experimental use of prod­ ucts of genetic manipulation (vii) health monitoring and training of those undertaking genetic manipu­ lation activities ( v i i i ) the nature of any controls to be ap p l ied gene r ally in laboratories and other workplaces engaged in ge­ netic manipulation by way of regu­ lations codes of practice and guid­ ance (ix) such other matters as may be refer­ red to the committee by the HSC o r HSE

Such d e v e l o p m e n t s led the government to institute a r e v i e w of GMAG by civil servants from DES and t he Health and Safety Execu­ tive ( HS E ) . The re s ulting report (April 1 983) concluded t h a t :

clear that the HSC ( Health and Safetv Commission ) and the HSE ( H e a l t h a;1d Safety Executive) will con­ t i n ue t o need advice in order to dis­ charge their responsibilities, and that Heal t h . A griculture and Environment Ministers ;n ay well require advice on t ec h n i c a l advice in their fields. There are good reasons for reconstituting the pres� nt Ci M A G as an HSC Advisory Com m i tte e with provision for advice to be available to Minist e rs of other De­ partme nt-.. and there is considerable . support .,.. i t h i n government and outside for t h i s so l u tion. The likely structure and fu n c t i o n s of an H SC Advisory Committe e and the way in which it w o u ld work. are set out in the report. The c o n c l u s i o n of DES and HSE offi ciah is tha t such a committee would be us efu l and workable and that, subject to t h e agre e m e n t of Ministe r s and the H SC and t o the views of interested or­ ga n i sat i o n , . it should be established in place of G M A G as soon as possible. " " I t appe a r s

­

­

.

­

ACGM: Terms of Reference GMAG sory

was

in

Com m i t t t: e

with the

follo-w i n g

1 984 replaced by t h e Advi­ fo r

Genetic Modification, of reference :

t e rm s

Advist: t h e Health a n d Safety Com­ Health and Safety Exe· c u t i v e . in Co n nection with Their Re­ sponsibilit ies U nder the Health and Sa­ fe tv a t Work A ct 1 974 on

575

B.

To Advise the Health , Agricu l tu re, Envi­ ronment, Indu s t ry and Northern I re lan d Ministers on such matters relating to ge n et i c manipulation as may be referred to the committee by those ministers and offer comment on the techni­ cal or scientific aspects of any new developments in genetic manipula­ tions which may have implications for their departments."

"A. To

m i s s i o n and t h e

(i)

t he ge n e ral mg

standards of safe

w ork­

to be observed by those under-

As sensitivity to the adverse public image of the word ''manipulation" developed, the ti­ tle was subsequently revised to "Advisory Committee on Genetic Modification " . The ACGM continued over the following decade and curr e n t l y to fulfi l the advisory role thus defi ne d . This mandate proved to be robust ,

576

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

and the operational performance was widely appreciated for its competence, including in­ novations and adaptability as necessary. As a result, the ACGM remained the central ex­ pert advisory body in the U K throughout a period of rapid expansion and innovation in biotechnology, which saw various major re­ ports and legislative events at national and European Community levels. The Committee focused largely on con­ tained research and industrial work involving GMOs, its general approach including: - the establishment of properly consti­ tuted genetic manipulation safety committees at each location where such work was conducted; - the dissemination of guidance on pro­ cedures and risk assessment; - the inspection of laboratories and ad­ vice on good practice. ACGM established a working group to de­ velop guidelines on the release of GMOs in the environment, including both ACGM members and additional experts and civil ser­ vants. The working group later became estab­ lished as the "Intentional Introductions Sub­ Committee of the ACGM", following the is­ sue, with the approval of the HSC, of its guid­ elines. These guidelines, issued in April 1986, recommended that: - the HSE should be notified of any proposal to release GEOs; - the notifier, when making his initial assessment of the environmental con­ sequences of a release, should be ad­ vised by an appropriately constituted local body including relevant scientific expertise and, where appropriate, a local environmental health officer; and - a case by case examination of propo­ sals should be carried out on behalf of the HSC on the basis of risk assess­ ment material provided by the pro­ poser in accordance with the guide­ lines. These arrangements were implemented by the HSE largely on a voluntary basis, which

in 1 989 became statutory with the issue of the new Genetic Manipulation Regulations (see below). Report of the Royal Commission on Environmental PoUution

The UK was (and remains) an active parti­ cipant in the discussions of biotechnology sa­ fety and regulation in international fora, par­ ticularly in the European Community and in the OECD; often contributing to these from a basis of strong national expertise and inter­ ests. An important example was the role played by the long established Royal Com­ mission on Environmental Pollution (RCEP). This Commission, under a new chairman at the start of 1 986, Sir JACK LEWIS (Professor of Inorganic Chemistry in the University of Cambridge, and past President of the Royal Society of Chemistry), decided on its priority tasks over the following year or so, and in­ cluded among these "the release of genetical­ ly engineered organisms into the environ­ ment". An invitation for evidence was issued in July 1986; their report was presented to Parliament three years later (RCEP, 1989). The report gave a comprehensive overview of the subject of genetic engineering, its appli­ cations, and its regulations. It reviewed, albeit briefly, developments in many countries; no­ ting Denmark's legislation; Germany's Caten­ husen report (which had appeared in 1987); the US "co-ordinated framework" ; and the related arguments. It summarized develop­ ments at the OECD, and in the European Community. Given the timing, the RCEP commented closely on the contemporaneous proposals for the EC Directives: both on con­ tained use, and more particularly that on field release. The RCEP report gave a strong and une­ quivocal recommendation in favor of statuto­ ry control of releases; the first five of its 67 recommendations were as follows: " 1 . Statutory control of releases of genetically engineered organisms (GEOs) to the envi­ ronment must be put in place . 2. Both the Secretary of State for the Envi­ ronment and the Health and Safety Com­ mission (HSC) (acting on behalf of the Sec-

5 Policy Frolution at National Le vel. in Differen t Cominents. Countries and Cultures n:t arv of St,ttc for Employme nt) should be i n vo l ve d i n decisions on release. 3 . The Secre t a rY of State for the Environment s h o u l d t a k e pri m a r y responsibility

for con­ rc-.pect to the e nvironmental con­ se4ue nces o f such re leases. 4 . The co n t rol of releases o f ge netically e n g i n e e red orga n is m s should be gov er n e d by a s t a t u t e esta b l ishing con trols in respect of e n v i ron m e n t a l protection and p rov i d i n g a framework \\ i t h i n which the Secre tary of State would be e mpow e r e d to make re g ul ations i nc l u d m g a system for l icensing. T h e stat ute sho u l d . i n addition. impose a duty of c a re o b l l gmg. a l l t h ose responsible for t he r e l e ase of a GEO. whether for experi­ m e n t a l or commercial purposes. to take a l l reason able s t e ps for t h e protection not only of h u m a n h e a l t h and safe t y but also of t he e n v i ronme n t . 5 . A l i ce n ce w h ich w e refer t o a s a r e l e ase l i ­ cence . should be r e q u i re d before t he re­ le ase of a �e n e t ically engineered organism mav a lso t a k e p lace . I t should be an of­ fe n c e . c ar n i n g a su b s t a nt i a l penalty, to re­ l e ase a GEO w i t hout having first o bt a i n e d a re le ase lice nce or to fail to comply with a n y co nd i t i o n s attached to the l ice nce . " t rol w i t h

­

­

.

•

T h e re port st mngly endorsed t h e EC's pro­ posed Directive on field re lease . noting ex­ tensive s i m i la r i t i e s t o its own conclusions and recom mendations: its main criticisms of the Directives bei n g their i nadequacy in two re­ spects:

577

VI of the Environmental Protection Act ( 1 990) specific regulations relating to envi­ ronme ntal protection from the possible ris k s of releasing G MOs. This Act required a safe­ ty assessment to be made and submitted to the Depa rtm e nt of the Environment. in cer­ tain cases requiri ng a consent. The Advisory Committee on Releases to the Environment ( ACRE) was created from the ACGM's In­ tentional Introductions Sub-Committee, as an advisory body to the Department of the Envi­ r onmen t Given the RCEP report ( 1 98 9 ) the adop­ tion of the EC Directives on contained use (90/21 9) and field release (90/220), and the Environmental Protection Act ( 1 990) the Gove rnment updated the HSE regulations (based on the 1 974 Health and Safety at Work Act) and published new field release regulations under the Environmental Protec­ tion Act, thus giving guidance on the imple­ mentation of the latter and fulfilling its obli­ gations under European legislation. The two sets of regulations. which are the current basis for the regulation of biotechnology in the U K . are: Part

.

,

,

•

•

the Genetically Modified Organisms (Contained Use) Regulations 1 992 (HMSO. 1 992a) ; th e Genetically Modified Organisms ( Deliberate Release) Regulations 1 992 ( H MSO. 1 9 92b ) .

( i ) the pr o p m ed sectoral e x emptions, in

areas where Community-wide legisla­ ti o n did not e x i s t - pesticides were particu l a r l v cited: (ii ) in s u ffici e n t recognition , in the provi ­ sions for Community-wide mark et au­ t horiza tion . t h at the environmental risk assessme n t must be specific to lo­ cal e nvironments. Environmental Protection Act, AC RE, EC Directives, the 1992 Re gulat ions

The Government did not ful l y accept these recomme ndations. making clear in its posi­ tions at t h e EC Council Meetings its view fa­ vori n g sectora l legislation. However. in re­ sp on se to the RCEP report. it included as

The HSE and the DoE back these up with further clarificatory documentation, in the form of guidance ( HMSO, 1 993; DOE, 1 993) and the "ACGM Newsletter" published by HSE. The development of biotechnology in the UK has been rapid, and the advisory bodies ACGM and ACRE have devel o ped a reputa­ tion for integrity, and scientific pragmatism. The UK has actively initiated in the EC Com­ mittee concerned. proposals for simplified procedures for various classes of field release, on the basis of ACRE's advice; simplifica­ tions for which the pressures have come from t he U K scie ntific communities, academic and industrial; and from the consideration of the impact of regulations on i nternational compe­ titiveness.

578

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

House of Lords Report, 1993, and Government Response, 1994

The latter topic was the subject of particu­ lar scrutiny by the House of Lords Select Committee on Science and Technology, who established a subcommittee to conduct an en­ quiry into "Regulation of the UK Biotechnol­ ogy Industry and Global Competitiveness". The sub-committee was chaired by Lord H o ­ WIE OF TROON, and its report was published in October 1 993, with an accompanying press release, volumes of evidence received, written and oral, and considerable publicity ( H o usE OF LORDS, 1 993). The report was quite blunt, the Committee concluding that: "- Early fears of scientists relating to geneti­ cally modified organisms (GMOs) in con­ tained use turned out to be unfounded. As a general principle, except where pathog­ ens are involved, separate regulation of GMOs in contained use is unnecessary over and above current good laboratory practice; and deliberate release of GMOs, except where bacterial or virus vectors, live vaccines or modification of the ge­ nome of animals are involved, is not in­ herently dangerous. - United Kingdom regulations, which are in turn based on E.C. Directives, take an ex­ cessively precautionary line based on a view of the technology, which, in terms of scientific knowledge, was already obsoles­ cent when the directives were being pre­ pared in the late 1 980s. In framing them the Commission appears to have been im­ pervious to advice tendered to it by scien­ tists, industry, and national experts. Not only does this place the UK at a competi­ tive disadvantage vis a vis principal over­ seas competitors like the USA and Japan but even within the EC implementation is so uneven as to create serious inequali­ ties." By way of remedy, the Committee recom­ mended that: - "The Government must press for amend­ ment of the EC contained use Directive so as to substitute a risk assessment system in

place of the current classification of risk ac­ cording to size of operation and pathoge­ nicity; meanwhile, as interim measures, use of safe organisms should be subject only to a simple notification procedure whatever the scale of the operations; and the Health and Safety Executive should aim to give consent for use of unsafe organisms well within the 90 day maximum. - The Byzantine structure of deliberate re­ lease regulation must be reformed so as to enable certain activities, as selected by a group of EC national experts, to be exempt from the present provisions; meanwhile, as interim measures the current number of questions to be addressed in the risk assess­ ment questionnaire should be reduced by making them specific to the type of organ­ ism involved; applications should be proc­ essed in not more than 30 days; and univer­ sities and research councils should be ex­ empt from paying fees on their applica­ tions. - As a matter of principle, GMO-derived products should be regulated according to the same criteria as any another products. The present process-based system should be retained only for the limited areas where regulation is required - that is to say all work involving pathogenic organisms and for deliberate release of GMOs outside the low to negligible risk category; work on further process-based regulatory EC draft Directives on GMOs should cease forth­ with. - Promotion of public understanding of bio­ technology is important but should not be carried out so far as to preclude evolution of regulation; because of its implications for competitiveness, DTI is ultimately re­ sponsible for ensuring that public percep­ tions are based on reason and knowl­ edge." In spite of the critical tone of the House of Lords report, the government's published re­ sponse in a White Paper (DOE, 1994) was to express its broad agreement with most of the observations and recommendations, and to emphasize the ways in which it was moving in the direction advocated. This was in part be­ cause the publication of the report coincided

5

Policy Evolution at National Level, in Different Continents, Countries and Cultures

with a period when the UK government was emphasizing on a broad front its commitment to a deregulatory philosophy regarding social legislation, the cost of which was claimed to be a significant factor in Europe's relative loss of competitiveness. The members of the House of Lords Committee were at pains to emphasize that there had been no deliberate intention on their part in this sense. Some quotations summarize the tone of the govern­ ment response: "The Government welcomes this timely and detailed report from the Select Committee on how regulation of biotechnology affects the competitiveness of the United Kingdom industry. The section of the enquiry dealing with the difficult issue of public understand­ ing and acceptance of this fast moving tech­ nology is welcomed. The Government believes that modern bio­ technology has far-reaching implications for the UK economy and will have a major im­ pact on products and processes across a wide range of sectors. It is a key enabling technology which has the potential to en­ hance significantly the competitiveness of many sectors of British industry. The Gov­ ernment recognizes the need to get both an appropriate regulatory framework and the right climate for investment to enable UK industry to remain competitive. Sensible reg­ ulation is crucial and, in line with Govern­ ment policy, should be founded on the best scientific evidence available and be propor­ tionate to any risk involved. The Government considers that the regula­ tory system now existing in the UK leaves industry well placed to compete in global markets but recognizes that industry has not always shared this perception. However, rap­ id evolution has taken place in biotechnolo­ gy regulation in the UK and elsewhere over the past few years, resulting in the introduc­ tion of fast track procedures for clearance of some deliberate releases of genetically mod­ ified organisms (GMOs) and simplification of notification procedures governing the contained use of GMOs. Similarly, the evolution from process- to product-based regulation of GMOs, which the Committee supports, was foreseen dur­ ing the drafting of the two relevant EC di­ rectives. The Government has been at the

579

forefront of discussions in Brussels to ensure that GMO products are regulated together with equivalent products derived by conven­ tional means. The safety criteria applied to these products should not be affected by the way they are subjected to regulation. The Government will continue to press in the European Community for the evolution from GMO regulation to a product-based approach where this is practicable. Because the need for flexible approach to regulation in this field was anticipated from the outset, the Government is able not only to endorse but also to implement the great majority of the recommendations in the re­ port . . . "

Similar remarks referred to the evolution of EC-level legislation and the Biotechnology Co-ordination Committee. Responding to the specific accusation by the House of Lords Se­ lect Committee that: "In framing the Directives on which the United Kingdom regulation are based the European Commission took an excessively precautionary line which, in terms of scien­ tific knowledge, was already out of date when they were being prepared in the late 1 980's. Advice to that effect appears to have been ignored",

the Government replied that: "Biotechnology is a fast-moving technology and it is therefore appropriate that legisla­ tive and administrative controls regulating the use of GMOs are in a state of continuing evolution. As scientific experience accumu­ lates, regulations will be reviewed and tigh­ tened or loosened as is appropriate to risk. It is therefore no surprise that the Select Committee views some of the detailed provi­ sions of the two EC directives governing the use of GMOs now to be dated and the Gov­ ernment agrees with this view. However, notable progress has been made in revising aspects of each directive in recent months, and the Government is committed to con­ tinuing to pursue the development of Euro­ pean legislation in line with the best scien­ tific advice available."

The Government endorsed the view of the Committee regarding the importance of the

18 The Regularion of Modern Biotechnology: A Historical and European Perspective

580

work of t h e European Community's Biotech­ nology Co-ordination Committee .

5.3 Ge rmany: The Catenhuse n Enquiry, the 1 990 Gentechnikgesetz, and the 1 993 Revision

Ge rma ny. the largest and economically most powerful count ry of Western Europe and of the European Community or Union. has acted as a leading scientific and industrial force in biotechnology. and also as its sternest and most conscientious or concerned cri tic: but not simultaneously . nor from the same in­ ternal constituencies. In the early 1 970s. it was a leader. Through the 1 980s, German sensibilities, and the pressure of German pub­ lic and _political o_pinion ex_pressed at three levels the Land (or . at least, certain Uin­ der); the federal Parliament, in both cham­ bers; and the European Parliament - were the most conservative and obstructive factors af­ fecting biotechnology in Europe, contributing to the construction of a restrictive regulatory framework. Finally in the 1 990s, with all the zeal of a reformed sinner, German industry and government have been again in the lead­ ing position , pressi ng for reform and simplifi­ cation of biotechnology regulation, at nation­ al and European levels; particularly during the German Presidency of the Council of Ministers. J uly to December 1 994. Such a brusque summary runs the risk of caricature . The particular intensity of the public debate in Germany reflected a close fusion of two strands of discussion which in other countries were for most of the time more or less separate: on the one hand, the usual and necessary deliberations and discus­ sions on technical aspects of risk assessment in scientific and industrial contexts, including the ecological uncertainties associated with field release: on the other, the wide-ranging and troubling analysis and debate concerning ethical aspects arising in the use or possible abuse of the new knowledge and techniques. in areas such as pre-natal diagnosis. in vitro fertilization. and '"human genetic engineer­ ing'' . i .e . , gene therapy, somatic and germ-

line: and extending to fundamental philo­ sophical debates about the relation between man and .. Nature". Reaction to the disastrous and tragic ex­ perience of the nazi period led in the period of postwar reconstruction to the creation in Germany of a federal constitution and a judi­ ciary particularly attentive to separation of powers and to propriety of procedure. Throughout the developed world, as KEVLES has particularly clearly expounded ( " I n the Name of Eugenics", 1 99 1 ) , and from fRANCIS GALTON ( '" Hereditary Genius", 1 869) through the first half of the twentieth century, respected members of the scientific commu­ nity repeatedly displayed a combination of hubris, naivety and indifference to moral standards and ethical values (at least as judged a posteriori by the standards of later generations). This was exemplified by the close working partnerships between scientific experts and public authorities in more and more fields of public policy as the cen tury progressed: from genetics to eugenics was a short and (in the context of those decades) a natural step. The culmination of these trends, in the specific German experience leading up to 1 945 , cast a long shadow. To this traumatic experience, Germany in common with other Northern European countries added a centuries-long romantic tradition, whether rooted in an instinctive an­ imism, or arising in the last two centuries from a natural revulsion at the destructive, disruptive and ugly characteristics of the in­ dustrial revolution. From an anti-industrial sentiment to an anti-intellectual suspicion of science and scientists was a short step. Such matters require deeper historical and socio­ logical analysis than can be offered in the context of this paper. Their current influence is in some measure illustrated by the results of opinion surveys referred to in Sect. 7.5. The practical consequences for biotechnology and its regulation are summarized in the fol­ lowing paragraphs. Industrial Fermentation -

DECHEMA

The German chemical and pharmaceutical industry has been and remains one of the

5 Policy

Emlution at Narional Level, in D(fferelll Continents. Countries and

largest and strongest in the world. since the beginnings of these industries. I n the postwar years. its stren gths were reflected both in the traditional food and drink fermentation sec­ tors, and in a rapid build-up of fermentation pharmaceuticals in giants such as Bayer . BASF, and Hoechst. A leading role in education and innovation was played by the German Chemical Equip­ ment Man ufac t u re rs· Association. DECHE­ MA, under the leadership of DIETER BEH­ RENS for three decades. from 1 960 to 1 990. Among DECH EMA staff and the academic experts in their circle of advisers. there was in the 1 960s and early 70s already a lively aware­ ness of progress and potential in applied mi­ crobiology; and a far-sighted report was pub­ lished in 1 974 (DECHEMA. 1 974). A devel­ oped version of this report was subsequently financed by t h e Federal Ministry for Re­ search and Technology. BMFT. From that time . BMFT has played a key leading role in strengthening t he scientific base of biotechno­ logy in Germany, and in trying to stimulate the more effect ive transfer of scientific and technical knowledge from academic into in­ dustrial contexts. It was therefore natural for BMFT to encourage the role of DECHEMA. placed precisely at the interface between the academic and i ndustrial communities. Mention should also be made of the build­ up of the national research capability through BMFT support for the GB F ( "Gesellschaft fiir Biotechnologische Forschung'') at Braunschweig; but this is less relevant to the story of biotechnology regulation . The long history underlying the industrial tradition in biotechnology - in which German scientists played no small part - has been re­ searched and narrated by ROBERT Buo ( 1 993 ). The strength of the German industrial fermentation tradition and the alertness of DECHEMA gave an early and vigorous im­ pulse to biotechnology. This was from a base which had little connection with the scientific i nnovations in recombinant DNA research ; there seemed for several years to be a delib­ erate maintenance of distance between the in­ dustrial fermentation industry and the new genetics. I n the BM FT -financed D EC H E M A study published in 1 976, the definition of bio­ technology was as follows:

Cultures

581

" Biotechnology is concerned with the use of biological activities in the con­ text of technical processes and indus­ trial production. It involves the applica­ tion of microbiology and biochemistry in conjunction with technical chemistry and process engineering. '' The separation was similarly reflected in the early history of the European Federation of Biotechnology (see Sect. 6. 1 ). But from the mid-70s. another strand was developing which would come to dominate the regulatory de­ bate . and profoundly shock and shake the leaders of German industry; and not simply because the successes of rDNA research were beginning to indicate the need to prepare for the move to large-scale production of a few particular molecules of pharmaceutical inter­ est. rONA Research - The Guidelines

The Federal Ministry for Research and Technology ( B M FT) , in response to the US and international debate launched by the Asi­ lomar Conferences ( 1 973 and 1 975 - see Sect. 1 .3 ) , appointed a committee of experts which drafted a proposal for safety guidelines in 1 976, modelled after the N I H Guidelines, and relating to laboratory work with recombinant organisms. Following public discussion, the Guidelines were formally enforced in 1 978. These Guidelines were legally binding on l y on research funded by the Federal Govern­ ment, but in practice were followed by indus­ try on a voluntary basis, as in the US. Again similarly to the NIH Recombinant DNA Ad­ visory Committee in the US, the Guidelines were repeatedly ame nded - five times, up to 1 986, before the adoption in 1 990 of the Gene Technology Law (see below). The Guidelines allowed genetic manipula­ tion work to be undertaken only in registered laboratories or institutions, of which by 1 990 there were about 1000 . The Guidelines cov­ ered a range of topics - definitions, registra­ tion . categorization of experiments, supervi­ sion of rONA work, health monitoring of workers, transport of GMOs, and a detailed appendix containing recommendations on the

582

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

handling and containment of pathogenic mi­ croorganisms. Four laboratory safety levels were designated, ranging from low-risk, Ll , to the riskiest, L4. Two biological categories were also defined, B 1 and B2, in terms of lists of the microorganisms and strains corre­ sponding to each. For production of microor­ ganisms in volumes greater than 10 liters, sa­ fety measures LP1 to LP3 were also defined in the fifth edition, in accordance with the OECD "Blue Book" which was appearing at that time. The degree of scrutiny of recombinant re­ search was defined as a function of the degree of risk. In a registered and approved labora­ tory, L1 experiments could take place without further registration or approval. (This was an innovation in the fifth edition of the guide­ lines.) After 28 May 1986, only experiments at levels L2 to L4 required individual approv­ al from ZKBS, the Central Commission for Biological Safety. Established in 1 975 within the Federal Health Board (BGA: Bundesge­ sundheitsamt), ZKBS had 12 members: four experts in rONA technology, four experts in biological research, and four persons from other fields - e.g., trade unions or industry. Prior to the fifth edition, every experiment of greater than 10-liter volume required individ­ ual authorization from the BGA. In accor­ dance with the OECD Guidelines, the BGA could reduce safety requirements for working with low-risk organisms (such as can be han­ dled under GILSP: Good Industrial Large Scale Practice) . I n 1 979, the B M FT conducted a closed hearing, involving both foreign and domestic experts, on "The Chances and Risks of Ge­ netics Research". This was described by FR ITZ GLOEDE ( 1 992) , of the Technology Assessment Unit of the Bundestag (TAB) as an occasion "in which scientific-technical, ecological and social risks were discussed con­ troversially for the first time".

in 1984, and this mainly in the area of the ethics of reproductive medicine and human genetics. Such ethical debate led to a series of commissions, in particular the establishment in May 1 984, jointly by the Ministers for Re­ search (HEINZ RIESENHUBER) and Justice (HANS ENGELHARD) of a Working Group on "In Vitro Fertilization, Genome Analysis and Gene Therapy", under the chairmanship of Professor ERNST BENDA. Their report (BEN­ DA, 1 986) published the following year, con­ taining for each of the areas mentioned in the title carefully reasoned recommendations for legislation, or pointing to possible future needs. In conjunction with other debates, this led eventually to the adoption of the Law on the Protection of Embryos, in 1 99 1 . The Catenhusen Commission o f Enquiry

Also in 1 984, the Bundestag launched a Commission of Enquiry, on "Prospects and Risks of Gene Technology" ("Chancen und Risiken der Gentechnologie"; the official English translation renders the last word as "Genetic Engineering"). Its terms of refer­ ence were as follows: "I. The Commission is required to describe the prospects and risks of genetic engineering and concomitant new biotechnological re­ search in their main current applications, par­ ticularly in the fields of health, nutrition, raw materials, energy production and environ­ mental protection. Prime consideration should here be given to economic, ecological, legal and social effects and safety aspects. Particular attention shall be given to the border area of genetic engineering as applied to humans, including its ethical aspects. When preparing to make recommenda­ tions and laying the groundwork for political decisions the Commission shall be at particu­ lar pains:

Ethical Aspects and Human Genetics - The

1 . to investigate any possible conflict of

Benda Report

aims between the constitutionally gua­ ranteed freedom of research and other basic rights, 2. to elaborate criteria for limits on the use of new genetic engineering and cell

The nineteen-seventies debate interested primarily the scientific community .and indus­ try. Widespread public debate emerged only

5 Policv Evolution at National Level. in Different Continents, Countries and Cultures

biology methods on human cells and on humans as a whole . 3. to produce cri teria and recommenda­ tions for directives and safety standards in the industrial application of genetic engineering methods. 4. to promote measures for promoting ge­ netic engineering research in important fields of usc . " The 1 7-person Commission comprised 9 members of the Bundestag (in the propor­ tions 4 : 3 : 1 : 1 between the Christian Demo­ crats. Social Democrats, Liberals ( FDP), and Greens). and 8 experts. Elected as Chairman was WOLF-MI C H A E L CATEN H U SE N , Social Democrat. The Comm ission worked for over two years, and produced in January 1 987 a major. 400-page report ( D E UTSC H E R B U N D ESTAG. 1 987 ) . In view of the Bundestag's explicit aim to contribute a lso to the international and European debate on genetic engineering, and to promote corresponding harmonization , it was translated and published in English later that year. The Catenhusen Commission gave careful attention to the legal basis and constitutional­ ity of the existing safety guidelines which had been promulgated under the executive au­ thority (as a re!>earch funding agency) of the Research Ministry. The Commission 's conclu­ sion was that a n explicit legal basis from Par­ liament was essential . Their specific recom­ mendation - after considering the scope and applicability of various existing statutes - was that the existing Federal Law on Epidemics should be appropriately extended and re­ named, as the "Law on the Regulation of Biological Safety". The Commission also considered the con­ stitutionality of a general ban on genetic engi­ neering: but rejected this. remarking that "An obligation on the legislature to impose a gen­ eral prohibition on genetic engineering could only be held to apply if any use whatever of genetic engineering were to involve a sub­ stantial danger to the legal position of citizens protected by the Basic Law, so that it would clearly fall i n the socially harmful category. In the Commission's view. however, this is not the case " .

583

The Green participants in the Commission (initially E R I K A HICKEL, from March 1 985 H E I D E M A R J E D A N N ) did not agree the final report and recommendations, but sought to make political capital by publicizing their dis­ agreement. Contrary to the unanimously agreed rules of procedure for minority re­ ports. a lengthy document was submitted to the Commission on 17 December 1 986, one day before the final session, "and was pre­ sented to the public on the same date at a press conference as the comments of the Greens group on the Commission's report". (The quotation is from the Commission's own comments on the text submitted by Ms DANN). The Commission comments add, aft­ er reviewing other procedurally unacceptable aspects. that "Nevertheless the Commission has decided to include the submitted com­ ments in the Report, [seeing] no reason to af­ ford Mrs D A N N and her group any pretext for representing themselves as a persecuted mi­ nority." These matters might seem relatively trivial, but they foreshadowed and exemplify the contentious and polarized debate of the fol­ lowing years: in which the efforts and views of the Greens group were at least highly influen­ tial. whether or not they accurately repre­ sented popular sentiment. The G reens' com­ ment ended with a demand that the develop­ ment of research and technology be oriented to the needs of society, and a recommenda­ tion to the B undestag "to call upon the Fed­ eral Government: - to stop any application of genetic engineer­ ing. as this technology is not supported by a broad consensus of society; - to create opportunities for a broad discus­ sion on the ethical principles, aims, useful­ ness, the social and ecological tolerability of biomedical research and its practical ap­ plication , the participants to come from so­ ciety at large and not merely a small e lite of parliamentarians, representatives of indus­ try and scientists; - to set up for this purpose a wide-ranging system of commissions at local, regional and national levels with the following char­ acteristics, duties and authorities: - equal representation of men and women;

584

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

- at least 50% participation by people who have neither any involvement whatsoev­ er in the research, or in its industrial or any other use nor profit therefrom; - representation of relevant civil initia­ tives, organizations, consumer associa­ tions, environmental and women's groups, and the like; - monitoring of adherence to safety regula­ tions and ethical, social or ecological re­ strictions; e xami n i n g propos e d research plans and the right to have a saying the allocation of monies for research; - initiating research in neglected and so­ cially useful areas or matters; - the work of these commissions, and also of other relevant State organizations and a u t h o riti es in res ea rch and technology policy to be open and public." -

The agreed recommendations of the Com­ mission itself ran to some 50 pages, the princi­ pal recommendations and findings being the fo l l o wi n g : - The Safety Guidelines should apply to all genetic research establishments and pro­ duction plants, and they should register with a central body. Violations of the Safe­ ty Guidelines should be punished. - In general, the Com m i s s i on agreed with the existing Safety Guidelines and UVVs (see below). In some areas they should be fur­ ther developed, including more precise de­ scriptions of safety measures in laborato­ ries, pilot plants and production plants. An­ imal cell cultures and hybridomas should also be covered, an d a review of safety guidelines for retroviruses and oncogenes should be undertaken. - Biotechnology should be encouraged by the government and research institutions, in the usual range of application areas. In human genetics, genome analysis of em­ bryos, newborns and adults should be al­ lowed, subject to restrictions to prevent misuse of information by employers and in­ surance agencies. - Somatic gene therapy should be allowed, germ-line therapy should be forbidden.

- Genetically engineered viruses should be used only for vaccines. The potential risks of releasing such viruses as pesticides should be very carefully evaluated. - The release of GM Os should be banned for 5 years, whereupon the Parliament should assess whether to lift the ban. During this period, research should develop risk assess­ ment techniques. - Large-scale release of microorganisms might be allowed if they had not been ge­ netically altered, or if they had been altered using conventional techniques only, or had only a single gene deleted. Such release must be authorized by the Federal Ministry of Health and the ZKBS (Central Commis­ sion for Biological Safety). The release of organisms pathogenic for humans and farm animals should not be allowed. - The deliberate release of plants genetically engineered through biotechnology should be allowed, following risk evaluation, all re­ quests to be reviewed by the ZKBS. There should be evaluation of toxic effects, and of whether the plant's genes could transfer to other plants. Genetically altered animals might be released, providing that they could be "recovered". - There should be strict liability for any inju­ ries caused through activities requiring ap­ proval under the Safety Guidelines. From

Catenhusen Law, via Hessen

to the

Gene

Technology

The Catenhusen Commission's recommen­ dation for legally binding safety guidelines was initially opposed by science and industry. DECHEMA, for example, included among its many activities in biotechnology a Working Group on Safety, which had produced in 1982 a collection of the various sectoral regulations concerning pharmaceuticals, agrichemicals, food, feed and chemicals, which were relevant to biotechnology (DECHEMA, 1 982). FROM­ MER (1989), a leading member of the this Working Group on Safety (and on behalf of Germany, also of the OECD Group of Na­ tional Experts on Safety in Biotechnology) commented that "In most cases, the existing regulations provide an adequate framework

5 Polin· Evolmion

at

National Level, in Different Continents, Countries and Cultures

for ensuring the safety of products developed biote c hnology . The re are. however, some ongoing efforts to adapt the current reg­ ulatory eleme nts to biote c hnology without havi ng t o change the p r esent regulatory struc­ ture " . At the t ime when FROM M E R was writ­ ing this, there \\ as ongoing in Germany a ma­ jor debate about the need for legislation fol­ lowing the Catenhusen report, and in the pe­ riod lea d ing up to the debate and adoption of the 1990 Gene Law. FROM M E R c i ted also the worker safety rule s promulg a ted by the B erufsgenossen­ schaften (the I nsurance Association for Occu­ pati o nal Safety and Heal t h ) . which have sta­ tutory force, and are stringent . These rules ( "Unfallverhiitungsvorschriften'' - UVV) had been issued for work in areas/activities such as chemical laboratories and medical labora­ tories. A UVV for biotechnology was issued in 1 990. Other existing environmental protec­ tion laws could also potentially apply to bio­ t echnology e . g those relatin g to human pa­ thogens animal pathogen s plant pathogens, and harmful e m iss ions However. a general change in attitudes was trigge re d by problems with l icensing practice under the Federal Emission Protection Act and partly in response to the negative deci­ sion reached by the Administrative Supreme Court in Hessen r e lating to the commission­ ing of the Hoechst insuli n factory at Frankfurt (No v ember 1 989) . Agai n. the central issue was the lack of legal basis for genetic engi­ neeri n g and t h e Safety Guidelines. At the same period, the G reens movements were mounting an effective political campaign against ''Gene technology Moreover. the Europea n Co m mission s proposed Commu­ nity legi slation was published in May 1 988. and finally adopted in April 1 990. making it inevitable that some legislation must take place at national leve l, in Germany as else­ t hrough

.

-

..

,

.

.

.

".

'

where.

The l e g i slat i ve process in Germany was ini­ tiated in 1 989. a timing which thus enabled its progress and p r ovisions to be closely co-ordi­ nated with the progress of the Community Directives. In the European Parliament, both the Social Democrat rapporteur G E R H A R D SCHMI D . and the Greens biotech nology spokesman B E N E D I KT H A R L I N , we re clearly '

585

a pplying in the European context ideas simi­ larly in vogue in their national debate in Ger­ many - e.g. , the Catenhusen Commission pro­ posal for a five-year moratorium on field re­ lease, against which the scientific community had so strongly lobbied in May 1 989 and Fe­ bruary 1 990 - see Sect. 4.7. A series of pa rlia­ mentary hearings took place in the B undestag in 1 989, and the Gene Technology Law ( G entechnikgeset z " ) was adopted on 1 1 May 1 990. TAB . the Technology Assessment Un i t of the Bundestag merits mention as an illustra­ tion of the efforts of the B undestag to inform i tself effectively on complex matters, in a role similar to that fulfilled by the US Congres­ sional Office of Technology Assessment ( OTA) In May 1 990, the same month as the new Gene Law was adopted, the Parliamenta­ ry Committee for Research, Technology and Technology A ssessment asked the TAB to conduct a study on "Biological Safety in the Use of Genetic Engineering . This was to ad­ dress uncertainties which had been high­ lighted in the Catenhusen del i berations The new law also had provisions refe rring to the "current state of science and technology thus demanding consideration of the question whether new knowledge with relevance for biological safety had emerged since the Com­ mission's considerations some four years pre­ viously. However, there was a change in the climate of Bundestag debate after the December 1 990 elections (when the Greens, falling b elow the 5% threshold, were no longer represe n ted ) ; with the growing availability of international experience on the basic safety issues, by the time TAB gave an interim report in March 1 992, their work was criticized as peri pheral within the context of international discussion and too narrow in focus. By early 1 992, com­ plaints about the Gene Law were of more in­ terest to the p oliticians (see G LO E D E , 1 992) . The 1 990 Gene Law imposed heavy costs and restrictions on academic and industrial biotechnology, in both research and commer­ cialization. From early 1 989, major G erman companies, contrary to their traditionally "strong, silent" style, began to express their critic i sms publicly and vociferously . Hoechst was a founder member of the the Senior Ad"

,

.

''

.

'',

586

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

visory Group for Biotechnology (SAGB), in 1 989 (see Sect. 7 . 1 ) . Similar criticisms were being expressed no less publicly by academic leaders from the Max Planck Institute, and the Basic Research Institute (DFG). A public hearing was organized in Februa­ ry 1992, under the auspices of the Parliamen­ tary Committee for Research, Technology and Technology Assessment, at which a wide range of individuals and representative asso­ ciations expressed their grievances. The Asso­ ciation of German Chambers of Industry and Commerce (DIHT) was especially outspoken in its criticisms, emphasizing that research and production were being driven out of Ger­ many, and small firms inhibited from starting up. The Chemical Industry Association (VCI) submitted a joint statement with the Federal Pharmaceutical Industry Association (BPI), pointing out that the Gene Law had meant a more than fivefold increase in the cost to companies of preparing applications and ob­ taining approval, without in any way raising safety standards in genetic engineering. The hearing was informed by eminent academic professors that level 1 or "no risk" experi­ ments constituted over 80% of all biotechno­ logy experiments, and similar figures were given for industry's use of low-risk organisms. Formal authorization had to be obtained, even for level 1 work; and the volume of doc­ umentation required differed little between level 1 and level 4 experiments. The BGA and ZKBS supported the simpli­ fication of procedure, the BGA representa­ tive pointing out that the immense workload created by the authorization procedures for level one projects would have adverse effects on the quality of the assessment of projects falling within higher safety levels. Restrictive provisions on the movement of genetically engineered organisms would gravely impede German participation in international colla­ borative research. Public hearings on deliberate release were another contentious matter. These had on oc­ casion degenerated into media circuses, giv­ ing protest groups ample opportunity to hin­ der the approval process. In Spring 1 994, for example, some 20 campaigners turned up at a hearing in the northern town of Einbeck,

dressed as giant sugar-beets; and occupied test sites to protest against the planned re­ lease of recombinant plants. The protesters were greatly outnumbered by journalists, gua­ ranteeing extensive media coverage. In more sinister vein, it had been found necessary to provide a 24-hour police guard for the Director and his family of a Max Planck Institute research station conducting the first field release trials in Germany, in 1 990. That such direct action and the regula­ tory framework had an inhibiting effect was evident when in 1 993 the OECD published an analysis of worldwide field releases (OECD , 1 993d): of a world (OECD) total of 878 ex­ perimental release authorizations by end of 1992, Germany accounted for only 2 - against totals of 62 for Belgium, 77 for France, 45 for the UK, and 330 for the USA. A further three were authorized in 1993. Vandalism against trial plots continued; for example, in Summer 1 994, AgrEvo, an agrochemicals joint venture between Hoechst and Schering, suffered the destruction of an outdoor test of genetically modified plants, the reported value of the damage being over OM 10 million. Large bio-industrial companies expanding their R & D and their pilot plants in countries with less restrictive regulatory measures, small and medium sized enterprises and aca­ demic research institutes unable to afford the burden: the message was not lost on the Par­ liamentarians, at a time of soaring unemploy­ ment. The absence of the Greens from the Bundestag, since the December 1 990 Bundes­ tag election, may have reduced certain pres­ sures on the two large parties. The Christian Democrats proposed a revised Gene Law in May 1992. Although agreeing with the major­ ity of revisions, the Social Democratic Party (SOP) threatened to block the measure in the lower house (Bundesrat), over amendments relating to the elimination of public hearings at field releases, and shortening of the re­ quired period for authorizations; but the would-be-blocking group within the SPD was over-ruled, compromises were finally agreed, and the changes to the Gene Law were finally enacted at the beginning of January 1 994. As a reaction to the general discussion of the Gene Law and its enforcement, the Bun­ destag Research Committee enlarged the

5 Policy El'olmion at National Le�·e/, in Different Continents, Countries and Cultures

terms of r efe r e n c e of the TAB study ( see above) , a sking for a comparative i n ternation­ al review of re g u lations in other countries (in parti c ular the U SA and Japan ) . and experi ­ ence with its pract ical enforcement: request­ i ng delive ry of the r ep o rt in mid- 1 993. Since the change of pos i tion in Germany which could be defended as a natural evolu­ tion i n response to accum ulating experience. national and international - the Ge rma n gov­ ernmen t has in the context of the E uropean U nion been a strong advocate of a more posi ­ tive and less restrictive stance vis - a -vis bio­ te chn o logy . in cl uding both simplification and review of the existing Contained Use and De­ liberate Release Directives ( see Sect. 7.4) . Not e n ti rel y hy chance . the senior German Commissioner. Vice - Preside n t M A RT I N B A N ­ O E M A N N . an F O P politician o f liberal eco­ nomic views, was re s ponsible for industrial policy and Directorate-Ge neral I I I . both in the 1 989-92 and 1 993-94 Commissions . He was thus we l l- p l a c ed to promote a renewed thrust for bio t e c hnol og y from the Commis­ sion. as was s u cce s sive l y e xemplified by the Apri l 1 99 1 com m u n i cation ( see Sect . 7.2). the White Paper o f D e c e m ber 1 993 on " Growt h . Competit i veness and E mp l oymen t ' ' . and the follow-up com munication on biotechnology at the Corfu E uropean Council (see Sect. 7.4). Fu rther action on the EU regu l atory framework for b i otechnology was therefore a natural e xpectation during the German Council Pr esid e n cy . J uly-December 1 994; and the outcome of the election on 16 October 1 994. a l though bringing the Greens back into the B undestag . docs not seem likely to per­ turb the now broadly-based c on s e n sus behind the ''de-regulatory" thrust.

587

TEUR. the founder of modern microbiology. The 1 995 centennial of h i s deat h provided an occasion for ostentatious celebration of the nationa l tradition in this discipline . French scientists from Pasteur I nstitute and othe r laboratories were to be found in the fron t ranks of mo l ecular biology in the 1 970s. and were fully au fait with the c h a l lenges and concerns voiced at the Asilomar confer­ ences. I n M arch 1 975. a month after the Asilomar conference and in pa r a l lel with t he deve l op ­ ment of the N I H RAC and its guidelines, the DG RST (Deh!gation Generate a Ia Re­ cherche Scientifique et Technique) estab­ lished a " Commission N at i onale de C l asse­ ment des Recombinaison s G e n e tiq u es in vi­ tro " . charged with formulat i ng safety rules to be applied to each case of genetic recombina­ tion which it received. At the same period, there was w i despread interest in the ethical is­ s ues arising . an interest pa r ticular l y stro n g in France . lbe Royer Report, "La Securite des Applications Industrielles des Biotechnologies": One Element of a Strategic Approach to Biotechnology

In 1 980, at t h e request of the Ministry of Ind u stry . PIERRE RoYER of the DG RST pre­ pared a report on the safety of industrial ap­ pli c at i on s of bio t echnology (ROYER, 1 981 ) ; including a review o f the regulati o ns existing at that period . B efore s u mma ri z ing these, it is illuminating to set the specifics of regulation i n the context of a broader s trategi c view; for throughout the period we are discu ssing. French public policy vis-a-vis biotechnology has been characterized by a consistency and determination i n d e pendent of indi v idua l s , 5 .4 France: The Two Ministries and administrations. Commissions, G allic Pragmatism In agricultural policy or in GATT negotia­ tions. it is evident that there are tensions be­ France has many reasons to be a maj or tween the h i storicall y dirigiste traditions of pla yer in biotechnology: as the m aj or agricul ­ French government (a brief obeisance to N A ­ tural producer in Europe . n umber 2 to the US POLE O N , COL B E RT, and ''managed t rade " is in terms of w o r l d exports of agro - food prod ­ customary) . and the " A nglo - Sa x on " , liberal ucts; and as a country with a proud scientific model of an open world trade system, and t rad i t io n going hack to L A VO I S I E R (for chem­ non - interventionist government. As France. istry ) , but above all foc used o n LOU I S PAS- host of the OECD and signatory of the

588

18

The Regulation of Modern Biotechnology:

GAIT agreement, progressively privatizes great state-owned companies, promising the European Commission that the next subven­ tion to support restructuring of another of its major nationalized industries (Air France, Bull, Credit Lyonnais, . . . ) is positively the last, it is evident that the differences may be more of style than of substance. Nonetheless, in spite of the common and international con­ straints which tend increasingly to unify the policies pursued by all governments of the "Western" world (the adjective itself is an anachronism), France retains much more strongly than, say, the UK, an assumption of the responsibility of the state to identify stra­ tegic trends and to develop appropriate pub­ lic policy responses to the challenges thus identified. This emphasis on long-term forecasting, analysis and formulation of strategy - remin­ iscent of Japan's MITI or Science and Tech­ nology Agency, and perhaps returning to fashion in the UK with the "Foresight" exer­ cizes of the Office of Science and Technology - was strong in France in the 1970s. The Nora-Mine report on "L'Informatisation de Ia Societe" ( 1 978) was a government-commis­ sioned report, and paperback best-seller. Faced with the dramatic developments in the life sciences, it was therefore wholly unsur­ prising that the French government commis­ sioned from three "eminences grises" of the life sciences the report which appeared in 1979, "Les Sciences de Ia Vie et Ia Societe". This report, by F R A N�O I S GRos, FRAN�OIS J A CO B and P I E RR E ROYER, became the foundation stone for the elaboration of suc­ cessive policy commitments by French gov­ ernments to ensure that France corrected its current weaknesses, and did whatever was necessary to ensure that she became a major player in biotechnology on the world scene. The Gros, Jacob and Royer report was general, strategic and inspirational; it there­ fore had to be accompanied, followed and complemented by more detailed, practical and operational works, such as the inventory of industrial activities and capabilities assem­ bled by J O E L DE ROSNAY (1980), the Pelisso­ lo report (1981 ) , and the report by RoYER al­ ready cited. The Prime Minister ( RAYMOND BARRE ) charged JEAN-CLAUDE PELISSOLO

A

Historical and European Perspective

with preparing proposals to ensure, without calling into question the competences of the various Ministries concerned, the coherence of the different programmes, and to bring about the conditions enabling France to occu­ py its proper place in the field of life science applications, particularly biotechnology. It was in a similar perspective that the Minister for Industry, A N D R E GIRAUD, charged PI E R R E R oY E R with the leadership of a study group on the safety of the industrial applica­ tions of biotechnology. The mission was to: "enumerate, if there are any, the acci­ dents or incidents which have occurred in the past through the industrial use of microorganisms; and try to extrapolate to the future the results of this enumer­ ation, with an appreciation of the de­ gree to which novel risks may appear. In the light of this analysis, the group should finally reflect upon the safety measures which may be required in the industrial sector." The Royer report (in a chapter prepared by CHARLES MERIEUX ) reviewed the exist­ ing "bio-industry" sectors, noting that beyond general risks of industrial accidents, there were few specific to these sectors, whose rela­ tively "ordinary" conditions of temperature and pressure rendered their general risks less than those in sectors using physical and chem­ ical means of transformation. The report did not address risks in hospitals, pathology labo­ ratories or animal rearing establishments, in which it acknowledged that greater risks would be found. The following chapter (by J E A N - P I E RR E ZALTA ) reviewed the potential dangers of the new biotechnologies, including recombinant DNA, discussing in detail the concept of ''po­ tential" danger, whose significance was in in­ verse relation to the progress of knowledge. Such potential dangers should therefore be continually re-assessed. An objectively iden­ tified danger could be addressed depending on its nature, e.g., by experimental protocols for the confinement of pathogenic bacteria; the nature of a potential danger similarly al­ lowed one to conceive without difficulty the means for handling it.

5 Polin· Et·olwion at National Level, in Differenr Conrinenrs. Countries and Cultures

Further chapte rs reviewed existing regu la­ tions. in France and abr oad ; methods of avoiding accidents in biotechnology : and pub­ lic opinion aspects. The report summed up its conclusions in five area s : Regarding exis t i ng dange r s . of infection and a l lergi c react ion. t he vast maj orit y we re of agricul t ural or hospital origi n ; for th e r e m a i nd e r . t he occa si onal cases of i n ­ fection had led to the development of re­ fined s a fet y �ys t e m s i n certai n French in­ dustrial com p a n ies. and were often requi­ rements for i nternational trade. The pro­ posal was to c o n sider the generalization of th e applica t i o n of best industrial safety pract i c e . 2. Rega rding t h e potential dangers of bio­ technology. there would be con ti nui n g rap­ id evolution of t he state of knowledge . The proposal was therefore that safety rules should not he t oo fixed; there should be in o pera t i o n a con tinuing system for the revi­ sion of the r ul e s . at both national and in­ ternational levels. to ensure that they cor­ respond to t h e c u rr e nt state of knowl­ edge. 3. Rega r ding e x i s t i n g regulations. many al­ ready appl ied to the b i o-industries. For new activities arisi n g from molecular and cellular biology. existing leg i sl a tion for worker. environmen t al protection and product authorization largely provided the necessary means. The proposal empha­ sized the need to launch fuller studies, re­ viewing the e volu t ion of legislation in oth­ e r countrie s and at Co m munity leveL and to maintain ind ustrial confid en t iali ty . spee­ dy proced ure , and the poss ibi l i ty for slack­ e ning confinement rules if t he progress of knowledge j ustifi e d it. 4 . O n me as ures for the prevention of acci­ dents. the instruments wer e technical measures, methods of organization . train­ i ng and information. for workers. the pub­ lic. and use rs. Various proposals could be made. on risk measurement. surveillance measu res as nece s sar y . the acceptance of reference data in the form of st a ndards. and codes of good pra ctice or of profes­ sional standards. I.

589

5 . Regarding public perception in a field little understood but which touched the sources of life . concern could lead to opposi t ion to industrial scale work - the st u dy group had conducted an opinion survey - and their proposals related to four poi n ts : • create a climate of awareness: • increase the press services of scientific organizations: • es t ab l ish press agencies devoted to the problems of scienti fi c research and tech­ nological innovation • update the teaching of biology in schools and colleges. The final conclusion of the study group was that faced with the rapid changes, and the need to avoid a r i gid regu l at i o n , i ts h ope was that their work should serve as a poi nt of de­ parture for a co n tinuing assessment of the k nowledge . dangers. regulations and tec h ­ niques for preventing these, training, and public information on these problems. S u ch a Study Commission on Safety in B iotechnolo­ gy would certainly be of value to sc i ence, in­ dustry and the French public. The Committee on Genetic Engineerin g

The philosophy of the Roy e r report re­ mained that of the French authorities during the followi ng years. The work of the DG RST Commission was maintained, subsequently under the a u thorit y of the M i n i stry of Re­ search. and under the chairmanship of Profe s­ sor Z A LT A . By an inter-ministerial decree, No 89-306 . its role was enlarged and re i n­ forced . and it was renamed the " Commission du Genie G e n e tique" . the Commi t tee on Ge­ netic Engineering. This bod y has sole compe­ tence to draw up a scientific classification of exis t ing or new o rgan i sms in all biotechnolog­ ical applications, on the basis of the real or po ten t i a l h az ards they present. Up to 1 989 . the system in operation was in effect one of self-control by the sc i e nti fic community for rONA research. The Co m m i t ­ tee comprised entirely scientist s . The research i nstitutions signed an agreement o f standard form with the DG RST. and undertook to es­ tablish a local oversight body ( "i n s t an c e lo­ cale de s u rveillance " ) , including represen ta-

590

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The Regulation of Modern Biotechnology: A Historical and European Perspective

tives of the personnel, responsible for ensur­ ing respect of the conditions imposed by the Committee for the conduct of experiments. The applicant for a project would propose the level of risk classification, and complete a questionnaire, on the basis of which the Com­ mittee assesses the adequacy of the training of the researcher, the existence of the local oversight body, and decides upon the confine­ ment category required. A standard letter of notification is then transmitted to the appli­ cant, the Director of the laboratory, and the local oversight body.

The Committee has a significant role in en­ couraging technical progress, with strict re­ spect for consumer and public safety, and protection of the environment. It can request research and study as necessary for the evalu­ ation of the potential risk from new tech­ niques, and has on several occasions empha­ sized to the relevant Ministries the impor­ tance of national and Community pro­ grammes in this respect.

The Biomolecular Engineering Committee ("Commission do Genie Biomoleculaire")

Following the adoption in April 1 990 of the European Community Directives, legislation was prepared which resulted in the adoption, on 13 July 1 992, of Law No 92-654 concerning the control of the use and dissemination of genetically modified organisms, and modify­ ing Law No 76-663 of 1 9 July 1 976 concerning establishments classified for the protection of the environment. This law covered confined use, field release, and placing on the market of genetically modified products. For confined use, in research or at indus­ trial scale, the Genetic Engineering Commit­ tee remains the authority responsible for clas­ sification of genetically modified organisms, and for prescribing the conditions for their production and use. For evaluating the risks associated with field release, the Biomolecular Engineering Committee was replaced, or renamed, as the Committee for the Study of the Dissemina­ tion of Products resulting from Genetic Engi­ neering; including also the risk assessment for placing on the market of products composed wholly or in part of genetically modified or­ ganisms. Further details relating to the practical im­ plementation of the new law were fixed by decrees of the Council of State; for example, that of 23 February 1993, Decree 93-325, fixed the composition of the new or renewed " Biomolecular Engineering Committee" , now placed under the twi n authorities of the Min­ istry of Agriculture and Forestry, and the Ministry of the Environment. Its composition was expanded to eighteen members,including (among other new members) a representative of an environmental protection association , a

As the prospect of field release developed, the Ministry of Agriculture and Forestry created on 4 November 1986 the Biomolecu­ lar Engineering Committee. In the agricultur­ al and agro-food sectors, the Committee is charged with the formulation of an "opinion on the risks associated with the use of prod­ ucts resulting from biomolecular engineering, in particular the risks of dissemination of liv­ ing organisms resulting from these tech­ niques". For each dossier examined, the Committee formulates recommendations on the precautions to be taken, and the condi­ tions of use considered necessary. It pro­ nounces on the usage of the modified organ­ isms, and not on the host-vector systems, whose classification belongs to the Commit­ tee on Genetic Engineering (see above). The Committee's opinion is sought by re­ searchers and practitioners of the sector, whether from public or industrial organiza­ tions. The submissions may occur at any stage from research and development, through pro­ duction , to placing on the market of a prod­ uct. It can even advise on the design of a re­ search programme. Currently (and since its inception ) chaired by Professor AXEL KAHN of INSERM (l'ln­ stitut National pour l'Enseignement et Ia Re­ cherche Medicale ), the Committee originally comprised fifteen members drawn from agronomic, medical or veterinary research, medicine, industry, and law, and representa­ tives of consumers and professional and trade union organizations.

Implementation of the Community Directives 90/219 and 90/220

5 Policy Evolution at

National

Level. in

Different

consumer representative . and a Deputy from the OPCST (Office Parlementaire des Choix Scientifiques et Techniques). The role of the Committee was enlarged to include human vaccines. and gene therapy. (The new membership includes several medi­ cal specialists. and a representative of the Ministry of Health). The first gene therapy proposals were received (and approved) in 1 993. France was an active participant in the OECD Group of National Experts on Safety in Biotechnology, particularly in the work on "Good Industrial Large Scale Practice " as de­ fined in the 1 986 Blue Book. France also took the initiative to host in April 1 992 an O ECD seminar in Jouy-en-Josas (near Paris), at which the scie ntific advisers to the field re­ lease authorities in various countries were in­ vited to exchange views on how they handled dossiers relating to three of the most com­ monly transformed crops: potato, oilseed rape, and maize ( O ECD. 1 993a). Areas of disagreement and consensus were identified. At this workshop, the degree of molecular characte rization necessary for assessing safety in field tests of transformed plants was a ma­ jor subject of discussion . Although all coun­ tries require molecular analysis of transfor­ mants, two fundamentally different points of view were expressed. The French authorities prefer extensive characterization of transfor­ mants before the first field trials, including determination of the limits of the DNA being transferred, whereas representatives of other countries appeared more willing to allow small-scale tests for establishing gene efficacy with transformants that are less well charac­ terized, or that contain genes of unknown function. The success of the French regulatory sys­ tem for field releases may be judged, first of all by the absence of any reported adverse ef­ fects; and by the fact that by the end of 1 992, 77 authorizations had been granted - the largest figure for any European country (OECD, 1 993b ). Moreover, the French au­ thorities were the first to propose, in J anuary 1 993 , at the "Article 2 1 " Committee for the field release Directive 90/220, the institution of simplified procedures at national and Com­ munity levels. for experimental release appli-

Continents. Coun tries

and

Cultures

591

cations which fulfilled the following condi­ tions: 1.

2.

"plants whose interaction with the envi­ ronment has been studied during a number of field trials with transgenic plants follow­ ing an authorisation from the Competent Authorities. Tobacco , sugar beet and rape seed could fall in this category. precisely described inserted sequences (constructs) whose behaviour in the trans­ genic plant species has already been stud­ ied. For example: herbicide resistance (genes) in constructions transferred with the Agrobacterium tumefaciens system, which ( inserted sequences) contain only known marker genes, e.g., kanamycin or hygromycin resistance gene, or the herbi­ cide resistance gene itself. "

The acceptance of this proposal was an im­ portant step forward, in maintaining some convergence between European and US prac­ tice - it will be recalled (see Sect. 5 . 1 ) that the US was at precisely the same period (Novem­ ber 1 992 through spring 1 993) proposing and approving a substantial lightening of over­ sight for six of the main US crop plants. Role of Standards and AFNOR, and of Organibio

France attaches more than average impor­ tance to the role of industrial standards, the national body being AFNOR ( Association Fran�aise pour Ia Normalisation) . It was also France which earliest and most effectively created a multi-sectoral representative body, " Organibio" (Organisation Nationale Inter­ professionnelle des B io-industries) to repre­ sent the spectrum of economic actors inter­ ested in biotechnology. Organibio provided and continues to provide an effective focal point for biotechnology interests, and has oft­ en interacted with the four government Min­ istries most involved in biotechnology: Indus­ try; Research and Higher Education; Agricul­ ture; and Environment. In 1 985, the Chairman of the Inter-M inis­ terial Group for Chemical Products (GIPC) a body reporting to the Prime Minister, and ,

592

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

the Commissioner for Standards at the Minis­ try of Industry, gave a joint task to AFNOR and Organibio. They were charged with studying the conditions for the establishment of coherent provisions for ensuring safety in biotechnology, but sufficiently flexible to al­ low for progressive adaptation to scientific and technological progress and taking into ac­ count the "potential risk" as defined in the 1 981 Royer report (CADAS, 1 993) . AFNOR has developed a standards pro­ gramme proposed by Organibio with the sup­ port of the many other parties, public and pri­ vate, involved in the vast field addressed by the totality of the biotechnologies. These cov­ er sound research and production practices. Reference has been made to the role of AF­ NOR as secretariat of the CEN Technical Committee 233 on biotechnology - see Sect. 7.2; a role in which the French national work on biotechnology standards could immediate­ ly make an appreciated contribution to the advance of the work at the European level. 5 . 5 Japan: The Attentive Spectator Strong Background in Fermentation

Japan has a long tradition of fermented foods and drinks. With the modernization that started in the late 1 9th century, the rapid industrial and technological developments were accompanied also by basic scientific de­ velopment. Among the areas of success were the identification of key enzymes and organic acids, and an enhanced understanding of the traditional fermentation organisms and pro­ cesses. During the 1 920s, the dependence of the growing chemical industry upon imported oil was recognized as a strategic weakness. SA­ KAGUCHI ( 1 972) summarized the period as follows, in his opening address to the 4th In­ ternational Fermentation Symposium, 1 972, which for the first time was held in Japan, at Kyoto: "The most serious problem in Japan before World War II was how to supp­ ly aviation fuel, synthetic rubber and synthetic resins with inadequate petro-

leum resources. It was decided as a matter of fundamental national policy that plant resources which were derived from solar energy be converted into ba­ sic raw materials for the synthetic chemical industry through biochemical means. Plans included ethanol, butanol, acetone, isobutanol and 2,3-butanediol. This policy was a major factor stimulat­ ing studies of the Japanese fermenta­ tion industry to change from a food-in­ dustry to a non-food industry. It also resulted in mechanization and an in­ crease in the scale of the fermentation industry, and a great stimulus to re­ search, which led to the studies on fer­ mentation engineering by Terui and Aiba after the war." After the Second World War, there was thus already a strong industrial and scientific base to assimilate the developments in fer­ mentation production of antibiotics - by 1 948, some 70 companies were engaged in penicillin production. A similar phenomenon took place four decades later, with the widespread development of capability to manufacture in­ terferon by rONA: although few companies would ultimately develop profitable sales from these specific molecules (penicillin, in­ terferon), there was a widespread consensus in recognizing the importance of the field, and these chosen target molecules repre­ sented a sort of standard entry test and dem­ onstration of capability. Again, both cases re­ cognized the essential need to import knowl­ edge, to develop international scientific links, and to build industrial collaborations, initially in R & D. In the field of molecular biology, a similar emphasis on international links is highlighted in a historical paper by HISAO UcHIDA ( 1 993), for many years Japan's ac­ tive leader in OECD biotechnology. The Regulatory Context: Caution, Commitment, and the International Dimension

The title, "attentive spectator", would be unfair as a summary of Japan's strengths in biotechnology, when one considers its

5

Polin• Evolution

m

National Level. in

Different Continems.

strength in fermentation. For example . the new fermentation technology for the produc­ tion of amino acids was established in Japan ( by Kyowa Hakko ) . and ope ned a new era in the J apanese fermentation industry. Aji no­ moto has long been world leader . e .g. in glu­ tamic acid and lysine production. And the pioneering (by Dianippon I n k etc. ) of a hy­ drocarbon-base d single-cell protein (SCP) process preceded and provided the technolo­ gy for the subseq uent European develop­ ments. However, in the context of regulation of biotechnology. Japan has proceeded cautious­ ly. and with close attention to international developments - particularly at the OECD. This caution re flects a strong sensitivity to public opinion. which cannot be . and is not. taken for granted. Simplistic Western descrip­ tions of J apan a s a "consensus" society do not sufficiently distinguish between habits. prac­ tices and policies aimed at achieving consen­ sus - sometimes through lengthy arguments stretching over years. and with the search for consensus more evident than its achievement - and the reality of the usual differences in interests and opin ions between different sec­ tors of society. and between different Minis­ tries and agencies of government . The " Minamata" poisoni ngs of the 1 960s ( caused by the discharge of mercury-contain­ ing industrial wastes. which accumulated in the food chain and hence poisoned fishermen and other consumers of fish ) . severely shook public trust in industry and in the authorities. and emphasi ze d to the Ministries their re­ sponsibilities a s defenders of the public inter­ est and public safe t y . This climate of re s pon s i ble caution is illus­ trated by the story of the development of n­ paraffin-based SCP for human consumption. Dossiers submitted to the Ministry of Agri­ culture, Fisheries and Food by the companies concerned - Dianippon . Kaneka, Kyowa Hakko - gave satisfactory evidence of safety . and the in itial decision was favorable. B ut fol­ lowing protests from the Consumers· Union. a political decision was made to impose (in 1 973 ) a 5-year moratorium. Ajinomoto aban­ doned the com mercialization of a monosodi­ um glutamate made from the same sub s t ra t e

­

.

Countries and Cultures

593

The Mitsui Petrochemicals production of shikonin by fermentation culture of plant cells. and the marketing of a "Bio-Iipstick" based on this. is sometimes cited as an illus­ tration of the readiness of the Japanese con­ sumer to accept new technology. (Shikonin, a red coloring substance with supposed benefi­ cial properties. extracted from the dried roots of a plant. has long been used in cosmetics.) But there was considerable concern in Tsuku­ ba . the "Science City'' . about the construction of a high security ("'P4") containment facility for RIKEN, t he Institute for Physical and Chemical Research of STA . the Science and Technology Agency. The decision of the pub­ lic authorities was challenged by local citizens (albeit unsuccessfully) in the courts. In prac­ tice . although construction of the facility was completed, it is rarely used. There is also some doubt among industrialists as to wheth­ er "bio" still has positive connotations for the consumer. I n recent years . the fragmentation and change in political parties and the impact of global economic developments (trade, reces­ sion. arguments about protectionism and the ope ning up of agricultural markets) have shaken long-standing relationships and as­ sumptions wi thin Japanese society, and rein­ forced the recognition of the need for (bio-) technological innovation to proceed with cau­ tion. At the same time, the leaders of Japa­ nese society, in government, industry and academia, recognized clearly from an early stage the significance of biotechnology for their economy and society. In an inte nsively developed industrial society, short of indige­ nous natural resources, the pursuit of contin­ ued economic growth and the constraints of space, environment and quality of life, all point to the need for economic development to be increasingly based upon information and knowledge . Thus both the traditional strength in fer­ mentation, and the clear perception of long­ term economic interest and necessity, have led Japan to a very clear-cut identification of biotechnology as a key area of technology for future development. The public authorities are therefore deeply committed to a policy context which will encourage its develop­ ment; but at the same time they recognize the

594

18 The Regulation of Modern Biotechnology:

strategic necessity of achieving a broadly­ based consensus throughout the society. A comprehensive picture of public policy on biotechnology would therefore emphasize: - the major life science developments which figure significantly in the regular ( quin­ quennial) 30-year forecasts produced by the Science and Technology Agency (STA); - the significant and long-term priority ac­ corded to various areas of biotechnology in publicly-funded R & D, in collaboration with industry, and with the promotion of industrial collaborative research group­ ings; - the commitment by the public authorities to safety and responsible regulation, on lines consistent with international stand­ ards (in particular, as defined by the OECD); - the energetic efforts devoted to public in­ formation, through networks of teachers to reach schools i n every prefecture, through an annual highly-publicized STA seminar (with strong television coverage), through publications, and through the exhibitions organized by the Japan B ioindustry Asso­ ciation, in Tokyo and Osaka in alternate years. In the context of this paper, the remainder of this section summarizes the regulatory de­ velopments, which should be seen as parts of the broader national pattern and policy com­ mitment emphasized above.

A

Historical and European Perspective

compliance would create, constitute an effec­ tive constraint. The administrative guidelines can be, and are, regularly adapted and updated to take account of accumulated experience and scien­ tific progress, within Japan and worldwide. The process of adaptation involves extensive consultation and discussion; and the consulta­ tion is particularly attentive to international developments - at the OECD, in the US, and in the European Union. The various guidelines administered under the different Ministries are briefly presented below. In summary, one could say that Japan has followed more closely the American reasoning and practice, in that the guidelines can be regularly adapted, j ust as the US agen­ cies can make and modify their regulations; but with the difference that the process in the US is conducted on a defined statutory ba­ sis. Intellectually, the Japanese leadership ac­ cepts and emphasizes the point, expressed in both OECD and US statements, that there is no scientific basis for discriminating against rDNA products. In practice, and bearing in mind what has been said about attentiveness to public perceptions, the guidelines have specifically addressed rDNA activities and products; and the progress to field release ex­ periments has been relatively slow. Only five releases of recombinant plants or microor­ ganisms had occurred by the end of 1993 - a figure similar to Germany; and contrasting with the several hundred (research) releases by then authorized in Belgium, Canada, France, the UK and the US.

Regulatory Philosophy: Administrative Guidelines

The Agencies and Their Administrative Guidelines

The regulation of biotechnology in Japan has been achieved, and is maintained, through administrative guidelines. These are in principle voluntary, and in practice, fol­ lowed. Although no laws define sanctions for non-compliance, the issue has not arisen; and the consequences of non-compliance in terms of public opprobrium, and the breach of rela­ tionships with government and other compa­ nies or laboratories which deliberate non-

Following Asilomar, the initial regulatory debates concerned only rDNA research - in both academic and industrial laboratories, and public research institutes. Two guidelines were created, essentially similar in content, concepts and definitions: that relating to uni­ versity laboratories is administered by the Ministry of Education; that for all other labo­ ratories, by the Science and Technology Agency.

5

Policv

Evolution at National Level, in Different Continents, Countries and Cultures

rDNA Experiments

The guidelines define basic conditions to he observed by researchers and research managers. to ensure the safety of rONA ex­ periments. They incl ude definitions. safety standards for containment. and organization­ al matters. The guidelines categorize rONA experiments into three classes: •

•

•

institution-notified (requiring prior notifi­ cation to the Director of the institution) ; institution-aut horized (requiring the prior approval of the Director of the institu­ tion); non-standard experiment (requiring con­ duct under governmental guidance ) follow­ ing approval of the experimental plan by the Director of the i nstitution.

For non-standard experiments, prior to starting the experiment . the "planning sheet" is referred to t he government, for review by the national Committee for Recombinant DNA Technology. under the Council for Science and Technology. Containment requirements are specified in terms of: •

•

physical con tainment - below 20 liters ( P I , P2, P3 . P4) - above 20 liters ( LS-C. LS- 1 . LS-2) biological containment - B l level (defined in terms of E. coli K I 2, Saccharomyces cerevisiae. Bacillus subtil­ is, and conditions on the introduced plas­ mid or phage ) - 82 level.

Further details are tabulated in KATA Y A ­ ( 1 993). Some 3000 "standard" experi­ ments took place in STA 's institutes in 1 99 1 : non-standard, 282. The inclusion of statistics for universities (from the Ministry of Educa­ tion) would bring the total number of experi­ ments to some 50 000 . The ST A G uidelines give extensive details on experime ntal systems. laboratory design. and laboratory practices. There have been si nce 1979 at least nine modifications. all in the direction of lightening and simplification. MA

595

The Ministry of Agriculture, Fisheries and Food (MAFF)

M AFF is the administrative guidance au­ thority for the application of rDNA organ­ isms in agriculture , forestry, fisheries, the food and related industries. MAFF has three GMO advisory committees, corresponding to microorganisms. plants and animals. Plants are seen as potentially eliciting strong public reactions, but the procedure is established, full information is made publicly available, and by mid-1 994 four plant releases had taken place . and eleven more were at greenhouse stage - mainly focusing on rice and tomato. MAFF established in 1 989 its "Guidelines for the Application of Recombinant DNA Organisms in Agriculture, Forestry, Fisheries, the Food Industry and Other Related Indus­ tries", with the aim of promoting the safe pro­ gress of agro-industries. The principles of the Guidelines are: ( 1 ) safety assessment of rONA plants on the basis of greenhouse experiments and lim­ ited small-scale field trials, conducted in a step-by-step procedure, and aiming at preparation for wider use under appro­ priate cultural practices, without specific confinement requirements; (2) for rONA microorganisms, appropriate confinement conditions ( GILSP, category 1 ,2,3 ) ; for GMMs to be released in the en­ vironment, further studies are needed; (3) for rONA small laboratory animals, ap­ propriate containment conditions have to be applied, enabling them to be put into commercial use . (Transgenic mice, such as " onco-mice" . h ave been approved since 1 992. ) These details are from HASEBE ( 1 993 ) . The Ministry o f Health and Welfare (MHW)

M HW, conscious of Japan becoming the country with the longest life expectancy in the world , has defined as a national objective to build "an animated society of longevity". I n this context, the importance of advanced tech-

596

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

nologies including biotechnology is recognized for pharmaceuticals and medical devices. The private sector has created in April 1 986 the "Japan Health Sciences Foundation" (JHSF) , a non-profit organization for the de­ velopment of high technology including bio­ technology; the contributing companies in­ cluding pharmaceuticals, chemicals, foods, fi­ ber and other areas. The Ministry itself, also in 1 986, estab­ lished the "Basic Research Project on Human Sciences", to promote government-private sector joint research projects in medical and pharmaceutical sciences. The JHSF has been implementing this research programme in four areas: • • • •

application of biotechnology, development of glycotechnology, development of medical materials, and elucidation of immune response mechanisms.

Again in 1986, the MHW established guidelines concerning the manufacture of rDNA products by biotechnology, closely based upon the OECD 1 986 "Blue Book" (above MHW information based on Hom, 1 993) . M H W also h a s responsibilities in the area of food additives, and in December 1 991 is­ sued a policy statement called "Basic Princi­ ples on Safety Assurance for Foods and Food Additives Produced by Biotechnology". This was accompanied by two guidelines on rDNA techniques in food production: a) a Manufacturing Guideline ("GMP" ­ Good M anufacturing Practice), and b) a Safety Assessment Guideline. These were enacted in April 1992. Drawing upon the concept of "substantial equival­ ence" developed in the OECD context, these apply to foods and food additives, "which are substantially equivalent to traditional coun­ terparts, and in which recombinants them­ selves are not to be consumed" (SuzuKI, 1 992; for the Guidelines, see MINISTRY OF HEALTH AND WELFARE, 1 992) . Further work is continuing on guidelines for foods and food additives produced by oth-

er biotechnology; discussion includes such to­ pics as labelling, novel foods, selectable anti­ biotic resistance markers, etc. The Ministry of International Trade and Industry (MITI)

MITI is responsible for application of the guidelines on industrial application of rDNA technology. It began its study of safety meas­ ures in the Chemical Product Council in 1 985 , based on the OECD work which led to the 1 986 "Blue Book". In parallel with the OECD publication, the Chemical Product Council in M ay 1 986 submitted a report on "Ensuring Safety for I ndustrial Application of Recombinant DNA Technology" to the Minister of M ITI. B ased on this report, the M inister announced the "Guideline for In­ dustrial Application of Recombinant DNA Technology", which completely follows the OECD recommendation. MITI has examined almost 300 applica­ tions under the guidelines by mid-1 994, and so far no problems have been encountered. The Environment Agency

Within the Environment Agency, an Ex­ pert Group on Biotechnology and Environ­ mental Protection published in February 1 989 an interim report on "Basic Points of View of Environmental Protection with Outdoor Use of rDNA Organisms" . This outlined a proce­ dure for evaluating the indirect impacts of re­ leases of rDNA organisms (it being assumed that such releases would only be of organisms whose direct impacts were already considered highly safe). In the following year (March 1 990) , the Expert Group produced two fur­ ther reports: - "Technical Items on Ecosystem Impact Assessment for the Field Utilization of GMOs", and - "Procedures of Risk Assessment for the Utilization of GMOs" (draft). Administrative guidance on GMO releases (for research) is based on these reports. I n

5 Polin· El'OIIIlion at National Level. in Different Continents, Coun tries and Cultures

1 99 1 , the Age ncy. e ncouraged by contacts with the European Commission's Directo­ rate-General XI ( Environment). sought to have the guideline procedures translated into Jaw; hut this was strongly resisted by industry and other Ministries. and the proposal has re­ . mained " froze n Consideration of environmental risks was still continuing in 1 994. with a final view not expected for a year or two. Existing guide­ lines cover rese arch . and will be retained for this stage: the future situation for develop­ ment and commerci alization remains unclear. and new guidelines are under discussion. The J apanese government. the Diet. has requested a review of gu i deline s The Environment Agency is examining bioremediation. both as a potential user of the technology. and as a defender of the envi­ ronment: and is developing guidelines for this application; which are also likely to involve prefectural governments. .

.

.

5.6 Other Countries

To give a comprehensive history of the evolution of the regulatory debate in each and every coun try where it occurred would be time-demanding and tedious. because of the i nevitable similarities: the same scientific challenges, the same value-laden fears about tampering with t he great fundamentals of life . reproduction and the natural environment. Yet i n spit e of these basic similarities . and be­ cause they deal with values intimately bound up with national cultures. with each national psyche , the debates in each country were and continue to be i n te n s ely national or even lo­ cal. On basic matters. people wish to control their own destiny; not to submit to a techno­ cratic logic of economic efficiency. nor to im­ po rt u nc r i tica l ly the conclusions of argu m e n ts and evidence accepted elsewhere. " M u t ual acceptance of data" seems a desirable and l o gi c a l goal to the international bureaucrat or the rational economist but in sensitive areas . i t must he recognized also as an act of trust. The choice of what constitutes a "sensitive" area is i t self clearly a political o n e . I n the following sub-sections. a few notes and observations are recorded about other

597

countries. to counter the impression that the debate in a few of the world's major develop­ ed countries sufficiently summarizes the glo­ bal debate . and as basis for some generaliza­ tions in Sect. 5 . 7 . A legislature is a legislature, whether the nation n umbers one. ten, one hundred or one thousand million inhabitants; the length of the debates, and of the resulting texts. are not in proportion to population. Moreover, the take-up of the debate by m u l t i -agencies at many levels - the European Community, the OECD. the U N agencies - forced all coun­ tries. i n as much as they were members of some of these bodies, to give thought to their national positions, whether or not they had previously been active in biotechnology. While initially . a quick response might be of­ fe red by a •·follow-my-leader" stance, vis-a­ vis the USA or other, the progressive devel­ opment of biotechnology would sooner or lat­ er throw up in every country some specific case . some specific challenge, which it was not acceptable to treat i n such simplistic terms. These points will be illustrated by some ex­ amples.

5.6. 1 The Netherlands The Dutch have played major roles i n the public policy debates about biotechnology, including i n p a rt i cula r i ts re gulat i o n Their domestic situation combines several factors which have underlined their interest in bio­ technology: .

(i}

a strong and broad scientific base in the universities: the Agricultural University at Wageninge n and the nearby public ag­ ricultural research institutes; and the many other centers of excellence i n the universities. G roningen (Protein Crystal­ lography), Amsterdam (Microbial Physi­ ology). Leiden (Pharmacology. and Pl a n t Molecular Genetics - the first demon­ strated transformation of monocotyle­ donous plants). Delft ( Enzymology and Fermentation Science) , are a part ia l list of some of their i n t ernationally k n ow n strengths;

598

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

(ii) significant (bio-)industrial activities Akzo in pharmaceuticals (their subsidi­ ary Organon launched the first genetical­ ly engineered product to be commercial­ ized, a scours vaccine for piglets), Uni­ lever's food research center at Vlaar­ dingen, Gist-Brocades's pre-eminence in ' the production of penicillin and of en­ zymes; (iii) an agricultural (and horticultural/orna­ mental) tradition of intensive, science­ based, export-oriented production (lying behind only the US and France in value of agricultural exports, from a popula­ tion base of some 15 million) ; (iv) a public opinion attentive t o nature and conservation (cf. Tab. 2 in Sect. 7.5: Ne­ therlands lies third after Denmark and Germany in its risk perception of bio­ technology), in spite of the massive and centuries-long interventions in - or against - nature, on which depend the very creation and survival of the "Low Countries" as a habitable and prospe­ rous location for human settlement and activity; (v) related to (iv), a strong public expecta­ tion of transparency and commitment to open dialogue, reflected in systematic public information provision and strong consumer movements (whose research arm, SWOKA, has published several re­ ports on public attitudes to biotechnolo­ gy, especially in foods; e.g., "Impacts of New Biotechnology in Food Production on Consumers", SMINK and HAMSTRA, 1 994). The CCGM

Given the strength of life sciences research in the Netherlands, the Dutch responded to the international debate at and around Asilo­ mar with alacrity. A delegation of three Dutch scientists had been at Asilomar, and reported back to the Ministry of Science and Education. Following exchanges of letters be­ tween the scientific community, through KNAW (the Royal Netherlands Academy of Arts and Sciences), and the Ministry, a "Com­ mittee in Charge of the Control over Genetic Manipulation" (CCGM) was established in

1 976 (reporting to the Ministry of Science and Education, but largely overlapping in its membership a similar Committee on Genetic Engineering set up to advise the Health Council). The CCGM was strongly internationalist in outlook, acknowledging its use of the work and reports of the US NIH RAC, the U K Ashby and Williams reports, and the work of the European Molecular Biology Organisa­ tion (EMBO) and the European Science Foundation (ESF). Its first report (March 1 977) covered the introductory and background materials, from the 1 973 Gordon Conference to date; re­ ported an inventory of all ongoing and plan­ ned rDNA research in the Netherlands; refer­ red to ethical questions (but set them aside for evaluation elsewhere); and gave clear and conservative conclusions, including an explicit demand for legally based regulation. The Committee recommended that: " 1 . In consideration of the great scientific impor­ tance of recombinant DNA research, this also be developed in the Netherlands. 2. This research be conducted with strict precau­ tions, according to clear guidelines. 3. Legal regulation of this research be laid down shortly in the form of a lex specialis. Such regu­ lation must provide for a required registration of research projects in this field and must make binding the guidelines and supervision of their observance. 4 . Within the framework of this legal regulation a Supervisory Commission for recombinant DNA research composed of the various scien­ tific disciplines and branches of society, which will continue the work of the committee of the KNAW in charge of the Control of Genetic Manipulation be initiated. 5 . For experiments at the C IV level the facilities which will be established outside this country in European connection be used. 6. In Holland, at least one laboratory be estab­ lished at C III level according to the "Report of the Working Party on the Practice of Genetic Manipulation" in England. 7 . Financial and material support be given in the training and education of research workers in this field, by participation in training courses and probationary periods in this country and outside it as well as in scientific congresses con­ cerning the safety techniques for working with pathogenic organisms".

5 Policv Evolution at National L evel, in Different Continents, Countries and Cultures

The CCGM argued for specific legislation on rONA research, because much haste is needed'': and its language in this first report repeatedly implied an assumption of inherent danger. The year 1 1.}77 was acrimonious for those interested in rONA research. The Minister. the State Secretary of Science and Education . following some exchanges in Parliament, sent to the Governing Boards of Institutes of Scientific Education a letter referring to "ut­ most restraint in concluding contracts" , a phrase which caused confusion . and appeared to ignore the risk differentiation advocated by the CCGM . The Committee fe lt ( and said so in its next report) . that "the majority of its recommendations had been disregarded. The Government had. for example . not retained the first recommendation that in view of its great scientific importance . recombinant DNA research should be developed in the Netherlands". Public arguments were given extensive me­ dia coverage , with the issue of a counter-pro­ posal " to the CCG M ' s first report . by the U nion of Scientific Workers ( B W A) and the General Association of Amsterdam Students ( ASV A), in May 1 977. At the request of the BWA/ASVA, the CCG M studied the "count­ er-proposal'', and concluded that the Amster­ dam project group "had given a tendentious and in many instances distorted picture of the CCGM and its proposals" . A similar ex­ change of arguments took place with the Uni­ on of Scientific Research Workers (VWO ). The CCGM was also irritated by the failure of the government to act promptly on their recommendation for early legislation, and had therefore found itself obliged to proceed with a system of "voluntary" registration of rON A research based on "gentlemen's agree­ men ts". Full details o f these arguments were pub­ lished in the second annual report which the CCG M published in J une 1 978 ( English t ranslation. March 1 979). Summing up the history of the preceding year. the report noted that: "a number of important develop­ ments have taken place in the field of recom­ hinant DNA research:

599

1 . The application of recombinant DNA technology in fundamental molecular-bio­ logical research yielded many new exam­ ples of the scientific importance of this technique. 2. Its application in the production of biologi­ cally important compounds was given a re­ alistic foundation in experiments. 3. The appreciation of the security aspects of research increased and its foundation was improved. 4. In the growing public debate on recombi­ nant DNA research political aspects of de­ cision-making regarding science policy have played an important role .·· The 1 1 0-page report, the Second Report of the CCGM, provided a detailed review of the state of the arguments, both national and in­ ternationaL about rONA risks and their man­ agement during 1 977-78. This full picture was the basis against which the Committee ex­ pressed their concern that Dutch research was lagging behind, as a result of the uncer­ tain situation. Their Conclusions and Recom­ mendations had a note of asperity: ·· J . The recombinant DNA

t e ch nology is

of

essen­

tial importance for fundamental molecular-bio­

logical

research. As a

result

of the absence of

p a r t of the gov­ e rnment. confusion has arisen as to decision ­ ma k i ng about recombinant DNA research. An­ ot her result is that the Netherlands lags behind

clear policy intentions on the

several other countries where this process of de ci s io n - m a k i n g is co n cer ne d .

This in

turn

has

caused

the N e t he r lan d s to drop behind i n mo­ lecular-biological research in comparison to the

rest

of the world. The

CCGM

considers this

to

be a s ign that molecular-biological research is underval ued and feels this to be contrary to the pr iority given by

ZWO ( the D utch Organiza­ Pure Sc i e n t ifi c Research) to the devel­ opment of molecular biology in the Net h e r ­ l ands . 2. The CCG M stands by the recomme ndation it made to the government last year t h a t a le gi s l a tive framework for this kind of research be set up as soon as possible. The CCGM co n sider s such le g a l regulation of essential importance for the regulation of social control on the d e ­ v e lopm e n t of recombinant DNA research and the applications that may result from it. 3 . The CCGM feels it is of the utmost importance that uniform international guidelines be tion for

­

600

18

The Regulation of Modern Biotechnology:

created for recombinant DNA research and recommends that this position be brought for­ ward in i nternational discussions. 4. The CCGM advocates co-operation in an inter­ national framework to evaluate the conjectural risks of recombinant DNA research. In a Euro­ pean framework, the EMBO is designated to co-ordinate such research. 5 . The CCGM has come to the conclusion that the Dutch guidelines for recombinant DNA re­ search are too strict on a number of points and intends to review these guidelines in the short term in the light of new insights into the hypo­ thetical risks of recombinant DNA research , and to modify them wherever necessary."

These recommendations and the report en­ capsulate a paradox or dilemma which has persisted throughout the regulatory debate on biotechnology, in several European coun­ tries. Faced with scientific uncertainties and public fears, a legal framework is advocated: to provide authorization for researchers to continue their work, legal security for their institutions, and public reassurance. The pub­ lic and political debate inevitable to the legis­ lative process then tends to strengthen both the general demand for control , and the weight of the detailed safety requirements which are then imposed. Meanwhile, the ob­ jective evidence on the seriousness of the risks themselves indicates that they have been overestimated, and the regulatory require­ ments exaggerated. From

CCGM

to

VCOGEM

In the Netherlands, the blunt and critical l anguage of the CCGM may have helped to accelerate some resolution of their demands. As the CCGM noted in their third and final report (KNAW, 1 980) , the Minister of Public Health and Environment on 21 June 1 979 an­ nounced the establishment of an "Ad Hoc Committee for Recombinant DNA Activi­ ties" which would take over the work of the Academy Committee. In autumn 1 979, the Minister of Science Policy established also a "broad" committee to study the social and ethical aspects of activities dealing with here­ ditary material. As to CCGM's first point, concerning sup­ port for research, the government responded

A

Historical and European Perspective

in 1 981 with the creation of an "Innovation­ oriented Research Programme for Biotechno­ logy", and the creation of a high-powered "Programme Commission for Biotechnology" to oversee its implementation, spending 70 million guilders over the following five years. The new Ad Hoc Committee for Recombi­ nant DNA Activities (known as "VCO­ GEM") was charged with: a. an inventory of recombinant DNA techniques and their classification in risk categories; b. drawing up guidelines, based on the classification in risk categories, for safe­ ty measures for activities with recombi­ nant DNA, and the level of expertise of the persons involved in these activi­ ties; c. assessing the potential dangers of con­ crete activities with recombinant DNA and their classification in risk catego­ ries. Although its function was advisory, the com­ mittee was connected to the statutory respon­ sibilities of the authorities by a further article in the Ministerial decree: "On the request of the person doing the research or other activities with re­ combinant DNA, the government insti­ tution authorized to issue a permit re­ garding such activities, the regional in­ spector of the State Inspection of pub­ lic health in charge of the control of the environment or the district manager of the Labour Inspection in whose dis­ trict such activities are carried out, or the Minister of Social Affairs, the com­ mittee classifies a project involving such activities in a risk category it finds suit­ able and advises the applicant with re­ gard to the safety measures that must be taken during this project." Thus the control of research, large-scale pro­ duction, or environmental release involving recombinant organisms was effectively con­ nected to the statutory authority relating to existing responsibilities such as those implied

5 Polin• Evollllion

ar

National Level, in Different Con tin en ts . Countries and Cultures

by the referenct.!s in the preceding paragraph (in particular, the Public Nuisance Act ). This solution had the drawback that because of the regional struct ure of these other authorities. additional information might sometimes be demanded by a local authority. adding an ele­ ment of uncertainty to the regulatory burden (a more centralized procedure was instituted i n 1 993 ) . However. t h i s solution was pragmatic and effective. It enabled the V C O G E M to pro­ vide national oversight. without requiring a new statute: and it enabled the Netherlands to present itse lf as a country welcoming for­ eign investment in biotechnology. and not stigmatizing the new techniques. Thus in an attractive two-volume broch ure on "Biotech­ nology in the Netherlands " . prepared by the Committee on Foreign I nvestment. and pub­ lished in 1 986. the subject was addressed as follows under the heading of: ''Additional Advantages'" The Netherlands offe rs a number of fa­ vorable factors . . . of special importance for biote chnological firms. Attainable regulations in the field of health . safety and e nvi ronment As for recombi nant DNA activities. a DNA commission reported in August 1 983 to the Dutch parliament that ge­ netic engineering is controllable and ac­ ceptable. The parliament has used this advice to decide that there will be no special law or regulation promulgated for genetic engi neering. The existing regulation will be maintained. but cen­ tralized "' advice " pertaining to the risks . of genetic e ngineering will take place . . The development of European Community legislation obliged the Dutch to give further consideration to the regulation of biotechno­ logy . and to modify the above view for pro­ duction and fi eld release . An order based on the Che mical Substances Act came into effect on I st March 1 990. regulating all genetically modified organisms. and anticipating the re­ quirements of the Community Directives ad­ opted in April that year.

601

In a publicity brochure for " Biotechnology in the Netherlands: Vigorous and Varied", is­ sued later in 1 990. the section on " Rules and . Regulations . stated: .. A realistic set of rules and regulations covering biotechnological research or industrial applications significantly con­ tribute to the favorable biotechnologi­ cal climate in The Netherlands. Safety legislation:

R& D

phase

In the mid-eighties, the Dutch govern­ ment adopted recommendations, for­ mulated by a recombinant-DNA com­ mittee. regarding work involving ge­ netic engineering. These recommenda­ tions stated that: - work on genetic engineering is con­ trollable : - existing regulations guarantee safety satisfactorily; the introduction of genetically-engi­ neered organisms into the environ­ ment should be covered by general rules and regulations addressing e nvi­ ronmentally hazardous substances; safety aspects for personnel should be covered within the framework of the already existing Workers Safety Act. Thus the need for new rules and regul­ ations is eliminated, while at the same time optimal safety is guaranteed with­ out hampering the progress of biotech­ nological innovations. This was clearly evidenced when The Netherlands be­ came one of the world's first countries where field tests with genetically trans­ formed plants (virus-resistant potatoes) were carried out. Safety legislation: produ ction p hase

In 1 990. rules for both contained use and environmental release of genetical­ ly modified organisms have been pub­ lished. creating a good formal frame­ work for the development of biotech­ nology."

602

18 The Regulation of Modern Biotechnology:

The situation of biotechnology in the Ne­ therlands remains tense in the mid-1990s. For in spite of the clearly positive attitude of gov­ ernment, and the successful establishment of several biotechnology companies, Dutch and of foreign origin , there remains considerable public suspicion and hostility for some appli­ cations. Test plots of transformed plants have been vandalized. The Eurobarometer surveys of 1 991 and 1 993 indicate in regard to the creation and use of transgenic animals a high level of opposition. On the positive side, government Minis­ tries such as Environment, Economic Affairs and Agriculture, all continue to address with intelligent transparency and determination these challenges; conscious of the essential role which biotechnology must increasingly play in many of the major sectors of the na­ tional economy. Legislation proposed in late 1994 by the Minister for Agriculture is in­ tended to provide a clear basis for the contin­ ued progress of work with transgenic animals, under appropriate safeguards. Dutch internationalism expresses itself ac­ tively in biotechnology, particularly through the support for ISNAR (International Service for National Agricultural Research) in The Hague, from the Directorate General for In­ ternational Cooperation (DGIS) in the Minis­ try of Foreign Affairs and for the former "B lOT ASK" Task Force of the International Agricultural Research Centres funded through the Consultative Group for Interna­ tional Agricultural Research (see Sect. 6.3); through initiatives such as the Anglo-Dutch proposal on safety guidelines, described in Sect. 6.4; and through a vigorous participation in international fora such as the European Union, the OECD, and UN activities such as those deriving from the UNCED ( Rio, Earth Summit). In the OECD, VCOGEM Chair­ man PETER DE HAAN was for many years Chairman of the Safety Working Group re­ sponsible for drafting several of the OECD key reports on safety in biotechnology. 5.6.2 The Scandinavians

There are strong objections to grouping and summarizing the behavior of groups of

A

Historical and European Perspective

countries, given the diversity of opinions and cultures which even a single small country may contain: the days of cuius princeps, huius religio are unlikely to return in the era of the global electronic village. Yet for various com­ pelling reasons, there have developed region­ al political-economic groupings such as the European Union, or the Nordic Council. To some degree, their geographical proximity, shared historical experience, common or in­ teracting cultures, and joint multi-national in­ stitutions appear to display common elements distinctive to that grouping, and inspire simi­ lar policy responses to similar challenges. We describe briefly some of the Scandinavian ex­ perience of the biotech regulatory debate, be­ fore advancing to some more ambitious and broader generalizations. In the national, European, OECD and world-level debates about the regulation of biotechnology, the Scandinavian countries have expended energies and exerted in­ fluence to a degree out of proportion to their size in economic or population terms; reflect­ ing the strong public and political interest which the subject has elicited in these coun­ tries. The subj ect of biotechnology risks was usually linked with environmental and with ethical concerns. Nor are these subjects in two water-tight compartments - rather, they are the two halves of the permanent discus­ sion of the relation of Man and Nature; a re­ lation which (in Scandinavian eyes) should concern all of mankind, Scandinavian and other. Thus to take a recent example from Norway, two reports which have recently been published (in English) are: - "Ecological risks of releasing genetical­ ly modified organisms into the natural environment", Directorate for Nature Management, 1992; - "Biotechnology related to Human Be­ ings", Ministry of Health and Social Af­ fairs, 1993. Both are competent and well-written reports, treating subj ects already much treated else­ where, but with a seriousness of purpose, re­ spect for "Nature", and intensity of expressed concern typically Nordic; one would not ex-

5 Policy

Evolution at National Level. in Different Continents, Countries and Cultures

pect identical reports from Brazil. or China. or Nigeria. It is not difficult to cite examples illustrat­ ing the readiness of Nordic Council countries to offer a world lead in environmental mat­ ters - the Stockholm Confere nce on the Hu­ man Environmen t in 1 972. the continuing work of the Stockholm Environment Insti­ tute. or the chairing by Norwegian Prime Minister GRO H A RLEM BRUNDTLAND of the World Commission on Environment and De­ velopment (established in 1 983 at the request of the UN General Assembly. and charged with the preparation of long-term environ­ mental strategies for sustainable deve lopment - a sign ificant precursor of the 1 992 Earth Summit at Rio) . Denmark

As is discussed in Sect. 7 . 5 on public per­ ception, the Danes have long displayed in comparison to the other European Commu­ nity nations by far the highest level of risk perception in relation to "gene splicing" or biotechnology. At the same time. the authori­ ties were never blind to the importance of biotechnology for companies of great signifi­ cance to their economy - Novo Nordisk (until the late 80s, two separate companies). Danis­ co, Carlsberg and others - and for the long­ term competitiveness of their agro-food in­ dustry, a highly successful. science-based and export-oriented sector. Conscious of the risks of exotic " i nvasions" ( such as the cow parsnip. introduced as an or­ namental but now out of control) . the Danish government in October 1 983 set up a commit­ tee to consider the need for regulatory con­ trols. The committee was described by Envi­ ronment Ministry staff as pursui ng a ''balanc­ ing act'' between the promotion of biotechno­ logy and the prevention of adverse conse­ quences.

I n response to the argument that legisla­ tion should be pursued on an international basis. Denmark argued that. here as in many other areas (e .g. acid rai n ) , individual coun­ tries should take the first steps in setting standards. Th e " Environment and Gene Technology Act" was passed on 4th J une

603

1 986. and widely reported as the world's first such legislation. The Act was in six parts, and its general goal was defined in Article 1 ( 1 ): "The purpose of this Act is to protect the environment. nature and health, in­ cluding considerations of nutrition in connection with the applications of gene technology." The Act was comprehensive in wording and restrictive in tone; but Article 3(2) allowed for exemptions: "The Minister for the Environment may lay down rules to the effect that certain genetically engineered organ­ isms and ce lls and certain applications thereof shall be exempt from the provi­ sions of this Act on such conditions as may be specified." All deliberate release was formally banned, under Article 1 1 (1 ) ; unless exempted (under Article 1 1 (3 ) ) as one of "certain cases" which the Minister could approve ; the Minister un­ de rtook to debate in Parliament the first field release to be so authorized. This took place three years later - a herbicide-resistant sugar­ beet developed by Danisco, in a test plot; the parliamentary debate in fact focused mainly on the characteristics of the herbicide con­ cerned. During the three years following the 1 986 Act. there was an intense and widespread de­ bate. and three amendments were introduced to remove some of its most problematic fea­ tures. One allowed pilot plants to be treated as research rather than production facilities, and so be subject to less stringent regulations. A second relaxation removed the provision by which a company automatically had to stop work whenever a complaint was lodged with the Environment Appeal B oard. The pa­ perwork nonetheless remained heavy, al­ though civil servants from the Environment Ministry emphasized that there had been a fast learning curve: the time required for ap­ provals had diminished sharply (and the first two approvals had been delayed by appeals). What was emphasized throughout the Danish experience was the absolute need for

604

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

public debate and transparency - particularly through "consensus conferences", and through the development of special initiatives for the preparation of educational materials for schools. Again from the Eurobarometer surveys, it may be noted that the Danes have within the EC context the highest level of trust in government as a source of informa­ tion on new technologies. Although these commitments to debate and transparency weighed heavy upon the scientific communi­ ties, academic and industrial, continuing sub­ stantial research funding for biotechnology confirmed the government's basically positive view of the technology. Sweden

In Sweden, "scientists tried to interest the government in regulation during the early 1 970s, but when that failed, implemented reg­ ulation through research councils, following the NIH guidelines" (McKELVEY, 1 994). The Asilomar debate rekindled interest, and around 1 977, a heated public debate occurred in Sweden, with calls even from industry to regulate genetic engineering; thus pushing the government into investigating legislative changes. As a result, special regulations were introduced in 1 980. At the same time, the Swedish Recombinant-DNA Committee was established. McKELVEY in her thesis on "Evolutionary Innovation" selected as case material the pro­ duction by genetic engineering of human growth hormone; a story involving a partner­ ship from the mid-70s between the recently started San Francisco based Genentech, and the Swedish pharmaceutical company Kabi. Although her central interest is in the process of innovation, her account casts interesting side-lights on the early policy debates in that country. From the start of the rONA regula­ tory debates, the discussions touched upon matters of specific significance for some local players, thus providing some counter-balance to the natural (Nordic?) tendency to debate philosophical generalities. Sweden also had a strong academic scien­ tific tradition in key areas such as protei n crystallography and molecular biology, and

their international connections were under­ lined by L ENN A RT PHILIPSON 's decade as Di­ rector-General of the European Molecular B iology Laboratory, EMBL - an institution deriving from the scientific community repre­ sented by EMBO, which played a maj or part in the European debates on regulatory policy for biotechnology. On the industrial side, Pharmacia should also be mentioned as a Swedish based multi-national of outstanding importance for the technology, instrumenta­ tion and separation/filtration/purification ma­ terials which it supplies to research and pro­ duction facilities in the bio-sectors, and for genome sequencing. The Swedish debates have reflected tensions between the interna­ tionalist and scientific traditions, academic and industrial, and the more introspective tendencies expressed by intense and inter­ minable debate on ethical and philosophical issues. The history of official developments has been conveniently summarized in the 1 992 re­ port of a Parliamentary Committee of Enqui­ ry, set up in 1 990, "The Committee on Ge­ netic Engineering". The following quotation is from the (English-language) summary of their report (SW E D ISH GOVERNMENT COM­ MITIEE ON GENETIC ENGINEERING, 19 92 ) starting with the 1 980 regulations: ,

"In the Labour Environment Act a demand was introduced for preliminary approval of the use of a working method employing recombinant-DNA technology in a way as to constitute either an un­ t ried approach to research into recombinant-DNA technology or its industrial application. The author­ izing authority was the Swedish National Institute of Occupational Health. Changes to the Environment Protection Legisla­ tion were also introduced in 1980. After further changes, advance approval was required with re­ gard to plants for activities involving recombinant­ DNA technology, albeit not for plants for such re­ search considered by the Swedish Recombinant­ DNA Advisory Committee to belong to the lower risk classes P l and P2. The authorizing authority was the Swedish National Licensing Board for En­ vironment Protection. At the time when these special rules were first introduced, the Swedish Parliament took the view that the administrative and legal consequences of establishing a special authority for the control of genetic engineering should be the subject of an en-

5

Policy Evolution at National Level, in Different Continents, Countries and Cultures

quiry. According to the report of the subsequently appointed Committee, the use of recombinant­ DNA technology hardly gave rise to any reason for concern provided that accepted protection and se­ curity measures in the area of microbiology were adopted. With this risk assessment, the arguments for an authorization procedure had weakened and the Committee proposed that the regulations which had been introduced for advance approval should be waived with regard to both the labour environ­ ment and the external environment. These regula­ tions were waived with effect from July 1 , 1 987. Another Committee appointed by the Swedish government in 1984 made proposals mainly con­ cerning ethical standards for the use of genetic en­ gineering on human beings. The Swedish Ministry of Agriculture, in a special report issued in 1990, has surveyed genetic engineering research on plants and animals."

Subsequent legislation addressed ethical aspects of human genetics. The ( 1990-92) Committee on Genetic Engineering ad­ dressed in depth a wide range of issues, atten­ tively studying a diversity of international opinions. Their report clearly acknowledged the point that risk lay in the nature of the or­ ganism, modified or not by recombinant­ DNA techniques; but noted also that there was no accepted classification specifying which plants and animals are to be regarded as dangerous. More pragmatically, the report acknowl­ edged the general consideration, since the country was preparing for accession to the European Community, that "Swedish control of GMOs should not be incompatible with the EC's directives " . This consideration clearly in­ fluenced many of the subsequent recommen­ dations; and Swedish legislation based on these recommendations was developed over the following years. A framework, Gene Technology Act, was passed by the Swedish parliament in June 1 994. Together with a governmental ordi­ nance and more detailed regulations written by different agencies with responsibility in the field, EC Directives 90/21 9/EEC and 90/220/ EEC were accepted to be fully implemented in Sweden in the fall of 1 994 (SCREEN, 1 994) , and thus just prior to accession to the European Union in January 1 995.

605

5.7 Generalizations: From Concrete to Abstract, from National to Global

If time and space permitted, there are many interesting national experiences which should be added to a fuller history of biotech­ nology and its regulation, from countries large and small: •

•

•

•

Belgium, against a noisy background of constitutional argument and national/ regional restructuring, quietly pion­ eered not only the science but the com­ mercialization of vast areas of modern biotechnology - hepatitis-B vaccine made in a recombinant yeast; the elimi­ nation of rabies in the wild population of foxes by the first large-scale field re­ lease of a live recombinant viral vac­ cine; pioneering the use of the Ti plas­ mid for genetic engineering of crop plants; developing reliable diagnostic test kits for the AIDS virus . . . China, one hundred times greater in population, and certainly not indiffer­ ent to the potential of modern biotech­ nology, boldly testing the effects of growth hormone in animal husbandry, conducting large-scale field releases of transformed plants (CHEN, 1 992, 1 995 ) , and microorganisms, developing the production and exploration of the inter­ ferons and their activities . . . and in the 1 990s, gradually increasing participation in the international debates; India, from an early start based on the 1 979 version of the NIH Guidelines, re­ cognizing the potential and adopting scientific priorities for a biotechnology adapted to India's vast needs; Russia, emerging from the wreckage of the USSR, and an inheritance of envi­ ronmental irresponsibility, in SCP plants as elsewhere, seeking to rejoin the "Western" world, accepting US FDA drug approvals, drafting in 1 994 legislation crudely modelled on earlier European laws, themselves in course of recycling through the crucible of revi­ sion and review, but asking (through

606

•

•

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

UNESCO) to have their draft law in­ ternationally reviewed; Switzerland, home base to several of the world's leading pharmaceutical companies, nonetheless witnessing some of the most fundamentalist oppo­ sition to genetic engineering (RYSER and WEBER, 1990) , sufficiently wide­ spread to threaten (by a public referen­ dum on genetic engineering, to be held in 1 996 or 1 997) the whole future of teaching, research and investment in modern biotechnology. in Latin America, in Africa, and in South-East Asia, from the early 1 990s, conferences of countries - or a few in­ dividuals trying to speak for their coun­ tries - seeking to "jump-start" the crea­ tion of regionally harmonized bio-safety regulations, importing selectively some of the concepts and principles develop­ ed elsewhere . . . (cf. VAN DER M EER et al. , 1 993) .

The preceding sections, o n t h e major early players and on the Scandinavians, offer some basis for cautious generalizations. Cautious, since the countries discussed in detail - fewer than ten in number, some 10% in total of the world's population, and all of them OECD Member countries - are far from being a "random sample" of the world's peoples. In historical, scientific, industrial and other terms, they cover many of the most salient features of the early years of the "recombi­ nant DNA story"; but it is precisely the uni­ versality of DNA, and the universality of bio­ technology's fields of application - food, health and environment - that forces policy advisers to consider which aspects of the early experience are transient or locally specific, and which aspects are appropriate for more permanent and universal application. That is the challenge particularly to the agencies of the United Nations, whose actions relevant to the regulation of biotechnology we review in the following section. The big, rich and scientifically advanced countries discussed at the start of this section had a natural monopoly in the early years of the debate. The recommendations of the US NIH RAC, and the UK GMAG , therefore

had enormous initial influence. Because they were discussed principally in scientific circles, the natural internationalism of science and its culture of critical scrutiny limited the extent to which these early guidelines were mere ex­ pressions of national self-interest. They repre­ sented an "honest start" to a debate about conjectural risks. From that start, the debate developed in three directions, which might for brevity be summarized as objective/scientific; national self-interest; and global-idealist. 1 . objective/scientific the accumulation of practical experience , and continued scientific discussion and ex­ change, enabled the uncertainties to be diminished, and the risks more clearly characterized - to the point where the fo­ cus of concern shifted away from the re­ combinant techniques, to the organisms, inserted materials, and the nature and con­ text of intended uses; 2. national self-interest in national contexts, as practical implica­ tions and applications became apparent to local constituencies - scientific, industrial, agricultural, environmental, political, reli­ gious or whatsoever - special interests and local preferences made themselves felt, and influenced both the agenda and the outcomes of the national debates; 3. global-idealist given the continuing conjectural nature of the risks, those individuals, agencies or in­ stitutions not having a direct or concrete interest, what the French might call a "de­ formation professionnelle", were free to indulge both in unfettered speculations, and in globalist and universal prescriptions about the better ordering of the world. It would be offensive and inaccurate to pretend that some countries are more honest than others, or that scientists have greater in­ tegrity than "laymen". Nor is it our intention to imply that any of these three tendencies is morally superior: the intention is descriptive, and we use these three terms to summarize what has been observed. The objective/scientific approach is univer­ sally valued, and because of the universality

6

International A ctors: European. the OECD. the

of its approach has particular value in provid­ ing com mon ground for international rela­ tions and agreements. The US and European experience has contributed much of interna­ tional validity and value . hut the US Congress a nd the European U nion institutions are not the government of the world: the O ECD (see Sect. 6.2) may have greater authority in some respects. because it has to find the common ground between 25 diverse governments. and because it collaborates with the UN agencies with their wider responsi bilities. The pursuit of self-interest . individual or national. is inevitable . (whether or not one sanctifies it, like A D A M S M IT H , as the work­ i ng of the "invisible hand " of divine Provi­ dence) , and is the business of politics and government. The interest of the Scandinavian experience often lies at the points of potential or actual collision between ideals and inter­ ests. A "Hands off' approach to Nature may he difficult to reconcile with the development of a productive and competitive salmon-farm­ ing industry. or the maintenance of a long-es­ tablished tradition of whaling. The definition and pursuit of broader mul­ ti-national aims. on a regional or global basis, is in some areas clearly the most effective, or the only and essential way . to defend all our local interests: the defence of the "global commons" makes co-operation a non-zero­ sum game , and it can be formulated in terms of ideals: the rights of man. sustainable devel­ opment. But implementation depends on lo­ cal i nstitutions and interests. Thus good poli­ cy-making for biotechnology has to recognize all three strands.

6 Intern ational Actors: Europea n , the OECD , the

UN Agencies and Rio Introduction

Responses to the policy challenges posed by biotechnology were initially national, and the previous section has described develop-

UN

Agencies and Rio

607

ments in several countries, including those who have been major or significant players in the debates on the regulation of biotechnolo­ gy. I n this section, we consider the major spheres of action at international or suprana­ tional level, starting with Europe; enlarging the scope to the OECD area; and finally con­ sidering the agencies and actions at the global level represented by the UN agencies (which themselves have regional agencies, some of them significant in the biotechnology de­ bates). A tension which has been touched upon in the preceding section, is between processes which are rooted in local, national experi­ ence , and work up from there; and the more "global-idealist" attempts to develop and if necessary impose. " top down" , a global agreement or convention. Given that some problems must be addressed in the latter mode, international action becomes neces­ sary, to seek consensus, and to establish and use international mechanisms and fora for in­ formation, debate, decision and ultimately enforcement. Difficult though the latter might appear . there are precedents, some of them potentially relevant to biotechnology. Refer­ ence has already been made to at least the following four: (i}

the scientific conse nsus regarding the two-year moratorium, 1 984-86, i n re­ sponse to the (July 1 984) Berg letter which led to the Asilomar conference (see Sect. 1 ): (ii) the Directives adopted through the Trea­ ties and institutional machi nery of the European Community/Union (discussed extensively throughout this chapter, see Sects. 2, 3, 4, 7 and 8); (iii) Decisions and Recommendations ad­ opted by the Council of the OECD (see Sect. 6.2 below, and in the history of chemicals control); (iv) the history of international agreements and Conventions adopted through the actions of UN agencies (see remarks concerning chemicals control, in Sects. 4.4 and 6.3 below) . In the following sections, w e consider more generally the historic and continuing activities

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18

The Regulation of Modem Biotechnology: A Historical and European Perspective

of the international bodies - scientific and in­ tergovernmental - which have been signifi­ cantly involved in discussion and/or decisions affecting the regulation of biotechnology. The first of the four examples referred to above was, and was widely seen and re­ marked upon as, a "first" and "once off': a voluntary moratorium, proposed by the scien­ tists themselves, and subsequently endorsed where necessary by national research funding bodies in the US, the UK and in other coun­ tries. Asilomar was not only a "first", but a starting point: the scientific communities have since been obliged, often reluctantly, to main­ tain their engagement in political and public dialogue. This section therefore includes in­ ternational action of both scientific and politi­ cal (or intergovernmental) character. The progressive shift to international or global bodies can also be viewed as a third re­ run, now at global scale and in developing countries, of the surge and ebb of bio-safety concerns, the learning cycle, which has taken place successively in the US and Europe. Rather than a "cycle", the "learning curve" is a better metaphor - in which those furthest down the curve should surely (and in their own commercial interests) help those starting (or stuck) on the upper slopes. 6 . 1 Other Europes, Scientific (ESF, EMB O , EFB ) and Political (EC/U , CoE , ECE) Scientific: (1) The European Science Foundation, and (2) The European Molecular Biology Organization

these opinions was made by many others, in­ cluding political authorities at national (cf. Sect. 5.6. 1 , The Netherlands), and at Euro­ pean Community level. Scientific: (3) The European Federation of Biotechnology

The European Federation of Biotechnolo­ gy was also introduced in Sect. 3. 1 . Founded in 1 978, it rapidly expanded to become a fed­ eration of over 60 learned societies, reflecting the multi-disciplinary character of biotechno­ logy (albeit with some delay in recognizing its links with molecular biology and genetic engi­ neering). Its greatest strength and vitality arose from its various working groups; but after its early collaboration with the FAST programme (see Sects. 3.1 and 3.2), its work had little direct political impact upon the reg­ ulatory debate in Europe. The Safety Working Group of the EFB maintained over many years, and continues to maintain close links with the European Com­ mission, particularly with those responsible for defining the elements of the research pro­ gramme relating to risk assessment. The group itself produced a series of technical pa­ pers, on matters such as the definition of safe­ ty categories for biological agents (see refer­ ences to KOENZI et. a!., and FROMMER et a!. the successive Chairman; MARTIN KOENZI also chaired for several years the OECD Group of National Experts on Safety in Bio­ technology). By the overlapping networks which were created, through individuals ac­ tive in several contexts (e.g. national, Euro­ pean, sectoral, professional, standards bodies, OECD, . . ) close concertation was achieved between scientists in these different contexts, and consequently between the regulations based on such scientific advice. Where the regulations departed from scientific advice, under the pressure of other political forces, tensions arose (see Sect. 7.3, the Frommer letter), and the EFB Safety Group had difficulty in making its advice in­ fluential. In the long-term, the continued good quality work by the EFB Safety Group contributed significantly to the underpinning work. B ut as regulatory developments be.

The ESF, founded 1 974, representing the research councils of Europe, and the EMBO, founded 1 964, representing individual scien­ tists in this discipline, have both been intro­ duced in Sect. 2. In their respective roles, they played from the earliest years a significant part in the European area of the post-Asilo­ mar debates. Both were still doing so two de­ cades later in the 1 990s, in the debate on the reform of the European Community legisla­ tion - see Sect. 7 .4. Their Resolutions are quoted in the sections cited, and reference to

,

6 International A ctors: European, the

came more politicized. its participants were not of a culture or disposi tion to descend into the political arena. and the burden of lobby­ ing for national and scie nce-based regulation fell on other shoulders. In Septemb e r 1 988. the EFB held a l Oth­ anniversary I n t ernat i onal Workshop at Inter­ laken, and produced ··strategy Papers" from its Working Parties. under the heading " 1 0 Years o f Biotechnology i n Europe and Stra­ tegic Planning for a S econd Decade": but these had little public or political impact, as attention focused on the progress of the then recently proposed " Biotechnology Direc­ tives". Political: (1) The Euro pean Community/Union

Reference has been made in earlier sec­ tions (2, 3 . 4) t o th e actions taken by the Eu­ ropean Community/Union institutions. first in 1 978-82. and again from 1 986 onwards. The further evolution is described in Sect. 7. and much of the final section . 8. addresses specifi ­ cally this dimension. In effect . it is difficult to separate the history of biotechnology regula­ tion in Europe from the evolution of the Community institutions themselves. In wider political arenas. such as those further dis­ cussed below. the European Commission on behalf of the Community also became an in­ creasingly significant player - again. reference has been made to the influential example of the development of regulations and agree­ ments for the control of chemicals. Political:

(2) The Council of Europe

The Council of Europe was created by a Statute signed i n London on 5th May, 1 949. as the association of the democracies of West­ e r n Europe. By mid- 1 994 . with the recent ac­ cession of ex-communist states from Eastern Europe . it had J2 members. including all the Member States of the E uropean U nion and the European Free Trade Area. I n the preamble to the founding statute . the mem­ bers affirm the ir devotion to various com­ mon ly held values . the common heritage of

OECD,

the UN Agencies and Rio

609

their peoples and the true source of individu­ al freedom . political liberty and the rule of law: principles which constitute the basis of all genuine democracy. They also express their belief that for the furtherance of these ideals and in the interests of economic and so­ cial progress. there is a need for greater unity among like-minded countries of Europe. The stated aim is: "to achieve greater unity between its Members for the purpose of safeguard­ ing and realising the ideals and princi­ ples which are its common heritage and facilitating their economic and social progress". Although the pursuit of these aims has bee n partly overshadowed by the creation and progressive enlargement of the European Community. the Council of Europe has none­ theless maintained its distinct and important activities. It pursues its aim through the or­ gans of the Council by discussions of ques­ tions of common concern and by agreements and common actions on economic, social, cul­ tural . scientific. legal and administrative mat­ ters: as well as the maintenance and further realization of human rights and fundamental freedoms. Its organs are the Committee of M inisters, which is the decision-making body, and the Consultative Assembly . composed of mem­ bers of national parliaments. The two legal in­ struments are Conventions, and Recommen­ dations. A Convention is a multilateral treaty representing a Europe-wide consensus; once approved by the Committee of Ministers, it is open for signature by Member States, who on ratifying it commit themselves to respect the obligations defined in the Convention. On to­ pics not suited to Conventions, the Commit­ tee can adopt Recommendations. addressed to governments of Member States, providing guidelines for national legislation or adminis­ trative practice. The Council of Europe has been a signifi­ cant player in the development of common agreements on the labelling and classification of chemicals. It has also been responsible for the Convention on the European Pharmaco-

610

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

poeia; for work on Flavoring Substances; and on Pesticides; among various other topics. Some of its Recommendations have been tak­ en over by the Council of the European Com­ munity in Community Directives. On other occasions, Community Recommendations including the 1 982 recommendation concern­ ing the registration of rONA work - have been taken over by the Council of Europe. The Council of Europe on several occa­ sions addressed aspects of biotechnology. The Parliamentary Assembly, at Helsinki in 1 98 1 , had debated the challenges o f new technolo­ gies, including biotechnology. In 1 984, the Council adopted a Recommendation con­ cerning national registration of recombinant DNA work, closely based on the 1 982 Coun­ cil Recommendation of the European Com­ munity (see Sect. 2.8). The Council's report and resolution of 1982 (see Sect. 2.8) emphasized not only safe­ ty aspects, but the ethical issues raised by the possible applications of modern genetics di­ rectly to human beings. The subsequent work of the Council of Europe continued to ad­ dress ethical questions, particularly through the CAHBI group, described below. In 1 983, the Council decided to set up an Ad Hoc Committee of Experts on Genetic Engineering, "CAHGE". Its task was to study the ethical and legal problems raised by new techniques of artificial (or medically as­ sisted) procreation, and by the new DNA­ based technologies. The ultimate objective was the harmonization of the policies of Member States. After some initial confusion about the relationship between in vitro fertili­ zation and genetic engineering, it was decided at the first meeting (December 1 983) to start with a detailed study of the ethical and legal aspects of artificial procreation. The group subsequently changed its title to "Ad Hoc Committee of Experts on Progress in the Biomedical Sciences", known as "CAHBI". A succession of plenary meetings over the following years addressed a range of related subjects, and greatly clarified differing views regarding the status of the human embryo; but without achieving consensus on this fun­ damental question. The Council published in J une 1 994 the draft of a proposed "European Convention

on Bioethics", announced as the first interna­ tional treaty explicitly addressing the poten­ tial risks of progress in biology and medicine to the rights and freedom of human individu­ als. The Convention itself is described (e.g., B UTLER , 1 994) as " little more than a lowest common denominator of member states' wishes"; but supporters indicate that it pro­ vides a basis of broad common principles, to which member states in their legislation could add more detail or stricter terms. The Council's activities underline the con­ tinuing sensitivity of Europeans to ethical questions raised (or potentially raised) by modern biology, and the readiness of both politicians and public to see genetic engineer­ ing as part of a single spectrum of activities including genetic screening, in vitro fertiliza­ tion, gene therapy and other biomedical ap­ plications of modern genetics. The UN Economic Commission for Europe

The UN bodies of global scope are dis­ cussed in Sects. 6.3 and 6.4; it will be appro­ priate to mention here one of their regional offices, the UN Economic Commission for Europe, or ECE. The ECE played a significant role in the post-war years in Europe in the response to problems of chemicals safety and control which were widely shared across Europe, East and West. It became the global office for certain activities and Committees, including those relating to the international transport of hazardous substances. The ECE was alert in the 1 980s to the posi­ tive potentials of biotechnology, for example organizing in September 1986 a seminar in Bulgaria on "Biotechnology in the Chemical Industry". Also in that year the Conference on Security and Cooperation in Europe held a meeting in Vienna, and one item from its Concluding Document stated: " 1 8. Taking note of the progress made in, and the new opportunities offered by, research and development in bio­ technology, the participating States consider it desirable to enhance the exchange of information on laws and

6 International A ctors: European, the O ECD, the UN Agencies and Rio

regulations relating to the safety as­ pects of genetic e ngineering. They will therefore facilitate consultation and exchange of information on safe­ ty guide lines. In this context . they emphasize the importance of ethical principles when dealing with genetic engineering and its application." ECE therefore recommended to its "SAST" (Senior Advisers to E CE Govern ­ ments in Science and Technology) that it as­ sume responsibility for t he inventory on exist­ ing safety guidelines in biotechnology; a rec­ ommendation subsequently agreed. Since 1 988, on a regular basis. ECE has invited gov­ ernments to transmit such materials to them. which it has issued as monographs. It acts as a depository for national reports. regulations and legislation related to safety in biotechno­ logy, and by 1994 had materials from 29 gov­ ernments, as well as from UN I D O . the Euro­ pean Commission. and the OECD. The Se­ nior Advisers at a meeting in September 1 994 underlined the importance attached to this work . and decided to publish the following year a compilation of the most recent sum­ maries of na t i o n a l s u bmissions. The U N ECE's Committee on the Trans­ port of Hazardous Substances was also the venue for discussion of the treatment of GMOs in i nte rna t i o n a l trade. Fol lowing the April 1 990 adoption of the European Com­ munity Directives on Contained Use and Field Release . DG X I with DG V I I (Trans­ port ) initiated proposals for the categoriza­ tion of G MOs into existing hazard categories for the purposes of transport. The proposals did not lead to any new Community legisla­ tion, as it was recognized that existing rules regarding the transport of cell lines . medical samples etc. would apply . and it was the char­ acteristics of the biological materials rather than the fact of genetic engineering that was r e l eva n t t o the risk classification .

61 1

6 . 2 The OECD Role in

Biotechnology and Safety Introduction: An AuthoritatiYe Position, Based on Four Strands

In May 1 992. the World Bank and ISNAR (the Inte rnational Service for National Agri­ cultural Research - see Sect . 6.3) published for widespread diffusion throughout their client c o u n t r i es (effectively, the whole of the developing world) a 40-page report entitled, "Biosafety: The Safe Application of Biotech­ nology in Agriculture and the Environment " . In i t s Executive Summary, t h e report outlined its purpose; its main recommendation; and a remarkable reference to the work of the Or­ ganisation for Economic Co-operation and Development (OECD): "The purpose of this document is to provide a practical guide for policymak­ ers and managers with limited time and restricted access to the extensive docu­ mentation that is accumulating on the safe use of biotechnology . . . This document recommends that a na­ tional biosafety system should be est a b ­ lished within the existing regulatory framework and draw on existing institu­ tions. personnel, and current legislation to the greatest extent possible. I t rec­ ommends that the focus in the regula­ tory process should be on the nature of the product itself. not on the techniques used to prod uc e it . . . All these applications of modern bio­ technology are being developed under safeguards for good laboratory prac­ tices and recombinant-DNA safety con­ siderations, as described by the Organ­ isation for Economic Co-operation and Deve lopment (OECD) i n 1 986 for la­ boratory-based e xpe r i me n tat i on and e x­ tended in 1 992 to guidelines for smal l­ scale field trials. They remain the most authoritative set of internationally a g reed - u pon guidelines presently avail ­ able a n d provide a sound basis for na­ tional policymakers in all countries." (PERSLEY et al., 1 992).

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The Regulation of Modern Biotechnology: A Historical and European Perspective

In the following section, the history is re­ viewed of the activities through which the OECD's international standing was gradually achieved. The history can be summarized in terms of four strands, treated further below or elsewhere as indicated: 1. the OECD from the 1 960s onwards played a major role, in conjunction with the UN agencies, in developing the systems and procedures for ensuring the safety of chemical products (being placed on the market, entering into world trade, etc.) : this work is referred t o in Sect. 6.3, along with the roles of the UN agencies con­ cerned; 2. starting in 1 98 1 , the OECD published a se­ ries of authoritative study reports on var­ ious aspects of biotechnology of interest to public policy-makers (and many others); 3. also starting in the early 1980s, the OECD worked intensively on, and published a se­ ries of reports on, generic safety matters concerning recombinant DNA research and products (see below, the work of the "GNE"); 4. in the 1 990s, continuing work on safety led to reports which increasingly discussed this and other aspects of biotechnology in terms specific to particular sectors. The general policy reports and the series of safety-related studies both document a pro­ gressive evolution of perspective, from gener­ ic biotechnology issues, to essentially sectoral aspects. The Historical Background

The Organisation for Economic Co-opera­ tion and Development was created out of the earlier Organisation for European Economic Co-operation, an ad hoc instrument to assist with postwar reconstruction in Europe and the implementation of the Marshall Plan. The value was recognized by the Member coun­ tries, of having such a forum for discussing policy matters of common interest, and . for developing instruments of value to all. Focus­ ing originally on the collection of economic statistics and harmonization of terms and def­ initions, the scope of the organization's activi-

ties slowly expanded, as did its membership (to 25 Member countries by mid-1 994) - com­ prising the countries of the European Com­ munity/Union, the European Free Trade Area, North America (all three NAFfAns), Australia, New Zealand, Japan; and Turkey. The Committee for Scientific and Technol­ ogical Policy, CSTP, had been created in 1 972; and soon after the Asilomar meeting (1975 ), the Secretariat raised the possibility of recombinant DNA and genetic research as one example among others, of areas which might be studied, "not to describe new scientific advances nor to analyse in depth the technological or other consequences of scientific research. Rather, the aim is to determine what mecha­ nisms, procedures and other capabilities gov­ ernmental or paragovernmental bodies pres­ ently have or may require for anticipating, monitoring and controlling the consequences stemming from advances in certain areas of scientific research, and to assess their ability to deal effectively with the attendant policy implications. Thus, the emphasis would be not so much on what the specific content of such science-related issues are, but on how the necessary capabilities can be marshalled so as to ensure that the implications of re­ search and the procedures for its conduct are integrated with major science policy con­ cerns." (OECD, 1 976) Such pre-occupations remain fully current two decades later, perhaps tinged with greater cynicism about the ability to forecast long­ term technology trends, and still less long­ term economic and political developments, normally of greater significance than most technologies. But in the 1 970s, such needs were widely felt: reference has been made to the European Community's FAST Pro­ gramme of Forecasting and Assessment in Science and Technology. This itself was partly stimulated by the existence and perceived usefulness of the US Congressional Office of Technology Assessment (created 1972). In the mid-80s, the European Parliament estab­ lished its "Science & Technology Options As­ sessment" group, STOA. Further examples could be multiplied around the world - POST in the UK, OPCST in Paris, NOTA in the Ne­ therlands, TAB in Bonn, etc.

6 International A ctors: European. the

Returning to OECD. it was only in 1 980 that the CSTP agreed to include biotechnolo­ gy in its work programme for the following year. CSTP. supported by the corresponding Directorate for Science . Technology and In­ dustry, was the first . and for a number of years. the only body of the OECD to deal ex­ tensively with biotechnology. due to the science-based origins of this technology. More recently. the increasing "pervasiveness" of biotechnology a pp l ic a t i o n s has led other Committees of the OECD to develop inter­ ests and relevant activities - particularly the Environment Committee and Directorate : still more rece ntly the Committee for Agri­ culture: and most recently . the Industry Com­ mittee. CSTP work on biotechnology started in 1 98 1 . The subject has remained on the agenda of the Committee ever since . thus becoming a continuous feature of OECD work. Content and direction of the Committee's biotech nol­ ogy work followed a logical plan. but one which significantly reflected biotechnology developments i n the world at large; and ac­ quired some influence upon the m. The first act ivity reviewed the dominant scientific and technological trends and pointed to the main policy problems. leading to the publication BULL et al 1 982. ..

The GNE, and the Work on Generic Rio-safety Issues

Based on the 1 982 broad report. the Com­ mittee decided to carry out four follow-up ac­ tivities: two on urgent and specific policy is­ sues (safety and patent protection ) . and two on more general policy areas (government policies in R & D . and long-term economic impacts). Of these four. the safety issue was recognized to be of overriding importance and thus become a continuous activity. with a series of major publication s : m ajor both in the scale of resources invested in their prepara­ tion and negotiation. and in their influence . For although consensus was difficult to achieve. given wide divergences both in the p e rc e pt i o ns of risk i n biotechnology . and in the state of scientific developmen t in different

OECD,

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61 3

Member countries. there remained a persis­ tent and common interest in mutual learning. and a willingness to compromise. Work on safety started with the completion of the preceding activity on trends and per­ spectives. An i n i t i a l meeting of Secretariat ex­ perts in Decembe r 1 982 defined a number of principles. the first of which was about scien­ tific rationale: "Guidelines, rules and regula­ tions have to be based on the best available scientific knowledge, and they have to be suf­ ficiently flexible to adapt to new knowledge ." This simple postulate, uncontroversial for the scie ntific community and basic to all rational discussion . has been much argued about, and has politically not always been accepted. As safety assurance came to dominate gov­ ernment policies with regard to biotechnolo­ gy. it consequently also became an ongoing OECD activity. the centerpiece of OECD's biotechnology work . The organization thus responded to the public and government con­ cern about genetic modification. in a political atmosphere marked by environmental move­ ments which mirrored or reinforced those concerns. The work on biotechnology safety acquired a significance for Member countries, for rea­ sons other than those which had led to the or­ ganization 's long-term involvement in nuclear safety and in the control of chemicals. These two OECD activities responded to a history of serious risk problems and accidents, some of which endange red the e nvironment or hu­ man health. In contrast . the biotechnology sa­ fety activity accompanied the very first devel­ opments of the new technology and even pre­ ceded them, and was maintained with high in­ terest in spite of a continuing excellent safety record. Interest in the safety activity strengthened in 1 983 . as the applications of biotechnology began to take place outside contained labora­ tory conditions. and the first products were moving towards commercialization. In that year, the Committee created an "Ad Hoc Group of National Experts on Safe t y and Regulations in Biotechnology ". This group was charged with establishing scientific crite­ ria for the safe use of genetically engineered organisms in industry, agriculture and the e n ­ vironment.

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18 The Regulation of Modern Biotechnology: A Historical and European Perspective

Approximately eighty experts, including representatives of scientific research, indus­ try , government and regulatory bodies, as well as members of national rONA Commit­ tees, worked for three years under the chair­ manship of Dr. ROG E R NOURISH from the U K Health and Safety Executive, td'draft the report rDNA Safety Considerations (OECD , 1 986). This was subsequently widely cited, worldwide; and became popularly known as the "Blue Book". The European Commis­ sion , through DG XII as chef de file, was an active member of the expert group; practical­ ly all members were also active in their na­ tional contexts, concerning biotechnology regulation. The report devised general guidelines for the evaluation of large-scale use of rONA or­ ganisms, and represented a major step for­ ward in the history of biotechnology since Asilomar. The earlier NIH RAC and GMAG guidelines related to small-scale research. Agreement in the expert group constituted a first step in the harmonization process of safe­ ty principles and practices among the Mem­ ber countries of the OECD. The OECD Council adopted in 1 986 the recommendations of the report, which, though not formally binding, expressed a high degree of commitment by Member countries to adopt the common scientific framework set out in the report. The government representatives in the group came from a number of different gov­ ernment ministries and agencies, all having some direct i nterest in biotechnology safety: science and technology, environment, public health, agriculture and others. Thus, the main task, but also the chief difficulty, of the group was to reconcile the different perspectives of these agencies and to promote an interdepart­ mental and interdisciplinary approach - as well, obviously, as an international one. The discussions of the group often reflected these i nter-departmental differences, particularly between agencies for science and technology and agencies for the environment. To facili­ tate dialogue, the OECD Environment Direc­ torate, and through it the Environment Com­ mittee, actively participated in these discus­ sions and used the Group for help with policy analysis and programme co-ordination.

The 1 986 " Blue Book" included the Coun­ cil Recommendation, and made three funda­ mental points which convey the general ap­ proach of the experts: - any risks raised by rONA organisms are expected to be of the same nature as those as­ sociated with conventional organisms. Such risks may, therefore, be assessed in generally the same way as non-recombinant DNA or­ ganisms; - although rONA techniques may result in organisms with a combination of traits not observed in nature, they will often have in­ herently greater predictability than organisms modified by conventional methods; - there is no scientific basis for specific leg­ islation to regulate the use of recombinant DNA organisms. On the basis of these general assumptions, a new concept was defined for the safe han­ dling at large scal e of industrial applications of low-risk rONA organisms. This concept advocates a minimum level of control, "Good Industrial Large Scale Practice " (GILSP), based on existing good industrial practices. A number of criteria were also set out which rONA organisms should meet in order to be assigned "G ILSP" status, and to be handled under GILSP: these were set out in Appendix F of the "Blue Book" (reproduced below). They were also subsequently used as the defi­ ning criteria for "Type I" microorganisms in the European Community legislation on "contained use". It was nonetheless later ar­ gued (THORLEY, 1 994) that these conditions reflected too closely the experience and re­ quirements of the pharmaceutical industry; but at the time, no other sector of the "bio­ i ndustries" was present in the debate. Appendix F of " Recombinant DNA Safety Consid­ erations ": Suggested Criteria for rONA GILSP (Good Industrial Large Scale Practice) Micro-or­ ganisms

Host Organism: • • •

Non-pathogenic; No adventitious agents; Extended history of safe use; OR

6 •

International A ctors:

European. the

B u i l t - i n e n v i ro n m e n t a l limitations per m i t t i n g optimal grow t h in industrial setting but limited surv i v a l w i t h o u t a d v e rse consequences in envi­ ron ment.

rDNA Engineered Organism : Non-Pat hoge n i c • A s safe in indust r i a l se t t i n g a s h o s t organism . b ut w i t h l i m i t e d surviuval without adverse conse­ •

quences in

t h e e n v i ronme n t .

Vector/Insert: Well cha racte rized a n d free seq u en ce s

•

from k nown harmful

•

Lim i t ed in size as much as possible to the D N A to pe r fo r m the i n t e n d e d function: should not i ncre ase the s t a b i l i t y of t h e construct in the environment ( u n l e s s t h a t is a requirement of the i n t en d e d funct ion ) Should not transfe r r esi s t an c e markers to micro­ organisms not k nown to ac q u i r e them naturally req u i re d

•

(if such

acq u isit ion could

drug to control

compromise use

disease a ge n t s ).

of

I ndustrial input to these deliberations was relatively limited. and restricted to individuals with backgrounds in the pharmace utical in­ dustry. Again. THORLEY ( 1 994) pointed out (THORLEY , 1 994) that criteria such as the precise characterization of the vector insert were not necessarily appropriate to all the re­ search and industrial contexts to which they were subsequently applied . The importance of the G I LSP concept was nonetheless great. given that the vast majority of industrial applications typically used intrin­ sically low-risk organisms. A specific recom­ mendation was made for industry to utilize, wherever possible . such low-risk organisms in industrial app lications of rONA techniques. The approach of the 1 986 report to the safety of agricultural and environmental appli­ cations was, of necessity at that time . conser­ vative. The OECD experts felt that the safety assessment of organisms for agricultural and environmental applications was less develop­ ed than for industrial applications. General safety guidelines or criteria were . therefore. premature and a provisional case-by-case ap­ proach was recommended. They acknowl­ edged, however. that considerable data were available on the environmental and human health effects of living organisms and that this should be used to guide risk assessment.

O ECD.

the UN Agencies and

Rio

615

Thus. a largely e ncouraging expert view had replaced the concerns of the 1 970s: the risks long associated with biotechnology re­ mained purely conjectural. OECD Member countries, as well as India and Latin American countries, adopted in their national safety guidelines or legislation the general O ECD safety principles. These principles often became a guide to the minis­ tries and government departments sharing re­ sponsibility for biotechnology, and thus con­ tributed to building up a common national, as well as international. approach. As the flexible approach adopted in the " Blue Book" called for the adaptation of sa­ fety assessments to new knowledge , a revision was undertaken in 1 988 by a fol low-up "Group of National Experts on Safety in B io­ technology", widely referred to thereafter as "the GNE". This revision aimed at the elaboration of G I LSP criteria and the identification of gen­ eral safety principles for agricultural and en­ vironmental applications of plants and micro­ organisms. As the G I LS P concept was relatively new, the G ILSP criteria were elaborated to assist countries in their correct interpretation. The revision provided , for each criterion . an illus­ tration of the nature of the different require­ ments and of the way these should be met. The second major area of revision con­ cerned the safety of the introduction of gene­ tically modified organisms into the environ­ ment for agricultural or environmental pur­ poses. The increasing number of field tests performed since 1 986, and the increasing number of those planned, led the OECD ex­ perts to define a set of ''Good Developmental Principles" (GOP). These principles were to guide researchers in the design of small-scale field experiments with genetically modified plants and microorganisms. By early 1 993. more than 800 experiments, at more than 1 1 00 sites, had been carried out in the world. New knowledge and this experience enabled the development of GOP, judged to be pre­ mature in 1 986. But simplification for the oversight of low-risk releases was becoming essential: by end of 1 984, there had been over 3000 site-releases in the US alone, numbers having doubled annually for several years.

61 6

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

GDP identifies three key safety factors: the characteristics of the organisms, the charac­ teristics of the research site, and the use of appropriate experimental conditions. It also defines the different ways in which GDP can be met. While existing national or interna­ tional codes of good practice for the safe con­ duct of research address primarily human health and worker safety, GDP also takes into account environmental safety. The revision was published with the title Safety

Considerations for Biotechnology

-

1 992 (OECD , 1 992).

Large-scale Release, and Sectoral Applications of Microorganisms

After 1991, the GNE broadened its activity to cover a number of areas, some of these new. Safety work in the Secretariat had been carried out in close co-operation between the Directorate for Science , Technology and In­ dustry (DSTI) and the Environment Directo­ rate, which shared the tasks. These areas were: (i) Guiding principles for large scale re­ leases of genetically modified organisms, ex­ tending to plants, microorganisms, and ani­ mals. This work included the completion of gen­ eral statements of safety principles for all modified organisms (the "Preamble" docu­ ment; OECD, 1 993c), as well as specific work on crop plants, leading in particular to the production of the reports: Safety Considera­ tions for Biotechnology - Scale-up of Crop Plants, Traditional Crop Breeding Practices: A

Historical Review

Transgenic Plants,

and

Field Release of

1 986-92 (OECD, 1 993d, e ,

f) . I t also includes programmes of work on various categories of microorganisms: biofer­ tilizers, live vaccines, bioremediation/biomin­ ing, biopesticides, biofeeds, all leading to­ wards corresponding reports. This shift to­ wards sectoral safety studies reflected the general development of biotechnology and of related risk assessment work and regulatory developments. The report on the Langen workshop of No­ vember 1 993 (OECD & lABS, 1 994) was an important example. This considered the non-

target safety aspects of live recombinant vac­ cines, addressing both human and animal vac­ cines, viral and bacterial, with leading experts in each field drawn from many parts of the world. Speakers reviewed the past successes and problems of vaccines in relation to var­ ious diseases, demonstrating the great in­ crease in understanding which modern molec­ ular genetics was bringing to established vac­ cines, as well as opening the way to new and safer ones. Various potential problems specif­ ic to recombinant vaccines were reviewed, and the means of addressing these. In conclu­ sion, it was reported that, "While recombi­ nant should therefore be investigated with caution, it does not seem j ustified to treat them differently from other live vaccines". (ii) Safety assessment of food produced by biotechnology, from terrestrial and aquatic organisms (by the Environment Directorate in co-operation with DSTI) was again a secto­ ral example with sectorally specific aspects. Work focusing on terrestrial organisms, in­ cluding a workshop in Copenhagen in 1 991 , led to the publication Safety Evaluation of Foods D erived by Modern Biotechnology -

Concepts and Principles, 1 993 (OECD, 1 993g). This book was timely. It came at a critical moment, responding to public con­ cerns and discussions in some Member coun­ tries about new foods based on biotechnolo­ gy. The book elaborates scientific principles to be considered in making evaluations of new foods or food components based on a comparison with foods that have a safe histo­ ry of use. The most practical approach to de­ termine the safety of foods derived by mod­ ern biotechnology is to consider whether they are "substantially equivalent" to analogous traditional food products. The case studies in this report illustrate the application of the concept of substantial equivalence. For new foods to which this concept was not applica­ ble, further work continued. An OECD workshop in Oxford, UK, in September 1 994 opened the consideration of a broader class of questions on the safety evaluation of foods in general, particularly novel foods; and the close interaction with the UN WHO/FAO activities in this field was en­ sured by the presence of key experts also working in these other contexts (particularly

6

International Actors: European. the O ECD, the UN Agencies and Rio

in relation to the WHO/FAO expert consulta­ tion on food safe tv assessment methods of au­ tumn 1 995 ). This a llowed the participating in­ dividuals, and hence their organizations . to define the respective roles of the different or­ ganizations in a coherent manner. thus faci li­ tating the widespread acceptance of common scientific principles as the bases for regula­ tions in this vast and fundamental sector. (iii) Reviews of monitoring methods for genetically modified organisms in the envi­ ronment ( OECD. 1 994a. b). based on the 1 992 workshop in Ottawa: and the computer­ ized poi nter system for releases. leading to the annual publication on diskettes of the ''BIOTRACK '' pointer system ( Environment Directorate). The mandate of the GNE ended in March 1 994. There was widespread consultation and debate over what should succeed it. General agreement on the need to address a wider range of issues than safety carried the discus­ sion into areas of i nterest to several Com­ mittes and Directorates. underlining a greater need for co-ordination. The solution adopted at the end of 1 993 was to establish an Internal Co-ordination Group for Biotechnology. chaired by a Deputy-Secretary-General, as a Secretariat responsibility. with involvement of the various interested Directorates (see OECD, 1 994d ) . The parallel with the Euro­ pean Commission 's .. Biotechnology Coordi­ .. nation Committee (see Sect . 7.2) is evident. The CSTP itself agreed to establish a new .. .. Working Party on Biotech nology . with the broader mandate reproduced below: Wo r k i n g P a r ty on B i o t e ch nol o gy Of the Commit t e e for Scie n t i fic and Tech n o l og i c a l Policy

I . The gen er a l objective

of

the G r o up shall be to

keep under re\ iew and ad v i se upon scie nce . tech­ nology a n d i n n o v a t ion issues in b i o t ec h n o lo gy . w i t h

a view to as s i s t i n g the devdopmcnt of its safe and e ffective usc . by inter alia, e ncou r a g i n g the i n t e r n a ­ t i onal harmonization of scie nce-based p r i ncip l e s a n d pract ices. a n d facilitating i n t e r n a ti ona l scien­ t ific and technological col l aboration and exchange . 2. The r e le van t clements of t h e Work Programme of the Committee for Scie n t i fic a n d Technological

Policy ( CSTP) shall determine t h e scope and con-

6 17

tent of the G roup's activities. Th e G ro up ' s func­ i nc l ud e : - pro v i d in g a forum for Member countries to m a k e k nown and to discuss their needs a n d p r i o r itie s ; - he nce e n ab l i n g t he i d e n t i fi c a t i o n of si gnifi c a n t is­ sues fo r t h e W o r k P rogra m m es of relevant OECD Committees: - advising t h e CSTP upon the p r i o r i t iz at i o n of sug­ g e s t e d activities for future Work Programmes; - m a n a g ing the implementation of the biotechno­ logy e le ments of the curre n t CSTP Work Pro­ gramm e , i n c l u d i ng p roj e c t a c t i vi t ies . 3. The G r ou p will report to t h e Committee for Scientific a n d Te c h n o l o g ic a l P o l i c y , w h ich shall k e e p other Com m i t tees - i n particular the E n v i r on ­ m e n t a l Po l ic y Committee. the I n d ustry C om m it te e a n d the A gr i cu l t u r e Committee - i n formed on the progress of work relevant to their i n t e res ts ; in p a r t i ­ c ul a r . t h r oug h the Internal Co-ord ination Group for B iotechnology. This should lead to avoidance of du p l i cati on . and the p ro m otion of joint activities, w h e re app ro p r iat e . 4. The M andate shall run from 1 A p r i l 1 994 to 3 1 A ugust 1 998, s u bje ct to modification b y d e c i s i o n of the CSTP: w i t h a m i d- t e rm review t o assess th e val­ u e . i m p a c t a n d e ffective ness of the work of t h e

tions s h a l l

Group.

The new Working Party first met in J une 1 994. within a Work Programme specification set by their parent Committee and with spe­ cific projects in all the three major areas of application: agro-food; health care: and envi­ ronment. As in the earlier work, the OECD was not directly involving itself in the drafting of regulations: but continues through various Directorates and Committees to make two fundamental contributions: - developing common scientific concepts and principles. to underpin regulation where this necessary: - conducting enquiries in co-operation with Member governments, and in rela­ tion to various sectors of relevance to biotechnology (e.g., i n 1 994, on bio-pes­ ticides: in 1 995 , on intellectual proper­ ty), to encourage mutual understanding of the data requirements of regulators in different countries, and hence facili­ tate movement towards common ap­ proaches and ultimately mutual accept­ ance of data, and of product authoriza­ tion decisions.

618

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

6.3 The UN Agencies (1 ) : WHO , F AO, ILO , IPCS , UNID O , the

World B ank and CGIAR, ICGEB , UNESCO and I CSU

The pervasive character of biotechnology has brought it onto the agenda of practically every agency of the United Nations (UN). The perspectives would differ from agency to agency, but usually involved some aspects of promotion and/or regulation. Some of the sal­ ient developments are presented below. Al­ though many of these UN initiatives were slow to develop or late in starting, they con­ tinue to demand political attention, and to promote or elicit calls for regulatory action at global level. Such calls have been encouraged by parallels with other topics in which global agreements or conventions have been ad­ opted and are implemented, or moving to­ wards implementation. A list may serve to summarize and intro­ duce the following sections. 1. World Health Organization (WHO) - ex­ perience of developing and diffusing safe working practices, i nterested in the potential of biotechnology for vaccines and other bio­ logicals, and responsible for the publication of many Technical Reports on guidelines and requirements for such products (cf. WHO, 1 983, for an early example). In later years, WHO became an outspoken advocate of the importance of biotechnology and genetic en­ gineering for world health (WHO, 1 994). 2 . Food and Agriculture Organization (FAO) - interested in the potential of bio­ technology for enhancing the quantity and quality of food production; involved in issues concerning conservation and use of genetic resources, particularly relating to crop plants. 3. UN Educational, Scientific and Cu l tural Organization (UNESCO) - longstanding pro­ grammes in applied microbiology, particular­ ly the worldwide network of Microbial Re­ source Centres (MIRCENs), the international GIAM conferences (Global Impacts of Ap­ plied Microbiology), support for ICSU, the I nternational Council of Scientific Unions.

4. UN Industrial Development Organization (UNIDO) - interested to promote the safe development and application of biotechnolo­ gy in the interests of developing countries; launching of ICGEB , the International Cen­ tre for Genetic Engineering and Biotechnolo­ gy; related service, B INAS (Biotechnology Information Network and Advisory Service); leadership of the inter-agency (UNIDO/ U NEP/WHO/FAO) Working Group on B io­ technology Safety (Voluntary Guidelines on GMO Release: UNIDO, 1 991 ) ; co-ordinating role for Chapter 16 ("Biotechnology") in AGENDA 2 1 (see Sect. 6.4). 5. The World Bank - not only financing a growing number of projects involving bio­ technology, but chairing the CGIAR (Consul­ tative Group for International Agricultural Research) , and thus involved in advising all the 18 IARCs (International Agricultural Re­ search Centres) on policy questions of com­ mon interest - including those relating to in­ tellectual property rights, and bio-safety and regulation. (cf. PERSLEY et al., 1 992). 6. UN Environment Programme (UNEP) see Sect. 6.4. Involved in the inter-agency Working Group formulating Guidelines for Deliberate Introductions. 7. Advanced Technology Assessment System (AT AS) - preparation and diffusion of infor­ mative reports on biotech applications of in­ terest to developing countries, e.g., "Biotech­ nology and Development: Expanding the Ca­ p acity to Produce Food" (UN, 1 992) . From the Control of Chemicals t o the Control of Biotechnology - A False but Influential Analogy

In describing the history of the biotechnol­ ogy regulatory initiatives in the European Community (Sect. 4.4), extensive reference was made to the prior and continuing interna­ tional developments concerning the regula­ tion and control of chemicals. The hi s to ry of the international development of regulations and control for chemicals has been written elsewhere, in documents ranging from the de­ tails of regulatory texts and technical annexes, to partly autobiographical overviews by some of the individuals involved; the review by LbNNGREN (1 992) is particularly valuable.

6 lmernational A cto rs: European, the O ECD. tire UN Agencies and Rio

As the che mical industry developed and expanded - and especially i n the postwar de­ cades - the control of chemicals was recog­ nized to be essential. because of their effects upon human ht.!alth - either directly. or via residues in the food supply: and (a later de­ velopment in regulatory terms). because of their effects upon the environment. Thus the challenge of chemical safety engaged the re­ sponsibilities of several of the UN agencies. created in 1 944 and subsequent years: parti­ cularly those concerned with public health . worker safety . food an d agricult ure . a n d the environment. All these areas of regulatory re­ sponsibility would also be later considered in relation to the applications of biotechnology. and its (or their) regulation. Although the problems are in principle universal. the responsibilities for establishing and operating systems for regulation and con­ trol are necessarily local and national. Thus the development of the present systems for controlling the safety of chemicals involved several '' levels'' . political or geographical, in­ cluding the following: - national (the US TOSCA being of par­ ticular significance also in international terms) - European ( see Sect . 4.4 . concerning the evolution of the ··Sixth Amendment" Directive ) - OECD ( since most new chemicals. and the bulk of trade . origi nate i n the OECD area) - UN agencies. particularly WHO. FAO . I LO and UN EP. The relative success of those efforts. at all the four leve ls and in the various contexts cited above. has strongly underpinned the as­ sumptions and efforts of the same agencies often the same individuals - when they sought to repeat in the context of biotechno­ logy and/or ge netically modified organisms the successful story of chemicals control. The history of biotechnology regulation . and the evolution of the debates scientific and ( later) political. indicate that attempts to ap­ ply to biotechnology the concepts . ap­ proaches and regulatory instruments develop­ ed for chemicals may be based upon a false

61 9

analogy : but the attempts to make such a transfer were of major influence. It is there­ fore important to an understanding of the ini­ tiatives of UN agencies vis-a-vis biotechnolo­ gy to include also some elements summariz­ ing their roles in the earlier ( and continuing) success story. More rece ntly. as biotechnology moves into routine application in different sectors, the influence of the generic approach adopted in regard to chemicals might be expected to diminish in re levance. However. the three major sectors of application themselves coin­ cide with the sectoral responsibilities of three of the UN agencies most active in the earlier work on chemicals: • •

•

agriculture and food (FAO) health care and pharmaceutical prod­ ucts (WHO) environment ( UNEP).

Thus the role of these and other UN agen­ cies vis-a-vis biotechnology remains of con­ siderable. or even increasing, importance. Historical Developments - WHO and FAO - Additives and Residues in Food

The signing of the Charter of the United Nations at San Francisco, in 1 945 . provided a fresh starting-point and basis for international machinery to address common challenges such as health and food. The near-parallel founding of the " B retton Woods" institutions, particularly GATT, reflected a similar will­ ingness to design a world system more open than that of the pre-war period, and in which the growth of world trade would require com­ mon machinery to address such issues as the safety of chemicals. medicines and foods, and to avoid obstacles to trade in these products. The Food and Agriculture Organization of the U nited Nations (FAO) was also created in 1 945. and the constitution of the World Health Organization (WHO) was signed the following year. In the immediate post-war years. basic food supply and n utrition were obvious priorities, and the role of chemicals as fertilizers and to reduce losses to pests was obvious. But from the 1 950s, concerns were

620

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

shifting from assuring the quantity of food, to considerations of its quality and safety. Concerns about chemical (particularly pes­ ticide) residues in foods, and synthetic food additives, led WHO a n d FAO to collaborate in joint activities to bring the best scientific expertise in the world to bear upon these problems. The World H ealth Assembly - the governing body of the WHO - noted in 1 953 that the increasing use of various chemicals in the food industry had in recent decades created a new public health problem. In re­ sponse, WHO and F AO initiated two series of annual meetings: on food additives (Joint F AO/WHO Expert Committee on Food Ad­ ditives, JECF A), and on pesticide residues. The first meeting on food additives was held in 1 956, and that on pesticide residues in 1963 . Joint Meetings of the FAO Panel of Ex­ perts on Pesticide Residues in Food and the Environment, and the WHO Expert Group on Pesticide Residues, are usually referred to as the Joint FAO/WHO Meeting on Pesticide Residues, or JMPR. In 1 980, the WHO activities concerned with the safety assessment of food chemicals were incorporated into the International Pro­ gramme on Chemical Safety (IPCS), whose genesis and activities are described below. In 1 962, the Codex Alimentarius Commis­ sion was established, to implement the Joint FAO/WHO Food Standards Programme. The Commission was created as an intergovern­ mental body, which now has more than 1 20 Member nations, whose delegates represent their countries. The Commission's work is carried out through various Committees, such as the Codex Committee on Food Additives (CCFA). JECFA serves as the advisory body to the Codex Alimentarius Commission on all matters concerning food additives. Since the early 1 960s, the JMPR has evalu­ ated a large number of pesticides. The WHO component of these Joint Meetings relied upon procedures developed by other expert groups - particularly JECF A - and developed specific principles for evaluating the various classes of pesticide that are used on food crops and may leave residues on them. The WHO issued a series of publications on "En­ vironmental Health Criteria", of which num­ ber 70 on "Principles for the safety assess-

ment of food additives and contaminants in food" (WHO, 1 987) summarized the assess­ ment procedures used by JECF A. A later ( WHO, 1990) publication, on P ri nciple s for the Toxicological Assessment of Pesticide Residues in Food" gathered to­ gether and updated the assessment principles relevant to this field. By that date, it seemed appropriate to include a page specifically on biotechnology, because of three areas of emerging concern: "

- the production of chemicals of biologi­ cal origin with pest control activity (e.g., pyrethrin and derivatives) - the use of microbial pest control agents - the development and use of genetically altered (bioengineered) organisms for specific purposes. Biotechnology in Foods FAO/WHO Initiatives

Current

The shared interests in food safety of FAO and WHO over several decades have been in­ dicated by reference to the work of the joint bodies JECFA and JMPR, both conducted since 1980 under the aegis of the IPCS. It be­ came evident in the 1 980s that modern bio­ technology would find applications in the or­ ganisms used by the food industry (for fer­ mentation, enzymatic processing, etc. ) or in t he foods themselves (either by improvement of traditionally used strains, or as novel foods). A "Joint FAO/WHO Consultation on the Assessment of Biotechnology in Food Pro­ duction and Processing as Related to Food Safety" was held in Geneva in November 1 990. The conclusions of the consultation em­ phasized the long historical experience with various biotechnologies in food prod uction, and its tone was positive. "The newer biotechnological tech­ niques, in particular, open up very great possibilities of rapidly improving the quantity and quality of food availa­ ble. The use of these techniques does not result in food which is inherently less safe than that produced by conven­ tional ones."

6 International A ctors: European, the

A fter citing examples . the report (WHO.

1 991 ) stated that "whenever changes are

made in the process by which a food is made or a new process introduced . the implications for the safety of the product should be exam­ ined. The scope of the evaluation will depend .. on the nature of the perceived concerns . The conclusions of the report conti nued: "' 5 . The e va l u a t ion of a new food sh ou l d cover b o t h sa fe t y and nutritional v a l u e . Similar conve n t ion a l foo d pro d u c t s should be used as a s t a n d a rd and a ccoun t will need to be

t a k e n of any processing that the food will u n d e rgo as well as t h e intended u s e of the .

food.

6. Comparative d a t a o n the closest conven­ t i o n a l counterpart are c riti c a l l y i mp o r t a n t in the ev a l ua t i o n of a n e w food. in c l u d in g data on chemical co mpos i tio n a n d n u t ri tional va lue . The Consult at ion believed that such data are not w i d e l y available at the p r e se n t t i m e . 7 . A n e w . multidiscipl i n a ry a pp ro ach to t h e safety ev a l uat i o n of new foods is d es i ra b l e based on a n u n d e r s t a n d i ng of the mecha­ nisms unde rlying cha nges i n composition. Detailed k n o w l e d ge of the chemical c o m ­ po si t i on of t he food. to ge t h e r with informa­ tion on the ge netic m a k e - u p of t h e organ ­ isms involved. should form t he b as i s o f the evaluation and will i ndicate the n ecess i t y for to x i c i t y testing in animals. The ap­ p roa c h will be facilitated by t he in t e g ratio n of molecul a r biology into the evaluat ion process. H . The Consu ltation agre e d a set of scient ific p ri n ci p l e s to be applied to t h e e v a l u a t ion of the safety of foods produce d by biotech­ nology. a l t h o u g h at present they w o u l d ­

.

need to be applied on a case-by-case basis.

9. In due course it will be possible to develop a framework for the evaluation of a l l new food s , including those produced by

biotech­

nology. This will need to be flexible. the data needed d e p e nding on the n a t u re and use of t h e product. There is at present l i ttl e e x pe r i e n ce from which to deve lo p general criteria for such a framework and. u n t i l such time as t hese criteria can be dev e l op ­

ed. a case -by-case a pp roac h is required. 10. As far a� t he products of the newer bio­ t e c h n ologie s a re c on c e r n ed . detailed knowl­ edge of t he i r mol ec u l a r b iolog i c al prope r­ ties w i l l faci l i t a t e the evaluation process. I t is a l re a d y possible t o identify many of the categories of data t h a t w i l l

be n e ce s s ary I n .

OECD,

the

621

UN Agencies and Rio

d u e co u r se it w i l l be p oss i b l e to identify the ge n e t i c elements that are likely to be ac­ ce p t a b l e for use in food p rod u c i n g orga n ­ -

isms. I I . To facilitate

the safety e v a l u ation of foods p roduce d by means of biotechnology, ac­ t i o n at t he international level will b e neces­ sary to provide t i m e l y expert advice i n this matter to Member States of FAO and WHO. the Codex A l i m e n t a ri us Commis­ sion. t he Joint FAO/WHO Expert Co m m i t tee on Food Additives and the Joint FAO/ WHO M e eti n g o n Pes ti c i d e R e si d u e s

­

.

1 2 . The Consultation concluded t h a t , because of the rapidity of t ec h n o l o g ica l advances in t h is are a . further consultat ions on t h e safe­ ty i m p lic a t ions of the ap p l ic a t i o n of bio­ te c hn ology to food production and proc­

e ss i n g

will

be

advisable

in

t h e near fut ure . "

This report was in part consistent with the contemporaneous OECD work on food safe­ ty. Point 6 on comparison with the "closest conventional counterpart" being closely con­ sistent with the concept of "substantial equi­ valence'" advocated in the O ECD report (OECD, 1 993g): but much of the language of Points 6 to 10 was in fact hugely ambitious, or could be so read. The FAO/WHO report's Recommenda­ tions went on to set out what was in effect an outline programme for work over the follow­ ing years. or simply a broad statement of in­ tent: "' 1 . C o m p re hens i v e well e n fo r ced food regu l a ­ .

t ions a re i m portant in p rot e ct ing consumer health, a n d all national gove rn m e n t s should e nsure t h a t s uc h re g u l a t ion s k e e p pace with d e v e l o p i n g t echn olog y . 2. National regu l ato ry a ge nc i e s should adopt

the strategies iden t i fi e d in this report for the safety of foods derived fro m

e va l ua t i ng

biotech nology.

3 . T o facilitate the ev a l uat i o n of foods pro­ duced by b i ote c h n o lo gy data bases should ,

be established on: - t he n u t ri e n t and

toxicant

content

of

foods;

- the molecular a n alysis of o rg a n is ms used i n food production ; - the molecu l a r , n u t ritional a n d toxicant co nt e n t of g e ne t ic a l l y modified organ isms i n t e n de d for use in food p roduct i o n 4. Co n su m e r s should be provided w i t h sound, sci e n t i fically based i n formation on t h e ap.

622

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

plication of biotechnology in food produc­ tion and processing and on the safety is­ sues. 5 . F AO and WHO, in cooperation with other international organizations, should take the initiative in ensuring a harmonized ap­ proach on the part of national governments to the safety assessment of foods produced by biotechnology. 6. FAO and WHO should ensure that timely expert advice on the impact of biotechnolo­ gy on the safety assessment of foods is pro­ vided to Member States, the Codex Ali­ mentarius Commission, the Joint FAO/ WHO Expert Committee on Food Addi­ tives and the Joint FAO/WHO Meeting on Pesticide Residues. 7 . FAO and WHO should convene further consultations at an appropriate time to re­ view the Consultation's advice in the light of scientific and technical progress."

As biotechnology advanced from making marginal, well-characterized changes, towards its use (and/or with other modern technolo­ gies) in producing novel foods, the scope of discussion had to broaden , as illustrated by four events or activities in the 1 990s: (i) The European Commission's draft Council Regulation on Novel Foods included genetically modified organ­ isms in its scope; but the Commission sought to avoid any stigmatization of the techniques of biotechnology by setting them in the broader context indicated by the title of the regula­ tion, and maintained a risk-based ap­ proach (subject to the obligatory ref­ erence to the environmental risk as­ sessment requirements of the Field Release Directive 90/220 - obligatory if GMO food products were in future to fall under the new Regulation). (ii) The O ECD work on food safety was advanced by a workshop held in Ox­ ford in September 1 994, under the aegis of the former Group of Nation­ al Experts on Safety in Biotechnolo­ gy, (which in March 1 994 was re­ placed by a body of broader mandate - see Sect. 6.2) but addressing the more general issue of "safety assess­ ment in food". As biotechnology-re-

lated aspects moved from minor con­ stituents or marginal changes, to pro­ viding foods which would constitute major elements of the whole diet, it was recognized that different prob­ lems were posed, different methods required: techniques, toxicological and other, designed to appraise mi­ nor or potentially toxic constituents, could not be scaled up by a multiply­ ing factor as safety margin, if they were envisaged as major components of the whole diet, of man or of a test animal. Principal scientific issues were rather nutritional, including problems of extrapolating from ani­ mals to humans in the knowledge that the nutritional requirements of different species are far from identi­ cal. (iii) The Danish Government in Novem­ ber 1 994 hosted a WHO workshop to develop in more operational detail the concept of "substantial equival­ ence". (iv) WHO and FAO prepared for late 1 995 an expert consultation on the safety assessment of foods produced by biotechnology, addressing these broader issues. In the context of the European Union, the debate on the Novel Foods Regulation be­ came for a time the focus of political demands for GMO labelling, on the grounds of con­ sumer information and transparency. While this seemed plausible in the context of prod­ ucts such the Calgene "Flavr Savr" tomato, it was clearly unrealistic to envisage for fungible products such as grains, where distinct labell­ ing would imply a separation and duplication of the whole storage, transport and distribu­ tion systems, from the farm to the final bake­ ry outlet or animal feed-lot. Against this background of politicization and controversy, the continuing international and science-based approach of the UN Agen­ cies FAO and WHO, and of the OECD , pro­ vided and continues to offer an important source of objective and internationally ac­ ceptable advice and reference materials.

6 lntemational A ctors: European, the

Chemicals Control: ILO, EC, IPCS OECD

Agencies and Rio

623

ists. bioche mists. ec o l ogi s ts - a l l pouring

and

A major role in the control of chemicals was played by the I nternational Labour Or­ ganization. ILO: a surviving element from the 1 9 1 9 Peace Treaty of Versailles. One of I LO's primary concerns was and remains occupa­ tional safety. In 1 950. the ILO Chemical In­ dustries Committee called for a classification and labelling system for hazardous chemicals. In 1 956. it published a "List of Dangerous Substances Presenting an Occupational Haz­ ard". The evolution of an integrated approach to the risk assessme nt. regu lation and control of chemicals had several strands: including both UN agencies. and the OECD. In addition. aft­ er the signing in 1 957 of the Treaty of Rome . establishing the European Economic Com­ munity. the E E C also became a significant playe r in the international arenas concerned. The OECD itse lf. although based on the ear­ lier ( 1 948) Orga nisation for European Eco­ nomic Co-operation. was created in its cur­ rent form only in 1 960. Through the 1 960s. concerns about the en­ vironmental impacts of pesticides and other chemicals continued to rise . The publication of RACHEL CARSON 's "Silent Spring" in 1 962 is often cited as a landmark in the recognition of the need for more effective control of chemicals. particularly pesticides. In the con­ text of biotech nology . we note in passing the plea . less known but no less worth citing. which CARSON made for a more biologically­ based technology:

OECD, the UN

t he i r k n ow l e dge a n d t h e i r creative i n s p ira ­ t ions i n to the formation of a n ew science of . biotic co n t ro l s . .

This plea. preceding the arrival of modern biotechnology. may yet be answered by it; but we return to the history. L6NNGREN's ( 1 992) " Historical Overview" incl udes a rich chronology of events, which summarize some of the defining moments in the evolution of i nternational approaches to chemicals control. From L6NNGREN and oth ­ er sources can be compiled the following: 1 96 1 : Joint FA O/W H O expert

m e e t i n g on the use

of p es t ici d e s i n agriculture 1 962: Establishment

of

the Codex A l i me n t a r i u s

Commission Publication b y t h e Council of E u rope of the first edi tion of " Ye l low Books" with l ists of

some 500 chemicals a n d recommendations for l a b e l l i n g 1 963:

Fi rst Joint Resid u e s

FAO/W H O m e e t i n g on Pesticide

1 966: O E C D meeting. Jouy-en-J osas. France. on

" U n i ntended Occurre nce of Pe s t i c i de s in t h e E n v i ro n m e n t " 1 967: Adopt ion by the C ou n c i l of the E ur o pe a n Communities of Direct ive 67/548, on " t h e ap­ p rox i m a t ion of the l aws, regulations and ad­ m i n istrative pr ov i s io ns re l at i n g to the c lassifi ­ cation. pack a g i n g and labelling of dangerous

substance s " 1 968: U N G e n e r a l Ass e m b l y decision to co n v e ne

in 1 972 a " Con fe r e n ce on the H u m a n E n vi ­ ro n m e n t " 1 969: Establis h m e n t b y I C S U ( t he I n t ernational

Council of S c i e n t i fic U n i o n s ) of SCOPE. the

Standing Co m m i t t e e on P ro b l e m s of t h e En­

v i ronment

" A t ru l y e x t r a o rd i n a ry va ri e t y of a l t e rna tive s to t he chemical cont rol of i n sec t s i s a v a i l a ­ ble. Some are a l r ea d y i n u s e a n d have achieved b r i l l i a n t s uc c e ss . Others are i n t h e

OECD convenes a Stu d y G ro u p on t h e U n ­ inte nded Occurre nce of Pesticides 1 970: O E C D Council e st a b l i s h m e n t of Environ­ ment Com m i t t e e

st age of la b or a to ry test i ng. S t i l l ot hers are

W o r l d H e a l t h A sse m bl y request t o W H O

little mo re t h a n ideas i n t h e minds of i m a g i ­

D i rector- G eneral t o d e v e l o p a l ong- t e rm programme for e nvi ron m e n t a l health

native scie n t ists. w a i t i ng for t h e o p port u n i t y

to p u t them to the t e s t . A l l have t hi s in com­ mon: t h e y

a rc

b i o l ogical s o l ut i o ns . based on

understanding of t he l i v i n g o rga n is m s they se e k to co n t rol . and o f the whole fabric of l i fe to wh i ch these o rga n ism s b e lon g . Spe­ cialists re pre se n t i n g various a r e a s of t h e vast field of biology are con t ri b u t i n g - e ntomo­ l o gis t s . pat hologists. genet icists. ph y siol og -

( l a unched i n 1 973. as t h e E n v i ronmental Health Criteria P rogra m m e )

1 97 1 : O E C D establish m e n t of

a Sector G roup on the U n intended Occurre nce of Chemicals i n the E n v i ronme n t ( w h ic h from 1 975 b e co m es t h e Chemicals G ro u p ) U N ESCO l a u nc h of t h e progr a mm e Man a n d B i os p h e re

624

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

1 972: UN Conference on the Human Environment,

1 987: UNEP Governing Council adopts the Lon­

Stockholm Establishment of the UN Environment Pro­ gramme, UNEP OECD Council adoption of a Recommenda­ tion on Premarketing Assessment of the Po­ tential Effects of Chemicals on Man and his Environment WHO Resolution 30.47, expressing concern about the toxic effects of exposure to chemi­ cals, and requesting the Director-General of WHO to study the problem and propose long-term strategies OECD Council adoption of a Recommenda­ tion concerning Guidelines in respect of the Procedures and Requirements for Anticipat­ ing the Effects of Chemicals on Man OECD Council decision to set up a Special Programme on the Control of Chemicals EC Council adoption of the "Sixth Amend­ ment" of Directive 67/548 The Heads of UNEP, ILO and WHO sign a Memorandum of Understanding establishing the International Programme on Chemical Safety (IPCS) OECD Council Decision concerning the Mu­ tual Acceptance of Data in Assessment of Chemicals Publication of OECD Test Guidelines Publication of OECD Principles of Good La­ boratory Practice (GLP) OECD Council Decision concerning the Minimum Pre-marketing Set of Data (MPD) in the Assessment of Chemicals WHO expert meeting on " Health Impact of Biotechnology", in Dublin OECD Council adopts three Recommenda­ tions concerning problems on confidentiality of chemicals data and proprietary rights OECD Council adopts a Recommendation concerning Mutual Recognition of Com­ pliance with GLP Formal agreement between OECD Chemi­ cals Programme and IPCS, calling for reci­ procal use of guidelines, methodologies and evaluations developed by the two organiza­ tions IPCS Programme Advisory Committee sup­ ports the development of Health and Safety Guides and I nternational Chemical Safety Cards, as complements to Environmental Health Criteria documents FAO Conference adopts the International Code of Conduct on the Distribution and Use of Pesticides OECD publishes "Recombinant DNA Safety Considerations" ; OECD Council adopts re­ lated Recommendation.

don Guidelines for the Exchange of Informa­ tion on Chemicals in International Trade Incorporation of "Prior Informed Consent" (PIC) procedure in the FAO Code of Con ­ duct on the Distribution and Use of Pesti­ cides ILO General Conference adopts a Conven­ tion concerning Safety in the Use of Chemi­ cals at Work The UN Conference on Environment and Development in Rio de Janeiro, Brazil; in­ cluding adoption of the Convention on Bio­ logical Diversity, and of the report, "AGEN­ DA 21 " (see Sect. 6.3 ) OECD publishes "Safety Considerations for Biotechnology - 1 992". OECD workshop, Langen, Germany, on "Non-Target Effects of Live Recombinant Vaccines" WHO Conference, Geneva, on " Biotechno­ logy and World Health: vaccines and other biologicals produced by genetic engineering, review of risks and benefits" OECD Workshop, Tokyo, on "B ioremedia­ tion": coinciding with publication of "Bio­ technology for a Clean Environment" First Conference of the Parties to the Con­ vention on Biological Diversity, launches a one-year consideration of the need "for a Protocol on Bio-safety.

1 974:

1 977:

1 978: 1 979: 1 980:

1 98 1 :

1 982:

1 983:

1 984:

1 985:

1 986:

1989:

1 990: 1 992:

1993: 1 994:

These specific decisions and events are a shorthand representation, the tips of icebergs, of a great and ever-increasing volume of in­ ternational activity; the events and the activi­ ty reflecting a political will, and/or a per­ ceived necessity to address the problems of chemicals control, and to develop the corre­ sponding machinery on an international basis. Much of the activity could be characterized as reactive, an attempt to repair situations of al­ ready severe damage; but the same percep­ tions and experience argued for attempting to shift to a more anticipatory, "pro-active" mode. LbNNGREN notes that "by the early 1 970s, officials in many advanced industrialized countries realized that the burden of carrying out the necessary research and development for effective chemicals control was too great for any single country. Member countries of the OECD , for example, began to explore ways in which they could effectively share necessary technical, manpower and financial

6 International A ctors: European, the O ECD. the

resources. Given the s ig nificant trade in chemicals . another ince ntive to international c o - operation was the r e cognition that inde­ pendent or i so l ated national action could lead to i ntern a t i onal confusion and the view of such a cti o n s as technical barriers to trade "". Sig nifi c a n t roles in the evolution of inter­ national c o- o p e ration in chemicals control were played also b y the UN Economic Com­ mission for Europe: and by the C ouncil of Europe (see Sect. 6. 1 ) . Th us for all of the bodies mentioned above, there developed around chemicals control an awareness and perception of need. and a corresponding p olitical will: with the cons e que nt resource commitments: and the gra t ifying experience of successful de v elop­ men t and ado p tion of man y international in­ struments. This e x per i ence a nd its timing in­ fluenced in various ways the responses of the various bodies involved to the diverse chal­ lenges of biot e chnology . As indicated a l ready . the W H O was i nter­ ested in both the positive poten t i al. and t he safety aspects. of biotechnology for health care applications. I n 1 982 . an expert meeting was convened in Dublin. I reland. by the Eu­ ropean office. Its conclusion s were ca u tiously positive. including the following:

··- Th e conj e c t u ra l risks of the application of recombinant DNA and o t h e r techniques of biotec h nolo gy can be assessed and managed with current risk assessment s tra tegies an d c ontrol m e thods. - Bio technology in general is regarde d as a safe industry . To ensure t hat future devel­ opments take place in an equall y safe manner, the implement a t i on of new bio­ technological techniques and processes should be monitored for long-term, ad­ verse effects. - Biotechnology contri butes in several ways to the i m pro ve m ent of human health . and the extent of th i s contribution is expected to increase sig n ific a ntly in the near future. To s u pport this development further . the free exchange of info rmat i on in this area between all parts of society . as well as be­ t we e n nations . should be strongly e ncour­ aged.

UN Agencies and Rio

625

- A general responsibility of all those con­ cerned with biote c hno l ogy is to inform the public of its impact on health and the en­ vironment. Pamphlets and other educa­ tional materials on biotechnology should be developed and distributed to those in­ volved i n the education of the public . ·· (WHO. 1 984) The promise of biotechnology for health applications took some years to be con­ firmed. but the 1 980s provided sufficient con­ crete successes of biolog i cal producti o n me t h­ o ds (interferons. interleukins, g rowth hor­ mones, monoclonal antibodies) , diagnos t i cs (monoclonals . enzymes, PCR), and safe and effective new vaccines through genetic e ngi ­ neering . By the end of the 1 980s, the methods of b iotechno l ogy were figuring ever more s ignif­ icantly in the toolbox of the WHO's develop­ ment programmes. For vaccines especially . the goal of a multi - valent , single - shot live vac­ cine for the m ain childhood diseases could be considered attainable. In November 1 994, the WHO Conference in Geneva on "Biotechno­ logy and World Health" made clear the value of modern biotechnology to the aims of the Organization (WHO, 1 994) .

c are

UNIDO

The UN I ndustrial Development Orga ni za ­ tion ( UNIDO). WHO and UNEP in 1 985 or­ ganized an informal working group to consid ­ er biosafet y in relation to research institu­ tions. industry and the environment. The Working Group took into account the fact that UNIDO was then in course of estab­ lishing the In ternational Cen tre for Genetic E ngineering and Biotechnology ( ICGEB) and pressed for its active role i n the study of actual and conjectural hazards. i n de v elopin g a risk assessment methodology, i n co n duct i n g assessments. and in developing biosafety g uidelin e s for its Member countries. Of the ambiti o us obje c tive s defi ned in 1 985, many have since been addressed by oth­ er bodies . or changed in significance ; but the working group grad u ally focused upon the drafting of a Voluntary International "Code

626

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

of Conduct" for Biosafety, with particular ref­ erence to the release of GMOs into the envi­ ronment. It was envisaged that the code could provide a minimum framework or guideline to help governments in developing their own regulatory infrastructure and in establishing standards, or in obtaining appropriate advice and support in cases where a regulatory infra­ structure did not yet exist. The key elements of the Code of Conduct could be summarized as follows: comprehensive , in principle cov­ ering all types of GMOs (plants, ani­ mals, microbes) and their products; General Principles: focus on the prod­ uct, rather than the process; work with well-characterized sequences; safety precautions should be appropriate to the level of risk; monitoring; public in­ formation; reporting of adverse inci­ dents; science-based risk assessment; re­ view systems adaptable in the light of scientific information;

- Scope:

-

- A ctions for Government and Regulatory

designation of a national bio-safety authority; examination of ex­ isting regulatory mechanisms to consid­ er their application to GMOs, if neces­ sary with revision; independent risk as­ sessment of proposals, possibly using experts from another country; respect for confidential business information; exchange of information;

A uthority:

- Responsibilities of the Researcher/Pro­ poser: risk evaluation, record keeping,

notification, obtaining approval, disclo­ sure of all relevant information, sugges­ tion of independent review mechanisms if the country does not yet have a de­ signated national authority. Where regulatory review within a country was not feasible, it was suggested that those wishing to conduct such GMO releases might call upon a supranational "Biotechnology In­ formation Network and Advisory Service", B INAS, based on UNIDO/ICGEB. The draft code of conduct (UNIDO, 1 991 ) met with widespread agreement, and was completed in the early 1990s. The Preparato­ ry Committee for the UNCED conference

(see Sect. 6.4) acknowledged the work of the UNIDO/UNEP/WHO/FAO group (FAO having now joined it), and commended it to the Conference Secretariat. World Bank/CGIAR

Since the early 1 970s, donor funding (from national governments and private founda­ tions) for International Agricultural Research Centres (IARCs) has been channelled through the Consultative Group for Interna­ tional Agricultural Research (CGIAR). This ensures transparency, and provides a basis for information exchange and policy develop­ ment on matters of common interest - such as biosafety, and intellectual property rights. The CGIAR Chair and Secretariat are pro­ vided by the World Bank. I n addition to the IARCs in the various re­ gions - e.g., the I nternational Rice Research I nstitute ( I RRI) in the Philippines, CI MYTT in Mexico for wheat and maize, etc. , there is in the Netherlands, at The Hague, the Inter­ national Service for National Agricultural Research (ISNAR). With the support of the Dutch Government (through DGIS, the Di­ rectorate for International Development Co­ operation), a B IOTASK Task Force was es­ tablished, based at ISNAR, to provide for all the IARCs some common guidance on the policy challenges of biotechnology. Secretary of BlOT ASK was GABRIELLE PERSLEY, editor of a collection of World Bank Technical Papers on Biotechnology and Agricultural Development, and author of a summary report based on these (PERSLEY, 1990a, b). PERSLEY with the collaboration of VAL GIDDINGS of USDA and CALESTous JUMA of ACTS (the African Centre for Tech­ nology Studies, Nairobi), wrote for World Bank/ISNAR a short report on B iosafety. The report commends existing work by OECD (see Sect. 6.2) and the UNIDO/ UNEP/WHO/FAO group (see above); advo­ cated the creation of National Biosafety Committees; but emphasizes primarily the use so far as possible of existing national reg­ ulatory structures for the product categories concerned (PERSLEY et al. , 1 992) .

6 International A ctors: European. the

6.4 The UN Agencies (2 ) : U N EP, Rio. A G E N D A 21, CSD and the Convention on B i ological Dive rsity UNEP, the Rio "Earth Summit", and the Con-vention on Biological Diversity

The UN Environme nt Programme launched at the Stockholm Conference in 1 972 has a much shorter history than most of the UN agencie s mentioned above: and there­ fore has not had the opport u ni t y to build up the long and widespread track record of ex­ pert activity such as WHO and F AO have achieved. Moreover. although the scientific problems of food produc t ion nutrition, toxi c ology and human health are complex, their comp l exity is relatively well explored and un­ derstood as co m pa red with the vast uncer­ tainties and complexities of the whole plane­ tary ecosystem. and human interactions with it. Th us in terms of scie ntific mastery of its domain of responsibility. UNEP is at a much earlier point on i ts learning curve than WHO and FAO. Yet the urgency of the environ­ me nta l challenges has demanded an accelera­ tion of efforts and action. not only s cientific but political and regulatory/operational. Cur rent industrial practices and consum pt i o n ha­ bits in both the developed world, and the de­ veloping world . are environmentally poll u ting and unsustainable in many obvious respects. The most opti m istic rebuttal of the Club of Rome's "Limits to Growth" scenario (MEAD­ ows et a!. , 1 972) would argue that resource shortages price rises. market responses and human ingenuity may yet evolve an adapti v e trajectory to continue economic growth and development in a sustainable manner. B ut the current evidence of pollution and damage : the populat i on forecasts: and the fo recasts and e xpec tati o n s of rapid economic growth in the developi n g world: combine to indicate that the costs of the transition to s ustainabili ty will be high: and higher still, the longer necessary changes are deferred. Such was the widely accepted reasoning ar­ ticulated by M A U RICE STRONG, S ec retary of t he preparat ory group for the June 1 992 .

.

­

.

­

,

.

­

OECD.

the UN A gencies and Rio

627

" Earth Summit" , the UN Conference on En­ vironment and Development, held in Rio de Janeiro two decades after the Stockholm Conference of '72. Rio was highly publici zed in the world's media. and served to highlight environmental challenges: and its various ac­ tivities inevitably included extensive consider­ ation of biotechnology matters. The treatment of biotechnology at Rio was nonetheless ambivalent, for several reasons: acknowledging its importance to the aims of sustainable development, but tending to rei­ terate in the global forum the long-rehearsed arguments about conj ectu r al risks and uncer­ tainties associated in particular with the field release of genetically modified organisms Four reasons may have contributed to this less than balanced picture: .

(i) The conference itself had a strong presence of non-governmental organ­ i z ations (NGOs), a presence empha­ sized by their ability to attract media attention: and many of the NGOs were hostile to biotechnology, not least because they distrusted the de­ veloped countries and industrial in­ terests see n as promoting biotechno­ logy: although there was industrial representation and communication (e.g., a written statement by the In­ ternational Biotechnology Forum I B F, 1 992) , this made relatively l ittle impac t (ii) UNEP's l ack of historical scientific tradition (e.g. , as compared with WHO and FAO ) , and an apparent tendency to favor political visibility over scientific reasoning if the two were in conflict. (iii) I n the government delegations at Rio and i n its preparatory activities, there was a predominance of Environment Min i st r y rep resentat i on, naturally enough: but given the breadth of the topics addressed, the exclusion of other parts of government weakened the quality and credibility of some of the resulting outputs. For example, the European Commission was repre­ sented by DG X I , who were strongly resistant, e.g., to a DG XII presence .

628

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

at the Rio conference to cover bio­ technology policy aspects. (iv) Although the scientific dimensions of the challenges of environment and development were explicitly ad­ dressed by a special ICSU conference in Vienna, in November 1 991 - AS­ CEND 21 - both in the Rio confer­ ence and in the subsequent follow-up and instrumental developments, the scientific aspects were not strongly sustained; a complaint strongly voiced by the President of the I nternational Union of Biological Societies, in their journal Biology International, and at the UNESCO-IUBS-Diversitas Con­ ference in Paris, September 1 994 (DI CASTRI, 1 994) . Preparatory work, including the substan­ tive negotiations on the texts of UNCED doc­ uments and agreements, took place over the preceding three years; there were many meet­ ings, in New York, Nairobi and elsewhere. "Agenda 21 ", a 700-page, 40-chapter re­ port, endorsed at the Rio Summit, outlined the trajectory to a sustainable development path in the 21st century. It sought "to provide a blueprint for a global partnership aimed at reconciling the twin requirements of a high quality environment and a healthy economy for all peoples of the world", and to act "as a guide for business and government policies and for personal choices into the next cen­ tury". It "lays out what needs to be done to reduce wasteful and inefficient consumption patterns in some parts of the world, while en­ couraging increased but sustainable develop­ ment in others"; "offers policies and pro­ grammes to achieve a sustainable balance be­ tween consumption population and the Earth's life-supporting capacity", and "de­ scribes some of the technologies and tech­ niques that need to be developed to provide for human needs while carefully managing natural resources". (Quotations from K E AT­ ING, 1 993). Rio produced five documents, comprising two international agreements, two statements of principles, and "Agenda 21 " as an agenda for action on world-wide sustainable develop­ ment. The statements of principle were:

•

•

the Rio Declaration on Environment and Development; 27 principles defini­ ng the rights and responsibilities of na­ tions as they pursue human develop­ ment and well-being; a statement of principles to guide the management, conservation and sustain­ able development of all types of forests, which were emphasized as essential to economic development and the mainte­ nance of all forms of life.

Two international conventions were nego­ tiated separately from - in parallel with - pre­ parations for the Earth Summit, and were signed by most governments meeting at Rio: •

•

the UN Framework Convention on Cli­ mate Change, aiming to stabilize green­ house gases in the atmosphere at levels that will not dangerously upset the glo­ bal climate system, requiring a reduc­ tion in emission of "greenhouse gases" such as carbon dioxide; the Convention on Biological Diversity ( C BD) requiring that countries take action to conserve the variety of living species, and to ensure that the benefits from the exploitation of biological div­ ersity would be equitably shared. ,

UNEP participated in the UNIDO-led in­ teragency group that produced the Code of Conduct on Releases (UNIDO, 1 991 ), and re­ cognized the potential of biotechnology, for environmental as for other aims. But the nat­ ural constituency of Environment Agencies to which it looked for support and by whom its priorities and actions were governed, did not display a strong commitment to scientific methods, and the rhetoric of "conjectural risks of GMOs" tended to be endlessly re­ peated, irrespective of whether microbes, palm trees or elephants were the organisms concerned. Agenda 21, Chapter 16; the CBD; and the Problems with Biotechnology

Chapter 16 of AGENDA 21 made clear the promise of biotechnology to contribute signif-

6 International A ctors: European, the O ECD. the UN Agencies and Rio

icantly to health. increased food production. better reforestation . more efficient industrial processes. decontamination of water and the cleanup of hazardous wastes. Noting that most of the developments in biotechnology had been in the industrialized world . Chapter 1 6 referred to the " new op­ portunities for global partnerships between these countries - rich in technological exper­ tise - and developing countries. which are rich in biological resources but lacking in funds and expertise to use them" ( K EATI NG . op.cit). This concept of bargaining access to developing country germplasm for access to developed country biotechnology was written into the CBD, particularly its Article 1 6; and tended to foster several illusions. Firstly. the illusion that biotechnology applied to biodiv­ ersity would ge nerate economic benefits suffi­ cient to pay for conservation of the latter: sec­ ondly. the illusion that the barrier to such ex­ ploitation was the intellectual property held by the developed world; and thirdly . a confu­ sion between the powers of governments in the developed world. and the property rights of companies. Such weaknesses caused US President B usH to refuse signature of the CBD: and although President CLINTON on Earth Day in April 1 993 indicated his inten­ tion to sign, Republican opposition made clear that US ratification . requiring a two­ thirds majority in the Senate . would require bipartisan conse nsus. Certainly i t proved unattainable in the summer of 1 994 . in time for the deadline after which non-signatories could not be full participants in the first " Conference of the Parties". This. the deci­ sion-making body under the Convention , held its first session in the Bahamas, in No­ vember-December 1 994. The Republican vic­ tories in the �ovember 1 994 Congressional elections did not appear likely to soften the US opposition. Chapter 1 6 of Agenda 2 1 also spoke of sa­ fety i n biotech nology: " Care must be taken that new techniques do not damage environ­ mental integri ty or pose threats to health. People need to be aware of both the benefits and the risks of biotechnology. There is a need for internationally agreed principles on risk assessment and management of all as­ pects of biotechnology." These Chapter 1 6

629

references t o safety were brought u p in 1994; the more intense discussions of biotechnology safety and regulation took place in the con­ text of the CBD. It was a general problem of the CBD that the subject attracted more passion than preci­ sion . A scientifically vast and complex topic became the object of debates which drifted ever further from the original obj ective of conservation. Reference has been made al­ ready to the illusory "bargain" of Article 1 6. I n the ASCEN D 2 1 scientific conference in Vienna, December 1 99 1 , and the resulting re­ port ( I C SU . 1 992) . many references had been made to the need for biotechnology; nowhere was it suggested as a threat to biodiversity. But as the negotiations towards Rio pro­ gressed, biotech safety and regulation was an­ other field of argument imported into the preparation of the CBD. Rio-safety in the CBD

During 1 989 to 1 992, the European con­ troversy over the biotechnology Directives adopted in April 1 990 had become intense. DG XI's chef-de-file position i n the Rio pre­ parations, aided by Environment Ministry representatives from other European govern­ ments (particularly Scandinavian), enabled them to press for similar elements at Rio - if the Community Directives were sound and beneficial. why indeed should their benefits be restricted to Europe , and why should not the Europeans offer their benefits world­ wide?

H owever, as indicated elsewhere (Sects. 2 and 5 . 1 ) , the U nited States had taken a strongly different view of the need for bio­ tech nology-specific regulation, as had the OECD (Sect. 6.2). The discussions on biotech safety references within the CB D text there­ fore became contentious. A paper on "Bio­ technology and Biodiversity" was commis­ sioned by UN EP. from G I DDINGS of USDA. and PERSLEY of the World Bank (G I DDINGS and PERSLEY . 1 990). Their paper detailed the various tech­ niques of biotechnology which could contri­ bute directly to biodiversity conservation, and noted the indirect benefit attributable to pro-

630

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

ductivity-enhancing technology which by in­ creasing output of currently cultivated areas could take the pressure off marginal lands and ecologically sensitive areas; but did not identify any significant risks to biodiversity specifically attributable to biotechnology. The outcome of the negotiations, the final text of the CBD, was a compromise. In Arti­ cle 8(g), there was the warning of biotechnol­ ogy risks: "Each Contracting Party shall, as far as possible and as appropriate: (g) Establish or maintain means to regul­ ate, manage or control the risks asso­ ciated with the use of release of living modified organisms resulting from bio­ technology which are likely to have ad­ verse environmental impacts that could affect the conservation and sustainable use of biological diversity, taking also into account the risks to human health." More significantly, under Article 19, "Han­ dling of Biotechnology and Distribution of its Benefits", in Article 1 9.3, the argument about the need for a binding international measure was during the negotiations with difficulty de­ ferred, by including instead the commitment to "consider the need": "The Parties shall consider the need for and modalities of a protocol setting out appropriate procedures, including, in particular, advance informed agree­ ment, in the field of the safe transfer, handling and use of any living modified organism resulting from biotechnology that may have adverse effect on the conservation and sustainable use of bio­ logical diversity." The reference to "prior informed consent" (PIC) drew concept and language from the long discussions of PIC procedure which had taken place in the late 1980s in the context to the London Guidelines for the Exchange of Information on Chemicals in International Trade, and the FAO Code of Conduct on the Distribution and Use of Pesticides. Article

19.4 added emphasis to the obligations in terms of an information requirement:

"4. Each Contracting Party shall, directly or by requiring any natural or legal person under its jurisdiction providing the organisms referred to in paragraph 3 above, provide any available infor­ mation about the use and safety regul­ ations required by that Contracting Party in handling such organisms, as well as any available information on the potential adverse impact of the specific organisms concerned to the Contracting Party into which those or­ ganisms are to be introduced."

Following the Rio Conference and in rela­ tion to the steps towards implementation of the CBD, UNEP Executive Director MosT A­ FA KEMAL TOLB A set up Expert Panels to advise on 4 aspects: 1. Priorities for action for conservation

and sustainable use of biological diver­ sity and agenda for scientific and tech­ nological research 2. Evaluation of potential economic impli­ cations of conservation of biological diversity and its sustainable use and evaluation of biological and genetic re­ sources 3. Technology transfer and financial is­ sues: Issues and options 4. Consideration of the need for and mo­ dalities of a protocol setting out appro­ priate procedures including, in particu­ lar, advanced informed agreement in the field of the safe transfer, handling and use of any living modified organ­ ism resulting from biotechnology that may have adverse effect on the conser­ vation and sustainable use of biological diversity. The panels, each of some 15-20 people were constituted by UNEP's, invitation, most countries participating in at most one panel; but the US, on all four. The European Com­ mission, via DG XI's representative, partici­ pated in panel 4, on bio-safety. They met three times in 1 992-93, the panel reports be-

6 International A ctors: European,

ing finalized at Montreal in March '93; and presented at a conference i n Trondheim M ay '93; hosted by the Norwegian Government. The report of expert panel 4 did not achieve consensus. A m i nority of the panel, including the U S representative expressed themselves unconvinced of the need for a protocol; a ma­ jority were in favor: and the report recorded the arguments of the two sides. Given the ar­ b itrary choice and small to tal number of pan­ el participants, the terms majority and "mi­ nority were of little significance . The panels were advisory to the Executive Director of U N E P (TOLBA was in January 1993 succeeded by ELIZABETH DOWDES­ WELL); fo r the preparation of the agenda of the Conference of the Part i es an I ntergov ernmental Committe e on the Convention on Biological Dive r sity ( ICCBD ) was convened. supported by the creation of a small Interim Secretariat. The ICCBD first met for a wee k , 1 1 -1 5 October, 1 993 . i n Geneva. Procedural argu­ ments dominated most of the week . particu ­ larly over the financial mechanism envisaged in A r ticle 20 of the CBD. The discussion on the need for a bio-safety protocol was com­ pressed into the fi nal half-day . and indicated the con tinuing division of opinion. The US and Japanese delegati o ns expressed their clear opposition to a pro tocol; the Euro pean Community gave a more am b iguous signal the Belgian representative ( speaking on be­ half of the Community because his country held the Presidency of the Council of Minis­ ters in the second half of 1 983) having re­ ceived conflicting b riefings. Various developing countries emphasized the need for a bi o safety protocol. a demand also vociferously supported by some of the non-governmental organizations Given the a b ridged nature of this and oth­ er debates. it was agree d that the ICCBD should meet a second time . for a longer pe ri­ od: and a two-week meeting took place in Nairobi from 20th June to 2nd July 1 994. The debate on a bio-safety protocol again proved d i visive and con troversi a l : the followi n g ele­ ments are taken from Earth Negotiations B ulletin ( ENB ) . an objective reporting ser­ vice funded by Canadian Governme n t and other sources. ,

.

"

''

"

.

­

.

,

-

.

the O ECD, the

UN Agencies and

Rio

631

""Germany, on behalf of the European Uni­ on, stated that i n the short-term the devel­ opment of technical guidelines on biosafety was favored without prej udice to the me­ dium-term development of international le­ gal instruments on biosafety, while assessing the need for and modalities of a protocol. The Netherlands stated that an international agreement on safety i n biotechnology should eventually be given the form of a legally­ binding agreement and that such an agree­ ment should pay attenti o n to both capacity building and timing . . . The U K referred to joint work with the Ne­ therlands and announced its plan [to] co­ host a meeting on biosafety in 1 995 in Asia. The US stated that a protocol on biosafety is not warranted, but it did recognize the needs specified in Article 19 and stated that guidelines were not a substitute for scientific evaluations and did not replace needs-based requirements. Japan stated that decisions on this issue should be made on the basis of ac­ cumulated scient ific knowledge and on-going examinations. such as t hose conduced by t h e OECD.

[ Regarding] a Protocol : Many [developing] countries . . . supported the need to h av e a legally-binding agreement on biosafety. Ma­ laysia was concerned about the issue of t ransnational corpor a t io ns using developing countries as a place to transfer and test liv­ ing modified organisms (LM O s) Supported by Sweden , Malaysia called for the establish­ ment of a subsidiary body to consider the is­ sue and report to the COP. Sri Lanka also noted that LM O s are subject to mutations. Sweden, supported by Norway and India, pointed out t hat concerns expressed in the report of UNEP Panel 4 , regarding potential threats to biologica l diversity of LMOs from biotechnology, were not adequately reflected in the initial document prepared by the In­ terim Secretariat. China wanted guidelines based on regional initiatives that would then lead up to a legally-binding international in­ strument . Greenpeace, Third World Network and Ge­ netic Resources Action I nternat ional (GRAIN) stressed the need for a legally­ binding international re g ulatory mechanism. The Third World Network proposed an ad­ dition supported by all three of the NGOs who had intervened: 'They stressed t he ur­ gent need for a protocol because of the seri­ ous risks posed b y the transboundary nature .

632

18 The Regulation of Modern Biotechnology:

of the export of LMOs and examples were given that northern companies had already started carrying out hazardous genetic engi­ neering experiments in the South. They also asked that the destabilising socio-economic aspects of biosafety form part of such a pro­ tocol. ' There was heated debate on the report of the discussion, [ leading a small drafting group to summarise it by the sentence: ] 'A significant number of representatives ex­ pressed support for immediate work on a protocol, while others expressed support for the Conference of the Parties establishing a step-by-step process to consider the need for and modalities of, a protocol.' [ But this was not accepted by the Plenary session. ] The only area where there was general agree­ ment was that the Committee should recom­ mend that the issue of biosafety should be on the agenda of the first meeting of the COP. "

The matter of biotechnology regulation at global level, by an international binding pro­ tocol, thus remained open and unresolved, as the first Conference of the Parties (COP) took place in the Bahamas, 28 November-9 December 1 994. Preoccupied with formal business of rules of procedure, methods of working, and the more central issues such as the financial mechanism, and the institutional and geographical location of the CBD Secre­ tariat, the COP might have deferred further substantive discussion of matters such as the need for a bio-safety protocol to its medium­ term work programme; but there was an insis­ tent demand from both the Nordic countries and the "077" group of developing countries to initiate work more rapidly on building a protocol. The compromise was an agreement to give the matter intensive consideration over the following year, including a week­ long open meeting (in Madrid), and gathering all relevant information and experience of risk assessment, guidelines and legislation. The Anglo-Dutch, "Chapter 16" Initiative

Following the endorsement at Rio of Agen­ da 21, a Commission on Sustainable Develop­ ment (CSD) , located at UN Headquarters in New York, was charged with responsibility for its follow-up.

A

Historical and European Perspective

Within the Ministries of the Environment in the Hague and London, staff were con­ vinced of the importance of a framework of safety guidelines for biotechnology as a basis for its responsible and acceptable application world-wide. Based on the safety references in Chapter 1 6 of Agenda 2 1 , it could be said that there had been international agreement on the development of such guidelines; and a draft was prepared by the two Ministries. This was discussed at working meetings in the U K (March 1 994), and in the Netherlands, (May 1 994); and at international conferences in Ha­ rare, Zimbabwe (African Regional Confer­ ence on Safety in Biotechnology, October 1 993 - see VAN DER MEER et al., 1 993) and in Colombia (June 1 994) , and Indonesia ( Octo­ ber 1 994). The draft was put forward in Brussels at the April 1 994 meeting of the "Article 21 " Committee of National Competent Authori­ ties responsible for Directive 90/220 (see Sect. 7.3), where it was favorable received; al­ though it was not discussed at the Commis­ sion's Biotechnology Co-ordination Commit­ tee, nor adopted as Commission policy. The two Ministries (or governments) also put forward the draft guidelines at the meet­ ing in New York, June 1 994, of the Commis­ sion on Sustainable Development. The pro­ posal was also debated at the second ICCBD meeting in Nairobi, June 1 994; but it did not attract significant interest, nor divert atten­ tion from the more noisy and polarized de­ bate on CBD Article 1 9.3. Rather belatedly, the UK-NL draft guide­ lines incorporated reference also to the UNI­ DO/UNEP/WHO/FAO guidelines on "intro­ ductions" (see Sect. 6.3); it being claimed that they were more precise and operational than the latter. However, as UNIDO was the UN agency responsible for co-ordination of activi­ ty on Chapter 1 6 of Agenda 21 , its staff tended to prefer the existing multi-agency guidelines. The text of the UK-NL guidelines also gave rise to ambiguity, some industrial parti­ cipants in the working meetings being led to believe that they were not about "genetically modified organisms", and therefore could not be said to stigmatize them. In fact, this was playing with words, since the draft guidelines

7 Re -thinking and Review: 1 990-1 995

refer repeatedly to ··novel organisms" - hav­ in g defined them as ··organisms produced by modern gene tic modification techniques whose genetic make-up does not occur natu­ rally··. The basic political case for the Anglo­ Dutch initiative was that they could be rap­ idly adopted. like the U N I DO guidelines, on a voluntary basis: and th e ir existence would not preclude the development of a binding protocol on the lines e nvisaged under the CBD Article 1 9 . 3 . In a somewhat defensive article i n t h e Dutch -govern m e n t -supported B iotechnology Development Monitor of September 1 994. BERT VI S S E R of DG IS summed up the uncer­ tain situation of the initiative at that stage: ··Assum i n g t hat t h e g u i d e l i n e s a ppe ar to be a val uable practical tool in i ntrod ucing safe­ ty mechanisms and foste ring growing i n t e r­ n a tional co-ope ration and harmonization. three maj or questions rema i n . The

first

q uestion i s which organization can

function as t h e i n s t i t u t i o n a l basis for these guide l i n e s . Without a n institutional home to

promote and guide t h e i r implement ation. t h e impact of t h e guide l i nes may re main l im i t e d . Alt hough the United Nations Environment Programme ( U N E P ) has been mentioned as a pote n t i a l candidate. i t is unclear whether t he organization is able t o give sufficie n t pri­ ority to the i n i t i a t i v e . However. the issue has been taken up by t he orga n iza tion a n d will be t horou ghly d i sc ussed . T h e second q uest ion. which is re l at ed t o t he first one. is how deve loping count ries. which might most benefit from the guidelines. per­ ceive the i n it i a t i v e . The orga nizers hope t h a t many cou ntries will real ize t h e need for safe ­ t y mecha n i sms soon. and t h a t t h e y may be n ­ e fit from a readi l y a v a i l a b l e . technical docu­ m e n t . Many delegations prese nt a t the m eet ­ ing of the lntergcn-ern mental Committee o n the Con vc•ntion on Biological Di versity. which took place in N a i robi in J une 1 994. supported t he i n i t i at i v e . and t h is warrants optimism. The third question is whether suf­ ficient resou rces will become available to a l ­ l o w developing cou ntries to implement the guidelines. I nt e rn a t ional orga n izations and donors may have a n i m port a n t role to play h e re . "

I n their November 1 994 statement, timed for the first Confere nce of t he Parties to the

633

t h e bioindustry emphasized the posi­ tive potential of biotechnology for biodiversi­ ty. and the use of existing guidelines for safe­ ty . possibly through a Task Force led by rele­ vant UN agencies such as UNIDO and UNEP ( I B F, 1 994) . CB D .

7 Re-thinking and Review: 1 990-1 995 7 . 1 The B io-Industries in Europe Find Their Voice

The demise of the Biotechnology Steering Committee after its fi nal meeting of July 1 988 appeared to carry with it as it sank the pros­ pects of renewing and strengthening the co­ ordinated strategic view of biotechnology, which had been initiated by D AVIGNON i n 1 983. D i d this matter? The significance of the loss was not imme­ diately evident. It has been said (CYERT and MARCH, 1 96 3) of companies, that they do not have obj ectives; individuals have objectives. Analogously, o n e could say that industry sec­ tors and associations do not have interests; their member companies do. The develop­ ment of biotechnology-based i ndustry in Eu­ rope may well be in the public interest; but the joint-stock corporation's primary formal responsibility, in the open economies of the western world, has been to its shareholders, and to secu ring a profit able return on their in­ vestment. The managers of European "bio-in­ d u s t ry companies had indicated at the De­ cember 1 984 m e eti n g with Vice-President DAVIGNON (see Sect. 3.7), and subsequently by their behavior. their reluctance to devote e ffort and resources to lobbying or represen­ tational activities on behalf of biotechnology in Europe. A vacuum had developed, which others filled. Speaking at the Toxicology Fo­ rum in Berlin in October 1 987, Sir G EOFFR EY PAlTI E (the former U K Science Minister) had warned the bio-industries that if they fai led to "occupy the high ground" of public "

634

18 The Regulation of Modern Biotechnology:

opinion in advance of their critics, it would be difficult to recapture it later; his warning was accurate, and ignored. The situation changed at the end of the 1980s. Several major companies were not only recognizing the significance of biotech­ nology for their own capabilities and competi­ tiveness; but were recognizing that the actions being undertaken by the Community institu­ tions and/or national authorities in relation to biotechnology would impinge directly, and perhaps adversely, upon their own activities. Three examples illustrate this. I CI in 1 984 were still at an early stage in their strategic decision to enter the seeds sec­ tor. By the end of the 1 980s, it was clear that the whole basis of protection of agricultural crop plants would ultimately be transformed by the new knowledge. Plant protection would shift away from simply spraying pesti­ cidal chemicals on fields, towards the incor­ poration of self-protective capacity in the plant genome, and to subtler effects depend­ ing on interactions between the protection products administered and the characteristics of the plant (and target pests). The whole public policy framework vis-a-vis transgenic plants - affecting research, development, test­ ing, patenting, safety rules, and commerciali­ zation - would be of crucial significance to their business. Hoechst in Germany had encountered cost­ ly opposition and legal delays to operating in Hessen their plant for producing insulin by a recombinant bacterium, and had the frustra­ tion of seeing competitors Lilly and Novo Nordisk develop their businesses in this area in less hostile policy climates. Their immediate costs, and in the longer term the location of their research, development, pilot plants, and full-scale production facilities, would be in­ creasingly influenced by decisions in Frankfurt (for Hessen), Bonn, and Brussels. Monsanto had from the early 1 980s in­ vested heavily in checking the safety, demon­ strating the efficacy, and developing and test­ ing the production technologies and systems for bovine growth hormone, and for its ad­ ministration to cows. By 1 989, saw the dark shadow of the steroid hormone debate falling over the topic; the regulatory approach ad­ opted by the European Community would be

A

Historical and European Perspective

similarly crucial to the prospects for commer­ cialization in Europe of their peptide hor­ mone. They had visited the Commission to discuss the project in 1 984; a decade later, the product would be on the market in three con­ tinents, including the US; but the decision in the European Union would still be deferred. Debate on hormones had been widened in the European Parliament - in particular by Environment Committee Chairman KEN Co LLI N S - into a broader demand for a fourth criterion, of "socio-economic assess­ ment" to be added to the established criteria of quality, safety and efficacy - familiar in the context of pharmaceuticals. The vague men­ ace of this "4th hurdle" - a menace to which the ban on steroid hormones gave credibility - was seen by industry as a threat and disin­ centive to research and development in any area where innovation might affect estab­ lished and influential interests. The Senior Advisory Group for Biotechno­ logy (SAGB) was created, under the aegis of CEFIC (the Council of the European Chemi­ cal Industry) in 1 989. The three companies mentioned above joined with a French (Rhone-Poulenc), an Italian (Montedison, by then part of the Ferruzzi Group), a food com­ pany (Unilever) completing the range of sec­ tors represented, and Sandoz from B asel, bringing a link to the Swiss pharmaceutical majors. GONTER M E TZ of Hoechst, President of CEFIC, wrote in July 1 989 to Commission President JACQUES DELORS, to inform him of the creation of SAGB and its aims; and in January 1 990, their first publication was deliv­ ered to various Commissioners in their re­ spective languages (SAGB, 1 990a). The January 1 990 booklet, "Community Policy for Biotechnology: Priorities and Ac­ tions" introduced SAGB and its purpose: "to promote a supportive climate for biotechno­ logy in Europe". It advocated a "coherent and supportive Community policy", noting that the USA and Japan were ahead of Eu­ rope in this respect. Among the specific pro­ posals, under "Community Safety Regula­ tion" SAGB endorsed five guidelines for Community regulation: "- Clearly define and assign responsibility for regulation;

7 Re-thinking and Review: 1 990-1 995

Apply e x isti n g , n o n -discrimi n atory ap­ pro ach es for s a fe ty in research and in­ dustrial processes: - R egulate pr o ducts on t he basis of their inherent characteristics and intended use: - Observe c omm o n pri nciples for prod­ uct sect or re gulati o n : - D evelo p r e g ulatory approaches in common wi th major co mpeti t ors . ··

-

Ge n t l y though these points were stated . they were cle arly opposin g i n p ri nci p le the two rO NA - sp e c ific draft Directives by that stage movi n g towards seco n d readi n g in t h e European Pa r liam e n t . Other state ments in the January 1 990 booklet e mp h asi zed the need for a common mar ket for bi o t e ch n o lo gy processes and p rod­ ucts. the need to st r engthe n the Community role i n pre-competitive R & D, the need for patent p rotectio n for inventions of biotech n o ­ l ogy . and the need for market authorization based only on objecti ve scie ntific criteria fo r safety, quality and efficacy - i.e . . by i m plica ­ t ion opposi ng the "fourth hurdle" . A section on social and ethical issues s t re s s ed that broad debate on these aspects of biotechnology was esse ntial: and e x plicitly noted that the commun i catio n t o ok n o poli c y posi tion on ge n etic modification of the hu­ man ge r m - li n e , an activity in which none of the member compa n ies was engaged . Vice-President BANGEMANN, respo n sible for I ndustrial Affairs. reacted b r isk l y to the SAGB and other p ress ure s rel a ti ng to bio­ tech nolo gy . aski n g his DG I l l staff to pr e pa re a Comm ission comm unication for the Council meeting of Industry Ministers in March . A DG III worki n g paper was indeed p rodu ce d for t h at deadline: but to complete a new Commission communication embraci n g the whole range of major issues raised by bio­ t ec h n ol ogy was to take n o t three , but si x tee n busy and con ten tious months. e n g aging th e e n e r gie s of staff in several DG s , and de m and ­ ing the resolution of several maj or ques­ tions. Fe b rua ry and March 1 990 saw the delivery to Parliament of the Nobel pri ze-winne rs ' l e t­ ter ( see Sect. 4.7), no doubt with some in­ t1uence on the v o t i n g . But the com m on posi -

635

tion of the Environment Ministers was little altered in the final comp rom i ses , and the Di­ rectives were a d op t e d on 23 Ap ri l 1 990; in s pite of last-minute uncertainties by Belgium , France and t he UK, a n y of w hose M i n i sters migh t have opposed , had one of the othe r s give n a lead, and who together could have been a block in g m i no rity . The concern in scientific circles, academic and industrial , was i m medi a tely sh ar pe n ed . A second SAGB communication (SAGB , 1 990b ) , on " Community Policy for Biotech­ nology: Economic Benefits a n d Europea n C om p e t itiveness " , describ ed i n b l unt la n ­ guage , suppo r ted by unfavorable statistics on patents an d investment, industry's answer to the question, ·'Why can't Eu r ope compete for com mercia l biote ch n ol ogy i n vestm e n t? ": ·· - The U nited States has a strong climate of support for b i ote ch n olo g y . The European climate for biot ec h nol ogy is viewed as nega­ tive. - Europe 's hostile political attitude toward biotechnology. re flected in incohere n t and a d v ersarial regu lat o ry systems, creates unac­ cept a bl e risk and cost for all b iotech n ol ogy investors. - Small start-up com pa ni es suffer dispro­ por t io n a tely from i n effi c i e n t regulation be­ cause they c a n n o t afford to move their opera­ tions elsewhere to escape the impacts. - American investment culture and incen­ tive schemes remain i n n ately more attractive for risk capital, especially start-up venture capital . ·· I n parallel with the developm e nt of the SAGB, the n atio n a l bioi n dust ry associations of B elgium (BBA), De nmark (FB ID ) , France ( O R GAN I B I O ) , I taly (ASSOBIOTEC) , Spain (Asociac i on de Bioi n dustrias ) , The Ne­ therlands ( N I ABA ) and UK (BIA) develop­ ed within their countries, and established ( in 1 99 1 ) , a " Europea n Secretariat of Natio n al Bioindustry Associat i ons " ( ESNBA ) . Thi s b rou ght a useful additional voic e into the pol­ icy debates in B russ els : and in spite of the dif­ fe rent scales of their member compa n ies or orga ni z at i ons . the SAGB a n d ESNBA were gene r ally co ncorda n t i n t he ai ms pursued and arguments advanced.

636

1 8 Th e Regulation of Modern Biotechnology: A Historical and European Perspective

7.2 The Birth of the B CC, and the April 1 991 Communication

The growing controversy over biotechnolo­ gy did not escape the attention of the Presi­ dent's office, and in summer 1 990 the Presi­ dent's Chef de Cabinet PASCAL LAMY called on D Gs III, XI and XII to produce short pa­ pers covering respectively the international competitiveness, regulatory, and ethical is­ sues. Following these, the Secretary-General DAVID WILLIAMSON convened on 15 No­ vember a meeting of the Directors-General concerned, to consider the policy issues of biotechnology and related problems of coor­ dination. Thus was born the "Biotechnology Co-or­ dination Committee", or BCC, although some further months and meetings were required to finalize its terms of reference, which were then accorded official standing by a Commis­ sion decision, in March 1 991 . Since transpar­ ency was one of its watchwords, a press re­ lease was then issued, announcing its terms of reference, which included these statements: "The European Commission recognizes the im­ portance of biotechnology for Europe's future. Clear signals are needed to interested parties of the Commission's intentions in this field. Biotechnology is an increasingly important ele­ ment in many areas of Community activity. It is im­ perative that interdepartmental co-operation in this field be reinforced . . . The Commission therefore has created a new high-level interservice group to develop a well-bal­ anced Community policy in biotechnology. The Biotechnology Coordination Committee (BCC) is chaired by the Commission's Secretary General, Mr. DAVID F. WILLIAMSON. The BCC covers all sectors and activities of the Commission in the field of biotechnology, with the participation of all relevant services. Its main tasks are three-fold. First, it is to examine new initiatives made by the Commission's services and to prepare the Commission 's final decisions. Second, it will create, if need be, a system of Round Tables involv­ ing the Commission, industry and other interested parties. Third, it will evaluate the existing Commu­ nity policy on biotechnology."

The B CC was born in the middle of the int­ er-service battlefield over the biotechnology

communication being prepared under DG III leadership, at the request o f Vice-President BANGEMANN. Given the mounting demands on the Secretary-General, in the months lead­ ing up to the "Maastricht" Treaty on Euro­ pean Union, and with the accession negotia­ tions developing for several candidate coun­ tries seeking membership of the Community, it seemed clear that he could not long afford to devote personal attention to the BCC. In­ deed at its first meeting, in November 1 990, he indicated his intention to transfer the re­ sponsibility to "the service most concerned". However, some tens of meetings and four years later, DAVID WILLIAMSON was still in the chair; res ipsa loquitur. The B CC provided the essential central machinery to resolve the inescapable inter­ service conflicts over biotechnology, which neither the Biotechnology Steering Commit­ tee (1984---88 ), nor its creation, the B iotechno­ logy Regulation I nterservice Committee ( 1 985-90), had had the authority to do. Al­ though the B CC had no formally delegated authority from the "college" of the 17 Com­ missioners, it was clear that a service , or ser­ vices, isolated or in a small minority at BCC, would be unlikely to obtain a different result by taking the issue to the Commission. The Commissioners, chaired by President DEL­ ORS and with the Secretary-General as secre­ tary, would normally ask for the B CC view. It was thus potentially, and sometimes in prac­ tice, more powerful in its inter-DG co-ordina­ tion role than the US interagency Biotechno­ logy Science Coordination Committee ( see Sect. 5 . 1 ) The communication was finally published in April 1991 (EuROPEAN COMMISSION, 1 991a), under the title "Promoting the com­ petitive environment for the industrial activi­ ties based on biotechnology within the Com­ munity" - a precise and carefully negotiated, committee-crafted title. It was easier to refer simply to "the April 1 991 communication". Since the formal establishment of the BCC by Commission decision had taken place the pre­ vious month , and was advertised in the April communication as the means of ensuring a co­ hesive approach to biotechnology, the birth of the B CC and the April 1 99 1 "Bible " were in their origins closely associated.

7 Re-th inking a n d Review: 1 990-1995

The significance of the April 1 99 1 commu­ nication was underlined over the following years. I t was the spur to the preparation of a .. fresh "own initiative report by the European Parliament: an appropriate response . since al­ most six years had elapsed since the 1 995 Vie­ hoff hearings ( see Sect. 4.2 ) . But the responsi­ bility of rapporteur for drafting this was given to a German Green MEP . H I LTRUD BREY­ ER; whose very entry into politics had bee n triggered by her concerns about . . ge ne tech­ nology··. The resulting working papers ( B REYER, 1 992. 1 994) were not a balanced re­ flection of the diverse opi nions in the parlia­ mentary committees concerned; and although a relatively balanced public hearing was held finally in March 1 994. the initiative was over­ taken by the J une 1 994 elections: it would be left to the new Parliament to pick u p the threads . or start afresh. B R E Y E R ' s critique - de veloped in various ways by her advisers (e . g .. WHEALE and McNALLY, 1 993) - was that the Commission was effectively being dictated to by industry . in particular through the SAGB: was ignoring the special risks of genetic engineering; and was (via the Apri l 1 99 1 communication and its re-emphasis on sectoral legislation) seek­ ing to dilute or dismantle the April 1 990 Di­ rectives (219 and 220) through which control of these risks was to be achieved. It was a crit­ ique inviting and receiving several strong re­ sponses. Legally, the Commission was on clear ground, for the Single European Act had strongly emphasized industrial competitive­ ness as an aim of Community policy - for ex­ ample, by adding to the founding EEC Treaty articles such as 1 30F. within the new Title VI on Research and Technological Develop­ ment: "The Community's aim shall be to stre ngth­ en the scientific and technological basis of Eu­ ropean and to encourage it to become more . competitive at international level. . Politically, against a background of soaring unemployment and documented charges that over-regulation was rendering companies un­ competitive and driving investment out of the Community. the Commission could hardly be reproached for being attentive to industrial demands for a policy environment less hostile

637

to a key technology. Indeed leading socialist MEPs were among those in close dialogue with SAG B . Factually. i t was ironic t o see the bio-indus­ try accused of over-effective or even counter­ productive lobbying (e.g., see TAIT and LEVI­ o o w . 1 992), when the problems of industry in the 1 990s could in part be attributed to their inadequate responses to the Davignon invita­ tion of December 1 984 (see Sect. 3.7) and over the following years. Within the Commission, Vice-President M A RTI N B A N G E M A N N as Commissioner re­ sponsible for industry. presented the Ap ril 1 99 1 communication to the Council of ( Indus­ try) Ministers in November that year, where it was favorably received. The sensitivity of B A N G E M AN N and his cabinet to the needs and problems of the bio-industry was height­ ened by the intense arguments over gene technology in Germany itsel f (see Sect. 5.3). leading eventually to the revision of the 1 990 Gene Law; arguments in which both the ma­ jor companies (Hoechst and others) and the research organ izations (e.g., the Max Planck Gesellschaft) played leading parts. B A N G E M A N N gave the communication fur­ ther prominence by combining it with two other commission communications, under the heading "European Industrial Policy for the 1 990s", and having it published in an attrac­ tive format as a special supplement to the Bulletin of the EC ( E u RO P E A N COMMISSION, 1 99 1 a) . The other papers in this booklet were a general communication on "Industrial poli­ cy in an open and competitive environment: guidelines for a Community approach"; and a communication on the information technolo­ gy and electronics industries, which like bio­ technology. were of strategic significance, in rapid evolution, and generating challenges to public policy. This 3-piece "Bangemann Com­ munication" foreshadowed in its content and policies the "Delors White Paper" of Decem­ ber 1 993 (see Sect. 7.4); and signalled clearly that biotechnology had now achieved a prom­ inence in the context of industrial policy which it had lacked in the mid-80s. Similarly it signalled that DG III was now a leader for Commission policy in biotechnology, and would be a major player within the Biotech­ nology Coordination Committee.

638

18 Th e

Regulation of Modern Biotechnology:

The follow-up to the April 1 991 communi­ cation was intimately linked with the charac­ ter of the B CC and the content of its discus­ sions. Increasingly and significantly, it was re­ ferred to as "the Williamson Committee"; and it was becoming evident why the Secre­ tary-General could not easily escape or dele­ gate the chairmanship, but had to remain, like a medieval monarch wrestling with his frac­ tious barons. Four major baronies were now contending in the biotech policy domain; and while none sought or claimed the whole terri­ tory, there were boundary disputes to be re­ solved, and with the whole kingdom expand­ ing, new opportunities to be seized and dis­ puted: - DG III (Industry), the natural interlocu­ tor for SAGB and the national bio-industry associations, was the general advocate of in­ ternational industrial competitiveness, as well as specific defender of sectoral legislation , particularly in pharmaceuticals a n d foods; (in chemicals, the main authority lay with DG XI); - DG VI (Agriculture) , generally preoccu­ pied with the management responsibilities and political problems of the common agri­ cultural policy, and especially the GAIT ne­ gotiations in 1 990-93, discovered that their 'in'-trays were full of biotechnology, in both the research and the legislation Directorates within DG VI: • the modest and neglected agricultural research activity had to collaborate with DG XII and join (under the common "Frame­ work Programmes") in fast expanding, inte­ grated agricultural and agro-industrial pro­ grammes of research, development and dem­ onstration, intimately involving biotechnolo­ gy; • the "hormone wars" had spilled over to the BST (bovine somatotropin) battle, with transgenic animals in the not-so-distant fu­ ture, these and other specific challenges be­ coming generalized into the "Fourth Hurdle" argument for socio-economic assessment; • other agricultural legislative responsibili­ ties included those relating to plant breeders' rights (interacting with patents, and changed by the international revisions from the March 1 991 meeting of UPOV, the International Convention on Plant Varieties); and specific

A

Historical and European Perspective

sectoral legislation on topics such as pesti­ cides (see Sect. 4.8), transgenic animals (DG VI being chef de file for the welfare of agri­ cultural animals), and transgenic plants (both as inputs to agriculture, via seeds, or as out­ puts, for placing primary produce - e.g., fresh fruit - on the market); - DG XI (Environment; and, until 1 991 , Consumer Protection), as advocate and guar­ dian of the two April 1 990 "biotechnology" Directives (DG III's co-interest in 90/21 9 was seldom obtrusive before 1 993), had the un­ comfortable position of having simultaneous­ ly to pursue the implementation of these Di­ rectives through national legislation; to man­ age (after 23 October 1 99 1 ) the Commission's executive responsibilities under the Direc­ tives; and to defend the horizontal Directives against a rising volume of criticisms, internal and external, before they had even been im­ plemented in national legislation to become operational; - DG XII (Science, Research & Develop­ ment), although at times seeing themselves primarily as a research funding agency, with broad responsibilities and a fast-expanding budget, had also to recognize that they were part of the Commission , and were expected by the scientific communities outside (upon whom the burdens of biotechnology-specific regulations were falling) to act as the voice of scientific reasoning and i nterest inside the Community institutions. In addition to these four "baronies", the B CC had to include many lesser but not insig­ nificant voices. DG I (External Relations) had to cope with the fall-out of trade wars over technical standards (cf. the EC-US dis­ pute over hormones), with international con­ sequences of conventions such as those at Rio (see Sect. 6.4) , and their repercussions in oth­ er international contexts (e.g., GAIT and the new World Trade Organization, WTO). DG V's role in worker safety legislation has been mentioned (Sect. 4.7). D G VIII (Develop­ ment) had several potentially significant rea­ sons to participate, but in practice rarely did so. Other services such as DG VII (Trans­ port) and Consumer Policy Service would similarly have occasional points where bio­ technology interacted with their interests. After January 1 993, in the Third Delors Com-

7

mission, responsibility for the much-debated Directive on the Protection of Biotechnologi­ cal Inventions, the " Biotech Patents" Direc­ tive, shifted from DG I I I to DG XV ( I nternal Market and Financial Services), but co-opera­ tion on this dossier. with DG III and through BCC. remained close. The April 1 991 communication provided, in its preparation and for several years subse­ quently. a permanent agenda. a Vade Mecum , for the Biotechnology Co-ordinating Com­ mittee. At each BCC meeting, an updated "State of Play" document would summarize the various dossiers, particularly those con­ cerning legislation . A review of progress on the commitments in the communication was published in October 1 992 (EUROPEAN CoM­ MISS ION , 1 992b ) , but did not significantly al­ ter the agenda. whose main headings had emerged during (and before) the 1 990-9 1 months of drafting. The communication ob­ viously included statements about the impor­ tance of biotechnology. of European competi­ tiveness, and of Community R & D pro­ grammes; but in the context of a history of biotechnology regulation. five topics merit special mention : • • •

•

•

intellectual property rights ethics socio-economic impact assessment: the "Fourth Hurdle "" the relationship between "horizontal"" legislation (the April 1 990 Directives) and sectoral. or "vertical " legislation standards.

On intellectual property issues in biotech­ nology, the need to clarify and harmonize many questions of interpretation and princi­ ple in patent law had been addressed by the Commission's October 1 988 proposal (EuRo­ PEAN COMMISSION, 1 988) . Points where the inventions of genetic engineers interacted with plant genomes required that the discus­ sion await the proposal for a harmonized Community system of plant breeders' right , which was put forward (drafted b y DG VI) i n 1 990 ( E U ROPEAN COM M ISSION. 1 9 90a ). The international UPOV meeting of March 1 99 1 introduced changes requiring amendments t o the Commission proposal, a n d causing further

Re-thinking and Review: 1 990-1995

639

delay. Parliamentary concerns about ethical aspects of the patenting of life, particularly animals, and about patenting parts of the hu­ man body, deferred agreement throughout 1 994. The differences between Parliament and Council brought the matter up, on 28 No­ vember 1 994, as one of the first examples for the new "conciliation procedure" established by the Maastricht Treaty; illustrating again the arbitrary but inevitable interplay between the evolution of Community policies for bio­ technology, and of the constitution and insti­ tutional procedures of the Community itself. In response to the ethical issues raised re­ peatedly in Parliamentary debates on bio­ technology proposals of all kinds (whether dealing with R & D programmes, patent law, or safety regulation) . the Commission ac­ knowledged their significance in the April 1 991 communication, itemizing several of them, and indicating the need for "an adviso­ ry structure on ethics and biotechnology". Soon afterwards. the Commission established the "Group of Advisers on Ethical Implica­ tions of Biotechnology". This group of 6 emi­ nent persons held their first meeting in March 1 992 , with an opening welcome by President DELORS. The group was the subsequent source of balanced and thoughtful opinions on a range of topics addressed to it by the Commission, or chosen on their own initia­ tive; it was subsequently ( 1 994) increased to 9 persons. A report was published on their first two years' act ivities (EU ROPEAN COMMIS­ SION, 1 994e ). The preparation of the April 1 991 commu­ nication coincided and interacted with the ongoing debate on socio-economic assess­ me nt. summarized as the "Fourth Hurdle " (i.e . , additional to those of quality, safety and efficacy, long used in pharmaceutical legisla­ tion) , the controversy and subsequent Com­ munity ban on steroid hormones and ana­ logues spilling over onto the biotechnology­ produced peptide hormones, particularly bo­ vine growth hormone or somatropin, known as BGH or BST. The expressions of consum­ er concern , the opposition of some farming interests, the inconvenience of productivity increases for the managers (at Community and national levels) of a Common Agricultur­ al Policy already wrestling with surpluses, the

640

18

The Regulation of Modem Biotechnology:

concerns of the animal welfare movements, and the resulting opposition in the European Parliament, were all given political expression and focus by demands for a socio-economic impact assessment as an element of product approval procedures. To these demands, the Commission in its April 1 991 communication gave a carefully reasoned but clear-cut negative; at least so far as concerned the routine systems for product authorization. The Commission was not indif­ ferent to the socio-economic dimensions, and had indeed its means of assessing such as­ pects; but these dimensions had to be ad­ dressed in ways other than the standard au­ thorization criteria for products. The commu­ nication referred to th e FAST programme and the work of the European Foundation for the I mprovement of Living and Working Condition ("the Dublin Foundation") which had undertaken and published extensive work on the social assessment of biotechnolo­ gy (YOXEN and DI MARTINO, 1 989). The Commission reserved the right on exceptional occasions to over-rule the three science-based crit eri a for acceptance, "in the light of its gen­ eral obligation to take into account other Community policies and objectives". Regarding the Regulatory Framework, the April 1991 communication, published just one year after the Council Decisions on the B iotechnology Directives 90/21 9 and 90/220, and six months before the required deadline for implementing national legislation by Member countries, considered these regula­ tions and announced its intention to review them. The description of the "Regulatory Frame­ work" in the April 1 991 communication started by noting that "not all products de­ rived through biotechnological methods will require a specific assessment and/or authori­ zation procedures." The vast majority of bio­ t ech n o logy products, it continued, were pro­ duced through traditional methods; and "As far as new biotechnology products are con­ cerned which involved gene manipulation, each product will have to be considered on a case-by-case basis and assessed as neces­ sary". The communication described the " Regul­ atory Framework" in terms carefully bal-

A Historical and European Perspective

anced between the "horizontal" (DG XI and DG V) Directives, adopted the previous year, and product legislation (DG I I I and DG VI), with its diverse strands and different histories for the various sectors: "Those products which do require governmental activity may be assessed and authorized under the regulatory framework for biotechnology which has been developed by the Community. This regulatory framework, which is based upon scientific analysis and evaluation, covers horizontal (environmental and worker protection) and product legislation. This latter is based on the three criteria of safety, quality and efficacy,* which are also applied when assessing whether a product can be authorized for distribution on the open market. The horizontal framework ensures that all stages of pre-industrial development and environmental aspects are cov­ ered. * It should be noted that these three criteria are nowadays considered to include impact on nature and safety for the environment."

That was the current picture; the communi­ cation went on to outline the Commission's intended actions, and clearly acknowledged the need for adaptation and change. The hori­ zontal directives had provisions relating to adaptation to technical progress, which would be used. The Commission would examine whether existing product legislation was ap­ propriate, or could be slightly amended, to take account of action specific to biotechnolo­ gy. The horizontal legislation would cover the gaps between sectoral legislation. The dynamic and innovatory nature of bio­ technology posed a challenge for legislators, and this meant "a constant assessment of the appropriateness of existing and proposed leg­ islation" . Duplication of testing and authori­ zation procedures would be avoided; and the Commission would ensure that "one inte­ grated assessment and notification procedure covers all that is required for product authori­ zation". Thus was stated emphatically what became known as the "one door, one key" policy. Standards Programme in Biotechnology, Through CEN

The April 1 991 communication also an­ nounced the intention of the Commission to

7 Re-thin king and Review: 1 990-1995

institute a programme of development of standards for biotechnology. This suggestion had been raised in the context of BRIC . the Biotechnology Regulation I nter-service Com­ mittee, some years before . by DGs I I I and XII. Encouraging the development of Euro­ pean standards had long been one of the most obvious means of creating a harmonized sin­ gle European market. just as the use of na­ tional rules about technical standards was one of the easiest ways in which national authori­ ties could practice an effectively protectionist policy under respectable cover. The complete harmonization of national standards proved exceedingly time-consum­ ing in cases of eve n moderate complexity, and after 1 991 . the Community switched to the "new approach" . emphasizing mutual accept­ ance of products which satisfied national standards in any EC Member State. However . in a new area such as biotechnology in which few or no standards existed. the case for a di­ rect drive for European standards was easy to make . The procedure for the development and adoption of standards is a well-developed procedure . operated through the CEN: Com­ ite Europeen de Normalisation . with defined voting rules. working in three languages ( English. French and German) . and covering not only the E C countries. but the European Free Trade Area ( EFT A ) . The working groups which prepare the draft standards gen­ erally comprise experts, nominated by nation­ al standards bodies. and drawn from relevant expert circles. industrial or other. It has there­ fore been quite common for Community leg­ islation to be kept short and flexible by a ref­ erence to "accepted international standards". The original suggestion i n BRIC was not well-received by DG XI. who were not Chef­ de-file for standards (it was a DG I I I respon­ sibility), and feared that such a step might open their drafting of the biotechnology Di­ rectives to technical criticisms from indepen­ dent sources. The Directives were conse­ quen tly drafted in considerable technical de­ tail - inevitably reflecting technical percep­ tions of Environment Ministry and DG XI advisers as of the mid-1 980s: a drawback un­ derlined by the Ministers' decision in Council t o remove from the scope of adaptation to

641

technical progress the Annexes defining (in some technical detail) the scope of the Direc­ tives. H owever. the April 1 991 communication re-opened this issue with a clear commitment to a programme for the development of standards for biotechnology. A mandate was prepared and ( after some inter-service argu­ ment) agreed for CEN, Vice-President B A N ­ G EM A N N emphasizing that "standards are not an alternative but a useful complement to leg­ islation". The CEN programme referred to the two Biotechnology Directives 90/2 1 9 and 220. and the Worker Safety Directive, 90/ 679 . CEN established a Technical Committee, TC 233 (Biotechnology), and clarified some points of potential overlap with other areas of ongoing work on standards development. De­ tails of the 54 standards under development have bee n summarily described by KI RSOP ( l 993a . b), and full details are available from the TC 233 Secretariat: a function which for this Committee was awarded to AFNOR, the French standards organization. Elected as first Chairman of TC 233 was SAGB Director B R I A N AGER, a former ex­ pert adviser to the European Commission (DG X I I ) and to OECD , previously secretary of the UK Advisory Committee on Genetic Modification. The standards development work was subdivided between four Working Groups (the examples quoted are not a com­ prehensive list ): 1 . Laboratories for research, development and analysis: 10 standards (e.g., categoriza­ tion of laboratories, reporting on existing lists of animal and plant pathogens, examining classification work in support of the classifica­ tion work required under the Worker Safety Directive 90/679, codes of good practice) 2. Large-scale process and production: 7 standards (e.g . . building and equipment speci­ fication , according to degree of hazard , con­ trol procedures for materials and e nergy, codes of practice, waste handling, inactivation and testing) 3. Standards relating to modified organisms for application in the environ ment: 13 stand­ ards (e.g. . inse rt characterization and se­ quencing, methods for detection and determi-

642

18 The Regulation of Modern Biotechnology:

nation, sampling methods, molecular mark­ ers, quality control of diagnostic kits) 4. Equipment: 24 standards (testing proce­ dures for cleanability, sterilization, leak-tight­ ness, performance criiteria for the various classes of components - pumps, valves, shafts, filtration, etc). This extensive work on standards was another illustration of the operational and practical work resulting directly from the April 1 991 communication.

7.3 Implementing the 1 990 Directives: DG XI , the Committee of Competent Authorities, and National Developments

The Directives 90/21 9 and 90/220, on con­ tained use and field release, were adopted on 23 April 1 990; the final Article in each case requiring Member State governments to have legislation in place to give effect to them within 18 months, by 23 October 1 991 . At the start of the 1 990s, these regulatory developments were the most prominent fea­ ture of public policy in Europe, concerning biotechnology. The leading role was played by the Environment Directorate-General in the European Commission (DG XI), chairing on behalf of the Commission the Committee of N ational Competent Authorities (NCA) set up, generally under a corresponding Min­ istry or agency in each national capital , but with significant variations from country to country. Many other developments were oc­ curring in parallel, as indicated in the preced­ ing section; interacting with and complicating the implementation under national law of the Directives 90/219 and 90/220. The Directives themselves would not come into effect until 23 October 1 991 , eighteen months after their adoption. During that peri­ od, the Commission through DG XI energeti­ cally organized a series of "National Experts Meetings on Environmental Aspects of the Use of GMOs", the first on 2-3 April 1 990, three weeks before adoption of the Direc­ tives. Seven more such meetings took place

A

Historical and European Perspective

before 23 October 1 99 1 , in Brussels or in pleasant locations in host countries. The meetings were efficiently organized, and con­ tributed to the development of a certain esprit de corps among members of the nascent au­ thorities. The practical business of the meetings was substantial, as many details had to be ad­ dressed in preparing for the implementation of the two Directives. Reporting on the pro­ gress of corresponding national legislation in each Member State became a routine item. The meetings were an opportunity to discuss questions of definition, interpretation, clarifi­ cation. Combining formal business with op­ portunities for informal interaction, they ena­ bled problems to be identified and discussed, various solutions considered. National au­ thorities - particularly those with significant experience of national legislation, or who had addressed in detail some specific issue - could offer presentations; whose merits as models for Community-wide application could then be debated. The agenda was often broadened beyond the formal business, to address other matters of interest; for example, interaction with sec­ toral legislation, in sectors such as pharma­ ceuticals, pesticides, seeds, and novel foods. After 23 October 1 991 , the meetings be­ came formal meetings of the competent au­ thorities set up under each Directive: typically three meetings being held adjacently, one in relation to Directive 90/219, one in relation to 90/220, and a joint meeting where matters of wider common interest could be raised. Deci­ sions under Article 21 of either directive re­ quired formal convocation of the "Article 21 Committee" , or a Commission decision by written procedure. B RIC, the former Biotechnology Regula­ tion Inter-service Committee, had held its fi­ nal meeting on 19 November 1 990, and had been formally dissolved on the creation of the Biotechnology Co-ordination Committee. Al­ though many topics were in progress or under discussion in various services, it was clear that the BCC would be the future forum for their discussion. Indeed, there were some early ref­ erences to it as "Super-BRIC"; but it was made clear that its mandate would include de­ termining the overall objectives for Commu-

7 Re-thin king a n d Review: 1 990-1 995

nity action in biotechnology. thus resuming the concept of strategy that had fallen into abeyance after 1 988. but had been restated by Vice-President B A N G E M A N N . Few tears were s h e d for t h e demise o f BRIC. Although the April 1 99 1 communica­ tion had indicated the need to review con­ stantly the regulatory framework. this was merely a statement of Commission policy and intentions. and did not have the legal force and authority of the 2 1 9 and 220 Directives. Thus the meetings of the national competent authorities. under the chairmanship of DG XI, were for them a more satisfactory forum than B RIC. These meetings could become a quasi-autonomous policy-making center for biotechnology ; provided that the topics dis­ cussed were connected to regulatory aspects . and avoided direct conflict with other ser­ vices, e.g. responsible for sectoral legislation. Other Commission services would in any case be reluctant to dispute with DG XI in front of the Member States: and the representatives of Member States present would in most cases be from agencies sympathetic to DG XI and the aims of the Directives. .. From this "power-base . a global policy might conceivably be launched; and indeed. if the European Community had undertaken some pioneering and successful work . why should they not seek to spread widely its ben­ efits and the Community's infl uence and in­ tellectual authority ? But the basis of such in­ fluence building remained contentious, not to say flawed: for it had always to be related to the control of genetically modified organisms (GMOs) as defined in the Directives. Thus. under "international activities . . . the meeting of competent authorities held in Denmark on 10 July 1992 discussed seven topics: (i) European Free Trade Area. EFT A (ii ) EC/US bilateral discussions (iii) CEN. the European Standards Com­ mittee (iv ) O ECD ( see Sect. 6.2) (v) U N Conference on Environment and Development: (the " Earth Summit or Ri o Conference ) ( see Sect. 6.4) (vi) Council of Europe (vii ) U N E P B iodiversi t y Convention ( see ...

"

Sect . 6 . 4 ) .

643

In parallel with this expansionist develop­ ment of the Committee of Competent Au­ thorities, the Biotechnology Co-ordination Committee was seeking to enhance policy coherence, and ensure greater transparency between the Commission services. During 1 993-94. a series of Commission decisions and communications reflected a general com­ mitment to greater openness (see E u RO P E A N COMM I S I ON , 1 993 c, d; 1 994 g). DG V II (Transport) collaborated with DG XI in drafting a Directive relating to the transport of GMOs; and in participating at Geneva in the U N Economic Commission for Europe's Committee on the Transport of Dangerous Substances. On that topic, indus­ trial representatives at the Geneva Commit­ tee made known to other Commission ser­ vices (e.g., Industry, DG I I I , and Science, DG X I I ) their concerns, thus enabling other DGs to attempt to join in the discussion; such in­ formation did not flow freely within the Com­ mission until the BCC was involved. DG XIL for example, in conj unction with the curators of the microbial culture collections in Europe. and in the MINE project (Microbial Informa­ tion Network for Europe) , had extensive net­ works of experts familiar with the packaging and labelling of dangerous organisms, but their advice was not invited , because their opinions were critical. The OECD conclusion about the absence of basis for legislation spe­ cific to rONA organisms was similarly not evident in the transport discussions, and a DG X I I offer to co-finance with DG V I I an expert workshop received no reply. Item (vi) above referred to the inclusion of specific reference to G MOs in the Council of Europe Convention on Civil Liability arising from Dangerous Activities; again, there was no i nternal consultation of scientific advice within the Commission services. There was a cohere nce in these actions, if the assumption was maintained that there were special risks inherent in GMOs. Howev­ er. this was not being borne out by scientific opinion, or from reports being published in the US. The basis remained conjectural ; regu­ latory initiatives including the Community Directives increasingly justified themselves by refe rence to the need for public reassurance; and yet the suspicion was voiced, that the em-

644

18 Th e

Regulation of Modern Biotechnology:

phasis on regulatory activities focused on GMOs was itself reinforcing the message of inherent riskiness, and stigmatizing the tech­ niques. DG XI encouraged the widespread inter­ national imitation of the Community legisla­ tion , for example, encouraging by direct visits and discussions the Japan Environment Agency to introduce similar proposed meas­ ures in the Diet in 1 99 1 ; an initiative which, having short-circuited the usual diplomatic channels and other Ministries interested, once discovered found little favor with the Minis­ tries principally involved in biotechnology, and was quickly withdrawn. In the preparations for the Earth Summit at Rio, DG XI were chef de file, biodiversity conservation being an "environment" matter; and dicouraged attempts by other services to follow closely the evolution of the debates. The resulting Convention on Biological Div­ ersity is discussed in Sect. 6.4, including refer­ ence to the patenting and bio-safety articles which might have benefited from broader perspectives in their drafting; the latter again stigmatizing GMOs. (An exception was the Prieels report, 1 991 , on the New Delhi meet­ ing of 23-25 October that year. Her report highligh ted the curious dialogue, between de ­ veloping country scientists asking for access to biotechnology and its benefits; and envi­ ronmental experts from the developed world insistently offering regulations.) The UK House of Lords Report (see Sect. 5.2), published in 1 993, was critical of the drafting of the Directives, as having been "based on out-of-date science", and "imper­ vious to scientific advice". There was some substance to this reproach, particularly prior to adoption of the Directives, when scientific criticism was feared as threatening the success of the political process. For example, when the draft directives were about to be adopted in April 1 990, copies of draft technical guide­ lines relating to their implementation which had been sent to Member States were for­ warded by several Member State experts to the Working Party on Safety in Biotechnolo­ gy of the European Federation of Biotechno­ logy (see Sect. 6. 1 ) , with requests for their opinion. This was the most broadly represent­ ative e x pe rt group of biotech safety specialists

A

Historical and European Perspective

in Europe. In response to their having circu­ lated the Commission drafts , LAURENS JAN BRINKHORST, Director-General of DG X I , wrote to the Safety Group Chairman in angry and threatening terms. The Chairman, Professor FROMMER, re­ sponded (2 October 1 990): "I have to say that we were most taken aback by both the content and the tone of your letter which is critical of attempts to a rrange up to date scientific i n p ut to the production of technical gui deli n es in biotechnology. We understand that DG XI is engaged in pro­ ducing a series of guidelines under the GMO Direc· tives and yet you appear to indicate that the scien­ tific community who, along with industry, will be most directly affected by your activities, has no place in commenting on your proposals. As far as access to the documents is concerned, given that they had been distributed by your staff at a "national experts" meeting in April and, given also that several EC countries, quite properly and democratically, seek the views of interested parties (scie n tists , i ndus try, trade unions and so on), i t can surely be no surprise that they found their way to the EFB Working Party from several different sources. We suggest that you contrast the transparent, consultative approach of various Member States with that of your services. A secretive approach is the last way to generate confidence either with the practitioners of biotechnology or the public. You will recall that the Working Party has in the past offered to advise and provide scientific guid· ance and, notwithstanding the above comments, this offer remains open."

Similar sentiments internally made clear the reluctance of DG XI to accept advice from the Directorate-General for Science, Research and Development, DG XII. The Environment DG preferred to consult its own experts, for example in a study report on re­ combinant vaccines (McNALLY and WHEALE, 1 991 ), which it refused (in spite of repeated requests) to share with DG XII, al­ though DG XII was managing research pro­ jects in this field, within the Community R & D programme; whose results were of course routinely published. These matters were not simply differences of house style; they contrasted with a central feature of the US regulatory approach, which was its openness to crit ici s m and de b a te , and

7 Re-thinking and

the consequently better scientific basis and adaptability of the US regulations. Draft tech­ nical guidelines were routinely published in the Federal Register, with a 60 or 90 day peri­ od for public comment; a similar openness characterized the meetings of the NIH Re­ combinant DNA Advisory Committee. However, it was politically desirable to be seen to be receiving scientific advice; and pro­ vided that it was not overtly subversive of the basis of the Biotechnology Directives, this was increasingly acceptable to and sought by, DG XI. The (closed) meetings of national competent authorities were ideal for this pur­ pose . and DG XI I were invited to give pres­ entations of their risk assessment research. Similarly i n the context of the bilateral envi­ ronmental meetings between EC and US, a permanent technical working group on bio­ technology was set up between DG XI and staff of the US Environmental Protection Agency, and through exchange of views at this group, convergence on various practical aspects of regulation could be encouraged. DG XI's longstanding contacts with the Com­ munity's Joint Research Centre's facilities at Ispra could similarly be used to strengthen the appearance of scientific basis. In October 1 993, the UK competent au­ thority organized a workshop on environmen­ tal risk assessment for releases of GMOs; and in May 1 994, DG XI organized an EOUS workshop on release of transgenic plants. It was becoming increasingly clear that microor­ ganisms, plants and animals required distinct treatment. Moreover, a "tiered" approach of successive questions was inevitable encourag­ ing the development of the concept of catego­ ries meriting exemption from regulatory over­ sight; as was the "competitive pressure" from the simplification of the US regulations (e.g., on the main crop plants, in 1 993) but Annex I, defining scope. could not be amended by the committee procedures. A "Risk Assessment Group" was set up in J une 1 994 under the Committee of Compe­ tent Authorities, to build up in a controllable way the committee's scientific capability; and enable them more effectively to use or resist independent scientific advice or criticism, from DG XII or elsewhere . DG I I I and DG XU's attempts to strengthen independent

Review:

1 990-1 995

645

scientific advice - reflected in the December 1 993 White Paper and subsequent communi­ cation to the Corfu Summit (see Sect. 7.4) were strongly resisted by DG X I , using in particular the Committee of Competent Au­ thorities. Regarding the implementation of the Di­ rectives in national legislation, the Commis­ sion was required to produce triennial re­ ports, of which the first was due in 1 993, but publication delayed by translation and other difficulties until the end of 1 994. Details are presented in Sects. 5 . 1 to 5.5 of historical de­ velopments in some of the major countries; the overall situation regarding implementing legislation in the European Union for the Contained Use Directive, 90/219, could by end of 1 994 be summarized as follows. In the United Kingdom the Genetically Modified Organisms (Contained Use) Regu­ lations (adopted under the Health and Safety at Work Act 1 974) came into force on the 1 st February 1 993, replacing the Genetic Manip­ ulation Regulations of 1 989. The principles of notification, risk assessment, application of containment, etc. found in Directive 90/21 9/ EEC were already features of the UK's exist­ ing legislation. In Denmark , the 1 986 Gene Technology Act was reviewed following the adoption of the EC Directives and revised in 1 99 1 . The new law (Law No 356 of 6 June 1 991 on the Environment and Genetic Engineering) en­ tered into force on 23 October 1 991 , with six associated Orders. For the working environ­ ment, an amended Order (Labour Inspecto­ rate Order No 684 of 1 1 October 1 99 1 ) en­ tered into force on the same date . In Germany, the Genetic Engineering Law (Gentechnikgesetz) and its implementing Regulations were adopted in July 1 990 in or­ der to transpose D irective 90/21 9/EEC of 23 April 1 990 on the contained use of genetically modified microorganisms into national law; a revised form of the law was formally adopted in January 1 994 (see Sect. 5.3). In Ireland, the Environmental Protection Agency Act, 1 992, enacted on 23 April 1 992, includes a Sect. 1 1 1 on Genetically Modified Organisms which enables the Minister to give full effect to the Directive by means of regu­ lations, after consultation with the Minister

646

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

for Industry and Commerce and any other Minister of the Government concerned. These Regulations under Sections 6 and 1 1 1 were issued i n November 1 994, by Statutory Instrument 345/94. In France, the Directive was transposed by the adoption by the French Parliament of Law no. 92.654 of 13 July 1992 concerning the control of use and release of genetically mod­ ified organisms and modifying Law no. 76.663 of 19 July 1 976 concerning installations con­ trolled for environmental protection. A num­ ber of detailed regulations have been adopted (Decree nr 93-774 of 27.3.93, Decree nr 93773 of 27.3.93). In Spain , a framework legislative text was presented to Parliament in 1993, and adopted in 1 994. In Portugal, framework legislation imple­ menting Directive 90/21 9/EEC was adopted by the Council of Ministers on 28 January 1 993. Detailed regulations have since been adopted. In Luxembourg, a draft legislative text was presented to Parliament in 1 993. In Greece, no legislation had yet been pre­ sented to the decision making bodies by mid1994. A draft text was being discussed at in­ ter-ministerial level. In Italy, the Framework Law enabling the transposition of a number of EEC Directives including 90/219/EEC was adopted in Februa­ ry 1 992. The Legislative Decree laying down the details of implementation was adopted in March 1 993 (Decreta Legislativo nr 91 , 3.3.93, Gazz etta Ufficiale nr 34, 3.4.93). I n Belgium, implementing legislation for Directive 90/21 9/EEC was adopted in the re­ gion of Flanders in December 1 992 by the ad­ option of VLAREM II. In the Brussels Region, a draft of regula­ tion transposing Directive 90/21 9/EEC into regional competences as regards environment was submitted to the regional Council of En­ vironment for a first reading on July, 12th 1 993 and for a second reading on September 1 3th 1 993. As a first step, Directive 90/219/EEC had been transposed into the framework of the General Law on Work Protection. As a sec­ ond step, the same decree would be adopted and integrated into the framework of the new

regional law for environmental licensing when it came into force. The draft regulation extends the field of application of the Direc­ tive to all GMOs; and to human, animal and plant pathogens. A list of 1765 pathogens was established, with a class of risk assigned to each pathogen. In the Wallonia region, a draft text was un­ der discussion in 1993 and 1 994. In the Netherlands, the Directive 90/2 1 9/ EEC had been largely implemented by the Nuisance Act. To fulfill all the obligations en­ forced by the Directive 90/21 9/EEC a para­ graph was added to the "Genetically Modif­ ied Organisms Decree pursuant to the Chem­ ical Substances Act" (GMOD, enforcing Di­ rective 90/220/EEC, Bulletin of A cts and De­ crees, 25 January 1 990, 53). In this paragraph procedures and classification for contained use were described. Technical details are reg­ ulated by a Ministerial Regulation which gives the possibility of quick response to new developments. Both the modified GMOD and the Ministerial Regulation came into force on 1 st October, 1993. The Commission is expected (indeed, un­ der Article 1 8.3 of the Directive, is required) to produce a report giving details of the ap­ pointments of competent authorities, meas­ ures taken for practical implementation, and a short summary overview of activities and in­ stallations in each country and experience with the implementation of the Directive. Late submission of national data delayed this beyond its scheduled appearance in 1 993 (E U RO PE A N COMMISSION, 1 994d). Other simplifications and streamlining of procedures - formats for the summary notifi­ cation of information, revisions of the techni­ cal annexes - advanced steadily through the Committees of NCAs, as recorded by succes­ sive decisions of the E U ROPEAN COMMIS­ SION (1994b, C, f). Given this extended and complex process of implementation of the directives, involving the legislative processes in both national and (for federal countries such as Belgium and Germany) regional parliaments, followed by the development of new administrative proce­ dures to give effect to these laws, it was un­ derstandable that there was little enthusiasm in the Committee of National Competent Au-

7 Re-th inking and Review: 1990-1995

thorities for reviewing the l e g i slatio n I ndeed. there was considerable opposition. But while the leg i slative and admi n i strative processes. debates. and accompanying uncer­ tainties persisted, there was a sort of "plan­ ning b l ight on the investment in research . development a n d innovation which the new oppo rtu n i ties were eliciting i n the US, a n d (to a lesser de g re e ) i n the more pragmatically gove rn e d parts of Europe . This ho st i l e cli­ mate, or perceived hostile climate , led the Commission to rec o gn i ze the need to revise and simplify proc e d ures so far as possible within the existing Directives; but beyond that, to consider r evising them more funda­ mentally in revised proposals to the Euro­ pean Parliament and Council, even be fore t h e 1 990 Directives were fully implemented. This revisionist driv e pr essed by industria l lobbies such as S A G B with strongly argued and well pre sen ted documentation . brought the need to review strategy for biotechnology into prominence in the December 1 993 ''Delors White Paper .

"

.

".

7.4 The White Paper and the Next

Stage: From Corfu to Esse n , and the 1 995 Review Political Priority

By

Shifts to Employment

unemployment in the devel­ economies of the OECD area had reached 35 million. In his successful presi­ de n tial campaign up to the November 1 992 election candidate B I LL CLI NTON defeated incumbent President GEORGE B usH in a campaign featu r ing the slogan, "It's the econ­ omy . stup i d In Fe b ru ary 1 993, w i thi n a few w ee k s of inaugurat ion. the new President and Vice-President issued in their own names the policy docume nt, "Technology. Growth and Employment: re new i n g the American econo­ my t h ro ugh technology" ( CL I NTON and mid- 1 994 ,

oped world

,

".

GORE, 1 993) .

This policy statement reflected Vice-Presi­ well-known enthusiasm for the concept of "information h i g h ways ; but biotechnology also featured prom i ne n tly in the report. The following q uotation s illustrate dent AL G O R E · s

''

647

the flavor; i ncl u din g the very explicit refer­ ences to the impact of the regu latory frame­ work: "Technology is the engine of economic growth . . . . Breakthroughs such as the transis­ tor, computers. recombinant DNA and syn­ thetic materials have created entire new in­ dustries and millions of high- p aying jobs. We can promote technology as a catalyst for economic gro wth by: supporting the development, commercialization, and deployment of new technology; - fiscal and regulatory polic ie s that indi­ rectly promote these activities; - investment in educati o n and trai nin g ; and, - support for critical t ra nsp ortation and communication infrastructures. -

d irectly

In many technology areas, missions of the agencies coincide with commercial interest or can be accomplished better through close co­ operation with i n dustry ."

U nder the heading. " A W orld C l a ss B usiness Environment For Private Sector Investment", item 7 stated: -

"Ensure that federal regulatory policy en­ courages investment in innovation and tech­ nology development that achieve the pur­ poses of the regulation at the lowest possible cost: Regulatory policy can have a significant impact on the rate of technology develop­ ment in energy, biotechnology, pharmaceuti­ cals, telecommunications, and many other areas. The caliber of the regulatory agencies can affect the international competitiveness of the agencies they oversee . At the same time, skillful support of the new technologies can help business reduce costs while comply­ ing with ambitious environmental regula­ tions. A well designed regulatory program can stimulate rather than frustrate attractive directions for innovation. We will review the nation's regulatory "infrastructure" to en­ sure that unnecessary obstacles to technical innovation are removed and that priorities are attached to programs introducing tech­ nology to help reduce the cost of regulatory compliance . ··

648

18

The Regulation of Modern Biotechnology:

The US job situation was bad, but in terms of job creation over the 1 980s, the European performance was significantly worse. Within the European Community, or European Uni­ on as it became known after the November 1 992 ("Maastricht") Treaty on European Union, continuing high unemployment in all Member countries made incumbent govern­ ments of whatever political position unpopu­ lar; improving economic performance to re­ generate growth and expansion of employ­ ment became the top priority of national gov­ ernments and of the European Commission and Council. The global character of the chal­ lenge was underlined at the Detroit Summit of the G7 group in April 1 994. Similarly at the OECD Ministerial meeting of Economics Ministers in June 1 994, the basic document was the OECD report on measures to combat unemployment, a report commissioned two years previously. The OECD report's diagnosis emphasized human resources, and the need for govern­ ments to facilitate and to enhance the flexibil­ ity of operation of labor markets. Within Eu­ rope, and particularly under the influence of UK criticisms and the British decision to opt out of the "Social Chapter" of the Maastricht Treaty, the accusation gained political curren­ cy that the weight of regulation - particularly social legislation, adding to the costs _of em­ ployment, and rendering it difficult to dismiss labour - was rendering Europe inadequately competitive, and thus contributing to and maintaining the high level of unemployment. To the slight political embarrassment of Lord HowiE (a Labour Party member of the House of Lords) , his Committee's report (October 1 993 - see Sect. 5.2), criticizing the inappropriate or excessive regulation of bio­ technology, tended to be seen as part of the same "deregulatory" drive. It was a natural confusion. In spite of the high unemployment, the as­ sociated rise of political demands for protec­ tionism did not prevail; the North American Free Trade Area was approved in the US Congress, with bipartisan support. The long­ drawn-out Uruguay Round of GATT nego­ tiations was finally agreed in December 1 993, and signed at Marrakesh in May 1 994; in De­ cember 1 994, ratification by both houses of

A

Historical and European Perspective

the US Congress confirmed this success. The new World Trade Organization was estab­ lished, starting in January 1 995. The econom­ ies of the Western world remained committed to the open world trade system on which the Bretton Woods institutions and the OECD were founded. This general background, including parti­ cularly the accusation that excessive Euro­ pean regulation was damaging competitive­ ness, interacted strongly with the ongoing ar­ guments about the regulation of biotechnolo­ gy. There was consensus that economic growth and new jobs might derive from new­ technology-based industries; but that in any case the pervasive impact of new technology, particularly of new information technologies, made them impossible to ignore if competi­ tiveness was to be maintained. B iotechnology was also demonstrating a similar tendency to pervasiveness, its supposed risks remained conjectural, and it continued to offer no evi­ dence to give concrete justification for tech­ nology-specific regulation. The "Delors" White Paper: "Review the Regulatory Framework for Biotechnology"

Through 1 993, the Commission services prepared a major policy document, which President D ELORS presented to the Euro­ pean Council in December: on " Growth, Competitiveness and Employment"; also known as the "Delors White Paper" (EuRo­ PEAN COMMISSION, 1 993b). Given the above background, it was not surprising that bio­ technology featured prominently as one of the three technologies explicitly addressed in this document, along with information tech­ nology and the audio-visual sector(s). On biotechnology, the White Paper refer­ red to its emergence "as one of the most promising and crucial technologies for sus­ tainable development in the next century"; and noted that the Community was highly competitive in the sectors to which biotechno­ logy was particularly relevant; "sectors which cover chemicals, pharmaceuticals, health care, agriculture and agricultural processing, bulk and specialized plant protection products as well as decontamination, waste treatment and

7 Re-thinking and Review: 1 990-1 995

disposal. These sectors where biotechnology has a direct impact currently account for 9% of the Community's gross value added ( + /450 billion E c u ) and 8% of its employ­ ment( + I- 9 mio) " . Having compared the growth rate o f these sectors i n Europe with growth rates for the U S and Japan a n d estimates of the growth of the total market. the paper concluded that "the Community growth rate will have to be substantially higher than at prese nt to ensure that the Community will become a major pro­ ducer of such products. thereby reaping the output and employment advantages while at the same time remaining a key player in the related research area" . Going on to review the adverse factors. however. it e m ph a s i z ed : - publicly financed research and develop­ ment expenditure lagging behind US lev­ els; - privately financed R & D insufficient to compensate for the shortfall in public; rath­ er. "available indicators identify a delocali­ zation - an investment outflow": - "regulation concerning the safety of appli­ cations of the new biotechnology is neces­ sary to ensure harmonization. safety and public acceptance. However, the current horizontal approach i s unfavorably per­ ceived by scient ists a n d industry as intro­ ducing const raints on basic and applied re­ search and its diffusion and hence having unfavorable effects on U K competitive­ ness; - technology hostility and social inertia in re­ spect of biotechnology have been more pronounced in the Community in general than in the US or Japan . . . "

In its concl usions a n d

the paper

recommendations.

stre ssed :

.. ove rcoming e x i s t i n g constraints by creating appropriate channels for biotechnology poli­ cy development and co-ordination and by act­ ing o n the fol l owing recomme ndations: a) Given the importance of regulations for a st a ble a n d pred ictable d ustry and g i v e n

environment for in­ that they influence locali-

649

zation factors such as field trials and scien­ tific experimentation , the Community should be open to review its regulatory framework with a view to ensuring that advances in scientific knowledge are con­ stantly taken into account and that regula­ tory control is based on potential risks. A greater recourse, where appropriate, to mutual recognition, is warranted to stimu­ late research activities across Member States . Furthermore , if the Community is to avoid becoming simply a market rather than a producer of biotechnologically-de­ rived products then it is vital that Commu­ nity regulations are harmonized with in­ ternational practice. The development of standards will supplement regulatory ef­ forts. b) The Commission intends to make full use of the possibilities which exist in the pres­ ent regulatory framework on flexibility and simplification of procedures as well as for technical adaptation. To sustain a high level of environmental protection and to underpin public acceptance it is important to reinforce and pool the scientific support for regulations. An advisory scientific body at Community level for biotechnolo­ gy diffusion drawing on the scientific ex­ pertise within and at the disposal of the existing committees could play a crucial role in intensifying scientific collaboration and in providing the support needed for a harmonized approach to the development of risk assessments underlying product ap­ proval. This body could also advise on the development of a further Community strategy for biotechnology. The remaining recommendations stressed strengthening R & D, with improved co-ordi­ n a t ion between Community and Member State efforts; the creation of ''a network of ex­ isting and new biotechnology science parks": and additional incentives to " improve the in­ vestment climate for biotechnology a n d facili­ tate commercialization . "

650

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

Follow-up at Corfu: The "Next Stage" and the "Two-track Approach"

Under the Biotechnology Coordination Committee, the recommendations of the Del­ ors White Paper were developed in greater detail by the services concerned, and present­ ed to the European Council (of Prime Minis­ ters) at the Corfu Summit in June 1 994, near the end of the Greek presidency (E u ROPEAN CoMMISSION, 1994a). The communication, entitled "Biotechnology and the White Paper on Growth, Competitiveness and Employ­ ment: Preparing the Next Stage", was ad­ dressed to the Council, the European Parlia­ ment, and the Economic and Social Commit­ tee, and had chapters on: • • • • • • •

Regulatory Framework Strengthening of Scientific Advice Research and Development B iotechnology and SMEs The Investment Climate Public Understanding Ethics.

An Annex presented the "State of Play of the B iotechnological Regulatory Frame­ work", thus further underlining the major role which regulatory issues now played in the Commission's proposed Community strat­ egy for biotechnology. In the chapter on the Regulatory Frame­ work, the Committee referred to the growth of knowledge and experience, from which "it may be concluded that the risks involved in the contained use of GMMs are substantially less than were once foreseen . . . the potential for horizontal gene transfer resulting in novel and harmful properties being acquired by mi­ croorganisms has not been shown to present hazards to human health and the environ­ ment . . . evidence is accumulating to the effect that genetically modified plants do not differ from non-modified plants other than in the specific character conferred by the introduced gene". After further references to the impact of the regulatory framework on industrial com­ petitiveness, but also the results of surveys in­ dicating its important role in building public confidence in biotechnology, the document

announced the Commission's intention to ap­ ply "the following two-track approach for the future development of the biotechnological regulatory framework: - the exploitation of existing possibilities for revising measures/procedures/degree of oversight/requirements, through use of the "light" procedure of adaptation to technical progress (regulatory Com­ mittee procedure); (internal amend­ ment) - the bringing forward of amendments to existing legislation in order to incorpo­ rate changes which cannot be achieved by technical adaptation while leaving the basic structure of the framework in­ tact (external amendment). The immediate intentions focused on the "contained use" Directive, 90/219, where four objectives for action were identified: streamlining and easing of the admin­ istrative/notification/consent require­ ments where this does not compro­ mise safety; (ii) ensuring that the classification of the genetically modified microorganisms and of the activities in which they are used is appropriate to the risks in­ volved; (iii) ensuring that the conditions of use are appropriate to the risks involved; (iv) extension of the flexibility of the Di­ rective so that it can be more easily adapted to technical progress by reg­ ulatory Committee procedures. (i)

Some of these aims could be achieved by using the Committee procedure of the Direc­ tive itself; in particular the Annex II defini­ tion of "Type I " microorganisms could be simplified from the original requirements, based on the 1 986 OECD "Blue Book", to simpler statements about microorganisms un­ likely to endanger human or animal health, or the environment. This was subsequently pro­ posed to the "Article 21 " Committee for 90/ 219, and adopted in November 1 994 (Eu Ro­ PEAN COMMISSION, 1 994f). Coincidentally, the Commission published

7 Re-thin k ing and Review: 1 990-1995 a report ( THORL E Y , 1 994 ) by a consultant who had studied sector-by-sector the inter­ pretation in 12 sectors of the OECD concept of " Good Industrial Large Scale Practice " . H i s conclusion was that, insofar a s industrial experience had been taken into account dur­ ing the definition of ··G ILSP". it had been ex­ clusively that of the pharmaceutical industry, with the high standards for characterization and purification corresponding to the needs of pharmaceutical products. As biotechnolo­ gy moved into application in other sectors, the inappropriateness of the horizontal legis­ lation became more apparent. The Commission saw the need to lighten the Directive in other respects, but as this could not be achieved within the curre nt terms, it would require specific amendments to the Directive :

- replacing the consent requirements by record-keeping. or notification for in­ formation purposes. for certain low-risk activities: - replacing t he explicit consent require­ ments by implicit consent for certain higher-risk activities: - reduction of time periods involved in implicit/e xplicit consent procedures: - adapting the present risk classification system for G M Ms. in accordance with new safety considerations : - removal of the differentiation between activities in research laboratories and production plants. The Commission stated its intention to con­ sult widely, and place its proposals for amendment be fore the Essen Summit at the end of 1 994. Regarding field release and Directive 90/ 220, the Corfu communication pointed out the changes which the Commission had alrea­ dy been making ( following proposals from seve ral Member States). through Commission decision procedures. These concerned in par­ ticular simplification of the notification requi­ rements fo r rele ases of plants ( E U ROPE A N COMMISS I O N . 1 994b. c). ( I t may be noted that simplifications of procedures for major crop plants had been introduced in the United States in 1 99 3 : see Sect. 5 . 1 . ) H owever, the

65 1

document announced that "further experi­ ence is necessary in order to determine the right balance between the need for safety . public reassurance and the minimum restraint on industry and research work ". The Com­ mission undertook to review the Directive during the first half of 1 995, under the French presidency . to assess the need for proposals in relation to: - extending the flexibility of Directive 90/ 220/EEC, so that its scope and the pro­ cedures to be followed are always ap­ propriate to the risks involved, and are easily adaptable: - strengthening more uniform decision­ taking between Member States in the case of research and development re­ leases; - introducing further opportunities for notifiers (industry and researchers), so that they can benefit more from the ex­ istence of a uniform Community sys­ te m: - facilitating the link between this Direc­ tive and product legislation. The Annex to the Corfu communication reviewed progress on the implementation of the horizontal Directives 90/2 1 9 (contained use ) and 220 (field release), and the worker safety Directive 90/679, whose transposition into national law was proceeding more slow­ ly. On specific product legislation, a similar review noted Directives (or amendments to Directives) adopted (on additives in feeding­ stuffs, and on high technology/biotechnology­ based medicinal products), or in preparation (on plant protection products, amending 90/ 4 1 4); as well as those under discussion, in par­ ticular the draft Regulation concerning novel foods and food ingredients. The Annex also presented a succinct sum­ mary statement of the underlying principles of the Community's biotechnology regulatory framework: .._

N e cessity: the Commission w i l l propose legisla­ tion in this area only i f i t is shown to be neces­ sary by a t horough examination, on a case-by­ case basis. of the cha racte ristics i n h e re n t in spe­ ci fic biotechnological applications.

652

18 The Regulation of Modern Biotechnology:

- Efficient interaction: biotechnologically-derived products will be subject to only one authoriza­ tion and assessment procedure before being placed on the market. - Evaluation criteria: product evaluation will take place in accordance with the three established criteria of safety, quality and efficacy. The Com­ mission will normally follow scientific advice. In exceptional cases, however, it reserves the right to take a different view in the light of its general obligation to take into account other Commu­ nity policies and objectives. - Adaptation to progress: the regulatory frame­ work will be kept up to date with scientific and technical progress. This is of particular impor­ tance in a rapidly developing field such as bio­ technology. - Standards: the development and existence of standards may be used to complement legisla­ tion, particularly on technical details of good practice and safety procedures. - International obligations: the Commission will ensure that all decisions in the field of biotech­ nology will be in conformity with international obligations, in particular with the provisions re­ sulting from the Uruguay Round negotia­ tions."

Although the Commission's communica­ tion attracted widespread coverage in the spe­ cialist biotechnology press, its timing virtually coincided with the election for the European Parliament; with the result that in the imme­ diate pre- and post-election period, there was no immediate political reaction. The Corfu communication was welcomed by the Council of (Industry) Ministers, on 29 September 1 994, who called upon the Com­ mission to present by the end of the year pro­ posals on modifying Directive 90/219, and to envisage changes to 90/220 "in the short term". They called upon the Environment Council - which met on 4 October - to exam­ ine the subject "without delay"; but the sub­ ject was not placed on the agenda, and was barely discussed. Doubts therefore persisted about the prospects for change. Industrial Reaction - the SAGB "Yellow Book"

Following the Commission's December 1 993 White Paper, the Senior Advisory Group for Biotechnology (see Sect. 7.1) pre-

A

Historical and European Perspective

pared, and in April 1 994 published, a 20-page yellow booklet entitled: "Biotechnology Poli­ cy in the European Union: Prescriptions for Growth, Competitiveness and Employment: a response to the Union's 1 993 White Paper on Growth, Competitiveness and Employment" (SAGB, 1994a) . Listing its 29 members, it noted that their combined turnover was $ 305 billion; their annual R & D expenditure $ 1 7 billion, and investment $ 24 billion; and that they provided employment for nearly 2 mil­ lion people world-wide. A parallel publica­ tion analyzed more specifically the policy needs to stimulate innovation, and the devel­ opment of start-up businesses (SAGB, 1 994b). Responding in positive tone to the Com­ mission's White Paper, the SAGB yellow booklet noted that the White Paper identified the causes of increased challenges for the Eu­ ropean Union as including "lack of adapta­ tion to new technologies, in particular bio­ technology"; and went on to propose a five­ point action plan for facing the challenges: • • •

• •

Regulatory Reform Lowered Barriers to Investment B iotechnology-Supporting Fiscal Meas­ ures Increased Labor Flexibility Provision of Leadership in Wealth Creation, Competitiveness and Prosper­ ity.

It further proposed the creation of a "Spe­ cial Economic and Competitiveness Task Force for Biotechnology"; the management to comprise appropriate expertise in the in­ vestment and economic domains, with repre­ sentation from " Ministers of Industrial and Economic Affairs, Industry, Agriculture, Academia, the Investment Community, Em­ ployment Representatives, and the Commis­ sion 's Representatives for Industrial and Eco­ nomic Competitiveness" . On the first Priority Action, Regulatory Reform, its message was blunt. It emphasized that "A viable regulatory structure is essential for a stable and predictable environment in which to operate, develop and maintain com­ petitiveness and which can cope with rapid

7 Re-thin king and Review: 1 990- 1 995

technological advances. In the Union. this means using the best experience of individual Member States. recourse to mutual recogni­ tion where possible and regulatory structures based on scie ntific evaluation of real and measurable risk . " Citing the U K House o f Lords report (see Sect. 5.2), the German Ministry of Health and their own earlier reports (see Sect. 7. 1 ). the SAGB paper stated that a viable regulatory structure should e n comp ass: " Rapid construction of an agreed legal framework within which regulations on biotechnology issues should be encom­ passed. Evaluation of existing regulations (in­ cluding those currently under develop­ ment) to determine fit and compatibili­ ty with the framework. Due to the mul­ ti-discipli nary nature of the application of biotechnology. the evaluation proc­ ess must involve all those involved in using and regulating biotechnology. Where necessary. replacement of exist­ ing regulatory structures by new struc­ tures which a r e both consistent with the framework and with scientific progress. Institution of transparent consultation processes with the prime users of regul­ ation to ensure viability of regulatory proposals before any new proposals are put forward."' It concluded t hat fundamental changes were needed, in view of the recognition that "the horizontal biotechnology process-based Eu­ ropean Directives which touch on many other regulations are basically flawed": and there­ fore called for "a halt to the development of new regulatory structures until the [SAGB proposed] act ion plan has been put in place and the basic framework has been developed and agreed". H owever. i n several countries. national bio-industries that had laboriously estab­ lished working arrangements with their na­ tional competent authorities began to lose heart for conti nued struggle. or for perturbing public opinion by even the appearance of "deregulation · · . H their local appeasement

653

was successful , why should they pursue quix­ otic battles for broader or abstract concepts of European public interest? No lobby ar­ gued for the non-existent firms, products or services deterred from coming into being: "les absents ont toujours tort" . Scientific Reaction - the ESF Resolution of July 1994

In parallel to the industrial initiatives, the European Science Foundation (see Sects. 2.6 and 6. 1 ) had been brought back i nto the re­ combinant DNA debate, because of the im­ pact which genetic engineering legislation was having on their members. A survey of EMBO scientists had indicated considerable concern ( RABINO, 1 991 . 1 992) . Similarly, among the researchers involved in the Community's own biotechnology R & D programme, an investi­ gation (offering strict anonymity, to elicit frank responses) confirmed that the legisla­ tion - in some countries more than others was felt to be onerous, time-consuming, and irrational in several respects. The ESF in 1 994 responded to the Delors White Paper of December 1 993, with a Reso­ lution "welcoming . . . the opportunity to com­ ment on the existing legal framework for bio­ technology and for genetic engineering", and agreeing that "the present regulations go beyond what is necessary to control the risks (real or potential ) . . . and may therefore act as a disincentive to the development of the Eu­ ropean biotechnology research and industry". I t urged the Commission "to correct and im­ prove the conditions for effective research in Europe by providing for an amendment of the legal framework and for an adaptation of its regulations to the state of the art in re­ search and technology . . . Such changes are possible without increasing the risk and can thus be easily realized while fully upholding the present standards for the safety of human health and the environment". A "Resolution on the Legal Framework for Genetic Engineering" was adopted by ESF in mid- 1 994, culminating in a statement of nine principles to be observed in changing the legal framework for genetic engineering and biotechnology:

654

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

Genetic engineering is a method which has led to important progress in many ar­ eas of biological and medical research (including new methods of diagnosis and therapy) and of ecological research. Giv­ en its scientific potential, Europe should play a great role in the industrial applica­ tion of this method. Otherwise Europe may face the danger of becoming a mar­ ket rather than a site of innovation and production. In this respect legal frame­ works can exhibit different effects: where­ as the United States of America has not passed laws on the use of genetic engi­ neering techniques, the European frame­ work restricts research and the applica­ tion of new research results in industry by exaggerated administrative requirements. If this development were to continue, it could soon lead to reduction in activities and in educational and research incen­ tives, to a deterioration in the quality of university education and of research qual­ ity in the respective fields in Europe. 2. Over 20 years of experience with recom­ binant DNA and modern biotechnology in general has established that the risks involved can be assessed and minimized and controlled by adequate safety meas­ ures drawn up according to the state of the art, especially in biological research. As with regulations concerning the use of unmodified organisms, the legal frame­ work for the contained use of genetically modified microorganisms should only be concerned with organisms with a risk po­ tential and should differentiate the rele­ vant procedures more effectively in ac­ cordance with this potential. Therefore:

"1.

- for the contained use of genetically modified microorganisms classified as safe or with no risk, no notification to the competent au­ thority should be required; - for the contained use of genetically modified microorganisms classified as with low risk potential, only information to the competent authority should be required, so that such use may commence immediately without any further consent by the authority; - for the contained use of genetically modified microorganisms classified as with high risk potential, the requirement should be for the

notification to the competent authority be­ fore such use commences, as prescribed in the existing Council Directive 90/21 9/EEC. The classification of genetically modified or­ ganisms (GMOs) used by the US National In­ stitutes of Health (Guidelines for research in­ volving recombinant DNA molecules) might be a good example to be followed. To adapt those regulations might also ease communication and exchange between scientists in Europe and the United States and even beyond.

3. For the definition of operations (at pres­ ent "Typ A" for teaching, research, devel­ opment, or non-industrial or non-com­ merical purposes, and "Typ B" for any other operation), neither the scale ( cul­ ture volume) nor the purpose seems to be appropriate as the sole and exclusive cri­ terion. In consultation with academic and industrial research scientists, a workable risk base approach should therefore be developed. 4. For a better implementation of the legal provisions, the Council Directive should clearly differentiate between the active use , i.e. operations directly resulting in a genetic modification of (micro )organisms, and the more passive handling of GMOs, i.e. operations connected with storing and inactivation of GMOs and waste treat­ ment. For the latter operations, the exist­ ing regulations for hazard goods should be applied as far as possible. 5. Considering the fact that risks for human health and the environment in the case of microorganisms are limited to operations with microorganisms with a high risk po­ tential, the D irective should provide for the possible consultation of specific groups or the general public only on as­ pects of the proposed contained use of microorganisms with such a high risk po­ tential. 6. Possibility to exchange material is a key issue for research, since it permits to achieve verification of results prior to and after publication and for subsequent work at other laboratories. In the case of GMOs, there should be no doubt possible that the international exchange of sam-

7 Re-thinking a n d Review: 1 990-1 995

pies for purposes of research should not depend upon prior authorization and should not be subject to regulations gov­ erning the ··placing on the market"" of GMOs. 7. World-wide . the majority of field trials in which GMOs are deliberately released into the environment are carried out with plants. Nevertheless. very few such trials have been carried out up until now in most European countries compared with. for example, other OECD countries. This is mainly due to existing European regul­ ations. Simplification of these regulations should be possible without creating an unacceptable increase in risk to human health and the environment. and should follow the ··one stop. one shop" princi­ ple: - Once the criteria for a simplified con­ sultation procedure have been estab­ lished as sufficient in one case . all sub­ sequent applications concerning that GMO or GMO-combination should au­ tomatica lly be dealt with in the same way. - When the risks caused by a release are restricted to a limited area (location) . and thus human health and the envi­ ronment in other countries are not in danger, the necessary decision should be a purely national one: a prior con­ sultation procedure within the E U should therefore no longer b e required . being replaced . if deemed necessary . by notification of the other competent au­ thorities. 8. I n order to impleme nt research achieve­ ments for the benefit of medicine and public health. genetic engineering in the field of human and veterinary medicine aims to develop new diagnostic and ther­ apeutic methods and new pharmaceuti­ cals. To promote such research and to further its impleme ntation , for the sake of mankind: - applications of diagnostic or therapeut­ ic methods using genetical modification techniques should be explicitly ex­ cluded from the provisions of "deliber­ ate release" or "placing on the market" of G M O s :

655

- a human being or an animal to whom substances containing GMOs are ap­ plied for diagnostic or therapeutic pur­ poses or to whom individual cells are reintroduced after genetic modification should not be regarded as GMOs them­ selves: - procedures for the permission to intro­ duce new pharmaceuticals developed in a European laboratory into clinical trials or onto the market should ensure that the chances for success of an appli­ cation are not dependent on the coun­ try in which the laboratory or the com­ pany making the application has its le­ gal or effective base. 9. Gene therapy . in general, is one method among others which aims at maintaining and restoring health, especially of human beings. The use of such therapy in a spe­ cific case must be the sole responsibility of the physician and be subject to the same regulatory framework as other ther­ apeutic methods. Such therapy should. however, be applied in close consultation with and under the scientific control of persons competent in the particular field of genetic engineering. Furthermore, it is recommended to establish national regis­ ters to collect data on cases where gene therapy has been applied. No special legal framework should therefore be promul­ gated for gene therapy at European or national levels." This was transmitted to President J ACQUES DELORS with an accompanying letter on 1 1 June 1 994, on behalf of the "Board and Exe­ cutive Council of the European Science Foundation . representing 55 member re­ search councils, academies and institutions devoted to basic scientific research in 20 Eu­ ropean countries". The letter urged the Com­ mission to amend the legal framework on ge­ netic engineering, and in doing so to adhere to the following guidelines: "- The legal framework for the use of geneti­ cally modified microorganisms should dif­ ferentiate the relevant procedures more effectively in accordance with their risk potential.

656

/8 The Regulation of Modern Biotechnology:

- The definition of criteria for operations with such microorganisms would benefit from a new and workable risk assessment based approach which would be develop­ ed in consultation with academic and in­ dustrial research scientists. - The regulations concerning field trials with genetically modified organisms should be simplified. The European Science Foundation under­ lines that the amendments proposed in the enclosed Resolution do not create any unac­ ceptable increase in risk to human health and the environment." German Industry and Science Visits the President

On 26 July 1 994, in the first month of the German Presidency of Council, Dr. ERNST­ LUDWIG WINNACKER of the Max Planck In­ stitute , and Dr. HANS-JORGEN QuADBECK ­ SEEGER of BASF, President of the GDCh, the Society of German (industrial) Chemists, visited Commission President JACQUES DEL­ ORS, to discuss improvements in the EU regu­ latory framework for biotechnology. They left with him a 4-page statement, referring to the reasons why reform was needed, its scope and objectives, details of the changes required to 90/21 9 and 90/220, and proposed accompany­ ing measures to ensure the continued success of biotechnology in the European Union. Such a formidable combination of indus­ trial, scientific and (some) governmental pres­ sure for change of the 1 990 Directives might seem irresistible; but beyond the individual or i nstitutional sensibilities defending the Direc­ tives, loomed vaguely a much larger conserva­ tive force. At a time when new biotechnology products were starting to come to market, in such sensitive areas as consumer foods and animal productivity enhancers, the major un­ certainty for investors and governments alike was "public opinion".

A

Historical and European Perspective

7.5 Public Opinion: The Joker in the Pack - or the King? A

Tense and Dynamic Trilogue

It may seem illogical to have an opm10n about a topic of which one is largely ignorant; and where strong opinions co-exist with igno­ rance, the knowledgeable may reasonably de­ scribe it as prejudice, and therefore - less rea­ sonably - dismiss it. This is not an option for elected politicians, who must respect, or at least take some account of, the views of their electors - even when these are dismissed as ignorant prejudice by the experts. The ex­ perts are vulnerable to charges of elitism if they dismiss the opinions of the general pub­ lic, who are taxed to finance publicly sup­ ported research; and who may resent the im­ position of risks (real or conjectural) that may flow from such research. This triangle of tensions and communica­ tions between the general public, the scientist and the politician is shifting and ill-defined, but has in recent decades become increasingly significant in many areas of new technology, from irradiated food to nuclear power. Inevi­ tably, it has been and remains a major in­ fluence on the evolution of biotechnology regulation; changing over time, and varying widely from country to country and between different areas of application, and different techniques. In the USA, the post-Asilomar debate in the late 1 970s has already been described (Sect. 1 .4) as a dialogue - more correctly, a trilogue - of scientist, public and regulator. Yet in spite of the public ignorance and fears about conjectural risks, in the US conditions at that time, the pressures on Congress did not lead to legislation, and the counter-argu­ ments for using existing statutes prevailed. A major factor in that outcome was the level of trust, by both public and Congress, in some of the scientific leaders, and particularly in the leadership of the science-based agencies such as FDA and the National Institutes of Health. The role of the NIH RAC (Recombinant DNA Advisory Committee) has been refer­ red to (Sects. 1 .4 and 5. 1 ) and the transparen­ cy of its public meetings has been frequently ,

7 Re-thinking and Review: 1 990-1 995

cited as a factor in its credibility. Although the transparency in Europe has been less . the need for the involvement of lay participants and representatives of public interest has been acknowledged in the constitution of na­ tional committees such as the UK's GMAG and ACG M (see Sect. 5 . 2 ) . Reports Link Perceptions, Regulations and Trust

The importance of public perception for the progress of biotechnology was evident, from the Asil omar debate of the late 1 970s and subsequently. Many authors or analysts made the parallel with nuclear power . or more generally with chemicals. Such parallels would emphasize the initial overselling in the early years of the technology: the naivety, hubris or dishonesty of scie ntists or engineers: the sacrifice of safety to personal. political and economic interests: and ultimately the trust-demolishing discovery or disclosure of side-effects and consequences previously un­ foreseen or deliberately concealed. The first FAST report ( FAST. 1 982) had for these reasons emphasized the need for public information and education: "education for the Bio-Society has a wider dimension. The strategic projects to be pur­ sued through the key ce ntres should respond to (or anticipate ) the needs expressed, through market-pl ace or political decision . by a democratic socie ty; and must in that context be capable of winning the political, financial and social support necessary for their imple­ mentation. Such support depends upon a de­ gree of public acceptability and comprehen­ sion . Obtaining such support can be more dif­ ficult than solving the technical problems, and the consequences of failing to do so can be more costly th an the development of the tech­ nology itself. General education , through the school system and the public media. should therefore aim to provide widespread under­ standing. sufficient to permit informed discus­ sion and appraisal of the acceptability of pro­ posed developments before expensive com­ . mitments are made On the other hand. it was already evident that excessive caution could strangle innova.

.

657

tion. and might already be doing so; PERUTZ ( 1 981 ) was quoted in the FAST report: "The time taken from patenting a new compound to its marketing averaged three years in the early 1 960's, it rose to 7 years and a half in the early 1 970's and to nine years in 1 978-79, largely as a result of the demand for ever more elaborate trials and safety tests . . . The number of chemically new drugs put on the market is falling and the fraction being spent on development continues to rise at the expense of research. " The FAST report emphasized that: "There is a growing evidence that we are mismanaging the processes of societal learn­ ing and self-improvement of which technolo­ gical progress is an element. Lead-times for innovation are increasing, with associated greater costs. The balance between broader societal interests and defence of the existing (products, jobs, institutions, ideas) is typically counter-productive in the medium- or long­ term." The FAST report, among its "Contextual Recommendations", emphasized both atten­ tion to the public education in the life sciences throughout the school system; and ''the creation of clear and consistent regul­ atory frameworks, applicable throughout the Community. on all aspects of laboratory de­ velopment. factory manufacture, testing, and marketing of products and services; with par­ ticular reference to the novel products and services likely to arise in the fuel, food, chem­ ical and pharmaceutical industries. These ac­ tivities are already being pursued within the Commission Services through committees." Similar concerns arose, somewhat later, in the United States. By 1 985, in a National Academy of Sciences conference on "Bio­ technology: An Industry Comes of Age", a recurrent concern at the meeting was voiced by McGI NTY (OLSON, 1 986): "In the end. whether or not these new bio­ technologies really get off the ground in this country is going to depend upon whether we can erect a regulatory regime that can secure public trust." Thus on both sides of the Atlantic (and in­ deed in Japan: see Sect. 5.5), there was recog­ nition of the linkage between public percep-

658

18 The Regulation of Modern Biotechnology:

Historical and European Perspective

May 1987 (OTA, 1987). The poll was based on a national sample of 1273 adults. The sur­ vey, using an extended questionnaire, sought information about knowledge and opinion on science and technology issues in general, and on genetic engineering and biotechnology in particular. Summarizing the results, the OTA noted that "nearly half ( 47% ) of the adult popula­ tion of the United States describe themselves as very interested, very concerned, or very knowledgeable about science and technolo­ gy"; and defined this population as "the science observant public". 80% of all Americans expected develop­ ments in science and technology to benefit them and their families; 7 1 % expected at least some risks; but when directly faced with the choice between the risks and the benefits to society from continued technological and scientific innovation, 62% felt that the bene­ fits outweighed the risks, as against 28% holding the opposite view. The report made clear the range of views, and the high uncertainties; but on balance gave fairly clear support for continued but cautious progress. Its tone is conveyed by these quotations from the Executive Summa­ ry of the (OTA, 1 987) report: " . . . 52% believes that genetically engi­ neered products are at least somewhat likely to represent a serious danger to people or the

tions of risk, regulatory regimes, and public trust in these. The linkage seems wholly prop­ er in democratic societies; although the exis­ tence of the linkage does not give any obvious conclusion as to how to manage a situation in which public perceptions of risks (of biotech­ nology, or of black magic) diverge significant­ ly from scientific perceptions. In any event, the recognition of this linkage led to the need to measure public understanding and opinion, so far as possible objectively; rather than de­ pend upon self-appointed activists claiming to represent "the public interest". A paper in Swiss Biotech (CANTLEY, 1 987) reviewed the situation and the available US and European data, noting in the European context the heterogeneity of national opin­ ions, at least as suggested by general surveys (in 1977 and 1 979) of public attitudes towards science and technology (EUROPEAN CoM­ M ISSION, 1 977b, 1 979) . Tab. 1 was reproduced from the 1 979 Community-wide survey. The OTA

A

Poll, 1986187

The first quantitative survey work on pub­ lic opinion specifically on biotechnology was a nation-wide (US) survey commissioned by the Congressional Office of Technology As­ sessment (OT A), conducted in October-No­ vember 1 986. The results were published in

Tab. 1.

Biotechnology-Relevant Questions and Responses, fro m the Survey of Attitudes to Eight Research Areas (All Figures Represent % of Respondents), 1 979

Country/Question

EC

B

DK

D

F

IRL

33 19 35 13

38 20 22 20

13 10 61 16

22 16 45 17

29 22 37 12

41 20 22 17

49 19 22 10

100

100

1 00

1 00

1 00

100

23 21 49 7

16 26 44 14

13 21 50 16

34 16 36 14

10 20 66 4

1 00

1 00

1 00

1 00

1 00

Genetic Research

Worthwhile Of no particular interest Unacceptable risks Don 't know

I

L

37

NL

UK

36

18 14

41 6

32 21 36 11

1 00

1 00

1 00

100

23 29 38 10

11 20 65 4

25 39 25 11

23 30 42 5

34 25 36 5

100

100

100

1 00

1 00

31

17

Development o f Research o n Synthetic Food

W ort h while Of no particular interest Unacceptable risks Don't know

7 Re-thinking and R eview:

environment. Nonetheless. a two-thirds ma­ jority of the public (66% ) says that it thinks that genetic engineering will make life better for all people. When all othe r factors are equal, the public says it is more favorably disposed toward ge­ netic alteration of plants. animals and bacte­ ria than manipulation of human cells . . . . A large majority of the public (82% ) favors environmental applications of ge netically al­ tered organisms on a small-scale. experimen­ tal basis. In fact . 53% would favor and 1 4% say they would not care if their community were selected as a site to test a ge netically al­ tered organism. However. only 42% of the public think commercial firms should be per­ mitted to apply genetically altered organisms on a large-scal e basis . . . . The issue of human cell manipulation is more se nsitive than other forms of genetic en­ gineering. While a majority of the public (52% ) believes it is not morally wrong to change the genetic make-up of human cells. a significant minority ( 42% ) says that it is. When confronted with specific applications of human ce ll manipulation. however. many Americans relax their position . . . a majori ty of the public says it favors the correction of potentially fatal genetic defects in germ line cells as well as somatic cells. A majority of those who feel human genetic manipulation in general is morally wrong nonetheless says it would approve its use in specific therapeut­ ic applications . . . . A large majority of the American public (82% ) believes that research in genetic engi­ neering and biotechnology should be contin­ ued. Support for this research appears in all segments of the population . . . . The public believes that Federal age ncies are distinctly less able than university scien­ tists to assess potential risks. Moreover, in disputes between Federal agencies and envi­ ronmental groups over risk statements, the majority of the public says it is inclined to be­ l ieve the environmental groups . . . . The survey finds that while the public ex­ presses concern about genetic engineering in t h e abstract . it approves nearly every specific environmental or therapeutic application. And. while Americans find the end-products of biotech nology attractive , they are suffi. . .

1 990-1 995

659

ciently concerned about potential risks that a majority believes strict regulation is neces­ sary. Moreover, the majority of Americans be lieves a government agency or an external scientific body should be responsible for de­ ciding about environmental use of genetically altered organisms. At the same time, a major­ ity (55% ) believes that the risks of genetic engineering have been greatly exaggerated, and 58% feel that unj ustified fears of genetic engineering have seriously impeded the de­ velopment of valuable new drugs and thera­ pies. . . . people favor the continued develop­ ment and application of biotechnology and genetic engineering because they believe the benefits will outweigh the risks. And, while the public expects strict regulation to avoid unnecessary risks, obstruction of technologi­ cal development is not a popular cause in the United States in the mid- 1980s." The results of the OTA poll were seen as relatively reassuring for the progress of bio­ technology, and the fact that there have been few . if any, subsequent nation-wide polls in the US is itself an expression of that confi­ dence . There were major challenges to bio­ technology activities, academic and industrial or agricultural - especially concerning the early fie ld release experiments; and to Feder­ al agencies such as EPA and N I H . But these challenges were mainly through the courts, by isolated or numerically insignificant activists. Such actions did not appear to catalyze major or lasting public or Congressional concern; and neither did isolated events, either of van­ dalism to test plots, or of widespread reports, alleging irresponsible behavior by individual scientists or companies. Federal agencies undertook efforts at pub­ lic communication - particularly USDA, through various public information initiatives, such as widely advertized regional confer­ ences, open alike to the press and the critics as well as the interested public. In general, a continuing openness to questions and trans­ parency to public and press, together with a continuing absence of adverse incident. proved sufficient to maintain, if not whole­ hearted acceptance. at least an absence of se­ rious opposition to continuing research and innovation in the US.

660

18 The Regulation of Modern Biotechnology: A Historical and Eu ropean Perspective

The OT A study foreshadowed similarly divided views in other countries and times. The relative rankings, e.g., of different appli­ cations, are very similar from country to country, although the numbers vary widely between countries. But the methodological problems of conducting public opinion sur­ veys are great in general, and particularly so in establishing meaningful, unbiased and con­ sistent measures of something as nebulous as attitudes to topics about which the general level of awareness and technical understand­ ing are naturally low. Slight differences of wording can make substantial differences to the results. For example, the principal conclu­ sion of the OTA study (see highlighting in fi­ nal paragraph of the quotation above) was contradicted in a study the following year conducted on behalf of the firm Novo Indus­ tri: " . . . the same mixture of ignorance, optim­ ism and worry as previous surveys. Nearly 40% of about 1000 respondents had never heard of genetic engineering. Of those who had, most expect it will yield significant bene­ fits. On the other hand, a full 70% do not be­ lieve that the benefits will outweigh the per­ ceived risks of genetic engineering. And an equal number favor 'strict limitations on the kinds of genetic engineering research that scientists can do' . Regulations should be for­ mulated primarily by scientists in collabora­ tion with the government, two-thirds of the respondents say; only one-third favor involve­ ment by private firms. Also, the poll finds broad support for international controls on biotech research." (Novo INDUSTRI, 1987) Danish Sensibilities: First to Legislate, Inventors of "Consensus Conferences"

This poll may have been one of the factors which in subsequent years led Novo Nordisk (their name changed following the merger with Nordisk Gentofte) to adopt a particular­ ly energetic and high profile effort to publi­ cize themselves as a "green", environmental­ ly-friendly and biotech-based company. It may also be because they are Danish; and of all countries significantly involved in biotech-

nology, none has more energetically than Denmark pioneered and promoted wide­ spread debate by the entire citizenry about the nature, merits and possible risks of ge­ netic engineering and biotechnology. The Danish experience is of special interest in several respects. Even in the 1 970s, general public opinion surveys about attitudes to var­ ious areas of science in different European countries indicated in Denmark an exception­ al sensitivity to the possible risks of genetic research (see Tab. 1 above). Germany was in second place ( EUROPEAN COMMISSION, 1 977, 1979). These two countries were respec­ tively the first and second in the world to in­ troduce legislation specific to "gene technolo­ gy". Denmark also pioneered carefully struc­ tured "consensus conferences", to bring pop­ ular or lay opinion into dialogue with the bio­ technology experts, and to force the experts to explain in comprehensible language what they were doing or attempting. National opinion surveys in Denmark over the years following the 1 986 Gene Law indi­ cated quite significant shifts in opinion (Bo RRE , 1 990) , with at least a suggestion that, while the perception of risks remained high, there was some shift towards greater ac­ ceptance (see Tab. 2). Danes are in the Euro­ pean context also exceptional in the level of trust in their government as a source of infor­ mation on new technologies - twice the Euro­ pean average, and approaching 50% ; so that the national policy to support and promote biotechnology (in spite of the fears) may have been significant in influencing the shift to­ wards acceptance. But this observation antici­ pates the results of the Eurobarometer sur­ veys in the early 1990s, described below. BORRE himself (1 990) discusses the effects of other variables - educational, political, etc., noting considerable politicization of the gene technology debate on left/right lines. Calls for Measurement and Research

In a paper on public perception of biotech­ nology, prepared for the International Bio­ technology Symposium at Hannover, T AIT ( 1988b) paid tribute to the "pro-active risk regulation" being developed in the field (in

7 Re-thinking and Review: 1 990-1 995 Tab. 2. Agreeme n t

and Disagreement i n D e n m a r k

with

661

Opinions on Gene Te c h n ology Perce nt, ,

1 987-89

Sept.

May

May

1 987

1 988

1 989

Agree

59

67

69

Disagree Don't know

32

24

8

9

20 11

1 00

1 00

1 00

Agree

77

Disagree

18

70 22

77 15

1 . I t is i mp orta n t t h a t we do n ot get behind when the potential of gene technology is to be ex p l o i t e d

Total

2. It is m o ra l l y w rong t o inte rfe re animals and h u m a n beings

w i t h the natural ge netic

m a te r i a l s of

Don ' t k now

5

8

8

1 00

1 00

1 00

Agree

35

43

35

D is a g ree Don't k now

38 27

32

40

25

25

100

1 00

1 00

Agree

39

29

25

D is a g r e e Don't k now

51

60

11

61 14

1 00

1 00

Total 3 . The risk that dangerous n e w m icrobes ge ne splicing. is strongly exagge r a ted

e sca pe d u r i ng experiments with

Total

4. A n international can should be i m po se d

on any kind of

ge ne spl ici ng

10

Total 5.

Only expe rt s

1 00 and s e t t l e

qu e s tio n s on gene s pli c i ng

-

or d ina ry p e o pl e know

too little abo u t it

Agree

72

76

D isagree Don't k now

24

20

4

4

1 00

1 00

Agree

61

52

46

Disagree D o n t k n ow Tota l

28 11

36 12

37 17

1 00

1 00

1 00

Total 6. I

would protest

if

a factory in my ne ighbourhood were pe rm it te d

to work

with ge ne - s p l i ce d b a c t e r i a

'

Sou rce : B o R R E . 1 990

the E C ) : b u t comme nted that such regulation "reinforces the need for more detailed infor­ mation on public perception of the industry". Although some in d ustry managers and gov-

ernment were ophmtshc, feeling that "the thoroughness of these regulatory initiatives is out of all proportion to the real extent of the risks", T AIT stressed that

662

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

"Serious outbreaks of public resistance to new biotechnology developments, for exam­ ple in the United States, West Germany and Denmark, should, however, warn against un­ due complacency. The industry does have the potential to arouse strong passions, not least because it raises genuine moral and ethical is­ sues for society. A small minority, if suffi­ ciently committed and vocal, can change the attitudes of the majority." The article summarized the results of the polls referred to above, and of a similar U K poll conducted for the Department of Trade and Industry; but she was critical of opinion polling as a 'broad-brush' technique: "Opinion polling is inevitably a 'broad­ brush' technique. It does not provide detailed information on the nature of perceptions about an issue, why they are favorable or ad­ verse, whether these perceptions will remain latent or are likely to be translated into ac­ tions and for which groups this is most likely to be the case. Most important, it does not in­ dicate the extent to which any potential con­ flict is motivated by concern for the interests of protagonists or by ethical and value-based considerations. The former is epitomized by the well-known NIMBY syndrome ('not in my backyard') (GERVERS, 1987) but the dis­ tinction between this and the alternative NIAMBY ('not in anybody's backyard') is rarely recognized. NIMBY tends to be used as a blanket term to describe all conflicts over potentially hazardous or otherwise unwanted activities. " She argued for methodological develop­ ment, calling (TAIT, 1 988a) for a complete programme of research on perceptions to in­ clude the fol lowing elements: - an opinion poll carried out on the general public, as for the OTA survey described here; - identification of specific sections of the public likely to have an important influence on the biotechnology debate; unstructured, tape-recorded interviews with representatives of such groups to provide material for a struc­ tured questionnaire to be answered by a ran­ dom sample of group members; data analysis to indicate the contributions of values and of interests to various perceptions, the relation-

ships between perceptions and relevant be­ haviors, and the policy implications of the survey results; - research on the customers for new biotech­ nology products - how are they likely to use new biotechnology products in relation to what regulators will expect of them; what will be the pressures on them to violate regula­ tions; how can monitoring systems be made more effective (see, for example, Ref. 8); - research on interactions and relationships among scientists, regulators and the business community; what is the range of perceptions among them of the hazards presented by bio­ technology developments; how could the ef­ fectiveness of their communication with one another and with the general public be im­ proved; - broad-ranging research on the social, envi­ ronmental and political impact of biotechno­ logy developments, individually and in com­ bination with the existing systems of, for ex­ ample, land use and health care. Similar sentiments were being expressed, needs articulated, elsewhere in Europe; a thoughtful review was provided by vAN D E N B R OC K ( 1 988), in which both industry (through NIABA, the Netherlands Industrial and Agricultural Biotechnology Association) and the Parliament's NOTA (Netherlands Organization for Technology Assessment) stressed the need for research and measure­ ment. LYDI STERRENBERG, co-ordinator of the NOTA biotechnology programme, was quoted: "With all scientific and technological in­ novations that are expected to have a dramat­ ic impact, the public opinion, knowledge and attitude towards the new developments should in fact always be investigated. The public should also be informed more systema­ tically about the developments at an early stage." Opinion research and survey measure­ ments were undertaken in many European countries from 1 990 onwards. A critical re­ sume of the surveys was presented by LEM­ KOW ( 1992) as the background to research which he undertook in several European countries for the European Community's "Dublin" Foundation (see below):

663

7 Re-thinking and Review: 1 990-1995 · · i t can

be

a rg u e d that diverge n t results arc a

product of markedly d i ffe re n t societies. values and systems of acces� to i n formation. Another conclu ­

sion of

a n a nal y s i s of the q u a ntitat ive studies of

p u bl i c opi n i o n

m ight

be

t h at

the methodology pro­

tion a bout the usefulness of biotechnology and t he poss ible risks attached to some of its applications. - Regulation should be fre e from t h e interfe rence of

co m me rci a l

or industrial inte rests.

- Some groups propose d that supra- n ational or­

vides an incom ph: t c . e v e n misleading pict ure of

ganizations pl ay a more active role i n the regulation

public attitudes and acceptance of biotechnology.

and cont rol of new biotechnologies."

Other ( q u a l i tative J approaches can be used, such as discussion/focus groups. workshops and i n -depth i n terviews. to sharpen the picture . The quantitative

st udies

h a v e prov ided some

t a n t a l izi ng

clues and

have shown the ambivalence of p u b l ic opinion t o new biotech nology a n d its applications. T h e d a t a which they h a v e provided h a v e been u s e d as t h e basis or the desi11-n of much of t h e m o s t rece n t q u a l ­

itative research and v ice versa. I t w a s precise l y beca use of the

cont radictory a n d

somewhat confusi n g results of earlie r s u rv e y r e ­ search that T h e E urope a n Foundation for the Im­ provement of Living and Working Condit ions and D i rectorate G e n e ral

XI of t h e European Commis­

sion opted to support some q ua li ta t ive research to a bet t e r u n d e rsta n d i n g of the complex set of

ga i n

attitudes

to

biotechnology

ide n t ified

in

e a rli e r

q uant i tat i v e st u d i e s . This has i nvolved rese a rch i n B ritai n , France , G c r m a n y a n d Spa i n a n d w a s base d

on focus/discussi o n gro ups with members of the · ' i n formed public"' in each of t he fou r count ries as we l l as worksh ops i nv o lvi ng represe ntatives of pressure groups

and

interested pa rt ies ( pharmace u ­

t i c a l and food processing i ndustries, agricult ural i n ­ terest s , medical profes s ion , trade unions. environ­ mental groups. public administrations)."'

He described at some length the results of the "focus group" discussions, their strengths and weaknesses. and the difficulties in ad­ dressing a little - known and complex subject of widespread significance . All groups fo­ cused at length on risks: they ··felt that re­ search could get out of hand. and adequate controls were lacking". On "' Regulation and Control ". LEMKOW summarized the outcome as follows: "' R e gu l a t i o n was a n ot he r of t he m aj o r t h e m e s raised in a l l the g ro ups. T h e re was a n e v i d e n t " ' l ack of fai t h " in the compe t e nce and will of gove rn­ ments to control deve lopme nts i n ge netic e n gin e e r­ ing or othcr areas of research w h e re t h e re are po s ­ s i b l e safety and p ub l ic h e a l t h risks. A fee l i n g of vul­

manifest i n a l l t h e groups - being LJUite independent of the ide o l o gica l positions of

nerability was

the respondents. -- I t w a s repeate d l y a rgued t ha t regu lation should he ba sed on so u n d . ho nest and obj ective informa-

Clearly such results could be cited in sup­ port of a clear-cut regulatory framework for biotechnology . including international dimen­ sions. L E MKOW also stressed information" : · · i n formation issue was the "star•· t h e me i n the

"'focus'" groups among the i n te reste d public. The workshops were no exce ption and many

of

the in­

te rventions of articulate professionals, experts i n the field of biotech nology. paralleled t hose of t h e non-specialist public. I t was unde rstood by all t h e participants that t h e ge neral p u b l i c w as eager

for

information on biotechnology but with certain con ­ ditions at t ached: - I n formation should be provided i n clear, accessi­ ble and understandable language , and couched i n lofty specialist terminology . - It

s hould

not

be objective and truthful.

- It should come from a reliable so urce which should be ident ified. The

above

were

seen

as

prerequtsttes

for

strengt h e n i n g public confidence . This is as far as consensus

we n t .

Represe ntatives

tended to argue that

the

from

i ndustry

facts spoke for themselves.

I n formation could not always be provi ded because of the need for confide n t i a l i t y in the face of compe­ tition i n the deve lopme nt of new produc t s for the market. Interest groups i n t h is context

often gave

the i mpression t h a t i ndustry regarded the principle of secrecy as more i m port a n t than

the

provision

of

i n formation. Consumer organ izations and e nviron ­ mental groups w e re highly critical of current i n for­ mat ion pol icy i n biotechnology which they consid­ e red to be inadequate. Access to i n formation was a right and there should be mechanisms for guarante­ h e alth

e i ng this where risks for the environmen t ,

and safety may be involved. The withholding of i n ­ formation would on ly reinforce t h e e x i s t i n g lack o f

confidence in commercial a ctiv i t i e s i n the scientific and technological fie l d . "

I n fact the European Commission under the B R I DGE programme grant supported a growing number of publications and initia­ tives for public information - the various lan­ guage versions of " B iotechnology for All"

664

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

(KATZ and SATTELLE, 1 991 ), consumer dia­ logue workshops and related publications, an EC-US bilateral workshop in D ublin on "Communicating with the Public about Bio­ technology" (US E C TASK FORCE, 1993), a network of teachers in the European Initia­ tive for Biotechnology Education, and sup­ port for the EFB Task Group on the Public Perception of Biotechnology. -

The Eurobarometer Surveys

LEMKOW, T AIT and others recommended more "depth" in the research - for example, taking account of the socio-economic circum­ stances of the consumer, clarification of the relationship between attitudes to science in general and perceptions of biotechnology, the need to distinguish more clearly attitudes to different applications of biotechnology, the need to analyze the (in)stability of attitudes over time, and the need to take into account ethical questions. Although LEMKOW saw surveys as provid­ ing "at best, only a superficial impression of the state of opinion on scientific applications in such areas as genetic engineering", in fact all the points noted in the preceding para­ graph could be addressed through surveys, given large enough sample sizes, adequately structured questions, full analysis of the re­ sults, and repetition on two or more occa­ sions. These conditions describe the Eurobarom­ eter biotechnology surveys conducted in March/April 1 991 and March/April 1993. The twice yearly Eurobarometer exercise, con­ ducted since the early 1970s, is a very profes­ sional operation. Survey firms are competi­ tively selected, to cover each of the countries of the European Community or Union, in its national language(s). A sample of approxi­ mately 1000 adults is interviewed in each country; including (since the 1990 reunifica­ tion) an additional lOOO in (former) East Ger­ many; only 500 in Luxembourg; and 300 in Northern Ireland, in addition to 1000 in Great Britain. In addition to standard questions about Europe, it is open to any department of the Community institutions to "purchase " ad­ ditional questions.

With the B RIDGE programme , the re­ sources devoted to the concertation action enabled the Commission to undertake a com­ prehensive Community-wide survey, of public attitudes to biotechnology - or genetic engi­ neering. It was typical of the care devoted to the study that the samples were split - half being asked about "biotechnology" (a word now existing, give or take spelling differences, in all 9 languages), and half about "genetic engineering" (or similar terms), or (for Ger­ man and Dutch samples), " gene-technology", and for Danish, "gene-splicing". (In some countries, the choice of words made major differences to responses, "genetic engineer­ ing" being more negative; elsewhere , differ­ ences were slight.) The questions addressed essentially four is­ sues: •

• • •

knowledge (for subsequent questions, each was preceded by a short explanation) opinion about regulation and applications sources of information trust in different sources.

The results of the survey were published in Europe-wide and national reports by the Eu­ ROPEAN COMMISSION ( 1 991b), and reported elsewhere (e.g., by MARLIER, in DURANT, 1 992) ; and the data tapes placed in public data banks in Europe and America. A similar exercise, using some of the same questions, and some additional questions on ethics, was conducted in the spring of 1 993; and ERIC M A RL I E R again prepared the report, (EUROPEAN COMMISSION, 1 993a), including extensive comparisons with the 1 991 data. The "key results" are reproduced below. The full results are available from the Com­ mission, and the depository data banks. Marlier Summary

For the purposes of the present paper, on the evolution of regulations, Eurobarometer results offer several points of interest: - they confirm the earlier ( 1 979) data indicat­ ing wide differences of attitude between dif­ ferent Community countries;

7 Re-thinking and Review: 1 990-1 995

t h e reporte d a t titudes, e . g . . to risk . appear well correlated with political behavior - e.g . . the highest a n d s ec o nd - hi g hest risk percep­ tions are found in the countries who were first (Denmark ) and second (Germany) to leg i s­ late on b i ote chn olo g y: - the ran k in gs of countries on various topics appear to be consistent over time. even with the 1 979 surv e y (when it touched genetic re­ search ).

-

Some Key Results of the Spring 1993 Survey (EU ROPEAN CO M M I SS I O N . 1 993a : Report Prepared by E R I C MARLIER)

- A large number of persons interviewed particularly i n Greece . Spain . I reland and Portugal - were unable or unwilling to answer certain questi o ns . Compared to the pre v ious survey carried out on the same subj ec t (spring 1 991 ). this pro porti o n has droppe d however. - As in the 1 99 1 poll. the two main sources of information used hy E ur o peans for what con­ cerns "new de ve lopments that affect our way of life" are, in ranking order, te l evision ( the supremacy of which has yet again been con­ firmed) and newspapers. - In ranking order. the m ost r eliable sources of i n formation on biotechnology/genetic engi­ nee r ing are considered to be environmental organizations . consume r organizations and schools/universi ties. In 1 99 1 . consum e r or gan i z ations slightly s up p lanted environmental o r gani z ation s . If consumer or g anizations have lost the i r predominance as .. the most reliable source " it is not because they have become le s s popular than in 1 99 1 but because environmental or­ ganizations have themselves made considera­ ble progress. - Less than one r e s pondent in fi ve believes that Public a uthorities pr ov i de a reliable s o u r ce o f i nfor m at i on regarding biotechnolo­ gy/g e netic engineering. In Denmark . howev ­ e r . t h is percentage is nearer one in two. In 1 9Y I . the situation was similar but not as p ro n o u nc e d : t h e Danish result was weaker and the E urop e a n average slightly higher. - Each of the seven new technologies ana­ l yzed is perceiwd by a large maj ority of per­ sons interviewed as ·· impro ving our way of life in the next 20 years " .

665

The only two technologies for which this majority is not absolute but relative are ge­ netic engineering (as opposed to biotechnolo ­ gy) and space exploration . As in 1 991 these find. overall less favor. The level or " optimism " regarding genetic engineering has lessened considerably since the last survey. This drop is very pronounced in Ger­ many and pa r ticular l y in the five new Lander. - 48% of interviewees believe that biotech­ n ol ogy/ genetic enginee ring "will improve our way of life in the next 20 y ears " ; 1 5 % think the opposite. In 1 991 , "optimism" was at 50% and " pessimism " at 1 1 % . - I n general . when there exists a s ignificant difference, the term "genetic engineer i ng " is less well known and has a more negative con­ notation than the term "biotechnology". This was already the case in 1 99 1 . - Support for biotechnology/genetic engi­ neering. as wel l as "optimism" regarding it, is a posit i ve function of what is known on the subject. As in the survey two years ago it de­ pends to a great extent on the ty p e of applica­ tion and is lin k ed to t he risk associated with it: a risk which is considered to be neither ne­ gligible nor dramatic , regardless of the appli­ cation analyzed. - Except for research on farm an i mals and. to a lesser extent, food research, where opin ­ ions are mixed. those interviewed "tend to agree" that the various kinds of research int o biotechnology/genetic engineering disc u ssed in the questionnaire are "worthwhile and should be encouraged " . It was already the ca se in 1 99 1 . - Regardless o f the nat i on al ity and the appli­ cation of biotechnology/genetic engineering i n q u estion , demand for governmental control of the various applica t ion s is massive. This was even clearer in 1 99 1 . - The c l assi ficat i on o f the different types of research according to the degree of support given to t hem is identical in 1 991 and 1 993. I t i s t h e same for the classifications lin k e d t o the associated risk or related to the level of "de ­ mand for control " . - Since the last survey. support for the differ­ ent a ppli cation s analyzed has, overall, slightly dropped . In Germany and especially in the five new Lander this d rop in "global supp ort " is particularly p ronounce d .

666

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

The "global risk" associated with these ap­ plications has remained stationary whereas the level of "global demand for control" has somewhat dropped. - Whereas the perception of risk is p ar ticu ­ larly high in Denmark (it is the highest in the Twelve), the support recorded here is around the European average. Although weaker than that registered in Denmark, the perception of risk is also very high in West Germany (it is the second high­ est in the Community). On the other hand, support here is a great deal lower than the Community average (it is the weakest in the Twelve). This divergence in attitudes has increased in comparison to 1 991 . One plausible expla­ nation of this result is that the Danes (see above), even more now than two years ago, are proportionally many more than the West Germans to trust Public Authorities "to tell the truth about biotechnology/genetic engi­ neering". - In Luxembourg, global support, perception of risk as well as global demand for control have n ot ice ably increased since th e previous survey. In Portugal, on the other hand, we ob­ serve a considerable rise in the global percep­ tion of risk, accompanied by a significant drop in global support and global demand for control. - As for research into biotechnology/genetic engineering involving human beings as well as animals and plants, at least three out of four interviewees declare that "there should be clear ethical rules" indicating when research "may not in any way" be undertak­ en. - There is the usual ranking of seven applica­ tion areas, similar across countries, from med­ ical applications (most acceptable) down to the modification of farm animals (least); - for all application areas, there is a high and uniform demand for control: regardless of ap­ plications 83% to 87% (1991 : 82% to 89% ) of EC citizens agree that it "should be con­ trolled by the government"; - on the key question of trust, the public in­ terest groups (for environment, or for con­ sumers) are seen as more credible by far than government, and still more so than industry, sources.

On the last point, a disturbing trend be­ tween the 1 991 and 1 993 results was summar­ ized by the headline in BBN (Biotechnology Business News, 1993) , " Eurobarometer results discouraging". They presented the results as follows: "The results of the second Eurobarometer survey on awareness and attitudes about bio­ technology have been published in a full re­ port. A major goal of the second EC-wide public opinion poll was to identify trends with respect to the first biotechnology survey of this type conducted in March of 1 99 1 . A total of 1 2 500 persons were interviewed. A first analysis is not encouraging, consid­ ering the results summarized below: - The number of people that believe biotech­ nology will contribute to life and living condi­ tions has decreased. - There is speculation that public attitudes are being based on feelings rather than fac­ tual knowledge. - There is an increase in risk perception in almost all applications of biotechnology, com­ bined with a decrease in readiness to support research in each area, except in the case of pharmaceuticals. - There is a generally reduced demand for public control which, in light of a higher risk perception, indicates a reduced trust in those who do control. - This is supported by the unchanged rank­ ing order of various organizations that act as a source of information."

Tab.

3 . C omparison

of 1 993 and 1 99 1 Polls

Who do you t r u s t most to tell yo u the truth about

(% mentioning)

biotechnology?

1991

1 993

Environmental organizations Consumer organizations Schools, universities Animal welfare groups Public authorities Religious orga n iza t ions

52.6 52.3 37. 1 29. 1 20.4 9.7 6.0 5.2 4.9

60.8 55.5 38.5 32.2

Industry

Trade unions Political organizations

16.8

8.2 5.6 5.2 4.0

8 Synthesis and Conclusions:

The outcome of these surveys and the anal­ ysis of public opinion can be summarized as fo llo ws : •

•

•

•

•

Public ignorance and uncertainty about b i ote c hnol og y or genetic engineering gives rise to a high level of apparent demand for regulation. Depth interviews with ··focus groups " sug ­ ge st a strong demand for transparency, and for comprehensible and trustw orthy infor­ mation . G o v e r n me n t is lit tle t rusted . industry still less, as a source of information, so that either sta t u t o ry or voluntary regulation may still not build trust : (though clearly this w o u ld not j ustify any govern ment ' s abandoning regulatory activity when they believe it to be objectively n e cessary) . In these circumstances. there is both an op­ portunity for e nvironmental and consumer o rganiz ati o n s , and a responsibility on them. to provide objective information and reasoned opi nions about developments in biotechnology . T her e is little evidence for the view that government re g u lation itself builds or would build trust in biot e chnology .

A comprehe nsive comparative summary of poll s was pre s ented by ZECH E N DO R F ( 1 994 ) . Activities on research and communication continued to be promoted in the mid-90s by the Task Group on Public Perception of the European Fe deration of Biotechnology, un­ der the chairmanship of JOHN D U R A NT. the UK. and perhaps the world's first professor of the "public understanding of science .. . The Commission, through the Biote c hnology Co­ ordination Committee. and with continuing encouragement from the European Parlia­ ment to accompany R & D programmes by studies on social . ethical and other dimen­ sions. seemed likely to continue through the 1 990s the Eurobarometer measurement proc­ ess launched in 1 99 1 and 1 993.

Learning from History

667

8 Synthesis and Conclusions: Learning from History In 1 98 1 . the Nobel pri ze-winning Ameri­ can, J A M E S WATSON , and the Secretary of the European Molecular Biology Organiza­ tion . J O H N Too z E . pub l i shed "The DNA Story: A Documentary History of Gene Clon­ ing " . With their narrative, they interspersed the principal documents associated with the pre- and post-Asilomar discussions, from 1 973 thro u gh to the end of the 1 970s, docu­ ments which illustrate the rise of the once­ threatening tide of Congressional legislation, and of the widespread public concern and c riticism which drove it . A few of the same elements are briefly reviewed in the first sec­ tion of this review; the WATSON and ToozE compendium fills over six hundred pages. In the closing paragraph of their final section, " Ep i logue " , the authors conclude with evi­ dent relief: " Politics and politicking preoccupied the first years of the recombinant DNA story. but that phase , fortunately, is fast becoming history. This book is our epi­ taph to that extraordinary episode in the story of modern biology . " More than a decade later, n o such facile conclusion can be offered in a history of bio­ technology regulation: one thinks rather of a contemporary historian in Eu rope ' s Thirty Years· War . or in the Anglo-French 1 00-year conflict, invited at year 10 or year 20 to give an overview and prediction of outcomes . . . For the "politicking", although it pa u se d i n t h e early 1 980s, picked up momentum there­ after and has increased ever since , pari passu with the progress of the science and the diffu­ sion of biotechnology. In Europe . the pol i ­ ticking was more intense, and the initial out­ come less happy than in the US; for the surge of knowledge and innovations coincided with two other historic processes. The mid-80s saw a surge of political support for environmental movements, which in parts of Europe tapped

668

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

into older romantic traditions, containing strong anti-intellectual and anti-technological elements. LONNGREN ( 1 992) speaks of "the politicization of chemicals control". At the same time, the political will and leadership in Europe, at both Community and national lev­ els, was ready to drive forward the processes of constitutional change and development. The potential for such development had al­ ways been present in the founding EC Treaty, but the drive was accelerated from the mid1 980s by an impatience with slow progress, and by a will to "build Europe". These were given concrete expression by the 1 992 target date for completing the common internal market, and by the Single European Act (ad­ opted 1 987, effective 1989) as the instrument for its completion. Majority voting for propo­ sals under Article 100A (the legal basis for harmonizing legislation) , and for specific R & D programmes within a (still unanimity­ requiring) multi-year Framework Pro­ gramme, were among the several significant innovations of this Act. The momentum was maintained, through the three successive Commissions during the ten-year presidency of JACQUES DELORS at least to its penultimate year, 1993, which saw the ratification of the Treaty on European U nion, signed at Maastricht in December 1 992. By 1 993, however, it was "a damn close­ run thing" (as WELLINGTON remarked at an earlier defining moment in European histo­ ry) , with a second plebiscite required in Den­ mark, a wafer-thin assent even in France, and the ruling British Conservative party almost mortally split. The continued decline in num­ bers voting in European Parliamentary elec­ tions (in June 1 994), and the divisive political arguments accompanying the 1 994 plebiscites in Austria, Finland, Sweden and Norway, on accession to the European Union, underlined the slackening of political will. This political backdrop interacted re­ peatedly, and often unnecessarily and unhelp­ fully, with the development of biotechnology in Europe. The politicking hindered, where it should have facilitated, the effective integra­ tion of the new knowledge into the activities and sectors that needed it. Conversely, the history of Community strategy for biotechnol­ ogy in Europe, and the history of biotechnol-

ogy regulation to which for some years it seemed to be reduced, illuminated structural weaknesses within the Commission, and with­ in the Community's institutional structure. These structures were ill-adapted to manag­ ing the challenges and complexities of bio­ technology; for even when these were clearly identified and described, in good time, the communication to the political level was gen­ erally ineffectual; and political action was blocked or diverted into irrelevant and un­ helpful actions by the weight of other inter­ ests. Many factors render obscure the legislative and other actions of the Community institu­ tions, shielding them from effective demo­ cratic scrutiny, and limiting their transparen­ cy: the multi-institutional complexity (Com­ mission, Parliament, Council, etc. ) of the ma­ chinery; the distance from national politics (where "Brussels bureaucracy" is a conve­ nient scapegoat for nationally unpopular measures), and from citizens and local com­ munities; and the inescapable diversity of Eu­ rope's languages and cultures, at once its glo­ ry and a permanent political constraint. This lack of transparency means that on complex subjects, only a sustained and deter­ mined effort of communication can ensure that all parties with relevant interests and knowledge have the opportunity to partici­ pate in preparing proposals and decisions; and when the mass of information and opin­ ions is effectively elicited, there has to be a radical condensation and filtering to summar­ ize the debate into the drafting or amending of a legislative text, or to enable the elected parliamentarian to cast his vote. Both in the communication, and in the condensation, the opportunities for distortion, accidental or willful, are legion. Complexity without transparency allows, even encourages, the pursuit of individual and institutional self-interest. Key individuals involved in the biotechnology regulatory agenda differed widely in their interests, their style of operation, and their attitudes to science, innovation and industry. Within the Commission, each Directorate­ General has its "deformation professionelle ", and the linguistic barriers are trivial in com­ parison to those between DGs. The Commis-

8 Synthesis and Conclusions: Learning from History

sion as a whole is by constitution naturally ac­ tivist, and that constitution reflects the politi­ cal aims of the founding Treaties: there was much to be done. This maps down to the level of the individual . particularly in the Directo­ rates-General concerned with legislation: suc­ cess tends to be equated with the adoption of a new Directive or Regulation . however flawed. Thus in DG I I I . legislation was essential to creating a com mon market - for food prod­ ucts . pharmaceuticals. etc .. and ultimately to achieve new structures such as the European Medicines Evaluation Agency. Similarly for DG XI. the control of chemical products for the protection of human health and the envi­ ronment . was a major challenge . the legisla­ tion a major achievement. and the basic need for such control - whatever the disputes about details - essentially an unquestionable i mperative. world-wide. DG V's responsibili­ ties for promoting uniform high standards of worker safety similarly demanded and brought forth a constructive and successful framework of Community law. The Commission embraces other aims and their corresponding cultures. The Common Agricultural Policy was the creation of the Community institutions. its management and defence the burden of D G VI: who had si­ multaneously to respond to world-wide pres­ sures for change - for the liberalization of ag­ ricultural trade under G ATT. for protecting rural interests under the pain of "rationaliza­ tion", and for reconciling the diverse Euro­ pean interests represented by the Ministers of Agriculture. Biotechnology, uninvited. came insistently onto the DG VI agenda via agri­ cultural research and agricultural legislation. offering productivity increases in sectors pla­ gued by excess production. The culture of DG X I I . especially in its earlier decades . was scientific in its sympa­ thies and roots. They were reluctant legisla­ tors i n 1 978. glad to retire from such matters in the mid-80s. Global trends - the move to­ wards knowledge-based economies. the natu­ ral i nternationalism of science. its perceived relevance to economic competitiveness, the increasingly expensive and specialized charac­ t er of research led to rapidly expanding bio­ technology R & D programmes at European -

669

level in the late 1 980s and 1 990s. The pres­ sures of managing these increasing resources with a static or declining complement of staff forced DG X I I to focus on the politics of win­ ning these heavier research budgets, and on managing efficiently the selection and admin­ istration of vast numbers of projects. These pressures further diminished the appetite for inter-DG arguments over legislation: but par­ adoxically increased the need for such inter­ action, as the expanding R & D activities. and the global trend to more knowledge-based economies, were inexorably increasing the scientific content in the agenda of other DGs. DG X I I I - responsible for the large R & D programmes in information technology and telecommunications - was from the mid-80s closely involved in the full range of research , industrial policy, and related legislative activi­ ties. For biotechnology, no such monopoly was conceivable , as the pervasive significance of the new knowledge obtruded across the range of DG interests, and no single D G could pretend to a monopoly of scientific wis­ dom, even within the life sciences and tech­ nologies. The first FAST programme, and the Com­ mission's 1 983/84 responses, establishing the Biotechnology Steering Committee, reflected an adequate perception and analysis of the challenges, followed by apparently appro­ priate action . The "need for an integrated ap­ proach" was similarly endorsed by Parlia­ ment, in the 1 987 Viehoff report and the reso­ lution adopted. The subsequent fading of the Biotechnolo­ gy Steering Committee has been described. As the new techniques of genetic engineering were emerging from the laboratory to cross the road to the market-place, the bus of envi­ ronmentalism was accelerating; and although the new techniques could fairly claim a place on the bus. as "Clean Technologies", the in­ teraction in Europe was more a collision than an accommodation or a welcome. The self-confidence of success led to an un­ critical and inappropriate transfer of the cul­ ture of chemicals control to legislation fo­ cused on. and by inescapable implication stig­ matizing. a technology. Many factors rein­ forced this strategic blunder: widespread scientific illiteracy, sensationalism in the me-

670

18

The Regulation of Modern Biotechnology: A Historical and European Perspective

dia, bureaucratic and political opportunism, agricultural protectionism, mistrust of indus­ try, an anti-industrial, anti-intellectual popu­ lism - and the usual scientific uncertainties and caution. Oversight in the form of notification and monitoring is a rational response to uncer­ tainty, and enables uncertainties to be dimin­ ished by the accumulation of experience, and resources for risk assessment and manage­ ment to be rationally deployed. This was the approach adopted by the Community in the 1 982 Council Recommendation; and it worked satisfactorily, not least because there was no attempt by DG XII, the service chef­ de-file, to exploit the opportunity to build up a permanent bureaucracy. In the United States, the effective dialogue between scientific and political communities headed off the threat of technology-specific legislation; and even those who (unsuccessful­ ly) advocated and prepared such legislation in the 1970s and 1 980s, typically incorporated in their Bills a "sunset clause" , which would au­ tomatically terminate the legislation after a set period, if there was no further Congres­ sional action taken to renew or amend it. Such a "provisional" or "learning" ap­ proach was a rational and scientific response to uncertainties about a new phenomenon, such as a new technology. B ut for new chemi­ cal substances, or pharmaceutical products, there is the practical certainty of a continuing stream of new entities requiring testing and oversight; and the corresponding administra­ tive structures are therefore conceived on permanent lines, give or take some future ad­ aptation. The imposition of this "permanent" char­ acter on novel technologies both stigmatized them, and built a bureaucratic structure at Community and national levels with an in­ built tendency to justify and defend its contin­ ued existence. Within the European Parliament, the ac­ tive members, coping with a flood of docu­ mentation, and a complex and exhausting life-style (between home, committee work in Brussels, and plenary sessions in Strasbourg) , could in general devote little time to under­ standing complex dossiers such as biotechnol­ ogy.

While there could be real concerns about ethical aspects of the use and abuse of new technologies (e.g., in relation to human ge­ netics or animal welfare) , and popular suspi­ cions of "mad scientists" and mistrust of in­ dustry, in general the esoteric character of ge­ netic engineering meant that practically all MEPs would leave such a dossier to the rap­ porteur - or, if the rapporteur was not of their political group, would designate a member of their group to follow the dossier. The basis for formulating the parliamentary opinion on legislation relating to biotechnology was therefore typically a very narrow one; in an area which shared (with nuclear energy) the most concentrated attention of the "Greens" fraction in the Parliament. Moreover, even MEPs not of this fraction, were in many coun­ tries acutely conscious in the late 1 980s that the major political parties were losing ground to the Green movements; and to recapture these votes, were anxious to demonstrate their own " Green" credentials. A severely re­ strictive approach to the highly publicized new gene technology appeared to be a pain­ less and popular way of doing so. Against this coincidence of popular fears, political self-interest and bureaucratic oppor­ tunism, the voices of scientific protest were few, feeble and disregarded. DG XII lost the arguments inside the Commission, and had at the critical moments no interested allies. The protests to Parliament by Nobel prize-win­ ners did not represent a politically significant constituency. The OECD report on rDNA sa­ fety, indicating no scientific basis for legisla­ tion specific to recombinant DNA, was quoted for its prestige and authority, in sup­ port of precisely such legislation. The advice of the safety specialists of the European Fed­ eration of Biotechnology was aggressively re­ jected by the Director-General of DG X I . The House of Lords Committee's report noted that in drafting the legislation, the Commission had been "impervious to scien­ tific advice"; in fact the efforts of DG XII to offer such advice , as they were (by the Coun­ cil Decisions on BAP and B RIDGE pro­ grammes) required to do, were vigorously re­ pulsed and successfully counter-attacked. A similar "knee-jerk" reaction greeted the suggestion (in the Biotechnology Regulation

8 Synthesis and Conclusions:

Inter-service Commi ttee . around 1 987 ) that the details of a fast-changing and complex field might best be addressed by technical ex­ perts in standards committees. DG XI was chef-de-file for biotechnology legislation. but not for standards. As a result, technical de­ tails of scope - a central issue in the US de­ bates - were defined in Annex I of each " Bio­ technology" Directive. 90/2 1 9 (contained use). and 90/220 (field rele ase ) , in terms spe­ cific to the legislators· unde rstanding of the science of the 1 980s. as modified by the ex­ perts chosen by the Environment Ministers: who then removed these defining Annexes from the scope of the committee procedure for adaptation to technical progress. The con­ sequences in costs. delays and controversies would dominate the regulatory debate throughout the 1 990s. The silencing of G A L I L E O no doubt seemed to contemporaries a matter of limited significance, beyond the scientific and theo­ logical communities: but by 1 990. biotechno­ logy was beginning to matter . and counter­ vailing forces were coming into play. to cor­ rect the strategic error. I ndustry in Europe , following the widely publicized meeting with DAV I G N O N of December 1 984 . had estab­ lished a communication network for the ex­ pression of bio-industrial interests . but failed to endow this with muscle. By continuing to devote their main energies to sectoral chan­ nels. they confirmed a similar conservatism within the Commission. The change of perspective from 1 989 was attributable to the significance accorded to biotechnology in less constrained environ­ ments ( such as the USA ) . or in those where long-term strategic vision was taken seriously (as in Japan ). Multi-national companies oper­ ating in several continents could most readily compare the differences of approach, and their implications for regulation. Although they could to some extent re-locate their ac­ tivities and investments to adapt to circum­ stances. this had costs and discomforts. parti­ cularly for those whose base operations and major investments were in Europe; and for all firms. wherever based. the European market was a major clement of the global total . The loss of investment (actual and threat­ ened) . and the loss of R & D activities and

Learning from History

671

personnel. the seed corn for future industries, inevitably attracted political concern, particu­ larly once linked with the rising political con­ cerns about employment. The constitution of the SAGB at European level, the various na­ tional bio-industry associations. and the US examples, ensured an attentive hearing for in­ dustry once it started to express itself vigor­ ously at political level, from 1 990 onwards; but their intervention was late, and did not have enough momentum to divert the legisla­ tive j uggernaut in that year. Within the European Commission, the consequences of the failure of inter-service co-ordination were gradually recognized at the highest level; and in 1 990 the Secretary­ General at the request of President DELORS initiated the Biotechnology Co-ordination Committee. More importantly, he maintained and developed the central role of the BCC within the Commission services; thus acting as a brake on the autonomous behavior of indi­ vidual DGs. and enforcing a greater degree of horizontal transparency within the house. Also during the early 1 990s, the Commission was responding to the need and political de­ mands for greater external transparency (Eu­ R OPEAN COM M ISSION, 1 993 ) ; and within the BCC framework, " Round Tables" with indus­ try and with a wide range of ngo (non-govern­ mental organization) interests became a regu­ lar feature of its activities. The 1991 commu­ nication similarly announced that CEN (the European Standards Committee) would be charged with a mandate to develop standards in biotechnology. These deve lopments were neither trivial nor obvious: the suspicions and hostility vis-a-vis biotechnology which had driven, and been reinforced by, the 1 990 legislation were far from being dissipated. If a Directorate-Gener­ al was disgruntled at BCC, a 'phone call or a fax could quickly trigger a forceful letter from a sympathetic MEP to the Secretary-General, and there would not be lacking groups and ac­ tivist organizations to carry the argument to the public domain . m u tatis mutandis - and the mu ­ tations could be remarkable. Moreover, the "public domain" for argu­ ment was dramatically enlarged as the UN agencies progressively recognized the need or opportunity for each of them to engage with

672

18 The Regulation of Modern Biotechnology: A Historical and European Perspective

biotechnology. Particularly damaging were the renewed and amplified opportunities for stigmatization offered by Article 19.3 of the Convention Biological Diversity, with its invi­ tation to consider the need for an internation­ al "bio-safety" protocol. Using these interna­ tional fora to reinforce one 's local position was an instinct as natural to the conflicts in B russels as in B osnia. The prominence of biotechnology regula­ tory matters in the Commission's December 1 993 White Paper on "Growth, Competitive­ ness and Employment" has been noted in the previous section, along with the follow-up ac­ tion in the communication at the Corfu Sum­ mit, and in the regulatory proposals submit­ ted during the German and French Council presidencies of 1 994-95. These developments clearly display the ca­ pacity of the European Commission, of indus­ try, and of national political leaders to be re­ sponsive, and to limit and reverse the past mistakes. But as HERACLITUS observed, one cannot step twice in the same river. The wa­ ters of public opinion have been muddied by misrepresentation, and there remains enough continuing uncertainty and concern to slow the work of reorienting policies and of adapt­ ing or dismantling the legal and administra­ tive structures whose foundations are now questioned. The European Parliament has yet to re-ad­ dress the central issues of biotechnology regu­ lation. As the renewed European Parliament ( after the June 1 994 election) struggles for in­ creased power in the Union's inter-institu­ tional debate of the mid-90s, it is difficult for it to acknowledge that it goofed in earlier years. Institutional face-saving is no less en­ demic in the national Ministries concerned, and within the Directorates-General of the Commission. However, bureaucratic drafting skills, changes of government, and internal reorganization are all instruments through which such changes can be respectably man­ aged, and all will have their role. Parliamentary debates - and votes - on specific challenges such as the Directive on the Protection of Biotechnological Inven­ tions, or the Novel Foods Regulation, contin­ ue to give cause for concern to those focusing on Europe's economic competitiveness. Bio-

technology is not yet recognized as integral to the future competitiveness of agriculture and of major sectors of industry, as well as to the effective improvement of public health and the protection of the environment. Ethical is­ sues, such as those highlighted in the Council of Europe's draft Convention on Bioethics (1994), will continue to attract greater promi­ nence in Europe; with the risk of consequent relative neglect and damage to the bases of Europe's economic (and consequent political) weight in the 21st century. To paraphrase the Watson and Tooze "Epilogue" quoted at the start of this section: politics and politicking preoccupied the first years of the recombinant DNA story, and that phase, in Europe and more than a de­ cade later, became, unfortunately, not "histo­ ry", but a story of arrested development. The internal conflicts within the Commission are for the moment better controlled, but much energy in Brussels is still devoted to inter-in­ stitutional and Community-national conflicts, on constitutional matters which the USA set­ tled thirteen decades ago; and to the geogra­ phical expansion of the Community. Insofar as wider international relations and activities come into play - for example, through EC-US bilateral, OECD, or UN agencies - the tendency is for the contending interests, within the Community institutions and at national level, to use such wider di­ mensions to reinforce their position in domes­ tic conflicts. As Europe's political leaders and public servants battle for control on the bridge of their Ship of State, and prepare for the Inter­ Governmental Conference of 1 996--9 7, they must remember there's ocean out there (and rocks) - not just more and more ship. On the swelling and stormy oceans of knowledge, not least, of the life sciences and technologies, forecasting and navigational skills, and insti­ tutional and political structures capable of us­ ing them i ntelligently, will be more than ever essential. Personal Statement

Opinions expressed engage only the au­ thor, and not his current or previous em-

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Index

APHIS ( Animal and Plant Health I n specti on Se rv i ce ) 52, 1 99. 241 . 46 1 ff, 57 1 ff - biotechnology regulations 201 ff - - notification 205f. 250, 252 - - petition 205. 250, 253 approval. fo r GMO rel ease , decision t ree 1 83 ff - of rDNA p rod u ct s 1 73ff

A

ABC ( A ssoc i ati o n of B iot e c h n ology Co m pan i e s ) 535 ABRAC (Agricult ural Biotechnology R ese a rc h A d v i sory Co m m i t t e e ) 207. 470 Acci d e n t P rev e n t i on R eg u l a t i ons for B iotechnol­ ogy. in G e rm a n y 1 02 ACGM ( Advisory Committee for Genetic M od ifi cati o n ) 575f ACRE ( Ad v i s o ry Co m m it t e e on R ele a s e s to the E n v iro n ment) 577 AFNOR ( A ssoc i a t i o n Fran�aise pour Ia N or m a li sat ion )

591 f,

­

64 1

Agency for Te c h n o l ogy Assessme nt a n d tion see BPPT Agenda 2 1 628 f

A p pl i ca ­

agricult ural biotechnology. development of trans-

ge nic p l a nt s 1 97ff. 358f - in developing countries 358ft - - crops 360ff - - entry barriers 344f. 36 1 - product labeling 465 f - public opinion 484 - technology as s e ss m e nt 358ff te c hnol ogy transfer 363ft animal ce ll cultures 94ff - biosafetv 94f t - con tami� at i o n with viruses 97 - con tinuous ce l l lines 94 - hybridomas 95 - immortalized cells 94 - p ri m a ry cell c u l t u res 94 -

- vectors. adeno-associated

- - derived from

1 00

adenoviruses BP V 1 l OOf H S V - 1 1 00

99f

- - derived from derived from - derived from poxvirus 98 - - derived from re t roviruses 98f animal r i gh t s 1 20 anima ls. moral status 1 20 a n t i-biotechnology e ffort 475ff - in t he U . S . 476ff -

·-

-

­

- - decision trees

1 75

A R C (Austra l i a n Research Council)

425

A R I PO (African R e gi o na l I n d ust ri a l P ro p e rt y O rgan i s a t i on) 3 1 4

ARS ( Agricu l tu ral Rese arch Service) 205 Art icle 2 1 , E uropea n Com mission 650 ASCEND 21 628f ASEAN. m e m be r states 409ff

A s h b y report 5 1 6

Asian n e wl y i n d u strial ized co u n t ri e s

(NICs)

A s i a n P a ci fic nations, agriculture 374 - biotechnology 369ff - - patents 37 3

344ff

-

- - publications

373

- status of science and technology 372 Asilomar Conference 101 , 1 58, 242, 461 , 467 , 5 1 I ff A S M ( A m e ri ca n Society of M ic rob iol ogy ) 514f ASTEC ( A ustralian Science and Te ch n o l ogy Co u n c i l ) 425 A ustralia. biotechnology. companies 422ff - coope ra ti v e research centers (CRCs) 427ff - - indust ry 422ff - - research centers 426ff - - universit ies 426f - b iot e c h no l ogy regulatory policy 424ff. 429 - public opi n io n survey, on biotechnology l 26ff Autonomous Service for the Environment Devel­ opment of Amazon Federal Te r r i t orie s see -

SADA

-

a u tonomy, of i n d i viduals

1 1 7ff

B

bacteria 73f - classification, risk groups

74

684

Index

84ff - specific p rope rtie s 74 BAK (Bioindustry Association of Korea) 394f Bangemann Communication 637 BAP (B iotechno logy Action Programme) 534f, 537ff BBC { Bi otechno l ogy Coordination Commi tte e ) 636ff BCC (Biotechnology Coordination Committee) 56 Be lgi u m , biotechnology regul at i ons 605 Benda R epo rt 582 beneficence 1 1 8, 137, 1 40 BEP (Biom olecul ar E n gineeri ng Program me ) 5 1 8, 528ff Berg letter 5 1 1 f BIDEA {Taiwan Bioindustry Dev e l opment Associ a t ion) 406 BIO {Bio-lndustry O rga nizat i on ) 535 biodiversity 121, 644 - conservation 438ff - - i nte rn at io n a l coope ra ti on 442f - impacts on 294ff - i n t h e t ropics 433ff - research 443 - utilization 43 8ff Biodiversity Conven tion see Conv e ntion on Biolog ica l Diversity (CBD) bioethics 1 1 5ff, 582, 639 see also ethics - and rONA p ro du cts 189ff - conflicts 1 35ff - cross-cultural 122 - de cision - ma k ing 121f - Eu rop e an Convention 610 - limits for biote chn ol ogy 1 50f bioinformatics 324ff - Europe a n activities 331 - U.S. activities 331 bi olog ica l pest control, p ub l ic opinion 125 biological revolution 5 1 1 Biomedical Institute of Taiwan 403 biomedicinal products see also pharmaceutical p rod ucts - de vel opment 213ff, 352f - - pha s e s 229ff - - p lan 228ff - from tropical forests 437f - m a rk e t rese a rch 2 1 6 ff - pat e n t a pplica tions 299ff - project management 234f - quality assurance schemes 226f - regis t rati on requirements 221ff - - efficacy 223f - - qu al ity 221 ff - - safe ty 222f - E. coli

bio-pesticides

563

- Code of Conduct 626 - ISNAR report

61 1 f

- o f anim al cell cultures 94ff

- - viral vectors 98ff biosafety levels 73ff, 244ff - at large-scale p rac tice s 247 biosa fe ty regulations, E u rope an app roach 532ff BIOTASK 626 BIOTECH (N ation al Institutes of Biotechnology a n d Ap plied Microbiology) 416 biotechnology, bioethical conflicts 135ff - - ecological risks 138 - - future 139ff - - health concerns 138 - - human misuse 139 - - reg ulato ry concerns 1 38f - conservation

of

tropical forests 440ff

- databases 323ff - - b i bliograph ic - 327 - - factual - 325ff - - full-text - 3 2 8 - - hosts 328ff - - referral - 327f - - use 334ff - definition 41, 65, 581 - ethical - 1 15ff, 1 89ff - - perceptions 123ff - ethical limits 150f - ethicity assessmen t , criteria

15lf

- h i story 341 - in Asi an - Pa ci fic nations 369ff - in Au st r a li a 422ff - in China 396ff - in developing countries 339ff, 343ff - - capital base 347 - - company strategy 346 - - horizontal technology t ra nsfe r 345f - - human res ou rce base 347f - - industry structure 346 - - marke ting and distribution 345 - - p r oduct ion 344f - - R & D costs 344 - information services 330 - in Japan 375ff - intellectual property 281 ff, 350f - in the ASEAN member states 409ff - - Indo nesi a 409ff - - Malaysia 417f - - Philippines 413ff - - S ingapo re 41 8ff - - Thailand 420ff

- in the Republic of Korea 386ff - myths 41ff, 475 - p ublic education programs 148f - public opini on surveys 1 23ff, 146ff, 449ff, 658ff - regulations, history

biosafety 63ff, 349

- - in Belgium 605

- CBD 629ff

- - in China 605

505ff

Index in D e nma rk

E u ro pe in Fr a n c e in

in --

- in

- - in

-- - in - - in

---

603 f 5 1 6 ff

5H7ff

685

C E B C (China-EC B i ot e ch n ol og y Center) 398 CEFIC (Council of the E uro pe a n Chemical Indus­ t ry) 3 3 1 536f, 634 CEN ( C om i t e E ur opeen de Normalisation) 640f CGIAR ( C o ns u l t a t i ve G rou p on Inte rnational ,

Germany 580ff In di a 605 Japan 5 92ff R ussi a 605 Swede n 004f Sw i t ze r l a n d 606 The N et he r l a n d s 597ff the United K i ng dom 5 73 ff t h e U n i t e d States 5 1 3 ff. 566ff

- in - in - in - in risk sce narios 463ff safe de v e l op m e nt of p r od u c t s 1 99ff

- standards 64 1 f

- strategic regu l a t ions. s c i e nce base d 200f - - transparency 20 1 ft - t r i gg er s 1 99 ff - Taiwan 403ff - U . S . policy objectives 1 99f u t i liz a t io n o f t ro p i c al forests 438ff b i ot e c hno l o gy i n fo r m a t i o n 324 ff i nt e r n a t i o n a l org a n i z a t io n s 33 0f - pr e c o n d i t i o ns 332f - problems 332 B M FT ( fe d er a l M i n is t ry for Rese arch a n d Tech­ n o l ogy ) 581 ff BPI ( Federal P h a r m ac e ut i c a l I n d ustry Associa­ t io n ) 586 BPM ( Bioprocessing- Prototype M a n u fa c t u r i ng Fa c i l ity of Mal aysia) 41 7 BPPT ( Agency for Te chno l o g y Assessment and A pp l ic a t i o n ) 4 1 2 BRAIN ( Bio-oricnted Te c h nolo gy R e se a rch Adv a n ce me n t I nst i t u ti o n ) 3 83 f breeders · privilege 284f BRIC ( B i o t e c h nol o g y Regulation Inter-service Comm ittee ) 5 4 1 ff. 64 1 ff BRIDGE 663f BSC ( Biotechnology S t e e r ing Committee ) 534. 543ff BSCC ( Biotechnology Science Coo rd in at i ng Com­ mittee ) 570ff BTS F ( E u rope a n Biotechnology S t r a t e gi c Forum) 330 B u d a pe s t Tre a ty on the I nternational Recognit ion of the D eposit of Mi croo rga ni s m s for the Pur­ poses of Pa t e n t Procedure 283. 385. 395 . 429 - deposi tory a u t h o r i t i es 3 1 0f -

-

-

-

-

Agricultural Research ) 364f, 440, 626 - centers 364 chaebols 387 Chemical Industry Asso cia t i on of Ge r m an y see VCI chemicals control 623ff - chronology 623f China, bio-products 397 b iotechn o log y c o mp an i e s 403 - - history 397 - biotechnology regulatory policy 399ff, 605 - H i g h Te ch Science Parks 399, 402 - joint venture projects 402 - National State Key L abora tories 399, 401 pu b l i c o pinio n survey, on biotechnology 127 - Science Economic Zones 399. 402 - st ructure of S&T 400 Chinese Patent Office 399 C I A A (Confede ration of the A g r o - F oo d Indus­ try) 536 C I E C ( C h in a N e w I n ves t men t E n te rp rise Company) 398 CI MYTT 626 CIP ( International Potato Center) 439f clinical t ri a l s ph a se s 223 , 230f Club o f Rome 529f CNCBD ( C hi n a National Center for B iotechnolo­ gy ) 398 COD AT A ( Co mm it t ee on Data for Science and Technology ) 330 C OG ENE ( Scientific C om m i t t e e on Genetic Experime ntation) 46, 527, 555 commitment building, interactive 22ff Comm i t t e e for Responsible G e n et i cs 465 common mortality 1 23 competence 1 62 confidentiality 1 20 - a gr ee m e nt s 3 01 c onj ug atio n 80, 93f, 1 63 consumer acceptance . of rONA p roduc ts 1 35, 1 57ff. 1 92f Consumers' U nion 465 co n t ai n e d use, of G M Os 555 - Council Directive 555ff containment levels 73. 77, 246f, 25 7f f 261 ff, 468 con t a i n me n t measures 72f Convention on B i ol o gi c al Diversity ( C B D ) 1 43, 296. 442. 628ff copyright 301 C o u n c i l o f Eu ro pe 525, 609 -

,

-

-

-

.

-

,

c CAS (Chinese

A cade m y of Scie nce ) 398 Commission 582ff CBO ( Co n g res s i o n a l B u d ge t Office ) 24 CCG M ( Comm i t tee in Charge of the Control over Genetic Man ipulation) 598ff eDN A sequence�. of human genes 1 42f. 291 . 305

Catenhusen

- organs

609f

CREST (S c i e n t i fi c and Technica l Research Com ­ m i t tee ) 5 1 8ff

686

Index.

CRIFC (Central Research Institute for Food Crops) 412 CRS (Congressional Research Service) 24 CSIRO (Commonwealth Scientific and Industrial Research Organization) 425f CSTP (Committee for Scientific and Technologi­ cal Policy) 612f, 617 CUBC (China United Biotechnology Corpora­ tion) 399 CUBE (Concertation Unit on Biotechnology in Europe) 450ff, 534, 544 CVI (Children's Vaccine Initiative) 358 D

databases, further development 333f - relevant to biotechnology 323ff - - bibliographic - 327 - - factual - 325ff - - full-text - 328 - - referral - 327f - - use

334ff

DCB (Development Center of Biotechnology of Taiwan) 403ff DECHEMA 526ff, 580ff decision-making, ethical 121f - in product deve lopment, delegation of responsibility 232f - - project failure 233 - - routine schemes 232 - interactive rational - 32 decision tree, evaluation of rDNA products 1 89f - for approval, of GMO release 1 83ff - for food components 1 79 - for foods 175ff - - containing rONA-encoded materials 1 77ff - - derived from GMOs 1 82f - - derived from new plant varieties 176ff - - derived from transgenic animals 181 - - derived from transgenic plants 1 80 - for rDNA products 175ff Delors White Paper 648ff - follow-up 650ff Denmark, biotechnology regulatory policy 603f - public opinion survey, on gene technology 660 dependent patents 309 depositories, for microorganisms 210f - - in Australia 429 - - in Japan 385 - - in Korea

395

Deutsche Gesellschaft fiir Technische Zusammenarbeit see GTZ developing countries 339ff - biotechnology regulatory approaches 56f, 350 - entry into biotechnology 343ff - - agriculture 358ff - - barriers 345ff - - health care 352ff

-

- innovations 345ff - threshold factors 344ff food s u ppl y impacts of biotechnology 361ff health care problems, impacts of biotechnology 353ff - immunization programs 357f - national biotechnology policy 348f - R & D capabilities 343f - tropical - 438 DG XII see European Commission's Directorate General for Science, Research and Develop­ ment D GRST (Delegation Generale a Ia Recherche Scientifique et Technique) 587ff directory databases 327f DNA, cassettes 1 65 - changes 161 - duplication 161 DOST (Department of Science and Technology of Philippines) 416f drug design, use of databases 335 Dutch Institute for Consumer Research 1 92 ,

.•

E E.

coli K12 1 62 - biological features 84f - classification 85f - properties 168 EBCG (European Biotechnology Co-ordination Group) 536f EBI (European Bioinformatics Institute) 331 , 333 EC Commission, Community Plant Variety Rights 289 - Council Directive, on the Legal Protection of Biotechnological Inventions 287ff ECE (UN Economic Commission for Europe) 610f ECRAB (European Committee on Regulatory Aspects of Biotechnology) 537, 550ff EDB (Economic Development Board) 4 1 8 EEC, Council Directives 547ff - - Sixth Amendment 547ff - chemicals control 623ff EEC Directive, contained use of GMOs 266ff - protection of workers 271 - release of GMOs 269 EFB (European Federation of Biotechnology) 526, 608f EFPIA (European Federation of Pharmaceutical Industry Associations) 536 electroporation 93 ELSI 1 5 1 EMBC (European Molecular Biology Confer­ ence) 522 EMBL (EB I ) Data Library 326 EMBO (European Molecular Biology Organiza­ tion) 520ff, 598, 608

687

Index

Enlightenment view. ce rtainty-based 1 9. 25 - completely-obj l!ctivistic 1 9 E n vi ronme n t a l Defense Fund 465. 476ff Environmental I mpact Statement ( E I S ) 204 EPA ( U . S. Env i ronmental P ro t e ct i o n Agency )

4 1 . 53. 1 98. 207 . 24 1 . 461 ff. 570ff EPA "s B iotech n o l o gy Science Advisory Commit­ tee ( B SAC) 470 EPC ( E u rope a n Pat e n t Convention) 1 42. 283.

Science. Research a n d Deve lopment ( D G 5 1 8ff. 543ft.

XII)

638ff, 644f

E u ropean Comm unity. Council Recommenda­

t ions 5 1 8ft European Union, biotechnology regulatory policy 24 1 ft - - E E C directives 264ft " E u rope + 30" report 529

287ff, 302ff. 532

EPI ( Expanded

Programme

o n I m m un ization )

357 EPO ( E u ropean Patent Office ) 3 1 4 - Examina tion G uidelines 291 - practice 291 ff - Technical Board of Appe a l 292f ESC (Economic and S oc i a l Com m i t t e e ) Escherichia coli

lee

52 1 ft

E. coli

- Liaison Committee on Recombi nant D N A 523f ESN B A ( E u rop e a n Secretariat of N ational B ioin­ dustry Assoc i a t ions) 635 ESPRIT ( European S t ra t e gi c Programme of R & D i n I nformation Technology) 529 et hical biotechnology 1 1 5 ff. 1 89ff - pe rceptions 1 23ft - - of benefit and risk 1 24ft eth ics, key principles 1 1 7ft - - animal righ t s 1 20 - - benefice nce

1 1 7f 1 1 8f

- - confident i a l i t y

1 20

- - environme n t al e t h ics 1 2 1 - - j u s t i ce l l 9f - - non-m alefi cence 1 1 9 - - rights 1 1 8 e u ge n ics . pu b l i c opinion 1 33 f Eurobarometer s u rv e ys 450ff. 602, 660. 664ff Eu rope , biotechnology regulatory policy 55ff.

349,

486ff

-

- Che m icals Legislat i o n 546ff - Concertation Action 538ft - history 5 1 6ff Common Agricult ural Pol i c y 535 - n at ion al b ioindustry associations 635 - public o p i n i on survey . on b i o t ech n o l og y 1 33 (. 658 - rece nt conflict� 633tf E u rope a n Biotechnology Information St rategic Forum

see

BTSF

E uropean Com m ission . Article 21 650 - D G I I I 535f. 543 tf. 635ff - D G VI 543 ff. 638ff DG XI 544ff. 638ff. 642 ff - D G XII S H iff. 5 4 3 ft, 638ft. 644 f E uropean Com m ission's Di rectorate General for -·

363,

6 1 9ff

ESF (European Scie nce F o u n d a t io n ) 5 20ff. 526. 598, 608. 653

- - autonomy

F FAO ( Food and Agricult ure O rganization)

fa rmers· privi lege 285 , 287. 289 FAST ( Forecasti ng and Assessment in Science and Tec h nol o gy ) 5 29t, 535f. 543f, 640, 657 FCCSET (Federal Coordinating Council for S c i ence . Enginee ring and Technology ) 570ft F D A ( U . S . Food and D rug Administration) 4 1 ,

53. 1 44. 1 50. 1 98, 207. 241 . 243, 248f, 349, 46 1 , 568ff - Statement of Policy. on foods derived from new plant varieties 1 76ft Federal M in i st ry for Research and Tech nology see B M FT Federal Pha rmace utical Indust r y Association see BPI Fede ral Plant Pest A c t (FPPA) 20l ff FET ( Foundation on Economic Trends) 463ft field t rials 1 49. 250ff. 260ff, 359, 463ff, 555ff,

570ff - cost 472 - h i s t o ry 463 - ice-min us/Frostban bacte ria - in Japan 260ff - in the USA 250ff - noti fication

-

205f.

463ff

250, 252

permits 52, 202, 205f. 250ff. 466, 472 - analysis 487 - for microorganisms 206 - for plants 206 - pe t i t i o n 205 . 250 - risk assessment 46ff, 463f FlFRA (Federal I nsecticide , Fungicide , and Rodenticide Act) 53, 462ff, 571 Finding of No Significant I mpact ( F O N S I ) 204 FI R D I ( Food I ndustry Research and Develop­ ment I ns t i t u t e ) 404 Food Additive Act 478 Food Additive P rovisi o n s of the Fo od , Drug and Cosmetic Act 466 food biotechnology . pu b li c op i nio n 453 - risks 465ff food products 564 - compone nts 1 79 - decision trees 1 75ff - derived from, G M Os 1 82ff - - new plant varieties 176ff

688

Index

- - transgenic animals

181

- - transgenic plants 1 80 - labeling 465f - microorganisms 168f - quality 620ff - risk assessment 469f - safety 616f, 620ff - with rDNA-encoded materials 1 77ff food safety 465 frameshifts 1 65f - minus-one 166 - plus-one 1 65f France, Biomolecular Engineering Committee 590 - biotechnology regulatory policy 587ff - Committee on Genetic Engineering 589f - public opinion surveys, on biotechnology 449ft Frostban bacteria 463ff fungi, allergies to 90 - classification 76f - - risk groups 77 G

GAO (General Accounting Office) 24 GA TI (General Agreement on Tariffs and Trade) 144, 350, 545, 587f, 619 - agreement on patent protection 289f GenBank 326 gene banks 1 44 gene expression 1 64 gene flow, by pollen 1 64 - horizontal 161ff, 191 - - conjugation 163 - - mating 1 63f - - p o ll en e x ch an ge 1 64 - - transduction 1 62f - - transformation 162 - vertical 161ff, 191 genes, species-specificity 78ff gene therapy 568 - bioethical conflicts 1 39ff - ethical limits 150 - patentability 288 - public opinion 133, 453 genetically modified organisms see GMOs genetic engineering see also rDNA technology - creation of pa t hog en s 44f - history 41 ff, 509ff - novel organisms 44 - press coverage, in Germany 495ff - public opinion 1 25, 482 - - in the U.S. 659 - representation 496ff - - journalists' attitudes 50l ff - risks lOlff, 474 genetic manipulation, public opinion 128ff, 451 ff, 473 - - benefits 130f, 1 33

- consumption of products 1 35 f - reasons for unacceptability 1 28f - risks 1 30, 132f risk assessment 46 - U.K. regulations 517, 576ff ge ne t i c resources, exploitation 295 genetic revolution StOff gene transfer 93f - horizontal 81f, 94 - mechanisms 80ff genome sequencing, in Japan 385 GERI (Genetic Engineering Research Institute) 390ff German Epidemics Law 7 1 German Federal Supreme Court 282 - Red Dove decision 284 German Gene Technology Act 73f, 102f, 274, 584ff German Genetic Engineering Law 486f, 645 German Human Embryo Protection Act 288 German Patent Act 288 Germany, biotechnology regulatory policy 580ff - public opinion survey, on ge ne tech no l og y 660 glycosylation 166f GMAC (Genetic Manipulation Advisory Commit­ tee) 429, 5 16f, 524, 573ff - risk assessment 5 1 7 GMOs (genetically modified organisms), contained use 555ff, 578 - definition 555, 570 - field tests 260ff - - permits 250ff - - regulations 149 - - risk assessment 46ff - food prod u cts 182 ff - labelling 622 - large-scale use 614 - NIH guidelines 241 - public opinion 134f, 148 - regulatory policy 49ff - release 269f, 555ft, 570ff - - approval 1 83ff - - GDP 615f - - German regulations 584 - - in Europe 55 0ff - - large scale 616f - - risk assessment 1 84ff - - risks 527f - - transgenic plants 1 98ff, 25 1 f - safety categories 49ff ONE (Groups of National Experts on Safety in Biotechnology) 61 3ff Good Clinical Practice ( GCP) 227 Good Developmental Practice (GDP) 572 Good Developmental Principles (GDP) 208f, 615f Good Industri al Large S ca l e Practice (GILSP) 73, 260, 264, 614f -

-

Index

Good La bo r a t o ry Practice ( G LP) 69. 73. 227 G ood Large-Scale Practice ( G LSP) 246f G ood M a n u fa c t u r i n g Practice ( G MP) 2 2 7 Good M icrobio logical Practice ( GM P ) 5 1 7 Gordon Confere ;ce on Nucleic Acid s 5 1 1 f GTZ (De utsche Gesellschaft f u r Technische Zusammenarbeit ) 440 H

Harvard Onco �ouse 290. 293f haza r d , definition I O l f. 1 60 H ea l t h a n d S a fe tv at Work Act

5 17.

522 p ro duct

h e a l t h ca re biotec h n o l ogy. biomedicinal

de ve l op m ent 2 1 3 ff. 3 5 2 f - in de ve lopin g countries 353ff - - en try barri..-rs 344£. 356 -- p ublic opinion 4R4 - technology a ssl! ssm e n t 352f - t e c h no l ogy t r a ns fe r 3 5 4 ff - t echno lo gy tre nds 354 h e l pe r prote i n s 1 68 HEW ( D e pa r tm e nt of H e al t h . Education and Welfare ) 5 1 4 Highly Advanced National Project ( HA N ) 388ff HSC (H e a l t h and Safety C om m is s i on ) 575ff HSE (Health and S a fe t y E x e c ut ive ) 5 1 7 . 57 5 ff human genes, eDNA seq uences 1 42f, 29 1 . 305 human ge n om e p r oje c t 1 43. 305 . 385 human rights 1 1 8

! ARCs ( I n te r n a t i on a l Agricultural Research Ce n te rs) 364f, 626 I B A ( I nd ust ri a l B iot e chn o l og y A s soc i a tio n ) 535 IBC ( I nst i tu tio n al B i os afe t y Committee ) 243ff I BPGR ( International Board for Plant G e n et i c R e so u rce s ) 30.5 ICBG (I nternational Coope rative Biodiversity G roup). program 295f ICCBD ( I nte rgovernme ntal C o mmi t t e e on the Con ve nt ion on B i ol o gic a l D i v e rs i t y ) 63 1 I CEIT ( I n terna t i o n al Ce n ter for E nviro n m en t a l Te c h no l o gy Transfer) 386 ICGEB ( I nte rn a t i on a l Ce ntre for G e ne tic En­ gineering and Biotechnology ) 330. 625f !CPS ( I nte rnat ional P rog r a m m e on Chemical S a fe t y ) 620tf ICSU ( I nternat ional Council of Sc i e ntifi c U nions) 46 . 5 2 7 I DRC ( I nternational Development Research Cen­ t e r of Canada ) 440 ILCA ( I n t e r n a t i o n a l Livestock Center for Afri­ ca )

440

I LO ( I n t e rna t i o n a l La bour Organiza tion)

623f I MCB ( I n s t i t u t e of Molecular and Cell Biol ogy of Singapore ) 4 1 9

689

I m pe r i a l Ep idem ics Law 7 1 INBio ( l nstituto Nacional de Biodiversidad) 295 I ndia. b iot ec h n olog y reg ula t i on s 605 I ndonesia. b i ot e ch n ology 409 ff - - com p a n i e s 4 1 1 - - ind u s t ry 4 1 0f

- - instit utions 409f - - research i nstitutes

421 f - - universi ties 4 1 2 . 4 1 5 - structure of S&T 4 1 4 indus t ri al pro pe rt y r i g ht s 294 i nd u s t r i a l revolution . first wave 27 - fourth wave 28 - second wave 27f - third wave 28 inte llectual p rop e rt y 28 l ff, 350f - protection 1 42f. 301 , 350f, 531 - r i gh t s 282f, 350. 538. 639 - t rade-related 350 i n t e r a c t i ve com m i t m e n t b u i l di ng , characte ristics 22ff

I nte rnational Agreement on Sanitation 7 1 International Bioe thi cs S u rv e y 1 2 1 f, 1 24ff, 1 37, 1 43 . 1 46 lnt ernational Comm i t te e on B i oe t h i cs 5 1 0 lnte r n a t i on a l Patent B ureau 3 1 4 I nternational P a t ent Cooperation Tre at y ( P CT ) 3 14

I nternational Potato Center see CIP I nternational Trop i cal B ioresources I nst i t ut e 386, 443ff - concept 444 International Union for the P rotect i o n of New Varieties of P la n ts see U P O V in \'itro fertilization , public opinion 1 24ff I PG R I ( International Plant Genetic Resources I n st i t ute ) 440 I R R I ( I nt e r n a ti o n a l Rice Research Institute ) 626 I SN A R ( I nternational Service for National Agri­ c u ltural Research) 6 1 1 , 626 ISO ( International Organization of Standardiza­ tion). g ui d e l i n e s 22 7 ITRI ( I ndustrial Technology Research Institute of Ta i wa n) 404

J

Japa n . b io - p rod u c t s 377 - biotechnology. associations 38 1 f - - companies 376 - - ERA TO p roj e c t s 383f - - Frontier Research P ro gram 384 - - history 375 - - i n d ust r y 376f - - research associations 381 f - - re s ea rch compan ie s 38 1 ff - - universities 380f

690

Index

- biotechnology regulatory policy 55, 241 ff, 253ff, 349, 378, 385, 592ff - - institutions 253f - Environment Agency 596f - public opinion surveys, on biotechnology 124ff, 146ff - - on genetic manipulation 128ff - structure of S&T 379 JBA (Japan Bioindustry Association) 255, 376, 434 j ustice, and ethics 1 1 9f K

KAERI (Korea Atomic Energy Research Insti­ tute) 393 KAIST (Korea Advanced Institute of Science and Technology) 393 KIST (Korean Institute of Science and Technol­ ogy) 392 KOGERA (Korea Genetic Research Association) 388ff Korea, bio-products 388 - biotechnology 386ff - - associations 394f - - industry 387f - - patents 395 - - universities 394 - biotechnology regulatory policy 388ff - education 386f - structure of S&T 391 Korea Academy of Industrial Technology 393 Korea Ginseng and Tobacco Research Institute 393 Korea I nstitute of Energy Research 393 Korea Research Institute of Chemical Technol­ ogy 393 Korup Project, Cameroon 439, 443 KOSEF (Korea Science and Engineering Founda­ tion) 392 L

less-developed countries (LDCs) 342ff licensing, of patentable inventions 320 LIPI (R&D Center for Biotechnology of Indonesia) 4 1 2 M

MAF (Ministry of Agriculture and Fishery of Korea) 392 MAFF (Ministry of Agr iculture, Forestry and Fisheries of Japan) 254ff, 378ff, 595 Malaysia, biotechnology 417f Malaysian Industrial Development Authority 418 Malaysian Technology Development Corporation 418 Manhattan project 28

market approval see registration market assessment 216 market research 216ff - background information 217f - cost-benefit analysis 21 8ff - product profile 218ff mating 163f ME (Ministry of Education of Korea) 393 MHSW (Ministry of Health and Social Welfare of Korea) 393f MHW (Ministry of Health and Welfare of Japan) 149, 253ff, 378ff, 595f microorganisms see also pathogenic microorganisms - classification 244f, 267, 554ff - domestication 41f - GILSP 614f - risk groups 554 - safety levels 582 MITI (Ministry of International Trade and Indus­ try of Japan) 253ff, 376, 378ff, 596 Molecular Biology Institute of Taiwan 403 Monbusho ( Ministry of Education and Science of Japan) 378ff mortality 123 MOST (Ministry of Science and Technology of Korea) 390ff MPKSN (Malaysian National Council for Scien­ tific Research and Development) 417 mRNA, recording 165f MTIE (Ministry of Trade, Industry and Energy of Korea) 393 MURS (Universal Movement for Scientific Responsibility) 151 mutagenesis, random 167 - site-directed 167 myths of biotechnology 41ff N

NAA (The North Atlantic Assembly) 524f NAS (U.S. National Academy of Sciences) 16, 47, 468, 5 1 1 f National Audobon Society 465 National Biotechnology Policy Board 469 National Commission for the Preservation of Plant and Animal Genetic Resources of Indone­ sia 412 National Institutes of Biotechnology and Applied Microbiology see BIOTECH National Wildlife Federation 465, 476ff Nature Conservation Foundation 439 NCDB (National Committee on the Development of Biotechnology of Indonesia) 4 1 1 f NCGEB (National Center for Genetic Engineer­ ing and Biotechnology of Thailand) 420f New Zealand, public opinion surveys, on biotech­ nology 124ff, 146f

691

Index - - on ge net i c

p

N I ABA

parasites,

m a nip u l a t i o n 1 28ff I n d us t r i a l and Agricultural B iotechnology A sso c i a t i o n ) 662 NICs see Asian newly industria lized co un t r ies ( Ne t h e r l a n ds

classification 76f Paris Conve ntion for the Pro t e c t i o n

of Industrial

- O ffice of Rt: co m h i n a n t D N A Activities ( O R D A ) 243f

294 patentability 2 8 7 f. 53 1 - basic r e q u i re me n t s , industrial a pp l i cab i li t y - - non-obviousness 302f - - n o v e l ty 302 - - u t i l i t y 303 f

non -gov e rnme n t a l org a n i zatio n s ( N G Os ) 627 non -malefice nce 1 1 9 North America n Plant Protection Org a n iz a t i o n

- exclusions 305ff - - by the E PC 287f - i n p u b l i c op i n i o n 1 4 3

40 . 68.

N I H ( U .S . National I nstitutes of Healt h )

1 42, 1 9R . 241 . 29 1 . 46 1 . 5 1 2 ff . 566ff

- D i rector

208 NOTA

24.l 5o7

( Netherlands O rg a n iz a t i o n

NSC

- of b i ologi ca l

for Technology

662

Assess m e n t )

noti ficat ion 54 7 f NRC ( U . S . N a t i o n a l 242, 46 3 . 468f. 5 1 2

(Na t i o n a l

4 7 . 200.

Research Counci l )

Science C o un c i l of Taiwa n )

( National

404ff

Sc i e n c e a n d Te c hn o l o gy Devel­

opment Agency of T h a i l a n d ) 420f n ucleot ide seq u e n ces. d a t a bases 325

- of d i scov e r i e s

OAPI ( O rganisation A fr i ca i n e de Ia P ro p r i e t e l n ­

OECD

3 14

( O rganisation for Eco n o m i c C o ope ra t i on

and D e v e lopme n t ) 29ff. 48, 58. 204. 285 , 359, 372ff, 469. 5 1 0. 5 3 3 . 5 86 ff . 6 1 1 ff - B l ue Book 6 1 4ff. 650 ··

c h e m i ca l s con t ro l

623ff

- Good De v e lopme n t a l

-

h i st o ry

- of products of nature

- of use

(GDP)

208f

p a tentab l e inventions. cha racteristics

Co­

29

polls see pub lic opinion surveys ORDA ( Office of R e co mb i na n t DNA A c t i v i t i e s ) 244f

O rg an ibi o ( Orga nisat ion N a t ionale l n t e r pro fe s -

591 . 635

Orp h a n Drug Act 1 45 OSHA ( Occupational Safety and H e a l t h A d m i n i s ­

tration ) 243. 570 OSTP ( lJ . S . Office of Science and Tech nology Policy ) 1 99. 568ff OT A ( O ffice for Te c h n ol og y Assessment ) 1 2ff. 5 5 f. 473. 482. 5 29f. 534,

M a nagement Board

- view o f assessmen t . -·

305 ff

EPC

544.

- selling

- CIP 3 1 5 - d e po sit i o n

object i ve overall

ment 1 8ff - subject ive ove rall assessment

assess-

o f microorganisms

- view of technology 1 6ff OTS ( O rganizat ion for Trop i ca l Studies)

309f

3 15

patent databases

3 1 8. 327

1 42f

- of

living o rg a n i s m s - - history 283f patent laws,

1 42

WIPO e ffo r t s 286 pr ac t ice . EPO 291 ff

p a t e n t offices.

- - U.S. Pa t e nt a nd Trademark Office ( PTO) 290f patent protect ion, d u r a t io n 3 1 6 - o f b i o m ed i c i na l products 2 1 5 patents, costs 3 1 7 f - defi n i t ion 282 - dependent - 309 -

de sc r i p t i o n 309f 312

- opposition

3 1 8f 317

- process - 308f - product - 308 440

3 1 0f

3 1 0f

biomedicinal products 299ff

- patent descr i p tio n

- priority 3 1 5f 20f f

309ff

- - depository authorities - fi l i n g 3 1 3ff

- i n formation

21

320

3 1 9ff

patent applica t ions

- eq uivale nts

569. 658

306

- l ice nse cont racts. l u m p sum payments - - ro y a l i t i es on sales 320

patenting

op i n io n

·-

the

302ft

patent claims 3 1 l ff

- work on biotechnology

sionnelle des Rio-industries ) orph an crops 36 1 . 364

304f

309

- p u b l ica t io n

safety 61 3ff OEEC ( O rg a nisa t io n for European Economic

EPC 29 l ff

- definitions 306

- for

P ri n c i p l e s

6121

opera t i o n )

304f 302ft

- of p roc es se s 308f - of pr o d uc ts 308

- excl usions

0

306

- o f living o rg a n is ms , under the

- - by

t e l lectue lle )

subject matter

303f

- - restrictions 307 - of i n ve nt i o n s

NSTB ( N ation a l Scie nce and Tec h nology Board of S i n g apo re ) 4 1 9 NSTDA

Prope rty

- purpose

300f

692 - use

Index - of science and technology

309

pathogenicity, characteristics 44f - classification 66ff - E. coli 84f - Saccharomyces cerevisiae 89f pathogenic microorganisms 89 - bacteria, E. coli 84f - classification 67ff - contained use 71ff - risk evaluation 66 - risk groups, bacteria 73f - - fungi 76f - - parasites 76f - - viruses 75f PCASTRD (Philippine Council for Advanced Science and Technology Research and Develop­ ment) 416 People ' s Republic of China see Ch i n a pesticides, public opinion 125 pharmaceutical development, chances 214ff - risks 214ff pharmaceutical products see also biomedicinal products - efficacy 223f - - tests 223f - extensions of patent duration 316f - patent restrictions 307 - process development 224f - quality 222 - s a fe t y 222f - - regulations 222 pharmacopoeias 224 Philippines, biotechnology 413ff PIR International Protein Sequence Database 326f

planned introductions see field trials plant breeders' righ ts 284f plant breeding, crop breeding plan 477 Plant Pest Act 462, 472 plant protection products 563 Plant Quarantine Act (PQA) 201ff plant varieties, protection 284ff plant variety rights 289 plasmids 9 1 f - naturally occurring, genetic properties 80f - safety 80 - stability

1 70f

pollen exchange 164 post-translational modification, glycosylation 166 PPD (Primary Production Department of Singapore) 420 press coverage, of a gri c ul t u ra l biotechnology 482 - of genetic engineering, articles 497 - - authors 498 - - in Germany 495ff - - shortcomings 502f - - tendencies 500f - - topics 498f

48 1

problem of the commons 142 process patents 308f process versus product controversy 39ff, 460 product development, biomedicinal 312ff - cost

-

-

215

decision making 232f managing 228ff motivation 235f organizational structures 235f - matrix organization 235 - project steering committee 235 ph ases 230ff planning 228ff - risk-oriented 229ff pre-development phase 232 rules 214

- technical aspects

224ff

- time 215 product efficacy 223 product patents 308 product profile 21 8ff - benefits 220 - contents 220 product quality 222, 224ff product safety 218, 222f - regulations 149f project manager, qualities 234f - responsibilities 234 PROSAMO study 138 protein design, use of databases 335 protein folding 1 67f protein sequences, databases 325 protooncogenes, in tissue culture cells 95 PTO (U.S. Pa te n t and Trademark Office) 350 - practice 290f public opinion surveys, on biotechnology 123ff - - in Australia 126ff - - in China 127 - - in Denmark

-

-

660f

in in in in in in

Europe 133f, 658 France 449ff Germany 660 Japan 124ff, 146ff New Zealand 124ff, 146f The Netherlands 1 92, 602 - - in the U.K. 124, 1 26, 1 92, 662 - - in the USA 1 33, 1 46ff, 473, 658ff - on genetic manipulation 128ff - - in France 451ff - - in Japan 128ff - - in New Ze a l and 128ff Pure Food Campaign 479 R

RAC ( rDNA Advisory Committee)

243ff, 47 1 , 514, 524, 566ff

68,

1 50,

Index RAFI ( R ural Advance ment Fund I nternational )

regist ration. of b iomedici nal products, regulations

221

365 RCEP ( Royal Com m ission on E nvironmental Pol­ lution) 576f R & D Ce nter for Biotech nology of I ndonesia see LIPI

rDN A . pote nti a l biohazards S l l f prot ection of work ers 2 7 1 - tra nsformation 1 62 rDN A containin!! organisms. large-sca le uses 246ff, 6 1 4 - shipment 249f - transport 249f rDNA experi m e n t s . classifica t ion 69. 243ff. 256f. 5 1 2. 5 1 7 - J a panese reg ulat ions 595 - notifica tion 2h8 - risks 5 1 2f rDN A ope rations. h iosafety 63ft' - cl assifica tion 267ff - construction of faci lities. for production 259f - - for research 259 - - pe rmits 248 - permits 267f - regulations 239ff - supervision in Japan 253ff - - institutions 253f - supervision in the E uropean U nion 266ff - supervision in the USA. N I H guidelines 241 ff rDNA products. applications 1 75 - consume r acce pta nce 1 35 . 1 57 ff. 1 92f - decision trees 1 75ff. 1 89f - development . phases 1 73 f - E C regulat ions 533 - free ci rculation 533 - hazard analysis 1 59ff - labeling 465 f - market approv a l 248f. 270 - of J apan 377 - of Korea 388 - risk assessme nt 1 5 7 ff. 563ft' - types 1 75 rDN A technology 1 59ff - dange rs 44ff - et hical aspects 1 35ff. 1 89ff - metabolic re programming 1 72 - public controve rsy 5 1 3ff - - periods 5 1 3f - t echnica l aspects 1 59ff - use 1 60 rONA work, C ouncil Directive 5 1 8ff recoding. of m R N A . hopping 1 66 - - sele nocys t c i n e i ncorporation 1 66 recombinant organisms see G M Os (ge netically modified organisms) recombinant plants see transgenic pl a n ts recording. of mRN A 165f - - frameshift i ng l 65f -

693

rele ase . of G MOs 1 83ff, 555 - - Cou ncil Di rective 5 5 5 ff - - permits 25 1 , 269( - - regul a t ions 1 49 - - risk assessment 1 84ff - - sites in the U . S . 25 1 - - transgenic plants 1 98ff. 251f Re public of China see Taiwan Rese a rch Inst i t ute for B iological D iversity 443 RITE ( Rese arch Institute for Environmental Tech nology for the Earth) 386 Rio "Earth Summit" 627f ris k . defi n ition 1 0 1 f. 1 60 - pe rcept ions 658 - - governmental 47 1 - - public 471 risk assessment 349(, 453f, 464 - concepts 39ff - field re lease of G MOs 1 84ff, 528 - for GMO products 563ff - G M A G 5 1 6f - governme ntal 486f - horizont a l approach 58f - of gene tic m anipulation 574 - of rDNA products l 5 7ff - rese arch, in Europe 540 608 risk groups. bacteria 73f - fungi 77 - viruses 75f risk scenarios 463ff R N A spl icing 1 64f Royer report 587ff R ussia. biotechnology regulations 605 ,

s

86ff - biologic a l feat ures 87 - transformation 91 f S A D A ( A utonomous Se rvice for the Environment Deve lopment of Amazon Federal Territories) 439. 443 safety categories. for G MOs 49ff S A G B ( Se nior Advisory G roup for Biot echnol­ ogy) 586. 634ff - Yellow Book 652f Scandinav i a , biotechnology regulatory policy Saccharomyces cerevisiae

602ff sce nario, assessment 1 7 . 463ff science policy, governme ntal, history - industrial 26ff - i nformation 33f - int eractive 30ff - OECD activities 29f - origins 26ff - U . S. Congress 7ff

28ff

694

Index

Scientific and Tech nical Re s earch Co m mi tt ee see CREST SCOPE ( S cie n tific Committee on Problems of the E nv i ron ment) 46 second re gi st ra ti o ns 301

sequence databases 325ff - and bioinformatics 331 - de scription of 326f - - EMBL (EBI) Data Library 326 - - GenBank 326

- - PIR International Protein Sequence Database 326f Shanghai Research Center of B i otechnology 398 S in ga por e , biotechnology 418ff - - research cen ters 4 1 9

- - universities 419 Singapore B i otechnology Directory 419 SISIR ( S i ng ap ore Institute of St a n d ards and Industr i al Research ) 420 Sixth Amendment 547ff S m i thson ia n Institution 440, 443 Southeast Asia 436ff SPA (strategic proj ec t assess m ent) 217 space travel 9 species-specificity, of genes 78ff SSTC (S tate Science and Tech no l ogy Commission of China) 397 STA (Sc ie nce and Te c hn ol ogy Agency) 253ff, 378, 594f S t a ndard Oper at in g Proced u re s ( S O P s ) 227 standards, for biotechnology, in Europe 64 1 f STEP! (Science and Technology Pol icy Institute) 388 STOA ( Sci ence & Tech n olo gy Optio n s Assessm e nt) 612 sust a i n ab l e dev elopme n t 1 42

sustainable technology 1 38, 144 Sweden, biotechnology regulatory policy 604f Switzerland, biotechnology re g ul a tions 606 T

TAB (Technology Asse ssm ent Board) 2 1 , 24 Taiwan, bio -prod ucts 405 - biotechnology 403ff - - compa n ies 405 - - industry 404ff - - universities 404 - biotechnology regulatory policy 408

Taiwan Bioindustry Development Association see

BIDEA

technological developments, controllability 1 7f - predictability 17 technological innovation, biolo gical revolution 8 - electronic revolution 8 - nuclear revolution 8 - use of p last i cs 8 technology, be nefi ts 7ff _

- - economic welfare 8 - - m a i nt ai nin g peace 9 - - pres t i ge 9 - - social welfare 8 - critical evaluation 9ff - - costs lOf - - socia l rel ev ance 1 0

-

information 33f interactive assessment 22ff pot e nt i a l d a ngers 1 1 social consequences 32 techn ology assessment (TA) 5ff - failure 15ff - history l lff - me t h odology 12 ff - office 13ff - predictions 1 7 techno l ogy pla nn ing , institutionalization 35{ - - decentralized 36f - - multiform 36f technology p ol icy , governm e n t a l , history 28ff - industrial 26ff - information 33f - interactive 30ff

- OECD act i v it ies 29f - origin s 26ff - U.S. Congress 7ff Thailand, biotechnology 420ff - forest conservation 438f, 443 The Netherlands, biotechnology re g ul atory policy 597ff - gu i de l in es, for foods containing rD NA-enco d e d materials 177ff - pub l i c op inion survey, on biotechnology 1 93, 602

threshold factors, of biotechnology 344ff TISTR (Th a i land Institute of Scientific a nd Tech ' n o l ogi ca l R e search) 421 TOSCA (Toxic Substances Control Act) 548. 571 , 619 trade secret 301 transduction 80, 162f transformation 80, 162 transgenic ani m a l s 359 - public opin i on 453 t r a n sge n ic p l a nts , APHIS re g u l a t ions 203ff - dev e l op m ent 197ff, 359ff - - domestic concerns 207 - - international needs 207ff - in developing countries 362 - marketing 253 - re g u l a ti o n s 1 97ff - release 1 98ff, 251f translation, regulation mechanisms 165f - - frameshifting 165f - - hopping 166 transposons, stability 170f t ropica l forests, biodiversity 435ff

Index

- - hypot hesis of disturbance 435f - conservat ion 437ff -- - by biotechnology 440ff - products 437f - utilization 4�7 ff - - by biotechnology 438ff - - sustainability 442 t ropical regions. cl assification 436 -- ge netic resources 442 - organizations 438ff - research facilities 438ff - state of biotechnology 44 1 TSCA 462ff

u

UK House of Lords Select Committee on Science and Tech nology 56 UN Food and Agricult ure Organ ization 1 44 U NCTAD ( U nited Nations Conference on Trade and Developmen t ) 294 UNEP ( U nited Nations Environment Program ) 439, 627f UNIDO ( U N I n d us t r i a l Development Organiza­ tion) 625f U nion Chemical Labor atories ( U CL) 404 U nited Kingdom . biotechnology regulatory policy 573ff - - history 5 1 6 -- guideli nes, o n the assessment o f novel foods and processes 1 7 5 f - public opin ion survey . on b i ot e c h no lo gy 1 26. 1 93 , 662

United Nations ( U N ). agencies 6 1 8ff United States. biotechnology history 461 ff - biotechnology regulatory policy S l ff. 1 98ff. 241 ff. 349, 461 ff. 566ff - - agriculture 57 f. 46 1 ff - - biopharmaceutical sector 5 7 , 46 1 ff - - Coordinated F ra me w o r k 568ff - - history S U ff - patent laws 2 90f. 302 ff -- - Continuation-in- Part ( C I P ) 3 1 5 - - swearing-back 3 1 6 - public opinion survey. o n biotechnology 1 33f. 1 46ff. 473. 658 Universal Move ment fo r Scientific Responsibility see MURS UPOV ( I nterna t ional U n ion f o r the Protect ion o f New Varieties of Plants ) 284. 638f UPOV Conve ntion 284ff. 292 - New Act 286f U.S. Congress 5 1 4ff

695

- technology assessment (T A ) 1 2ff U.S. Departments of I nt e ri or and Agriculture 42 U . S . Environmental Protection Agency see EPA U . S . Food and Drug Administration see FDA U.S. Human Ge nome Program 33 1 U . S . National Academy of Sciences see N AS U.S. National I nstitutes of Health see N I H U . S . National Research Council see NRC U.S. Office of Science and Technology Policy see OSTP U.S. Pate nt and Trademark Office see PTO U.S. Plant Genome Research Program 33 1 U.S. science policy 7ff. 461 U.S. Supreme Court. Chakrabarty case 284, 290 U . S . technology policy 7ff. 46 1 U S D A ( U .S. Department of Agriculture) 198f, 207 , 24 1 . 359, 46 1 ff. 570ff use patents 309 v

VCI ( Chemical Ind ustry Association of Ge rma­ ny) 586 VCOG E M ( Ad Hoc Committee for Recombinant DNA Activities) 600ff vectors. food grade - 1 7 1 - integration 1 7 1 - plasmid - 9 1 f - stability 1 7 1 - viral 98ff Viehoff report 540ff viral vectors, adeno-associated 1 00 derived from ade noviruses 99f - d e r i v ed from B PV- 1 1 00f - derived from HSV- 1 1 00 - derived from poxvirus 98 - derived from ret roviruses 98f vi ruses 74ff - classification. risk g ro u p s 75f - contamination of cell cultures 97 - horizontal transmission 75 - vertical transmission 75 -

-

w

WHO ( World Health Organ ization) 6 1 9ff Children's Vaccine I n itiative (CV I ) 358 - Expanded Programme on Immunization (EPI) -

357

Williamson Committee 638 Williams report 5 1 6. 52 1 WIPO ( World Inte llectual Property Organiza­ tion) 286 WTO ( World Trade Organizat ion) 290