Beyond Consent: Seeking Justice in Research

Beyond Consent

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BEYOND CONSENT Seeking Justice in Research

EDITED BY

Jeffrey P. Kahn, Ph.D., M.P.H. Anna C. Mastroianni, J.D., M.P.H. Jeremy Sugarman, M.D., M.P.H., M.A.

New York Oxford OXFORD UNIVERSITY PRESS 1998

Oxford University Press Oxford New York Athens Auckland Bangkok Bogota Buenos Aires Calcutta Cape Town Chennai Dar es Salaam Delhi Florence Hong Kong Istanbul Karachi Kuala Lumpur Madrid Melbourne Mexico City Mumbai Nairobi Paris Sao Paulo Singapore Taipei Tokyo Toronto Warsaw and associated companies in Berlin Ibadan

Copyright © 1998 by Oxford University Press Published by Oxford University Press, Inc. 198 Madison Avenue, New York, New York 10016 Oxford is a registered trademark of Oxford University Press All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data Beyond consent: seeking justice in research / edited by Jeffrey P. Kahn, Anna C. Mastroianni, Jeremy Sugarman. p. cm. Includes bibliographical references and index. ISBN 0-19-511353-5 1. Human experimentation in medicine—Moral and ethical aspects. 2. Clinical trials—Moral and ethical aspects. 3. Social justice. I. Kahn, Jeffrey P. II. Mastroianni, Anna C. III. Sugarman, Jeremy [DNLM: 1. Informed Consent. 2. Human Experimentation. 3. Research—legislation. 4. Bioethics. 5. Health Policy. W 20.5 B573 1998] R853.H8 1998 174'.28—dc21 DNLM/DLC for Library of Congress 97-44169

135798642 Printed in the United States of America on acid-free paper

To our mentor and source of great professional inspiration, Ruth Faden, who brought us together, and who seems to accomplish more than seems realistically possible with humor, grace, wisdom, and humanity.

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PREFACE

The Advisory Committee on Human Radiation Experiments began its work in 1994 following revelations in the popular press of human radiation experiments that were conducted without the consent of the subjects. We were fortunate to have worked together as staff to this White House Advisory Committee. In our work, which spanned approximately 18 months, we wrestled with difficult ethical questions about the conduct of research involving human subjects. While many of these questions related to important aspects of consent, others went beyond consent to justice. It became clear to us that questions related to justice in research did not find ready answers. Moreover, similar questions were being posed not only about research that had been conducted in the past, but also about contemporary research. Indeed, questions about justice in research seemed to surround us. Patients were making powerful pleas for inclusion in research, hearings were being held regarding research with psychiatric patients, debates were focused on the acceptability of conducting research in emergency settings, and new regulations were being implemented to include women and minorities in research. Such questions prompted our work on this book. Although we all work in bioethics and share an interest in public health policy, each of us approaches the field from a different primary discipline: law (A.C.M.), medicine (J.S.), and philosophy (J.P.K.). In addition, we recruited contributors to the book with a diverse set of backgrounds in the expectation that such a multidisciplinary group would make the book relevant and appropriate for a broad readership. During the iterative process by which this book developed, we have learned much from each other and from all the authors. We greatly appreciate the efforts of each contributor in preparing a chapter for this book. We also want to express our thanks to others who helped make this book a reality. We feel fortunate that our editor, Jeffrey House, provided good advice and was patient as we prepared the manuscript. Thanks go to Madison Powers for his willingness to review the work of other contributors so that his chapter examining some of the conceptual aspects of justice squared with the other chapters in the book, and for offering us valuable suggestions on the book as a whole. At various points, we received important guidance from Tom Beauchamp and Ruth

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Faden. Finally, we want to acknowledge the extensive assistance of those who helped with research and preparation of the manuscript: Wayne Hartley, LeeAnne Hoekstra, Kristen Hanzel, and office staff in the Division of General Internal Medicine at Duke and of the Center for Bioethics, at the University of Minnesota. October 1997

J.P.K. A.C.M. J.S.

CONTENTS

List of Contributors 1 Changing Claims About Justice in Research: An Introduction and Overview JEFFREY P. KAHN, ANNA C. MASTROIANNI, AND JEREMY SUGARMAN 2 The Evolving Story of Justice in Federal Research Policy CHARLES R. MCCARTHY

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3 Research on the Vulnerable Sick BARUCH A. BRODY

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4 Children As Research Subjects ROBERT M. NELSON

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5 Gender and Research NANCY KASS

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6 Race, Justice, and Research PATRICIA A. KING

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7 Convenient and Captive Populations JONATHAN D. MORENO

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8 Justice in International Research RUTH MACKLIN

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9 Theories of Justice in the Context of Research MADISON POWERS

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10 Implementing Justice in a Changing Research Environment JEFFREY P. KAHN, ANNA C. MASTROIANNI, AND JEREMY SUGARMAN

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Appendix

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Index

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LIST OF CONTRIBUTORS

Baruch A. Brody, Ph.D. Director, Center for Medical Ethics and Health Policy Leon Jaworski Professor of Biomedical Ethics Baylor College of Medicine Houston, Texas Jeffrey P. Kahn, Ph.D., M.P.H. Director, Center for Bioethics Associate Professor of Medicine, Public Health, and Philosophy University of Minnesota Minneapolis, Minnesota Nancy Kass, Sc.D. Associate Professor of Health Policy and Management Johns Hopkins School of Public Health Baltimore, Maryland Patricia A. King, J.D. Carmack Waterhouse Professor of Law, Medicine, Ethics and Public Policy Georgetown Law Center Washington, DC Ruth Macklin, Ph.D. Professor of Bioethics Department of Epidemiology and Social Medicine Albert Einstein College of Medicine Bronx, New York Anna C. Mastroianni, J.D., M.P.H. Assistant Professor of Public Health Genetics School of Law, and School of Public Health and Community Medicine University of Washington Seattle, Washington

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Charles R. McCarthy, Ph.D. Senior Research Fellow Kennedy Institute of Ethics Georgetown University Washington, DC Jonathan D. Moreno, Ph.D. Kornfeld Professor of Biomedical Ethics Director of the Center for Biomedical Ethics University of Virginia Charlottesville, Virginia Robert M. Nelson, M.D., Ph.D. Department of Pediatrics Medical College of Wisconsin Milwaukee, Wisconsin Madison Powers, J.D., Ph.D. Senior Research Scholar, Kennedy Institute of Ethics Georgetown University Washington, DC Jeremy Sugarman, M.D., M.P.H., M.A. Associate Professor of Medicine and Philosophy Duke University Durham, North Carolina

Beyond Consent

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1 CHANGING CLAIMS ABOUT JUSTICE IN RESEARCH: AN INTRODUCTION AND OVERVIEW J e f f r e y P. Kahn A n n a C. M a s t r o i a n n i Jeremy Sugarman

Patients with life-threatening, devastating diseases, perhaps most notably cancer and acquired immune deficiency syndrome (AIDS), clamor for access to clinical trials.1 Federal policies governing research in the United States that once emphasized protecting subjects from dangerous research through such measures as informed consent and an assessment of risks and benefits of this research by institutional review boards (IRBs) now also promote access to clinical research. New requirements in these policies emphasize issues of selection of subject populations and the equitable distribution of the benefits and burdens of research participation across society.2 All this points to a series of critical questions related to justice: What does fairness demand in terms of selecting subject populations? How should we think about the equitable distribution of the benefits and burdens of research participation? Ethically and practically who should be included and excluded? Who should decide and according to what criteria? How is fairness to be interpreted in regard to the distribution of benefits to those participating in research, and to the relevance of this research for society? What are the impacts and implications of both real and perceived injustices in biomedical research on recruiting and retaining research subjects? How do they affect the public perception of biomedical research? And what are the effects on health-care for the population in general? Such questions are both conceptually and practically difficult. Nonetheless, ethically acceptable 1

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research is contingent on answers to these questions. Thus, a comprehensive consideration of research with human subjects goes well beyond the still difficult issues regarding informed consent, towards incorporating multiple considerations of justice. This is not to say that the importance of justice is only recently recognized. Indeed, justice has long been a crucial part of the ethical analyses of research. For instance, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (The National Commission) specified in the Belmont Report3 the need to consider the principle of justice as well as the principles of respect for persons and beneficence. The National Commission found two senses of justice to be important: Who ought to receive the benefits of research and bear its burdens? This is a question of justice in the sense of "fairness in distribution" or "what is deserved." An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly. Another way of conceiving the principle of justice is that equals ought to be treated equally.4

In the context of research, the National Commission invoked the principle of justice in determining the fair selection of subjects. This selection was considered at the individual and societal level: Individual justice in the selection of subjects would require that researchers exhibit fairness: thus they should not offer potentially beneficial research only to some patients who are in their favor or select only "undesirable" persons for risky research. Social justice requires that distinction be drawn between classes of subjects that ought, and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear burdens and on the appropriateness of placing further burdens on already burdened persons.5

Holding this view of justice, the National Commission saw certain populations ("racial minorities, the economically disadvantaged, the very sick, and the institutionalized") as "vulnerable," thereby requiring special protection.6 While the National Commission's conception of justice is able to accommodate shifting social conditions, the dominant interpretation of justice used by the National Commission, as well as many others wrestling with issues related to research with human subjects at that time, was one of protection. Thus, although the principle of justice has long been an important part of research ethics, its interpretation and accompanying application seems to be changing. Specifically, there seems to be a new interest in access to research, both at the individual and societal level. This new calculus seems to go beyond obtaining consent to endure the risk and burdens of this research towards an appeal concerning fairness in the distribution of the benefits of research. In addition, this shift demands thinking differently about subject populations than has historically been the case. It may, for instance, mean

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creating opportunities for fair access to research and its potential benefits, while simultaneously developing mechanisms of protecting subjects from exploitation. This balancing is a critical challenge for research ethics. It is now not uncommon to hear claims for increased access to experimental therapies, such as bone marrow transplants for patients with breast cancer and drug trials for those with AIDS.7 In other instances, claims may be made for compensatory justice. For example, a broad claim for compensatory justice might call for additional research efforts directed at understanding the problems faced by groups, or classes of persons, which have not had access to research in the past.8 At an individual level, a claim for compensatory justice might relate to developing a means of compensating those who were in some way injured or harmed in the context of research.9 Given such multiple claims about justice, we focus on the task of examining the concept of justice in research. At times, this task involves trying to make explicit aspects of justice that have been somewhat implicit. At other times, we examine why a particular approach to justice dominated public discourse and policy development. To begin our efforts, in Chapter 2 Charles McCarthy sketches a history of both the explicit and implicit federal policy stance towards justice in research that in many instances followed the revelation of scandals in research with human subjects. Punctuating this history is a series of offensive cases that, when brought to public attention, strongly influenced attitudes and approaches towards research. Some of the most notorious cases of research with human subjects involve violations of justice in research: African-American men in the Tuskegee Syphilis Study who were not given treatment even after effective therapies had become available, elderly patients in the Jewish Chronic Disease Hospital who without their consent were injected with live cancer cells, and mentally retarded children in the Willowbrook State School who were purposely exposed to hepatitis. In such cases, research subjects seem to have been selected because of their relative lack of power compared to other potential, and less vulnerable, research subjects. In each of these cases, the risks or burdens of participation were borne by the subjects, yet there was very little prospect of direct benefit to them. Indeed, in light of cases such as these, it is not surprising that the regulatory stance adopted in the landmark federal legislation governing research with human subjects in the United States that was adopted in 1974 took a protectionist stance. On the heels of the Ad Hoc Committee charged with investigating the scandal associated with the Tuskegee Syphilis Experiment, as described above, the National Commission for the Protection of Human Subjects invoked two primary notions of justice: the distribution of burdens and benefits should be fair; and equals ought to be treated equally.10 These notions provided conceptual support for the largely protectionist federal policy towards research. Nearly 20 years later, in response to a variety of forces and influences, research policies began to empha-

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size inclusion of research subjects—not only in terms of actual participation in research but also in terms of research design, setting research priorities, and making funding decisions. This emphasis focuses considerations of justice in somewhat different ways. After this historical policy overview, a series of chapters examines how the concept of justice has been either ignored or applied in the selection of particular groups of research subjects. This is followed by some suggestions about how the concept should be applied today and in the future. The groups examined are patients, children, women, racial and ethnic minorities, captive and convenient groups, and international populations. It is important to note that these categorical groupings overlap substantially, making it somewhat difficult to categorize all the relevant considerations of justice for any particular individual. Similarly, our examination does not capture the full range of relevant considerations that must be given to other important populations, such as the disabled, the elderly, and gay men and lesbians, groups that have in large part eluded special attention regarding inclusion in research at the federal level despite their unique concerns. In addition, the claims and uses of the concept of justice vary across the chapters, demonstrating the complexity, yet utility, of the concept. This should not be terribly surprising, since such divergent claims have long been part of conceptual work on justice. In theNichomachean Ethics, Aristotle used two definitions for justice: (1) "the whole of virtue" and (2) "fairness in distribution."11 In taking a hard look at questions regarding justice from the perspective of the vulnerable sick, in Chapter 3 Baruch Brody touches on some competing values of justice in this context: the social need for research, benefit to subjects, and protection from exploitation and harm. In actual cases no one of these values is controlling. Rather, Brody argues that a "balancing" conception of these values, and of the competing claims of protection and access, must be employed. Brody uses the balancing conception in examining three intriguing cases. First, he examines the conduct of research in the emergency setting where clinical circumstances may at times necessitate overriding obtaining informed consent for research. While our commitment to informed consent is quite strong, the competing values of access to experimental treatments that may benefit (or harm) the subject and the social need to conduct this research must be balanced in order to apprehend the complexities of the situation. Second, in describing the push for effective treatments for human immunodeficiency virus (HIV) infection and AIDS, Brody demonstrates how the balancing conception of justice accommodates the desperate claims of those persons with HIV infection with the social need for sound scientific data so that other persons are not exposed to the risk of experimental treatments that have not been adequately tested. Third, Brody examines Phase I oncology trials, using the balancing conception of justice to suggest alternative trial designs that may be more commensurate with the concerns of patient-subjects than are current designs.

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Research with children also raises some very obvious and knotty concerns about justice. While on the one hand our intuitions might seem to weigh on the side of protection, since young children are not be able to provide meaningful informed consent for participation in research, on the other hand such a stance would preclude the possibility of children to benefit from research, both as individuals and as a group. Just as in the case of emergency research with adults who are not capable of giving consent, at an individual level certain children would be deprived of the possibility of benefit from new therapies if research is not permitted. Moreover, if research with children is not conducted, children, as a group, will subsequently not have access to safe and effective treatments. Yet, despite these tangible concerns about access to potentially beneficial therapies, the history of research with children, along with our intuitions that gravitate towards protecting children, suggests a need for some caution and deliberation. Such is the substance of Chapter 4 authored by Robert Nelson. Nelson begins with an account of some of the most notorious cases in research ethics involving institutionalized children: the Willowbrook study mentioned above where subjects were injected with hepatitis and studies at the Walter E. Fernald School (Fernald School) in Waltham, MA where subjects were fed radioactive oatmeal. Given cases such as these it is not surprising that federal regulations leaned towards protection, outlining the situations in which research with children is acceptable. As a rule, research with children that is not evaluating a therapy must expose subjects to no greater than "minimal risk."12 Nevertheless, considerable controversy surrounds this rule since other standards may be more responsive to claims about justice that argue towards increased access and greater inclusion of children in research. Other standards might set the level of acceptable risk at the risks encountered in daily life, the level of risk determined by an individual's parents to be acceptable, or simply the risk assented to by an older child. The recent controversies surrounding the determination of whether it is acceptable to conduct clinical research with human growth hormone make it clear that understanding these competing methods of determining risk is critical, since the extent to which children are given access to, or are protected from, research hinges upon such an assessment. As in the case of children, until recently many women were not been included in research for a variety of reasons. One explanation is based on protectionism. That is, women were excluded because of an intent to protect the fetuses of pregnant women and the childbearing potential of nonpregnant women. Such a stance might not seem terribly surprising in the wake of the thalidomide tragedy of the early 1960s in which women who had received thalidomide while they were pregnant gave birth to infants with severe malformations. Another argument that has been used to support the exclusion of women from research suggests that the data obtained from clinical research with menstruating women will potentially be confusing due to the influence of this (normal) hormonal variation. While surely the science might be more complex (compared to men) in the setting of this varia-

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tion, it is precisely these same variations that will remain following the investigational phase of drug development, leaving us without drugs being properly evaluated prior to clinical use. In addition to these explicit arguments, it is also likely that the historical exclusion of women from research reflected a broader social attitude towards women, an argument that certainly raises questions about social justice. Regardless of the cause of this historical tendency to exclude women from some types of research, as in the case of children, such an exclusion may affect both women as individuals and as a group. In Chapter 5, Nancy Kass focuses on these issues, using three case examples to demonstrate a range of important considerations regarding justice and women in research. These examples are derived from research in pharmacology, cardiovascular disease, and HIV/AIDS. In aggregate, these examples suggest the need for the appropriate inclusion of women in research. This conceptual move from protection to access is mirrored in recent regulatory and policy statements that will undoubtedly have an influence on the conduct of clinical research. In parallel with initiatives to include more women in research has been the promulgation of regulations to enhance the representation of members of racial and ethnic minorities in research. As Patricia King describes in Chapter 6, issues of justice related to race and the legacy of degrading and exploitative experimentation and research in the African American community, most notably the Tuskegee Syphilis Study, led to an understandable lack of trust in the research enterprise by African-Americans. This lack of trust undoubtedly contributes to the hesitancy of some African-Americans to participate in research. Furthermore, working at a time soon after the public revelation of the Tuskegee Syphilis Study, it is not surprising that the federal bodies deliberating about the appropriate policy stance towards involving African-Americans and those of other racial minorities in research leaned towards protection. Indeed, the language of the time evoked a notion of distributive justice in which the ethical calculus hinged on the fair distribution of harms. In this calculus, the need to protect those who were deemed to be vulnerable, in terms of their prior education, socioeconomic status, or relative lack of power, deserved special attention. While concerns about vulnerability are essential, overprotection combined with a lack of trust in the research community may result in a failure to address properly the health needs of those in racial minorities—clearly another relevant concern about justice. In considering these competing claims about justice, it is crucial to recall that findings from research must redound in appropriate treatment to the participants, as individuals and as groups. There has also been considerable attention focused on captive and convenient populations, with the paradigmatic example being prisoners, but also including other institutionalized persons, military personnel, and those in status relation-

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ships such as students and employees. At first glance, it seems that the rigorously protective stance towards research with these populations would be appropriate as a result of being cognizant of the Nazi prisoner experiments. Nevertheless, in Chapter 7 addressing the special issues associated with these populations, Jonathan Moreno describes a more complicated picture. While prior to the 1970s prisoners were subjects for a large amount of clinical research that included compensation for participation, regulations were later promulgated to constrain this research because of concern about the vulnerability of those who are imprisoned. Similarly, while prisoners may lack the ability to make decisions free from coercion, the same may be true for those who are in the military, those who are students, or those who are in some other situation where a difference in power and authority exists. Finally, institutionalized persons may also be affected by similar forces, compounded in many instances by difficulty in making decisions about participation in research due to the condition that prompted their institutionalization, such as profound mental retardation or debilitating psychiatric illness. Thus, each of these cases raises questions about justice; questions that not only involve the distribution of burdens and benefits of research, but also procedural justice in which the abilities of those to make decisions may be compromised due to the environment in which they find themselves. While concerns about appropriate protection of such populations are obvious, justice would also seem to require some access to research for these populations, again so that benefits from this research might accrue, both to individuals and to the group as a whole. That is, without research, little will be known about conditions that are unique to these groups, such as advanced Alzheimer's disease and severe psychiatric disorders. International research raises similar concerns about the need to balance protection and access, as well as the risks and burdens of research. In Chapter 8, Ruth Macklin delineates some of the vexing issues associated with international research. She first describes some of the littered history of research that has been conducted across international borders. This research includes a study in Puerto Rico, that could not have been conducted in the United States at the time, in which poor women were not told of the risks of pregnancy inherent to participating in a trial on oral contraceptives. This history also includes the problems associated with the approval and use of Depo-provera (DMPA) due to insufficient consideration of the context in which the research was conducted. In addition to her review of these historical cases, Macklin tackles some perplexing current cases: the quinacrine affair; trials of RU-486; and placebocontrolled HIV studies. The quinacrine story involves the continued international use of an agent that has not been tested for use in sterilization. Arguments that lean towards access highlight the benefits of an easy and effective means of sterilization. However, complicating the picture are early data that indicate that there

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may be toxicological effects of this method of sterilization, suggesting the need for protection and careful retrospective research before continued use. Whether to conduct trials of RU-486 in Bangladesh also entails considering similar arguments about access to a potentially effective abortifacient, which are countered by claims about protecting these women from the risks of the research. Finally, the palpable need to decrease the vertical transmission of HIV infection from mothers to infants across the globe has been associated with a critical need to address matters of justice. While the burden of HIV disease is high in the developing world, governments of developing countries are unable to support the expensive treatment shown to be effective in mitigating vertical transmission rates in developed countries. Accordingly, clinical trials using less expensive agents and protocols have been initiated with the hope of finding an affordable solution to this overwhelming problem. However, some of this research has used placebo controls even though doing such a study would not be acceptable in the developed world because of an available alternative. Macklin describes the importance of different risk-benefit calculi in considering justice in this context. Following her analyses of these past and present cases that center on considerations of distributive justice, Macklin proposes a framework of procedural justice to facilitate ethically sound research across cultures. Once armed with these rich descriptions of how justice might be applied in particular populations, in Chapter 9 Madison Powers addresses some of the conceptual aspects of justice that seem relevant to its application in the context of research with human subjects. Like many of the authors in this volume, Powers finds that the dominant norm of justice for biomedical research has traditionally focused on the need for protection of those who are vulnerable from the harms and risks of research. Powers finds strands of this dominant norm of protectionism embedded in the process of clinical research. Obtaining voluntary informed consent is one important aspect of the protective conception. Similarly, the riskbenefit assessment of IRBs bolsters the protection of individuals by assuming that an individual's assessment may not be adequate; IRBs must make an independent determination of the risks and potential benefits in order to protect against the exploitation of individuals for the sake of others. Finally, considerations of fair subject selection and the protection of certain populations, contribute to the protection of research subjects. Nevertheless, biomedical research is but one of three major spheres of health policy—the others are health care resource allocation and occupational and environmental protection. Each of these spheres has traditionally invoked its own dominant conceptualization of justice. Justice with respect to health care resource allocation, especially inequalities in access to medical care, has followed classical egalitarian lines viewing health care as a good to be distributed fairly; and, in the occupational and environmental arena, health is viewed as subject to tradeoffs within broadly utilitarian calculi such as cost-benefit analyses. Upon reflect-

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ing on the cases, examples, and analyses found in the preceding chapters, it becomes apparent that these latter norms have now crept into the sphere of biomedical research, once dominated by a protective conception of justice. Therefore, understanding justice in research today needs to incorporate an understanding of these different, and sometimes competing, conceptions of justice. With this conceptual scheme before us, in Chapter 10 we offer some suggestions about how to implement considerations of justice in the context of research. Such decisions need to be made explicitly at each stage of the research process from the formulation of a research study, to the design of a clinical trial, to the reporting of results. Moreover, this involves a wide range of participants in the research enterprise including: researchers, IRB members, policy makers, funding agencies, and pharmaceutical companies. Only by considering justice at every point and by each relevant participant can we move beyond consent, towards seeking justice in research.

NOTES 1. Charles Wiener, "Evolving Ethical Issues in Selection of Subjects for Clinical Research," Cambridge Quarterly of Healthcare Ethics 5(3):334-345; Summer 1996; Jean E. Johnson, "Patient Access in Research," Oncology Nursing Forum 9(2):81-82; Spring 1982; Udo Schuklenk and Carlton Hogan, "Patient Access to Experimental Drugs and AIDS Clinical Trial Designs: Ethical Issues," Cambridge Quarterly of Healthcare Ethics 5(3):400-409; Summer 1996; Nancy E. Kass, Holly A. Taylor, and Patricia A. King, "Harms of Excluding Pregnant Women from Clinical Research: The Case of HI V-infected Women," American Journal of Law, Medicine, and Ethics 24(1):36-46; 1996; Carol Levine, "Women and HIV/AIDS Research: The Barriers to Equity," IRB 13(l-2):18-22;JanuaryApril 1991. 2. NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research, 59 Fed. Reg. 14508 (March 28, 1994). 3. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects, Federal Register Document 79-12065, April 18, 1979. 4. Ibid., p. 5. 5. Ibid., p. 7. 6. Ibid., p. 8. 7. Jean E. Johnson, "Patient Access in Research"; and Udo Schuklenk and Carlton Hogan, "Patient Access to Experimental Drugs and AIDS Clinical Trial Designs: Ethical Issues." 8. Nancy E. Kass, Holly A. Taylor, and Patricia A. King, "Harms of Excluding Pregnant Women from Clinical Research: The Case of HIV-infected Women"; and Carol Levine, "Women and HIV/AIDS Research: The Barriers to Equity." 9. See Anna C. Mastroianni, Ruth Faden, and Daniel Federman, eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. 1, (Washington, DC: National Academy Press, 1994); and President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Compensat-

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ing for Research Injuries: The Ethical and Legal Implications of Programs to Redress Injured Subjects, Vol. I, Report (Washington, DC: GPO), June 1982. 10. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report. 11. Aristotle, Nicomachean Ethics, Book V. 12. See 45 CFR 46.406 (b).

2 THE EVOLVING STORY OF JUSTICE IN FEDERAL RESEARCH POLICY C h a r l e s R. McCarthy

This chapter attempts to describe the diverse meanings and applications of justice as it has come to be understood and implemented in federal policies pertaining to human subjects who participate in biomedical research. However, even after 30 years of public efforts to create a framework of laws, regulations, and guidelines to protect the rights and welfare of research subjects, the role that justice plays, or should play, in research policy is far from clear. The term "justice" as applied to human subjects was discussed in The Belmont Report, issued in 1979.1 But, in other public policy documents and proceedings concerning human subjects research, this term has rarely been used. Meanings of justice that can be discerned in public policy are varied and individually incomplete. They include: 1. equitably distributing the burdens and benefits of research across the general population;2 2. treating like situations in the same way; 3. offering equal opportunity for all qualified persons to participate in research;3 4. treating all research volunteers with the respect due them as collaborators in the pursuit of scientific knowledge;4 5. providing appropriate oversight of studies involving human subjects, including follow-up care and compensation for research-related injuries; 11

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6. protecting the general population from misinformation or from exposure to unnecessary risks;5 7. not invading the bodily integrity or privacy of research subjects without obtaining their informed consent; and 8. preventing, ameliorating, or curing disease without transgressing the dignity of individuals.6 These understandings of justice often overlap, and in specific contexts can be difficult to distinguish from principles of beneficence, nonmaleficence, and respect for the autonomy of research subjects. Nevertheless, historical examination indicates that the principle of justice (along with the principles of autonomy and beneficence) is deeply embedded in the United States policy governing research with human subjects. The evolution of public policy in any area is complex, and a certain amount of personal interpretation is necessary. Moreover, the fact that social and political forces compete and interact to influence policy make it difficult to trace the evolution of any particular theme. This task is made more difficult when considering the principle of justice because, as noted above, the term "justice" has rarely been explicitly employed. Consequently, it is difficult to trace the use and interpretation of the concept of justice in research policy purely in chronological fashion. The chapter begins with a look at early considerations in the treatment of patient-subjects and healthy normal subjects, and then examines our understandings of justice through the turbulent social period of the 1960s, the surge in Congressional and public interest in medical research, and the revelations of scandals in research in the 1970s. This leads to the question of how commissions charged with examining issues of research ethics understood and utilized the concept of justice. The chapter concludes with a discussion of the shift in public policy from protection of research subjects against research that was perceived to be dangerous, to access, to advocacy by potential subjects to be included in promising research that was perceived to offer great benefits at little cost. Some women and many persons with AIDS considered regulatory protections to be over-protective and unfair.

EARLY DISTINCTIONS BETWEEN HEALTHY VOLUNTEERS AND PATIENT-SUBJECTS

The National Institutes of Health (NIH) issued its first policy in 1953 when it opened the Clinical Center, a 500 bed facility dedicated exclusively to research conducted under the auspices of the federal government. Research projects at the Clinical Center involved both healthy subjects and patient-subjects, although each category was treated differently. It was clearly understood in 1953 that healthy

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volunteers who participated as normal controls in clinical investigations were distinguished from patients and did not have a traditional physician-patient relationship with investigators. They stood to gain no direct medical benefit from their participation in the research and it was considered unjust to invade their bodily integrity or trespass on their privacy without their consent. Accordingly, two features characterized the guidelines7 for normal volunteers at the Clinical Center: (1) informed consent would be obtained before participation in each research study, and (2) each research project would be required to undergo prior review and approval by a committee of scientists. Once a study was approved, the primary responsibility for protecting the rights and well being of the normal volunteers was placed on the investigator in charge of the research project who was expected to follow the advice of the committee. In striking contrast, policy makers at the NIH uncritically assumed in 1953 that experimental procedures involving patients at the Clinical Center fell under the then revered doctor-patient relationship—a relationship of trust. Therefore, the Clinical Center's policy did not extend to patients who were research subjects because: "A positive decision was made that it would be intrusive [in the doctorpatient relationship] for an administrative body to interfere with that relationship."8 Although the 1953 NIH policy at the Clinical Center was periodically updated in succeeding years, little substantive change occurred for more than a decade. The relationship between research investigators and patient-subjects was not officially recognized as being different in kind from the relationship between physicians and patients until the promulgation of a new Public Health Service (PHS) policy in 1966. Of note, normal volunteers involved in extramural research (research that was funded by the NIH but conducted elsewhere) were not protected by any federal policy until 1966.

THE DECADE OF THE SIXTIES: A TIME OF CHANGE Explicit expressions of justice began to find their way into public policies regarding research between 1958 and 1970. That decade (loosely referred to as the "sixties") stands apart as a time of unusual change in the history of the twentieth century. "The 'sixties' are often regarded as a storm that came and passed, a cyclone that blew through. . . ."9 The turmoil of the decade affected virtually every individual and most institutions of American society. The "establishment" was criticized by the media, academia, and by college students who were determined to change the status quo. The practice of medicine and medical research did not escape searing criticism. The research establishment that was criticized included the federal agencies grouped under the PHS; the committees of the U.S. Congress that exercised oversight over the PHS; the American Medical Association (AMA); the Association

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of American Medical Colleges (AAMC); the pharmaceutical and medical devices industries; and the biomedical research community comprised of research administrators and investigators in universities and clinics throughout the country. As is well known, the turmoil of the sixties was infused with widely held convictions that industrial giants were polluting air and water and threatening the earth's ecosystems; and that the Cold War, with its threat of nuclear destruction, was endangering civilization. Viewed in this light, virtually every kind of sciencebased technology was cast as a potential force for evil unless properly restrained. The prevailing pessimistic mood eclipsed the lingering enlightenment view that human progress was inextricably linked to advances in science and technology. The Environmental Protection Agency (EPA), the Occupational Safety and Health Administration (OSHA), and the Department of Energy (DOE), to name only a few federal agencies, produced reams of regulations in response to public fears and complaints that technological applications of science were endangering public safety, the environment, and public health. Nevertheless, not all segments of society were sympathetic to the new wave of skepticism about scientific progress. Many persons, particularly those involved in medicine or medical research, held fast to the view that the moral integrity of each research investigator was both necessary and sufficient to provide safeguards for the rights and well-being of research subjects and for the well-being of science itself. Many of those in the research establishment held that: ... a basic tenet of the philosophy upon which the scientific method rests [is]:the integrity and independence of the research worker and his freedom from control, direction, regimentation, and outside interference.10

Persons who held this view feared that attempts to regulate research would hobble scientific progress.11 The Seeds of Change

None of the discussions that took place in the early and middle sixties concerning appropriate protections for human subjects included explicit discussion of justice. The phrase "subjects' rights" was often used, seldom explained, and almost never defended in terms of a principle or theory of rights or a theory of justice. Nevertheless, the policy documents of the period include discussions about public accountability, fairness, quality of research, and public health and safety. That is, these discussions were about social justice. Most of the discussions about the rights of individual patients and subjects dealt overtly with what have subsequently come to be known as the principles of autonomy, beneficence, and nonmaleficence. Nevertheless the context of the discussions suggests that there were considerations that went beyond individual autonomy, maximizing benefits, and minimizing risks to subjects. The creation

Justice in Federal Research Policy

15

of public confidence in the safety and efficacy of medical interventions was of paramount importance. Not only was it considered wrong to allow harms to society in the form of unsafe or ineffective therapies, but it was considered obligatory to report to society that public moneys were supporting high quality research with minimal infringement of the rights and welfare of research subjects. Gradually there was an erosion of the view that the integrity of research investigators and reliance on remote peer review of the scientific merit of research protcols provided sufficient protections for research subjects. Ethical evaluation by nonscientists as well as scientists at the local level was needed. In the words of NIH Director James Shannon: The absence of written guidelines on the use of investigative drugs or procedures on sick patients was no longer tolerable ... a set of basic guidelines to govern this activity had to be developed.12

Although there are some references in the sixties to fairness to subjects,13 and despite the fierce political battles taking place in other settings concerning the way that justice ought to find expression in civil rights as they pertain to housing, employment, law enforcement, military service, and race relations, there continued to be little explicit mention made of justice in the context of biomedical research. When Dr. Shannon appeared before the Surgeon General's National Advisory Health Council (NAHC) in 1965, he said: [research] investigation departs from the conventional physician-patient relationship, where the patient's good has been substituted for by the need to develop new knowledge, that the physician is no longer in the same relationship that he is in the conventional medical setting and indeed may not be in a position to develop a purely or a wholly objective assessment of the ... ethical nature of the act which he proposes to perform. ... I am searching for some way of creating a more profound sense of an institutional awareness of the importance of this aspect of the problem without tying them down and immobilizing them in their capabilities.14

Dr. Shannon's statement constitutes one of the earliest examples in which research subjects are sharply contrasted with ordinary patients. As noted above, patients who participated in research up to this time were seldom regarded as having a relationship to research investigators fundamentally different from the relationship of nonresearch patients to their physicians. This distinction now constitutes one of the foundational pillars of the ethics of research. 15 Expanding Federal Expenditures for Medical Research

The medical research budget of the United States government expanded dramatically between World War II and 1969. Historian David Rothman writes,

16

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Thus in 1945, the lesson learned from both the battlefield and the laboratory was to reorganize the National Institutes of Health (NIH) along the lines of the CMR (the Defense Department's wartime Committee on Medical Research) and fund it generously—in effect, involve an army of investigators from universities and hospitals in the war against disease and await the impressive results.16

Despite the movement for scientific restraint that began during the sixties, the budget of the NIH rose from less than a million dollars in fiscal year 1944 to more than a billion dollars in fiscal year 1969.17 The growth in the medical research budget stemmed from the enthusiasm generated in the wake of World War II that a united American society could subdue any enemy, and that it would eventually conquer the major diseases that were also killers. A carefully constructed lobbying effort orchestrated by Mary Lasker,18 included an influential constituency of scientific leaders and University officials, and continually pressed the Congress to support health research. The health lobby stimulated the expansion of NIH budgets each year from 1948 to 1969. Unable to mount a solid argument against the investment of public moneys in health research, and unable to derail the lobbying efforts of the Lasker group, the critics of science and technology sought to control federal health research through regulation. Congressional staff members frequently warned NIH officials that once the budget of any agency exceeded a billion dollars, the Congressional oversight of that agency is greatly intensified.19 The warning proved to be prophetic for the entire PHS of which the NIH was the most visible agency with the highest level of funding. Regardless, Congressional oversight of research has long played an important role in considerations of justice. In 1959, Senator Estes Kefauver held Congressional hearings20 that focused on the economic impact of drugs on health care costs. However, the concurrent public media revelation that infants born to mothers who had taken the drug thalidomide were often grotesquely deformed, changed the character of the hearings. Although most of the affected infants in the thalidomide tragedy were born in the United Kingdom, Canada, and Europe, the impact of the tragedy was increased by dramatic and shocking U.S. television news coverage. The implications of this debacle were not lost on the Congress and the Kefauver hearings quickly shifted their focus to the safety and efficacy of drugs being brought to market. When the Kefauver-Harris bill came to the Senate floor it contained provisions requiring the Food and Drug Administration (FDA) to determine that each drug that received market approval by the FDA had passed rigorous testing for both safety and efficacy. Senators Jacob Javits and John Carrol persuaded their colleagues to add an amendment requiring that informed consent of each subject involved in research be obtained prior to the testing of drugs. Congress passed the Kefauver-Harris amendments to the Food, Drug, and Cosmetic Act in 1962. The amendments made profound changes in the scope of authority of the FDA, to provide for safety and efficacy of drugs, medical devices,

Justice in Federal Research Policy

17

and biologies. The amended law was the first federal statute that imposed significant restrictions on research involving humans.21 The legislative history of the Kefauver-Harris Act makes it clear that Congress intended that fair play, full disclosure, respect for subjects, and honesty in dealing with the public, should characterize research, whether conducted with public funds or private dollars. Similarly, although the Kefauver-Harris amendments technically applied only to research involving FDA-regulated test articles, it was clear to all agencies within the Public Health Service that Congress intended all research that was regulated, conducted or supported by any agency of the PHS to meet similarly rigorous scientific and ethical standards. These standards of safety and efficacy, directed toward the good of society as a whole, square with the concept of social justice, whereas the informed consent provisions are concerned primarily with a libertarian view of justice that privileges the autonomy of individual subjects. The accounts that surfaced during the Kefauver hearings set a tone that encouraged additional publicity regarding ethical shortcomings in research. Perhaps best known of these abuses was a research project conducted at the Jewish Chronic Disease Hospital—a joint venture with the Sloan-Kettering Cancer Research Institute. In this case two research investigators, Drs. Southam and Mandel, were found by the New York State Board of Regents to be "guilty of fraud or deceit and unprofessional conduct for injecting live cancer cells into patients."22 Because the patients were elderly, indigent, and in many cases incompetent, the story generated extensive publicity and resulted in the withdrawal of privileges of the physician-scientists involved.23 Another case involved the transplantation of a sheep's heart into a human patient.24 The investigator, Denton Cooley, did not consult with anyone prior to performing the transplantation which was subsequently judged to be scientifically naive as well as ethically flawed. Officials at the NIH, including its Director Dr. Shannon, were in close touch with the Congress about these issues. The NIH came to believe that the Congress would hold it responsible for misconduct in NIH-supported research even though the NIH, at that time, had virtually no control over the conduct of extramural research. Shannon realized that not only were the research subjects vulnerable to abuse, but also the PHS was vulnerable to negative criticism occasioned by such misconduct.25 Intense discussions began to take place in Dr. Shannon's office about the rights of research subjects, fairness to subjects, informed consent, limiting risks to subjects, obligations of investigators to consult with and be accountable to professional peers, compensating injured research subjects, what constitutes research misconduct, and appropriate professional standards for research. These discussions implicitly and explicitly involved multiple interpretations of justice. For instance, the NIH recognized that it must be able to assure fairness to subjects, absence of battery, and protection of privacy. NIH officials also came to under-

18

BEYOND CONSENT

stand that when society funds research, both society and the institution that carries out the research bear ethical responsibility for treating subjects in a just manner. It gradually became apparent that the NIH could impose ethical behavior as a condition of granting an award to carry out research on behalf of the public. This was because NIH's authorizing legislation to make awards in support of research implicitly included the authority to place conditions, including ethical conditions, on awardee institutions and on research investigators. This insight soon led to the development of a comprehensive public policy for the protection of human subjects. The NIH based this policy in part on some earlier efforts it had made to understand what mechanisms were already in place to protect human subjects. In 1960, the NIH made an award to the Law-Medicine Research Institute at Boston University to conduct a 3 year study to examine the ethical, legal, and moral issues of research practice in the United States. The study was completed in 1963.26 One study finding was that only 16 of 86 departments of medicine in U.S. medical schools used special forms to document informed consent from potential research subjects. Although the report suggested the need for enhanced protections for human subjects, it did not provide much guidance as to how the policy should be formulated. Shannon therefore created a committee headed by Dr. Robert Livingston to recommend a suitable set of protections for NIH-supported research involving human subjects.27 Livingston's report issued in 1964 recommended (1) a careful assessment of the wisdom of a government agency undertaking an examination of "ethically responsible relationships" and procedures for carrying out the assessment; and (2) "an examination of the 'range and tenor' of present professional [ethical] practices." Dr. Shannon was supportive of these two initiatives. However, the Livingston report concluded that: "the NIH is not in a position to shape the educational foundations of medical ethics ...". Shannon found this conclusion to be "wholly unsatisfactory."28 While the NIH was considering how best to provide protections for human research subjects without unduly interfering with clinical research, the World Medical Association issued its 1964 Declaration of Helsinki setting forth standards of conduct for research in both therapeutic and nontherapeutic settings.29 Nevertheless, there is little evidence that the Helsinki Declaration had significant influence on the PHS policy. The influence of congressional oversight

Daniel Flood chaired the House of Representatives Program Oversight Committee during the 1960s. Flood drew the attention of the popular press to poor management, waste, and inefficiency in congressionally mandated programs across

Justice in Federal Research Policy

19

the entire federal government. Year after year, Flood conducted hearings on the administration of research in the PHS and the growing expenditure of public research dollars for biomedical and behavioral research. Each year's hearing was more rigorous than its predecessor. Flood's staff members were vigilant to identify any misuse or mismanagement of public research dollars. Although Flood did not demonstrate major mismanagement of research expenditures, his hearings compelled the NIH to audit its own administration of research and to make its processes for evaluating research applications as fair as possible. Each year, NIH officials pledged to Flood's committee that the steadily increasing flow of federal dollars to research would be fairly distributed according to merit. As a result, NIH steadily improved its peer review system to assure impartial funding of the most promising research projects. Although treatments of justice in research usually make only passing reference to the quality of research, the fact is that sound research design is a necessary, although not a sufficient, material condition of just research.30 Over time, the peer review committees and boards, created to prioritize the funding of research applications, learned to pay attention to provisions for the protection of human subjects as well as the scientific quality of research proposals.31 Ensuring the quality of science and the minimization of risks to potential future subjects (consistent with sound research design) constitute a recognition of accountability to the public as well as to individual research subjects that constitutes a concrete application of social justice.

THE NEED FOR AN ETHICAL FRAMEWORK IN RESEARCH

Dr. Shannon took seriously the need for an explicit and workable ethical framework for the conduct of research involving human subjects. In a letter to the Surgeon General transmitting his proposals for a policy of protection for human subjects, he said: To win general acceptance within not only the medical research community but also our society at large, the final statement of principles should probably emerge from a group which includes representatives of the whole ethical, moral and legal interests of society.32

As a first step, Shannon recommended that the PHS initiate a policy for the protection of human subjects. In response to Dr. Shannon's request, Surgeon General William Stewart issued the following policy statement: The awardee institution is to provide prior review of the judgment of the principal investigator or program director by a committee of his institutional associates. This

20

BEYOND CONSENT review should assure an independent determination: (1) of the rights and welfare of the individual or the individuals involved [as subjects], (2) of the appropriateness of the methods used to secure informed consent, and (3) of the risks and potential medical benefits of the investigation.33

Concern for the ethics of research was heightened by an article published by Henry K. Beecher in the New England Journal of Medicine in June of 1966.34 The article cited 22 research projects that had been published in refereed research journals that, in Beecher's judgment, had violated the rights of the human subjects involved. Because of Beecher's prestige as a researcher, his criticisms stirred intense debate. Beecher's critique, coming on the heels of the publication of the PHS policy and its endorsement by the New England Journal of Medicine, contributed to wide negative publicity about the state of ethics in the research community of the United States. The PHS Policy underwent clarifying revisions in 1966, 1967, and 1969. The most important revision, in 1969, made it explicit that the policy extended to PHSfunded research involving behavioral and social science research as well as to biomedical research. The Origin of the Concept of a Research Ethics Commission

Spurred by the dramatic news that Dr. Christian Barnard of South Africa had performed the first human heart transplant late in 1967, and recognizing that Barnard's feat was accomplished in a research setting, Senator Walter Mondale, introduced in 1967 (90th Congress) Senate Joint Resolution 145 (SJ RES 145). The bill called for creation of a National Commission on Health, Science, and Society to evaluate the integrity and direction of research and to assess the impact of technological advances on society, including issues of social justice generated by research.35 Because SJ RES 145 generated little support when first introduced, Senator Mondale introduced it again in subsequent congresses in 1969, (SJ. RES. 75), in 1971 (SJ. RES 71), and in 1973 (S J. RES 75). Each succeeding Congress seemed to give the bill a little more support, but it was never enacted in anything like the form that it had when it was introduced. Senator Mondale called for assessments of the social and cultural impacts of science-based technological advances. Vague as these concepts were, it is clear that the Senator was interested in creating an ethics commission to assess social justice and to make social justice a hallmark of research. Mondale was more concerned with maximizing the distribution of the benefits of research to all segments of society and minimizing harmful effects of research on society than he was with possible benefits or harms for individual human research subjects. Eventually Mondale's efforts changed the research landscape despite the fact that his proposals were only partially incorporated in legislation.

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21

The Creation of the Yellow Book In 1969, Dr. Donald T. Chalkley in the Division of Research Grants of the NIH was assigned the task of preparing a policy for the protection of human research subjects that would be applied uniformly throughout all agencies and programs within the Department of Health, Education, and Welfare (DHEW). Chalkley completed his work, and the Policy, known as the "Yellow Book" because of the color of its cover, was issued for the entire Department in 1971.36 The Yellow Book not only set forth requirements for awardee institutions to assure the Department that subjects would be protected, it also contained a commentary that justified and explained reasons for the policy provisions. This educational aspect of the new policy was a major new mechanism for the protection of human subjects. Two events precipitated actions by which the Secretary of the DHEW placed the weight of authority behind the policy for the protection of human subjects. First, the revelation that Dr. Denton A. Cooley of the Baylor University Artificial Heart Program, who had previously implanted a sheep's heart into a cardiac patient, had implanted an artificial heart into a patient in violation of the existing PHS policy. This intervention enabled the subject to survive for only 63 hours.37 Second, the findings of a study of the PHS Policy for the Protection of Human Subjects conducted by sociologist Bernard Barber38 indicating that the PHS Policy was plagued by (1) some failures to review research projects as required; (2) long administrative delays; (3) failures on the part of institutions to conduct required continuing review of research; (4) inappropriate committee membership; and (5) extraneous assignments to review committees that distracted them from their primary purpose. The Tuskegee Syphilis Study While the DHEW was struggling to improve its approach to the use of human subjects, in July of 1972 the press uncovered details of the infamous Tuskegee Syphilis Study. "If there was one event which most triggered public concern with the issues of human experimentation, it would have to be the public disclosure in July 1972 of the Tuskegee Syphilis Study involving 600 black male subjects."39 In this study, at least 28 men died as a direct result of untreated syphilis, and many others suffered from manifestations of the disease including blindness and insanity. The Senate hearings concerning Tuskegee, that were chaired by newly elected Senator Edward (Ted) Kennedy, emphasized the investigators' failure to obtain informed consent and to provide treatment for the subjects involved in this study. Other violations of the civil rights of the subjects were only partially recognized at the time. As discussed in Chapter 6, the study is now remembered primarily because a vulnerable cohort of poor, illiterate, minority subjects and their families were unjustly exploited.

22

BEYOND CONSENT

After the Tuskegee Syphilis Study came to public attention, the DHEW recognized an obligation to attempt to "make whole" the damage it had caused. As a part of the settlement of the Tuskegee Syphilis Study, the federal government has provided many millions of dollars in compensation to survivors of the study and to heirs of those who did not survive.40 Finally, on May 26,1997, President Clinton apologized to a handful of survivors on behalf of the nation.41

Protecting the Vulnerable

In the fall of 1972, Robert Q. Marston, who succeeded Dr. Shannon as Director of the NIH, recognized the need to protect research subjects in a growing research program. In an address to University of Virginia Medical School, he declared an obligation on the part of society to carry out research aimed at improving the health of vulnerable populations and to protect the rights of vulnerable research subjects in the process. Though he did not use the language of justice, Marston was describing a general obligation of social justice to the vulnerable, or least well-off, members of our society. In effect, he was saying: If public moneys are to be used for biomedical research, then a significant portion of those dollars should support research to aid the least well-off members of society. However, the research must never exploit research volunteers from these vulnerable populations. Among subjects identified as vulnerable were pregnant women, human fetuses, prisoners, children, and the institutionalized mentally infirm.42 After the speech was delivered, Marston created a Task Force chaired by Dr. Ronald Lamont-Havers, the NIH's Associate Director for Extramural Research, to examine the best ways to provide protections for subjects in these vulnerable categories. A group headed by Dr. Charles U. Lowe of the National Institute of Child Health and Human Development, already looking into ethical questions involving research relating to human fetuses, was folded into the Task Force. The Task Force was further expanded to include representatives from all PHS agencies.

More Scandals in Research

In 1973, Congressman Angelo D. Roncallo gave widespread publicity to a Finnish research project of neonatal glucose metabolism. In the study, 12 previable fetuses, obtained by abdominal hysterotomy, were decapitated and their heads perfused. As it happened, an NIH training fellow traveled to Finland to observe this research in a Finnish laboratory. He brought back specimens for analysis in his laboratory which was partially supported by NIH funding. Roncallo widely distributed pictures of the fetal heads separated from their bodies to the media and to other members of Congress, and contended that the NIH was supporting

Justice in Federal Research Policy

23

gruesome research on aborted human fetuses.43 The accusation, though incorrect, prompted a congressional ban on fetal research. Another issue that captured the imagination of the public and the attention of the Congress during this period was the investigational use of psychosurgery. While proponents and opponents of psychosurgery seemed to reach a stalemate in hearings before the Senate Health subcommittee, the popularity of the academy award winning movie, "One Flew Over the Cuckoo's Nest" turned public opinion sharply against frontal lobotomy and other forms of research involving psychosurgery and mental illness.44 Subsequently, psychosurgery would occupy a portion of the National Commission's agenda. Legislative Maneuvering

The hearings before the Senate Health Subcommittee concerning the Tuskegee Syphilis Study, fetal research, psychosurgery, and other health-related matters led to frenetic activity in Congress.45 A compromise bill was quickly passed by Congress and signed into law on July 12,1974.46 It constituted Title II of the National Research Act, (P.L. 93-348). Among other provisions, the Act required the PHS to promulgate regulations for the Protection of Human Subjects47 and placed a temporary moratorium on research involving human fetuses.48 The Act also provided for creation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The National Commission, chaired by Dr. Kenneth Ryan, was directed to report on the ethical principles underlying biomedical and behavioral research, as well as the future impact of advances in technology (a provision taken from the Mondale bill). In addition, it was charged with making regulatory recommendations regarding research with human fetuses.

THE NATIONAL COMMISSION FOR THE PROTECTION OF HUMAN SUBJECTS OF BIOMEDICAL AND BEHAVIORAL RESEARCH

Between 1974 and 1978 hearings and deliberations of the National Commission caught the attention of the research community and the press. The Commission's work uncovered little abuse of human subjects, and provided evidence that research subjects often receive better medical care than nonresearch patients. Nevertheless the view persisted, even among some commissioners, that participation in research was a heavy burden and that its potential for danger required stringent protections for subjects. In this climate it was difficult to require that the burdens of research be equitably distributed. Equitable distribution, it was thought, would impose greater burdens on the least well-off in our society. Minorities tended to

24

BEYOND CONSENT

avoid participation in research because of the fear of exploitation generated by publicity about the Tuskegee scandal.49 Influenced by the thalidomide tragedy, pregnant women feared that their offspring could be adversely affected by their participation in research.50 Investigators and research sponsors feared litigation if women of childbearing potential were involved in drug studies.51 Research was widely considered to be a risky burden rather than an opportunity to receive stateof-the-art medical care at reduced cost.52 The National Commission produced 17 reports that included approximately 125 recommendations to the Secretary of the DHEW. Perhaps its most important contribution was to provide academic validation to the ethical propriety of the DHEW Regulations for the Protection of Human Subjects. All of the recommendations of the National Commission were accepted by succeeding secretaries of the DHEW, although the Department ultimately failed to publish final regulations for protection of institutionalized mentally infirm research subjects. While a detailed evaluation of the work of the National Commission is beyond the scope of this chapter, the Commission's work on the subject of justice is relevant. The Commission discussed fairness in the selection of subjects: Justice is relevant to the selection of subjects of research at two levels: the social and the individual. Individual justice in the selection of subjects would require that researchers exhibit fairness: thus, they should not offer potentially beneficial research only to some ... or select only 'undesirable persons' for risky research. Social justice requires that distinction be drawn between classes of subjects that ought and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear burdens, and on the appropriateness of placing further burdens on already burdened persons. Thus, it can be considered a matter of social justice that there is an order of preference (e.g., adults before children) and that some classes of potential subjects (e.g., institutionalized mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain conditions. . . . Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings where research is conducted. Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research . . . for . .. convenience, .. or because they are easy to manipulate. . . ,53

After the Commission disbanded, the DHEW asked the PHS to modify the DHEW's Regulations for the Protection of Human Subjects to incorporate the recommendations of the Commission. The FDA participated in the drafting process so that the resulting revised regulations promulgated by the DHEW (45 CFR 46) and by the FDA (21 CFR 50 and 56) were essentially congruent with respect to the protections provided for human subjects. The revised regulations, reflecting the views of the National Commission, were promulgated in January 1981.54

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COMPENSATION FOR RESEARCH INJURIES AND THE ROLE OF FEDERALLY-CREATED BODIES

One of the justice issues raised by the Tuskegee Syphilis Study, but not included in the agenda of the National Commission, was the matter of care and compensation for subjects injured in the course of their participation in research. DHEW Secretary Caspar Weinberger created a task force in 1975 to consider the Department's obligation to compensate injured research subjects. The task force completed its report in 1977. The Task Force likened research volunteers to military personnel who undertake risky missions on behalf of society. It argued that just as military personnel are entitled to receive compensation for service-related injuries, so research subjects should be compensated for that amount of injury that is in excess of that which is reasonably associated with the illness from which the subject may be suffering, as well as treatment usually associated with the subject's illness. The report of the Task Force was completed in 1977, but the DHEW took no action on its recommendations. New DHEW Secretary Joseph Califano was prepared to follow the Task Force's recommendations for compensation of injured research subjects when he was summarily fired by President Jimmy Carter in 1979. The task force report was forwarded by Secretary Harris, who succeeded Califano, to the DHEW Secretary's Ethics Advisory Board. However, the Board was disbanded in 1980 before it could consider the Task Force's Report. The Report was then forwarded to the newly formed President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. The President's Commission, discussed below, issued its own report on the matter of compensation for injured research subjects. In its rather ambiguous report,55 the President's Commission concluded that compensation for research is probably ethically justified, but called for an experiment to test the feasibility and cost of such a compensation system. However, no legal basis on which to initiate such an experiment could be discovered, and the experiment was never devised or conducted.

THE PRESIDENT'S COMMISSION

In 1978 the Congress authorized the creation of the President's Commission.56 The Commission served from 1980 to 1983. Although most of the work of the Commission was directed to ethical issues in health care delivery, it issued two reports that dealt directly with the system of protections for human research subjects,57 and a further report on genetic engineering.58 Perhaps its most important contribution to the ethics of research involving human subjects was a recommen-

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BEYOND CONSENT

dation that the Department of Health and Human Services (DHHS) regulations issued in 1981 serve as a model for the development of a Common Rule that would govern research involving human subjects conducted or supported by any agency of the federal government.59

CHANGES IN THE APPLICATION OF JUSTICE TO RESEARCH In the 1980s, attitudes towards research began to change. Congruent new regulations were jointly promulgated by the DHHS and by the FDA in January of 1981. Research institutions took seriously their responsibility to develop comprehensive programs for the protection of research subjects. Administrators and investigators in all parts of the country attended workshops sponsored jointly by the NIH Office for Protection from Research Risks and the FDA. Ten years had passed since a major research scandal had shaken confidence in the system of protections for human subjects. In the meantime, the cost of medical care skyrocketed, making participation in research more attractive to persons who lacked health insurance. By the end of the 1980s, the NIH research budget had exceeded 10 billion dollars, and large scale, multicentered research trials were designed that received much national publicity. Many no longer considered research to be a burden for members of society, but it came to be regarded as an opportunity to obtain state-of-the-art medical care.60 Also during the 1970s and early 1980s the feminist movement identified many forms of discrimination against women, and made women's rights a national issue. Along with concerns for women's rights came the awareness that many drugs administered to women had never been tested in women. Some physicians, fearing malpractice suits, began to warn female patients that they had only anecdotal evidence, or no evidence at all, that some of the drugs they were prescribing were safe and efficacious for women.61 Subsequently, Dr. Bernadine Healy, Director of the NIH from 1987 to 1992, made repeated calls for increased research efforts related to the health of women. Dr. Healy created the Office for Women's Health Research at the NIH and dedicated discretionary research funds to research projects related to women's health. In 1983, AIDS became perhaps the most feared disease in America. Physicians offered no standard treatment or hope of cure for infection with HIV, the virus that causes AIDS. Participation in research offered the best hope for infected persons. Instead of avoiding research, HIV-infected persons and persons with AIDS campaigned for more clinical studies, and they publicly protested when they were denied admission to studies that offered them at least a slim hope of improvement. Many physicians, uneasy and uncertain about how best to treat HIV-infected patients, were only too ready to recommend that their patients participate in research studies.62

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27

In the United States, AIDS was initially thought to be a disease primarily affecting gay men. Few clinical trials were designed to include women who were infected with HIV. When the incidence of the disease began to rise in women, an outcry of discrimination was made against the government and the research community.63 Although AIDS research was gradually modified to include women, complaints that women, especially pregnant women whose offspring might be infected with HIV, were excluded from highly desirable research were given wide publicity. Clinical studies which only a decade before were considered to be a heavy burden for pregnant women, were now considered to be a highly prized benefit. Thus, over a couple of decades attitudes had come full circle. Clinical studies once viewed as onerous, dangerous, and burdensome were now regarded as highly desirable because they offered low-cost, state-of-the-art medical treatment. On this view, exclusion from research for any reason could lead to charges of discrimination and violations of the principle of distributive justice.64

RADIATION RESEARCH, HUMAN SUBJECTS, AND THE NATIONAL BIOETHICS ADVISORY COMMISSION On January 15, 1994, President Clinton created the Advisory Committee on Human Radiation Experiments (ACHRE) to investigate reports of possibly unethical experiments funded by the government many decades ago. The ACHRE identified nearly 4000 human radiation experiments sponsored by the federal government between 1944 and 1974. Although much of the evidence concerning these studies is incomplete and fragmentary, the ACHRE identified some cases of clear abuse and recommended compensation for those who had suffered injury as a result of their involvement in such studies. Perhaps the most relevant finding of the ACHRE to this chapter is the finding that even today there are serious deficiencies in aspects of the current system for protecting the rights and interests of human subjects.65 Partly in response to the ACHRE's report, President Clinton issued an executive order establishing the National Bioethics Advisory Commission (NBAC). Among its many duties, the NBAC is expected to evaluate the effectiveness of the Common Rule for the Protection of Human Subjects, and to study the federal agencies' adherence and commitment to the implementation of the rule.66 The list of issues pertaining to the protection of human research subjects that need to be explored or revisited by the NBAC is nearly endless:67 ethical theory; gene therapy; the system of dealing with multi-centered research trials; techniques to manage privacy and confidentiality in a computer-driven world of research data; and the relevance of a communitarian view of ethics to traditional notions of justice.

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CONCLUSIONS

This chapter recounts the development of protections for human subjects in biomedical and behavioral research. However, it can only touch the surface of the efforts of countless ethicists, bureaucrats, members of Congress, research subjects, and scientists to bring the quality of the ethics associated with research to the highest possible level. Public policy concerning justice in research involving human subjects has evolved from a situation in the 1960s and early 1970s when the role of justice in research was implicit but seldom mentioned, to a point in the 1990s where it is now on center stage, even though understanding of the concept, role, and application of justice to research involving humans demands further development. Some will look at this history and take satisfaction in the fact that the U.S. appears to have a comprehensive system of protections for human subjects. Others will look at the same history and note that the system is far from perfect, and that certain aspects of the system, including the understanding and application of justice to human subjects, are not well understood, much less universally applied. However, all can agree that the effort to improve the nature and the implementation of the system of protections for human subjects is an enterprise worthy of our best efforts.

NOTES 1. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects, Federal Register Document 79-12065, April 18, 1979. 2. Ibid. 3. Anna C. Mastroianni, Ruth Faden, and Daniel Federman, eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. 1, (Washington, DC: National Academy Press, 1994), p. 209. 4. Mark Frankel, Public Policymaking for Biomedical Research: The Case of Human Experimentation, doctoral dissertation (George Washington University) (Ann Arbor, MI: University Microfilms, 1976), p. 144. 5. President's Commission for the Study of Ethical Problems in Biomedical and Behavioral Research, Protecting Human Subjects, First Biennial Report on the Adequacy and Uniformity of Federal Rules and Policies, and their Implementation, for the Protection of Human Subjects of Biomedical and Behavioral Research (Washington, DC: U.S. Government Printing Office, #040-000-00452-1, 1981). 6. Report of HEW Secretary's Task Force on the Compensation of Injured Research Subjects, (Washington, DC: HEW Publication No OS-77-003, 1977). 7. During World War II normal volunteers were often conscientious objectors who were required to serve as research subjects. Service as a research subject was often regarded as the equivalent of serving as a military draftee. For that reason, normal volunteers were considered to be subject to orders, and not free to refuse to participate in research. By the time the Clinical Center was built, the war was over, the draft was finished, and research volunteers were judged to have the right to consent or decline to participate in research.

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8. Group Consideration of Clinical Research Procedures Deviating from Accepted Medical Practice and Involving Unusual Hazard, a policy statement issued by the NIH Clinical Center, 1953. 9. Scott Turow, The Laws of Our Fathers (Toronto: HarperCollins, Canada Ltd., 1996), p. 423. 10. C. J. Van Slyke, Science 104:569;1946. 11. Stephan Strickland, Politics, Science and Dread Disease (Cambridge, MA: Harvard University Press, 1972), see particularly Chapter XI & ff. 12. Mark Frankel, p. 157. 13. See, for example, the "Analytic Summary" of a conference on the "Concept of Consent in Research" convened by the Law-Medicine Research Institute of Boston University; April 29, 1961. 14. Transcript of the Meeting of the National Research Council, Sept. 28, 1965, cited in Frankel, p. 155. 15. Title 45. Code of Federal Regulations Part 46.102 (d). Revised June 18, 1991. 16. David J. Rothman, Strangers at the Bedside, A History of How Law andBioethics Transformed Medical Decision Making (New York: Basic Books, 1991), p. 53. 17. Charles R. McCarthy, "Research Policy" in Encyclopedia ofBioethics, Warren T. Reich, ed. (New York: Simon Shuster Macmillan, 1995), pp. 2285-2287. 18. Mrs. Albert D. (Mary) Lasker and her husband established the Lasker Foundation in 1942. Its purpose was to support biomedical research. Although her husband died in 1949, Mary Lasker and her friend Florence Mahoney worked for more than 50 years to persuade the Congress and each succeeding administration to support medical research. The medical research lobby was closely allied with the NIH and with Senator Lister Hill and Representative John Fogarty who chaired the Appropriations Committees in both houses of the U.S. Congress. See Stephen P. Strickland, Politics, Science and Dread Disease, (Cambridge, MA: Harvard University Press, 1972), pp. 32-54. 19. During that period the author was working in the Division of Legislative Analysis at the NIH. He recalls receiving such warnings from Congressional staff members and relating them to the NIH Director's Staff in the course of staff meetings. 20. U.S. Senate Committee of the Judiciary, Subcommittee on Anti-trust and Monopoly, 86th Congress. Hearings were held in 1959 and 1960, but the amendments to the Food, Drug and Cosmetics Act were not passed and signed until 1962. 21. P.L. 87-781, October 10, 1962. 22. Mark Frankel, p. 68. 23. Elinor Langer, "Human Experimentation: Cancer Studies at Sloan-Kettering Stir Public Debate on Medical Ethics," Science 143:551-553; 1964. 24. D.A. Cooley, G.L. Hallman, R.N. Bloodwill, et al., "Human Heart Transplant: Experience with Twelve Cases," American Journal of Cardiology 22:804-810; 1968. 25. Mark Frankel, p. 153. 26. Irving Ladimer and Donald D. Kennedy, Clinical Investigation in Medicine: Legal Ethical and Moral Aspects (Boston: Boston University Law Medicine Research Institute, 1963). 27. Mark Frankel, p. 150. 28. Ibid., p. 151. 29. Declaration of Helsinki, Encyclopedia ofBioethics, Revised Edition, vol. 4, Warren T. Reich, ed., (New York: Simon-Shuster-Macmillan, 1995), pp. 2266-2271. 30. Even the monumental work of Tom L. Beauchamp and James F. Childress, Principles of Biomedical Ethics, 4th ed., (New York: Oxford University Press, 1994), makes no direct mention of sound research design as a condition of just research.

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31. In a typical year, peer review committees refer about 500 applications for research funding to the Office for Protection from Research Risks for resolution of ethical concerns. Each case must be resolved before an award can be made. 32. Mark Frankel, p. 152. 33. PHS Policy and Procedure Order 129, issued Feb. 8, 1966. 34. Henry K. Beecher, "Ethics and Clinical Research," NEJM 274:1360-1364; 1966. 35. Senator Mondale first introduced Senate Joint Resolution, 145 (S.J. RES. 145) in 1968. 36. Institutional Guide to DHEW Policy on Protection of Human Subjects (Washington, DC: HEW publication no. 72-102, Dec. 1, 1971). 37. Renee C. Fox and Judith P. Swazey, The Courage to Fail, A Social View of Organ Transplants and Dialysis (Chicago: University of Chicago Press, 1974), pp. 149-211. 38. Bernard Barber, John J. Lally, Juia L. Makarushka, and Daniel Sullivan, Research on Human Subjects: Problems of Social Control in Medical Experimentation (New York: Russell Sage Foundation, 1973). Although the report was not published until 1973, the findings were shared with NIH approximately 18 months earlier. The NIH began remedial action in 1971. 39. Mark Frankel, p. 183. 40. In FY 1995 $2.8 million, and in FY 1996 $1.88 million was paid in compensation to survivors and heirs of survivors of the Tuskegee Study. Personal Communication to the author from the Office for Protection from Research Risks, NIH. 41. In October of 1995, following disclosures by the President's Advisory Committee on Human Radiation Experiments of abuse of subjects in some studies, the President extended an apology, and the government provided monetary compensation to some of the affected families. Although care and compensation have been provided in these two instances, no general policy has been adopted to provide similar benefits for other subjects who have sustained injury in the course of research. 42. Robert Q. Marston, "Medical Science, the Clinical Trial, and Society," presented at the dedication ceremonies for the McLeod Nursing Building and the Jordan Medical Education Building at the University of Virginia, Charlottesville, Nov. 10, 1972. A preliminary draft of the speech was written by Mr. Storm Whaley, Public Affairs Officer, NIH, who had taught ethics at the University of Arkansas prior to coming to Washington, DC. 43. Mark Frankel, pp. 210-219. 44. Ibid., pp. 194-210. 45. Mark Frankel, pp. 232-285 provides a step-by-step description of hearings, bills, drafts, arguments and political compromises that culminated in the National Research Act, Title II (P.L. 93-348) signed into law on July 12, 1974. A detailed account is beyond the scope of this article. 46. For a fascinating and detailed account of the political process that culminated in the passage of P.L. 93-348 see: Eric Redman, The Dance of Legislation (New York: Simon & Shuster, 1973). 47. The Public Health Service Act As Amended by the Health Research Extension Act of 1985 [previously amended by the National Research Act of 1974] Sec. 491 and Sec. 498. The Act states in part: "The Secretary may not conduct or support any research or experimentation ... on a nonviable living human fetus in utero or a living human fetus ex utero . . . (Sec. 498). It also requires the Secretary, HEW, to issues regulations for the Protection of Human Subjects (Sec. 491). 48. The National Commission completed its Report on Research Involving the Human Fetus in May of 1975. The PHS Drafting Committee prepared implementing regulations

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that were promulgated in August of 1975. The ban on fetal research was lifted when the regulations were published. 49. Charles R. McCarthy, "Historical Background of Clinical Trials Involving Women and Minorities," Academic Medicine, 69(9):695-698; 1994. 50. Ibid. 51. Ibid. 52. Ibid. 53. The Belmont Report: Ethical Principles and Guidelines for the protection of Human Subjects of Research, U.S. Government Printing Office, No. 887-809, April 18,1979. 54. Federal Register, Vol. 40, No. 16, January 26, 1981, pp. 8366 & ff. 55. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Compensating for Research Injuries (Washington, DC: U.S. Government Printing Office, 1982). 56. Title III of P.L. 95-622 enacted on Nov. 9, 1978 authorized the creation of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. The Commission's life was extended to March 31,1983 by P.L. 97-377, Dec. 20, 1982. 57. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Implementing Human Research Regulations (Washington: DC: U.S. Government Printing Office, 1983). 58. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Splicing Life (Washington, DC: U.S. Government Printing Office, 1983). 59. The Model Federal Policy for the Protection of Human Subjects is also known as the "Common Rule." The rule addresses human subjects research conducted or supported by 16 federal departments and agencies, and was issued under the authority of each department or agency on June 18, 1991. 56 Federal Register 28002-28032 (June 18, 1991). 60. Charles R. McCarthy, p. 697. 61. Personal Communication from Hugh Farrior, M.D., concerning drugs prescribed in difficult pregnancies. 62. Charles R. McCarthy, p. 696. 63. The author served at the time on the PHS Executive Task Force on AIDS and remembers well the reports of epidemiologists from the Centers for Disease Control who began to report steep rises in the incidence of AIDS in heterosexual couples and in persons who used contaminated needles to inject illicit drugs. It took some time for new clinical trials to be developed that sought to address these health needs. 64. Charles R. McCarthy, 698. 65. Advisory Committee on Human Radiation Experiments, The Human Radiation Experiments: Final Report of the President's Advisory Committee (New York: Oxford University Press, 1996). 66. At this writing, it is too early in the history of NBAC to know what may come of its mandate or how that will affect the system of protections for human subjects or the role of justice in that system. 67. Three sources that address these questions are: Harold Y. Vanderpool, The Ethics of Research Involving Human Subjects: Facing the 21st Century (Frederick, MD: University Publishing Group, 1996); New Challenges in Biomedical Experimentation in Robert H. Blank and Andrea Bonnicksen, eds. Emerging Issues in Biomedical Policy, An Annual Review, Vol. II (New York: Columbia University Press, 1993); and A. Capron, "An Egg Takes Flight: The Once and Future Life of the National Bioethics Advisory Commission," Kennedy Institute of Ethics Journal 7(1):63-80; March 1997.

3 RESEARCH ON THE VULNERABLE SICK Baruch A. Brody

We are in the midst of a reconceptualization of the concept of justice in research. The older conceptualization, the protective conception, emphasized the protection of vulnerable subjects from being used without their consent and from being exploited in excessively risky research. The newer conceptualization, the balancing conception, incorporates access to the benefits of research as an additional demand of justice. As a result, justice in research is now seen as demanding a proper balance of access to the benefits of research with protection from unconsented use and from exploitation. This chapter includes a number of examples of this reconceptualization involving patients for whom established therapies are unavailable or unsatisfactory. The emergence of new experimental therapies that are both promising and risky, is also involved in each case. It is this combination of need, promise, and risk that makes these patients different from other patients and makes them both vulnerable to exploitation and in need of access to better therapies. The initial response in each example was to emphasize justice as protection. Each example raises questions about how protection and access should be integrated to provide us with a balanced theory of justice in research. The first example, research on patients upon their initial presentation in the emergency room, also requires us to look at the impact of the balancing conception of justice on such fundamental commitments as informed consent. The sec32

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ond example, research involving new treatments for HIV-positive patients, also requires us to examine the ways in which the balancing conception of justice has to be integrated with the social need for adequate evidence before new drugs are approved for general use. The third example, Phase I oncology trials, also requires us to consider how new research designs can improve implementation of the balancing conception of justice.

JUSTICE ACROSS TIME Research on Patients in the Emergency Room

Past and present Medical research in emergency situations where there is no time to obtain consent from a competent patient or his surrogate poses unique concerns. Under what conditions, if any, can this type of research be carried out legitimately without obtaining informed consent? Does it make a difference that there are no available adequate treatments for these patients? A protective approach was advocated for some years by the Office for Protection from Research Risks (OPRR) of the NIH.1 According to this approach, research without valid prospective consent in the emergency setting is acceptable only if (1) it involves no more than minimal risks, (2) does not adversely affect the rights and welfare of the subject, and (3) cannot otherwise be carried out practicably. With this approach, both therapeutic and nontherapeutic research could be approved without consent, because of its minimal risk. However, research could not be carried out without prospective consent, no matter what the possible benefit to the patient, if the risks were more than minimal or if other subjects (e.g., those who can consent or who are accompanied by someone who could consent for them) could be found. Consider, as one example, the NIH trial of tissue plasminogen activator (TPA), a clot-dissolving drug, for the treatment of patients with ischemic strokes produced by clots in the arteries leading to the brain.2 There is a desperate need to find better treatments for that often devastating emergency. TPA offered great promise (in light of both theoretical plausibility and the results of two small unblinded studies of escalating doses of TPA), but it involved considerable risks (especially the risk of bleeding). The trial was conducted on patient-subjects treated within the first 3 hours from the onset of symptoms, with half of them being treated within the first 90 minutes. While the authors report that informed consent was obtained for each patient-subject, the very narrow time frame makes it difficult to believe that most of those who consented really understood the complex issues relevant to participating when they consented. Moreover, their obvious anxieties and fears raise serious questions about whether their consent was due to desperation rather

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than a voluntary choice. Nevertheless, the trial was a great scientific and medical success, and TPA is now3 recommended for such patients. Given the realities of the consent process and the risks from bleeding, it is doubtful that this trial included meaningful informed consent or that it was acceptable by the standards of the protective conception of justice advocated by the OPRR. A number of points emerge clearly from this example. First, there is no doubt that prior independent review of such research protocols, required under all regulatory proposals, must be undergone; there is, after all, no reason not to have such research protocols reviewed in advance. This provides some measure of protection against exploitation of vulnerable subjects. Second, if meaningful prospective consent from the patient or a surrogate can be obtained, it should be, both to provide further protection against exploitation and to protect subjects from being enrolled in research without their consent or the consent of a surrogate. The question is what to do about planned risky but important emergency research that has been independently reviewed and approved but for which truly meaningful informed consent cannot be obtained. One approach, favored by some of the researchers in emergency medicine,4 attempted to justify the research by obtaining retrospective consent (often called "deferred consent") from the patient-subjects or from their surrogates. These researchers appealed to studies5 that showed overwhelming approval of this approach, but doubts can be cast both upon those studies and upon the rationale of using retrospective consent to justify earlier enrollment. In what sense is the patient's deferred consent relevant to justifying the earlier research given that a refusal would be irrelevant since the research has already been done? A second approach, advocated by a coalition of critical care researchers, proposed6 that emergency research without consent should be acceptable even if the incremental risks (those greater than the risks of receiving the standard treatment for the condition in question) are more than minimal as long as these incremental risks are still likely in the judgment of the independent review board to be acceptable to the vast majority of potential patients. They called this approach the appropriate incremental risk approach. Even this proposed liberalization might have difficulty justifying the stroke research since the intervention in question posed substantial incremental risks from bleeding. A third approach, adopted by the Council of Europe,7 emphasized that such research can proceed without consent provided that it is "intended for the direct health benefit of the patient." On this account, it is the benefits to the patient-subject that justifies research without consent. But this account fails to balance these possible benefits with the need to protect vulnerable subjects. It makes sense to balance all of these factors (the vulnerability of the subjects, the possible benefits to them, the need to protect them from the risks of the research, the possibility of getting some degree of consent beforehand, and the possibility of finding other subjects) in deciding whether or not to approve

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the research protocol. Just such an approach has recently been adopted by the FDA. On October 2,1996, the FDA issued final regulations allowing for a waiver (in certain cases of emergency research) of the requirement of obtaining informed consent from research subjects or their surrogates.8 Many of the commentators on the earlier proposed version of these regulations saw them as a major retreat from the fundamental moral requirement of obtaining informed consent before research can be conducted. But it is more appropriate to view them as a recognition of the existence of multiple values surrounding the research effort that need to be balanced in particular cases. What are these values? They include: 1. the social need for research in an emergency to test treatments for patients presenting with acute crises such as strokes for which there are few valuable treatments that limit the resulting disabilities; 2. the potential benefit to some patient-subjects (those in the treatment group) who receive new therapies if those therapies are successful; 3. the need to protect these individuals from being exploited by researchers and harmed by new therapies that turn out to be harmful; 4. the right of all individuals to not be used as research subjects without consent. In the nonemergency setting, all four of these values can be respected. Needed research takes place after informed consent from those subjects who decide that the potential benefits outweigh the potential risks. But in the emergency setting, this joint realization of all four values may not be possible. The subjects or surrogates may not be able to give informed consent. Even if consent is obtained, the pressure of time, fear, and anxiety raises serious questions about whether that consent is meaningfully informed or truly voluntary. The FDA's regulations offer a new balancing of the related values. They accept the possibility that conducting the research may be morally licit even if informed consent is not obtained. Instead, the research is justified when the other three values are present to a significant extent. This becomes clear by examining the requirements that must be satisfied before the waiver is authorized. Under the regulations, waivers may only be issued when "the human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence ... is necessary to determine the safety and effectiveness of particular interventions." (21 CFR 50.24 (al)) This requirement ensures that the value of social need is significantly present. The significant presence of the value of potential benefit to the patient-subjects in the treatment group is ensured by the requirement that "appropriate animal and other preclinical studies have been conducted, and the information derived from those studies and related evidence support the potential for the intervention to

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provide a direct benefit to the individual subjects." (21 CFR 50.24 (a3ii)) The significant presence of the third value of protecting vulnerable subjects from being harmed is ensured by a number of special mechanisms. These include, in addition to the usual IRB review, community consultation (21 CFR 50.24 (a7i)), supervision of the research by a data and safety monitoring board (21 CFR 50.24 (a7iv)), and FDA approval through its Investigational New Drug approval mechanism even when the drug being tested is already approved for other indications (21 CFR 50.24 (d)). If prospective informed consent is seen, as it was in the OPRR's earlier protective conception of justice in the research setting, as an absolute demand of justice, then none of this makes a difference. The research is still using people as subjects without their consent, and that is unjust. The injustice is heightened by the fact that their vulnerability may be exploited as there are serious risks associated with their involvement. But whatever the risk, it is unjust to use people this way. The FDA regulations make sense only when one stops seeing the moral world as governed by the protective conception of justice. Justice consists of balancing many independent values, none of which are absolute. These values may in some cases be jointly satisfiable. When they are not, their respective significance in different cases leads to different values being given different priorities in different cases. It is this balancing conception of justice that justifies the approach found in the FDA regulations. Future trends

This is not to say that all is in order with the regulations. There are two issues that deserve further thought. One is in cases where informed consent is obtainable if we are willing to accept a slower enrollment rate. The other concerns the control group. Suppose that the time available for using the experimental therapy is longer than 3 hours from the onset of symptoms. This allows for finding more surrogate decision makers to give consent if the patient-subjects cannot, although there will still be many surrogates who cannot be found in the time in question. It also gives the potential consenters more time to understand the issues and to give a more meaningful consent. Shall we then require that only those for whom consent may be obtained be enrolled? What if this means a significant delay in enrolling the needed number of patient-subjects to complete the study? Moreover, is this fair to those who lose the potential benefits of participation because they cannot consent and their surrogates cannot be found? How shall the values be balanced in such a case? This is not a purely theoretical question. A recent trial9 of free radical scavengers for patients with severe closed-head injury illustrates these difficult questions. Treatment was provided within 8 hours of the time of injury. Of the 463 patients enrolled, consent was obtained from surrogates of 408. The other 55 were enrolled

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without surrogate consent, using the concept of deferred consent. What should be done in such cases under these FDA regulations? Shall we enroll such subjects, enabling them to receive the potential benefit and enabling society to answer the crucial research question more quickly? Or shall we give a higher priority to informed consent, only enrolling those for whom meaningful consent is obtainable, and extending the time needed to answer the research question? The FDA regulations are not sufficiently clear on this point. They do provide (21 CFR 50.24 (a5-a6)) for seeking consent where possible even when the waiver has been issued. But the waiver can be issued as long as "the clinical investigation could not practicably be carried out without the waiver." (21 CFR 50.24 (a4)) This leaves the question open: how much of a delay in completing enrollment makes waiting for those for whom consent can be obtained impractical? IRBs and the FDA, both of whom have to approve such waivers, will have to engage in delicate casuistric balancings, deciding this question on a case by case basis; the balancing conception of justice is not mechanically applicable. The other issue relates to the control group. The FDA regulations specifically allow for emergency research using a placebo-controlled design (21 CFR 50.24 (al)). The scientific advantages of such a study are familiar. But is it ethically justifiable in such a case? I am not raising here the general question of the ethics of placebocontrolled research, an issue I have extensively addressed elsewhere.10 What I am raising is the issue of its justification in the situations in which a waiver of the requirement for informed consent can be issued. Under the regulations, the condition being studied must be life-threatening, available treatments must be unproven or unsatisfactory, and there must be evidence supporting the potential for a direct benefit as well as a favorable risk-benefit ratio. These are precisely the conditions under which, on many accounts,11 it is hardest to justify placebo-controlled trials even with consent. But here, those who are getting the placebo have not even consented to being in the trial, so justifying a placebo-control group is harder. I am not claiming that such placebo-controlled trials can never be justified in cases where a waiver has been issued. The best cases will be those in which the evidence supporting the potential for benefit is modest. But, of course, the more modest that evidence, the harder to justify the waiver on the grounds that it benefits the patient-subjects who receive the experimental treatment. Therefore, placebo-controlled trials run under a waiver will be justified only when there is some, but not enough, evidence supporting the treatment as beneficial. IRBs and the FDA, both of whom have to approve such waivers, will again have to engage in delicate casuistric balancings on a case by case basis as they decide whether a placebo-control group is justifiable when a waiver has been issued. In doing so, they will have to consider the possibility of alternative trial designs. Once more, the balancing conception of justice is not mechanically applicable. Neither of these issues is intended as criticism of the basic thrust of the new regulations. They are intended rather as clarifications of the balancings of values

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that will have to be made on a case by case basis as the new regulations are employed. We will learn a lot about the abilities of IRBs and the FDA to deal with delicate moral deliberations as we study their response to protocols submitted under the new regulations. For now, however, I conclude that the FDA regulations represent the triumph of the balancing conception of justice in research over the earlier protective conceptions of justice. Research on HIV-Positive Patients Past and present

A considerable portion of clinical research is designed to support claims of the safety and effectiveness of new drugs or devices so that they can be approved for general use by the FDA and other national regulatory agencies. This has significant implications for the balancing conception of justice. It means, among other things, that we cannot just balance protecting vulnerable subjects with assuring their access to the newest therapeutic agents. We also need to consider the rights of other patients who are not subjects in the research protocol both to protection against inefficacious and/or dangerous drugs and to quick access to these therapeutic agents if, and as soon as, the benefits of their use have been adequately established. This additional consideration played a role in our discussion of emergency research, when we factored in the issue of completing the study as soon as possible. But it was not the central issue in that discussion, which primarily focused on the research subjects themselves. It will be the central issue in our discussion of our second example of the emergence of the balancing conception of justice: research on HIV positive patients. Since the reforms of the 1960s in response to the thalidomide tragedy described in Chapter 2, new drugs are approved for use by national regulatory agencies only after their safety and efficacy have been demonstrated with great scientific precision.12 Because the protective conception of justice was very influential, approval has been a lengthy process, even when the new drugs are desperately needed. This emphasis on the protective conception came under challenge by AIDS activists in the 1980s who demanded quicker access to new drugs. As a result, two major programs have been adopted by the FDA for research on such patients and others like them. One is the Treatment Investigational New Drug (IND) program13 and the other is the Accelerated Approval (Subpart H) program.141 will begin by reviewing these two programs, and I will then discuss the issues of justice raised by them. The Treatment IND regulations apply to immediately life-threatening ("a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment") or serious (not defined in the regulations) diseases. It allows drugs to be used

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outside of clinical trials in treating such illnesses providing that "there is no comparable or satisfactory alternative drug or treatment available" and providing that the drug is being investigated in controlled trials or all trials have been completed and the sponsor is actively pursuing marketing approval. In the case of serious illnesses, the FDA may deny a request for a Treatment IND "if there is insufficient evidence of safety and effectiveness to support such use." In the case of an immediately life-threatening illness, the FDA may deny a request for a Treatment IND only if "the available scientific evidence, taken as a whole, fails to provide a reasonable basis for concluding that the drug (A) may be effective for its intended use in its intended population or (B) would not expose the patients to whom the drug is to be administered to an unreasonable and significant additional risk of illness or injury." The latter requirements are far less demanding than the former. In a very important passage in its discussion of these regulations when they were issued,15 the FDA had the following to say in support of this new standard against some of its critics who emphasized a more protective approach: Because of the different risk-benefit considerations involved in treating such diseases, FDA continues to believe there needs to be a separate standard for drugs intended to treat immediately life-threatening diseases . . . the level of evidence needed is well short of that needed for new drug approval—and may be less than what would be needed to support treatment use in diseases that are serious but not immediately life-threatening.16

Like the Treatment IND program, the Subpart H Accelerated Approval Program applies to all life-threatening or serious illnesses. Unlike the Treatment IND program, however, it constitutes final approval of the use of the drug, not just access while approval is being considered. The program applies to new treatments which "provide meaningful therapeutic benefit to patients over existing treatment," either because particular patients are unresponsive to or intolerant of the existing treatment or because the general response to the new treatment is an improvement over the response to the existing treatment. Most crucially, the Subpart H program explicitly authorizes approval based on surrogate endpoints (e.g., tumor shrinkage for cancer patients and improvements in CD4 counts for AIDS patients), endpoints that are thought to be predictive of clinical benefit. It is this provision that produces the acceleration of the approval, since it is often possible to get data on surrogate endpoints quicker than data on clinical benefits (length of survival or decreased morbidity). The spirit behind this new program is well illustrated in the following statement in the 1990 Final Report of the National Committee to Review Current Procedures for Approval of New Drugs for Cancer and AIDS (the "Lasagna Report"): The committee recognizes that, by making new drugs available for marketing at this early stage, when there is substantial evidence but not yet definitive evidence of effectiveness, there is an attendant greater risk of serious adverse reactions that have

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not yet been discovered. Cancer and AIDS patients have made it clear to the committee, however, that in light of the seriousness of the diseases involved, they are willing to accept this greater risk. Earlier approval of new drugs will mean that the patient will bear greater responsibility, along with the physician, for understanding and accepting the risks involved.17

The spirit behind these two programs, the Treatment IND Program and the Accelerated Approval Program, is clear. While sick patients who are not research subjects will continue to be offered protection against inappropriate approval of unsafe and/or inefficacious new drugs, there will also be an emphasis on assuring quicker access to drugs whose promise is supported but not fully established by research data when the patients are very sick and when existing treatments are not that helpful. The actual choice to use these new drugs will be made by patients with the advice of their doctors, and society will not stand in their way once some promising evidence becomes available. Is this new approach appropriate? It would seem that it is. As in the case of emergency research, justice demands that we balance values rather than treat any single value as absolute. The very need for official approval by such agencies as the FDA before promising drags can be used by patients who want to use them constitutes a commitment to protecting the vulnerably ill from exploitation. But it is at the same time a limitation of personal autonomy. There are those who treat personal autonomy as an absolute value. They would abolish the need for official approval and would at most allow official agencies to serve as clearinghouses for information that patients and clinicians might consider.18 They are wrong in making personal autonomy such an absolute value. When people are desperately ill, their illness makes them vulnerable and in need of some paternalistic protection, even if this means limiting personal autonomy. There are also those who treat protecting the vulnerably ill as an absolute value. Until the scientific evidence is complete, they would not allow patients to use promising new therapies. That is why they object to these new programs. They are also wrong. When there is promising evidence from trials, even from trials using surrogate endpoints, those who do not have other good treatments available should be free to take their chances with these promising new treatments, even while further clinical trials continue. The new programs constitute an appropriate attempt to balance respecting personal autonomy and protecting the vulnerable. By balancing these two fundamental values, they constitute an important addition to the balancing conception of justice in research. Future trends

This does not mean that all is in order with these new programs. Most crucially, it is important to ensure that both patients and clinicians better understand the ways in which the approval of drags under these programs differ from the approval of drugs under the conventional system. It is important to ensure that they understand the detriments as well as the benefits of Treatment INDs and of accelerated

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approval. The current regulations contain no provisions explicitly addressing this issue. While there are extra Subpart H provisions (21 CFR 314.550) relating to promotional materials, they are purely procedural provisions. These new programs may therefore need to be modified. But their existence is a welcome further triumph for the balancing conception of justice over the protective conception of justice in research. Phase I Trials in Adults with Cancer Past and present

Traditionally, the first step in the clinical testing of new cancer drugs is the conducting of Phase I trials. The primary goal of a Phase I trial is to identify the maximum tolerated dose of a new drug. The traditional approach is to administer the drug at a very low dose to an initial cohort of cancer patients who have failed traditional therapy and then to give increasing doses to later cohorts of subjects. Eventually, a dose is reached at which the level of toxicities is sufficiently severe so that it is treated as the maximum tolerated dose. The previous dose level becomes the recommended dose that is tested for efficacy in a subsequent Phase II trial. This is a very protective approach, emphasizing the safety of the early cohorts rather than the likelihood of their receiving a clinical benefit. This represents a protective approach to justice in research regarding these vulnerable subjects. A recent report19 from the M.D. Anderson Hospital, gives a good picture of how these trials are run and of their results. The report surveyed all 23 published Phase I trials conducted at that institution during the period 1991-1993. For the trials of drugs not previously tested in humans, a median of 10 dose levels were required before the maximum tolerated dose was reached, and the median resulting recommended dose was 40 times the initial dose given. For the trials of drugs or biologic agents previously tested in humans, a median of 5-6 dose levels were required, and the median resulting recommended dose was less than three times the initial dose given, except for the trials of some of the biologic agents. Of the 610 patients enrolled, 29% got less than 70% of the recommended dose. As can be seen, the conservative protective approach resulted in many subjects getting suboptimal doses of the drugs being tested. There was some response in 19 patients (3%), with four being complete responses and 15 being only partial responses. This is at the lower end of what is usually reported. In reviews20 of both adult and pediatric Phase I oncology trials from the early 1990s, the response rate was 4%-6%, with more than half coming only at the end of the Phase I trials, where the doses are higher. As can be seen, the conservative protective approach resulted in few subjects receiving any clinical benefit. In light of these data, two related ethical issues can be raised. They relate to the fact that the subjects in question are both vulnerable and needy because they have

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life threatening illnesses and few, if any, therapeutic options. The first concerns informed consent for phase I trials. Are the patient-subjects adequately informed about the realities (toxicities and likelihood of benefit) of these trials? Even if they are, do they agree based upon an understanding of the information, or is their agreement based upon a failure of understanding, perhaps related to their vulnerability, that undercuts the validity of the consent? The second concerns the risk/ benefit ratio for these trials. Given the substantial toxicities experienced by the subjects, especially those that are close to the end of the trial, and given the low response rate, even near the end of the trial, is there an acceptable risk/benefit ratio? Or is that ratio unacceptable and reflective of exploitation of these vulnerable subjects? Is that ratio improved by the social benefits of these trials, especially if subjects were to consent because of a sense of altruistic concern about future patients? In thinking about both of these issues, we will, of course, need to keep in mind this chapter's fundamental theme of the need to balance protection and access. Future trends

Two recent studies support the above mentioned concerns about the informed consent process. One21 studied 30 patient-subjects in Phase I trials to find out why they participated. The predominant reasons were the possibility of benefit (100%), lack of a better option (89%), and trust in the oncologist (70%). Only 33% talked about helping future patients, the benefit that is most likely to occur. It is certainly possible to interpret these data as at least suggesting that these desperate and therefore vulnerable subjects were exploited by the oncologists they trusted to participate in a trial in the hopes of securing a benefit that they were very unlikely to attain. This troubling possibility is not the only interpretation of the data; an alternative interpretation is that the patient-subjects clearly understood the situation and knowingly and freely chose to participate with the hope that they might be one of the lucky few who responded. The troubling interpretation is, however, supported by the facts that only one-third clearly understood the purpose of Phase I trials and that only 30% acknowledged that the no-treatment-except-forpalliation option had been discussed as an alternative to participation in the Phase I trial (although it was mentioned in the consent forms they signed). A 1996 report from the ACHRE also highlighted these issues. As part of its work, it conducted a project called the Research Proposal Review Project (RPRP) and concluded on the basis of it as follows: ... we reviewed consent forms that appeared to overpromise what research could likely offer the ill patient and underplay the effect of the research on the patient's quality of life. . . . Not surprisingly, this problem was the most acute in the RPRP among Phase 1 trials that, while not being nontherapeutic in the strict sense, appeared to offer only a remote possibility of benefit to the patient-subject. .. desperate hopes are easily manipulated.22

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These concerns about informed consent are obviously very serious. They cannot be overcome by the balancing of values that allowed for research without informed consent in the emergency situation, because here one cannot, among other things, appeal to the potential therapeutic benefits of participation. But these concerns are manageable if we can find better consent processes for Phase I trials. Among the suggestions that can be offered,23 even without the modifications in the trial designs discussed below, are the following: 1. patients need to be told very explicitly that the likelihood of any response is very low and that the few responses are not particularly significant; 2. patients need to be told very explicitly that the purpose of the trial is to learn about toxicities so that better trials can be run for future patients that might help them; 3. patients need to be told very explicitly that the trial is designed to keep on escalating the doses until significant toxicities are reached so that they are at risk of suffering those toxicities; 4. patients need to be told explicitly which cohort they are in and what is the significance of that fact both for the slim likelihood of benefit and the much larger risks of suffering toxicities; 5. patients need to be told very clearly about good palliative care as a legitimate alternative; 6. finally, patients need to be encouraged to think about the relative importance to them at this point near the end of their life of altruistic motives, even if that is not their major reason for enrolling. If all of this information could be conveyed so that it was understood, then the ethical concerns about informed consent would be alleviated. It remains to be seen what the enrollment rate would be in Phase I trials for which such consent was obtained. I now turn to the more difficult issues about the acceptability of the risk/benefit ratio. It needs to be remembered that even if subjects consent to participation in a research protocol, that protocol is illegitimate and against all the international standards for research ethics if the risk/benefit ratio is sufficiently unfavorable. Even when informed consent is necessary for legitimate research, it is not sufficient. Are then the risk/benefit ratios in Phase I trials acceptable? It seems to me that this issue of risk/benefit ratio is directly related both to current debates about the design of Phase I trials and to our discussion in this chapter about the balancing conception of justice. The traditional design of Phase I trials is quite conservative, emphasizing the protection of the research subjects from excessive toxicities. For example, the starting dose is chosen, based on animal toxicology data, to be at a level considered to be minimally toxic. As a result of that policy and similarly conservative

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policies governing the escalation of dosages, many subjects receive dosages that are significantly below the dosage ultimately recommended for study in the succeeding Phase II trial. While these dosages are safer, they are also more likely to be nontherapeutic. With this approach, an acceptable risk/benefit ratio is achieved for many subjects by protecting them from toxicities, but at the cost of lowering an already low likelihood of therapeutic benefit. Given what we know about why these subjects are enrolling in the Phase I trial, is that much protection appropriate? Is this approach downplaying the desired access to dosages that are more likely to be therapeutic? Several alternative approaches to the design of Phase I trials have recently been advocated. I am particularly interested in variations on the continual reassessment method (CRM).24 The basic ideas behind that method are to treat the subjects from the very beginning at the dosage anticipated to be recommended for study in the Phase II trial and to adjust that anticipation as toxicity data becomes available. This Bayesian approach (an approach relying upon initial estimates of likely results) offers the hope of more responses, but at the price of more experienced toxicities. The resulting risk/benefit ratio is acceptable because of the greater chance of benefit, the very chance that motivates enrollment. Access to potential benefit is emphasized more than protection from toxicities. It is important to keep in mind that the information conveyed in the informed consent process will have to be modified if such a design is adopted. Points (3) and (4), about how dosages are modified from one cohort to another and about the meaning of being in a particular cohort, will certainly have to be modified. But there may also be a need to modify what is said about the likelihood of responses and of toxicities. There is obviously balancing to be done here. We want to protect these vulnerable subjects from excessive toxicities. At the same time, we want to give them a better chance of access to dosages that are more likely to be effective. We also want to complete the Phase I trial as soon as possible so that trials of efficacy can begin. How to best balance these three goals in a proper trial design is unclear. However, there is good reason to take a less conservative approach than the traditional approach, given what motivates these adult subjects to volunteer. This would be more in keeping with the balancing conception of justice. The traditional design of Phase I trials saw dying patients as vulnerable and as requiring protection. That is why its approach, to the choice both of the initial dose and of the successive doses, is so conservative. It represents the protective conception of justice in research. Perhaps it is too conservative. We need to better balance protection with assuring access to promising therapies, both for those in the Phase I trials and for those who will be enrolled in the succeeding Phase II and Phase III trials. Newly proposed Bayesian designs may be more successful in achieving this needed balance. Developing better versions of these designs, and shaping an informed consent process that conveys what is involved in Phase I trials

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with these new designs, is a major challenge for the balancing conception of justice in research.

CONCLUSIONS

Reconceptualizations are often best assessed by their products. This chapter demonstrates the success of the recent reconceptualization of justice in research from justice as protection to justice as balancing. In this new balancing conception, justice in research involves balancing the values of protecting vulnerable research subjects, of promoting their access to new needed therapies, and of meeting the social need for research to validate new needed therapies. Adopting this balancing conception of justice has led to better standards for emergency research by emphasizing the value of meeting the social need for research as well as the value of protecting vulnerable subjects. Adopting this balancing conception of justice has led to valuable programs such as the Treatment IND Program and the Subpart H Accelerated Access Program by emphasizing the value of promoting access to needed therapies as well as the value of protecting vulnerable subjects. Adopting this balancing approach has led to the search for better designs of Phase I trials by emphasizing all three values. Few other reconceptualizations have been so productive.

NOTES 1. OPRR Reports 91-01; May 15, 1991. 2. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, "Tissue Plasminogen Activator for Acute Ischemic Stroke," NEJM 333(24):1581-1587; December 14, 1995. 3. Michael McCarthy, "New Guidelines Recommend rt-PA for Ischaemic Stroke," Lancet 348:741; September 14, 1996. 4. N. S. Abramson, et al, "Deferred Consent," JAMA 255:2466-2471; 1986. 5. N. S. Abramson, et al., "Deferred Consent: Use in Clinical Resuscitation Research," Annals of Emergency Medicine 19:781-784; 1990. 6. M. Biros, etal., "Informed Consent in Emergency Research," JAMA 273:1283-1287; 1995. 7. Recommendation R(90)3 , Principle 8. 8. Federal Register 61(192):51491-5\53l; October 2, 1996. 9. B. Young, et al., "Effects of Pegorgotein on Neurologic Outcome of Patients with Severe Head Injury," JAMA 276(7):538-543; August 21, 1996. 10. Baruch Brody, Ethical Issues in Drug Testing, Approval, and Pricing (New York: Oxford University Press, 1995), pp. 112-131. 11. AMA Council on Ethical and Judicial Affairs, Ethical Use of Placebo Controls in Clinical Trials, CEJA Report 2-A-96. 12. Brody, supra note 10, chapter III.

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13. The regulations governing Treatment INDs are found in 21 Code of Federal Regulations 312.34. 14. 21 Code of Federal Regulations 314.500-314.560. 15. Federal Register 52(99): 19468; May 22, 1987. 16. The views of the critics, including Representative Waxman and Senator Kennedy, are nicely summarized in Eaglstein, M.D., "Overview of the Reproposed and Final IND Regulations Concerned with the Treatment Use and Sale of Investigational New Drugs: The Congressional Perspective," Food Drug Cosmetic Law Journal Vol.43, pp. 435-442, 1988. 17. National Committee Final Report (August 15, 1990) p. 3. 18. Two versions of this position are advocated in H. G. Grabowski and J. M. Vernon, The Regulation of Pharmaceuticals (Washington: The American Enterprise Institute, 1983); and D. G. Green, Medicines in the Marketplace (London: IEA Health Unit, 1987). 19. T. Smith et al., "Design and Results of Phase I Cancer Clinical Trials," Journal of Clinical Oncology 14:287-295; 1996. 20. These surveys are summarized in C. Daugherty et al., "Perceptions of Cancer Patients and their Physicians Involved in Phase I Trials," Journal of Clinical Oncology 13:1062-1072;1995. 21. Ibid. 22. Advisory Committee on Human Radiation Experiments, "Research Ethics and the Medical Profession," JAMA 276:403-409; 1996. 23. Useful discussions are found in E. Emanuel, "A Phase I Trial on the Ethics of Phase I Trials," Journal of Clinical Oncology 13:1049-1051; 1995; B. Freedman, "CohortSpecific Consent" IRB, [12]:5-7; Jan./Feb., 1990; and Y. Willems, C. Sessa, "Informing Patients about Phase I Trials," Acta Oncologica 28:106-107; 1989. 24. J. O'Quigley et al., "Continual Reassessment Method: A Practical Design for Phase I Clinical Trials in Cancer," Biometrics 46:33-48; 1990.

4 CHILDREN AS RESEARCH SUBJECTS Robert M. Nelson

An individual child may benefit from participation in research in a variety of ways including access to new therapeutic interventions and close monitoring. While an alternative to participating in research is to receive the currently available treatment, assuming that these treatments are safer and more effective than interventions under investigation may not be justified. In fact, most drugs used to treat children have never been tested formally in children, making off-label use of medications the de facto standard of care in pediatrics. Indeed, only 20% of drugs approved in the United States have been labeled for use in infants and children and only 37% of new drugs in 1996, with the potential for pediatric use, had some pediatric labeling at the time of approval.1 It follows that inadequate information exposes children to unexpected adverse reactions or to suboptimal treatment. In addition, the lack of a pediatric formulation of a drug may deny a child access to an important therapeutic advance, or expose a child to a drug in homemade, poorly absorbed preparations. In other words, since children are not sufficiently included in research, adequate information is lacking to guide the pediatric use of a medication. Thus any particular child is exposed to greater risk, and may be deprived of potential benefit, when compared to an adult, given the same medication—an unfair difference based solely on age. This situation may be due to regulatory impediments, economic disincentives, or reluctance to require pediatric studies unless the primary use of 47

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a drug will be in children.2 Also, the logistics of performing pediatric research may be more difficult given, for example, the lower incidence of a disease in children, the complexity of developmental changes that may take place, and the limited market for the recapture of the costs of drug development. While a discussion of the full range of reasons for the underrepresentation of pediatric subjects in research is beyond the scope of this chapter, the chapter focuses on examining the extent to which current federal regulations governing the involvement of children in research and the conceptual basis for these regulations may contribute to this injustice by, for example, shifting research away from children or, by shifting research away from healthy children to children who are sick. The dominant interpretation of the requirements of justice in research has been to protect so-called "vulnerable" populations from exposure to an inappropriate share of risk in the absence of certain benefit. One way to protect against the involuntary assumption of research risk is the requirement for obtaining voluntary informed consent—a requirement which excludes persons who are incapable of informed consent (e.g., children and the mentally disabled) or who, if capable, may not be in a position to provide voluntary consent (e.g., prisoners). While perhaps reasonable for adults, such a consent requirement would preclude all research using children who are not legally or developmentally capable of providing voluntary informed consent.3 The inability of children to consent has led to restrictions based on the stratification of research proposals according to risk. The conceptual cornerstone of our current research policy, the Belmont Report, interprets the principles of respect for persons, beneficence, and justice as requiring the protection of children through limiting the risk to which a child may be exposed regardless of parental permission. The concept of "minimal risk" serves to anchor allowable risk to the risk encountered in the normal course of a child's everyday life. The challenge to enhance justice in regard to pediatric research is to broaden the participation of children who are not capable of consent while at the same time minimizing any exposure to risk that is not balanced by an appropriate benefit for that particular child. In order to address questions about the current approach and its implications for justice, this chapter looks at the history of research which prompted this approach. Specifically, this chapter begins with a brief examination of the Willowbrook hepatitis experiments, concluding that the children involved were exploited primarily through indexing acceptable risks and benefits to the everyday experience of institutionalized children. The failure to consider other nonresearch remedies to the social and physical deprivation created by the institutional living conditions exposed the children to more risk for less benefit than noninstitutionalized children. The institutional setting was also a factor in the radioisotope experiments conducted at the Fernald School. Although the Fernald experiments came to light after the development of federal research regulations, it was consistent with the research, such as Willowbrook, which led to regulations that sought to restrict

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children's research participation through standards of acceptable risks and benefits independent of parental permission. The chapter then describes and critiques the approach taken by The National Commission. The National Commission specifies the range of decisions about a child's research participation which properly fall under the discretionary authority of a parent or guardian. Generally a parent may enroll a child in a research project provided that the risks are comparable to the child's everyday experience—a level of risk that was further specified using the concept of "minimal risk." As discussed below, Paul Ramsey argued that a parent should not subject a child to any risk in the absence of benefit. According to Ramsey, parental permission for a child to participate in research is only justified by a parent's concern to benefit his or her own child, thus precluding a child's participation in nontherapeutic research. However, as will be discussed when considering research involving older children, a child's moral and social development may benefit from participation in research—a benefit that may only occur through a child's voluntary and informed assent. The concept of a child's assent thus emerges as an important aspect of research with children. Next, an analysis of the controversy surrounding recent trials of human growth hormone in children with short stature illustrates the complexities of risk assessment and child assent under the current federal research regulations. Therefore, alternative approaches will be examined and critiqued, such as that of Benjamin Freedman and his colleagues that recommend that acceptable risk be indexed to the experience of a particular child, effectively eliminating any absolute standard of risk in favor of parental judgment.4 Finally, this chapter recommends that the federal regulations should index minimal risk to the everyday experience of healthy children, strengthen the definition of, and requirement for, assent, and extend the allowable risk exposure by linking acceptable risk to the capacity of an individual child to assent to research participation. For those children incapable of assent, the limits of allowable risk in the absence of direct benefit may be extended through the use of advisory boards made up of parents with children who are affected by the condition to be studied. These recommendations ought to result in a more just and fair distribution of the burdens and benefits of research in pediatrics.

JUSTICE ACROSS TIME A History of Exploitation: Research at the Willowbrook and Fernald Schools

A series of studies of infectious hepatitis were carried out at the Willowbrook State School from 1955 through the early 1970s. To understand the natural history and prevention of hepatitis, Saul Krugman and his colleagues conducted a research

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project in which a small group of newly admitted children were deliberately exposed to the endemic strain of hepatitis virus. This research design was justified, according to Krugman, given that (1) all the children would eventually contract hepatitis, (2) hepatitis was mild in this age group, (3) the deliberate infection may have induced immunity to the endemic strain, (4) the children would be isolated from other infections by being admitted to a special ward, and (5) only children whose parents consented would be included. As recently as 1986, Krugman continued to claim that "our studies were ethical [given] the extraordinary conditions that existed in the institution [and] the potential risks and benefits for the participants." In response to charges that the research was performed at Willowbrook given the existence of a captive population, Krugman asserted that the fact that the children were mentally retarded was relevant "only to the extent that society placed them in an institution where hepatitis was prevalent." Neither Krugman, his research staff, nor the staff of the institution were responsible for the "overcrowded, unhygienic conditions" at Willowbrook—rather it was society that was responsible. According to Krugman, seven institutional, university, and state committees approved of the research. Finally, Krugman argued that "the overall risk for children in our special isolation unit was less than the risk for other children who were admitted to buildings in the institution where shigellosis and respiratory infections, as well as hepatitis, were endemic."5 Thus, Krugman's main defense of the Willowbrook hepatitis experiments is that the risks of participation in research were no greater than, and arguably less than, the risks of everyday life for the children in this institutionalized population. Theologian Paul Ramsey was one of the first to raise ethical concerns about the Willowbrook studies. Ramsey questioned the authority of any parent to enroll his or her child in a nontherapeutic study. Even if such authority was granted, however, Ramsey felt that research should not be performed in "homes for the retarded because they are a captive population." He details more specific criticisms. First, there was no attempt to enlist the adult staff in the research in spite of a similar risk of hepatitis. Second, no justification was given for withholding "an inoculation [gamma globulin] of some degree of known efficacy except the need to test, confirm, and improve the [viral] inoculum." Third, nothing appears to have been done to control the epidemic by "more ordinary, if more costly and less experimental, procedures." The consequence is that "the special moral claims of children for care and protection are forgotten, and especially the claims of children who are most weak and vulnerable." Finally, Ramsey criticized the letter which parents received offering possible admission into the hepatitis unit if they volunteer their child for the study, arriving days after a letter indicating the institution was full and their child was on a waiting list, as a clear example of coercion.6 Suggesting that the children at Willowbrook were especially vulnerable to exploitation, Ramsey asked "whether the doctors would have accepted the hepatitis as a 'natural' occurrence and even as an opportunity for study" if Willowbrook "had

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been an orphanage for normal children or a floor of private patients, instead of a school for mentally defective children."7 David Rothman argues that the fact that hepatitis was endemic to the institution does not justify the deliberate injection of infectious material nor qualify the study as a "natural experiment." He reasons that "there is an essential difference between taking advantage of social, as opposed to biological, conditions." The social deprivation that occasions the study "tend[s] to become self fulfilling." Seemingly "on the verge of discovering a vaccine," the Willowbrook research "continued even after the efficacy of gamma globulin to weaken (if not to prevent) an attack of hepatitis had been established." In addition, Rothman observes that the "consent form that parents signed to allow their children to be infected with the virus" read as though their children were to receive a vaccine. The researchers are placed in "an ethically untenable position" for "where the essential cause of a health problem is social deprivation, it is generally within the power of the research team to remedy the situation for their subjects." Rothman concludes that the "Willowbrook experiment offer[s] both practical and principled support for maintaining as rigid a distinction between social deprivation and biological conditions as possible."8 In a report published in 1995, the ACHRE examined 21 nontherapeutic studies using radioisotopes administered to children either conducted or funded by the federal government during the 30 years prior to 1974. The only information available concerning parental authorization and subject selection for these studies is from an investigation in 1994 by the Massachusetts Task Force on Human Subjects Research into research performed in 1946 and again between 1950 and 1953 at the Walter E. Fernald School located outside Boston. The first study exposed 17 children to radioactive iron, the second exposed 57 children to radioactive calcium in a series of related experiments. Letters addressed to parents dated November 1949 and May 1953 fail to mention any risks associated with the research, nor the use of radioactive isotopes. Both letters implied that the research was intended for the child's benefit—an assertion which is false. The children who were enrolled "voluntarily" into the studies were members of a so-called science club, who were provided with special privileges in exchange for their participation. As with Willowbrook, the investigators at Fernald were not responsible for the poor living conditions and may have truly believed that the opportunity to participate in the research "brightened the lives of these children, if only briefly." Nevertheless, "a particularly poignant dimension of the unfairness of using institutionalized children as subjects of research is that it permits investigators to secure cooperation by offering as special treats what other, noninstitutionalized children would find far less exceptional." The ACHRE report thus concludes that, regardless of limited risk exposure, the children at Fernald were wronged by inadequate attention to parental permission and the lack of meaningful assent by the children—both made possible by their vulnerability and lack of social privilege.9

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The Willowbrook and Fernald studies are examples of the type of research that the current federal regulations governing research are designed to prevent. Appealing to the formal principle of justice, the condition of these children as both mentally disabled and institutionalized should not count as a relevant difference in allowing them to be treated unequally. The condition of these children made them vulnerable to exploitation as research subjects and thereby exposure to an unfair share of research risk. The researchers involved claimed that participating in the research was to the advantage of the children being studied, an argument which does square with the notion of justice as fairness. According to this understanding of justice, differences in treatment may be justified as long as the difference results in an overall advantage or benefit to the individual being studied.10 However, either exposing an "at risk" child to increased risk or inducing a "deprived" child to participate through an otherwise meager benefit hardly seems fair, especially if the child's situation could have been improved through nonresearch interventions. The Development and Evolution of Standards The National Commission

The Report and Recommendations on Research Involving Children of the National Commission was published in 1977, and is the foundation for the federal regulations known as Subpart D of Title 45, Code of Federal Regulations, Part 46 (45CFR46). 11 As discussed in Chapter 2, the National Commission also issued the Belmont Report on the ethical principles that ground human subject research.12 The Belmont Report interprets the principle of justice to require "fair procedures [for] the selection of research subjects" so that persons are not included "simply because of their easy availability, their compromised position, or their manipulability." Persons who are "vulnerable" to such exploitation are defined either as someone who is incapable of giving informed consent (e.g., children or the mentally infirm) or, if capable, who may not be positioned to give that consent voluntarily (e.g., prisoners). Voluntary informed consent thus becomes part of the procedure by which justice is assured—"it [is] a matter of social justice that there is an order of preference in the selection of classes of subjects (e.g., adults before children) and that some classes of potential subjects (e.g., the institutionalized mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain conditions." These conditions are (1) the subject may personally benefit from the research or (2) "the research is directly related to the specific conditions of the class involved."13 The principle of beneficence assumes a central role in justifying research using children. The National Commission interprets beneficence to require actions con-

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sistent with "two general rules (1) do not harm and (2) maximize possible benefits and minimize possible harms." On this view, the conditions under which children may be enrolled as research subjects is expressed through the use of such standards as the research risk being commensurate with the child's everyday life experience and as presenting no greater than minimal risk.14 The "Everyday Experience" Standard. Parents typically make day-to-day decisions concerning their child's medical treatment. The National Commission applies this discretionary authority of the parent to "therapeutic" research regardless of the absolute level of risk, provided that the risk is justified by the anticipated benefit to the child and the relation of anticipated benefit and risk is at least as favorable as available alternative approaches. In fact, IRBs are explicitly advised to "evaluate [therapeutic] research protocols in the same way that comparable decisions are made in clinical practice."15 Thus, for research which may directly benefit a child, the acceptability of risk is left to the discretion of the parent provided that an IRB believes that the risks and benefits of the research project are comparable to other available options—a condition that has been referred to as "clinical equipoise."16 Under such circumstances, the assent of the child and/ or the permission of the parent are sufficient for participation in the research.17 The National Commission extends the scope of parental authority into research that offers no benefit to the child by comparing the child's research experiences to those that are normally encountered apart from being a research subject. Parents have the responsibility and authority "to choose activities and to define a manner of life for their children." The National Commission asserts, that "many of the experiences which parents generally allow to their children are somewhat risky and cannot be said, without forcing the case, to involve particular benefits." Consequently, "when risks entailed in research are equivalent to normal risks of childhood, parents may properly permit these risks."18 The National Commission assumes that parental discretion properly operates to balance the risks and benefits of everyday life. Nevertheless, the question of whether the risks and benefits of participating in research are similar to a child's nonresearch experience is not left up to the sole discretion of a child's parents, apart from the limited situation in which the child may directly benefit from the research. With a definition of "minimal risk," the National Commission seeks to create a research environment which resembles this everyday context and thus to specify the limits of parental authority in permitting a child to participate in nonbeneficial research. "Minimal risk" is defined as "the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical or psychological examination, of healthy children."19 Thus, the definition of "minimal risk" specifies the conditions under which parents may appropriately allow a child to participate in any activity. In effect, the scope of parental authority is extended to cover a child's participation in

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nonbeneficial research if the risks are reasonably commensurate with those of the child's nonresearch life.20 In doing so, the National Commission set up two further problems: first, should the risk that a child is exposed to vary depending upon their particular life experience, and, second, does a parent have the authority to expose a child to any increased risk when there is no hope for benefit for that particular child. The "Minimal Risk" Standard. The National Commission introduced the concept of "minimal risk" in an attempt to provide a boundary condition that serves to limit parental discretion to permit a child's research participation. In effect, before allowing a parent to permit a child's participation, an IRB is to determine the extent to which the research presented a range of risks and benefits commensurate with that child's situation. Recall that the federal regulations define "minimal risk" as "the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests."21 Note that this definition omits the phrase "of healthy children" that is found in the National Commission's Report, creating an ambiguity in that the risks of research may be indexed to the "ordinary" experience of sick children rather than healthy children.22 The National Commission suggested four perspectives which need to be considered in estimating the allowable risk: common-sense, the investigators' experience, statistical information, and the situation of the proposed subjects. This last perspective also raises the possibility of indexing allowable risk to the actual risks experienced by a particular child, and does not indicate whether the risks should be evaluated from an adult's perspective or from a child's perspective.23 The National Commission's decision to permit nonbeneficial research involving greater than minimal risk if the research investigated a child's "disorder or condition" presented the most controversy. The majority argument in favor of allowing children to participate in nonbeneficial research that presents greater than minimal risk was largely pragmatic. The National Commission was "impressed by reported examples of diagnostic, therapeutic, and preventive measures that might well have been derived from research involving risk that, while minor, would be considered more than minimal."24 Given the potential benefit to others, the National Commission thought it was reasonable to allow a parent to permit a child to participate in nonbeneficial research that presented more than a minimal risk. Nevertheless, the National Commission was unwilling to extend this parental authority beyond what was called a "minor increase" over minimal risk.25 One dissenting commissioner, Robert Turtle, characterized the majority argument as follows: first, sick children are subject to unique risks and experiences; second, added research "risks [should be] similar to the risks and experiences familiar to [sick] children"; finally, added research risks are normal for these chil-

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dren and thus should be permitted. The child's illness does not warrant additional protections, but rather is felt to be an appropriate difference on which to base exposure to greater than minimal risk.26 Against this majority view, Turtle argued that children who are exposed to greater risks due to their condition or treatment "cannot ethically be assumed to qualify for additional risk."27 In his estimate, such an argument perverts the anchoring of "minimal risk" to the "ordinary everyday risks of childhood." The result will be to direct "researchers to involve more sick children as research subjects" in greater than minimal risk research, thus ignoring aggregate risks and placing the burden of research on the sick child "in clear violation of [the] principle of justice."28 The Scope of Parental Authority. Paul Ramsey was a prominent critic of the National Commission's decision to allow a parent to enroll a child in nonbeneficial research that presented even a minor increase over minimal risk. According to Ramsey, for a parent to allow a child to undergo any risk for the sake of another person was "a violation of the nature and meaning of the responsibilities of parenthood."29 For a parent to permit such nonbeneficial research, "a need or interest on the part of the child-subjects must be discovered if substituted consent has moral warrant. Without that, or without sufficiently competent supplementary consent on the part of the subject accepting the risk, the responsibility of parenthood would be flawed or deflected from its primary role."30 Ramsey later picks up on the suggestion of William Bartholome that participation in research can be "an opportunity for moral growth."31 Accordingly, a parent may chose to permit a child to participate in nonbeneficial research yet remain faithful to the responsibility of parenthood out of a concern for a child's "moral education." Ramsey, however, remains concerned that we clarify the acceptable level of risk.32 Faithfulness to the covenant between parent and child requires that permission for the child to be involved in research be grounded in "some medical interest for a particular child, or in the moral nurture of the child or capacity in the child to give supplementary consent."33 The Assent of the Child. Bartholome argues that participation in nonbeneficial research, while not obligatory, can be one such opportunity that parents could select so that a child may "become sensitive to moral obligations and develop a disposition toward choosing that which is good."34 For this to occur, the experience would need to be one of which the child-subject was aware and had general understanding—thus precluding children under the age of 5 to 7 years from such participation. He concludes that a child could participate given his or her "consent" based on an age-appropriate level of "awareness and understanding." Nevertheless, Bartholome restricts the involvement of a child in nonbeneficial protocols to those which involve "no discernible risk or significant discomfort."35

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The National Commission felt that Bartholome's approach was too restrictive for it allows only those nontherapeutic research projects which provide "moral benefit to the child" for his or her voluntary participation. However, the National Commission adopted the language of parental permission, rather than consent, and the child's assent or dissent, as part of the informed consent process leading up to a child's participation in research.36 The concepts of permission and assent apply the principle of respect for persons to children. Together, the provisions for parental permission and child assent show "respect for the general prerogatives of parents in protecting the health and safety of their children and respect for the maturing autonomy of the child."37 The federal regulations, based on the National Commission's Report, requires both parental permission and child assent except under some clearly defined limits.38 Assent is defined as the child's "affirmative agreement to participate in research."39 In the adult context, the analogous requirement for voluntary informed consent may over protect certain classes of human subjects, such as those who are unable to provide informed consent yet may benefit from a research intervention. In the pediatric context, the requirement for assent does not run the risk of over protection in the therapeutic context as the child's assent may be waived. However, as discussed above, the regulations assume that parental permission (with or without child assent) is an insufficient protection against inappropriate research risks. Case study: The human growth hormone trial

The use of human growth hormone (hGH) for treating children with extreme short stature not due to endogenous growth hormone deficiency has created much controversy over the last decade.40 The deliberations of the NIH review committee, convened to review this study, illustrate the complexity of assessing and balancing benefit with respect to risk. Even if the acceptable risk is indexed to the everyday experience of short children, rather than to the healthy "average height" population, the committee clearly felt that the physical and psychological risks of the study were greater than minimal. However, "only one member of the committee argued that the risks and burdens from the short stature protocol exceeded more than a minor increase over minimal risks because it exposed children in the placebo arm to unwarranted discomfort, inconvenience, and psychological risk."41 This judgment, if accepted by the committee, would preclude approval unless the committee decided that the study holds out the prospect of direct benefit for the individual subject. In effect, a decision that the study may offer some direct benefit to the child would finesse any substantive differences over "minimal risk" as long as the risk to benefit ratio was favorable—thus shifting from an absolute to a relative determination of acceptable risk. Does the short stature protocol offer the prospect of direct benefit for the individual subject since children enrolled in the control group will receive placebo injections? Employing a postrandomization analysis of benefit, the University of

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Nebraska IRB decided that the placebo group did not directly benefit either on the basis of a placebo response or on the four-in-five chance of being assigned to the treatment group.42 The NIH review committee favored a prerandomization analysis for two reasons. First, potential subjects consider their prospects of benefit prior to randomization. Second, assuming clinical equipoise, a postrandomization analysis requires an IRB to prejudge what is precisely at stake in the study—that is, which arm of the study offers more benefit. Regardless, a majority of the NIH review committee felt that the protocol benefited each individual subject regardless of a pre- or postrandomization analysis. The benefits cited for the placebo group included access to quality medical care, the pride of participation, and the benefit of knowing as parents how to treat their future child who is more likely to have short stature as well. However, only a minority of the NIH review committee felt that the risks for both the placebo and treatment groups were justified by the anticipated benefit.43 The report of the NIH review committee has come under criticism since its release in 1992. One area of criticism is the committee's balancing of risks and benefits. Gladys White expresses dismay at balancing the risks associated with multiple injections and venipunctures, with the benefit of good health care or the "pride" of participation. She also criticizes the assessment of direct benefit as including knowledge that may be useful as a parent. "This kind of delayed benefit—one that a subject might encounter in a future role—cannot be included in a reasonable calculation of ri sks and benefits for the purpose of deciding whether it is acceptable to enroll a child in a research study."44 A more fundamental criticism is directed at the assumption that children with short stature are suffering from a disease; rather, the suffering "results from unjustified social prejudice" and the failure to adjust the design characteristics of "engineered products."45 If children with extremely short stature are viewed as healthy, but short, the research could not be approved given the committee's unanimous opinion that the interventions presented greater than minimal risk. The decision of the NIH review committee extends the federal regulations to create "a precedent for approving greater than minimal risk research with healthy children in order to study any condition researchers or clinicians would like to be able to modify."46 The short stature protocol serves as an example of the type of research that many believe should be possible under the federal regulations. In light of the above criticism, how may we permit greater than minimal risk research with healthy children that avoids controversial estimates of minimal risk or expanding definitions of a condition or disorder? One approach would be to place greater reliance on the informed and voluntary assent of the child-subject as a necessary condition for participation in greater than minimal risk research. The NIH review committee recognized that an understanding of "the children's experiences" would be helpful in "judging whether placebo injections constitute more than a minor increase over minimal risk."47

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FUTURE TRENDS Determining Acceptable Risk

One approach to expanding the range of pediatric research that can be performed under current federal regulations focuses on clarifying the interpretation of the standard of minimal risk. Loretta Kopelman argues that indexing minimal risk to the risk of ordinary life is problematic for it may be interpreted in one of three ways. Minimal risk may be "defined as the probability and magnitude of harm determined by estimating: (A) all the risks ordinary people encounter, or (B) the risks all people ordinarily encounter, or (C) the minimal risks all ordinary people ordinarily encounter."48 The first interpretation would allow studies that present more than minimal risk given that ordinary people may at times engage in activities that have significant risk—an argument that the National Commission cited in support of parental permission for children being subject to research involving a minor increase over minimal risk. The second interpretation implies that "we know the nature, probability, and magnitude of these everyday hazards well enough that they could serve as a baseline to estimate research risks for children." The third interpretation simply reduces the definition to a "useless tautology." The indexing of risks to those encountered during routine physical or psychological examinations or tests is equally problematic, for "it does not rule out what is frequently as great a worry in determining risk; namely, the invasion of privacy, breach of confidentiality, labeling, and stigmatization." Citing a study which "found considerable differences [among pediatrics department chairs and pediatric research center directors] on estimates about whether the procedures such as venipuncture, arterial puncture, and gastric and intestinal intubation were regarded as risky," Kopelman concludes that the apparent consensus that children may participate in nontherapeutic research "if the study is not too risky is illusory if we mean different things by "not too risky."49 The traditional model of risk assessment implies that an IRB, serving as an expert, identifies and quantifies risk while the parent and/or child simply evaluates risk. Analyzing the process of risk assessment, Eric Meslin argues that "subjective factors influence the entire risk assessment procedure, not just in the judgment of the risk's acceptability." Consequently, research subjects should participate in risk assessment rather than simply respond to the disclosure of risk information.50 Pediatric risk assessment involves more than differences in physiology and disease susceptibility and should include "psychological issues [which] vary both with the progress of development and with environmental circumstances."51 Bartholome applauds this emerging shift towards "the experience of the childsubject in discussions of risk assessment, rather than on attempting to develop objective measures of physical harm."52 That is, instead of attempting to quantitatively link the term "minimal risk" to "ordinary" life, the term should be an-

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chored so as to inform our categorical judgments about the risks of the research as experienced by the child. Bartholome provides a compelling example of the difference in the experience of an external genital examination between a 2 monthold baby girl compared to a 13 year-old girl. Bartholome concludes that "shifting the focus of the assessment from the nature of the intervention and measurable harms that may result to that of assessment of the experience of the child-subject can dramatically change the assessment of what constitutes minimal risk."53 Freedman and his colleagues argue that "permitting some small risk that falls below a specified threshold" is necessary in order to permit "incompetent persons to participate in clinical research" given the uncertainty that is endemic to clinical research. The authors agree with Kopelman in that "if these thresholds are quantitative measures, verbal surrogates for numbers expressing the probability and magnitude of potential harms of everyday life, the question [of defining a critical threshold of allowable research risk] is unanswerable."54 As an alternative, they suggest that an IRB should take the position of a parent in determining the acceptability of risk prior to the parent being involved.55 Here, "a judgment anchored to the risks of everyday life, whether arrived at by parent or IRB, must be made relative to the child's actual situation."56 This "principle of commensurate risks" therefore permits "that research risk for ill children may exceed that imposed upon their healthy counterparts." Thus, "the committee, acting in loco parentis, will need to debate whether the demarcated research intervention is similar to a common experience of this child, and whether the incremental research risks are similar to the risks this child or others like him runs on a routine basis."57 Freedman and colleagues make two assumptions that are problematic: (1) that minimal risk should be indexed to the daily experience of the child who is to be entered in the research; and (2) that an IRB should do no more than approach a research proposal from the perspective of a parent in evaluating acceptable risk. In so doing they ignore the lessons of Willowbrook. Remember that Krugman enrolled children in the Willowbrook studies only with parental permission. The current federal regulations do not preclude potentially beneficial research on institutionalized children given parental permission, provided the risk is justified by the anticipated benefit. As a matter of fact, a mild infection under carefully controlled circumstances may well have been beneficial when compared to the alternative of the wild-type infection, especially in the early stages of the research prior to the development of hepatitis immune globulin. It is likely that the risk to the children who were the subjects of Krugman's research was equal to or perhaps less than the risk of living in the crowded, unsanitary conditions of the general wards. If the research was judged to be nonbeneficial, a child at Willowbrook may be excluded given the inability to assent rather than an unacceptable risk if that risk was indexed to the situation of the institutionalized child. The error is to blur the distinction between social deprivation and biological conditions and then index the regulatory standard of

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no more than minimal risk to the actual situation of the sick child, rather than a healthy child. As Kopelman concludes, "It is unacceptable to place dependent persons in situations where the risk to them is increased and then use that increased risk as reason for redefining what constitutes a minimal risk to them."58 The Assent of the Child

The definition of assent in the federal regulations provides little guidance as to the operational meaning of assent. Although never incorporated into federal regulations, the National Commission had expanded on the description of assent in their report on Research Involving Those Institutionalized as Mentally Infirm. "The standard for "assent" requires that the subject know that procedures will be performed in the research, choose freely to undergo those procedures, communicate this choice unambiguously, and be aware that subjects may withdraw from participation."59 Bartholome suggests four "elements of assent" understood from the child's perspective. First, the investigator should help the child achieve a "developmentally appropriate" understanding of "the nature of her condition." Second, "the investigator must disclose to the child-subject the nature of the proposed intervention and what she is likely to experience in undergoing it." Third, the investigator should assess "the child's understanding of the information provided and the factors influencing how she is evaluating the situation." Finally, the investigator should solicit "the child's expression of willingness to accept the proposed intervention."60 Bartholome expresses disappointment that the National Commission's recommendation to respect the dissent of the child was not incorporated into the federal regulations except indirectly—that is, by the fact that the absence of dissent should not be construed as assent.61 The American Academy of Pediatrics (AAP) supports the importance of a child's assent to participate in research, and specifies that assent "should usually be obtained from any child with the intellectual age of 7 years or more."62 The AAP advocates extending the language of parental permission (rather than consent) and the assent of the child into the therapeutic arena, noting that the doctrine of informed consent has only limited direct application in pediatrics. Echoing the words of the National Commission, the AAP points out that the doctrine of informed consent cannot be applied to pediatric patients because (1) consent is something that a person can do only for him or herself, and (2) pediatricians should respond to the needs of a minor patient independently from parental desires or expressed wishes. The claim is that we have a moral obligation to obtain parental permission and assent of the child in all situations when the child is capable of assent. In situations in which both permission and assent are not forthcoming, there remain disagreements as to how to proceed; nevertheless, there is agreement over this central moral claim as prima facie binding.63

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Revision of the Federal Regulations The current federal regulations concerning research with children restrict the acceptable level of risk based on whether the child may benefit from the research. The level of acceptable research risk is anchored to that risk associated with a child's everyday life as expressed by the concept of minimal risk. However, the omission of the phrase "of a healthy child" from the definition of minimal risk contributes to an ambiguity as to whether acceptable risk should be indexed to a child's own experience and thus potentially increase the risk to which a child is exposed. The comparability of the research experience to the actual or expected experience of the child was intended to assist, not with the indexing of acceptable risk, but with the child's ability to comprehend and assent to the research procedures.64 The unintended result of this stratification according to risk is that more than minimal risk research is limited to other than healthy children, thus shifting the burden (and perhaps the benefit) of research to sick children. As the degree of acceptable risk is linked to informed consent in the adult setting, the question is whether the burdens and benefits of research can be more appropriately distributed in pediatric research through affirming the child's ability and privilege to assent. Should we allow greater-than-minimal risk research on healthy children given their voluntary and informed assent? The NIH committee that reviewed the human growth hormone trials expressed concern over the accuracy of the consent and assent forms as well as the assent process. The 1992 report supported renewing a child's assent on an annual basis so that "the child's accumulated experience will permit an increasingly more informed assent decision."65 Unfortunately, few empirical data are available about the adequacy of these procedures, the experience of the children, the presence or absence of subtle coercion from the child's perspective, the relationship with the "assent auditor," and so forth. Carol Tauer concluded her critique of the NIH Committee report with an appeal to revise the federal regulations to allow for the assumption of greater than minimal risk given an older child's assent to participate in research. She explicitly links the child's assent to the relaxation of current restrictions on research risk: "If minors are able to understand and process crucial information as an average adult would, then their assent could make it ethically acceptable for them to participate in placebo studies where the control group undergoes unpleasant but not harmful interventions."66 Gidding and colleagues effect such a policy through a creative stratification of the concept of minimal risk. As a rule, allowable risk can increase as the child's ability to reason and participate in the informed process develops.67 Consider research on tilt-table testing, where the subject is strapped on to a table and tilted to a predetermined angle in order to determine any predisposition to fainting under

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the conditions of the test. The diagnostic value of the test is limited without knowing what the false positive rate is, that is, how many healthy children who do not have a history of fainting would faint during the test. To answer this question, a study of healthy adolescent subjects was approved by an IRB with the explicit requirement for voluntary and informed assent from the children. As it turned out, one of the first ten subjects suffered a prolonged asystole during the test—a complication which resolved as soon as the table was returned to the horizontal position.68 The risk of asystole, though remote, was known prior to the study. As children are not normally placed on tilt tables, it is hard to argue that the risk is commensurate with ordinary life; however, there are many other risks that children are exposed to that can be considered comparable. Linking the acceptable risk to assent allowed the study to proceed, resulting in valuable knowledge. Subsequent confirmation of the rate of false positive tests may now be more safely performed in younger children as the risk in adolescent subjects has been minimized through serial testing. The following changes to the federal regulations governing research using children are suggested. First, the definition of minimal risk should be clearly indexed to the everyday experience of healthy children. Second, the requirements for assent should be strengthened by specifying an age (7 years) above which assent should be required, by creating an operational definition of assent, and by requiring that a child's dissent and lack of assent should be respected unless a waiver of assent is appropriate. Third, the level of allowable risk should be linked to the assent of the child. Finally, for children not capable of assent, parental permission can suffice for a child to participate in greater than minimal risk research provided that the research has been reviewed and approved by a representative panel of older children and their parents who are members of the intended research population.

CONCLUSIONS

The National Institutes of Health (NIH) issued a policy in March 1998 encouraging the inclusion of children in clinical research.69 The basis for this policy is similar to that which led to the mandate to include women and minorities in clinical research. Considerations of justice require an equitable distribution across socioeconomic, gender, racial, ethnic, and age groups of the benefits and burdens of participating in clinical research unless the scientific design of the protocol requires the selection of specific populations. The AAP asserts that "there is a moral imperative to formally study drugs in children so that they can enjoy equal access to existing as well as new therapeutic agents."70 The lack of pediatric clinical drug trials results in more children being placed at risk while reducing the opportunity to collect data that may contribute to understanding the risks and benefits.

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The FDA recently drafted a Proposed Rule which seeks to address this problem by "requiring that manufacturers of a limited class of new drugs and new biological products provide sufficient data and information to support directions for pediatric use for the claimed indications, before or soon after approval." Intended for products which represent a "meaningful therapeutic benefit" or would find wide pediatric use, the Proposed Rule does not address the issues of acceptable risk and assent that may impede appropriate inclusion of children in this research.71 Nevertheless the Proposed Rule, along with the NIH Policy on the Inclusion of Children, represent important and necessary steps in beginning to address the underrepresentation of children in clinical research. It would be unfortunate if increased awareness of past abuses of children who were enrolled as research subjects leads to further restrictions on the allowable risk to which a child may be exposed. This chapter has argued that such an approach—that is, restricting the acceptable risks in an attempt to protect a child— may contribute to an unjust distribution of the burdens and benefits of research. One may achieve enhanced protection while at the same time expand the group of children who share the burdens and benefits of research participation, not through further limits on allowable risk on the one hand or weakening the requirement for informed consent on the other hand, but through strengthening the child's permissibility to assent. We need to explore through careful research the capability and limitations of children to understand and agree to experience risks as part of a research project. A fair distribution of the burdens and benefits of research may be achieved in the pediatric setting through allowing the voluntary and informed assent of a child to influence the risk restrictions placed on a child's participation. The child's assent, especially that of healthy children, would allow an assumption of risk that may currently be considered more than a minor increase over minimal risk. Minimal risk should be indexed to the experience of a healthy child, thus establishing the same uniform standard of risk for all children. Finally, for children not capable of assent, parental permission may be sufficient to allow for a child's enrollment in greater-than-minimal risk research provided that the research has been reviewed and approved by a panel of older children and parents who are representative of the intended subject population.

NOTES 1. Food and Drug Administration. Proposed Rule: Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients, August 13, 1997. 2. Ralph Kauffman, "Off-Label Drug Use and FDA Review of Supplemental Drug Applications," Testimony by the American Academy of Pediatrics before the Subcommittee on Human Resources and Intergovernmental Relations, Government Reform and Oversight Committee, U.S. House of Representatives, September 12, 1996.

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3. For the purposes of this chapter, children are defined as "persons who have not attained the legal age of consent to treatments or procedures involved in the research." See 45 CFR 46.402(a). 4. Benjamin Freedman, Abraham Fuks, and Charles Weijer, "In Loco Parentis: Minimal Risk as an Ethical Threshold for Research upon Children," Hastings Center Report 23(2): 13-19, 1993. 5. Saul Krugman, "The Willowbrook Hepatitis Studies Revisited: Ethical Aspects," Reviews of Infectious Diseases 8(1): 157-162; 1986. 6. Paul Ramsey, The Patient as Person: Explorations in Medical Ethics (New Haven: Yale University Press, 1970), pp. 41, 48^49, 51, 54. 7. Ibid., p. 49. 8. David J. Rothman. "Were Tuskegee & Willowbrook 'Studies in Nature' ?" Hastings Center Report 12(2):5-7; 1982. 9. Advisory Committee on Human Radiation Experiments, Final Report (Washington, DC: U.S. Government Printing Office, 1995), pp. 321, 342-345, 347. 10. John Rawls,A Theory of Justice (Cambridge, MA: Harvard University Press, 1971). 11. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Report and Recommendations: Research Involving Children (Washington, DC: DHEW Publication No. 77-0004, 1977). Hereafter cited as Research Involving Children. 12. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Beltnont Report: Ethical Principles and Guidelines for the Protection of Human Subjects, Federal Register Document 79-12065, April 18, 1979. 13. Ibid., pp. 7-8. 14. Belmont Report, pp. 5, 7-8. See also Research Involving Children, pp. 123-144. 15. Research Involving Children, pp. 5-7. See also 45 CFR 46.405. 16. Benjamin Freedman. "Equipoise and The Ethics of Clinical Research," NEJM 317(3):141-145; 1987. 17. 45 CFR 46.405. 18. Research Involving Children, p. 137. 19. Belmont Report, p. xx. 20. Research Involving Children, p. 9; See also 45 CFR 46.406(b). 21. 45CFR46.102(i). 22. Research Involving Children, p. xx. 23. Ibid., pp. 8-9. 24. Ibid., pp. 126-127. The National Commission also noted that "parental authority routinely covers a child's participation in many activities [such as skiing and contact sports] in which risk is more than minimal, and yet benefit is questionable." 25. Research Involving Children, pp. 7-9; See also 45 CFR 46.404(a). 26. Ibid., pp. 147-148. 27. Ibid., p. 148. 28. Ibid. 29. Ramsey, The Patient as Person, pp. 25, 36, 39. 30. Paul Ramsey, "Ethical Dimensions of Experimental Research on Children" in Jan Van Eys, editor, Research on Children: Medical Imperatives, Ethical Quandaries, and Legal Constraints, (Baltimore: University Park Press, 1978), pp. 61-64. 31. Ramsey, "Ethical Dimensions," pp. 64-67; William G. Bartholome, "The Ethics of Non-Therapeutic Clinical Research on Children," in The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Appendix to Re-

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port and Recommendations: Research Involving Children (Washington, DC: DHEW Publication No. (OS) 77-0005, 1977), pp. 3-17. 32. Bartholome, "The Ethics of Non-Therapeutic Clinical Research" pp. 3-20. Ramsey thereby rejects Bartholome's proposal to permit "no greater risk or discomfort than would be encountered in family life" as ambiguous. 33. Ramsey, "Ethical Dimensions," pp. 64, 66-67. 34. Bartholome, "The Ethics of Non-Therapeutic Clinical Research," pp. 3-17. 35. Ibid., pp. 3-16-3-18, 3-20. 36. Research Involving Children, pp. 12-17, 113. 37. Ibid., p. 142. 38. Subpart D (45 CFR 406.404 through 407) requires that "adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in Section 46.408." 39. 45 CFR 46.402(b) 40. In 1989, subject enrollment began for a protocol approved by the National Institute of Child Health and Development (NICHD) using recombinant hGH in pre-pubertal children with extreme short stature and normal hGH secretion. An IRB at the University of Nebraska rejected a similar protocol aimed at improving growth in girls with Turner Syndrome given the inclusion of a placebo control group. The Foundation for Economic Trends filed suit to stop the NICHD study in February 1990. In response, the Director of the NIH convened an ad hoc committee charged with reviewing the two research protocols—the effect of hGH treatment on the stature of girls with Turner Syndrome, and the effect of hGH treatment on children with extreme short stature not due to endogenous growth hormone deficiency (the so-called "short stature" protocol). The committee issued a report in October 1992 supporting the trials and in May of 1993 subject enrollment resumed. The Foundation for Economic Trends and the Physicians Committee for Responsible Medicine again filed suit in June 1993 to stop the study, claiming that the study posed risks to the children that were clearly more than minimal, failed to hold out the prospect of direct benefit to the subjects, and was studying a condition that was not clearly a disease, that is, short stature. The "short stature" protocol is a randomized, double-blind, placebo-controlled study with the end-point of an increase in adult height. To qualify for the study, children needed to be 2.25 standard deviations below the mean of either height for age or predicted adult height. Eligible subjects needed to be physiologically capable of further growth, have normal HGH levels, and be between the ages of 9 to 14 for girls and 10 to 15 for boys. The study involved subcutaneous injections of either hGH or placebo three times a week for up to 7 years, with physical, radiological, and psychological testing at regular intervals. See National Institutes of Health, Report of the NIH Human Growth Hormone Protocol Review Committee, October 2,1992. Hereafter referred to as NIH Report; Ernest D. Prentice, Dean L. Antonson, Andrew Jameton et al., "Can Children Be Enrolled in a Placebo-Controlled Randomized Clinical Trial of Synthetic Growth Hormone?," 7/JB 11(1):6-10; 1989; Gladys B. White, "Human Growth Hormone: The Dilemma of Expanded Use in Children," Kennedy Institute of Ethics Journal 3(4):401-409; 1993; and Carol A. Tauer. "The NIH Trials of Growth Hormone for Short Stature," IRB 16(3):l-9; 1994. 41. NIH Report, p. 9. 42. Prentice, "Can Children Be Enrolled?" p. 7. 43. NIH Report, pp. 11-13; also see, Peter C. Williams, "Ethical Principles in Federal Regulations: The Case of Children and Research Risks," Journal of Medicine and Philosophy 21(2):177-183; 1996. 44. White, "Human Growth Hormone," p. 405.

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45. Ibid., pp. 407-409. 46. Tauer, "The NIH Trials," p. 7. 47. NIH Report, p. 38. 48. Loretta M. Kopelman, "When is the Risk Minimal Enough for Children to be Research Subjects?" in Loretta M. Kopelman and John C. Moskop, editors, Children and Health Care: Moral and Social Issues (Boston: Kluwer Academic Publishers, 1989), p. 95. 49. Ibid., pp. 95-98; and Loretta M. Kopelman, "Children: III. Health-Care and Research Issues," in Warren T. Reich, editor, Encyclopedia of Bioethics (New York: Simon and Schuster Macmillan, 1995), p. 362. 50. Eric M. Meslin, "Philosophical Considerations about Risk and Risk Assessment in Medical Research," in Gideon Koren, editor, Textbook of Ethics in Pediatric Research (Malabar, PL: Krieger Publishing Company, 1993), pp. 50-52. 51. Esther H. Wender, "Assessment of Risk to Children," in Michael A. Grodin and Leonard H. Glantz, editors, Children as Research Subjects: Science, Ethics, and Law (New York: Oxford University Press, 1994), p. 181. 52. William Bartholome, "Ethical Issues in Pediatric Research," in Harold Y. Vanderpool, editor, The Ethics of Research Involving Human Subjects (Frederick, MD: University Publishing Group, 1996); p. 352. 53. Bartholome, "Ethical Issues in Pediatric Research," pp. 353-355. 54. Freedman, "In Loco Parentis," pp. 14-16. 55. Ibid., pp. 16-17. 56. Ibid., p. 17. 57. Ibid., pp. 17-18. 58. Kopelman, "When is the Risk Minimal Enough?" p. 91. 59. Bartholome, "Ethical Issues in Pediatric Research," p. 356. 60. Ibid., pp. 360-361. 61. Ibid., pp. 347, 356. Also see 45 CFR 46.402(b). 62. American Academy of Pediatrics (AAP) Committee on Drugs, "Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in the Pediatric Population," Pediatrics 95(2):290; 1995. 63. American Academy of Pediatrics Committee on Bioethics, "Informed Consent, Parental Permission, and Assent in Pediatric Practice," Pediatrics 95(2):314-317; 1995. 64. Research Involving children, pp. 8-9. 65. NIH Report, pp. 21, 30-32, 37. 66. Tauer, "The NIH Trials," p. 8. 67. Samuel S. Giddings, Donald Camp, Mary Helen Flanagan et al., "A policy regarding research in healthy children." Journal of Pediatrics 123(6):852-855; 1993. 68. David A. Lewis, Jane Zlotocha, Laura Henke et al., "Specificity of Head-Up Tilt Testing in Adolescents: Effect of Various Degrees of Tilt Challenge in Normal Control Subjects," Journal of the American College of Cardiology 30(4): 1057-60; 1997. 69. National Institutes of Health, "Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" NIH Guide. 26; March 6, 1998. 70. AAP Committee on Drugs "Guidelines," p. 287. 71. FDA Proposed Rule. August 13,1997: Summary, and section five, paragraphs B(4) andD.

5 GENDER AND RESEARCH Nancy Kass

It is curious that the inclusion of women in biomedical research should have become an issue of justice. Women are different from other subpopulations addressed in this volume: unlike minority populations, women comprise 51% of the population; unlike children and mentally disabled persons, women are competent adults; and unlike prisoners, women have no legal constraints on their autonomy. Women are legitimately a focus of concern about justice, however, for reasons that will be described and there have been increasing efforts to expose this area in recent years. National expert panels have been convened,1 individual commentators have argued for greater participation of for women,2 data have been collected on the extent to which women have been included in clinical research,3 and federal policy has changed in order to be more inclusive of women.4 This chapter will examine how justice in research is defined for women, why it is important for women, and what harm can ensue if justice is not served. Data on women's inclusion in research will also be examined. Three examples will be presented of research that has not been inclusive of women and, consequently, has harmed women's interests. How federal regulations have reflected and, more recently, decreased gender inequality in research will be discussed. Other factors that have contributed to differential treatment of men and women by the research establishment will be covered. Finally, areas for further work to ensure that justice is more fully served with regard to women will be proposed. 67

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DEFINING JUSTICE IN RESEARCH FOR WOMEN

Distributive justice requires that the benefits and burdens of research participation be fairly or equitably distributed. Defining equitable inclusion in research is difficult, however. It is more complex than ensuring that the proportion of women in studies reflects the proportion of women in the population as a whole. Equitable inclusion additionally requires that health problems which are prevalent in only one or the other gender are given the same attention, and when health problems affect both women and men, that gender analyses are conducted to examine whether disease mechanisms or drug effects differ by gender. Further, justice for women as a group requires that the health conditions of all women are addressed. Including only white women in research does not necessarily serve the interests of women of color, and including only middle-aged women does not further our understanding of the health problems of older women. Discerning whether, or in what ways, inequities in research participation have occurred and whether any harms have ensued also is a challenge. In the past, harm related to research was viewed narrowly as harm (usually physical) that could result from participating in a research study. For example, women often were excluded from participation because of concerns about harm to a potential fetus or future child. Now, harm related to research is viewed more broadly to also include the harms resulting from knowledge foregone or individual opportunities denied as a result of exclusion from research. When women are not included in biomedical research, they experience harm both individually and as a group. To the extent that research provides benefits to the individual who enrolls, women are denied those benefits. Individual benefits from research participation may be direct clinical benefit derived from research with diagnostic or therapeutic intent; or benefits may be nonclinical—or less directly clinical—such as closer monitoring of health problems, free study medications, or the provision of child care during clinic visits. According to Vanessa Merton, "outside clinical trials, it is unlikely that poor women will find expensive blood work-ups, MRIs, and CT scans... ."5 Patients with serious illnesses who participate in biomedical research also report that enrolling in research gives them hope.6 To the extent that women with serious illnesses are denied inclusaccess to participation, they may be denied this hope. Women as a group may also be harmed by exclusion. This is the case where a lack of scientific information prevents women's own health needs from being addressed, or addressed appropriately, when they present for medical care. While there is more similarity than dissimilarity between how men and women experience most health problems, there also are significant and relevant differences in how diseases manifest themselves in men and women, as well as differences in

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how men and women respond to treatments. Examples of these will be provided below. Determining the extent of inequities in research is challenging. First, there are no central registries of clinical studies, which makes it difficult to document systematically who has or has not been enrolled in trials. Second, the terminology used to describe what constitutes equitable inclusion varies (e.g., as described above, it may mean proportionate inclusion of both genders, study of genderspecific conditions, gender-based analyses of studies of men and women, etc.), so determining what "fair distribution" means is difficult. Nonetheless, several bodies and individuals have attempted to answer the question of whether there has been inequity in research with regard to women. A 1985 report of the U.S. PHS Task Force on Women's Health Issues concluded that "The historical lack of research focus on women's health concerns has compromised the quality of health information available to women as well as the health care they receive."7 The Task Force's report prompted the NIH to recommend in 1986 that funding applicants include women in their studies. In 1990, the Congressional General Accounting Office (GAO) analyzed the effectiveness of the NIH policy recommendation and concluded that women remained under represented in clinical research, prompting further policy changes. Finally, a report of the AMA concluded in 1991 that medical research on men is generalized to women "without sufficient evidence of applicability to women."8 Among the AMA's recommendations were that more research on women's health should be pursued, results of testing done solely on men should not be generalized to women without evidence of safety and effectiveness, and there should be increased numbers of women physicians in leadership roles of teaching, research, and practice to raise awareness of gender issues. Undoubtedly the most comprehensive review of gender equity in research was conducted by a panel convened by the Institute of Medicine (IOM).9 The panel's report includes an annotated compilation of reviews as well as the panel's own findings. In contrast to efforts described above, the panel concluded that it was not able to establish that gender inequity existed in the whole of past clinical research, but it did find evidence of inequity in research on AIDS and heart disease. Thus, these sorts of concerns raise questions about distributive justice. To the extent that analyses of the suggest past inequities, however, there also is a role, at least in the short term, for compensatory justice. This is because ultimately what is important is to have a fair distribution of clinical knowledge. To the extent that research participation historically has not been equitable with regard to gender, there is a need to give disproportionate attention to women's health needs. This will remain true until the knowledge available to guide clinical care with men and women is equitable. Once that an equitable level of clinical knowledge is achieved, compensatory justice is no longer relevant.10

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JUSTICE ACROSS TIME How Has Research Injustice Harmed the Interests of Women?

Examples in pharmacology, cardiovascular disease, and HIV/AIDS, illustrate ways in which justice has been interpreted and applied in the past with regard to women. The choice of these examples is deliberate—other examples would not suggest so conclusively that gender inequities have occurred. These examples document that previous policy and pervading norms allowed research in three areas of health to be marked by gender inequities, and yet to be little recognized as such until the last decade or so. Pharmacologic research

Until a 1993 change in the FDA policy (see below), women were excluded from most clinical trials, thereby limiting the ability to study differences in drug response by gender. Documenting this, Schmucker and Vessell systematically reviewed almost 2000 clinical trials published between 1969 and 1991 in two major pharmacology journals, and found that women were underrepresented. Their conclusion was based on an examination of the proportion of trials that excluded women altogether or that did not report the gender distribution of the test population.11 Further, among published studies that did report using male and female subjects, the majority did not report whether or not data were analyzed for gender differences. That the question of whether women and men metabolize drugs in a similar way has historically received little scientific attention is in many ways surprising, given that it has been well known that drug dosing often is related to the patient's weight (which typically is lower for women than for men). Moreover, as early as the 1930s, studies demonstrated that the duration of action of similar doses of drug were markedly different for male and female rats,12 Nonetheless, most adult drug dosing, for both men and women, continues to be based on a standard, male weight.13 Although this can be inappropriate for both men and women, greater numbers of women are likely to be harmed by the practice. In one systematic review, it was concluded that women "suffer proportionately more adverse drug reactions [than men], even when controlling for dose and number of drugs prescribed."14 Paul Skett, in perhaps the most comprehensive review on the subject of sex differences in drug metabolism, wrote that "sex differences can lead to sexdependent toxicity."15 In addition to considerations of body weight, metabolic rates on average are greater in men than in women. Although drug metabolism based on gender has been rarely studied, certain drugs that have been studied by gender demonstrate differences. Among these are nicotine, aspirin, and the anticoagulant heparin.16 Similarly, psychotropic medications have been studied predominantly in men but are prescribed more often to

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women. 17,18 The studies that do exist by gender, moreover, demonstrate that these drugs are metabolized differently by women than by men.19 Women tend to have higher levels of the drug in their blood than men when taking the same dose, the potency of drugs changes over the phases of a woman's menstrual cycle, and women are more likely to suffer adverse reactions such as hypothyroidism and tardive dyskinesia.20 Hormones affect how many drugs work. For example, hormones affect the therapeutic response of antiepileptic, antidiabetic, thyroid, and, as just described, psychotropic medications.21 Further evidence of the relationship between hormones and drug metabolism is that sexgender differences in drug dosing often disappear after women reach menopause.22 It is perhaps ironic that an early justification for excluding women from biomedical research was the presence of cyclical hormone changes that might complicate findings,23 since it is because of these hormones that the metabolism of drugs and response to treatments differs. Cardiovascular disease Large cardiovascular trials of risk factors or interventions have been conducted exclusively or predominantly with men,24 with particular exclusion of childbearing and older women.25 Examples are the Veterans Administration Cooperative Study, which showed the benefits of cardiac surgery in patients with angina;26 the Multiple Risk Factor Intervention Trial (MRFIT), a study of risk factor modification in preventing cardiac events;27 and the United States Physicians Study, sometimes referred to as the Physicians Health Study in which aspirin was demonstrated to be effective in preventing heart attacks.28 Increasing recent evidence suggests that the presentation and course of heart disease in men and women are different. Therefore, extrapolation of findings from research with men to recommendations for women—as until recently was the practice—is proving in many cases to be inappropriate. Women with heart disease more frequently have "silent" myocardial infarctions.29 Women also are typically much older than men when they first present with cardiovascular disease.30 Therefore, the lack of cardiovascular research with women has particularly harmed older women.31 Corroborating that research inequity in this area has occurred, an expert panel of the National Heart, Lung, and Blood Institute could not make a firm recommendation about whether lipid-lowering therapy in women and the elderly would be an effective preventive measure against coronary artery disease (as it is known to be for men) because insufficient research with these populations has been conducted.32 Marianne Legato, in her book on gender-specific clinical care, further cites that data do not exist to suggest whether beta-blockers or diuretics would be helpful in reducing the risk of coronary artery disease in women with hypertension.33 It also has been documented that, following an acute myocardial infarction, women experience a delay relative to men in emergency treatment34 and are half as likely to receive medications to manage their condition when they leave the hospital.35 Although

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speculative, it is plausible that the lack of research with women is related to the decrease in care received. Perhaps physicians are slower to suspect cardiovascular disease in women, having seen fewer descriptions of this in medical practice, texts, and the research literature, and less likely to be aware of appropriate treatments, since those, too, have rarely been described with women. In recent years, there has been significant improvement in the study of heart disease in women. One key example was the creation in 1991 of The Women's Health Initiative, a longitudinal study of "the major causes of death, disability, and frailty among middle-aged and older women, including cardiovascular disease, cancer, and osteoporosis."36 The study has three components: a 10 year epidemiologic surveillance study that includes several hundred thousand women; a randomized clinical trial; and a prevention/intervention trial. HIV disease

HIV disease serves as another illustration of research inequitygender inequity in research. The IOM panel and others37 concluded that women have been underrepresented in clinical and epidemiologic HIV research. History substantiates this claim. In 1987, all epidemiologic studies sponsored by the federal Centers for Disease Control and Prevention (CDC) and the NIH targeted women only to the extent that the research question concerned their likelihood of transmitting the virus through pregnancy or as prostitutes. By 1991,10 years after the first case of AIDS in men and in women had been reported to the CDC, there still were no large studies of the effect of HIV infection on women's health, despite increasing publicity about such inequities, and despite $80 million having been spent on a single study of the natural history of HIV in gay and bisexual men.38 Not until 1993 did a CDC-funded study of the natural history of HIV in women begin enrolling participants, and in 1994 women were first enrolled in a similar study sponsored by the NIH. The potential harms to women of these inequities have been documented extensively.39 Foremost among these was medical professionals' lack of awareness of the uniquely female manifestations of HIV infection, such that innumerable HIV-infected women who sought health care went undiagnosed and, therefore, untreated. For example, HIV-infected women often experience severe and persistent gynecologic infections that obviously make their manifestation of HIV disease different from that of men.40 One early study revealed that 34% of women attending an inner-city HIV clinic had an active gynecologic problem at their first visit.41 Now HIV-infected women are often first identified in a reproductive health care setting.42 And yet in the early years of the AIDS epidemic, many HIV-infected women presenting with recurring gynecologic infections went unsuspected and undiagnosed.43 Further, the lack of systematic data documenting how HIV disease affected women prevented the CDC from including female-specific manifestations of HIV in their AIDS case definition until 1993.44 Since social service

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benefits often are based on a diagnosis of AIDS,45 many HIV-infected women were denied the public benefits that HIV-infected men were receiving, ultimately because the necessary research data did not exist. The Impact of Federal Research Policies on the Inclusion of Women

In addition to general policies that affect research with human subjects, certain policies exist that apply specifically to women. Whether they apply in a particular situation depends on the federal agency funding or reviewing the research. Although the NIH and the FDA are part of the DHHS, each has specific policies that apply only to research that falls under its respective domain. Federal policies in the past have reflected and perpetuated the prevailing attitude that women of childbearing potential and certainly pregnant women should not be enrolled in clinical research. These policies have changed significantly in recent years to become more inclusive of women. NIH and FDA policies regarding nonpregnant women Research funded by the NIH not only is subject to the general human subjects regulations of the DHHS but also to the guidelines regarding the inclusion of women. As mentioned above, the first guidelines created by the NIH to address gender were in 1986. These guidelines encouraged applicants for extramural funding to include women in their studies and to provide a justification if women were not included. Among the many critiques concerning inadequate implementation, the GAO asserted in its 1991 evaluation that the NIH had not made applicants and reviewers aware of the guidelines, and there was little institutional enforcement.46 Further, in a spot review conducted by the GAO of 50 applications concerning medical conditions that affect both men and women, 20% provided no information on the gender of study participants, one-third stated that both men and women would be included but did not describe in what proportions, and studies that included only men did not provide rationales for that design. The GAO also observed that the NIH had no policy addressing the inclusion of women in intramural research. In response to the GAO report, the NIH created the Office of Research on Women's Health (ORWH) and issued more rigorous guidelines for women's inclusion in research. Included in the mandate of the ORWH was "to strengthen and enhance research related to ... conditions that affect women and to ensure that research conducted and supported by NIH adequately addresses issues regarding women's health; [and] to ensure that women are appropriately represented in biomedical and behavioral research studies supported by NIH."47 The 1991 guidelines required participation of both genders in all extramural research. Monitoring of investigators' compliance with this requirement was to occur through annual reports to the NIH of numbers of male and female study participants enrolled and targeted for enrollment.

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Strengthening these requirements further, the NIH Revitalization Act of 1993 legislatively mandated the existence of the ORWH. Congress also required the inclusion of specific provisions in NIH guidelines, e.g., for the inclusion of women and minorities in research,48 that the Director of NIH ensure that "women are included as subjects in each project of such research;"49 that guidelines determine "the circumstances under which the inclusion of women ... is inappropriate;"50 that Phase III trials be designed to allow valid subanalyses of intervention effect by gender and minority subgroups; and that cost not be a reason for noncompliance with these guidelines.51 Therefore, the inclusion of women in late stage clinical trials and all other types of NIH-sponsored human subjects research is now required by law. Guidelines incorporating these legislative mandates were issued in 1994. Privately funded research is subject to human subjects regulation only under certain circumstances.52 If an institution (e.g., an academic medical center) is covered by a Multiple Project Assurance (MPA), which most academic institutions are, then all of their human subjects research, not just that which is federally funded, must be conducted in accordance with federal policies. If clinical research is conducted by a private company in preparation for market approval for a new drug or device, then the research is subject to oversight from the FDA.53 Historically, requirements of the FDA concerning exclusion of women have been considerably more restrictive than those of DHHS in that, not only pregnant women, but all women of childbearing potential were excluded from most research. Guidelines to address the inclusion and exclusion of women were issued by the FDA in 1977, 1988, and 1993. The 1977 regulations reflected a concern that all drugs could be potentially teratogenic, and they therefore excluded women of childbearing potential from Phase I and early Phase II trials.54 Even women on oral or injectable contraceptives and women whose partners had had vasectomies were excluded from early drug trials.55 If reproductive studies had been conducted previously with animals (which occurred less than half the time), then women of childbearing potential could enroll in later Phase II and Phase III testing. Exceptions were made for women for whom the investigational drug might be life-saving. Women who did enroll in later stage testing were required to undergo a pregnancy test and contraceptive counseling. Revised guidelines were issued by the FDA in 1988. For the first time, these were not protectionist in nature but rather had the goal of increasing scientific knowledge related to women.56 The 1988 guidelines called for assessments in doseresponse by gender when women were enrolled in the studies. Initial evaluation of these guidelines, however, proved that fewer than half of the new drug applications provided such subanalyses.57 In 1993 the FDA lifted the earlier ban on the enrollment of women of childbearing potential in early phase research. In their new guidelines, the agency acknowledged that women can modify their own behavior to reduce fetal exposure (i.e., can be trusted to use contraceptives), and

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concluded that decisions about maternal and fetal risk are best left to "patients, local IRBs, and sponsors, with appropriate review and guidance by FDA."58 The guideline informed investigators that they are expected, although not mandated, to include women in their trials and are expected to do subanalyses by gender. Policies regarding pregnant women Both DHHS and FDA policies address research with pregnant women. Subpart B of the DHHS regulations states that pregnant women must be excluded from research unless "(1) the purpose of the activity is to meet the health needs of the mother, and the fetus will be placed at risk only to the minimum extent necessary to meet such needs, or (2) the risk to the fetus is minimal."59 The regulations define minimal risk to mean risk not greater than that "ordinarily encountered in daily life or routine physical examinations or psychological tests."60 Subpart B further requires the mother and father to be competent and for both to provide informed consent before the woman can participate in research, unless the research is exclusively to meet the health needs of the mother, the pregnancy resulted from rape, or the father cannot be found. The 1994 IOM panel recommended to the federal government that Subpart B be changed from a presumption of exclusion of pregnant women to a presumption of inclusion; in other words, investigators should be required to justify any exclusions of pregnant women. The majority of the panel recommended that pregnant women be excluded only when "an IRB finds and records its findings in writing that. .. there is no prospect of medical benefit to the pregnant woman and a risk of significant harm to potential offspring is known or can be plausibly inferred."61 As of this writing, changes to Subpart B of the DHHS regulations have been proposed and are under review. Further reaching changes have been suggested62 that would mandate that trials be designed for pregnant women for medical conditions that coexist with pregnancy. While the FDA in 1993 lifted the ban on the inclusion of women of childbearing potential in drug trials, they did not change the policy for pregnant women. According to FDA guidelines, pregnant women are excluded from Phase III trials unless the drag is intended to save the life of the pregnant woman or is intended for a condition of pregnancy. As of this writing, no changes in FDA policy regarding pregnant women have been proposed, although the FDA has held a workshop exploring the issue.63 Other Factors That Have Influenced Women's Participation

in Research

Although federal policy has limited the inclusion of pregnant women in most clinical research and women of childbearing potential in much pharmaceutical research, those policies themselves are a reflection of more broadly held attitudes and con-

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cerns with regard to women, which stem generally from an approach that views women primarily in terms of their reproductive capabilities. Consistent with this view are concerns about legal liability if harm to a fetus were to occur as a result of a woman's participation in research that has contributed to women's exclusion; and more broadly held societal expectations of women. Women as reproductive beings

The phrase "beyond reproduction," recently coined by Susan Wolf,64 is apt for a vision of justice in research with regard to gender. In the research arena, women have been viewed primarily in terms of their reproductive capabilities. As described by Tracy Johnson and Elizabeth Fee, women's health needs have been "subsumed under obstetrics and gynecology or addressed through maternal and child health programs."65 Further, research specifically related to reproduction has been conducted much more extensively with women than it has with men. Not surprisingly, therefore, contraceptive technology for women is far more advanced than contraceptive technology for men. Two simultaneous concerns have been used as justification for these restrictions on participation in research, both related to women's reproductive capacity: first, there may be fetal harm as a result of women's participation; and second, women's cyclical hormones and menstrual periods might interfere with the research. Liability concerns

A significant justification for research exclusion for women is the fear of legal liability and the role it plays in selection of subjects. Since the thalidomide and diethylstilbestrol (DBS) disasters of the 1960s and 1970s, in which women took a medication during pregnancy only to have their offspring suffer serious damage, physicians and the public at large became aware that medications taken during pregnancy can sometimes cross the placenta and cause damage to the developing fetus. This worry, although real but perhaps exaggerated in likelihood,66 has led manufacturers and investigators to fear legal action if any harm to the fetus or future child were to occur as a result of the woman's participation. This fear of liability contributes to the hesitation to enroll women of childbearing age, and particularly pregnant women, in biomedical research. This remains true, despite the fact that no cases have been decided that would address liability for fetal injury during research when the woman has provided valid informed consent.67 Unfortunately, it is impossible to predict the circumstances under which legal action might be brought, and it is impossible to predict the circumstances under which an investigator or manufacturer could be found liable for fetal injury. A more extensive discussion of these issues can be found elsewhere.68 The key point here is that the fear seems to prevent research from going forward when most analyses suggest that legal actions could be brought either for inclusion of women

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in research or for exclusion. Legal action from exclusion would be based on unfairness to pregnant women as a class69 or harm (dangerous side effects or lack of effectiveness) resulting from the use of a drug by women when the drug had never been tested with women.70 The broader influence of gender expectations

The notion of women as reproductive agents is integrally related to how women are viewed in the larger society. Despite tremendous advances legally and socially, there remain significant differences in societal expectations of men and women. Early in the feminist movement, "the personal is political" was a pervasive slogan. The inference behind this phrase was that structures that exist in our personal lives reflect and perpetuate the structures that exist more broadly in society. For there to be change in any arena (e.g., research), we must recognize and seek to change those unjust relationships that exist closer to home. According to Nancy Hartsock, "Stressing the links between the personal and the political led women to conclude that, first, a fundamental redefinition of the self was an integral part of action for political change; and second, that the changed consciousness and changed definition of the self could occur only in conjunction with a restructuring of the social relationships in which each person was involved."71 Susan Moller Okin, in a discussion of justice and gender, has written, "We live in a society that has over the years regarded the innate characteristic of sex as one of the clearest legitimizers of different rights and restrictions, both formal and informal."72 Okin faults contemporary theories of justice—theories that are "centrally concerned with whether, how, and why persons should be treated differently from one another"73— for failing to discuss the gender structure of families and its influence on other societal structures and expectations. "The best theorizing about justice is not good enough if it does n o t . . . include women and their points of view as fully as men and their points of view."74 That many theories of justice tend to be silent on the role of gender in shaping our societal understanding of what is fair makes it of little surprise that specific applications of justice, such as who should participate in research, might also have ignored gender. Indeed, women's experiences in the broader society often are seen as gendermediated, in contrast to those of men, which are seen as gender-neutral. Debra DeBruin writes that men are characterized as "the standard of what it is to be a person."75 Women, by contrast, are referred to specifically: "women doctors" instead of doctors; "lady cops" instead of cops. Building on the work of Iris Marion Young, DeBruin maintains that how our society views women is classic of societies in which there is oppression: "Oppressive societies take the dominant group's identity and experience to be, not the particular identity or experience of one group in society, but the universal identity and experience—that is, the norm."76 DeBruin calls this concept "false universalism," and argues that it results in women being invisible. While the term "man" is used supposedly with the intention of being

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gender-neutral or all inclusive, she reminds us that very few people on hearing "man" have an image of women. If women are, in our subconscious minds, somewhat invisible, then it should not be a surprise that a national research agenda would be slow to include questions specific to women, believing that research with men answers health related questions for all of us. As a further example that justice in research regarding gender is consistent with justice regarding gender in other contexts, brief mention will be provided here of women in the health care arena. This context, too, makes evident that men and women are not treated identically or comparably. Many studies have shown that when male and female patients present with the same symptoms, they are provided different treatment. Women are likely to be treated less aggressively than appropriate when they present with chest pain or a heart attack, as described earlier; whereas women may be treated very aggressively for gynecological procedures, such as hysterectomy and Caesarean section.77 Significant in the advancement of justice in the health care system was the women's health movement.78 Spurred by the larger women's movement, women in the 1970s took interest in knowing their bodies, "regaining control" of femaleoriented procedures such as abortion and childbirth, and serving as patient advocates for other women. Critiques were offered of the traditional doctor-patient relationship, and women formed alternative, less hierarchical models of health care delivery, prompting the creation of feminist women's health centers in many cities throughout the country. Tremendous changes in the health care industry were achieved through this political movement, including greater visibility of women's health issues. It was understandable, then, that calls for a women's research agenda shortly followed.

FUTURE TRENDS

The first wave of addressing justice concerns in research with regard to gender has occurred. Federal policy now requires women's inclusion in much of federally funded research, and the NIH Office of Research on Women's Health is in place to ensure that the NIH research portfolio as a whole is attentive to the needs of women. Considerable thought and advocacy precipitated these changes, and, although time will tell the extent to which they improve women's standing in research, they are likely to be effective, and they are to be celebrated. At this point, the second wave of justice for women in research must occur. While women as a whole are included in research more than ever before, certain subgroups of women have seen little change. The next wave must be to address the research needs of these other women. This last section will describe this task, as well as other mechanisms to monitor and sustain the changes that already have been achieved.

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Pregnant Women An area in which federal policy prevents women from gaining benefits of research is research with pregnant women. With the exception of conditions specific to pregnancy, federal regulations still prohibit the inclusion of pregnant women in most clinical studies. It is understandable that a protectionist philosophy toward pregnant women would exist. As mentioned earlier, the thalidomide and DBS catastrophes of recent decades had tremendous influence on health care providers, researchers, and women. Consequently, fears about teratogenicity have caused practitioners to avoid giving pregnant women medications in the clinical setting at great costs,79 and there is great reluctance to include pregnant women in clinical research. One study found that 70% of AIDS clinical studies excluded pregnant women, citing potential teratogenicity as the primary reason.80 This is particularly notable since AIDS is a life threatening condition, and federal regulations permit the inclusion of pregnant women with life threatening conditions when the study is intended to improve their health. At the same time, pregnant women, like women generally, are harmed both individually and as a group by exclusionary policies. Individual pregnant women are harmed by exclusion when a drug that would be of benefit to them is available only through research, or when nonclinical benefits are available only through participation. Pregnant women as a group are harmed because knowledge to guide their clinical care lags behind knowledge to guide the clinical management of nonpregnant persons. There are almost no trials of the best medications to use during pregnancy in terms of safety and effectiveness, proper dosing, and other considerations of disease management. While it is well documented that weight, metabolism, and absorption all change during pregnancy, how this affects drug safety and effectiveness remains mostly unknown. This is particularly of concern given that 70%-80% of pregnant women need some form of prescription therapy during pregnancy,81 and American women take an average of four prescriptions or over-the-counter medicines (excluding vitamin supplements) during pregnancy.82 A well described anecdote comes from a physician-researcher who needed an antibiotic during her own pregnancy. She took the usual dose, found it not to be working effectively, and had her blood drawn for drug level. The level in her blood was considerably below the normal level. After pregnancy she took an identical dose of the drag, measured her the level again, and found that they were normal.83 Often forgotten in debates about research with pregnant women and protectionism is that the fetus usually is better off if the pregnant woman is treated appropriately, and appropriate approaches to treatment cannot be learned if research is not conducted. Work in maternal epilepsy, asthma, diabetes, and HIV all demonstrate that a fetus that develops in a maternal environment that is relatively healthy

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has a much better outcome and prognosis than a fetus that develops in the context of uncontrolled maternal disease.84 It goes without saying that unless studies are conducted to determine the best way to treat women while they are pregnant, these women will be treated inappropriately or be untreated, leaving them and their offspring with greater morbidity than might otherwise occur. No changes are under consideration by DHHS that would authorize the conduct of trials explicitly for pregnant women. Those caring for pregnant women then, still have nowhere to turn to find systematic data to inform treatment decisions, and pregnant women who would like to contribute to this knowledge gap will continue to be denied the opportunity. Since proposals to include pregnant women in clinical research often raise red flags, it must be clarified that it is not being suggested that pregnant women be enrolled in research with no attention to potential risks and benefits. Rather, the same prerequisites that must be met before human subjects research would still apply. IRBs would still need to determine that, on balance, the benefits of a given research proposal outweigh the risks, taking into consideration the severity of, and what already is known about, the problem. If federal policy required the conduct of animal reproductive studies before any research with humans could proceed, the decisions IRBs made about research during pregnancy would be better informed. Further, IRBs must be included in broader discussions of the justice concerns raised by systematically excluding pregnant women from trials and the harms that result from never allowing trials designed for the benefit of pregnant women to go forward. Until such research occurs, the health needs of pregnant women will continue to be slighted, and harms likely will occur both to pregnant women and to their offspring. Women of Color

Justice in research for persons of color is discussed in Chapter 6. Therefore, it will be given only brief mention here. The point must be made, however, that justice in research has not been achieved for women, despite greater numbers enrolled, and despite new policies, if women of color do not enroll in and receive the benefits of research. A task for the future is to give greater attention to which women are being enrolled, and whose health problems are being studied. It is clear that women of color fare more poorly than white women in terms of both morbidity and mortality. African-American women have 50%-80% greater risk of dying of heart disease and are more than nine times as likely to die of AIDS. Also, women of color are more than three times as likely to die in childbirth as white women.85 It must be determined whether the health problems included in the current women's health research portfolio are those that cause the greatest morbidity and mortality among white and/or middle class women or whether they are the problems that cause the greatest morbidity and morality among women of color and/or poor women. Is

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research being conducted to determine why women of color are not enrolled in greater numbers in biomedical research? Are these women not being invited to enroll, are the research requirements inappropriate for their lives, or are women of color disinterested or distrustful? Separate strategies would be required as next steps depending on the answers to these questions. An unacceptable answer, however, is to decide that women of color will not be included in research. Rebecca Dresser wrote in an early article on gender and research, "It was taken for granted that the white male subject stood for all of us."86 In creating new norms for research with regard to gender, we must guard against assuming that the white, female subject speaks for all women. Clearly a women's research agenda must address separately the unique health needs of all of its subgroups. Moreover, even in circumstances where a condition manifests itself similarly across racial and ethnic groups, it is still important for whatever individual benefits and harms come from research participation to be distributed among women of all racial and ethnic backgrounds. Older Women When older persons are not included in research, there is a disproportionate impact on women. Women constitute 59% of those over age 65 and 75% of those over age 85.87 Older women consume more medications than older men and are more likely to suffer drug-related adverse events, suggesting that drugs have not been well tested in this population. Older women experience different rates of chronic diseases than men. This means, again, that applying findings from research with men—even older men—to women, can be inappropriate and potentially harmful. Moreover, the prevalence of health conditions among older women differs by race.88 Older black women are more likely to have hypertension, heart conditions, and arthritis. This means that, in setting the research agenda for older women, consideration must be given to what are the pressing questions and problems for all groups of older women. Also, given that the research agenda is usually set by persons who are not elderly, sensitivity to the problems of older persons generally is important. Certain health problems such as loss of vision and hearing, for example, often are not given great attention in the research or clinical setting because they are thought of as a normal part of the aging process.89 These conditions greatly reduce the independence and functional status of older persons, however, and probably would be given greater attention if older persons were more integrally involved in setting priorities for research. Moving Foward In addition to greater inclusion of previously neglected subgroups of women, other tasks await. Rigorous monitoring of the recent policy changes must be conducted.

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There must be scrutiny: of the degree to which epidemiologic research is conducted with women to identify women's greatest health needs; of the clinical research portfolio to determine the degree to which women's health needs are studied; and, of treatment trials to see if gender effects are examined as a research question. Appropriate federal bodies as well as private researchers should provide this function, and both should voice publicly the areas where successes have occurred and where efforts have fallen short. Reevaluation of policy will be necessary if changes consistently do not meet expectations. At the same time, externally imposed policies always will have limited effectiveness if those implementing them do not come to believe in their importance. Medical students should be trained early on about gender-based medicine; they should be taught that, while most medical problems manifest themselves similarly in men and women, there are aspects of male and female physiology that can change how even the most common conditions and drags work in the two sexes. The more physicians are trained to ask routinely whether a condition or treatment works identically or differently in men and women, the clearer it will be when there is a knowledge gap concerning effects in women. Finally, as suggested by several others who have written on this topic, having women in leadership roles in medicine and research can only help to advance justice in research for women. Further, women in leadership roles cannot be limited to middle-aged, white women. Women of color and older women must fill those roles, as should lesbian women, and women both with and without children. The greater diversity there is among decision makers, the more likely it is that the needs of all persons will be recognized and included. It is unlikely that, in most cases of omission, subgroups or specialized research questions were considered for inclusion and rejected; rather, exclusions are more likely the result of an oversight: that researchers and funders set a research agenda based on the areas that were most familiar to their own experiences.

CONCLUSIONS

While in the past women have suffered harm due to research exclusion, women now, perhaps thanks to the women's movement, have greater "rights" to research inclusion than ever before. There remains a tremendous backlog of research questions that must be answered before there can be justice in the clinical knowledge available to men and women who seek medical care, however. Indeed, it is difficult to discern whether gender differences in clinical care have been due to the lack of gender-relevant knowledge, or simply were a reflection of broader societal gender expectations (i.e., women as reproducer/homemaker). In either case, gender differences in clinical care have reinforced a research agenda in which women have been short-changed. And while exclusionary practices are undoubt-

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edly a reflection of broader societal inequities but certainly not their cause, each additional example of inequity with regard to gender reinforces the seeming normalcy of such practices. By the same token, each step toward dismantling inequities has an impact beyond its own small world. The tasks ahead are clear. The true test will be not only in the research portfolio 5 or 10 years from now, but in determining the extent to which health care providers understand women's health needs and in examining future statistics with regard to morbidity and mortality for women.

NOTES 1. Anna C. Mastroianni, Ruth Faden, and Daniel Federman, eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. I (Washington, DC: National Academy Press, 1994). 2. Rebecca Dresser, "Wanted: Single, White Male for Medical Research," Hastings Center Report, 22:21-29; January-February, 1992; Vanessa Merton, "The Exclusion of Pregnant, Pregnable, and Once-Pregnable People (a.k.a. Women) from Biomedical Research," American Journal of Law and Medicine 19:369-451; 1993; Karen H. Rothenberg, "Gender Matters: Implications for Clinical Research and Women's Health Care," Houston Law Review 32:1201-1272; 1996; Nancy E. Kass, Holly A. Taylor, and Patricia A. King, "Harms of Excluding Pregnant Women from Clinical Research: the Case of HIVInfected Women," American Journal of Law, Medicine, and Ethics 24:36-46; 1996; and R. Alta Charo, "Protecting Us to Death: Women, Pregnancy, and Clinical Research," Saint Louis University Law Journal 38:135-167; 1993. 3. Douglas L. Schmucker and Elliot S. Vesell, "Underrepresentation of Women in Clinical Drug Trials," Clinical Pharmacology and Therapeutics 54:11-15; 1993; Chloe E. Bird, "Women's Representation as Subjects in Clinical Studies: A Pilot Study of Research Published in JAMA in 1990 and 1992," in Anna C. Mastroianni, Ruth Faden, and Daniel Federman, eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Volume II, (Washington, DC: National Academy Press, 1994), pp. 151-173. 4. 59 Federal Register 14,508 (1994). 5. Vanessa Merton, "Ethical Obstacles to Women in Biomedical Research," in Susan M. Wolf, ed., Feminism and Bioethics: Beyond Reproduction, (New York: Oxford University Press, 1996), pp. 216-251. 6. N. Kass, J. Sugarman, R. Faden, and M. Schoch-Spana, "Trust: The Fragile Foundation of Contemporary Biomedical Research," The Hastings Center Report 26: 25-29; 1996. 7. U.S. Public Health Service. "Report of the Public Health Service Task Force on Women's Health Issues," Public Health Reports 100:73-106; 1985. 8. Council on Ethical and Judicial Affairs, American Medical Association, "Gender Disparities in Clinical Decision Making," JAMA 266:559-562; 1991. 9. Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. I. 10. Ibid. 11. Schmucker and Vesell, "Underrepresentation of Women in Clinical Drug Trials."

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12. Paul Skett, "Biochemical Basis of Sex Differences in Drug Metabolism," Pharmacological Therapy 38:269-304; 1988. 13. Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. I, p. 86. 14. Jean Hamilton and Barbara Parry, "Sex-related Differences in Clinical Drug Response: Implications for Women's Health," JAMA 38:126-132; 1983. 15. Skett, "Biochemical Basis of Sex Differences in Drug Metabolism," p. 275. 16. Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. I, p. 86. 17. G. I. Cafferata, J. Kasper, and A. Bernstein, "Family Roles, Structure, and Stressors in Relation to Sex Differences in Obtaining Psychotropic Drags," Journal of Health and Social Behavior 24:132-143; 1983. 18. Kimberly A. Yonkers, Judith C. Kando, Jonathan O. Cole, and Susan Blumenthal, "Gender Differences in Pharmacokinetics and Pharmacodynamics of Psychotropic Medication," The American Journal of Psychiatry 149:587-595; 1992. 19. Yonkers et al., "Gender Differences in Pharmacokinetics and Pharmacodynamics of Psychotropic Medication." 20. Ibid. 21. Hamilton and Parry, "Sex-related Differences in Clinical Drug Response: Implications for Women's Health." 22. Skett, "Biochemical Basis of Sex Differences in Drug Metabolism." 23. Dresser, "Wanted: Single, White Male for Medical Research;" Report of the Planning Panel of the Institute of Medicine Division of Health Sciences Policy, Issues in the Inclusion of Women in Clinical Trials, as cited in Vanessa Merton, "Ethical Obstacles to Women in Biomedical Research," p. 224. 24. Dresser, "Wanted: Single, White Male for Medical Research." 25. Nanette K. Wenger, Leon Speroff, and Barbara Packard, "Cardiovascular Health and Disease in Women," NEJM 329:247-256; 1993. 26. M. L. Murphy, H. N. Hultgren, K. Detre, J. Thomsen, and T. Takaro, "Participants of the Veterans Administration Cooperative Study, Treatment of Chronic Stable Angina: A preliminary report of survival data of the randomized Veterans Administration Cooperative Study," NEJM 292:621-627; 1977. 27. Multiple Risk Factor Intervention Trial Research Group, "Multiple Risk Factor Intervention Trial: Risk Factor Changes and Mortality Results," JAMA 248:1465-1477; 1982. 28. J. E. Manson, D. E. Grobbee, J. M. Stampfer et al., "Aspirin in the Primary Prevention of Angina Pectoris in a Randomized Trial of United States Physicians," American Journal of Medicine 89:772-776; 1990. 29. Wenger et al., "Cardiovascular Health and Disease in Women." 30. This difference is perhaps related mostly to menopause, more specifically to a reduction in circulating estrogens, rises in LDL-C levels and declines in HDL-C levels. See K. A. Matthews, E. Meilahn, L. H. Kuller et al., "Menopause and Risk Factors for Coronary Heart Disease," NEJM 321:641-646; 1989. 31. Marianne J. Legato, Gender-Specific Aspects of Human Biology for the Practicing Physician (Armonk, NY: Futura Publishing Company, 1997). 32. National Cholesterol Education Program, Report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, (Rockville, MD: NIH Publication No. 89-2925, 1989). 33. Marianne J. Legato, Gender-Specific Aspects of Human Biology for the Practicing Physician.

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34. Raymond E. Jackson, William Anderson, W. Franklin Peacock et al., "Effect of a Patient's Sex on the Timing of Thrombolytic Therapy," Annals of Emergency Medicine 27:8-15; 1996. 35. Harald Herholz, David C. Goff, David J. Ramsey et al., "Women and Mexican Americans Receive Fewer Cardiovascular Drugs Following Myocardial Infarction then Men and Non-Hispanic Whites: The Corpus Christi Heart Project, 1988-1988-1990," Journal of Clinical Epidemiology 49:279-287; 1996. 36. Bernadine Healy, "The Yentl Syndrome," NEJM 325: 274-275; 1991. 37. Ruth Faden, Nancy Kass, and Deven McGraw, "Women as Vessels and Vectors: Lessons from the HIV Epidemic," in Susan Wolf, ed., Feminism and Bioethics: Beyond Reproduction, (New York: Oxford University Press, 1996), pp. 252-281. 38. Ibid. 39. Ibid.; Gena Corea, The Invisible Epidemic: The Story of Women and AIDS (New York, NY: HarperCollins, 1992); Kathleen D. Stoll, Women and the Definition of AIDS (Washington, DC: Center for Women Policy Studies, 1992). 40. J. A. Maier, A. Bergman, and M.G. Ross, "Acquired Immunodeficiency Syndrome Manifested by Chronic Primary Genital Herpes," American Journal of Obstetrics and Gynecology 155:756-758; 1986; M. A. Byrne, D. Taylor-Robinson, P. E. Muday et al., "The Common Occurrence of Human Papilloma-virus Infection and Intraepithelial Neoplasia in Women Infected by HIV," AIDS 3:379-382: 1989. 41. Jean Anderson, Janet Horn, R. King et al., "Selected Gynecologic Issues in Women with HIV Infection" (abstract), Proceedings of the 5th International Conference on AIDS, (Montreal, Canada, June 1989), p. 760. 42. Jean Anderson, "Gynecological and Obstetrical Issues for HIV-infected Women," in Ruth Faden and Nancy Kass, eds., HIV, AIDS, and Childbearing: Public Policy, Private Lives. (New York: Oxford University Press, 1996), pp. 31-62. 43. A particularly compelling journal of women's experience with HIV and the lag in attention to their health needs is captured in Gena Corea's book, The Invisible Epidemic: The Story of Women and AIDS, (New York: HarperCollins, 1992). 44. U.S. Public Health Service, "1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults," MMWR:41:1-17; 1993. 45. Carol Levine and Gary L. Stein, "What's in a Name? The Policy Implications of the CDC Definition of AIDS," Law, Medicine and Health Care 19:278-290; 1991; U.S. Congress, Office of Technology Assessment, The CDC's Case Definition of AIDS: Implications of the Proposed Revisions—Background Paper, (Washington, DC: U.S. Government Printing Office, OTA-BP-H-89 August 1992). 46. "Hearings Before the House Energy and Commerce Subcommittee on Health and the Environment," 101st Congress, 1st Session (1990), testimony of Mark V. Nadel, Associate Director, U.S. General Accounting Office. 47. Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies: Vol. I, p. 44. 48. PL 103-43. 49. Ibid., 492B(a) (1) 50. Ibid. 51. Ibid. 52. Legislation was introduced into the U.S. Congress in 1996 by Senator John Glenn, D-OH, that would make the "Common Rule" applicable to all public and private human subjects research. "The Human Research Subject Protection Act of 1997" did not pass.

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53. The FDA adopted regulations in 1981 regarding the protection of human subjects and the establishment of IRBs. These regulations were similar in content to Subpart A of the DHHS regulations and to the Common Rule. The 1981 FDA regulations were silent on the issue of women. 54. Phase I trials usually include small numbers of healthy volunteers and are designed to determine if the drug is safe and how it is metabolized. Phase II trials typically include a few hundred volunteers with the health condition for which the drug is designed. Phase II trials monitor both safety and effectiveness. If the drug is safe and effective after Phase II testing, Phase III trials, involving up to thousands of participants, determine safety and effectiveness among the larger population of participants. 55. Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. I, p. 67. 56. U.S. Department of Health and Human Services, Public Health Services, Food and Drug Administration, Guideline for the Format and Content of the Clinical and Statistical Sections of the New Drug Applications (Rockville: Department of Health and Human Services, 1988). 57. "Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs," 58 Federal Register 39406; 1993. 58. Ibid., pp. 39, 409. 59. 45 C.F.R. § 46.207. 60. 45 C.F.R. § 46.102. 61. Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. I, p. 198. 62. Kass et al., "Trust: The Fragile Foundation of Contemporary Biomedical Research," 1996. 63. U.S. Food and Drug Administration Regulated Products and Pregnant Women Conference, Crystal City, Virginia, November 7-8, 1994. 64. Susan M. Wolf, ed., Feminism and Bioethics: Beyond Reproduction (New York: Oxford University Press, 1996). 65. Tracy Johnson and Elizabeth Fee, "Women's Participation in Clinical Research: From Protectionism to Access," in Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. II, pp. 1-10. 66. Roy M. Pitkin, "Drug Treatment of the Pregnant Woman: State of the Art," paper presented at U.S. Food and Drug Administration meeting: Regulated Products and Pregnant Women, Crystal City, Virginia, November 7-8, 1994. 67. Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. I, p. 162. 68. Kass et al., "Trust: The Fragile Foundation of Contemporary Biomedical Research;" R. Alta Charo, "Protecting Us to Death: Women, Pregnancy, and Clinical Research Trials"; Karen H. Rothenberg, "Gender Matters: Implications for Clinical Research and Women's Health Care," Houston Law Review 32:1201-1272; 1996; Ellen Flannery and Sanford N. Greenberg, "Liability Exposure for Exclusion and Inclusion of Women as Subjects in Clinical Studies," in Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. II, pp. 91-102. 69. R. Alta Charo, "Brief Overview of Constitutional Issues Raised by the Exclusion of Women from Research Trials," in Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. II, pp. 84-90. 70. Flannery and Greenberg, "Liability Exposure for Exclusion and Inclusion of Women as Subjects in Clinical Studies," p. 95.

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71. Nancy Hartsock, "Political Change: Two Perspectives on Power," in Building Feminist Theory (New York: Longman, 1981), pp. 3-19. 72. Susan Moller Okin, Justice, Gender, and the Family (New York: Basic Books, Inc., 1989), p. 5. 73. Ibid., p. 8. 74. Ibid., p. 15. 75. Debra DeBruin, "Justice and the Inclusion of Women in Clinical Studies: A Conceptual Framework," in Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. II, pp. 127-150. 76. Ibid., p. 132. 77. Andrea Boroff Eagan, "The Women's Health Movement and Its Lasting Impact," in Emily Friedman, ed., An Unfinished Revolution: Women and Health Care in America (New York: United Hospital Fund, 1994), pp. 15-27. 78. Eagan, "The Women's Health Movement and Its Lasting Impact." 79. Roy M. Pitkin, "Drug Treatment of the Pregnant Woman: State of the Art." 80. M. B. Caschetta, W. Chavkin, and T. McGovern, correspondence, "FDA Policy on Women in Drug Trials," NEJM 329-1815; 1993. 81. Ruth Merkatz, "Overview," presented at U.S. Food and Drug Administration meeting: Regulated Products and Pregnant Women, Crystal City, Virginia, November 7-8,1994. 82. E. Zamula, Drugs and Pregnancy: Often the Two, Don't Mix (Washington, DC: Department of Health and Human Services, FDA 90-3174, 1989). 83. Lee Sabath, Agneta Philipson, and David Charles, "Ethics and the Use of Drugs During Pregnancy," Science 202:540-541; 1978. 84. Discussed further in Nancy E. Kass, Holly A. Taylor, and Jean R. Anderson, "Fetal Protection May Not Be Protecting the Fetus" (in review). 85. Risa J. Lavizzo-Mourey and Jeane Ann Grisso, "Health, Health Care, and Women of Color," in Emily Friedman, ed., An Unfinished Revolution: Women and Health Care in America, pp. 47-63. 86. Dresser, "Wanted: Single, White Male for Medical Research," p. 27. 87. Mastroianni et al., eds., Women and Health Research: Ethical, and Legal Issues of Including Women in Clinical Studies, Vol. I, p. 89. 88. "Report of the Public Health Service Task Force on Women's Health Issues," Public Health Reports 100:73-106; 1985. 89. Ibid.

6 RACE, JUSTICE, AND RESEARCH Patricia A. King

Race is an elusive and ambiguous concept that has played a prominent role in biomedicine and research. Historically, the concept has been used as an explanation of human differences in ways that subordinated and oppressed African-Americans.1 This chapter focuses on the concept of race in connection with the experiences of people in the United States who trace their ancestry to African slaves. Other racial and ethnic groups have separate and distinct experiences with American medicine.2 The major theoretical issue has been whether race is a biological or a socially constructed concept. The biological concept has not been substantiated. Gamble and Blustein define the two approaches as follows: Biological constructionists hold that races are genetic entities that are fixed, immutable, and genetically determined. . . . The social construction model holds that race is a social, historical, and political entity without any essential biological coherence. It is not a natural, fixed category; rather it has been created by society to recognize difference and establish social relationships. . . . [I]t cannot be understood outside of its historical and social context.3

Medicine provided much of the theory and data that supported beliefs about inherent biological differences between blacks and whites. These beliefs justified slavery, reenforced negative stereotypes about blacks, and in the postemancipation era supported efforts to deny African-Americans the opportunity to participate as full citizens in the life of the country.

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Medicine's interest in black health status was until recently substantially motivated by the self-interest of whites rather than the best interests of AfricanAmericans.4 To the extent that attention was paid to slave health status, it was because slaves were regarded as economic investments that should be preserved. After emancipation, medicine's interest in diseases that afflicted blacks was triggered by the fear of whites that they were at risk of contracting these diseases. In medical research African-Americans were selected as experimental subjects because of their powerlessness. They bore risks and burdens of participation that included callous infliction of pain and withholding of effective therapies. Although there is a long history of blacks being treated unfairly by medicine, the unveiling of the Tuskegee Syphilis Study in 1972 focused public attention for the first time on unjust treatment of blacks in research. The National Commission5 was created in part in response to public outrage at the Tuskegee Syphilis Study and other instances of abuse of vulnerable research subjects. The National Commission's deliberations and recommendations became the basis for subsequently promulgated federal regulations setting out requirements for ethical participation of human subjects in research. The National Commission'sBelmont Report addressed the issues of justice and subject selection. It stated: [T]he selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability, their compromised position or their manipulability, rather than for reasons directly related to the problem being studied.6

The Commission's work emphasized distributive justice, that is, fair allocation of research burdens and benefits. It was concerned that some groups, including African-Americans, were being subjected to undue burdens and risks of harm. More recently, public attention has turned in the direction of emphasizing the denial of health benefits to groups such as African-Americans. Denial of benefits may flow from failure to study diseases or conditions disproportionately affecting a particular group or from failure to appreciate that the procedure or drug being studied may affect groups differently. The distributive paradigm of justice put forth by the National Commission is useful in understanding the ways in which African-Americans have been unjustly treated in medicine and medical research. The paradigm also offers a basis for remedial action in the future. However, it fails to capture relevant features of the African-American experience that should be taken into account in future efforts to achieve fair participation in medical research. In this chapter, I use the term justice in the sense developed by Iris Marion Young to mean not only distribution, but also to include, "the institutional conditions necessary for the development and exercise of individual capacities and collec-

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tive communication and cooperation."7 Young's sense of the term justice incorporates the need for fundamental change in existing institutional arrangements if a just society is to be achieved. I focus particularly on the two disabling constraints to achieving justice that Young identifies: oppression and domination. Oppression is not caused by people's choices or policies, but rather emerges from "unquestioned norms, habits, and symbols, in the assumptions underlying institutional rules and the collective consequences in following those rules."8 Her point is that ordinary practices of wellintentioned institutions, organizations, and professions frequently result in creating injustice for some individuals or groups. Young identifies two facets of oppression, "exploitation" and "cultural imperialism," that are of particular relevance here. Exploitation refers to the steady transfer of a group's efforts to benefit others. This term, for example, captures some uses of black people in human experimentation.9 Cultural imperialism includes the "experience of having the dominant meanings of society render the particular perspective of one's own group invisible at the same time as they stereotype one's group and mark it out as the Other."10 Thus, the dominant group establishes its experiences as the norm. It then establishes its differences from other groups as negative and deviant. This process of establishing dominance and marking others as deviant occurs in the formulation and use of stereotypes that in turn draw attention to differences between groups. As Young states, "[t]he culturally dominated undergo a paradoxical expression, in that they are both marked out by stereotypes and at the same time rendered invisible."11 My goals in this chapter are twofold. First, I attempt to explain why merely increasing the numbers of African-Americans in clinical research or increasing research resources devoted to diseases of significance to African-Americans is necessary but insufficient to achieve fair participation of blacks in health care research. I begin with an historical examination of the relationship between race and American medicine that includes, but is not limited to, medical research. Such an analysis provides the context in which the nature of the injustices against African-Americans in medical research can be understood. From the perspective of African-Americans, experiences with medicine and biomedical research are not separate. Thus efforts to bring about just participation in research must take account of the full range of abuse, racism, and discrimination.12 Mari Matsuda argues that attention should be paid to the perspectives of those who have experienced injustice because their insights can assist scholars in defining the meaning of justice. She argues that the experiences, history, and culture of people of color constitute a valuable epistemological source. She states: When notions of right and wrong, justice and injustice, are examined not from an abstract position but from the position of groups who have suffered through history, moral relativism recedes and identifiable normative priorities emerge.13

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This historical analysis indicates that African-Americans suffered injustice in at least three ways. First, black health needs were ignored except to the extent that they were relevant to the health status of whites. Second, since blacks were not only regarded as inferior but were also powerless, it was permissible to exploit their helplessness in educational and experimental endeavors to further the health interests of whites. Finally, the assumptions, stereotypes, and myths that evolved and sustained faith in white superiority became obstacles to the creation, shaping, implementation, and interpretation of efforts to improve black health status. My second goal is to suggest directions that future efforts to include AfricanAmericans on a fair basis in medical research might take. Identifying the steps that might be required to remedy past injustices against African-Americans and to create a just system in the future is a vexing problem. Sadly, injustice is not simply a matter of historical interest. The need to protect African-Americans from unethical practices in medical research persists. There is still potential for exploitation and inappropriate selection. For example, in a recent government-sponsored measles vaccine study in which a large proportion of the subjects were African-Americans and other minorities, parents were not informed that the vaccine was experimental and not licensed for use in the United States.14 The FDA's adoption of regulations allowing waiver of informed consent from research subjects or their surrogates in certain cases of emergency research has also triggered concern.15 Annette Dula warns that African-Americans and other minorities are likely to be disproportionately the subjects of this emergency research. Dula offers three reasons why such research is problematic for African-Americans: the research will likely take place in poor communities with minorities as subjects because that is where hospitals with trauma centers are located and traumatic injuries are suffered; implementation of the regulations will be difficult because of the legacy of mistrust in the black community that results from past research abuses; and the community consultation requirement will be difficult to implement.16 A second problem is that remedying past injustice and providing for a just system in the future requires conscious attention to race. Focusing on differences between blacks and whites, however, poses a dilemma. On the one hand, targeting race is necessary to obtain important information or to increase resources that might improve black health status. At the same time conscious attention to the health needs of African-Americans risks feeding into established negative stereotypes and bias that have historically oppressed and stigmatized them. On the other hand, ignoring race and utilizing race-neutral remedial measures implies that blacks and whites are equal and may minimize the prevalence of bias, but this approach also has shortcomings. It may result in inadequate health care if in fact blacks are different from whites in important ways. Moreover, race-neutral approaches not only do not adequately remedy past injustice but they also cannot ensure a just research system in the future.

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Promoting just participation of African-Americans in medical research requires attending to race in ways that maximize the likelihood of benefit and eliminate or minimize practices and processes in medical research that are unjust. The starting point is to recognize and appreciate the experiences of African-Americans with American medicine and research. The more difficult task is to discern how to use that knowledge to achieve a fair and just system of medical research in the future.

JUSTICE ACROSS TIME The relationship between medicine and African-Americans was shaped by slavery and the South' s political struggles before and after the Civil War. In the formative years of the relationship the majority of blacks lived in the South and were tended by southern physicians. The southern medical profession played a critical role in establishing and defending the view that blacks were mentally and physically inferior to whites. Belief in black inferiority posed obstacles to the development of adequate health care for blacks. It also justified using blacks for experimental purposes. Race and Medicine

Medicine played a pivotal role in the identification, elucidation, and utilization of racial difference that stamped blacks as an inferior people.17 Concern about differences between blacks and whites goes back to the arrival of Africans at Jamestown. Obvious differences in skin color, hair, and appearance existed between Africans and white colonists. Race was a convenient explanation for observed differences in appearance and behavior. Understanding differences between the races was of practical and political importance. In the antebellum period, as a practical matter it was necessary to understand differences between whites and blacks in order to maintain the health of slaves. Slaves were economic investments whose value deteriorated or evaporated if their health declined or if they died. As a political matter, medicine played a critical role in providing "scientific" support for slavery.18 Justification was required to show that blacks should be slaves. The justification was that blacks were an inherently inferior people. Medicine provided the comparative analysis of blacks and whites that helped to support that claim.19 As a consequence, in the nineteenth century it was commonly agreed that there were significant anatomical differences between blacks and whites.20 These differences made blacks susceptible to disease. They resulted in making blacks prone to violence and crime.21 These ideas were taken to the extreme when behaviors that indicated black dissatisfaction with slave status were characterized as distinctly black diseases.22

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In some cases, perceived differences between blacks and whites were used to demonstrate that slaves were being treated humanely and in a manner consistent with their different and inferior status. For example, the argument was made that the slaves' physiological characteristics made them ideally suited to toil in the southern sun. Slaves could also work in rice fields because blacks were not as susceptible to malaria as whites.23 In the postemancipation period, as it became clear that many diseases were caused by microbes that could be transmitted from person to person, there was great interest in diseases such as tuberculosis and syphilis that affected blacks and whites. Whites were concerned about the implications of black health status for themselves.24 Thus, it became important to study blacks. Once again prevailing attitudes that blacks and whites were different fed hopes that the diseases in question, tuberculosis for example, did not affect blacks and whites in the same way or were really two different diseases. Sorting through the scientific complexities of specific diseases was made difficult, however, because researchers, while trying to be objective, were burdened by their own biases in interpretation of observations.25 Gamble and Blustein offer an example of the problem of scientific bias. They analyzed explanations offered by theorists for the greater decline in fertility rates among black women compared to white women between 1880-1940. Their analysis indicates that biological rather than socio-economic factors were put forth as explanations for differences in the rates between black women and white women. For example, it was argued that black women suffered from a higher incidence of venereal disease. Black women were sexually promiscuous and could not or would not use contraceptives. Gamble and Blustein also show that subsequent research has undermined the view that biological factors were chiefly responsible for the difference in rates. The authors point out, however, that the stereotypes that supported biological explanations endure. They conclude: The fecundity of both black and white women declined during this period. However, different interpretations were often sought to explain the event in the two racial groups. Racism frequently shaped these interpretations. The health hypothesis, a theory that reflected and reinforced stereotypical notions of African-American women, was the predominant paradigm for many years. In addition ... we see how a tendency toward biological explanations may obscure the significance of socioeconomic factors.26

During this same period, medical theories coupled with Social Darwinism supported the view that slavery had been beneficial to blacks and that freedom would result in their demise. Haller writes: "[T]he belief in the Negro's extinction became one of the most pervasive ideas in American medical and anthropological thought during the late nineteenth century. It was also a fitting culmination to the concept of racial inferiority in American life."27

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Census reports, insurance statistics, and military data all pointed to high mortality and morbidity rates among blacks.28 Explanations for these high rates were influenced by the racism of the era. Rather than consider the impact of social and economic conditions on the health of blacks,29 medicine and society continued to rely on race-based explanations for differences in health status between whites and blacks. For example, since blacks were thought to be peculiarly susceptible to disease, vice, and crime, insurance companies stopped underwriting life insurance for blacks as a group as opposed to making individual assessments.30 Moreover, arguments about health status and mortality rates supported the view that it was useless to try to involve freed blacks as full participants in the life of the community and the nation because they were a doomed race. Studying health and disease can be seen as a window on the rest of American society. One writer puts the issue succinctly: [Americans] wanted to know whether blacks, so uncomfortably situated in their midst, were beings of a different order from themselves. They wondered whether the 'benighted' race was on the increase and determined to outnumber them, or on its way to extinction. They were concerned about the prospects of racial intermixture, and so sought to document the mulatto's degree of disease susceptibility. And they worried about the immediate threat presented by the proximity of a race that was a reservoir of infection.31

In short, medical theories affirmed race-based explanations for disease and health status. They allayed the fears of whites and confirmed their superior position. Medical Research and Experimentation

Belief in racial difference that justified enslavement of blacks also made it easy to justify the use of blacks for medical, educational, and research purposes. Skin color alone made it easy to target both slaves and freed blacks. Moreover, blacks had no rights that whites were bound to respect. Whether slave or free, blacks were powerless. Ironically, in using blacks in research and experimentation, medicine was often willing to ignore the biological differences that allegedly existed between blacks and whites, in extrapolating its findings obtained from blacks for the benefit of whites. The rise of medical institutions made research with human subjects more widespread.32 In order to train medical students effectively, medical schools established clinics and infirmaries that primarily serviced those who could not be treated at home. Slaves were frequently sent to these institutions by their owners for treatment. Blacks and other poor clinic patients were considered suitable subjects.33 In exchange for care and treatment given by a benevolent society, these patients were expected to reciprocate by participating in efforts that might provide valuable information for the benefit of all.

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Blacks were also used as specimens for clinical instruction and public display.34 In the early part of the nineteenth century there was widespread public sentiment opposed to dissection and autopsy. No state permitted dissection. Grave robbing was a crime.35 Despite this, dissections were conducted and medicine procured its dead bodies from groups that could not effectively object. Thus, black cadavers (and sometimes those of poor whites) could be utilized with little expectation of protest.36 While experimentation on blacks sometimes produced important information, in the process many of these subjects were cruelly treated and suffered great pain. For example, in Georgia, Dr. Thomas Hamilton wanted to determine the best remedies for sunstroke. His experiments were conducted on a slave given various substances and then suspended on a stool over a makeshift heated pit until the subject fainted.37 In another well-known experiment, Dr. Marion Sims, considered by medical historians to be the "father of American gynecology" and a former president of the AMA, used slave women in developing surgical procedures to repair vesicovaginal fistulae or tears in the vaginal wall that resulted in chronic leakage from the bladder.38 In order to develop his surgical procedures, between 1845 and 1849, Dr. Sims operated repeatedly on three slave women, Anarcha, Betsey, and Lucy, who suffered from fistulae without benefit of anesthesia. The three slaves and later others were lent to Sims by their owners so that he could develop this technique. Sims agreed not to endanger their lives and to pay living expenses.39 The operations were painful, agonizing procedures, and according to Axelsen, it does not appear that Sims sought out current research on anesthesia even though this is the period in which the first reports about it began to appear.40 Only after success with slave women, did Sirns begin to use white women volunteers. Sims' use of the slave women in this fashion was made possible because of the dominant values of the time. The women were in no position to object to the surgical procedures used on them. Moreover, the women were victims of prevalent stereotypes. It was normal for women to accept pain because it was a natural feature of childbirth. It was also generally believed that slaves could withstand pain better than whites.41 Viewed through the prisms of race, gender, and class, it might have been difficult for Sims to see his subjects as humans and not objects. While slave women suffered from vaginal fistulae and might have benefited as a group from the experimental procedures, given the other aspects of slave life, it is not clear that these women would have ranked this problem high on their list of medical problems that needed attention. This early history shows that medicine exploited the disadvantaged position of blacks during slavery and afterwards to advance its own educational and research interests. Although individual blacks may have benefited from attention to their health needs, it was generally the economic interests and health status of whites that

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promoted concern for black health status. This examination also shows that medicine provided "scientific" support for perceived biological differences between blacks and whites that was used to justify slavery and later to deny equal status to blacks. From the perspective of African-Americans, the early history of what is known about their involvement with medicine has left a legacy of suspicion and mistrust about medicine, its professionals, and its institutions.42 Although the impact of this history on medical institutions and health care professionals is less clear, Savitt notes that "[s]outhern medical schools could and did boast that their cities' large black populations provided ample supplies of clinical and anatomical material. And white physicians trained at these institutions carried with them into their own careers this idea of the medical usefulness of blacks."43 The Tuskegee Syphilis Study

Patterns that defined the relationships between medicine and African-Americans in the eighteenth and nineteenth centuries also existed in the Tuskegee Syphilis Study. These patterns make clear that justice was an issue for American medicine long before it was discussed as a basic ethical principle in the Belmont Report. This study sponsored by the PHS began in 1932 in Macon County, Alabama. It involved 399 black men with syphilis and 201 controls. Originally intended to last less than a year, the experiment continued for 40 years.44 This experiment offered no promise of benefit to the participants. It was intended to track the effects of untreated syphilis in blacks. The subjects were never given important information about the study. Since the study participants were not offered the best available treatment of the time (even though in retrospect it would not have been of much help), the experiment was ethically flawed from the beginning. Moreover, the subjects were not given penicillin when it became available as an effective treatment for syphilis in the 1940s. Indeed extensive measures were employed to keep them from being treated. The Tuskegee Syphilis Study continued the historical pattern of relying on race to explain differences between blacks and whites. Negative stereotypes about blacks played an important role in shaping the design and implementation of the study. For example, the PHS doctors believed that blacks were of a different sexual nature than whites, that blacks would not seek treatment for syphilis, and that blacks were promiscuous.45 Historian Evelyn Higginbotham notes that the power of the belief in black promiscuity was so great that it blunted any concern for the black women in sexual relationships with black men in the study because black women inevitably would be infected.46 Although there had been a retrospective study of untreated syphilis in whites by a Norwegian investigator, the PHS physicians believed that the question of differences between blacks and whites had not been conclusively resolved. Assumptions about blacks embedded in the investigators' culture undoubtedly made

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it difficult for them to be objective. It would have been unusual for them to challenge the prevailing scientific view in the United States that syphilis affected blacks and whites differently. The doctors who conceived the Tuskegee Syphilis Study did not necessarily act with base motives. They may have simply been researchers intent on the pursuit of scientific knowledge, blind to the fact that the subjects were human beings not objects. It is even possible that at a conscious level they saw themselves as advancing the health needs of African-Americans.47 It is also important to acknowledge that if the PHS physicians had been correct that there were important differences in the course of syphilis between white and black victims of the disease, the study's findings might have provided a basis for better treatment of blacks. Regardless, whatever the motivation, it is clear that the study mirrored the racism of the times. How else can we explain the abdication of personal responsibility and lack of respect and concern about the health and lives of these men? Even after the revelation of the study, some continued to defend its worth.48 Brandt concludes: "In retrospect the Tuskegee Study revealed more about the pathology of racism than it did about the pathology of syphilis; more about the nature of scientific inquiry than the nature of the disease process."49 The participants in the study were exploited in another sense in that the PHS physicians took advantage of the subjects' bleak social and economic situation.50 The study took place in a rural, poor, and segregated community in the deep south. Access to basic health care and other valued amenities of life were minimal. Contrary to their expectations, the public health doctors found that only when health care, such as free physical examinations, was offered would blacks cooperate. The PHS could only obtain bodies for post-mortem examination by promising to pay burial expenses. Though there was a long standing aversion to autopsy in the Africian-American community, this reluctance was overcome by the promise that dignified burial, a critical aspect of black culture, was possible. The subjects did not give consent to participation in the study. Indeed, the Tuskegee Syphilis Study is generally viewed as being unethical for this reason rather than because the principle of justice was violated. This understanding of the experiment was in substantial part due to the influence of the Tuskegee Syphilis Study Ad Hoc Advisory Panel Report. The Panel was established in 1972 following press accounts of the experiment. Its charge was limited in scope and did not explicitly raise issues of race or the failure of the government to offer available treatment at the experiment's inception. The Panel was charged to "[d]etermine whether the study was justified in 1932 and whether it should have continued when penicillin became generally available." The Panel concluded: In retrospect, the Public Health Service Study . . . was unethically justified in 1932. . . . [O]ne fundamental ethical rule is that a person should not be subjected to

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What the Panel failed to explore was whether the study would have been ethical if consent had been obtained. As Robert Burt points out in connection with the Nazi experiments, "the consent of the experimental subjects would not have justified the experiments."52 These men lived in a coercive environment. They were accustomed in the deeply segregated south to being obedient to authority. They were at the mercy of others. These men were powerless. They were in no position to meaningfully influence what was happening to them. They needed health care not otherwise available to them. They did not participate in the creation and design of the study, and they could not participate in decisions about the course of the study. The Ad Hoc Advisory Panel Report's emphasis on informed consent served to obscure other important lessons of the Tuskegee experiment. Tuskegee teaches not only that the vulnerable can be easily exploited, but also that those in positions of authority cannot always be expected to act in the best interests of subjects. It demonstrates how scientific objectivity can be infected with bias prevalent in the broader society. It suggests that relying on informed consent to protect subjects has serious limits. Obtaining informed consent in clinical research is critical to the ethical validity of research but it is not the only requirement. In circumstances-where consent is compromised, other ethical considerations should be given priority. The Tuskegee experiment shows the need to examine critically other ethical principles if blacks are to be protected from abuse and treated fairly in research. Unfortunately these lessons were not fully appreciated by the National Commission, which followed the Ad Hoc Advisory Panel. Although the National Commission was concerned with protecting vulnerable subjects and recognized the importance of the principle of justice, it gave special emphasis to respect for persons and informed consent in its work. The National Commission concentrated on designing informed consent procedures for involving subjects who could not themselves consent to participation in research and on articulating the appropriate level of risk to which subjects could be exposed. In contrast to other vulnerable groups, the Commission did not issue a special report that detailed the circumstances in which AfricanAmericans could be included in research. Unlike the case of prisoners, there was no consideration given to conditions in the environment that might impair the consent of African-Americans. The Commission did recognize that care should be taken in including AfricanAmericans in research so as to fairly distribute risks and benefits of participation, but there was no detailed guidance for carrying out this requirement. Since it is difficult to obtain consensus on what constitutes fair allocation, proportional ad-

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justments are not easy to determine. Thus, the early federal response to the Commission's recommendations was to require that IRBs ensure that subject selection was "equitable" taking into account the context of the research.53 The research establishment lacking meaningful guidance about selection of subjects was understandably reluctant to involve African-Americans in research. While overprotection created another form of injustice,54 there was no immediate outcry for fair inclusion even by African-Americans who had reason to distrust medical professionals and their institutions. Moreover, the civil rights movement's initial emphasis on equality and integration of black and white may have contributed to acceptance of the idea that research findings obtained from white male subjects would be equally applicable to blacks. All this began to change in the mid-eighties, however, with the growing recognition that obtaining the benefits of research depended in part on participation in research. In 1984, the DHHS established the Task Force on Black and Minority Health to examine the health issues of blacks and other minorities.55 The Task Force's Report issued in 1985 marks a shift in the federal government's concerns about black health status.56 It called for greater inclusion of racial and ethnic minorities in medical research. The Report noted significant gaps in knowledge about the health status of African-Americans and other minorities that could not be explained by physiological, cultural, and other societal factors. The Task Force stated that "ongoing research, particularly basic research already conducted through DHHS, applies to all populations including minorities."57 It proposed research aimed "specifically at understanding the reasons underlying the longstanding disparity of health status [between minorities and whites] in the United States" in order "to prevent or reduce much of the illness and death experienced by minorities in disproportion to their representation in the American population."58 Since the issuance of this Report, the federal government has continually recognized and affirmed the importance of including African-Americans in research where appropriate.59 With this shift in focus has come an emphasis on promoting participation of blacks in research and attention to diseases that are of special relevance to blacks. Attempting to improve the health status of blacks must be done with care. Measures that are taken to bring about a more just distribution of burdens and benefits of research may not be sufficient to overcome stereotypes and bias that may be embedded in the norms, procedures, and practices of the research establishment and elsewhere in society. Although the development of sickle cell screening programs does not involve research, experience gained from this effort in the 1970s is a contemporary caution that even well intentioned efforts to improve black health status can go awry. Screening for Sickle Cell Trait and Disease

Sickle cell anemia is a genetic disorder of varying severity that occurs with greatest frequency in the United States among people of African-American descent.

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The disease emerged from relative obscurity in the early 1970s through the wellintentioned efforts of white and black leaders to make headway against a disease that was a scourge of the African-American community. As a result of their efforts, President Richard Nixon singled out the disease for mention in his health care message of 1971 and called for special efforts to combat the disease. In turn, states passed sickle cell screening legislation. In 1972, Congress passed the National Sickle Cell Anemia Control Act which substantially increased federal funding available for research and community services. Although the disease was not documented until 1910, sickle cell anemia nonetheless had played a role in the development of negative stereotypes and arguments to support slavery. Early on it had been observed that blacks were less affected by malaria than whites. (Subsequently, it was determined that carrying a single gene of the disease did indeed confer some protection against some forms of malaria.) This observation supported the view that blacks were different from whites and helped to justify the use of slaves in malaria infested areas. In the fifties and sixties, the disease's identification with blacks was used to justify white genetic superiority and support efforts to get blacks to move to Africa.60 The identification of the disease with African-Americans and the linkage of other genetic diseases with specific ethnic groups lent credence to the notion that other human characteristics might also be race-specific.61 There was vast public ignorance about the disease, especially about the distinction between sickle cell anemia (the disease) and sickle cell trait (the carrier status). While many persons with the disease suffer a host of medical problems, these are quite rare in those who are carriers. This confusion coupled with legislation promoting voluntary, and in some cases mandatory screening, compounded the situation as more and more people learned of their status. Many carriers of the trait, as distinguished from those afflicted with the disease, were discriminated against in employment and in insurance. Problems were severe enough that even employees of the NIH, who had not participated in the planning, rejected a screening program for themselves out of fear of the consequences of being identified as a carrier of the trait.62 Putting sickle cell anemia in the national limelight surely benefited the AfricanAmerican community. Public awareness especially among blacks was increased. Important services were made available in the black community where they had not existed before. Doors were opened to blacks interested in science, medicine, and the delivery of health care services. However, attention to sickle cell anemia brought with it other serious problems. These harms serve as a reminder that even well-intentioned efforts to address black health status must be carefully undertaken and potentially adverse consequences must be anticipated and ameliorated if possible. In contrast to sickle cell screening programs, programs for screening for Tay-Sachs disease (a genetic disease which primarily affects Jews) were implemented with relatively few adverse consequences, suggesting that it is possible to conduct genetic screening programs

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in a reasonable way. Efforts to provide benefits to African-Americans must take into account the continued existence of racism and the fact that health information may be used in a manner to disadvantage and to oppress a group.63

FUTURE TRENDS African-Americans historically and today are a "vulnerable" group not only because of their past experience of abuse and exploitation, but also because they are marked by the dominant culture in the United States as being different in ways that imply that they are inferior and deviant. In the language of the Belmont Report "injustice arises from social, racial, sexual and cultural biases institutionalized in society." At minimum, justice requires that past injustice should be remedied. Individuals harmed by past policies and practices should receive compensation. For example, the subjects in the Tuskegee experiment filed a lawsuit against the federal government in 1974.64 The case was subsequently settled and the government agreed to pay approximately $10 million dollars.65 On May 16, 1997, President Bill Clinton formally apologized on behalf of the federal government in a White House ceremony.66 In other circumstances, justice would require that discriminatory policies be abandoned. Harm results from failure to study diseases that particularly afflict blacks. Harm can also result from inadequate subject selection policies. Selection policies may be inadequate if blacks are selected for reasons of convenience and easy availability. They may also be unjust because they do not include AfricanAmericans in sufficient numbers to detect whether blacks respond differently to a new drug or intervention. These practices can be corrected by attending to selection procedures and instituting a fair standard for allocating resources. Remedial measures that merely reverse past unjust policies or provide monetary and other forms of compensation to individuals will not correct all the historical injustices suffered by African-Americans in research. As Debra DeBruin points out in discussing justice and women in research, a remedy must also address "cross-temporal perspective."67 She writes: ... [A] remedy must address the fact that our society's practices concerning [women in research] have created justice problems in the past, continue to create such problems in the present—both because their use in the past has deprived us of knowledge crucial to ... treatment. . . now and because the practices continue in the present—and will continue to create justice problems in the future unless something is done.68

DeBruin calls for preferential policies for women in research as the only way to insure that full justice is afforded women for past wrongs. Her argument is also applicable to African-Americans. At most, race-neutral allocation policies will

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prevent the gap between black and white health status from widening. They will not close the gap. Even affirmative efforts to remedy past injustice will not protect AfricanAmericans from some of the burdens that have accompanied attention to black health status. For example, increased resources available for services and research on sickle cell anemia did not protect carriers of the sickle cell trait from discrimination. In order to fully account for the role that stereotypes, bias, and other oppressive practices have played in disadvantaging blacks in research, institutional practices need to be evaluated and modified. Larry Palmer argues that institutional arrangements in the Tuskegee experiment should be studied to ascertain what, if any, role they played in the initiation and implementation of the study.69 In doing so, he hopes that we might abandon the search for bad professionals and examine instead bad institutional arrangements. As a starting point, he recommends examining the assumptions that drive professional behavior. He believes that one of these assumptions is the view that knowledge about disease, rather than socio-economic factors, for example, should determine the most efficient use of health resources.70 Evaluating and modifying institutional arrangements takes us beyond purely distributive concerns to an examination of decision making and other procedural aspects of research. Such an examination is necessary to insure a just research program in the future. I have already suggested in my discussion of the Tuskegee Syphilis Study that a research model that has at its primary focus defining, obtaining, and monitoring the informed consent process may not be the best model for protecting those who have suffered from past injustice. Another possible change in institutional arrangements is to increase the power and influence of African-Americans over the research agenda. Bowman urges that in addition to ethical and scientific guidelines "research among racial minorities also must be guided by what may be referred to as the principles of significant involvement and functional relevance. In this context, significant involvement calls for the members of the group under study to have a central role in the entire research process. Functional relevance dictates that studies should operate to promote the needs and perspectives of the study population."71 Proposals for increased enrollment of African-Americans in research have argued for community involvement in recruitment. Community involvement is desirable because it helps to overcome the legacy of black mistrust of medicine. However, not even community involvement can ensure that the interests of blacks will be protected in the absence of power and influence over the research agenda.72 First, such influence helps to ensure that the health interests of blacks, as perceived and understood by blacks, will receive attention. Setting a research agenda is not a purely objective process but rather the product of the values and biases of those who establish the priorities. For example, African-Americans may give higher priority to the social and economic determinants of disease rather than the genetic

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basis of disease. Second, African-Americans may have a different conception of the burdens of research in terms of the likelihood that some research might fuel and further shape existing negative stereotypes.73 Finally, the ability to shape and control the research agenda may go far in helping to ameliorate the fear and suspicion—the product of the long history of involvement with medicine—that resides in the black community about medicine and biomedical research. Focusing on institutional arrangements points to a matter that needs immediate attention—the clarification of the use of race in medical and epidemiological research. Race is used extensively as part of the normal discourse of clinical medicine and population-based research. It is used as a key variable along with gender and age.74 The assumption is that race tells us something important. The unanswered question is what does it tell us? Does the use of race as a variable refer to physiological/anatomical differences, genetic differences or is it just a proxy for social and economic status that is relevant to health status? The terms black and white in connection with persons has no inherent meaning. In the United States racial status is socially constructed. Historically, the group variously denominated Negro, colored, African-American or black legally included anyone who descended from African slaves.75 Fullilove accurately identifies the problem and the danger of using race as a variable in research: All to often, when race is found to explain a significant portion of the variation in some health outcome, little is done to explain the meaning of the association. The result is that medical researchers act as if there were inherent—if undefined—differences between racial groups that, once signaled, require no further explanation. In an odd way, there is little difference at times between our modern science and the discredited practice of using science and medicine to justify slavery in the antebellum South: each assumes that racial differences are of unquestioned importance.76

Using race as a category in medical research may confer some benefits. It can focus attention on those at greatest risk of disease or disability and in greatest need of care. For example, it may reveal that African-Americans are afflicted with some diseases and conditions with greater frequency or severity than others. This information might lead to clinical benefits. Data that indicate that blacks and whites metabolize the same drug differently can be important in providing adequate health care.77 Whether better information will actually be used to improve health care is of course another matter. Using race as a variable may also cause harm. For instance, research findings can be used to reenforce the view that health outcomes are due to biology rather than social and economic class or lifestyle.78 Research on racial differences is not only a problem in medicine, but in addition, supports the continued use of negative stereotypes and racist thinking in society generally. It has been suggested that this impact is multiplied because there is a tendency to conduct research with ra-

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cial comparisons in connection with diseases associated with sexually-transmitted diseases, intellectual performance, drug abuse, and violence.79 Viewing problems as issues of biology may distract attention from the need to correct social conditions that predispose to disease. In view of the potential risks and benefits of using race as a variable, researchers should pay careful attention to their conceptualization of race and be required to provide justification explicitly for its use (or exclusion) in investigation of possible racial differences.80 Where researchers find differences in results along racial lines, they should be clear about what is known or not known about the reasons—genetic or social or socioeconomic status—for such differences. In view of the deeply ingrained racism in American institutions, perhaps more far reaching requirements than just a plea to pay careful attention to race are warranted. For example, Osborne and Feit suggest notifying subjects when race is a category because they have a right to know the consequences of dissemination of questionable racial data.81 Guidelines that are more specific may be needed to assist those evaluating research protocols particularly where race as a variable is used. For example, research protocols that are relevant to African-American health but do not use race as a variable might be distinguished from research that employs the variable of race. Research using race as a variable might be further distinguished according to whether biological or sociological components of race are involved. Some types of protocols using race as a variable might require greater justification or be subject to multiple levels of scrutiny. For example, research involving biological differences in view of the historical tendency to use biological data to mark blacks as deviant might require greater justification than research directed at uncovering prevalence of disease in particular groups. In seeking justice for African-Americans in research, an historical perspective teaches that race matters and must be attended to. Clarifying the use and measurement of race as a variable in research incorporates this lesson. Closely scrutinizing how race is used in research emphasizes the significance of scientific merit, research design and methodology, and investigator competence as a means of protecting subjects and insuring that they are fairly treated. While these matters are incorporated in current procedures for reviewing and monitoring human subjects research, they do not receive the same level of attention by IRBs as do informed consent requirements.

CONCLUSIONS

The goal of just research policies is to protect African-American participants in research and at the same time avoid undue imposition of burdens on research that offers promise of improving their health status in the future.82 An historical examination of African-American experiences with medicine and medical research

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indicates that obtaining informed consent may not be enough. It also offers clues about the nature of the injustice that African-Americans have suffered. This examination indicates that African-Americans have been exploited, and they have suffered harm for which they should be compensated. This examination further shows that the burdens and benefits of research have not been fairly distributed. An adequate remedy for this unfair distribution that corrects past injustice and allows for just treatment in the future may require preferential policies. Finally, an historical examination demonstrates not only the need to attend to maldistribution but also to critically examine the institutional norms and arrangements that govern the research enterprise. Justice in research requires that all aspects of injustice be accounted for and addressed. NOTES 1. In this chapter the terms black and African-American are used interchangeably. For a brief discussion of the terms used to describe persons who descend from African slaves see "The Emergence of the Term 'African American' at Two Prestigious Institutions: The New York Times and the Supreme Court," The Journal of Blacks in Higher Education 16:12-15; Summer 1997. 2. The relationship between race and ethnicity is not well defined or understood. In general, ethnicity pertains to characteristics of a group of people who share a culture, religion, language or the like. In health research, classifying research subjects in terms of ethnic group identity may provide valuable information about lifestyle, diet or values that relate to health outcomes. Thus, different ethnic groups with the same socio-economic status might have different health outcomes. See Anna C. Mastroianni, et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. 1, pp. 115-119. 3. Vanessa Northington Gamble and Bonnie Ellen Blustine "Racial Differentials in Medical Care: Implications for Research on Women," in Anna C. Mastroianni, et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. 2, 174-191. 4. Todd Savitt notes that "[s]elf interest was an important factor in whites' use of blacks as objects of research and study in antebellum times." Todd L. Savitt, "Minorities as Research Subjects," Encyclopedia of Bioethics, 2nd ed. (New York: Simon and Schuster Macmillan, 1995), Vol. 3, pp. 1776-1780. Marion Torchia discussing Maryland's First State Conference on Tuberculosis notes: A central idea expressed by the conferees was that the self-interest of whites demanded an effort to cure blacks. It was pointed out that whites were necessarily in contact with the blacks who were their cooks and laundresses, and that segregation, though perhaps desirable as a social custom, could not offer protection against disease. This candid admission of self-interest led to the wholesome realization that the treatment of tuberculosis in blacks was not a matter of charity, but of public health.

Marion Torchia, "The Tuberculosis Movement and the Race Question, 1890-1950," Bulletin of the History of Medicine 49:152-168; 1975. 5. The author of this chapter was a member of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.

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6. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects, Federal Register Document 79-12065, April 18, 1979. 7. Iris Marion Young, Justice and the Politics of Difference (Princeton, NJ: Princeton University Press, 1990), p. 39. 8. Ibid., p. 41. 9. Ibid., p. 49. 10. Ibid., pp. 58-59. 11. Ibid., p. 59. 12. The importance of taking account of experiences in health care as well as research was noted in Anna C. Mastroianni, et al, eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. 1, p. 118. 13. Mari J. Matsuda, "Looking to the Bottom: Critical Legal Studies and Reparations," Harvard Civil Rights-Civil Liberties Law Review 22:323-399; 1987. 14. Charles Marwick, "Questions Raised About Measles Vaccine Trial," JAMA 276:1288-1289; October 23/30, 1996. 15. Federal Register, Vol. 61:192 (2 October 1996), pp. 51497-51431. 16. Annette Dula, "Bearing the Brunt of the New Regulations: Minority Populations," Hastings Center Report 27:11-12; January-February 1997. 17. See, for example, Atwood Gaines, "Race and Racism," in Warren T. Reich, ed., Encyclopedia of Bioethics, 2nd ed. (New York: Simon and Schuster Macmillan, 1995), Vol. 4, 2189-2201; and Todd L. Savitt, Medicine and Slavery: The Diseases and Health Care of Blacks in Antebellum Virginia (Urbana, IL: University of Illinois Press, 1978), pp. 7-47. 18. See, for example, James O. Breeden, "States-Rights Medicine in the Old South," Bulletin of the New York Academy of Medicine 52:348-372; March-April 1976. 19. John S. Haller, Jr., "The Physician Versus the Negro: Medical and Anthropological Concepts of Race in the Late Nineteenth Century," Bulletin of the History of Medicine 44:154-167; March-April 1970. 20. Ibid. 21. Ibid. 22. Two such diseases were drapetomania and dysaesthesia Aethiopis. The former was described as a disease that caused slaves to run away. The cure was to treat kindly, feed, and clothe, etc. The latter disease made slaves obstreperous, that is they created disturbances, wasted and destroyed materials, and were insensitive to pain when punished. James O. Breeden, "States-Rights Medicine in the Old South," Bulletin of the New York Academy of Medicine 52:358. For other diseases see, James H. Jones, Bad Blood: The Tuskegee Syphilis Experiment, new and expanded edition (New York: The Free Press, Macmillan, Inc., 1993), p. 17. 23. Todd L. Savitt, Medicine and Slavery; The Diseases and Health Care of Blacks in Antebellum Virginia, pp. 18-41. 24. Marion M. Torchia, "The Tuberculosis Movement and the Race Question, 18901950." 25. Torchia in writing about tuberculosis states "racial studies have always been beset by extraordinary hindrances to the achievement of scientific objectivity and factual documentation. "Marion M. Torchia, "Tuberculosis Among American Negroes: Medical Research on a Racial Disease, 1830-1850," Journal of the History of Medicine and Allied Sciences 32:252-279; July 1977. Breeden agrees with her assessment but urges that southern physicians were not solely propagandists. James O. Breeden, "States-Rights Medicine in the Old South," p. 348.

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26. Vanessa Northington Gamble and Bonnie Ellen Blustein, "Racial Differentials in Medical Care: Implications for Research on Women," in Anna Mastroianni, et al, eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. 2, pp. 174-191, 180-182. 27. John S. Haller, "The Physician Versus the Negro: Medical and Anthropological Concepts of Race in the Late Nineteenth Century," p. 155. 28. Ibid. 29. See, for example, William E. Burghardt Dubois, ed., The Health and Physique of the Negro American: Report of a Social Study Made Under the Direction of Atlanta University; Together with the Proceedings of the Eleventh Conference for the Study of the Negro Problems, held at Atlanta University, on May the 29th, 1906 (Atlanta: The Atlanta University Press, 1906). 30. John S. Haller, Race, Morality and Life Insurance: Negro Vital Statistics in the Late 19th Century," Journal of the History of Medicine and Allied Sciences 25:247-261; July 1970. 31. Marion M. Torchia, "Tuberculosis Among American Negroes: Medical Research on a Racial Disease, 1830-1850," p. 258. 32. William Bynum, "Reflections on the History of Human Experimentation," in S.F. Spicker et al., eds., The Use of Human Beings in Research (Dordrecht, Holland: Kluwer Academic Publishers, 1988), pp. 29-46. Bynum points out that from the eighteenth century onward, hospitals began to assume their modern character. They were teaching, service, and research institutions. 33. Todd Savitt, "The Use of Blacks for Medical Experimentation and Demonstration in the Old South," Journal of Southern History 48:331-348; August 1982. 34. Todd S. Savitt, Medicine and Slavery: The Diseases and Health Care of Blacks in Antebellum Virginia, p. 282. 35. David C. Humphrey, "Dissection and Discrimination: The Social Origins of Cadavers in America, 1760-1915," Bulletin of the New York Academy of Medicine 49:819-827; September 1973. 36. Todd L. Savitt, "The Use of Blacks for Medical Experimentation and Demonstration in the Old South," p. 337. 37. Vanessa Northington Gamble, "A Legacy of Distrust: African Americans and Medical Research," American Journal of Preventive Medicine 9 (6 Suppl.):35-38, November-December 1993. 38. Diane E. Axelsen, "Women as Victims of Medical Experimentation: J. Marion Sims' Surgery on Slave Women, 1845-1850," Sage 2:10-13; Fall 1985. Sims also developed the speculum which allowed visualization of the vagina and cervix. 39. David A. Richardson, "Ethics in Gynecologic Surgical Innovation," American Journal of Obstetrics and Gynecology 170:1-6; January 1994. 40. Diana E. Axelsen, "Women as Victims of Medical Experimentation: J. Marion Sims' Surgery on Slave Women, 1845-1850," p. 11. 41. Ibid., p. 12. 42. See Vanessa Northington Gamble, "A Legacy of Distrust: African-Americans and Medical Research;" and James H. Jones, "The Tuskegee Legacy: AIDS and the Black Community," Hastings Center Report 22:38-40; November-December 1992. 43. Todd L. Savitt, "The Use of Blacks for Medical Experimentation and Demonstration in the Old South," p. 341. 44. The seminal account of the Tuskegee syphilis experiment is found in James H. Jones, Bad Blood: The Tuskegee Syphilis Experiment, new and expanded edition.

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45. Allan M. Brandt, "Racism and Research: The Case of the Tuskegee Syphilis Study," Hastings Center Report 8:21-29; December 1978. 46. Evelyn Brooks Higginbotham, "African-American Women's History and the Metalanguage of Race," in Ruth-Ellen B. Joeres and Barbara Laslett, eds., The Second Signs Reader: Feminist Scholarship, 1983-1996 (Chicago, IL: The University of Chicago Press, 1996), pp. 3-26, at p. 17. Jones also points out that the physicians also ignored the plight of innocent black babies born with the disease. James H. Jones, Bad Blood: The Tuskegee Syphilis Experiment, New and expanded ed., pp. 22-23. 47. See, Stephen B. Thomas and Sandra Grouse Quinn, "Public Health Then and Now: The Tuskegee Syphilis Study, 1932 to 1972: Implications for HIV Education and AIDS Risk Education Programs in the Black Community," American Journal of Public Health 81:1498-1505; November 1991 (citing James H. Jones). 48. Allan M. Brandt, "Racism and Research: The Case of the Tuskegee Syphilis Study," p. 27. 49. Ibid. 50. Some argue that class is the key issue in the Tuskegee experiment. Indeed, it is important to understand the class issues that lurk in the study. It is unlikely that the inducements and incentives offered subjects to participate in the experiment would have appealed to middle class black persons. Moreover, black professionals helped to carry out the experiment. The fact remains, however, that the subjects were all poor black men and that those who conceived and designed the experiment were all white male physicians. 51. Final Report of the Tuskegee Syphilis Study Ad Hoc Advisory Panel, Department of Health, Education, and Welfare (Washington, DC: Government Printing Office, 1973), p. 7. 52. Robert Burt, "The Suppressed Legacy of Nuremberg," Hastings Center Report 26:30-33; September-October 1996. 53. Patricia A. King, "The Dangers of Difference," Hastings Center Report 22:35-38; November-December 1992. 54. See, for example, Stephen E. Toulmin, "The National Commission on Human Experimentation: Procedures and Outcomes," in H. Tristam Engelhardt, Jr. and Arthur Caplan, eds., Scientific Controversies: Case Studies in the Resolution and Closure of Disputes in Science and Technology (New York: Cambridge University Press, 1987), pp. 602-606. 55. U.S. Department of Health and Human Services, Task Force on Black and Minor-

ity Health, Report of the Secretary's Task Force on Black and Minority Health. 1 vols. (Washington, DC: U.S. Government Printing Office, 1985). 56. Todd L. Savitt, "Minorities as Research Subjects." 57. U.S. Department of Health and Human Services, Task Force on Black and Minor-

ity Health, Report of the Secretary's Task Force on Black and Minority Health, Vol. 1, p. 37. 58. Ibid. 59. See, for example, National Institutes of Health Revitalization Act: Subtitle B, Clini-

cal Research Equity Regarding Women and Minorities, P.L. No. 103-43, United States Statutes at Large 107 (1993): 133 (to be codified at 42 U.S.C. §§283-290 (1993)); NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research, Federal Register 59 (March 9, 1994): 11146-11151; Centers for Disease Control and Prevention, Agency for Toxic Substances and Disease Registry, Policy on the Inclusion of Women and Racial and Ethnic Minorities in Externally Awarded Research, Federal Register 60 (September 15, 1995): 47947-47951.

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60. Todd L. Savitt, "The Invisible Malady: Sickle Cell Anemia in America, 19101970," Journal of the National Medical Association 73:739-746; 1981. 61. P. Selvin, "The Raging Bull of Berkeley," Science 251:368-371; 1991. 62. Barbara J. Culliton, "Sickle Cell Anemia: National Program Raises Problems as Well as Hopes," Science 178:283-286; October 20, 1972. 63. George Lundberg, Editor of the JAMA recognizes that institutionalized racial discrimination has prevented substantial improvement in black health status. Lundberg, G., "National Health Care Reform: An Aura of Inevitability is Upon Us," JAMA 265:25662567; 1991. 64. See plaintiff's complaint, Pollard v. United States, 384 F. Supp. 304 (M.D. Ala. 1974) (No. 4126-N). 65. James H. Jones, Bad Blood: The Tuskegee Syphilis Experiment, New and expanded edition, p. 217. 66. John F. Harris & Michael A. Fletcher, "Six Decades Later, An Apology: Saying 'I Am Sorry,'President Calls Tuskegee Experiment 'Shameful,'" Washington Post, May 17, 1997, at Al. Persons involved in human radiation experiments at Cincinnati General Hospital have also filed a lawsuit. See In Re Cincinnati Radiation Litig., 874 F. Supp. 796 (S.D. Ohio 1995). At the time that this chapter is being written the parties are considering settlement. 67. Debra DeBruin, "Justice and the Inclusion of Women in Clinical Studies: An Argument for Further Reform," Kennedy Institute of Ethics Journal 4:117-146; June 1994 citing Thomas E. Hill, Jr., "The Message of Affirmative Action" in his Autonomy and Self-Respect, (New York: Cambridge University Press), pp. 189-211. 68. Ibid. 69. Larry I. Palmer, "Paying for Suffering: The Problem of Human Experimentation," Maryland Law Review 56:604-623; 1997. 70. Ibid., p. 613. 71. Phillip J. Bowman, "Race, Class and Ethics in Research: Belmont Principles to Functional Relevance," in Reginald L. Jones, ed., Black Psychology, 3rd edition (Berkeley, CA: Cobb & Henry Publishers, 1991), p. 754. 72. It is important to note that the PHS used recruitment strategies in the Tuskegee experiment that reflected a high level of understanding of the cultural context of the study and the need to involve professionals in the community. Thomas and Quinn note that "[t]he value of these community-based strategies should not be diminished by their association with the Tuskegee Syphilis Study." Stephen Thomas and Sandra Crouse Quinn, "Public Health Then and Now: The Tuskegee Syphilis Study, 1932 to 1972: Implications for HIV Education and AIDS Risk Education Programs in the Black Community," p. 1503. 73. See, for example, Lynne Duke, "Controversy Flares Over Crime, Heredity," Washington Post (August 19, 1992), p. A4. 74. Atwood D. Gaines, "Race and Racism," p. 2196. 75. The so-called, "one-drop rule" was one of the most frequently used definitions of race. Other legal and regulatory definitions have been employed. Vanessa Northington Gamble and Bonnie Ellen Blustein, "Racial Differentials in Medical Care: Implications for Research on Women," in Anna C. Mastroianni et al., eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. 2, pp. 174-191. 76. Mindy Thompson Fullilove, "Deconstructing Race in Medical Reseaxch," Archives of Pediatrics and Adolescent Medicine 148:1014-1015; October 1994. 77. Vanessa Northington Gamble and Bonnie Ellen Blustein, "Racial Differentials in Medical Care: Implications of Research on Women," in Anna C. Mastroianni et al., eds.,

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Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies Vol. 2, pp. 174-191. 78. See, for example, Newton G. Osborne and Marvin D. Feit, "The Use of Race in Medical Research," JAMA 267:3150-3151; January 8,1992; Trevor A. Shelton and Hilda Parker, "Race and Ethnicity in Health Research," Journal of Public Health Medicine 14:104-110; 1992. 79. Newton G. Osborne and Marvin D. Feit, "The Use of Race in Medical Research," p. 275. 80. African-Americans can be harmed by using as well as failing to use race as a variable in research. There are indications that failure to use blacks in some AIDS research might have disadvantaged blacks. See Paul Cotton, "Race Joins Host of Unanswered Questions on Early HIV Therapy," JAMA 265:1065-1066; March 6,1991. However, it is important to note that from an historical perspective most of the burdens come from using race as a variable. 81. Newton C. Osborne and Marvin Feit, "The Use of Race in Medical Research," p. 278. 82. Alexander Morgan Capron, "An Egg Takes Flight: The Once and Future Life of the National Bioethics Advisory Commission," Kennedy Institute of Ethics Journal 7:6380; March 1997.

7 CONVENIENT AND CAPTIVE POPULATIONS Jonathan D. Moreno

Clinical research is a complex, expensive and valued social activity. One of the conditions that makes clinical research possible is a subject population that is convenient, both in terms of availability for recruitment and for monitoring through the course of a study. Examples of such populations are prisoners, institutionalized persons, military personnel, and those in "status relationships" (those of lesser power) such as students and research staff.1 Some of these populations are convenient in the sense that they are readily available, such as students. Others are not only readily available but also captive, that is, constrained in their movements and choices by virtue of explicit conditions formally imposed on them by societal decision. The paradigm case of a captive population is those who are imprisoned. Other populations seem to occupy a middle ground between short-term hospitalized patients and long-term prisoners, including students, institutionalized persons, and military personnel. Among the ways that these populations differ from others are their degree of availability, the greater likelihood that those who are captive can be coerced or manipulated into participation by virtue of their dependent status, and that captive populations are more likely than others to be readily available for research activities for extended periods, enhancing their attractiveness to the research enterprise. 111

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This chapter suggests that the growing sensitivity to the use of such populations in research cannot be understood without an appreciation of the historical background. The history of research on these subject populations is important because it provides the rationale for classifying them as "vulnerable." Therefore, this chapter first reviews the historic roles of prisoners, institutionalized children and adults, military personnel, and students and staff in research activities. The discussion of each particular subject population also includes an account of the way the regulatory system has evolved to take account of historic abuses. Because these groups are not convenient or captive—or even vulnerable—in the same ways, crafting a just, efficacious, and reasonable public policy in the use of these populations in biomedical and behavioral research is not easy. For instance, a rough notion of justice may find it acceptable to impose greater burdens on prisoners because of their debt to society. Similarly, it might be argued that those who are institutionalized may need to be used to serve some important research goal, especially if no other population so readily presents itself for study. Nevertheless, historically, these attitudes have sometimes had baleful consequences. Further, our intuitions about justice in research may yield inconsistent results. For example, turning soldiers into "guinea pigs" may either be offensive to patriotic sensibilities or seem reasonable in light of soldierly duties; while students and laboratory workers could be viewed either as too easily coerced into research or as the most appropriate candidates due to their ability to understand an experiment's purposes. All these views have been represented in the history of medical research with these populations, indicating how important it has been to craft a coherent and historically informed conception of justice in research, forged to fit the special nature of convenient and captive populations. One element that crops up repeatedly in the research context for which a more general notion of justice is illprepared, is that human subjects are often used in research that is not intended to benefit them but other individuals. Likewise, a population may be used in studies that develop treatments intended mainly, or exclusively, to benefit other groups. Any reasonably well-formed conception of justice in research will need to reckon with these special circumstances. Discussions such as this tend to focus on ethical abuses or areas of potential moral concern. It should be remembered, however, that much human-subject research has contributed greatly to human well-being and has been conducted according to sound ethical standards. Such standards include efforts to prevent the burdens of research from falling unfairly on any particular person or group. This chapter will show how attitudes toward certain populations from which research subjects may be drawn have changed, and to indicate some of the issues that remain to be resolved. Because it is described in Chapter 3, the use of hospitalized patients in research will not be discussed in detail.

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JUSTICE ACROSS TIME Prisoners

There is none more fully captive than the long-term prisoner. Among the apocrypha of medical history are tales of the use of living criminals as subjects in various medical studies in the ancient world, including poison experiments and vivisection. In the eighteenth century, European physicians exposed prisoners to venereal disease, cancers, typhoid, and scarlet fever. An influential study of pellagra in 1914 used Mississippi convicts and presaged greater use of this population.2 During World War II in the United States, many prisoners agreed to participate in studies of conditions such as malaria and sexually transmitted diseases, partly as an expression of patriotism and partly in response to other motivations such as opportunities for payment and early parole. After the war, a trial of those accused of conducting horrific experiments on concentration camp inmates was held in Nuremberg, West Germany. The defense attorneys in the trial pointed to cases of prison research in the United States and elsewhere as part of their justification for their clients' conduct. Among the many instances cited by the Nazis' lawyers were the pellegra and malaria studies, as well as that of an American team of researchers who received permission from the governor of the Philippines to use condemned criminals and other convicts in typhus and beriberi experiments.3 Although the Nuremberg judges sentenced some of the defendants to death and others to lengthy jail sentences for experiments on concentration camp prisoners, there was little apparent effect on the conduct of research involving American prisoners. During the Second World War, American prisoners were known as and considered to be "volunteers," while the Jewish and other victims of Nazi experiments were seen as forced participants. In fact, at the same time that Illinois physician Andrew Ivy was authoring portions of what would become the Nuremberg Code (as the AMA's representative at the trial), he also chaired a committee appointed by the governor of Illinois to review the ethics of prison research. The committee argued for constraints on the use of prisoners in research but implicitly endorsed the continued use of this population. Reporting only a few months after the Nazi doctors' trial, Ivy's committee effectively forestalled the direct application of the results of the trials to American prison research.4 Several years later, an early draft of the Declaration of Helsinki that would have explicitly prohibited prison research was revised at the insistence of the United States.5 Over the next decade several drug manufacturers made substantial investments in prison research, and in some cases even erected buildings with state-of-the-art laboratory facilities at penitentiaries. By 1960, as many as 20,000 federal prisoners were participants in medical experiments.6 In 1973, the Pharmaceutical Manu-

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facturers Association estimated that about 70% of Phase I drug tests were carried out on prisoners, or about 3600 individuals.7 American prisoners and prison-based facilities were also being used to test drugs for researchers abroad.8 Some prison experiments were sponsored by the federal government. One involved the irradiation of the testicles of 131 prisoners in state penitentiaries in Oregon and Washington State between 1963 and 1973 and was funded by the Atomic Energy Commission (AEC). There were clear rules in place within the AEC that should have applied to these studies, including a requirement for written consent from subjects. However, in 1995 the President's ACHRE found that these rules were not fully observed in the testicular irradiation research. Among other things, ACHRE was critical of the failure to use the word cancer in listing possible risks, especially with these healthy, "volunteer" subjects.9 Among the attractions to research for prisoners were far higher pay than was afforded by other prison jobs, the possibility of a more favorable parole status, a break in the boredom of incarceration, and often better food and living conditions. A 1974 editorial in the Journal of Legal Medicine argued that as long as prisoners are free to enter and leave a research program at any time, and if they understand the hazards of participation, they should be free to make this choice. The writer suggested that it would be "immoral in itself to deny them this opportunity," and "an abridgment of whatever civil and constitutional rights they may possess." So it was argued that their very rehabilitation could turn on this decision. "There is no doubt," the editorial concluded, "that biomedical research is an absolute necessity if society is to survive." Implicit in this conclusion was that prisoners are a critically important subject pool in the advancement of science.10 In the mid-1970s the use of prison inmates in medical research in the United States began to decline sharply, and was finally reduced almost to the point of extinction. One reason for the change in practice was a recommendation by the National Commission in 1976 that a moratorium be declared on prisoner experiments pending the adoption of some standards. The National Commission's recommendation followed the revelation of the Tuskegee Syphilis Study, as well as a bloody prison riot at the Attica State Penitentiary in September 1971. The Attica disturbances met with a fierce response by New York State Police that left dozens of African-American prisoners dead and exposed the awful living conditions to which the prisoners had been subjected. The combination of Tuskegee and Attica cast a novel and unflattering light on the coercive nature of prison life, and, to many, the coercive nature of using prisoners in research.11 The National Commission's moratorium proposal met with harsh criticism from virtually every affected party: physicians, advocates, and prisoners themselves. One distinguished commentator, Louis Lasagna, charged that the National Commission's recommendations "illustrate beautifully how well-intentioned desires to protect prisoners can lead otherwise intelligent people to destroy properly performed research that scrupulously involves informed consent and full explanation and avoids coercion

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to the satisfaction of all but the most tunnel-visioned doctrinaire."12 The DHEW (Department of Health, Education and Welfare, a predecessor to the Department of Health and Human Services), instead promulgated regulations that effectively prohibit nearly all prison research. The premise that prison research is acceptable if prisoners are free to decline to participate is, admittedly, question-begging, and the proposition that society's survival depends on biomedical research is, if not hyperbolic, in need of defense. Yet, there may be validity in the claim that research participation can forge a sense of connection to society among those who otherwise have little opportunity to feel part of any community beyond the institution. As the National Commission heard from one inmate, "It makes a prisoner feel good to volunteer. It makes him feel like he's doing something productive." But, the National Commission also heard that the primary reason for volunteering was financial, because opportunities in prison to earn money for oneself or loved ones on the outside are few.13 During the early 1990s, prison research was allowable under federal regulations for only four highly restricted kinds of research: minimal risk research on incarceration and criminal behavior, studies of prisons as institutions or prisoners as incarcerated persons, research on conditions that particularly affect prisoners as a class, and studies of therapies likely to benefit the prisoner.14 Under the last two conditions prison studies have been conducted on HIV/AIDS and on multiple drug-resistant tuberculosis, a disease that can occur in prisons due to the combination of the density of living conditions and a high prevalence of HIV.15 There has, therefore, been a shift from well-established use of prisoners for research purposes to a protectionist regulatory framework. To find a proposed research project ethically sound, this protectionist philosophy requires a narrow construal of potential benefits to prisoners as a group or as individuals. There is considerable irony about the formation of the current public policy concerning prison research. In the most thorough scholarly analysis of the policy shift that took place in the late 1970s on the use of prisoners as subjects, historian Jon Harkness concludes that there was no contemporary social consensus on the matter. Instead, Harkness contends, retrospective consensus formed in opposition to prison research only after it had been banned by the DHEW for administrative reasons.16 In this case a widespread moral intuition seems to have come about without benefit of information about the facts of the practice in question. For example, an intuition about prison research that it invites exploitation of inmates, may also lead one to believe that the most vulnerable groups in our society would be most likely to be exploited in prison research. But it is well documented that for most of the post-World War II period African-American prisoners were, if anything, underrepresented as prison research subjects. The reason: participation in medical experiments was considered to be a privilege that would be afforded mainly to white convicts. This situation only began to change with the success of the civil rights

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movement.17 Similarly, by the 1960s untoward inducements for prisoner participation, such as time towards parole and high reimbursement rates, were being significantly curtailed.18 All this suggests that, if the potential for coercion is taken to be the main problem of prisoners' research participation, it may not have formed a credible basis for the ultimate strict curtailment of their inclusion. However, such a line of analysis presupposes that coercion is the only ethical problem with prison research. According to the Belmont principles, prison research would create ethical difficulties even if conducted in a manner consistent with respect for persons and beneficence, because it singles out a specific population for research participation which will then be disproportionate to that of other groups.19 Thus even if the problem of coercion was resolved to our complete satisfaction, and even if we knew that participation advances the rehabilitation process, there would still be a fatal flaw. Because prisoners have in fact played a disproportionate role in research whenever and wherever such research has been permitted, their use would normally be unethical no matter how ethically satisfactory the research was in other respects. Institutionalized Persons

The adjective "institutionalized" is used to indicate those who are chronically dependent upon professional care, as compared with those for whom dependence is relatively brief and episodic, as in the case of most hospitalized patients. Persons in this category of particular concern to an examination of justice in research are those institutionalized persons who are cognitively impaired or mentally ill. The history of the use of these populations is considerable. For example, during the Second World War, the federal Committee on Medical Research (of the White House's Office of Scientific Research and Development), approved the use of asylum patients in Mississippi in studies of influenza.20 In 1967, one year after Harvard anesthesiology professor Henry Beecher published his landmark paper identifying several instances of unethical research, British physician H.M. Pappworth described a number of ethically suspect medical experiments, among them a study of blood flow in the brains of 105 elderly demented patients. The research involved the insertion of two long needles into each jugular vein and a third in the femoral artery of the groin, and the subsequent inhaling of radioactive gas. As was true for the experiments described in the Beecher article, this study and several similar ones were published in major scientific periodicals, including the British Medical Journal and the Journal of Clinical Investigation, suggesting that research with cognitively impaired persons was both common and accepted.21 More recently, controversy has surrounded the use of schizophrenic patients in "drug free" research, also referred to as "washout studies," in which patients are taken off psychoactive medications so that a baseline of behavior can be estab-

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lished and new drugs introduced to assess their effects. Public attention was called to this practice by the suicide of a patient who had been a subject in such a study at the University of California at Los Angeles (UCLA) 2 years before. In their investigation of the UCLA study, the federal OPRR found nothing unethical in the conduct of the research, but was critical of the consent form's failure to indicate clearly that a patient's schizophrenic symptoms may recur.22 Although federal regulations were codified for prisoners in 1981, there are no federal regulations concerning the use of adults with diminished decision making capacity, in spite of the National Commission's recommendations concerning this population. As a result, conditions for the ethical participation of incapacitated adults in research is an unsettled area, not only for those whose source of incapacity is mental illness, but also those who become incapacitated secondary to another medical condition. However, public interest in revisiting the regulation of research with those who are "decisionally impaired" seems to be building.23 One element of this trend is the growing promise of interventions in Alzheimer's disease and associated dementias. These persons have varying degrees of capacity and it is argued that their mental status should be no reason for excluding them from their best therapeutic hope, namely the interventions available through research. At least two sets of ethics guidelines have been suggested for research with this population.24 While some advocate regulation that would enable research to proceed with greater confidence, others emphasize the risks associated with some research strategies, such as "drug holidays," in which psychoactive medications are withdrawn so that the patient returns to a baseline level of functioning.25 To some degree this difference of opinion about the need for protection for the decisionally impaired may stem from the specific study population, with greater support of research coming from those interested in conditions such as Alzheimer's disease, as compared with psychiatric diseases such as schizophrenia. Institutionalized children include mentally infirm minors as well as those who are simply indigent. Whatever the reason for their institutionalization, these children are captive in a double sense, for not only are they dependent upon the care of others in an artificial setting, but they are also legally and often practically incapable of making meaningful decisions on their own behalf. Therefore, decisions to permit their participation in medical research are generally out of their hands, and are the province of a parent or legal guardian; frequently in the history of research with institutionalized children, the state has been the decision maker. In 1759 Francis Home, a Scottish physician, attempted to protect 12 children from measles by inoculating them with blood taken from a measles patient, having promised a payment to their parents.26 During the next 100 years several other similar efforts to prevent measles were made with children, including residents of a Chicago orphan asylum.27 At the end of the eighteenth century, Edward Jenner tested his smallpox vaccine on his 1 year-old son. Institutionalized children were

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then used to test Jenner's vaccine, when Thomas C. James inoculated 48 children in the Philadelphia almshouse in 1802.28 The growing interest in diseases of childhood throughout the nineteenth century found ready research and training sites in the increasing number of schools, orphanages, reformatories, and foundling homes. Studies on institutionalized children were undertaken for pertussis, pellegra, sexually transmissable diseases, scarlet fever, diphtheria, tuberculosis, chickenpox, mumps, and whooping cough.29 By the turn of the century new technologies were being developed and applied to the study of the basic physiology of children, among them x-rays for the investigation of internal organs and stomach tubes for research on the mechanisms of digestion. Changing attitudes toward children and childhood during the first decades of the twentieth century soon heightened public suspicion of research practices, including the use of those who were institutionalized. In 1914, for instance, a Rockefeller Institute scientist used orphans in trials of a new test for syphilis. The New York Society for the Prevention of Cruelty to Children filed a complaint with the District Attorney. Although it was admitted that the physicians involved lacked authority to give consent, the charges were dropped. Calls to outlaw "vivisectionism" in children also resulted in proposed laws in the United States Senate and several state legislatures, none of which was passed. Nevertheless, during World War II the federal Committee on Medical Research, an arm of the Executive Office of the President, funded a number of studies in which children were subjects. In 1943, an Ohio orphanage was the site of research on dysentery; injections of killed bacteria caused serious side effects in some of the children.30 As discussed in Chapter 4, the most infamous recent study involving institutionalized children at Willowbrook State School on Staten Island, New York continues to excite controversy about its ethical standing. From the late 1950s to the early 1970s Dr. Saul Krugman and his team of infectious disease specialists from New York University conducted hepatitis research at Willowbrook. Most Willowbrook residents were severely mentally retarded and developed hepatitis through exposure to the bodily fluids of other children at the school. In order to study the natural history of the virus and in the hopes of developing a prophylaxis, Krugman and his colleagues systematically infected some newly admitted children with the virus. Parental consent was obtained, but Krugman was later criticized because those who agreed to have their children serve as research subjects were granted more rapid admission for their profoundly disabled children. Though scholarly opinion about the ethics of Willowbrook remains unsettled, and Krugman himself issued a spirited defense of his methods,31 it was one of the incidents that aroused public concern and advanced moves for greater federal regulation in the 1970s.32 Although the details of secret Cold War nutritional studies using institutionalized adolescents did not emerge until the mid-1990s, in the late 1940s and early

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1950s the AEC sponsored this research in cooperation with the makers of Quaker Oats cereal. The residents of the Fernald School in Waltham, Massachusetts were adolescents, but not as seriously disabled as those at Willowbrook. The work was performed by researchers from the Massachusetts Institute of Technology. Trace elements of radiation were introduced into the meals of male residents. Parents who gave their permission were told that their children would be in a "science club" that would include special meals, extra milk and field trips, but not that radiation was involved. The Fernald studies were subjected to official investigations many years later at both the state and federal levels. The Massachusetts Task Force on Human Subject Research concluded in 1994 that the researchers did not provide the students and their families with information critical to making an informed decision to participate in the studies.33 In 1995, the ACHRE concluded that the Fernald research, and a similar project at the Wrentham School, also in Massachusetts, "unfairly burdened children who were already disadvantaged, children whose interests were less well protected, than those children living with their parents, or children who were socially privileged."34 Current rules governing federally funded pediatric research grew out of concerns stimulated by revelation of the Willowbrook experiment and other cases. In the end, the National Commission's recommendations became the template for the rules that are now in place.35 Military Personnel

Military personnel are convenient subjects in the sense that they are typically healthy, "normal" persons who can be followed for data collection for a number of years. However, their disciplined environment raises questions about the extent to which any consent they give can be considered truly voluntary. Thus, they may be at risk for disproportionate representation in research, especially in studies relating to national security. Yet military officials have long considered voluntariness an important condition for participation in research by military personnel, as evidenced by the use of the term "volunteer" or "informed volunteer" from at least the 1940s.36 The precise significance to be given the term under the circumstances is, of course, a separate but vitally important matter. The American record in the use of military personnel in research has been mixed—a history of pioneering policies inconsistently applied. Around 1900, U.S. Army scientist Walter Reed obtained consent and asked potential subjects to sign a written contract for his yellow fever experiment in Cuba. The contract specified some of the risks, and offered nonmilitary personnel monetary compensation for participating; reportedly, soldiers declined the compensation. The $100 in gold Reed offered the Spanish workers who participated in the experiment was a significant amount of money at the time, perhaps enough to be considered coercive

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today. There was little opportunity to withdraw from the study. Reed's colleagues (but not Reed himself) on the Yellow Fever Commission also subjected themselves to the mosquito's bite that was correctly suspected as the source of infection. One of his colleagues died of the infection. Though Reed began his dangerous experiment without his superior's approval, he felt obliged to ask his commanding officer's permission when he thought it necessary to expand the study. Since at least the 1930s it appears that approval for soldiers' and sailors' participation in medical experiments was to be obtained at the highest level of the relevant uniformed service, usually from the service's surgeon general and often the service secretary as well. The assignment of military personnel to research is, after all, a deployment decision that should theoretically be made by the responsible officer in the chain of command. There are also significant potential risks to the armed forces if an experiment goes awry, especially in terms of public opinion and legal liability, constituting another reason for proper authorization of human research. During the Second World War the CMR declared that uniformed personnel were not to be used as "guinea pigs" in the war-related research it funded. Throughout this period there was significant concern that the public would not be sympathetic if their heroes were to be used in this manner. Nonetheless, during World War II naval personnel were forced to remain in mustard gas experiments against their will. By the late 1940s there was a growing view in the national security establishment that some human experiments were going to be necessary in the postwar environment, especially in reference to unconventional weapons: atomic, biological, and chemical. The effects of these weapons could not be gauged in animal studies, nor could their combat implications be assessed with other healthy subjects. Early 1950s' studies of flashblindness following atomic detonations, for example, were classified by the Pentagon as medical experiments, though most other exposures to the atomic battlefield were considered to be part of necessary training.37 The Department of Defense attempted to anticipate the problem of using military personnel in research by adopting the Nuremberg Code as its policy in 1953. Subsequently, troops deployed near the site of atomic tests were systematically observed and they sometimes filed self-reports of panic reactions near the blast site. "Release" forms were even filled out in at least some cases by troops who had "volunteered" to operate closer to ground zero than others, thus exposing them to a higher level of radioactivity. Yet in other studies involving military personnel and radiation there was no documentation of volunteer status except the statements of superior officers.38 In still other cases, such as the Air Force's mushroom cloudpenetration experiments that measured the amount of fission released by an atomic blast and its effects on crew members, there is strong evidence that at least some air force personnel were eager to experience the challenge and adventure associated with the project, while others viewed the job as part of their routine.39

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The military context presents a unique puzzle about distinguishing training, which does not typically fall under the constraints of medical ethics, from medical research, which does. For instance, the vast majority of the "atomic soldiers" deployed for exercises at the training facility at Camp Desert Rock in Nevada from 1951-1962 were kept at what was thought to be a safe distance from the atomic blast site; though any acute ill effects might have been noted, the primary goal of the activity was to learn about human factors such as panic reactions on the atomic battlefield. Although the tension between national security needs and ethical considerations was rarely a topic of public discussion during the Cold War, it played an important role in shaping the defense establishment's ambivalent posture toward human subjects issues.40 The implementation of the Nuremberg Code-based policy appears to have been sporadic at best, perhaps partly because there was confusion about its scope and application. The Army Inspector General found in 1975 that the Army had failed to comply with its own rules for the use of soldiers in research with psychoactive drugs, as thousands of men at Fort Detrick, Maryland were used in LSD experiments in the 1950s.41 Even in the courts the Code has not proven to be an effective standard. When one of the men brought suit against the United States government for injuries he incurred due to this research, the Supreme Court ruled in favor of the government by a five-to-four majority on the grounds that the judicial branch should not undermine discipline by inquiring into military matters. Only the minority argued that the Nuremberg Code must prevail.42 Today, medical research in the armed forces has both reduced its dependence on healthy, "normal" subjects and, like other sectors of American society, has established a very low threshold of risk tolerance in the development of new armaments, equipment, and materials. In 1991, the Department of Defense regulations on the use of human subjects were brought under the same requirements as other federal agencies that sponsor studies with human subjects.43 The additional regulatory obstacles to recruitment of military personnel for research are such that today this is among the most difficult populations from which to obtain subjects. Today, all research in the Army's infectious disease institute at Fort Detrick, for example, is governed by several regulations and all proposals involving significant risk must be reviewed by a local IRB, the Human Use Review and Regulatory Affairs Division of the United States Army Medical Research and Material Command, the Human Subjects Research Review Board of the Office of the Surgeon General, and the Office of the Surgeon General itself.44 In response to the recommendations of the ACHRE, in 1997 President Clinton ordered expanded training for senior officers on the nature of human subjects research, and instituted a new policy that precludes officers from involvement in the recruitment of research volunteers.45 Other recent events illustrate the special ethical difficulties associated with regulating the use of innovative drugs with military personnel during a national emer-

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gency. In late 1990 and early 1991, during Operations Desert Shield and Desert Storm, the Defense Department was concerned about possible exposure to biological and chemical warfare agents. The department successfully sought an amendment to the FDA's informed consent regulations that would enable medical professionals to determine that it was "not feasible" to obtain the informed consent of a person receiving an investigational drug or vaccine under combat conditions. The rule was published on December 21, 1990 and upheld by the courts.46 Shortly after the rule was published the Department of Defense requested and received waivers of informed consent for two investigational products: pyridostigmine bromide (PB) and botulinum toxoid (BT). Even though the waiver was obtained for both agents, Central Command elected on ethical grounds to give service personnel a choice about receiving BT, but not for PB, which was in common use as an approved drug for other populations and for which informed consent was not deemed necessary. The Pentagon estimates that about 8000 troops took BT and about 250,000 received at least one dose of PB.47 Months after the war some veterans began complaining about numerous symptoms that when grouped together are termed "Gulf War Syndrome." The vaccination program was shrouded in secrecy when it took place to deny information to the enemy about the Allies' defensive measures, but as the story emerged, the agents, especially PB, were theorized by some as a factor in the veterans' medical problems. A federal advisory committee was appointed to investigate the health problems of Gulf War veterans, including an analysis of the waiver process.48 However skeptical one might be about such claims of voluntariness against an admitted record of pressuring uniformed personnel to "volunteer," matters surely become far more complicated in the case of potentially prophylactic agents used under combat conditions. In this case it can be argued that access to compounds that have not yet been approved for use under ordinary circumstances may be ethical. The lack of approval could be due to technical or bureaucratic factors and there may be sound scientific evidence that the agent can be of significant potential benefit to troops in battle.49 Underlying much of the criticism of the Pentagon's conduct in the use of unapproved drugs is a suspicion that it was a deliberate effort to circumvent research requirements in order to assess the agents' efficacy under combat conditions. There is no evidence that this is the case. Indeed, one shortcoming of the Defense Department's handling of this episode is precisely the fact that no system was in place to document the response of service personnel to the medications, including a failure to establish appropriate baseline measures of subjects' metabolism.50 The use of these compounds "in theater" could theoretically have been justified on scientific as well as beneficent grounds if the operation had been treated as a research study according to established methodological standards. Had a systematic research dimension been part of the agents' use in Desert Storm, there then would have been an opportunity to assess the fairness of conducting re-

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search with military personnel. The assessment would have turned on the manner in which the study was conducted, for while soldiers facing combat conditions may be required to accept all medical interventions that hold the prospect of ensuring their availability for service, the innovative use of these drugs may not entail a requirement to accept them. But if the decision to use the agents could have been left to the troops themselves, with appropriate information at their disposal about known risks and benefits, then their participation would have been acceptable. Apparently this information was not made available in Desert Storm, in spite of an agreement between the Defense Department and the FDA that it would be provided.51 Students Students are captive in a different sense from any of the groups mentioned thus far. They exemplify persons who are not literally captive, and may even be among our most privileged citizens, but are in a social context characterized by power relations. In particular, their differential role is characterized by inherently lesser power than the other member of the relationship, in this instance a teacher. Students are by no means unique in this sense; other relationships that are characterized by power differentials are employers and employees, and supervisors and laboratory workers. In general, whatever recruitment policies are established for students in research will tend to apply to those who are similarly vulnerable by virtue of other power relationships. The potentially coercive nature of being a student may arise from a course requirement that they serve as a study subject. Or they may respond to campus or local advertisements offering cash in exchange for volunteering for research. As students are often unemployed or underemployed, even small monetary inducements can be important. Perhaps because the kind of research to which students are usually subjected is behavioral and presents minimal physical risk (though arguably some psychological risk), and there has been no great scandal about participation in studies as a course requirement, this population has received the least attention among those that may be said to be in a coercive environment. Some of the studies to which students are most likely to be exposed, especially undergraduates recruited for social science experiments, fall into the category known as "deception research." Social psychological studies involving deception increased greatly through the 1950s and 1960s. Few expressed concern about the ethical implications of deceit, or the potential psychological damage to the subject, until the mid-1960s, following Stanley Milgram's studies of obedience. Milgram's basic design called for two people to be told they were participating in a memory experiment, but one of the two was a "confederate," a member of the research team. The naive actual subject was instructed to shock the other "subject" (the confederate), if he or she failed to give the correct answer to word-pair questions. Most of the actual subjects gave the confederates "shocks" they were

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led to believe were dangerous because the experimenter told them to follow through on the punishment for making a mistake.52 In the years following publication, the scientific importance of Milgram's studies vied for attention with the ethical issues they raised. Many critics expressed concern about the emotional well-being of the subjects, once they realized both that they had been deceived and that they were evidently capable of inflicting harm on innocent people merely because they were instructed to do so by an authority figure, a scientist. There was no informed consent about this aspect of the research, and it is hard to see how there could be without confounding the study. Another celebrated deception research case heightened the debate shortly after Milgram's original publication, when in the late 1960s sociologist Laud Humphreys conducted research on the social status of those engaging in anonymous homosexual encounters in public restrooms. His data-gathering techniques included secretly recording car license numbers and later presenting himself in the subjects' homes posing as a health services researcher and asking questions about their personal lives. Humphreys succeeded in undermining numerous false stereotypes about gay men, but his approach caused an uproar that reached beyond his department and university to national newspapers.53 Obviously these famous cases are fairly extreme examples of deception studies, and they do not necessarily involve students, whose research participation is likely to occur under more benign circumstances. The American Psychological Association's code of ethics continues to permit deception in research, and does not address the disproportionate use of "captive" populations, such as those who may be required to serve as research subjects as part of satisfying a course requirement.54 Of the students who may be asked to participate as subjects in research, a smaller number is engaged in advanced biological or medical studies. In one sense they are close to ideal candidates because of their potential intellectual identification with the research; the only superior subjects in this sense are the principal investigators themselves.55 The creation of special obstacles to the enrollment of these students, who are generally regarded as the "best and the brightest" by their faculties and far less likely to be exploited than other societal groups, may be viewed as institutional paternalism.56 Nevertheless, there is evidence that medical students do not believe their professors' consent processes are adequate.57 Finally, there is again the issue of financial compensation. In order to avoid appearing coercive, remuneration for study participation should take into account the financial position of the population from which subjects are to be recruited. Many students live on loans that present them with a significant burden for many years. In the first instance, compensation may take into account expenses associated with study participation, such as travel. Additional amounts should be calculated based on a reasonable assessment of the value of the time invested by members of that population. Thus, for example, a 100 dollars an hour for an individual who could not otherwise earn a fraction of that amount would seem to be coercive.

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FUTURE TRENDS Because they are captive in very different ways, determining justice in research with these subject populations must be assessed quite differently. We have seen that the ready availability of institutionalized subjects like prisoners makes them prime research candidates, a circumstance that applies even more powerfully to those in medical institutions, for they have already been identified as in need of medical attention. The population of potential subjects in medical institutions is a complex one both because of the different ages and levels of capacity and because of the varied nature of the institutions in which they may be found. Further, not all the research for which they may be recruited will involve manipulations or procedures intended to benefit them, in spite of the fact that they are ill. Surely the subpopulation in this large and diverse group that is a likely candidate for new or expanded regulatory protections in the future is the mentally infirm, understood as those with chronic rather than acute cognitive deficits, such as Alzheimer's disease or schizophrenia; or, in the case of minors, deficits related to factors other than immaturity alone, such as mental retardation. A recent legal case at the state level invalidated regulations that permitted greater than minimal risk, nonbeneficial research on patients in New York State psychiatric hospitals.58 This case, and continuing uncertainty among investigators over consent procedures for important research with the mentally infirm, has caught the attention of the NBAC, which is likely to recommend some regulatory reform. Considering the absence of rules targeted to this population it seems likely that almost any explicit regulations will create more rather than fewer obstacles to their use. Thus one can expect that locales in which much psychiatric research was done with patients in the past will be doing few studies, or using fewer patients, in the future. Since the Gulf War, a primary public policy concern has revolved around waivers of informed consent provisions involving unapproved drugs for military personnel under combat conditions. The suitability of such waivers may be loosely characterized as a matter of justice in research, but only if the program for which a waiver is sought is intended mainly to yield information that can be used in later conflicts. Considering that the primary goal of the waiver is not research (and indeed medical data-gathering was not part of the Pentagon's mission in Desert Storm), the problem here does not seem to be one of discrimination against soldiers as disproportionately recruited to be experimental subjects. Rather, the dilemma stems from a wish to provide the troops with whatever medical benefit might theoretically be available without unacceptable risk. More pertinent to the topic of justice in research for the military in the future is whether and under what conditions men and women in the armed forces may be utilized in new research activities during peacetime. In general, for both political and moral reasons there has been a reluctance to use military personnel in research when others are available. This reluctance has been compromised when some new

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threat seemed imminent and other appropriate subjects were not available. Therefore, a source of tension in the future about the acceptance of using military personnel in research could be a suspected new and deadly weapons system in the possession of a foreign power or terrorist group, combined with regulatory restrictions on the use of other healthy subjects. Considering how much use is made of young people like students in medical and behavioral research, a few isolated tragedies can excite considerable public alarm. Some further restrictions on the use of students in research seem likely, at least at local levels, perhaps by prohibiting their recruitment by their current instructors. In 1996, a 19-year-old University of Rochester undergraduate died after participating in a study involving a bronchoscopy; the young woman succumbed 2 days following a reaction to a local anesthetic. She was to be paid $150 as a normal volunteer. Although harm to student volunteers is extremely rare, and mortality a virtually unheard of event, this case has excited understandable concern in New York. The state health commissioner appointed a panel to review the use of normal subjects and recommend improvements in the IRB system.59

CONCLUSIONS

Generalized discussions about justice are sorely limited concerning specific groups. In crafting a just public policy for the use of human subjects, especially those who may be considered convenient or captive, the historical and practical factors that could enter into judgments about justice will vary depending on what population is being considered. The respective situations of prisoners, institutionalized persons, military personnel, and students are quite different and require analyses tailored to each of them. Underlying all these cases are complex issues of social status and power as well as medical ethics. As experience in modern research with human subjects has accumulated, a "protectionist" attitude toward the participation of these groups has emerged. Prisoners are no longer a rich source of subjects, and specific federal regulations greatly restrict their involvement in studies. Institutionalized persons have long been considered to generate specific ethical issues in research, a trend that has lately accelerated. Research with military personnel, always a sensitive problem for defense officials, must navigate numerous obstacles for approval by command authorities. Participation in research by students, employees, and others in differential power positions is a simmering issue that may well be the next frontier for protectionist approaches. Historical experience has been accompanied by an evolution in the sense of justice in research, one that has tended to qualify crude utilitarian attitudes toward the use of human subjects. The notion that long-term prisoners owe a special debt to society that may be expressed in research participation, for example, is an im-

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plication of a once-popular notion of justice that has resonance only to the degree that it is abstracted from actual abuses associated with imprisonment, including the familiar problem of voluntariness. Similarly, the view that prisoners or other institutionalized persons may have to be used in risky studies addressing important public health problems must be tempered by the condition (already in current regulations), that they must themselves be likely to benefit from such research, either as individuals or, at the very least, as members of the affected group. Once a more refined conception of justice in research becomes available it may have implications for groups it was not even intended to address. The notion that military service does not include duties to be in research that is not intended to improve combat readiness is one that the armed forces were already coming to accept by the mid-1970s, but the Tuskegee Syphilis Study scandal and the work of the National Commission surely helped reinforce an awareness of research ethics in the military, as it did in all other areas. Under the auspices of a modern conception of justice in research, the proposition that the role of student or employee does not generate an obligation to serve in an experiment is now becoming more obvious. A protectionist stance towards special populations does not rule out the possibility that strong arguments for research participation can be mounted. Surely there are circumstances in which justice may permit, or even require, access to research for populations that have historically been abused by some researchers. One of these circumstances is the prevalence of a disease that poses a particular threat to members of that population, and which cannot be studied as effectively with other subjects. Protected status implies institutional and public scrutiny of proposed research participation, not a priori exclusion. With this understanding, and in light of the historical factors that have made these groups' participation in medical research a matter of special concern, protectionism continues to be a morally sound presumption.

NOTES 1. Another sort of readily available, captive population is exemplified by the AfricanAmerican men who were subject to the so-called Tuskegee Syphilis Study, better named the U.S. Public Health Service Syphilis Study. These men were available and convenient by virtue of their social status. Another example is that of the Navajo uranium miners and millers, who were observed for the carcenogenic results of their occupation for years, also by the U.S. Public Health Service. Observational studies arising from conditions that have not been created by investigators, but arise in nature, are also called "experiments of opportunity." See Advisory Committee on Human Radiation Experiments, The Human Radiation Experiments (New York: Oxford University Press, 1996), Chapter 12. 2. Elizabeth W. Etheridge, The Butterfly Caste: A Social History of Pellegra in the South (Westport, CT: Greenwood Publishing Company, 1972). 3. United States v. Karl Brandt et al. The Medical Case, Trials of War Criminals before the Nuremberg Medical Tribunals under Control Council Law No. 10 (Washington, DC: U.S. Government Printing Office, 1949).

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4. Jon E. Harkness, Research Behind Bars: A History of Nontherapeutic Research on American Prisoners (unpublished Doctoral Dissertation, University of Wisconsin Department of History, 1996). 5. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, Research Involving Prisoners: Appendix to Report and Recommendations (Washington, DC: U.S. Department of Health, Education and Welfare, 1976). 6. Renee Fox, cited in H.M. Pappworth, Human Guinea Pigs: Experimentation on Man (Boston: Beacon Press, 1967). 7. "Prison Research: Ethics Behind Bars," Nature 242:153; 1973. 8. Ibid. 9. Advisory Committee on Human Radiation Experiments, op. cit., Chapter 9. 10. Monroe E. Trout, "Should Research In Prisons Be Barred?" The Journal of Legal Medicine 2(5):2; 1974. 11. Jon E. Harkness, op. cit., pp. 251-252. 12. Louis Lasagna, "Prisoner Subjects and Drug Testing," Federation Proceedings 36(10):2349; 1977. 13. Victor E. Cohn, "Prison Test Ban Opposed," Washington Post, March 14, 1976, p. A7. 14. "Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects." 45 Code of Federal Regulations 46, subpart C, 1993. 15. Cathy Potler, Victoria L. Sharp, and Scot Remnick, "Prisoners' Access to HIV Experimental Trials: Legal, Ethical, and Practical Considerations," Journal of Acquired Immune Deficiency Syndromes 7(10): 1086-1094; 1994. 16. Jon E. Harkness, op. cit., 1996. 17. Ibid. 18. Robert J. Levine, personal communication, April 30, 1997. 19. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects, Federal Register Document 79-12065, April 18, 1979. 20. David J. Rothman, Strangers at the Bedside: A History of How Law and Bioethics Transformed Medical Decision Making (New York: Basic Books, 1991), pp. 32-50. 21. H. M. Pappworth, Human Guinea Pigs: Experimentation on Man, pp. 53-60. 22. Adil Shamoo and Timothy J. Keay, "Ethical Concerns About Relapse Studies," Cambridge Quarterly of Healthcare Ethics 5:373-386; 1996. 23. Robert Levine, "Proposed Regulations for Research Involving Those Institutionalized as Mentally Infirm: A Consideration of Their Relevance in 1996," IRB (1996) 18:1; Richard Bonnie, "Research With Cognitively Impaired Subjects," Archives of General Psychiatry (1997)54:105-111. 24. Dallas M. High, Peter J. Whitehouse, Stephen G. Post, and Leonard Berg, "Guidelines for Addressing Ethical and Legal Issues in Alzheimer Disease Research: A Position Paper," Alzheimer Disease and Associated Disorders 8(Suppl.4):66-74, 1994; Edward W. Keyserlingk, Kathleen Glass, Sandra Kogan, and Serge Gauthier, "Proposed Guidelines for the Participation of Persons with Dementia as Research Subjects," Perspectives in Biology and Medicine 38(2):319-362; 1995. 25. T.D. v. N.Y. State Office of Mental Health, A.D.2d, 650 N.Y.S.2d 173 (1st Dep't 1996). 26. G. F. Still, The History of Pediatrics (London: Dawsons of Pall Mall, 1965), pp. 430-431. 27. J.H. Cassedy,American Medicine and Statistical Thinking, 1800-1860(Cambridge, MA: Harvard University Press, 1984), p. 138.

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28. S. X. Radbill, "The Use of Children in Pediatric Research." Paper delivered at American Association for the History of Medicine, Pittsburgh, PA. May 4, 1979. 29. Susan E. Lederer and Michael A. Grodin, "Historical Overview: Pediatric Experimentation," in Michael A. Grodin and Leonard A. Glantz, Children as Research Subjects: Science, Ethics and Law (New York: Oxford University Press, 1994, pp. 3-28). 30. Ibid. 31. Saul Krugman, "The Willowbrook Hepatitis Studies Revisited: Ethical Aspects," Reviews of Infectious Diseases 8(1):157-162; 1986. 32. Ibid. 33. Task Force on Human Subject Research, April 1994 ("A Report on the Use of Radioactive Materials in Human Subject Research that Involved Residents of StateOperated Facilities within the Commonwealth of Massachusetts from 1943 to 1973") (ACHRE No. MASS-072194-A). 34. Advisory Committee on Human Radiation Experiments, op. cit., p. 213; in addition, on December 31, 1997, a group of former students at the Fernald School agreed to a settlement of $1.85 million in their class-action lawsuit against Quaker Oats and MIT. ("Settlement Reached in Suit Over Radioactive Oatmeal Experiment," New York Times, Jan. 1, 1998; p. A19.) 35. The current regulations are relatively detailed, though parents, investigators, and institutional review boards are still given wide latitude to approve studies. Using a "sliding scale" approach, restrictions vary according to the ratio of risk and benefit. Most difficult to perform with children is research involving significant risk that do not present the prospect of directly benefiting the subject. Certain kinds of research, such as anonymous educational test results, are exempt from the federal rules. Perhaps the most problematic concept in the pediatric regulations is that of minimal risk, upon which the permissibility of much research turns. In the federal rules, risk is said to be minimal when it does not exceed that encountered in daily life or in a regular physical or psychological examination, a standard that may not be very protective in light of the many hazards of ordinary childhood. Another feature of the current regulations that blunts their force is the absence of a requirement that investigators show that the work can only be done with children, unlike the prisoner requirements. See Leonard H. Glantz, "The Law of Experimentation with Children," in Grodin and Glantz, Children as Research Subjects: Science, Ethics and Law, pp. 123-125. 36. Advisory Committee on Human Radiation Experiments, op. cit., Chapter 1. 37. Ibid., pp. 291-293. 38. Ibid. 39. Ibid., pp. 294-296. 40. Ibid., Chapter 10. 41. Thomas J. Downey, "Report on Human Experimentation Conducted or Funded by the U.S. Army." Congressional Record 121, 27934; 1975. 42. United States v. Stanley, 483 U.S. 669 (1987). 43. Federal Policy for the Protection of Human Subjects; Notices and Rules, 56 Fed. Reg. 28002-28032 (June 18, 1991). 44. United States Army Medical Research Institute of Infectious Diseases, Department of the Army, USAMRIID Regulation Number 70-25, 4.b, 1, February 1995. 45. United States Government Human Radiation Interagency Working Group, Building Public Trust: Actions to Respond to the Report of the Advisory Committee on Human Radiation Experiments (Washington, DC: U.S. Government Printing Office, 1997), p. 16. 46. Advisory Committee on Gulf War Veterans' Illnesses; Interim Report (Washington, DC: U.S. Government Printing Office, 1996), pp. 20-21.

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47. Ibid., p. 21. 48. Ibid. 49. Carol Levine, "Military Medical Research: Are There Ethical Exceptions?" IRB ll(4):5-7; 1989. 50. Advisory Committee on Gulf War Veterans' Illnesses; Final Report (Washington, DC: U.S. Government Printing Office, 1996), p. 98. 51. U.S. House of Representatives Subcommittee on Government Operations, Hearings on Informed Consent, May 8, 1997. 52. Stanley Milgram, Obedience to Authority (New York: Harper & Row Publishers, Inc., 1974). 53. Laud Humphreys, Tearoom Trade: Impersonal Sex in Public Places (Chicago: Aldine Publishing Co., 1970). 54. American Psychological Association, Ethical Principles in the Conduct of Research with Hukan Participants (Washington, DC: APA, 1982). 55. Hans Jonas, "Philosophical Reflections on Experimenting with Human Subjects." In: Experimentation with Human Subjects, ed. Paul A. Freund (New York: George Braziller, 1970, pp. 105-131). 56. Nicholas Christakis, "Do Medical Student Research Subjects Need Special Protection?" IRB 7(3): 1-4, 1985. 57. Loretta Kopelman, "Cynicism Among Medical Students," JAMA 250(15):20062010, 1993. 58. T.D. v. N.Y. State Office of Mental Health, A.D.2d, 650 N.Y.S.2d 173 (1st Dep't 1996). 59. "New York Seeks to Tighten Rules on Medical Research," New York Times September 27, 1996, p. B4.

8 JUSTICE IN INTERNATIONAL RESEARCH Ruth Macklin

An array of ethical concerns regarding international research has arisen over the years, but those concerns have rarely been cast in the language of justice. Nevertheless, upon closer examination, it becomes evident that several of these concerns can be expressed in terms of justice. One often-heard objection is that researchers should not embark on studies in developing countries when for ethical reasons that research could not be carried out in a developed country. The prospect that people might be exploited in some way is another cause for concern in developing countries that lack protections for human subjects of research.1 DISTRIBUTIVE JUSTICE The supposition underlying the above-noted concerns is that to be a research subject is to be exposed to risks, possibly unacceptable risks. This ethical worry focuses on the potential burdens research subjects may experience. Recently, the opposite scenario has put a different twist on matters of justice. Here the relevant ethical concern is that of being denied access to a potentially beneficial treatment even before its efficacy is proven. In particular, AIDS research that provides access to experimental therapies has brought a shift from the perception of research as a risky endeavor to one that can provide benefits to subjects. 131

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Both of these concerns—the imposition of undue burdens and the denial of expected benefits—fit under the standard conception of distributive justice, which requires a fair distribution of the benefits and burdens of research. The concept of justice always relates to fairness in some way, but justice is not limited to the question of fair distribution. Other conceptions of justice address matters of equity, fair procedures, and fair compensation. It is hard to arrive at a precise general definition of what constitutes a fair distribution because the criteria for fairness may differ from one context to another.2 Equity is the core concept in fair distribution in the context of research involving human subjects. Equity requires that no one group—gender, racial, ethnic, geographic, or socioeconomic—receive disproportionate benefits or bear disproportionate burdens.3 A prominent concern in the international research arena has been that disadvantaged people in developing countries suffer a disproportionate burden of bearing the risks of research without the opportunity to enjoy any benefits that may accrue. Residents of developing countries may lack access to the products of research carried out in their countries if the medications are too expensive for individuals or the ministries of health to afford. This situation was reflected in the Belmont Report of the National Commission: "research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research."4 To meet the requirements of distributive justice in international research, then, it is necessary to fulfill two conditions: 1. The design and determination of acceptable risk/benefit ratios must be evaluated with the same standards as when such research is carried out in the sponsoring country. 2. Beneficiaries of the research outcomes must include people in the developing countries where the research is conducted, as well as in the developed country that sponsors the research.5 These conditions make it clear that it is not only the benefits and burdens accruing to the research participants, but also the potentially beneficial outcomes of the research that count in determining equity. This consideration relates mainly to the economic constraints in developing countries that make it difficult or impossible for them to purchase drugs once they are approved to supply the health needs of their population. This issue has been prominent in the planning for efficacy trials of AIDS vaccines in Africa.6 One writer puts the matter as follows: "Although there may be scientific interest in studying groups of Africans with different transmission risks in order to evaluate the efficacy of a vaccine, it would be unethical to subject Africans to a disproportionate share of the

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research risks without an equal share of the benefits."7 This author suggests that developed countries should make a commitment to provide an affordable or subsidized vaccine to African countries following international collaborative vaccine trials conducted there, a move that would satisfy this requirement of justice.

OTHER CONCEPTIONS OF JUSTICE This chapter explores several different conceptions of justice as applied to international research, in addition to the familiar notion of distributive justice. One conception is expressed in the formal principle of justice: "Treat like cases alike (and different cases differently)." This undisputed principle of justice lacks content and is often difficult to apply in specific contexts. The key to applying this principle is determining the relevant respects in which cases are alike or different. This formal principle of justice provides a justification for the following widely accepted rule: If it is unethical to carry out a particular type of research in a developed country, it is unethical to conduct that same research in a developing country. As we shall see, this statement requires interpretation and may create doubts or confusion when risk/benefit ratios are significantly different from one research context to the next. Another conception of justice is "procedural" justice. This notion is a different yet important expression of fairness, and relates to the process according to which decisions are made and actions are carried out. An example outside the research context is that of "due process," ensuring that people who are accused of crimes are given a fair hearing and a fair chance to defend themselves against the accusations. An example in the context of research is prospective review of protocols by a duly constituted body whose task is to protect the rights and welfare of human subjects of research. Still another conception of justice is "compensatory" justice. Providing monetary compensation for injured research subjects and paying research subjects for their time and inconvenience are examples of this conception. These notions also embody the overarching concept of justice as fairness, since they apply to circumstances in which people deserve something as recompense for their efforts or for harm they may have suffered. Finally, justice may require a remediation of past injustices by according preferential treatment to a group or class that has been discriminated against in the past. Not only is a past injustice remedied, but preferential treatment may also avoid perpetuating that injustice. This chapter deals mainly with distributive justice and the formal principle, "treat like cases alike," as these are the chief conceptions of justice that pertain to international research.

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JUSTICE ACROSS TIME Exploitation of Vulnerable Populations

One way that violations of justice can occur is by exploitation of vulnerable populations. Exploitation violates justice as fairness because in one way or another, people having greater power or resources take unfair advantage of those with less power or fewer resources. People can also be exploited based on their ignorance, weakness, or lack of sophistication. This is a subcategory of distributive justice, since the nature of the wrong is that of inequitable treatment. Populations in developed countries are less likely to be exploited than are populations in developing countries, so the resulting situation is an inequitable selection of research subjects across international boundaries. The Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines acknowledges this situation in a commentary under Guideline 8: Research involving subjects in underdeveloped communities, noting that "Individuals and families in such communities are liable to exploitation for various reasons."8 Allegations of past abuses have led to suspicion and even outright rejection of international collaborative research conducted in developing countries. Statements range from the need to protect vulnerable subjects to calls for a halt to some types of research and development altogether. A leading feminist, Susan Sherwin, has written about past abuses in contraceptive research: The case history of the development of birth-control pills .. . reveals the need to ensure that particularly vulnerable women are protected from exploitation as research subjects: the earliest tests on "the pill" were carried out on poor and uneducated women in Puerto Rico and Mexico."9

Sherwin quotes another author whose condemnation is more sweeping: "Third World populations are ideal research material for field trials, especially since the norms for such research are extremely stringent in the advanced countries and the public there is far too vocal and well-informed to allow rampant trials of potentially dangerous drugs."10 Studies on oral contraceptives

A widely cited study is one carried out in the 1950s on poor Puerto Rican women during the initial phases of testing the effectiveness of the oral contraceptive pill. Although the ethical grounds on which this study has been faulted are the absence of the subjects' informed consent,11 the implications for justice are clear: researchers would not have done the study on the United States mainland without informing women that they were involved in a research project or about the side effects

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they might experience, including the chance of becoming pregnant.12 At the time the study was conducted there were as yet no federal regulations and no federally mandated IRBs. So even though it would not have violated laws or regulations to carry out this type of study without properly informing women, it is likely that the scruples of researchers prevented their doing the same study on more educated women in the United States. The research that used poor women in Puerto Rico as subjects highlights the need to distinguish between an explanation of an event and an ethical justification. One writer surmises that the most compelling reason for choosing this subject population was convenience: "Lower income groups were more available for this type of mass experimentation . . . and were less likely than well-heeled mainlanders to mount political protests or initiate lawsuits."13 A more cynical supposition is that "perhaps there was also a latent racism at work. .. ,"14 Neither explanation can serve as an ethical justification. As one author has aptly put the matter: "Under the principle of justice, research subjects should be chosen for reasons directly related to the scientific question under study and not because of their easy availability, their compromised position, or their ability to be manipulated."15 The Depo-provera (DMPA) story

Implying (but not directly stating) that political factors prevented DMPA from being introduced into the United States until 1992, one author says that FDA approval in that year "culminated a 20-year effort to make a long-acting injectable contraceptive available to American women. Based upon the findings of extensive clinical research done outside the United States over a decade, the FDA determined that while some concerns remained, DMPA was considered to be as safe as other hormonal contraceptives already on the market."16 In 1991 and 1992, several multicenter studies finally demonstrated that DMPA does not increase the risk of breast, ovarian, endometrial, or cervical cancer in long-term users. The longstanding concerns about the safety of DMPA were at last put to rest in the scientific community.17 It was primarily the conduct of that research outside the United States that led to outcries from women's groups and others who claimed that Third World women were being exploited by First World pharmaceutical companies. During the 1970s and 1980s, the drug was licensed for use in many developing countries and in a few developed countries. In spite of a review by the World Health Organization (WHO) in 1981, which concluded that "clinical evidence from more than 15 years of use as contraceptive agents showed no additional and possibly even fewer adverse side effects than are found with other hormonal methods of contraception,"18 the FDA did not approve DMPA until 1992. The FDA continued to rely on earlier testing in animals that suggested possible carcinogenic effects. Many activist groups opposed the approval of DMPA, which may have been a factor delaying its introduction in the United States. As a result of the failure of

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the FDA to approve this contraceptive, many other countries did not permit its use either.19 The injustice of this situation stems from the great difference between contraceptive availability for American women and for women in developing countries. Lack of access to a 3 month injectable contraceptive has a greater negative impact on women in those countries, who have limited access and fewer family planning options, than on American women with a much wider range of contraceptive alternatives. It would be a mistake to insist that a corrective measure in response to past episodes of unethical research in developing countries should take the form of prohibiting future research in those countries before that research has been carried out in developed countries. For scientific, legal, and ethical reasons, research must be conducted on the population and in the area where the results will be implemented. "Treat Like Cases Alike": Current Controversies

Questions of justice are far from resolved in the context of international research. Let us turn to some current controversies that arise out of the formal principle of justice, "treat like cases alike." As noted earlier, one application of this principle is the rule, "If it is unethical to carry out a type of research in a developed country, it is unethical to do that research in a developing country." This premise requires interpretation and may create confusion if risk/benefit ratios are significantly different from one research context to the next. This point can be illustrated by situations that have sparked considerable controversy. The quinacrine affair is one variation on the theme of whether it is unjust to conduct research in developing countries that for one reason or another could not be carried out in developed countries. The quinacrine affair

Quinacrine is a drag known to have antimalarial properties and is being used in some parts of the world to sterilize women. It has the effect of producing tubal occlusion, and for that reason can be used as a method of sterilization. However, quinacrine has not been approved for use as a method for sterilizing women by any national drug regulation authority in the world.20 Despite the absence of appropriate studies with a finding that the drag is safe for use in women as a medical method of sterilization, it has been used extensively in Brazil and a number of countries in Asia, including Pakistan, India, Bangladesh, China, Indonesia, and the Philippines. In Vietnam alone, quinacrine has been used to sterilize more than 31,000 women.21 As of late 1994, an estimated 70,000 women in these and other developing countries have had pellets of quinacrine inserted into their uteruses. Appropriate toxicological testing of quinacrine administered in this way is lacking, and scientists do not know exactly how the drug affects the fallopian tube.22

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Physicians in the United States may use a drug that has been approved for one therapeutic purpose for a different purpose in treating patients. A prior requirement, however, is that adequate Phase I studies, in which drugs are tested for safety, have been carried out. However, drug manufacturers may not label a drug as indicated for a particular purpose unless the substance has been tested in Phase II and Phase III studies, which test the drug for its efficacy for particular purposes. And if the approved use specifies the route of administration of a drug, physicians are likely to be very cautious in deviating from the prescribed method. These rules are a part of the drug regulatory system that exists in the United States as well as in most developed countries. Some developing countries are largely or entirely lacking in any scheme for regulating the testing, labeling, and use of medications.23 The quinacrine affair illustrates one particular form of injustice as seen from a global perspective. The injustice does not lie in conducting research in developing countries that would be considered unacceptable in developed countries. Instead, it is a case of an unapproved drug being introduced into general use before adequate research is completed. While it would be rare for that to happen in the United States, both because of the FDA regulatory system and also out of physicians' fear of liability, no such barriers or safeguards exist in many developing countries. In effect, the use of quinacrine has become standard therapeutic practice instead of remaining an experimental procedure until adequate testing has been completed. A number of international organizations addressed this situation. In 1993 the International Planned Parenthood Federation's International Medical Advisory Panel stated that "until the toxicological situation has been clarified and further clinical trials have been conducted, the use of quinacrine pellets for female sterilization in family planning programs cannot be recommended."24 A consensus view emerged in 1994 from meetings of Family Health International and other organizations that there should be no further clinical trials or other use in women until toxicological and retrospective studies have been completed. Yet despite all these reservations, quinacrine has continued to have supporters, even among some prestigious members of the world medical community. The British medical journal, Lancet, published an editorial in April 1994 advocating the use of quinacrine in developing countries where clinicians have continued to provide it. The grounds for advocacy are that the drug is inexpensive, easy to administer, and especially in situations where few or no other choices exist, it is allegedly safer than pregnancy and better than nothing. One commentator notes that "Almost every instance of continuing provision of the method seems to be described (euphemistically) as a 'clinical trial.'"25 The Scientific and Ethical Review Group (SERG) of the Special Programme of Research, Development and Research Training in Human Reproduction (HRP) at the WHO issued a statement calling for toxicology testing of quinacrine before any further studies can be carried out in women.26 In addition, the statement asked that retrospective studies of the women already treated

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with quinacrine be continued and completed. The director of the WHO program wrote a letter to the Lancet saying that "The high standards of safety demanded in the testing and use of contraceptives should apply whether the subjects recruited to the studies are from the developed or the developing world."27 In reply to WHO's insistence on using the same standards for the developed and developing world, one of the leading advocates and users of quinacrine, Dr. Elton Kessel, published a commentary in the Lancet. After dismissing the WHO position as "feminist concerns," Kessel went on to argue for a double standard on safety and efficacy in the use of risk/benefit ratios. He wrote: A simple guide to determining benefits is the estimate for rural areas of South countries that each sterilization prevents two births. If maternal mortality is, say 3.8 per 1000 live births as estimated for Vietnam, then each 1000 sterilizations done by a new method such as quinacrine pellets will prevent 7.6 maternal deaths. No one has suggested that the method could kill that number of women... ,28

Rebuttals to Kessel's argument take several forms. One rebuttal contends that his position is scientifically flawed, since the risks and benefits of a sterilization should be compared only with those of other sterilization methods and not with the risks of maternity. This is because alternatives to pregnancy exist other than quinacrine sterilization.29 A different line of rebuttal holds that according to Kessel's logic, "everyone should be sterilized so that there would be no risk of maternal deaths at all."30 Finally, there is the ethical matter of the same or different standards of safety and efficacy applied to developed and developing countries. One critic of Kessel's view contends that this double standard has been rejected and condemned by the women's health movement, North and South, for many years: "It is precisely the demand for one standard of safety and efficacy for all women that decimates any justification for using quinacrine in women in developing countries, at least at this time."31 Several factors contribute to the injustice of a double standard for safety and efficacy of drugs in developing and developed countries. As illustrated by the quinacrine affair, even where a drug regulatory system exists, many developing countries have relatively poor mechanisms for oversight, reporting, and administering sanctions for violators. They may also lack clearly articulated criteria for what counts as research, clinical trials, or use in everyday practice. The methodological task of constructing appropriate risk/benefit comparisons is genuinely problematic and may enable strong advocates of an unapproved drug to overwhelm skeptics or more cautious individuals by pointing to the vast benefits or diminished risks of the new method. Clinical trials of RU-486 in Bangladesh

Two prominent women's health advocates objected to the initiation of clinical trials of the current method of medical abortion in which RU-486 is used into

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Bangladesh. They argued that this compound has been demonstrated to be an effective method of choice for a substantial number of women in France, a country with a strong health infrastructure.32 In Bangladesh, a country with weak health and family planning infrastructures, women would be likely to undergo greater risks both in the phase of clinical trials and after introduction of this method than they face in the use of the menstrual regulation technique now employed (this is typically suction abortion, when carried out by trained providers). These authors recommend conducting trials in several Northern countries and possibly in selected Southern countries where strong health infrastructures exist: Before women in Southern countries with weak health services are exposed to the risks of RU-486/PG, it is our strong view that, for health as well as political reasons, RU-486/PG must be further researched in several Northern countries especially the US.. . ,33 On the other side of this debate are those who argue that questioning the wisdom of conducting studies of RU-486 in particular settings inappropriately denies women a beneficial option.34 In this debate, both sides appeal to considerations of justice. Those who favor instituting the trials argue that to deny Bangladeshi women the benefits of RU-486 would be unjust. Those opposed contend that to subject Bangladeshi women to risks greater than they face in their present situation would be unjust. Interestingly, extensive trials of an RU-486 analog, sponsored by the WHO have been conducted in China, a developing country. But unlike Bangladesh, China has a very well-developed health infrastructure so the objections to conducting the trials in Bangladesh would not apply to China. These differences in risk/benefit assessments from one country to the next demonstrate the difficulty in trying to apply the rule, "If it is unethical to carry out a piece of research in a developed country, it is unethical to do that research in a developing country." The relevant principle of justice is "treat like cases alike, in relevant respects." China and Bangladesh are alike in the respect that both are developing countries, yet they are unlike in respect to the risk/benefit assessments of clinical trials. China's good health infrastructure yields a different risk/benefit ratio from Bangladesh's poor systems of medical research and service delivery. In respects relevant to assessing the risks and benefits of the research, China is more like France and the United Kingdom than like Bangladesh. Placebo-controlled HIV/AIDS clinical trials Still unresolved is the question whether different factors affecting risk/benefit ratios could justify doing a study in a developing country that would be unethical in a developed country. As in the quinacrine story, one side argued that different risk/benefit ratios provide ethical warrant for the use of an incompletely researched drug in a developing country whereas it would not be ethically acceptable to use the unapproved drug in a developed country. A similar argument was advanced

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for conducting a cost-effectiveness study of AIDS drugs in a South American country. The study design was a randomized controlled trial with the drug dideoexycytidine (ddC) in one arm and placebo in the other arm. That research design would be unethical in developed countries where life-prolonging drugs such as zidovudine (AZT) are available to patients; the ethically acceptable design would be to use the approved drug, AZT, instead of the placebo arm. However, in the developing country patients are unable to afford AZT and the government cannot afford to provide the drug to patients. Therefore, it was argued, "comparison of ddC to placebo is not unethical if the cost of zidovudine is beyond what the government could possibly afford.... [F]or the purposes of the ethical design of a research study it is as if zidovudine did not exist at all."35 This justification relies on the notion that if people are not made worse off by being research subjects than they would be if they were not enrolled in a trial, the study is not unethical. Since the vast majority of people with HIV disease in this developing country cannot afford zidovudine, they are no worse off in a placebo arm of a study than they would be if they were not enrolled in the research at all. Christakis and colleagues add the condition that the drug manufacturer and the sponsoring government should make a prior commitment to provide ddC, the investigational drug, to the population if the drug proves to be clinically active and cost effective. That promise would surely improve what is otherwise a highly questionable situation from an ethical point of view. An analogous situation in studies of perinatal transmission of HIV prompted a strong response by the Public Citizen's Health Research Group, which compared the CDC and NIH-sponsored trials to the Tuskegee Syphilis Study.36 In these studies, a portion of the women were given placebos instead of a proven regimen (AZT) that can reduce the rate of vertical transmission. The study was designed to measure the efficacy of a shorter regimen with lower doses than the proven treatment. The Public Citizen advocacy group argued that since a proven treatment regimen (AZT) exists, it is unethical to withhold that treatment from women in the trial. The reply by the sponsoring agencies has three parts: 1. the "standard of care" for HIV-positive women in these developing countries is no treatment at all, so they are not being made worse off by being in the study; 2. a placebo-controlled trial can be carried out with many fewer subjects and completed in a much shorter time than an AZT-controlled study, so useful information pertinent to this population will be available much sooner; 3. AZT is not now and will never be available to this population because of its prohibitive costs, but the experimental regimen is much cheaper and more appropriate for use by this population and will be made available. The conclusion of this argument is that thousands more children's lives will be saved by conducting the shorter, placebo-controlled trial than by the longer, AZTcontrolled study.37

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The Public Citizen's Health Research Group sought to rebut the argument, claiming that the research violates at least four of the ten principles of the Nuremberg Code, and further, they are in violation of Guideline 15 of the CIOMS International Ethical Guidelines for Biomedical Research involving Human Subjects.38 That guideline states that the ethical standards of the sponsoring agency's country should prevail when research is conducted in another country, and that the ethical standards should be no less exacting than those in the sponsoring agency's country.39 The Public Citizen Group claims that because these trials could not be conducted in developed countries today, the researchers "have chosen to ignore these standards of ethical conduct accepted the world over and have sunk to standards below those acceptable in their home countries."40 The opponents in this dispute can both claim that justice is on their side. The Public Citizen Group begins with the premise that the same study could not ethically be carried out in developed countries and concludes that therefore, it would be unethical to conduct it in developing countries. "Treat like cases alike" is interpreted to mean that the study itself is the same in both places, and if it is unethical in one place it is unethical in both. The sponsoring agencies begin with the premise that risk/benefit ratios are radically different in developing countries and in the sponsoring agencies' countries. In the developed countries, all women potentially have access to the effective treatment regimen but in the developing countries none do. In the developing countries, subjects are not being placed at greater risk than if they were not in the study at all, and many more people can potentially benefit much sooner from the shorter, placebo-controlled trial. Therefore, it is not a violation of the formal principle of justice, "treat like cases alike," since the two cases are not similar, but differ in relevant respects. Furthermore, since the potential benefits accrue only to the population in the developing country, an important feature of equity is fulfilled. Procedural Justice: The Role of Ethical Review Committees

One mechanism for seeking to ensure that the ethical standards adopted in developing countries are applied to international collaborative research conducted in developing countries is that of review by committees such as IRBs in the United States. I lack evidence of whether all IRBs require review of research conducted in other countries by faculty of the institution for which the IRB is responsible. But some do, and the results can be quite peculiar. The following episode illustrates what happens when an IRB fails to distinguish between ethical standards and mere procedural requirements. A researcher from the United States was doing a study in Bangladesh, for which he was required by his home institution's research ethics committee to use their standard consent form.41 The boilerplate portion of the form instructed subjects to place a collect telephone call to the research office of the university in the United States in case of any questions or problems about the research.

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The IRB insisted that the consent form for Bangladeshi subjects be identical to the form used in the United States and that it retain this sentence. This insistence on using the standard consent form is an example of a procedure that is utterly meaningless and irrelevant to ensuring that the research carried out in Bangladesh complies with the ethical standards in force in the United States. It is simply bureaucratic foolishness. Another example in which an IRB in the United States sought to impose its own requirements on a researcher from another country illustrates the importance of understanding cross-cultural differences while at the same time maintaining high ethical standards.42 The researcher, a social scientist from Latin America, was collaborating on a project with a social scientist from the United States, and the protocol was reviewed at the North American researcher's institution. The research was a study of forms of coercion in sexual relations among adolescents, ranging from efforts by male adolescents to persuade their girlfriends to have sex to cases of forcible rape. In an exhibition of 1990s "political correctness," the IRB insisted that the Latin American investigator define as "coercive" any situation in which a female adolescent at first says "no" to sex but eventually agrees. The investigator sought to explain the cultural context, in which sexual relations among adolescents are socially condemned in her country by adults, who deny the prevalence of adolescent sexuality. The society is undergoing changes. A female adolescent who is entirely willing to have sex with her boyfriend—and there are many—must nevertheless adhere to the mores that dictate she must first refuse, even adamantly, lest she appear to be promiscuous. The IRB refused to acknowledge the reality of this cultural difference, maintaining its insistence on the American criterion for sexual harassment: "No means no." This was an attempt by the IRB to alter the methodology of the research by assuming the universality of a cultural norm applicable to the United States but not to Latin America. In its review of the same study, the IRB sought to impose on the investigator a requirement to report to the police and to parents cases in which female adolescents told the researcher they had been raped. The researcher argued vehemently against this proposed requirement on several grounds: (1) reporting to parents or the police would violate the confidentiality the researcher promised the subjects; (2) rape victims in that country are further victimized by police, who are not appropriately trained and who maintain that women must have been acting in a way to provoke the rape; (3) parents may also blame the victim; further, because they are likely to feel shame when confronted by a stranger (the researcher) about such an intimate matter, they may further take punitive action against the girl; (4) the episodes reported to the researcher by subjects would have occurred sufficiently long ago that it would be impossible to do physical examinations or take additional steps that might lead to apprehension and conviction of the rapist. The researcher in this case complained about the inappropriateness of IRB review in the United States of a study she sought to conduct in her Latin American country.

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However, I maintain that the review itself is not inappropriate as the aim is to ensure that the ethical standards governing research are adhered to in international collaborative studies. What was inappropriate was the IRB's flawed risk/benefit assessment in ignorance of the cultural context in which the research was to be carried out, and its insistence on identical procedures to those that would be used in the United States.

FUTURE TRENDS Several procedural steps can aid in the attempt to secure justice in international research. The first is genuine collaboration between researchers in developed countries or in international agencies, such as the WHO or UN AIDS that sponsor or carry out clinical studies. Genuine collaboration requires research training and joint efforts, rather than allowing North American or European scientists direct access to populations in developing countries, as has occurred in the past. A second is to incorporate into the ethical assessment of proposed research a requirement of community or regional involvement in the research process. This includes both community consultation or consensus before and during the conduct of the research, and also a determination that the community or region is likely to benefit in some way from the research outcomes. A requirement of community consultation has evolved as a feature of AIDS research in the United States and is among the criteria for evaluation adopted by a recently formed Ethical Review Committee responsible for reviewing research sponsored by UNAIDS. A process that is different yet related to community consensus has been developed by HRP at the WHO. The Programme has launched a number of initiatives to accommodate women's perspectives into research sponsored by the Programme: the creation of a Gender Advisory Panel that addresses concerns related to the conduct of research on contraceptives, abortion, sterilization, sexually transmitted diseases, and human sexuality; holding conferences and establishing regional programs to build collaboration between researchers and women's health advocates; and broadening the usual risk/benefit analysis to take into account gender perspectives in evaluating the safety and acceptability of contraceptive methods. Justice also requires an appropriate setting of research priorities. The priorities of pharmaceutical manufacturers are probably not the same as those of community leaders and citizens in developing countries. The priorities of medical scientists hoping to win the Nobel Prize are not the same as those of the large numbers of people in the Third World who suffer from malnutrition, infectious and parasitic diseases. A stated objective of HRP in its program of National Reproductive Health Research is "To promote the participation of developing countries in all research aimed at improving reproductive health."43

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CONCLUSIONS

The attainment of justice in any sphere requires both the application of substantive principles of justice and the establishment of procedural mechanisms such as those described briefly here. As illustrated in this chapter, justice in international research cannot be analyzed separately from the more familiar concern of assessing the risks and benefits of research. In addition, it requires a careful evaluation of the relevant similarities and differences between conducting a particular type of research in developed and developing countries. Although justice has not occupied center stage in discussions of international research ethics in the past, it is a critical aspect in today's global context. International guidelines applicable to countries throughout the world seek to achieve justice by ensuring the universal applicability of ethical requirements of research involving human subjects. However, as demonstrated in this chapter, principles of justice may be open to different and conflicting interpretations, and disagreement can arise over their correct application. There is no single principle of justice, but fairness remains the underlying value.

NOTES 1. The author acknowledges the support of the Ford Foundation for two projects on Ethics and Reproductive Health carried out between 1992 and 1995. Some of the material in this chapter is based on those projects. 2. Anna C. Mastroianni, Ruth Faden, and Daniel Federman, eds., Women and Health Research: Ethical and Legal Issues of including Women in Clinical Studies, Vol. 1, (Washington, DC: National Academy Press, 1994), p. 76. 3. Ibid. 4. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects, Federal Register Document 79-12065, April 18, 1979, p. 5. 5. These two conditions are stipulated in Mastroianni, et al, Women and Health Research, Vol. 1, p. 78. 6. Nicholas A. Christakis, "The Ethical Design of an AIDS Vaccine Trial in Africa," Hastings Center Report 18:31-37; 1988. 7. Michele Barry, "Ethical Considerations of Human Investigation in Developing Countries: The AIDS Dilemma," NEJM 319:1083-1086; October 20, 1988. 8. Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO), International Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva, 1993), p. 25. 9. Susan Sherwin, No Longer Patient: Feminist Ethics and Health Care (Philadelphia: Temple University Press, 1992), p. 168. 10. Vimal Balasubrahmanyan, "Finger in the Dike: The Fight to Keep Injectables Out of India," in Kathleen McDonnell, ed., Adverse Effects: Women and the Pharmaceutical Industry (Toronto: Women's Press, 1986), cited in Sherwin, No Longer Patient n. 7, p. 258.

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11. Sue V. Rosser, "Research Bias," in Warren T. Reich, ed., Encyclopedia ofBioethics, 2nd ed. (New York: Macmillan Library Reference, 1995), pp. 2261-2266. 12. See also P. Vaughan, The Pill on Trial (New York: Coward and Macann, 1970). 13. Donald Warwick, "Contraceptives in the Third World," Hastings Center Report 5:9-12; August 1975. 14. Ibid. 15. Michele Barry, "Ethical Considerations of Human Investigation in Developing Countries: The AIDS Dilemma," p. 1085. 16. Michael Policar, "Fertility Control: Medical Aspects," in Warren T. Reich, Encyclopedia ofBioethics, p. 821. 17. Editors, "Safety of DepoProvera," Reproductive Health Matters l:101;May 1993. 18. Jane Cottingham and Suman Mehta, "Medical Barriers to Contraceptive Use," Reproductive Health Matters 1:97-100; May 1993. 19. Ibid. 20. "UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Progress in Human Reproduction Research" 31:8; 1994; Marge Berer, "The Quinacrine Controversy One Year On," Reproductive Health Matters 4:99-106; November 1994. 21. Berer, Ibid. 22. "UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction," Progress in Human Reproduction Research, p. 8. 23. One such country is Brazil. During a visit I made to that country several people told me that "control of medications is chaotic in Brazil." Ford Foundation project on Ethics and Reproductive Health II, visit to Brazil, April 1996. 24. Berer, "The Quinacrine Controversy One Year On," p. 99. 25. Ibid., p. 100. 26. "Scientific Review Body Voices Concern at Use of Quinacrine for Sterilization," Progress in Human Reproduction Research 31:8; 1994. 27. Giuseppe Benagiano, "Sterilization by Quinacrine" (letter), Lancet 344:689; September 1994. 28. Elton Kessel, "Quinacrine Sterilization Revisited" (Commentary), Lancet 344:698700; September 1994. 29. Berer, "The Quinacrine Controversy One Year On," p. 100. 30. Ibid. 31. Ibid. 32. Sandra Mostafa Kabir and Adrienne Germain, "Is RU-486/PG in its Current Form Likely to be Appropriate for Women in Bangladesh?" in Ghulam Mustafa Kamal, ed., Proceedings of the International Symposium on Antiprogestins (Dhaka, Bangladesh: Bangladesh Association for Prevention of Septic Abortion, 1992), pp. 48-57. 33. Ibid. 34. Ruth Macklin, "Antiprogestins: Ethical Issues," in Ghulam Mustafa Kamal, eds., Proceedings of the International Symposium of Antiprogestins, pp. 95-103. 35. Nicholas A. Christakis, Lorna A. Lynn, and Aduato Castelo, "Clinical AIDS Research that Evaluates Cost Effectiveness in the Developing World," IRB 13:6-8; JulyAugust 1991. 36. Public Citizen News Release, Media Advisory, April 22, 1997. 37. David Brown, "Medical Group Condemns U.S. AIDS Drug Tests in Africa for Using Placebo," Washington Post, April 23, 1997 p. A14. 38. Public Citizen, letter to Secretary Donna Shalala, April 22, 1997, pp. 3, 10.

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39. Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO), International Ethical Guidelines for Biomedical Research Involving Human Subjects, p. 43. 40. Public Citizen, letter to Secretary Donna Shalala, p. 3. 41. Ford Foundation Project on Reproductive Health I, Visit to Bangladesh, March 1994. 42. This incident was reported to me in personal conversation by the researcher. 43. Special Programme of Research, Development & Research Training in Human Reproduction, Information Bulletin, WHO, Geneva.

9 THEORIES OF JUSTICE IN THE CONTEXT OF RESEARCH Madison Powers

A central theme throughout this volume is the recent transition from a view of justice in research ethics, having an almost exclusive emphasis on the need for special protection of vulnerable populations, to an increased concern that members of disadvantaged populations (both individually and as a group) have greater access to the potential benefits of medical research and increased opportunities to participate as research subjects. However, the theoretical justifications offered in support of this fundamental change in view are diverse, and the implications for public policy vary accordingly. The purpose of this chapter is to make explicit some of the important differences among the theoretical rationales for reconceptualizing what justice in medical research demands, and to examine their relations to the conceptions of justice at work in the broader political tradition and to the specific norms of justice dominant within other health policy debates. Three themes emerge. First, the dominant norms of justice operative in any of the three major spheres of health policy—biomedical research, occupational and environmental protection, and health care resource allocation—have developed in tension with predominant norms of justice characteristic of the larger political culture. I argue that the dominant norms of justice in each of the three major spheres of health policy can be viewed as distinct responses to specific aspects of classical liberal political conceptions of justice embedded in the American political tra147

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dition. These responses are predicated on the claim that the classical political tradition with its primary emphasis on individual consent as the primary safeguard against injustice is an inadequate basis for public policy. Second, the three major spheres of health policy have been guided largely by a single dominant norm of justice applicable to each separate sphere. However, it is no longer plausible to assume that a single dominant norm of justice, such as the protective conception dominant in research contexts, will be sufficient to resolve questions of justice in any single sphere of health policy. Therefore, I consider how current controversies in research ethics reflect diverse strands of classical liberal, egalitarian, and other norms of justice found in the larger political culture. Third, understanding what is required by justice in a single sphere is not separable from an inquiry about justice in related spheres of health policy. The only way to determine what is fair, for example, in the setting of research priorities, or in establishing criteria for inclusion or exclusion in clinical trials, is to examine the distributive ramifications of such decisions in light of how health-care allocation policies and environmental and occupational policies also affect the distribution of health burdens and risks in society in general. Accordingly, I argue that the trend toward dismantling distinct norms of justice appropriate to separate spheres of health policy is a positive development, and I consider some reasons for carrying this program of dismantlement even further. Finally, I rely on this and other chapters in this volume to draw some conclusions about the complexity of the issues emerging in fashioning just policies in medical research. Reflection on the experiences of the last 30 years has moved us well beyond the early concern with ensuring voluntary and informed consent that is required by classical liberal conceptions of justice. We now must consider a host of other distributive and nondistributive matters that were largely invisible from the perspectives of those designing the current system of IRBs. Moreover, I conclude that we must look beyond the limited role of the IRBs to address many of the most pressing issues of justice in research.

JUSTICE IN THREE SPHERES OF HEALTH POLICY My thesis in this section is that recent changes and proposals for change in the status quo are best understood as reflecting multiple, rather than a single evolving set of norms of justice in research, and that they rest on diverse—not always fully explicit and perhaps not always internally consistent—theoretical underpinnings grounded in the larger political tradition of classical liberalism and its critics. The tenets of classical liberal thought have their origins in the seventeenth century work of John Locke and other political theorists concerned with setting limits to government authority and protecting the individual from interference with liberty. Lockean ideas informed the thought of founders of the American republic and are articulated with great clarity and passion in The Federalist Papers. John

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Stuart Mill in the nineteenth century further developed the liberal emphasis on protecting individual liberty, and the contributions of Locke, Mill, and the Federalists continue to shape the contours of political culture in contemporary American society. Indeed, these are the starting points for the most influential work on justice in the twentieth century.1 Classical liberalism, in short, provides the benchmark against which all other accounts of justice are evaluated. Classical liberal thought, or libertarianism as it is sometimes called today, relies on two core elements. First, the central concern of the classical liberal is the guarantee of liberty for the individual. Hence, injustice is a matter of interference with the freedom of individuals to make their own choices according to their own values and their own assessments of the risks and potential benefits. Accordingly, it opposes the substitution of the judgments of society for the judgment of the individual about what is best for that individual, and it opposes overriding the preferences of individuals to secure a greater benefit to society as a whole, or for the sake of some individuals or groups within society. Second, classical liberals reject what are called patterned conceptions of distribution.2 A patterned conception assumes that a particular distribution of benefits, burdens, risks or opportunities is fair, or just, to the extent that it conforms to some ideal pattern of distribution. Perhaps the most familiar patterned conceptions of justice are egalitarian theories which count a particular distribution as just if the object of distribution is allocated fairly or equally among all having valid claims to that object. Injustice, therefore, consists in some morally condemnable pattern of inequality in distribution. The proper focus of justice on a classical liberal view, by contrast, is the process by which a particular distributive outcome is achieved. That some individuals or groups fare less well, or that the collective benefits are not as great as they might otherwise have been, are not in themselves injustices. Whatever pattern of distribution that emerges from the voluntary choices and uncoerced agreements entered into by individuals satisfies the full demands of justice on the classical liberal view. Claims on behalf of the disadvantaged, the vulnerable, and even the collective welfare of society, have had the burden of arguing that production of a particular pattern of distribution is of sufficient moral importance to overcome the presumption that individuals should be free to make their own choices. However, the dominant norms of justice within each of the three main spheres of health policy offer different responses to that presumption. Access to Health Care

Consider first some critical discussions of the inequalities in access to health care in the United States that tend to follow the lines of egalitarian moral theorists. Such arguments are both the most theoretically developed accounts of justice in health policy and the most closely linked to larger issues of distributive justice within

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the broader political culture. Egalitarians differ, of course, in their answers to the question of what inequalities are the central concern of justice to combat. One prominent view, for example, favors equality in access to resources which meet basic human needs.3 An alternative egalitarian view takes equality of outcome as the proper aim of justice, and because individuals do not have equal needs, equality in the distribution of resources often does not necessarily translate into equality of outcome.4 A third alternative is committed to equality of opportunity as a criterion of justice, which if successfully met may neither require equality of resources (some with fewer needs require fewer resources) or produce equality of outcome (people differ in talent and efforts).5 A fourth, more modest view often counted as a species of egalitarianism, does not aim for strict equality of resources, outcome, or even of opportunity. The Difference Principle defended by John Rawls argues that social and economic arrangements are just when they maximize the welfare of the worst-off groups.6 It thus sets limits to how badly anyone in society may fare relative to others; it does not take equality of any sort to be the strict aim of justice. The theoretical strengths and weaknesses of these and other egalitarian conceptions of justice have been discussed widely, and I shall not rehearse them here.7 The key point for this discussion is this: the central challenge any egalitarian theory presents to the classical liberal view is the claim that equal liberty and the prevention of interference with individual choice alone are not all that matter to justice. All egalitarian theories emphasize the additional importance of access to those goods, benefits, or advantages which make human flourishing possible. Freedom of choice is important, but the availability of choiceworthy options also is important. A striking consequence of the egalitarian's focus on goods such as income, wealth, and health care, which persons need to flourish, is that the distribution of burdens and risks can remain largely ignored in the analysis. For example, Rawls's Difference Principle limits its application to the primary goods of income and wealth, which everyone is presumed to want, but it leaves out of its account a vast array of other matters that also bear on how well an individual fares. Even if the Difference Principle is applied to an expanded list of benefits and advantages, including access to health care, it would have to be supplemented by an explicit recognition of what burdens and risks persons also bear for it to be a comprehensive account of justice. I do not mean to suggest that there is any bright conceptual line to be drawn between the removal of an impediment or burden and the provision of a benefit or advantage. Burdens such as an unhealthful environment, for example, can be redescribed as the good of a healthful environment, and a theory of justice focused on the distribution of benefits and advantages can be supplemented by expanding its account of the relevant goods. However, thinking about social justice primarily in terms of benefits and advantages can have different practical impli-

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cations than a perspective focusing on protection from risks of harm as separate concerns. Once the focus is broadened to take account of risks of harms, the inquiry shifts from questions about the distribution of goods persons need to flourish to questions about how to protect some segments of society from bearing a disproportionate share of risks of harm. Research Policy

The focus on protecting the vulnerable from the imposition of greater healthrelated risks is precisely the animating concern of the dominant norm of justice in research as protection. This protective conception of justice can be elaborated as having three separate components. The first is the requirement of individual informed consent to medical experimentation. This requirement has been the central focus of much of the oversight by IRBs, and it is the part of the protective conception most resonant with the classical liberal conception. The requirement of informed consent for medical experimentation can be seen as an attempt to ensure that the medical research community lives up to the promise of the classical liberal demand that individual decisions are voluntary. The second component of the protective conception, however, moves beyond the classical liberal norms of justice, arguing instead that individual consent, though necessary, may not be sufficient as a means of protecting research subjects from harm. The requirement that IRBs review research protocols to ensure a genuine prospect of benefit and an acceptable level of risk is meant to restrict the permissible range of individual assessment of acceptable risk and benefit, and thus further protect persons from harm that might result from their own choices. The emphasis is on protecting those who are perceived as vulnerable to coercion or manipulation, exploitation, or deception, or persons otherwise thought to be less capable of relying on their own judgments to protect their own interests. Among those historically singled out for such protection are women, children, desperately ill patients, institutionalized or incarcerated persons, fetuses, persons with reduced or diminished decision making capacities, economically necessitous persons, and convenient populations. The central thrust of what might be called the antiexploitation element of the protection conception of justice extends at least as far back as Marx's critique of capitalism and remains today a central theme in antiliberal political thought. Although few in the historical defense of the antiexploitation principle in research ethics acknowledge its conceptual affinities with this antiliberal tradition, the protective conception nonetheless adopts as its own one of the central Marxian objections to classical liberal thought. The claim is that reliance on individual consent alone is not adequate to protect persons from exploitation under conditions of grossly unequal bargaining power, information, and human need. Under such conditions of inequality, some persons will bear greater burdens and receive fewer

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benefits of social cooperation. Justice therefore demands more than mere noninterference with voluntary agreements. Some role for government or other intervening institutions is needed to police such agreements and protect against exploitation. The third element of the protective conception takes the critique of the classical liberal view a step further. It is concerned not only about the prospect that some individuals may fare less well than others; it also reflects an emerging concern for how benefits and burdens are distributed among social groups within society. For example, the Belmont Report concluded that "research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research."8 The fundamental premise of this passage is that, contrary to the classical liberal's rejection of patterned conceptions of justice, distributive outcomes are of special and independent significance to justice in research. Occupational and Environmental Health Policy

Norms of justice dominant in the occupational and environmental health policy spheres in research contrast sharply with two aspects of the norms of justice in both research and health care allocation spheres. First, traditional approaches to environmental and occupational health issues reject the almost exclusive focus on either benefits or risks which both egalitarian and protective conceptions of justice employ. They adopt instead an approach which involves a simultaneous reflection on benefits and burdens. The assumption is that every option involves both benefits and burdens, necessitating some trade-offs, and often the trade-offs occur in cases where the burdens are not borne by the beneficiaries. In addition, no social option is viewed purely as a burden (such as participation in research) or as a benefit (such as access to health care). Second, traditional approaches to public health such as cost-benefit analysis are concerned with bringing about the greatest net balance of benefits over burdens, and they give no independent moral weight to individual or group inequalities in the distribution of burdens and benefits resulting from any trade-off. However, both egalitarian theories of health care allocation and the protective conception of justice in research, while treating distributive questions about risks and benefits separately, nonetheless agree in their opposition to the assumption that distributive patterns have no independent moral relevance for the justice of health policies and institutions. Divergent Spheres

The divergence of dominant norms of justice in three spheres of health policy suggests three kinds of issues that arise in various challenges addressed to the tra-

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ditional views of justice in research. First, to what extent can an adequate account of justice in research be indifferent to patterns of distribution of benefits and burdens that emerge from voluntary agreements between subjects and researchers? Second, to what extent can such an account focus on the protection against harms and ignore issues of distribution of potential benefits from participation in research? Third, to what extent can such an account retain its focus on research and ignore issues of inequality in access to ordinary or nonexperimental health care? In the sections that follow, we will see how each question is answered. The protective conception already reflects a substantial repudiation of the classical liberal emphasis on the adequacy of individual consent. Challenges to the protective conception follow the lead of those concerned with the fair allocation of healthcare resources, and increasingly, research contexts are seen as arenas in which the fair distribution of the benefits of research, as well as the risks, must be assessed. The wider lens offered by adoption of the public health approach points away from assessing the justice of research policies independently from issues of inequality in access to health care generally. The mapping of the distinct norms of justice in three spheres of health policy and their relation to tenets of classical liberal theory in this section can now be used as a basis for understanding the complexity and diversity of the contemporary challenges to the dominant norms of justice in research.

RETHINKING THE DEMANDS OF JUSTICE IN RESEARCH

Consider first the challenge to the protective conception presented by changes in research involving patients in emergency room settings and in the recruitment of subjects in developing countries. To the extent that either informed consent requirements are dispensed with (emergency rooms) or some researchers rely upon "culturally appropriate" mechanisms of community consent (research abroad) as an alternative to individualized consent, it is the first and most basic element of the protective conception that is under assault. Retreat from an unexceptional commitment to individual consent not only contravenes a principle of respect for autonomy; it is also contrary to the classical liberal conception of justice, which the protective conception adopts as the moral minimum in its own account of justice. Other challenges are lodged against applications and interpretations of the antiexploitation element of the protection conception. As Jonathan Moreno observes in Chapter 7, some charge that, in some instances, the protective conception is too stringently applied while other applications are not stringent enough. For example, Moreno notes that many object that blanket restrictions on prisoner participation in research is overly protective, wrongly judging the prospects of coercion or manipulation during incarceration as so great as to vitiate the possibility of informed consent in all instances. On the other side of the equation, it has

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been charged that some current practices fail to take seriously the profound threats to voluntary choice. The circumstances in which military personnel are subjected to medical research and the curious failure to develop federal regulations for research on persons with diminished decision making capacity are two often cited examples of an inadequate level of concern about exploitation. Other challenges to the antiexploitation component of the protective conception are more fundamental, and they reflect deep roots in the classical liberal tradition itself. Case studies cited by Baruch Brody in Chapter 3 reveal the extent that the protective conception has given way to a greater latitude for desperately ill patients to make their own judgments about potential medical benefits and acceptable risks of unproven therapies. The consequence of the new regulations on the use of investigational drugs and accelerated drug approval for drugs to fight HIV both lower the threshold of proof of what counts as sufficient potential medical benefit and increase the range of risks to which individual patients themselves may consent. Similarly, modifications in regulations of Phase I clinical trials (where toxicity, not efficacy is being investigated) allow research subjects in cancer drug protocols to receive a higher dose of a drug, the consequence of which is greater likelihood of a clinical benefit (if there is one) coupled with a greater likelihood of toxicity. As Brody observes, such changes represent a major retreat from the protective approach to justice in research. Behind that retreat is a resurgence of a type of argument straight out of the classical liberal tradition of justice. Against the grain of traditional antiexploitation concerns, a central theme in the AIDS activist literature of the 1980s was that justice required that individuals should decide for themselves what risks they should bear, and moreover, that the welfare of currently dying persons should not be sacrificed in clinical trials as a means of establishing the efficacy of these drugs for use by future patients with AIDS.9 Rather than seeing themselves as vulnerable, and in need of protection from their own improvident choices, they argued that justice required that these choices, perhaps more than many others, ought to be left to individual patients. AIDS activist Martin Delaney asked, "who should decide which risks are acceptable? .. . [o]bviously, patients acting with their physicians."10 Another undercurrent in the rethinking of research ethics has been the evolving perception of patients with cancer, AIDS, and other potentially lethal medical conditions that participation in medical research is more of a benefit to be sought than a burden or risk from which they needed protection. When viewed as largely a benefit, advocacy groups press for increased access to clinical trials, which many see as offering the latest and best treatments for individual patients. Moreover, the medical establishment itself often reinforces the view that a central aim of clinical trials is benefit to the subject. (As I am writing this chapter, an advertisement on the radio by a major regional medical center seeks volunteers of a clinical trial, and the clear implication is that persons who have failed to get relief from

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their current asthma medication may benefit). Indeed, it is difficult for researchers to recruit subjects for trials in which they do not believe that they are complying with the Declaration of Helsinki's ethical requirement that participants, including those in the control group, receive the best proven therapeutic agents and diagnostic methods.11 A major consequence of the partial shift in perception of participation in medical research from a burden requiring protection against to benefit to be sought has opened the door to new claims of justice. To the extent that the participation in or opportunity to receive the benefits of cutting edge medical research comes to be viewed as scarce goods, the renewed emphasis on individual liberty to assess risks for themselves gives way to questions of whose need is greatest and what entitlement some claimants have to the benefits of medical research. A protest slogan of the AIDS activist group AIDS Coalition to Unleash Power (ACTUP) illustrates just how far some attitudes have changed: "A drug trial is health care too."12 The emerging view that drug trials are valuable opportunities for patients and subjects to obtain health benefits for themselves obscures the original purpose of clinical trials. The original view of research, which emphasized the generation of knowledge that may improve the welfare of future patients, quite naturally regarded participation in medical research as more risk than opportunity.13 Consequently, the distributive concerns were quite narrowly focused on fairness in selection of subjects. The emphasis was on ensuring that burdens were not disproportionately borne by some vulnerable or disadvantaged groups, especially when the ultimate benefits might be enjoyed by a later generation of patients and perhaps by more fortunate groups within society. Once the line between clinical trials and ordinary health care gets blurred, as the ACT-UP slogan supposes, the natural extension of an egalitarian logic is to assimilate demands made in the name of justice in health care generally to new demands about what fairness in medical research entails. Just as some press egalitarian demands for a universal entitlement to access to health care without regard to ability to pay, disease-specific activists also pressed demands for similar entitlements to unproven therapies and for a more substantial share of public expenditures to be devoted to conditions affecting those claimed to be among the medically worst-off segments of society. Indeed, the increase in litigation, or the threat of litigation, against insurance companies and managed care organizations for failure to pay for services, for which clinical benefits are not well-established, is further indication of just how far the line between research and treatment has been blurred and of how far the new claims about distributive justice have found their way into the mainstream of public consciousness. One ironic aspect of the new claims about what justice in research requires is the tension between the resurgence of classical liberal arguments for individuals having more say in the acceptable risks and prospects of benefit and the

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activists' arguments that assimilate issues of fairness in clinical trials to egalitarian conceptions of what justice requires in the distribution of ordinary medical care. On the one hand is a classical liberal argument against interference with individual decisions about risk, and yet on the other, a demand for more government guarantees of access to costly experimental medical treatments for those unable to afford them. Classical liberal arguments, however, have supported government policies of noninterference on the assumption that patterned conceptions of justice of the sort egalitarians favor are to be rejected in favor of patterns of distribution that emerge as a product of individual choices. Thus, the new arguments represent a kind of hybrid approach to justice in research: a broadly libertarian attitude hostile to government interference with individual judgments about acceptable risks and an egalitarian attitude more favorable toward greater government involvement in bringing about a preferred pattern of distribution of the benefits of research. The move toward letting individuals have greater say in what risks and benefits are acceptable, however, puts pressure on the third element of the traditional protective conception of justice. The logic of leaving more decisions to individuals necessitates a greater social willingness to let the chips fall where they may. However, the ultimate implication of a commitment to avoiding disproportionate impact upon some groups is the rejection of such willingness. Some limits to individual choice are necessary to ensure that the cumulative consequence of many individual choices is not a pattern of gross inequality in which some groups bear disproportionate medical burdens. The commitment to a view of distributive justice as opposed to deep inequalities in burden among groups thus entails some serious limitations on how far the logic of classical liberal approaches to individual decision about risks can be accommodated by the protective conception of justice in research. For the protective conception endorses the moral significance of patterns of group inequalities which the classical liberal thinks unobjectionable if produced as a consequence of the sum of individual choices. The new egalitarian strands in the discussions of fairness in medical research also reveal deep divisions within egalitarian theories of justice more generally. Feminist contributions to the debates over justice and research are especially illuminating, and demands for inclusion of those historically excluded or disadvantaged by lack of access to other benefits in the health care system add an additional layer of complexity to any assessment of what justice in research requires. For example, the case for a presumption for inclusion of women, including women of childbearing potential has been defended on a variety of grounds, including standard egalitarian grounds and other views of what a commitment to equality entails. The arguments made by the IOM, which prepared a report on women's health and research for the NIH Office of Research on Women's Health, rested much of their case for greater inclusion of women in clinical trials on principles favoring an equality of medical benefit derived from research.14 In a new

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twist on an old egalitarian theme, however, some sympathetic observers of the IOM Committee report argued that justice required equality both at the level of the individual participants in clinical trials and for the population at large. One commentator characterized the IOM's arguments as involving an appeal to a "principle of justice with regard to who receives the benefits of clinical research and in assuring that an individual's right to participate in research [is guaranteed]."15 Although the IOM report did not cast their conclusions in the same way, two distinct egalitarian claims about justice are articulated in the above passage. First, it is said to be unjust when individual women are denied opportunity to benefit from new therapeutic interventions that might not otherwise be available to them. Such arguments for equality in opportunity to participate in clinical trials have especially strong appeal on behalf of members of medically underserved populations. Some who argue for a moral right to health care, even in an investigational setting, may be influenced by the fact that enrolling in a clinical trial may offer some an opportunity to get the health care that is otherwise not available to them.16 Second, exclusion of women harms women as a group, especially future female patients whose medical care might be adversely affected by the findings of a clinical study which does not examine evidence bearing on the beneficial and adverse effects of an intervention for female patients. Vanessa Merton argues that when the effects of therapeutic agents on women are not studied, women "become guinea pigs once the new therapy hits the market."17 It is estimated, she notes, that 70% of women use between three and 10 drugs during pregnancy, and yet the exclusion of pregnant women from research guarantees that huge numbers of women are subjected to risks of unknown magnitude.18 The distinction between individual and group claims for equality in the distribution of the benefits of medical research raises difficult questions about the proper focus of distributive justice in research. The real issue of justice, says Jonathan Moreno, is not the rights of subjects to be subjects, but that the long-term benefits of such research are not reserved for "the white, middle-aged, middle class men" who are the object of study.19 Moreno's view squares with the traditional view that the intended beneficiaries are future patients whose care will be improved by the knowledge obtained from the studies. Though participation may in fact be a benefit to a particular patient, that is not its aim. Nor is it a reasonable expectation in many cases. The concerns about exploitation that motivated the protectionist policies in the first place ought not be forgotten. Expanding access of poor and minorities to medical services not available, conditioned on the requirement of participation in research, asks some to assume a burden for that which, on the egalitarian account of justice, should have been available to all as a matter of right. Nor should we assume that tinkering with the criteria for subject selection will have the substantial and long-term effect of alleviating the larger burdens of inequality in access to health care the egalitarian theorist is principally concerned to achieve.

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Moreover, women, for example, already bear disproportionate burdens of medical research in matters such as fertility control or enhancement, and there is no guarantee that placing more burden on a group will lead to more benefit for that group. Even if women and other groups do not experience inequality in medical benefits as a consequence of exclusion from medical research, there are, however, other powerful reasons of justice to oppose their systematic exclusion. A substantial part of the argument against exclusion of women from research, for example, based on potential harm to the unborn, is an opposition to the second class social status such exclusions connote. Nancy Kass and her colleagues note that one reason for NIH removal of the exclusion of women from research protocols is that: Systematically excluding all women on the grounds that they are always potentially pregnant (1) does not respect the totality of who women are and (2) portrays women as agents incapable of controlling their fertility when a research intervention might be teratogenic.20

Such arguments exhibit a strong affinity to arguments found elsewhere in feminist theories of justice. They rest upon an egalitarian conception of equal citizenship. The thrust of this argument for equality of opportunity to participate as research subjects is analogous to arguments for equality in the opportunity to enter into military service. Military service is understood as neither purely a benefit for, nor a burden on those who serve. It entails risks of death and disability as well as opportunity to make a unique social contribution not possible if full participation is barred. Nor is the essence of the claim for equality a libertarian demand that each individual to be allowed to weigh up the risks and benefits for herself. The demand is that women be permitted to volunteer for military service or medical experimentation on equal terms with men. The ideal of equality appealed to is more abstract than the demand for equal benefits, equal opportunities, or even equal liberties. It is a demand for recognition of moral equality, for full standing as members of the moral community.21 These larger issues are matters of according to women equal dignity and the recognition of equal worth, which are prerequisite to the elimination of inequalities of power, privilege, or opportunity.22 Finally, recent arguments rooted in the egalitarian tradition go well beyond the demands for equality in the benefits of medical research or an equal right for all citizens to participate as subjects. If women as a group have been disadvantaged, both in medical research and in access to other important social opportunities as a consequence of past inequalities, then it is argued that mere equality or parity of access to participation in current research protocols by itself is not what justice now requires. Justice may require steps to eliminate the more fundamental sources of inequality that result in the inequalities in medical research. The deeper injustice is the cultural devaluation and social subordination of women which renders women's interests invisible in the formation of medical research priorities and

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policies. To address these deeper concerns, it will not be enough to adopt genderneutral polices of allocation; policies of preferential treatment will be necessary to redress past practices in which women's interests have been systematically left out of account. A policy of gender-neutrality would be objectionable if it leaves in place substantial inequalities between men's and women's health care. Men would continue to enjoy the advantages derived from the disproportionate share of resources that have been devoted to research affecting women's and men's health.23 Moreover, even if it should turn out that the failure to include women in substantial numbers in clinical trials did not harm the medical or health interests of women, the argument based on equal citizenship is that justice nonetheless requires preferential policies as part of what is required to change the conception of women that results in their subordinate status.24 To summarize this section: we have witnessed a kind of evolution of diverse norms of justice that have been used to challenge the protective conception of justice in research. Some changes strike at the heart of the minimal protections afforded by the requirement of individual consent that the classical liberal view of justice treats as both central and indispensable. Next we see challenges to the current interpretations of the antiexploitation principle, arguing both that some interpretations are overly protective while others are insufficiently protective. Increasingly, we see more fundamental challenges to the antiexploitation principle that embrace core elements of a classical liberal argument on behalf of greater individual freedom to decide what risks are acceptable. Many of the more recent claims made in the name of justice reflect egalitarian roots, and do not square easily with challenges rooted in classical liberal assumptions. The arguments presented by advocates of greater equality in access to health care are extended to justify greater inclusiveness for those historically denied equality of benefits derived from medical research. Egalitarians, however, seem divided on the issue of whether the proper focus of justice ought to be on individual rights to participate as research subjects, the larger patterns of inequality among groups that results from medical research policies, or both. Other egalitarians look beyond the questions of the distribution of benefits and burdens to consider the deeper significance of what equality of citizenship and moral status requires in the design of medical research policies. Still others argue for a theory of compensatory justice that requires public policies designed to provide a partial remedy for the injustices that historically have been imposed upon disadvantaged groups and perpetuate their unequal status today. BEYOND SEPARATE SPHERES The complexity and diversity of the various challenges to the protective conception offers a powerful case against the likelihood that any single norm of justice

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will be adequate to capture all that matters to a comprehensive account of justice in research. In this section, I offer a few brief additional remarks meant to suggest that matters are complicated even further than the picture emerging so far reveals. Here I want to claim that there are at least three reasons to doubt that the requirements of justice in research can be fully appreciated in isolation from issues of distributive justice in other spheres of health policy. First, issues of justice in the allocation of medical treatments cannot be divorced from issues of justice in research. Even if, as I have suggested, it is impractical and extraneous to the core purposes of clinical trials to make a medical research agenda the vehicle for remedying the problems of inequality of individual access to ordinary care, one cannot ignore the possibility that inequalities in the allocation of treatments may be a direct result of inequalities in research. What is known about the origins, history, and treatment of diseases determines the available opportunities for medical benefit. Thus, the exclusion of some groups from research may set in motion patterns of inequality of care that cannot be overcome without a substantial redistribution of the resources in research, including a distributive pattern deliberately characterized by inequalities meant to correct for inequalities in the sphere of health care allocation. Second, although the claim that justice demands inclusion of those left out, whatever the costs, may hold an initial attraction, especially as part of a phase of compensating for past injustices, there will be inevitable, and I suspect, increased pressures for setting research priorities according to efficiency criteria many find persuasive in other areas of health policy. For example, there are those who are, for a variety of imaginable reasons, relatively expensive to research. They may be expensive because they are geographically isolated or dispersed, outside the realm of routine contact with researchers, or have conditions for which there is a low baseline of knowledge. Efficiency arguments favor priorities for research which can be expected to yield the greatest aggregate medical benefits for the investment, and it may be argued, for example, that for conditions about which more is already known, scientific breakthroughs are more likely. Such arguments, while facially neutral with regard to the segments of the population, can reinforce existing patterns of inequality and discrimination in access to care. If considerations of efficiency dominate the decisions about allocation of health care and decisions about research priorities as well, then the currently disadvantaged will be doubly disadvantaged. Some may receive low priority for treatment because not enough is known about what is medically effective, and they may be given low priority for research because more clinical benefit may be expected when resources are devoted to conditions about which more is already known. Third, if it is implausible to view questions of health care allocation and research priorities as separate spheres with distinct norms of justice, then it is equally implausible to suppose that issues of environmental and occupational risks are

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not similarly intertwined. Arguably, justice in the allocation of the benefits of medical treatment should bear some relation to the overall distribution of health burdens in society. If some members of society bear substantially greater burdens of disease or ill health, especially when those burdens are a consequence of their greater contribution to the common good or their having been asked (or compelled) to make greater sacrifices, then the inequality of their burdens should figure into the setting of medical research priorities. All three suggestions in this section are highly schematic, but they point to one single insight: distributive policies in one sphere which seem fair in isolation may be unjust when viewed globally as part of a totality of health policies. It is to the totality of benefits and burdens and their distribution that we must look when thinking about what justice requires in medical research.

CONCLUSIONS

Future developments in the account of justice in research will require us to weave together a variety of strands previously seen as lying outside the scope of this seemingly insular sphere of health policy. While the final shape of that account cannot be predicted, several preliminary conclusions can be drawn from this and other chapters in this volume. First, because the protective conception goes well beyond the classical liberal account of justice, there is an inescapable role for government and other social institutions in policing the conduct of research to ensure that subjects are not exploited. Libertarian arguments for letting individuals have greater say in which research risks are acceptable, while plausible perhaps in some instances, must be viewed with caution. Just because the protective conception may have been exaggerated in some instances and thus operated to the detriment of some, it does not mean that the protective conception ought to be abandoned. The consequence of wholesale retreat may be the exacerbation of patterns of inequality. Health policies that merit special concern are those that take a step back even further than the classical liberal view finds acceptable. For example, policies that remove requirements of informed consent, such as those waiving consent in some emergency room research settings, represent a major departure from what has become a firmly entrenched floor of subject protection. As Patricia King notes in Chapter 6, such policies may disproportionately and adversely affect minority and poor communities where emergency care is more frequently rendered. Second, as King's example already suggests, the goal of protecting vulnerable individuals against the exploitation is not the only aim of the protective conception. A reasonable extension of the distributive principles of the Belmont Report requires a concern for the well-being of disadvantaged or powerless groups as well as safeguards against the abuse of particular persons. The consequence of a dual

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focus on groups and individuals is that individual decisions regarding acceptable risks and benefits may be restricted for the sake of avoiding injustice to a group to which those individuals belong. The concern for how groups fare thus, means that social policy makers cannot simply allow whatever patterns of distribution emerge from the product of individual choices. If inequalities that attach to groups are morally troublesome, intervention must be an option to ensure that such patterns of inequality do not persist. A further implication of a dual focus on groups and individuals is that justice for groups and justice for individuals may clash in ways perhaps more profound than limiting some individual choices for the sake of fair treatment of groups. One worry is that conceiving the requirements of justice through the lens of group interests is that it is a double-edged sword. On the one hand, attention to the potential for some research policies to have an unequal impact on some groups can help identify unjust inequalities that might have gone ignored. Yet on the other hand, as Patricia King argues in Chapter 6, thinking about the needs of individuals through the lens of group identities such as race can have a negative dimension. For example, it can contribute to racist genetic explanations of health and disease and perpetuate the disadvantages experienced by oppressed racial groups. Moreover, focus on patterns of distribution among groups can lead to problems in the way we conceptualize the demands of distributive justice. For example, it is not clear how our thinking about inequalities among the generations are best understood. As Nancy Kass points out in Chapter 5, a just public policy needs to be sensitive to inequalities in health care that are a consequence of failing to think about the special medical needs of specific groups such as the elderly. Vast inequalities in the benefits of medical research between the old and the young clearly offend any plausible principle of distributive justice. Yet, at the same time, we also think of the proper concern of justice as eliminating unjust inequalities among persons over their complete lives.25 From this perspective, the claim is that we ought not think in terms of distinct identifiable interests of the young versus the old. Whatever we owe the old is not due them because we think that they should not fare worse than their younger contemporaries. Some argue instead that, by virtue of having grown old, the old already have had a fair opportunity to live a complete life. Hence if the aim of justice is to combat certain inequalities in overall life prospects among persons, then justice will require giving priority to the young. That priority would be fair because it offers them a similar chance at a good life overall, rather than giving attention to the needs of the already more fortunate. The kinds of arguments discussed above have been made primarily in the context of allocating health care services but they may be applied equally well to questions of how best to distribute scarce research funds. I do not propose to offer a solution to these problems in this chapter. My only concern is to emphasize how complex matters become once the classical liberal focus on protection

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of individuals is expanded to include concerns about the distribution of risks and benefits among groups. Because the interests of groups and individuals who comprise them can diverge we sometimes have to balance them. Third, because no aspect of health care comes marked in advance as a potential benefit or a risk, justice in research must adopt yet another kind of dual focus. Distributive concerns regarding both benefits and burdens must be the object of simultaneous moral assessment. For example, research leading to a new genetic test for some medical condition may offer the prospect of benefit (and hence be justified) if it can be expected to lead to an effective (and available) treatment. However, if no treatment is likely to be forthcoming, research leading to new genetic tests may simply add new burdens in the form of loss of insurance or employment opportunities. The upshot of this dual distributive focus is that issues of fairness in recruitment of subjects is not by itself all that matters in evaluating whether some research proposal is acceptable from the perspective of justice. Fourth, once we adopt a dual focus on groups and individuals and a dual focus on the distribution of both risks and potential benefits, new questions emerge regarding the role of IRB's in ensuring justice in research. IRB's have limited institutional competence. Their members can be expected to look for unfairness in subject selection criteria, and similarly they can be on the lookout for group inequalities in risk-bearing. It is less clear, however, how well situated IRBs are to deal with the implications of some specific research proposals for the larger social inequalities that now concern us. The problem is that the authority of the IRB is quite far downstream from where public policy-setting research priorities are made. The responsibility for addressing the implications of research for health and other inequalities to which research (or lack of it) may contribute resides upstream. If justice in research now requires some concern for the larger social implications then we shall have to look beyond the role of the IRBs in meeting those demands. Consider one example of what an enlarged vision of what justice in research requires. A common theme in the chapters on race (Chapter 6) and gender (Chapter 5) is that justice in research will require us to confront issues that go beyond fair distribution of either risks or potential benefits. It is not enough, they claim, that some deliberative bodies (whether IRBs or national policy makers) take steps to secure greater inclusion of women and minorities so that they derive a fairer share of the benefits of research. In addition, justice will require a greater voice in setting those priorities and the opportunity to participate as equals in the design of all facets of health policy having the potential to affect their health outcomes. In short, the new demand is for an equal voice in setting the medical research agenda and in shaping the public conception of what counts as medically and socially beneficial research. While the protective conception already moves beyond consent alone as the core concern of justice in research, demands for upstream participation in the

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design of health policy takes another giant step beyond merely securing consent to the research agenda set by others—beyond also the demand for greater equity in the distribution of its benefits.26

NOTES 1. John Rawls, A Theory of Justice (Cambridge, MA: Harvard University Press, 1971). 2. Robert Nozick, Anarchy, State and Utopia (New York: Basic Books, 1974). 3. Ronald Green, "Health Care and Justice in Contract Theory Perspective," in Robert Veatch and Roy Branson, eds., Ethics and Health Policy, (Cambridge, MA: Ballinger Publishing Company, 1976), pp. 111-126. 4. Robert Veatch, The Foundations of Justice: Why the Retarded and the Rest of Us Have Claims to Equality (New York: Oxford University Press, 1986). 5. Norman Daniels, Just Health Care (New York: Oxford University Press, 1985). 6. Rawls, op. cit. I. For a survey and criticism of this search for the best single account of what egalitarian justice consists in, see Madison Powers, "Forget About Equality," Kennedy Institute of Ethics Journal 6:129-144; 1996. 8. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects, Federal Register Document 79-12065, April 18, 1979. 9. Andrew Shorr, "AIDS and the FDA: An Ethical Case for Limiting Patient Access to New Medical Therapies," IRB 14:1-5; 1992; Douglas Richman, "Public Access to Experimental Drug Therapy: AIDS Raises Yet Another Conflict Between Freedom of the Individual and the Welfare of the Individual and Public," The Journal of Infectious Diseases 159:412-415; 1989. 10. Martin Delaney, "Patient Access to Experimental Therapy,"X4MA 261:2444-2447; 1989. I1. Stuart Nightingale, "Challenges in Human Subject Protection," Food and Drug Law Journal 50:493-501; 1995. 12. George Annas, "FDA's Compassion for Desperate Drug Companies," Hastings Center Report 20:35-37; 1990. 13. Karen Rothenberg, "Gender Matters: Implications for Clinical Research and Women's Health Care," Houston Law Review 32; 1996; especially pp. 2118-2129. 14. Anna C. Mastroianni, Ruth Faden, and Daniel Federman, eds., Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Vol. 1, (Washington, DC: National Academy Press, 1994). 15. Eugene Hayunga, Karen Rothenberg, and Vivian Pinn, "Women of Childbearing Potential in Clinical Research: Perspectives on NIH Policy and Liability Issues," Food, Drug, Cosmetic andMedical Device Law Digest 13:711; 1996. 16. Ly-Le Tran, Ethical and Legal Issues in Bio-Medical Research and Investigational Treatments," Medical Trial Technology Quarterly 42:113-140; 1995; Vanessa Merton, "Review Essay: Women and Health Research," Journal of Law, Medicine and Ethics 22:272-279; 1994; and Nancy Kass, Holly Taylor, and Patricia King, "Harms of Excluding Pregnant Women from Research: The Case of HIV-Infected Pregnant Women," Journal of Law, Medicine and Ethics 24:36-46; 1996.

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17. Vanessa Merton, "The Exclusion of Pregnant, Pregnable, and Once-Pregnable People (a.k.a. Women) from Biomedical Research," American Journal of Law and Medicine 19:369-451; 1993. 18. Merton, op. cit., 1994, 227. 19. W. Bradford Patterson and Ezekiel Emanuel, The Eligibility of Women for Clinical Research Trials," Journal of Clinical Oncology 13:298; 1995. 20. Kass et al., op. cit., 40. 21. Carole Pateman, "Equality, Difference, Subordination: The Politics of Motherhood and Women's Citizenship," in Beyond Equality and Difference, Ed. Gisela Bock and Susan James, (New York: Routledge, 1992), pp. 17-31. 22. Evelyne Shuster, "For Her Own Good: Protecting (And Neglecting) Women in Research," Cambridge Quarterly of Healthcare Ethics 5:346-361; 1996. 23. Debra DeBruin, "Justice and the Inclusion of Women in Clinical Studies: An Argument for Further Reform," Kennedy Institute of Ethics Journal 4:135-139; 1994. 24. Ibid., pp. 136-141. 25. There are many discussions of this debate, but one of the best is Dennis McKerlie, "Equality Between Age Groups," Philosophy and Public Affairs 21:275-295; 1992. 26. My thanks to Annette Almazan for research assistance and to Ruth Faden for extensive comments. Many of the arguments in this chapter are based on ideas developed in a book manuscript coauthored with Ruth Faden. Funding for this research was provided by the Robert Wood Johnson Health Policy Research Investigator Awards Program, Grant # 26418, and by the National Library of Medicine, Publication Grant # LM05700-02.

10 IMPLEMENTING JUSTICE IN A CHANGING RESEARCH ENVIRONMENT Jeffrey P. Kahn Anna C. Mastroianni Jeremy Sugarman

When considered in aggregate, the cases and issues examined in this volume suggest that what justice requires varies among contexts. This is, in part, because the scope of concerns regarding justice is enlarging as the effects of medical research on the welfare of large numbers of people are increasing in significance. Moreover, the potential benefits of medical research make claims of competing interests for a fair share of these benefits quite relevant. As described in Chapter 9, the requirements of justice are increasingly the subject of public debate and scholarly controversy. Given the importance of these significant concerns about justice, in this final chapter, we (1) summarize the need to consider a variety of facets of justice, rather than consider it solely as a matter related to the selection of subjects; (2) delineate points in the research process at which considerations about justice go beyond consent; and (3) make some practical suggestions about how it might be possible to seek justice in research.

THE MANY FACETS OF JUSTICE

The chapters in this volume examine how the concept of justice has been and should be applied to particular research settings and groups of research subjects. All of the authors agree that justice is critical to research with human subjects. Yet the 166

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different situations and manners in which considerations of justice are applied indicate that justice is a concept with many facets; these facets may cause justice to look different depending on the perspective from which it is viewed. Regardless of the vantage point, however, justice in general is understood to be crucial in the consideration of the ethics of research with human subjects. We have seen throughout this volume that there are many facets of justice in research, not simply the traditional explicit concerns about justice, such as considering the selection of subjects by investigators and IRBs.1 While these and other considerations of distributive justice are critical, such a narrow application of justice is incomplete. For example, as suggested in Chapter 9, even the most dominant procedures associated with research ethics—informed consent and the prior review of research through IRBs—are based, in part, on a liberal view of justice. That is, our current system of protection of research subjects embodies a liberal conception of justice and is predicated on protecting individual liberty rights (to exercise autonomous decision making) and the welfare of subjects (to be free from imposition of unwarranted risk without offsetting personal benefit). Furthermore, while many of the issues of justice most widely recognized in the past were largely those that IRBs had the task of addressing, many of the newly recognized issues arise in a multitude of arenas involving a variety of decision makers at differing points in the process of research. Thus, the locus of decisions affecting justice is no longer solely that of IRBs. Concerns about justice are, in fact, applicable throughout the research process—from decisions about areas deserving research funding and what constitutes a relevant and important research question, to the recruitment and retention of subjects, to the interpretation and application of the results of research. Yet attention to considerations of justice in these diverse contexts has been largely implicit, perhaps to the detriment of individuals, populations, and the research enterprise in general. This detriment is illustrated by the examinations of different populations and cases in this book. A comprehensive understanding of justice in research therefore involves an understanding of how justice affects and is impacted at each decision point in the research process.

MOVING BEYOND CONSENT

Whether and which issues of justice are relevant in particular cases is sometimes influenced by who the decision makers are at various points in the research process. Moreover, many of the decisions and the issues about justice that go hand in hand with them are influenced by concerns outside the typical considerations of scientific design. Historical and dominant social forces, for example, may influence the selection of particular subject populations and the development of specific priorities in research. Further, decisions that have implications for justice take

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place at all levels of the research enterprise constantly, consciously or not. To address concerns about justice in research more effectively, it is essential to recognize the decision points and decision makers in the research process and the influences on them. This makes possible explicit recognition, examination, and consideration of relevant factors that affect justice. Each functional step in the development and conduct of research defines a decision point. These functional points include: the origination of a research idea, funding for research, study design, prior review, conduct of research, recruitment and retention of research subjects, analyses of data, interpretation of findings, and dissemination of results. These functions are performed and influenced by various individuals and groups that include: legislative bodies, governmental and organizational scientific advisory councils, research foundations, advocacy groups, federal and state agency administrators, pharmaceutical and biotechnology companies, research funding review committees, educational and noneducational institutions in which research is performed, IRBs, investigators, research subjects, journal editors, journal peer reviewers, international bodies, and professional organizations. By following the roughly chronological process of research, it is possible to examine the types of situations in which concerns about justice become relevant. Take for example a novel research idea, such as a particular mechanism in the development of heart disease, that may be discussed among members of the faculty of a medical school or the staff of a pharmaceutical or biotechnology company. By focusing on this question, another potentially important research focus may be forgone, raising questions about justice. Research ideas may be the product of scientific curiosity, but are also as likely to be prompted by funding announcements about research on a particular disease, institutional encouragement, or lobbying from advocacy groups. Regardless, the decision by an individual investigator—whether a university faculty member or staff scientist—to pursue a research idea has implications for the population(s) that will be the subjects of the research and that may potentially benefit from its results. Funding, however, is obviously necessary before even very promising research ideas can be pursued. More research funding means the possibility for research with more and different populations and the opportunity for the inclusion of additional members of particular populations in research. Yet funding determinations reflect a range of previous decisions in the public (e.g., NIH, WHO) and private (e.g. pharmaceutical and biotechnology companies, and private foundations) sectors. We obviously live in a time of increasing awareness the limits of our collective resources. This extends to the portion of overall resources devoted to funding of biomedical research compared to other societal goods, such as defense, education, and transportation. Nevertheless, when the U.S. Congress makes a decision to spend an additional $100 million on medical research or to cut research expenditures, there are serious implications for the quantity of research that can be performed, as well as the range of research ideas that can be examined.

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Within the private sector, research and development costs must be balanced against other corporate costs including personnel and marketing. Decisions about overall funding can also be influenced by advocacy efforts on the part of those receiving research support, such as research institutions, and on the part of those who stand to realize the potential benefit of the results of research, such as patientadvocacy groups. Thus, a cascade occurs through the system that raises questions about distributive justice, since the amount of funding available is limited and research can only be practicably carried out in small groups of subjects. Not only does this potentially burden particular populations, or conversely give them direct immediate benefits from participation in research, it also affects the appropriateness of using the results of research in a meaningful way within a population in which an intervention was not evaluated. Whatever the level of the research funding, whether it be in the public or private sector, decisions about research priorities raise obvious concerns about justice. For instance, Congress may assert its spending authority by earmarking resources for research on AIDS or breast cancer. Pharmaceutical and biotechnology companies make decisions about research and development with a potential market in mind, so may concentrate on diseases with high or increasing prevalence, and in the process may exclude those with less prevalent conditions. That is, eventual success in the marketplace is essential. A safeguard against this tendency are orphan drug policies that encourage the examination of low prevalence diseases that have small markets for drugs. These policies serve to encourage justice in drug development by subsidizing the cost of research and development, and providing some financial incentive to drug companies by guaranteeing a 7-year limited licensure for new drags that are developed through this mechanism.2 In addition, foundations generally make decisions consistent with their stated missions, whether they be disease-specific (e.g., the American Cancer Society, the American Heart Association) or issue-specific (e.g., the Robert Wood Johnson Foundation's focus on end-of-life issues, pain control, or managed care; the Ford Foundation's interest in specific international settings). Decisions by review groups of various types, whether peer review groups in the traditional NIH-style "study sections" or by those within private entities, can have implications for justice. For instance, a proposed research project in pediatrics may compete against projects addressing the health concerns of Native Americans or urban residents. Similar to considerations regarding broad funding decisions, in an environment where only a small proportion of proposed research is funded in a given year, decisions about which projects go forward and which do not have significant impact. While some explicit consideration is now given to "gender and minority representation" in government-sponsored research, the extent to which such considerations are effective, and the degree to which they are incorporated in other settings, is unclear.

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Once funded, individual research projects typically undergo prospective review at an institutional level. At this point, justice plays a role in determining how subjects should be selected, and the treatment subjects should receive once selected. The practical aspects of carrying out research, from recruitment and retention of subjects to the conditions under which participation ensues, also have implications for justice. For example, the process employed in choosing individual subjects must be fair. Access to participation in research is affected not only by the criteria by which eligibility is determined, but also by the mechanisms used to recruit subjects. For example, there is a site on the world wide web that acts as a clearinghouse for research participation; prospective subjects with access to the internet can "shop" for research trials. This service is advertised to researchers as an effective way to recruit subjects, which may well be true.3 However, its use skews access towards a particular population—those with computer access and acumen—and therefore introduces concerns about justice. Even recruitment through more traditional means, such as television commercials, classified ads, radio announcements, and flyers, introduces concerns about justice. That is, particular modes of recruitment may be more or less accessible to particular segments of the potential subject population. For example, an advertisement run on public radio may reach different potential subjects than would a flyer posted at a soup kitchen than would a classified ad in a foreign language newspaper. Finally, once research has been carried out, the reporting, analysis, and dissemination of results are critical steps between research and its applications. Decisions about how widely research results are reported typically lie in the hands of investigators and often the sponsors of research. Peer reviewers and journal editors then make decisions about which research is worthy of publication. In the most prestigious journals, editors may also wield considerable power in editorials about research findings or conduct.4 Subsequently, professional opinion may be shaped and popular media may disseminate this information to the public and to policy makers. In turn, this may have significant influence on establishing future research priorities, including the development of future research questions and the populations in which they will be explored. Thus, there exists a web of decisions and decision makers spanning the process of research. Awareness of this complex web is crucial for understanding the far reaching scope of justice in research that goes far beyond consent.

SEEKING JUSTICE IN RESEARCH

Given the complex web outlined above, we propose the following suggestions that ought to be considered in order to implement justice throughout the research

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enterprise. These suggestions emanate from considering in aggregate the analyses of cases and experience offered earlier in this volume. First, comprehensive attention to justice is of fundamental importance to building and maintaining trust in the research enterprise. Without trust, research with human subjects would be much more difficult since the large reservoir of trust on the part of subjects undoubtedly plays an important role in their willingness to participate.5 Without attention to justice it is conceivable that there will be further erosion of this trust. Second, justice in research requires recognition and attention at every level of the decision making process. Considerations of justice at each decision point must be conscious and explicit, or there is the risk that justice may be overlooked, as the contributors to this volume make quite clear. Third, decisions are made throughout the research process by a wide variety of actors, and these decisions are made largely without coordination with others who are involved in different aspects of the research enterprise. The research enterprise has no mechanism by which to coordinate this decision making. This lack of coordination undermines accountability for the effects of decisions. Whatever coordination exists is also influenced by individuals and groups outside those directly involved in the research, such as advocates. This is not to say that each decision point related to justice is totally isolated from every other. The structure of the research process is such that decisions affecting justice that are overlooked or misguided at one point in the process might be recognized at other points. The problem is that there is no mechanism for ensuring that such perceived missteps will be caught and addressed. It is therefore incumbent upon each actor in the research process to recognize and attend to justice. Fourth, biases and incentives influencing perceptions of justice in research need to be explicitly acknowledged and disclosed. Decision makers act in light of influences, incentives, and biases particular to their situations; decisions are not made in a vacuum. The incentives and perspectives these decision makers bring to the process, including conflicts of interest and individual agendas, have a clear impact on whether justice in research is served. If decision makers make such conflicts and biases explicit, it is more likely that the implications of their actions will be considered. Fifth, it is essential to incorporate a diversity of views and participation (e.g., gender, people of color, advocates) at each decision making point in the research process. The participation of subjects—the historically excluded "other" half of the research enterprise—in the decision making process, might make it more likely to meet the demands of justice, avoiding exploitation of some populations as well as the neglect of others. This could include representation and participation in existing advisory and oversight bodies in the research process (study sections, IRBs), as well as other groups that formulate and direct research agendas.

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Sixth, while pursuit of science should be the basis for doing research, it must be recognized that there are many influences on the determination of what constitutes a relevant scientific question. Values are implicit and inherent at every level of the decision making process, so it is unrealistic and descriptively false to claim that research is value free. Take for example the decision to carry out the Multiple Risk Factor Intervention Trial (MRFIT) of cardiovascular disease epidemiology on only men. Cardiovascular disease was a clearly recognized health problem in middle aged men, considered a near epidemic, and its importance and prevalence justified research into its epidemiology and the refocusing of research priorities the scale of the MRFIT study required. But, as a result there may not be sufficient recognition of the different yet very serious manifestations of cardiovascular disease in women. What we must realize is that research involves much more than what occurs with regard to the investigator and his or her decision on what questions carry sufficient scientific merit. Consequently, claims about science and scientific merit may implicate justice.

CONCLUSIONS

This chapter has attempted to describe the many ways and places in the research enterprise that justice needs to be considered. Concerns about justice arise at virtually every step along the process. While chronologically somewhat clear, the parts of the research process lack a sense of integration with each other. For instance, the connection between recruitment and retention issues in a single clinical trial, and funding and allocation decisions being wrestled over in Washington, seem quite disjointed. Paying attention to justice at each step, however, forces a relevant connection. The evolution of the regulations for the protection of research subjects and their local application has placed the focus of efforts to serve the rights and interests of research subjects on informed consent and determining acceptable levels of risk in research. While critically important, these issues have come to be the beginning and end of practical research ethics. However, this myopic view of how to achieve ethically appropriate research cannot accomplish its goal. As we have tried to show, justice is not a simple concept. The multiple conceptions of justice pose a challenge to us in finding ways to apply justice throughout the research process. This challenge must be taken up by all involved in research. We must first acknowledge the challenge, and second, rise to meet it. If we don't, we betray the trust that subjects place in the people, institutions, and processes that make up the research enterprise. It is only by looking beyond consent that the full range of ethical issues in research can be understood, and it is only in acting beyond consent that we can truly seek justice in research.

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NOTES 1. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects, Federal Register Document 79-12065, April 18, 1979. 2. Orphan Drug Act, P.L. 97-414, January 4, 1983. 3. Center Watch—Clinical Trial Trends Listing Service, http://www.centerwatch.com. 4. For example, an editorial discussion of the ethics of AZT trials for vertical transmission of HIV in Africa. Marcia Angell, "The Ethics of Clinical Research in the Third World," NEJM 337(12):847-849; September 18, 1997. 5. Nancy Kass, Jeremy Sugarman, Ruth Faden, and Monica Schoch-Spana, "Trust: The Fragile Foundation of Contemporary Biomedical Research," Hastings Center Report 26(5):25-29; September-October 1996.

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APPENDIX

Guide to Locating Policies

Locating information for the policies relevant to the issues discussed in this volume is provided below by chapter. The Federal Register (Fed. Reg.), Code of Federal Regulations (CFR), and Public Laws are available in the government documents section of libraries or via online information services such as Lexis-Nexis or Westlaw. Internet addresses are provided, where known. Many federal policies are accessible via the GPO Access website, at http://www.access.gpo.gov. All the internet-accessible policies listed here are also linked to a webpage of the University of Minnesota's Center for Bioethics website, at http://www. med.umn.edu/bioethics/.

Chapters 1-10 Model Federal Policy for the Protection of Human Subjects ("Common Rule") Citation Locator: 56 Fed. Reg. 28002 (1991). Government Contact: Office of Protection from Research Risks, National Institutes of Health, suite 3B01, 6100 Executive Blvd., Rockville, MD, 208927507, 301-496-7005.

Chapter 3: Research on the Vulnerable Sick A. FDA Waiver of Informed Consent Requirement in Certain Emergency Research Citation Locator: 61 Fed. Reg. 51498 (Oct. 2, 1996), amending 21 CFR 50, 56, 312, 314, 601,812, and 814. Internet: http://www.access.gpo.gov/nara/cfr/index.html Government Contact: Office of Health Affairs (HFY-20), Food and Drug Administration, Rockville, MD 20852, 301-443-1382. 175

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B. DHHS Waiver of Informed Consent Requirements in Certain Emergency Research Citation Locator: 61 Fed. Reg. 51531 (Oct. 2, 1996). Internet: http://www.access.gpo.gov/nara/cfr/index.html Government Contact: Office of Protection from Research Risks, National Institutes of Health, Suite 3B01, 6100 Executive Blvd., Rockville, MD 208927507, 301-496-7005.

Chapter 4: Children as Research Subjects A. Additional DHHS Protections for Children Involved as Subjects in Research Citation Locator: 45 CFR 46, subpart D. Internet: http://www.access.gpo.gov/nara/cfr/cfr-retrieve.htmlftpagel, by entering 45 CFR 46.401-409 Government Contact: Office of Protection from Research Risks, National Institutes of Health, Suite 3B01, 6100 Executive Blvd., Rockville, MD 208927507, 301-496-7005. B.

Policy on the Inclusion of Children as Subjects in Clinical Research Citation Locator: NIH Guide 27 March 6, 1998. Internet: http://www.nih.gov/grants/guide/notice-files/not 78-024.html Government Contact: Office of Protection from Research Risks, National Institutes of Health, Suite 3B01, 6100 Executive Blvd., Rockville, MD, 208927507, 301-496-7005.

Chapter 5: Gender and Research A. Additional Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization Citation locator: 45 CFR 46, subpart B. Internet: http://www.access.gpo.gov/nara/cfr/cfr-retrieve.htmlftpagel, by entering 45 CFR 46.201-211 Government Contact: Office of Protection from Research Risks, National Institutes of Health, Suite 3B01, 6100 Executive Blvd., Rockville, MD 208927507, 301-496-7005.

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B. NIH Revitalization Act of 1993 (Clinical Research Equity Regarding Women and Minorities). Citation Locater: Public Law 103-43, subtitle B Government Contact: Office of Research on Women's Health, National Institutes of Health, Building 1, room 203, 6100 Executive Blvd., Rockville, MD 20892, 301-402-1770. C. NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research Citation Locator: 59 Fed. Reg. 14508 (Mar. 28, 1994). Government Contact: Office of Research on Women's Health, National Institutes of Health, Building 1, room 203, 6100 Executive Blvd., Rockville, MD 20892, 301-402-1770. D. FDA Guidelines for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs Citation Locator: 58 Fed. Reg. 39406 (July 22, 1993). Government Contact: CDER Executive Secretariat Staff (HFD-8), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,301-295-8012. E. CDC/ATSDR Policy on the Inclusion of Women and Racial and Ethnic Minorities in Externally Awarded Research Citation Locator: 60 Fed. Reg. 47947 (Sept. 15, 1995). Internet: http://www.access.gpo.gov/nara/cfr/index.html Government Contact: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, 404-639-3311. Chapter 6: Race, Justice, and Research A. NIH Revitalization Act of 1993 (Clinical Research Equity Regarding Women and Minorities). Citation Locator: Public Law 103-43, subtitle B. Government Contact: Office of Research on Women's Health, National Institutes of Health, Building 1, room 203, 6100 Executive Blvd., Rockville, MD 20892, 301-402-1770. B. NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research Citation Locator: 59 Fed. Reg. 14508 (Mar. 28, 1994).

178

BEYOND CONSENT

Government Contact: Office of Research on Women's Health, National Institutes of Health, Building 1, room 203, 6100 Executive Blvd., Rockville, MD 20892, 301-402-1770. C. CDC/ATSDR Policy on the Inclusion of Women and Racial and Ethnic Minorities in Externally Awarded Research Citation Locator: 60 Fed. Reg. 47947 (Sept. 15, 1995). Internet: http://www.access.gpo.gov/nara/cfr/index.html Government Contact: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, 404-639-3311.

Chapter 7: Convenient and Captive Populations A. Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Citation Locator: 45 CFR 46, subpart C. Internet: http://www.access.gpo.gov/nara/cfr/cfr-retrieve.htmWpagel, by entering 45 CFR 46.301-306 Government Contact: Office of Protection from Research Risks, National Institutes of Health, Suite 3B01, 6100 Executive Blvd., Rockville, MD 208927507, 301-496-7005. B. Additional DHHS Protections for Children Involved as Subjects in Research Citation Locator: 45 CFR 46, subpart D. Internet: http://www.access.gpo.gov/nara/cfr/cfr-retrieve.htmlttpagel, by entering 45 CFR 46.401-409 Government Contact: Office of Protection from Research Risks, National Institutes of Health, Suite 3B01, 6100 Executive Blvd., Rockville, MD 208927507, 301-496-7005.

Chapter 8: Justice in International Research A. US AID Policy on Procedures for the Protection of Human Subjects in Research Supported by USA1D, April 19, 1995. Government Contact: U.S. Agency for International Development, Public Inquiries, 320 21st Street, NW, Washington, DC 20523-0016, 202-647-1850, FAX: 202-647-8321.

Appendix

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B. International Ethical Guidelines for Biomedical Research Involving Human Subjects, Council for International Organizations of Medical Sciences (CIOMS), 1993. Available in libraries, under the Library of Congress call number P853.H8168x 1993, or directly from CIOMS, at: c/o World Health Organization CH-1211 Geneva 27, Switzerland, Tel: + 41 22 791 34 06/67/13, Fax: + 41 22 791 07 46, Telex: 415 416.

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INDEX

Abortion, 78, 139, 143 Abramson, N. S., 45 Accelerated drug approval, 154 subpartH, 38, 39, 41,45 Acceptable risk, 5, 42, 44, 48, 49, 56, 59, 61, 62, 63, 132, 151, 154, 155, 162 Access to clinical trials, 1, 154. See also clinical trials Acquired immune deficiency syndrome. See AIDS/HIV AIDS/HIV, 1, 3, 4, 9, 12, 26, 27, 31, 38, 39, 40, 69, 72, 79, 80, 85, 107, 108, 109, 110, 131, 132, 140, 143, 144, 145, 154, 155, 164, 169 AIDS Coalition to Unleash Power (ACT-UP), 155 research, 27, 110, 131, 143 vaccines, 132, 133, 144n Ad Hoc Advisory Panel Report, 97, 98 Adolescents, 118, 142 Advertisements, 123 Advisory Committee on Human Radiation Experiments (ACHRE), 27,30,31,42,46,51,64, 114, 119, 121, 127, 128, 129 AEC, 114 African-Americans, 88, 89, 90, 91, 92, 96, 97, 98, 99, 100, 101, 102, 103, 104, 107, 110 Alzheimer's disease, 7, 117, 125, 128n American Academy of Pediatrics (AAP), 60, 62, 63, 66 American Medical Association (AMA), 13,45,69,83,95, 113

American Psychological Association, 124, 130 Code of Ethics, 124 Anderson, Jean, 85n, 87n Anderson, William, 85n Angell, Marcia, 173 Annas, George, 164 Antonson, Dean, 65n Aristotle, 4, 10 Army Inspector General, 121 Assent. See Children, assent Asylum patients in Mississippi, 116. See also institutionalized subjects Atomic Energy Commission (AEC), 114, 119 Attica State Penitentiary, 114 Autonomy, 12, 14, 17, 40, 56, 67, 153 Axelsen, Diane, 95, 107n Azidothymidine (AZT), 140, 173 Bad Blood: The Tuskegee Syphilis Experiment, 106n-9n Balasubrahmanyan, Vimal, 144n Barber, Bernard, 21, 30n Barnard, Christian, 20 Barry, Michele, 144n, 145n Bartholome, William, 55, 58, 60, 64n, 65n, 66n Brody, Baruch, 4, 32, 45n, 154 Beecher, Henry, 20, 30n, 116 Belmont Report, 2, 9n, lOn, 11, 28n, 31n, 48, 52, 64n, 89, 96, 101, 106n, 128n, 132, 144n, 152, 161, 164n, 173n Benagiano, Giuseppe, 145n

181

182

Index

Beneficence, 2, 12, 14, 48, 52, 116. See also principles Berer, Marge, 145n Berg, Leonard, 128n Bergman, A., 85n Bernstein, A., 84n Bird, Chloe, 83n Biros, M., 45n Blank, Robert, 31n Bloodwill, R. N., 29n Blumenthal, Susan, 84n Blustein, Bonnie, 88, 93, 107n, 109n Bock, Gisela, 165n Bonnicksen, Andrea, 31n Botulinum toxoid, (BT), 122 Bowman, Phillip, 102, 109n Brandt, Allan, 97, 108n Branson, Roy, 164n Breeden, James, 106n Brody, Baruch, 4, 45n, 154 Brown, David, 145n Burt, Robert, 98, 108n Bynum, William, 107n Byrne, M. A., 85n Cafferata, G. L, 84n Camp, Donald, 66n Camp Desert Rock, 121 Cancer, 1, 3, 17, 39, 41, 72, 114, 135, 154, 169 Caplan, Arthur, 108n Capron, Alexander, 31n, 110n Captive population, 50, 111, 112, 127n, 178 Cardiovascular disease, 6, 70, 71, 72, 172 Carrol, John, 16 Caschetta, M. B. 87n Cassedy, J. H., 128n Castelo, Aduato, 145n Centers for Disease Control (CDC), 31n, 72, 85n, 108n, 140, 177, 178 Chalkley, Donald, 21 Charles, David, 87n Charo, R. Alta, 83n, 86n Chavkin, Wendy, 87n Children, 3-6, 22, 24, 47-59, 61-67, 82, 112, 117-119, 129, 151 assent, 49, 51, 53, 56, 57, 59, 60, 61, 62, 63, 65 dissent, 56, 60, 62

minimal risk research, 57, 61 parental permission, 48, 49, 51, 56, 58, 59, 60, 62, 63 research on healthy children, 49, 53, 54, 57, 61-63, 66n Childress, James, 29n China, 136, 139 Christakis, Nicholas, 130n, 140,144n, 145n Civil rights movement, 99, 116 Clinical equipoise, 53, 57 Clinical trials, 8, 27, 31, 39, 40, 68, 70, 74, 137, 138, 139, 148, 154, 155, 156, 157, 159, 160 access to, 1, 154 as health care, 152, 155 exclusion from. See Exclusion of human growth hormone (hGH), 5, 49, 56, 61 inclusion in. See Inclusion in the developing world, 8, 134ff in the emergency setting, 5, 34, 35, 37, 38, 40, 45, 91 phase I, 4, 33, 41-45, 46n, 74, 86n, 114, 137, 154 phase II, 41, 44, 74, 86n, 137 phase III, 44, 74, 75, 86n, 137 recruitment of subjects, 153, 163. See also Drug trials Clinton, Bill, 22, 27, 101, 121 Closed head injury, 36 Code of ethics American Psychological Association (APA), 124 Coercion, 7, 50, 61, 114, 116, 142, 151, 153 Cohn, Victor, 128n Cole, Jonathan, 84n Committee on Medical Research (CMR), 16, 116, 118, 120 Common Rule, 26, 27, 85n, 175 Community, 6, 14, 19, 20, 23, 27, 36, 91,94,97, 100, 102, 109, 115, 135, 137, 143, 151, 153, 158 community consent, 153 community consultation, 36, 91, 143 community involvement, 102 Compensation, 7, 11, 22, 25, 27, 30, 101, 119, 124, 132, 133 for research injury, 11, 22, 25, 27, 28n, 30n, 101, 133

Index for research participation, 7, 25, 119, 124, 132 Compensatory justice, 3, 69, 159 Confidentiality, 27, 58, 142 Consent, 2, 3, 4, 9, 13, 24, 28, 32-37, 42, 43, 48, 51, 52, 55, 56, 60, 61, 64n, 97, 98, 114, 117-119, 122, 124, 125, 141, 148, 151, 153, 154, 159, 161, 163, 166, 167, 170, 172 deferred consent, 3, 37 waiver of consent, 35, 37, 91, 122, 125, 175, 176. See also emergency research, and clinical trials in the emergency setting Contraceptive research, 7, 74, 134-136, 138, 143, 145n Cooley, Denton, 17, 21, 29n Corea, Gena, 85n Cost-benefit analysis, 8, 152 Cottingham, Jane, 145n Cotton, Paul, 11On Council for International Organizations of Medical Sciences (CIOMS), 134, 141, 144n, 146n, 179 International Ethical Guidelines for Biomedical Research Involving Human Subjects, 134, 141, 144n, 146n, 179 Guideline 8, 134 Guideline 15, 141 Council of Europe, 34 Culliton, Barbara, 109n Culture, 90, 96, 97, 101, 105, 147150 cultural imperialism, 90 culturally appropriate, 153 Daniels, Norman, 164n Daugherty, Christopher, 46n ddC (See dideoexycytidine) DeBruin, Debra, 77, 87n, 101, 109n, 165n Deception, 123, 124, 151 Declaration of Helsinki, 18, 29n, 113, 155 Deferred consent, 34, 37. See also emergency research Delaney, Martin, 154, 164n Dementia, 117, 128n

183

Department of Defense (DoD), 120-122 Department of Health and Human Services (DHHS), 26, 73-75, 80, 86n, 87n, 99, 108n, 115, 128n, 176, 178 Department of Health, Education and Welfare (DHEW), 21, 24, 25, 28n, 30n, 64n, 65n, 115, 128n Depo-provera (DMPA), 7, 135 DES. See Diethylstilbestrol Detre, K., 84n Dideoexycytidine (ddC), 140 Diethylstilbestrol (DES), 76, 79 Difference Principle, 150 Discrimination, 26, 27, 90, 102, 109n, 125, 160 Dissent See Children, dissent Distribution of health burdens and risks, 148 DMPA. See Depo-provera Downey, Thomas, 129n Dresser, Rebecca, 81, 83n, 84n, 87n Drug holidays, 117 Drug trials, 3, 62, 74, 75, 155. See also clinical trials Dubois, William, 107n Duke, Lynne, 109n Dula, Annette, 91, 106n Eagan, Andrea, 87n Eaglstein, M., 46n Economically necessitous, 151 Egalitarian, 8, 148-150, 152, 155-159, 164n Emanuel, Ezekiel, 46n, 165n Emergency research, 5, 34, 35, 37, 38, 40, 45n, 91. See also clinical trials Employees, 7, 100, 123, 126 Employers, 123 Engelhardt, H. Tristram, 108n Equality, 99, 150, 156-159 in access to resources which meet basic human needs, 150 of outcome, 150 of opportunity, 150, 158 Etheridge, Elizabeth, 127n Exclusion, 5, 6, 27, 68, 71, 74, 75, 76, 77, 79, 82, 104, 127, 148, 157, 158, 160 Experiments of opportunity, 127n

184

Index

Exploitation, 3, 4, 8, 24, 32, 34, 40, 42, 50,52,90,91, 101, 115, 134, 151, 154, 157, 161, 171 of vulnerable populations, 34, 134 Faden, Ruth, 9n, 28n, 83n, 85n, 144n, 164n, 165n, 173n Fair distribution, 6, 49, 63n, 69, 132, 153, 163 Family Health International (FHI), 137

Federalist Papers, The, 148 Federman, Daniel, 9n, 28n, 83n, 144n, 164n Fee, Elizabeth, 76, 86n Feit, Marvin, 104, 11On Feminist movement, 26, 77 Fernald School, 5, 48, 49, 51, 119. See also institutionalized subjects Fetal research, 23, 3In Fetuses, 5, 22, 23, 151 Financial compensation, 124. See also recruitment Flanagan, Mary Helen, 66n Flannery, Ellen, 86n Flashblindness research, 120 Fletcher, Michael, 109n Flood, Daniel, 18 Food and Drug Administration (FDA), 16, 17, 24, 26, 35-40, 63, 66, 70, 73-75, 86, 87, 91, 122, 123, 135, 137, 164, 175, 177 policy regarding children in research, 63 policy regarding pregnant women in research, 70, 73-75, 86n, 87n Food, Drug, and Cosmetic Act, 16 Formal principle of justice, 52, 133, 136, 141 Foundation for Economic Trends, 65 Fox, Renee, 128n Frankel, Mark, 28n, 29n, 30n Freedman, Benjamin, 46n, 49, 59, 64n, 66n Fuks, Abraham, 64n Fullilove, Mindy, 103, 109n Gaines, Atwood, 106n, 109n Gamble, Vanessa, 105n, 107n, 109n

Gender, 62, 67-74, 76-78, 81, 82, 95, 103, 143, 163, 171 gender differences, 70, 71, 82 gender inclusion, 6, 9n, 73-76, 84n, 86n, 87n, 108n, 109n, 156, 163, 165n, 177, 178 General Accounting Office (GAO), 69, 73, 85n Genetics, 25, 27, 88, 100, 103, 163 Germain, Adrienne, 145n Giddings, Samuel, 66n Glantz, Leonard, 66n, 129n Glass, Kathleen, 128n Goff, David, 85n Grabowski, H., 46n Greater than minimal risk research, 55, 57, 61-63 Green, D., 46n Green, Ronald, 164n Greenberg, Sanford, 86n Grisso, Jeane Ann, 87n Grobbee, D., 84n Grodin, Michael, 66n, 129n Gulf War Syndrome, 122 Gauthier, Serge, 128n Haller, lohn, 93, 106n, 107n Hallman, G., 29n Hamilton, Jean, 84n Hamilton, Thomas, 95 Harkness, Jon, 115, 128n Harris, John, 25, 109n Hartsock, Nancy, 77, 87n Hayunga, Eugene, 164n Healy, Bernadine, 26, 85n Henke, Laura, 66n Herholz, Harald, 85n hGH. See Human growth hormone Higginbotham, Evelyn, 96, 108n High, Dallas, 128n Hill, Thomas, 109n HIV/AIDS, 4, 6, 7, 9, 26, 27, 33, 38, 70, 72, 79, 85n, 108n, 109n, HOn, 115, 128n, 139, 140, 154, 173n Hogan, Carlton, 9n Home, Francis, 117 Hormones, 71, 76 Horn, Janet, 85n Hospitalized patients, 111, 112, 116

Index HRP. See Special Programme of Research, Development and Research Training in Human Reproduction Hultgren, H., 84n Human growth hormone (hGH), 5, 49, 56, 61, 65n Human Subjects Research Review Board (of the Office of the U.S. Army Surgeon General), 121 Humphrey, David, 107n Humphreys, Laud, 124, 130n Inclusion, 4-6, 62, 63, 65, 67-69, 7376,78,79,81,82,99, 116, 148, 156, 160, 163, 168 Incremental risk, 34 IND program. See Investigational New Drag (IND) program Indexing of risks, 54, 58 Influenza, 116 Informed consent, 1, 2, 4, 8, 12, 13, 1618,20,21,32,33-37,42,43,44, 48, 52, 56, 60, 61, 63, 75, 76, 98, 102, 104, 105, 114, 122, 124, 125, 134, 148, 151, 153, 161, 172 Institute of Medicine (IOM), 69, 72, 75, 84n, 156, 157 Institutional review boards (IRBs), 9, 36, 46n, 53, 54, 57-59, 62, 65n, 75, 121, 126, 128n, 130n, 141, 142, 145n, 163, 164n, 167 Institutionalized persons, 6, 7, 111, 116, 126, 127 Institutionalized subjects asylum patients in Mississippi, 116 Fernald State School, 5, 48, 49, 51, 119 mentally infirm, 22, 24, 52, 117, 125 Willowbrook State School, 3, 49, 118 International Medical Advisory Panel, 137 Investigational New Drug (IND) program, 38-40, 45n, 46n IOM. See Institute of Medicine Ivy, Andrew, 113 Jackson, Raymond, 85n James, Susan, 165n James, Thomas, 118

185

Jameton, Andrew, 65n Javits, Jacob, 16 Jenner, Edward, 117 Jewish Chronic Disease Hospital, 3, 17 Joeres, Ruth-Ellen, 108n Johnson, Jean, 9n Johnson, Tracy, 76, 86n Jonas, Hans, 13On Jones, James, 106n-109n Jones, Reginald, 109n Journal editors, 168, 170 Justice, 1-9, 11-15, 17, 19, 20, 22, 24, 25, 27, 28, 31n, 32, 34, 36-38, 40, 41, 43^15, 48, 52, 55, 62, 67-70, 76-78, 80, 82, 89, 90, 96-98, 101, 104, 112, 116, 125-127, 131, 133136, 139, 141, 143, 144, 147-164, 166-172 classical liberal, 8, 147-156, 159, 161, 162 compensatory, 3, 69, 159 distributive, 6, 8, 27, 69, 89, 132-134, 149, 155-157, 160, 162, 167, 169 egalitarian, 8, 148-150, 152, 155159, 164n formal principle, 52, 133, 136, 141 libertarian, 17, 156, 158 procedural, 7, 8 Kabir, Sandra, 145n Kamal, Ghulam, 145n Kando, Judith, 84n Kasper, J., 84n Kass, Nancy, 6, 9n, 67, 83n, 85n-87n, 158, 162, 164n, 165n, 173n Kauffman, Ralph, 63n Keay, Timothy, 128n Kefauver, Eustis, 16, 17 Kefauver-Harris, 16, 17 Kefauver-Harris amendment, 16, 17 Kefauver-Harris bill, 16 Kennedy, Donald, 29n Kennedy, Edward (Ted), 21 Kessel, Elton, 138, 145n Keyserlingk, Edward, 128n King, Patricia, 6, 9n, 83n, 88, 108n, 161, 162, 164n King, R., 85n Kogan, Sandra, 128n

186

Index

Kopelman, Loretta, 58-60, 66n, 130n Koren, Gideon, 66n Krugman, Saul, 49, 59, 64n, 118, 129n Kuller, L., 84n Laboratory workers, 112, 123 Ladimer, Irving, 29n Lally, John, 30n Lamont-Havers, Donald, 22 Lancet, 137, 138 Langer, Elinor, 29n Lasagna, Louis, 114, 128n Lasagna Report, 39 Laslett, Barbara, 108n Lavizzo-Mourey, Risa, 87n Law-Medicine Research Institute (LMRI), 18, 29n Legato, Marianne, 71, 84n Lesbian women, 4, 82 Levine, Carol, 9n, 85n, 130n Levine, Robert, 128n Lewis, David, 66n Liability, legal, 76, 120 Libertarian, 17, 156, 158 Livingston, Robert, 18 Locke, John, 148 Lowe, Charles, 22 LSD experiments, 121 Lundberg, George, 109n Lynn, Lorna, 145n Macklin, Ruth, 7, 131, 145n Maier, J., 85n Makarushka, Juia, 30n Malaria, 93, 100, 113 Manipulation, 151, 153 Manson, J., 84n Marston, Robert, 22, 30n Marwick, Charles, 106n Marx's critique of capitalism, 151 Massachusetts Task Force on Human Subjects Research, 51 Mastroianni, Anna, 9n, 28n, 83n-87n, 105n-107n, 109n, 144n, 164n Matsuda, Mari, 90, 106n Matthews, K., 84n McCarthy, Charles, 3 McCarthy, Michael, 45n McDonnell, Kathleen, 144n

McGovern, T., 87n McGraw, Deven, 85n Measles vaccine study, 91 Medical institutions, 94, 96, 125 Mehta, Suman, 145n Meilahn, E., 84 Memorial Sloan-Kettering Cancer Research Institute, 17 Menstrual regulation, 139 Mentally infirm, 22, 24, 52, 117, 125 Merkatz, Ruth, 87n Merton, Vanessa, 68, 83n, 84n, 157, 164n, 165n Meslin, Eric, 58, 66n Milgram, Stanley, 123, 124, 130n Military personnel, 6, 25, 111, 119, 120, 121, 123, 125, 126, 154 Mill, John Stuart, 149 Minimal risk, 5, 33, 48, 49, 53-63, 75, 115, 125, 129 Minimal risk research, 57, 61, 115. See also Children, minimal risk research Mistrust, 91, 96, 102 Moller Okin, Susan, 77, 87n Mondale, Walter, 20, 30 Monetary inducement, 123 Moskop, John, 66n MRFIT (Multiple Risk Factor Intervention Trial), 71, 84n, 172 Muday, P., 85n Multiple drug-resistance, 115 Multiple Project Assurance (MPA), 74 Murphy, M., 84n Mushroom cloud-penetration experiments, 120 National Advisory Health Council (NAHC), 15 National Bioethics Advisory Commission (NBAC), 27, 31n, HOn, 125 National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission), 2, 3, 9n, lOn, 20, 23-25, 28n, 30n, 49, 52-56, 58, 60, 64, 89, 98, 105n, 108n, 114, 115, 117, 119, 127n, 128n, 132, 144n, 164n, 173n

Index National Committee to Review Current Procedures for Approval of New Drugs for Cancer and AIDS, 39 National Heart, Lung, and Blood Institute, (NHLBI), 71 National Institutes of Health (NIH), 9n, 12, 13, 15-19, 21, 22, 26, 29n, 30n, 33, 56, 57, 61-62, 63n, 65n, 66n, 69, 72, 73, 78, 84n, 100, 108n, 156, 158, 164n, 168, 176, 177 Clinical Center, 12, 13, 28n, 29n Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research, 9n, 108n, 177 Office of Protection from Research Risks (OPRR), 33, 34, 36, 45n, 175, 176, 178 Office of Research on Women's Health (ORWH), 73, 74, 78, 156, 177 Revitalization Act of 1993, 74, 177 Subtitle B, Clinical Research Equity Regarding Women and Minorities, 108n, 177 National Research Act, 30n National Sickle Cell Anemia Control Act, 100 Navajo uranium millers and miners, 127 New England Journal of Medicine, 20 New York Society for the Prevention of Cruelty to Children, 118 New York University, 118 Nichomachean Ethics, 4 Nightingale, Stuart, 164n Nixon, Richard, 100 Non-maleficence, 12, 14. See also Principles Nozick, Robert, 164n Nuremberg Code, 113, 120, 121, 141 Occupational and environmental protection, 8, 147 Office for Protection from Research Risks. See NIH, Office for Protection from Research Risks (OPRR) Office of Research on Women's Health. See NIH, Office of Research on Women's Health (ORWH)

187

Older women, 68, 71, 72, 81, 82 Operation Desert Storm, Operation Desert Shield, 122 Oppression, 77, 90 OPRR. See NIH, Office for Protection from Research Risks (OPRR) O'Quigley, J., 46n ORWH. See NIH, Office of Research on Women's Health (ORWH) Osborne, Newton, 104, HOn Packard, Barbara, 84n Paid volunteers, 126 advertisements, 123, 154, 170 Palmer, Larry, 102, 109n Pappworth, H.M., 116, 128n Parental permission. See Children, parental permission Parker, Hilda, 11 On Parry, Barbara, 84n Pateman, Carole, 165n Patterned conceptions of distribution, 149, 152, 156 Patterson, W. Bradford, 165n PB. See Pyridostigmine bromide Peacock, W. Franklin, 85n Peer reviewers, 168 Pellagra, 113 Pentagon, 120, 122, 125 Philipson, Agneta, 87n PHS. See Public Health Service Pinn, Vivian, 164n Pitkin, Roy, 86n, 87n Placebos, 7, 37, 56, 57, 61, 65n, 71, 140, 141 Planned Parenthood, 137 Policar, Michael, 145n Post, Stephen, 128n Potler, Cathy, 128n Power differentials, 123 Powers, Madison, 8, 164n Preferential treatment, 133, 159 Pregnant women, 5, 22, 24, 27, 73-77, 79, 80, 157, 176 policies regarding research on pregnant women, 22, 75-77, 79, 80, 86n, 176 Prentice, Ernest, 65n

188

Index

Principles, 2, 12, 14, 19, 23, 48, 52, 98, 102, 116, 141, 144n, 156, 161 Prisoners, 6, 7, 22, 24, 48, 52, 67, 98, 111-117, 125,126 Attica State Penitentiary, 114 Procedural justice, 7, 8. See also justice Prospective review, 133, 170. See also IRB Protectionist policies, 3, 74, 79, 115, 126, 127n, 157 Psychiatric hospitals, 125 Psychiatric research, 7, 116, 125 placebo controls, 116 schizophrenia, 116, 117, 125 washout periods, 116 Psychological risk, 56, 123 Psychosurgery, 23 Public health, 14, 97, 105n, 127, 152, 153 Public Health Service (PHS), 13, 16-20, 22, 24, 30n, 3In, 69, 83n, 85n-87n, 96, 97, 109n, 127 Pyridostigmine bromide (PB), 122 Quaker Oats, 119 Quinacrine, 136, 145n Quinn, Sandra, 108n, 109n

Research agenda, 78, 81, 82, 102, 160, 163, 164, 171 Research misconduct, 17 Research priorities, 4, 143, 148, 158, 160, 163, 169, 170, 172 Research Proposal Review Project (of ACHRE), 42 Respect for persons, 2, 48, 56, 98, 116 Retention of subjects, 167, 170 Retrospective consent. See Consent, deferred Richardson, David, 107n Richman, Douglas, 164n Risk, 2, 4, 5, 8, 32, 34, 36, 39, 42, 43, 44, 47-51, 53-59, 61-65, 71, 75, 80,89,98, 103, 119, 121-123, 125, 129n, 135, 138, 141, 151, 154-156, 163, 167, 171, 172 Risk-benefit ratios, 133, 136, 138, 139, 141 Roncallo, Angelo, 22 Ross, M., 85n Rosser, Susan, 145n Rothenberg, Karen, 83n, 86n, 164n Rothman, David, 15, 29n, 51, 64n, 128n RU-486, 7, 138, 139, 145n Ryan, Kenneth, 23

Race, 6, 15, 81, 88, 90, 91, 94-97, 103, 104, 105n, 109n, llOn, 162, 163 Race and ethnicity, 105n Racism, 90, 94, 97, 101, 104, 135 Radbill, S., 129n Ramsey, David, 85n Ramsey, Paul, 49, 50, 55, 64n Rawls, John, 64n, 150, 164n Recruitment, 102, 109n, 111, 121, 123, 126, 153, 163, 167, 168, 170, 172 Redman, Eric, 30n Reed, Walter, 119 Remediation of past injustices, 133 Remnick, Scott, 128n Research deception research, 123, 124, 151 fetal research, 23, 31In greater than minimal risk research, 55, 57, 61-63 life-threatening or serious illness and research participation, 39, 40, 42, 68

Sabath, Lee, 87n Savitt, Todd, 96, 105n-109n Schmucker, Douglas, 70, 83n Schoch-Spana, Monica, 83n, 173n Schuklenk, Udo, 9n Scientific and Ethical Review Group (SREG), WHO, 137 Selvin, P., 109n Senate Joint Resolution 145 (SJ RES 145), 20 Sessa, C., 46n Shamoo, Adil, 128n Shannon, James, 15, 17-19, 22 Sharp, Victoria, 128n Shelton, Trevor, 11On Sherwin, Susan, 134, 144n Shorr, Andrew, 164n Shuster, Evelyne, 29n, 30n, 165n Sick patients (as research subjects), 15, 32,40 Sickle Cell disease, 99, 100, 102, 109n

Index Sims, Marion, 95, 107n Skett, Paul, 70, 84n Smallpox, 117 Smith, T., 46n Socio-economic factors, 93, 102 Southam, Chester, 17 Special Programme of Research, Development and Research Training in Human Reproduction (HRP) of WHO, 137, 143, 145n Speroff, Leon, 84n Sponsors, 24, 75, 132, 170 Stampfer, J., 84n Stein, Gary, 85n Sterilization, 7, 136-138, 143 Stewart, William, 19 Still, G., 128n, 133, 139, 159 Strickland, Stephan, 29n Students, 7, 13, 82, 94, 111, 112, 119, 123, 124, 126 Subject selection, 8, 51, 89, 99, 101, 157, 163 Sugarman, Jeremy, 83n, 173 Sullivan, Daniel, 30n Surgeon General, 15, 19, 121 Swazey, Judith, 30n Takaro, T., 84n Task Force on Black and Minority Health, 99, 108n Task Force on Women's Health Issues, 69, 83n, 87n Tauer, Carol, 61, 65n, 66n Tay-Sachs, 100 Taylor-Robinson, D., 85n Taylor, Holly, 9n, 83n, 87n Testicular irradiation, 114 Thalidomide, 5, 16, 24, 38, 76, 79 Thomas, Stephen, 95, 108n, 109n, 118, 129n Tissue plasminogen activator (TPA), 33 Torchia, Marion, 105n-107n Toulmin, Stephen, 108n Tran, Ly-Le, 164n Treatment Investigational New Drug (IND) program. See Investigational New Drug Trout, Monroe, 128n Trust, 6, 13,42, 171, 172

189

Tuberculosis, 93, 105n, 106n, 115, 118 Turow, Scott, 29n Turtle, Robert, 54 Tuskegee Syphilis Study, 3, 6, 21, 23, 89, 96, 97, 102, 108n, 109n, 127n Ad Hoc Advisory Panel Report, 3, 97, 98, 108n U.S. Army, 119, 129n UCLA. See University of California at Los Angeles UNAIDS, 143 United States Physicians Study (Physician's Health Study), 71, 84n United States v. Karl Brandt et al, 127n United States v. Stanley, 129 University of California at Los Angeles (UCLA), 117 University of Nebraska, 57, 65n University of Rochester, 126 University of Virginia Medical School, 22 Uranium miners and millers, 127n Van Slyke, C., 29n Vanderpool, Harold, 31n, 66n Vaughan, P., 145n Veatch, Robert, 164n Vernon, J., 46n Vesell, Elliott, 83n Vivisectionism, 118 Waiver of informed consent, 35, 37, 91, 122, 125, 175, 176. See also consent Warwick, Donald, 145n Washout studies. See Psychiatric research Weapons (atomic biological and chemical weapons research), 120, 126 Weijer, Charles, 64n Wender, Esther, 66n Wenger, Nanette, 84n White, Gladys, 57 Whitehouse, Peter, 128n Wiener, Charles, 9n

190

Index

Willems, Y., 46n Williams, Peter, 65n Willowbrook State School, 3, 49, 118. See also institutionalized subjects Wolf, Susan, 76, 85n Women, 4-8, 12, 24, 26, 27, 62, 67-82, 83n, 85n, 86n, 93, 95, 96, 101, 125, 134-142, 151, 156-158, 163, 172, 176-178 NIH and FDA policies regarding women (See NIH and FDA) Office of Research on Women's Health (ORWH) (See NIH) women of color, 68, 80 Women's Health Initiative, 72

World Health Organization (WHO), 135, 137-139, 143, 144n-146n, 168, 179 World Medical Association, 18 Wrentham School, 119 Yellow Book, 21 Yellow fever experiment, 119 Yonkers, Kimberly, 84n Young, B., 45n Young, Iris Marion, 77, 89, 106n Zamula, E., 87n Zidovudine. See also AIDS/HIV; AZT Zlotocha, Jane, 66n