Nutraceutical and Functional Food Regulations in the United States and Around the World (Food Science and Technology)

Preface Historically, plants have been used as a valuable source of prophylactic agents for the prevention and treatme...

Author: Debasis Bagchi

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Preface

Historically, plants have been used as a valuable source of prophylactic agents for the prevention and treatment of diseases in humans and animals. Hippocrates conceptualized the relationship between the use of appropriate foods for health and their therapeutic benefits in his renowned quote: Let food be thy medicine and medicine be thy food Hippocrates (460–377 BC) This intimate relationship between food and drugs is even recognized in the American legal definition of a drug: §201(g)(1) The term ‘drug’ means…articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and articles (other than food) intended to affect the structure or any function of the body of man or other animals… (1). Within the last decade, consumers have made increasing reference to ‘nutraceuticals’ and ‘functional foods’, recognizing the relationship between nutrition and health, to the point of avoiding an overreliance on pharmaceuticals and regarding prescription drugs as often being unnecessary, too expensive and of dubious benefit once all the risks are considered. This combined with a more widespread understanding of how diet affects disease, health-care costs and an aging population, have created a market for functional foods and natural health products. According to market statistics, the global functional food and nutraceutical market is growing at a rate that is outpacing the traditional processed food market. A poll conducted by the Council for Responsible Nutrition (CRN) reported that 52 percent of Americans identify themselves as regular users of dietary supplements in 2007, up from 46 percent in 2006 (2). In the USA alone, consumer expenditures on dietary supplements and functional foods reached a reported $22.4 billion and $31.4 billion sales, respectively, more than double the amount spent in 1994 (3). Natural products industries face diverse challenges. In attempt to define efficacy and support marketing claims for the products, extensive safety studies including acute, subacute, subchronic, chronic and long-term toxicity studies, genotoxicity,

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reproductive toxicology, teratogenicity, molecular mechanisms of action both in vitro and in vivo, should be complemented with supplementation studies in animal models and clinical trials for human efficacy for specified indication. This book on Nutraceutical and Functional Food Regulations in the United States and Around the World formalizes an expert panel and provides descriptions of health food regulatory aspects from North America, the UK, Australia, New Zealand, Asia, Brazil, Africa, and other select countries in the Pacific Rim. Other topics include marketing insight, current good manufacturing compliance (cGMP), analytical validation, intellectual property, branding, trademark and regulatory approvals. Furthermore, the impact of World Trade Organization (WTO) regulations on the global food supply chain is reviewed. A special section on the safety assessment and assurance of nutraceuticals through obtaining generally recognized as safe (GRAS) status and the use of traceability technologies and nanotechnology is also discussed. A highly impressive group of professionals has immensely contributed to the successful accomplishment of this special issue. Part I: Introduction. A.L. Almada and Professors O. Hänninen and C.K. Sen discussed the scope and significance of global regulations on nutraceuticals and functional foods. Almada emphasized on market opportunities and future directions of nutraceuticals and functional foods. Part II: Regulatory hurdles for marketing were examined by C. Noonan and W.P. Noonan, and A.V. Maher. Noonan and Noonan reviewed the common reasons for rejection of new dietary ingredient submissions and discuss some tactics to help improve the odds for successful marketing in the USA. Maher explains how the Federal Trade Commission (FTC) evaluates the adequacy of scientific substantiation and provides numerous examples of how the FTC has applied the standard in law enforcement actions. Part III: Manufacturing compliance and analytical validation was reviewed by leading analytical researchers, Drs R. Crowley, L.H. Fitzgerald and D. Sullivan. Crowley and Fitzgerald emphasize the impact of cGMP compliance on consumer confidence in dietary supplements. Sullivan and Crowley give an overview of the development and validation of analytical methods for health foods and dietary supplements. Part IV: Importance of safety assessment was discussed by Drs G.A. Burdock and Dr P.A. Lachance. Burdock et al. enlightened on the importance of GRAS to the functional food and nutraceutical industries. Lachance reviews the concept of traceability of nutraceuticals and pharmaceuticals to prevent the covert introduction of chemical and microbiological hazards as agents of terrorism or counterfeiting. Part V: Regulations around the world was provided by a selected panel of world renowned professionals specialized in their respective country’s legislation on dietary supplements and functional food regulations. Drs J.E. Hoadley and J.C. Rowlands highlighted the Food and Drug Administration (FDA) perspectives on health claims for food labels in the USA. Dr S. Agarwal, a leading nutrition scientist, and S. Hordvik and S. Morar, well renowned regulatory legal counsels, focused their discussion on the nutritional claims for functional foods and supplements in the USA.

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Dr O.I. Aruoma summarized the impact of WTO and food regulation on the food supply chain. Drs S. Martyres, M. Harwood, and E.R. Nestmann reviewed the basic principles of Canada’s regulations and examples of major issues faced by the Natural Health Products Directorate. Dr P. Coppens, M.F. DaSilva and S. Pettman, and Drs O.P. Gulati and P.B. Ottaway, two well renowned professional teams, discussed in detail the legislation governing enrichment of foods and health claims made on botanical-sourced, functional and fortified foods and food supplements in the European Union. Dr S.A. Ruckman provided an understanding of European and UK food law and how they apply specifically to nutraceuticals and functional foods. Drs D. Ghosh, L.R. Ferguson and M.A. Skinner presented a succinct discussion on the roles of Therapeutic Goods Administration and the Medicine and Medical Devices Safety Authority in Evaluating Complementary and Alternative Medicines in Australia and New Zealand. Drs H. Ohama, H. Ikeda and H. Moriyama provided a detailed overview on Japanese regulations for health foods and foods, as well as intricate aspects of Foods for Specified Health Uses regulations. Korean FDA representatives J.Y. Kim and D.B. Kim, in collaboration with Professor H.J. Lee of Seoul National University gave a thorough update on Korean Regulatory aspects. A. Roberts and R. Rogerson discussed the regulations and requirements for regulatory approval within the Chinese market. Victor A. Tutelyan and Boris P. Sukhanov reviewed biologically active food supplements (BAFS) as well as food supplement quality, safety, efficacy and regulating the registration process in the Russian Federation. Drs. K. Shelke and C. Hewes gave an in-depth narration of the historical background and the current status of Indian nutraceuticals and regulation foods regulations. The authors concluded the chapter with an outlook of the regulatory challenges that lie ahead in the nutraceuticals and functional foods industry in India. Drs T. Bahorun and O.I. Aruoma focused on the regulatory status on botanical drugs, nutraceuticals and functional food in the African continent. Drs M.C. de Figueiredo Toledo and F.M. Lajolo described the legislation that is relevant in the marketing of supplements and functional foods in Brazil. Dr J. Zawistowski provided an extensive review on the regulatory system for functional foods in the eight countries of the Pacific Rim: Taiwan, Hong Kong, South Korea, Malaysia, Indonesia, Singapore, Philippines and Thailand as well as their diverse acts, regulations, and guidelines. Part VI. Intellectual property, branding, trademark and regulatory approvals in nutraceuticals and functional foods were discussed by L.K. Chong, L.J. Udell and B.W. Downs. Further discussion on the challenges of IP and branding were reviewed by the well known legal group at Marshall, Gerstein & Borun LLP. Although nutraceuticals and functional foods have significant promise in the promotion of human health and disease prevention, health professionals, nutritionists and regulatory toxicologists should strategically work together to derive appropriate regulations to provide the optimal health and therapeutic benefits to mankind.

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xiv Preface

References 1. 2. 3. 4.

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21 U.S.C. 343(r)(4) emphasis added. http://www.nutraingredients-usa.com/news/ng.asp?n ⫽ 80363-crn-ipsos-survey. Nutrition Business Journal (2007). Industry Overview, July/August. Nutrition Business Journal (2007). Feb/March, XII (2/3), 1–31.

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Contributors

Sanjiv Agarwal, Sara Lee Food & Beverage, Downers Grove, IL, USA Anthony L. Almada, President and CEO, GENr8, Inc., Laguna Niguel, CA, USA Okezie I. Aruoma, Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY, USA Theeshan Bahorun, Department of Biosciences, Faculty of Science, University of Mauritius, Reduit, Republic of Mauritius Peter Berry Ottaway, Berry Ottaway & Associates Limited, Hereford, UK George A. Burdock, Burdock Group, Vero Beach, FL, USA Ioana G. Carabin, Burdock Group, Vero Beach, FL, USA Leighton K. Chong, Udell Associates, Castro Valley, CA, USA Patrick Coppens, European Advisory Services (EAS) – Strategic Advice on Nutritional Products, Brussels, Belgium Richard Crowley, Covance Laboratories, Madison, WI, USA Bernard W. Downs, Udell Associates, Castro Valley, CA, USA Meggan F. Duffy, Marshall, Gerstein & Borun LLP, Chicago, IL, USA Maria Cecília de Figueiredo Toledo, Departamento de Ciência de Alimentos, Faculdade de Engenharia de Alimentos – Universidade Estadual de Campinas, Campinas-SP, Brasil Lynnette R. Ferguson, Department of Nutrition/ACSRC, The University of Auckland, Auckland, New Zealand Miguel Fernandes da Silva, European Advisory Services (EAS) – Strategic Advice on Nutritional Products, Brussels, Belgium Dilip Ghosh, Regulatory Affairs, National Centre of Excellence in Functional Foods, University of Wollongong, NSW, Australia Michael R. Graham, Marshall, Gerstein & Borun LLP, Chicago, IL, USA Om P. Gulati, Scientific & Regulatory Affairs, Horphag Research Management SA, Geneva, Switzerland Osmo Hänninen, Department of Physiology, University of Kuopio, Kuopio, Finland Libby Harvey FitzGerald, Covance Laboratories, Madison, WI, USA Melody Harwood, Cantox Health Sciences International, Mississauga, ON, Canada Christopher Hewes, Principal, Corvus Blue LLC, Chicago, IL, USA

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x Contributors

James E. Hoadley, FDA, Center for Food Safety and Applied Nutrition, College Park, MD, USA Stein Hordvik, ConAgra Foods Inc, Omaha, NE, USA Hideko Ikeda, Biohealth Research Ltd, Bunkyo-ku, Tokyo, Japan Dai Byung Kim, Nutrition and Functional Food Headquarters, Korea Food and Drug Administration, Seoul, South Korea Ji Yeon Kim, Nutrition and Functional Food Headquarters, Korea Food and Drug Administration, Seoul, South Korea Paul A. Lachance, The Nutraceutical Institute, The New Jersey Agricultural Experiment Station, New Brunswick, NJ, USA Franco M Lajolo, Departamento de Alimentos e Nutrição Experimental Faculdade de Ciências Farmacêuticas Universidade de São Paulo, São Paulo, Brasil Hyong Joo Lee, Program in Food Science and Biotechnology, School of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, South Korea Anne V. Maher, Kleinfeld Kaplan & Becker, Washington, DC, USA Stephanie Martyres, Cantox Health Sciences International, Mississauga, ON, Canada Sandra Morar, McGrath North Law, Omaha, NE, USA Hiroyoshi Moriyama, Laboratory of Pharmacotherapeutics, Showa Pharmaceutical University, Machida, Tokyo, Japan Vidushi S. Neergheen, Department of Biosciences, Faculty of Science, University of Mauritius, Réduit, Republic of Mauritius Earle R. Nestmann, Cantox Health Sciences International, Mississauga, ON Canada Chris Noonan, IMAGINutrition, Inc., Santa Monica, CA, USA W. Patrick Noonan, A Professional Corporation, Woodland Hills, CA, USA Hirobumi Ohama, Biohealth Research Ltd, Bunkyo-ku, Tokyo, Japan Simon Pettman, European Advisory Services (EAS) – Strategic Advice on Nutritional Products, Brussels, Belgium Ashley Roberts, Cantox Health Sciences International, Mississauga, ON, Canada Rebecca Rogerson, Cantox Health Sciences International, Mississauga, ON, Canada J. Craig Rowlands, The Dow Chemical Company, Toxicology and Environmental Research and Consulting, Midland, MI, USA Stephen A. Ruckman, Huntingdon Life Sciences, Alconbury, Cambridgeshire, UK Chandan K Sen, Davis Heart and Lung Research Institute, Department of Surgery, The Ohio State University Medical Center, Columbus, OH, USA Jeffrey S. Sharp, Marshall, Gerstein & Borun LLP, Chicago, IL, USA Kantha Shelke, Principal, Corvus Blue LLC, Chicago, IL, USA Alisa Simmons, Marshall, Gerstein & Borun LLP, Chicago, IL, USA Margot A. Skinner, Health and Food, The Horticulture and Food Research Institute of New Zealand Ltd, Auckland, New Zealand Boris P. Sukhanov, RAMS Institute of Nutrition, Moscow, Russia Darryl Sullivan, Covance Laboratories, Madison, WI, USA Victor A. Tutelyan, RAMS Institute of Nutrition, Moscow, Russia Lawrence J. Udell, Udell Associates, Castro Valley, CA, USA Jerzy Zawistowski, University of British Columbia Vancouver, BC, Canada

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PART

Introduction 1 An Overview on the Scope, Importance and Market Opportunities of Nutraceuticals and Functional Foods: A Special Emphasis on the Future Directions 2 Nutritional Supplements and Functional Foods: Functional Significance and Global Regulations

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An Overview on the Scope, Importance and Market Opportunities of Nutraceuticals and Functional Foods: A Special Emphasis on the Future Directions

1

Anthony L. Almada GENr8, Inc. Laguna Niguel, CA, USA

Abstract Nutraceuticals and functional foods (NFx) present an economically robust opportunity on a global scale. However, manufacturers and marketers of these products are confronted with the Herculean task of developing finished goods that exhibit excellent hedonics, create sustainable revenues, yield attractive investment returns, and give birth to multinational legions of brand zealots. The dearth of NFx products that enjoy a reputable evidence base affords a compelling opportunity for industrial and academic alliances that integrate consumer relevance—instantly understood, evidence-based, and confidence-inspired health benefits. Creation of an intellectual property composite from the inception point, cognizant of global markets and demographics, is critical to prolonging the product life cycle and maximizing market share. The provision of consumer nutritional goods that elicit preventive, therapeutic, or quality of life enhancing effects—substantiated by validation in relevant human target populations—can inject consumer confidence into a sector viewed with diffidence by both consumers and the life sciences and biomedical communities, while elevating industrial growth through science-driven revenues and valuable intellectual assets. Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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Copyright © 2008, Elsevier Inc. All rights reserved

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4 An Overview on the Scope, Importance and Market Opportunities

Introduction What factors overcome innovation inertia, compelling the nutrition industry to develop products that promise and deliver consumer-relevant benefits? Does a bright line of demarcation exist, delineating a natural product classified and regulated as a non-drug/non-medicine entity from its Janus twin? Does the clinical evidence on a natural product, or its express or implied claims, determine its regulatory destiny? Will an evidence base ever amass, fostering the standard of care for medical prophylaxis and treatment to embrace a specific nutritional product – offered as a consumer good – as a first line intervention that precedes pharmacologic or surgical intervention? The nutrition industry enjoys a global footprint and enjoys substantial economic momentum. In this chapter, I define ‘nutraceuticals’ – still nutrition industry/ scientific community parlance and lacking a regulatory definition – as supplements to the diet comprised of bioactives that occur in food, are produced de novo in human metabolism, botanicals intended to impart a physiological or medicinal effect after ingestion, and vitamins and minerals, delivered in forms that differ from conventional foods or beverages, e.g. solid dosage forms like capsules, tablets, or ethanolic liquid extracts. ‘Functional foods and beverages’ – another nutrition industry/scientific community descriptor without a regulatory parent – I define as the above, yet delivered in conventional food and beverage formats, e.g. a single serving beverage, a fermented dairy product or a food bar. Collectively, I shall refer to these two classes as ‘NFx’. Biologically, NFx are intended to impart a physiological or medicinal effect, without or in addition to a nutritional effect.

Scope of Hope The consumer promise of an NFx holds the allure of improved or preserved physiologic or metabolic function, beyond that of micronutrient and macronutrient essentiality. The spectrum of consumer expectation ranges from disease/condition prophylaxis to disease/condition treatment, to even cure. Seamlessly woven into the expectation spectrum are two elements often overlooked by both the scientific community and the NIC: consumer experiential response and consumer message ceiling. From this author’s perspective, the NFx products that enjoy (or have enjoyed) robust, sustainable revenues are those defined by one of two phenomena: 1. consumer experience and 2. high circulation, incremental media editorial messaging. Arguably the best example of an NFx that elicits a consumer experience – one that is seen (reduction in facial acne, psoriatic lesions), very easily and inexpensively measured by the consumer (body mass, blood total cholesterol, fasting blood glucose), or subjectively perceived by the end user (increased exercise endurance; enhanced mood) – rests with glucosamine salts and chondroitin sulfate. Marketed as a drug in certain

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Value Addition or Illusion? 5

countries outside of North America, these are sold as regulated dietary ingredients or as functional food/beverage ingredients in the USA and as a natural health product in Canada (even by the same manufacturer of the approved medicine forms). Since their introduction into USA commerce in the mid-1990s, they have grown to produce the majority of sales for joint health nutraceuticals, in excess of US $1.25 billion in consumer sales (1). The incremental and sustainable growth created by this duo is very likely due to the widespread consumer experience of reduced pain and enhanced function among users of this product. The second phenomenon that drives success for an NFx is continuous, incremental messaging by high circulation media, e.g. regional and national newspapers, high circulation weekly news magazines, syndicated or national television or radio and high traffic news websites. Invariably, an evidence base on a specific NFx bioactive or on a finished good can fuel positive editorial coverage within these media vehicles. The evidence base can be linked to a governmentally authorized health claim. A sterling example of this is phytosterols/phytostanols in yellow fat spreads and other food products. A compelling evidence base supports the safety and hypolipidemic efficacy of plant stanols and sterols, almost exclusively when consumed in a lipid-rich food form and not in solid dose or low/zero lipid food forms, with the innovative exception of phytosterol-enriched orange juice (2,3). They have been approved in a variety of countries for claims associated with lowering heart disease risk – singly by virtue of their blood lipid-lowering impact, as no intervention trials examining the prevention of myocardial infarctions or other cardiovascular events have been made public. The associated evidence base and authorized health claims has ushered in a palpable volume of media editorial over the past 8–10 years, fueled by the marketers of such products.

Value Addition or Illusion? A recent editorial that appeared in a journal published by the Nature Publishing Group offered an excoriating profile of the nutraceuticals industry – dubbed the ‘Nutraceutical-Industrial Complex’ (4). Despite the numerous myopic perspectives reflecting the author’s superficial knowledge, his message is distinctive: the vast majority of product offerings lack any reputable and compelling evidence base. Our own market and scientific research indicates that less than one out of a thousand finished NFx products – not individual bioactive ingredients but the final form purchased and ingested by a consumer – enjoys at least a single randomized controlled trial (RCT) performed against a placebo or a positive control (e.g. an appropriate drug) and demonstrating a statistically significant outcome superior to that of the placebo, or equivalent or even superior to a positive drug comparator. What is more unsettling is our finding that, of the approximately 250–300 RCTs conducted on NFx products in North America annually, only a fraction are made public (via presentation or publication). This underscores the prevalence of publication bias and reveals the far more haunting truth that data suppression is not uncommon. Sadly, the ‘gagging’

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of investigators related to dissemination of clinical trial data on NFx products reaches into the ranks of publicly traded and multinational NFx marketing entities. The ‘burial’ of these data is achieved by increasing numbers of studies being performed with contract research and clinical service organizations, where data ownership and intellectual property rights are exclusive to the study sponsor. The importance and utility of NFx is defined not by revenues, share price, the annualized number of product introductions, nor calculated annual growth rate of the sector. NFx should serve the consumer by making a favorable, measurable impact upon her/his biology, congruent with the claimed benefit of the product and perhaps beyond. A probiotic beverage that improved laxation and reduced low-density lipoprotein (LDL) cholesterol could become a product that has legions of brand zealots behind it. The provision of NFx products, in its purest form, can be viewed as a public health initiative, centered upon offering consumer goods that meet four criteria: 1. excellent tolerability and hedonics, at least equal to the conventional food or beverage category leader (for solid dose forms, excellent tolerability and ease of use) 2. demonstration of consumer-relevant efficacy through an incremental series of clinical trials 3. aligning with existing, demographically dense unmet or undermet needs, and 4. remaining within a retail price comfort zone. Aversion to ‘good for you’ foods and beverages can be a significant deterrent for many consumers. Creating an equal or superior sensory experience with a functional food or beverage can have a dramatic impact upon consumer trial and repeat purchasing. The post-ingestive experience also has significant import, especially in relation to gastrointestinal (GI) symptoms. NFx products that are intended to have a GI effect (e.g. prebiotics or synbiotics) have the highest likelihood of causing GI distress. Solid dose forms need to be delivered in a manner that do not require multiple dosing throughout the day nor large dose formats (e.g. large tablets or capsules). Liquids need to be easily measured and palatable, with masking/debitterizing agents considered for use. Powders need to be easily mixable and non-hygroscopic under normal storage conditions. One cannot emphasize the critical need for a series of clinical trials on an NFx. One of the elements lacking among consumers of NFx products is confidence: in the claims, in the taste and in the brand. A specific consumer product buttressed by even one well-designed RCT – where the number of servings or dose used in the study matches the labeled use directions and is not cost prohibitive – can exalt a brand into a new level of equity with consumers. It is a widely held misperception that sponsoring an RCT requires a budget in excess of $100 000. Harkening back to our finding of less than 0.1% prevalence of an NFx with at least one RCT demonstrating efficacy, even an RCT pilot study with a sample size of 12–20 (or half this, if employing a cross-over design) would confer distinction. A follow-up study – fueled by incremental revenues from the sales of the NFx – with a larger sample size and longer

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Value Addition or Illusion? 7

duration would allow for the creation of a foundation of evidence. Considering the allocation of resources by NFx companies to marketing, advertising, promotions and sales, it is typically highly feasible for even early stage companies to capitalize a clinical research program. It is not a matter of economics – it requires an executive commitment to invest in evidence-based NFx goods. Unlike pharma and life sciences industries, the vast majority of individuals leading NFx business entities is science illiterate and averse, and has raised the ranks through sales, marketing or business development capacities. This is coupled with an ignorance of how to monetize product-specific clinical science, which further magnifies the resistance to invest. A pivotal element in the monetization of product-specific clinical science is the public communication of positive results (oral or poster presentation at a national or international scientific/medical conference) and/or publication of the RCT (in a reviewed journal, ideally at or above the median impact factor for journals in the relevant category). This can become the axis of a strategic communications campaign that yields editorial mention in print (newspapers, magazines), online (health/medical news focused websites) and on air (television, radio). Editorial mention of science linked to a branded NFx can generate dialogue among consumers, elevate awareness and potentially increase demand and trial purchase velocity. The advent of consumer-generated content, e.g. blogging, message boards has fostered a novel form of media that has significant impact upon purchase behavior. A recent Nielsen online survey among consumers in 47 countries found a global average of 61% to consider blogs as a reliable source of information, highest in North America and Asia (5). The path to strategic innovation mandates both a keen awareness of consumer needs and linked demographics, those that are unmet and undermet. Latent needs (not readily apparent or acknowledged by the consumer), albeit a potentially viable pursuit, often require more intensive education and awareness generation. An unmet need would be an NFx that rapidly relieves tension or stress headaches without the use of analgesic drugs (there does not appear to be any NFx that enjoys any solid evidence of such). An undermet need would be an NFx that prevents or rapidly treats seasonal allergic episodes (a plethora of products exist but their efficacy is highly variable or questionable). Demographics and market size are important elements to consider for innovation direction. NFx products targeted to orphan applications, e.g. scleroderma or McArdle’s syndrome, are altruistic and admirable but may yield unsatisfactory yields if they are positioned as a primary revenue generator. These pursuits may also require higher retail pricing to obtain a satisfactory return on investment. Cost to the consumer – the price they must pay to begin enjoying the benefits of an NFx – must be determined before allocation of any resources. This will vary from country to country. The price will have a segmenting effect upon what socioeconomic demographic the product needs to be positioned to. One interesting phenomenon that could happen with higher/premium priced NFx products is the bandwagon effect (6). This is described as consumer demand increasing as the number of consumers buying the good increases. This is often achieved by the conspicuous consumption or overt recommendation of a good by a celebrity or media luminary. Part of the monetization strategy of NFx innovation and commercialization warrants the prudent selection of influential users or endorsers of a specific product, especially an

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endorser who aligns with the brand by personal/medical need (a celebrity living with diabetes or with a history of acne) or by vocation (a current or former professional footballer or cricketer, or Olympian gold medallist, plagued with injuries, advocating an NFx that has increased their mobility, pain-free performance, etc.).

Opportunity Awaiting The nutrition industry and academic communities continue to have a fascination with various ‘-omics’ platforms, from genomics to lipidomics to proteomics to metabolomics. This focus appears to maintain a myopic vista of consumer relevance. For the consumer, a personalized -omics profile offers a fascination to the innovator consumer only, which is a very small fraction of the population at large. The illusion of personalized nutrition via personalized biometric profiling has no relevance to what is a valued return on investment by the consumer: a novel, validated path to superior health and biofunctioning. What merits integration into –omics-centric business models in the nutrition industry is comparator trials that pose –omics-guided NFx intervention against conventional NFx intervention, with consumer relevant outcome measures. For example, -omics biometric profiling of a cohort of adults with chronic facial acne would lead to a select suite of NFx products that would be expected to be effective. Via a cross-over design (with an appropriate washout period) the subjects would receive the –omics-guided NFx and maintain their normal diet or pursue a nascent, evidence-based dietary intervention, at different times (7). If the NFx intervention proved superior in the outcome measures, which are easily quantifiable in this example, the economic and biological ramifications of this could have tectonic-plate shifting industrial and consumer impact. Unlike far more daring pursuits with long-term endpoints or outcomes, e.g. cognitive decline, secondary prevention of a cardiovascular event, etc., using the skin as a target organ incorporates two valuable consumer components: vanity and visibility. Few NFx innovations have centered upon demographically dense skin conditions. An example of a ‘skinceutical’ that has been amassing an evidence base is Dermylex™, a patented milk-derived peptide (marketed currently in several countries as a solid dose form) that has been the focus of an incremental research plan for psoriasis (8).

Conclusion The promise of nutraceuticals and functional foods is prodigious. The challenge of creating finished goods that create sustainable and robust revenues, and provide sufficient investment returns, coupled with large legions of brand zealots, is equally substantial. The paucity of NFx products that enjoy a reputable evidence base affords a compelling opportunity for industrial and academic alliances that integrate consumer relevance, from concept to container. Of equal importance is the need to insert an intellectual property strategy from the inception point, cognizant of global markets and demographics. Delivering on the promise of nutritional goods that exert preventive,

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References 9

therapeutic or quality of life enhancement can inject consumer confidence into a sector viewed with diffidence by both consumers and the medical community, and buoy industrial growth with science-driven revenues and intellectual assets.

References 1. Nutrition Business Journal. (2007). Condition-specific supplement sales, 1999–2006. New Hope Natural Media, Boulder. 2. Devaraj S, Jialal I, Vega-Lopez S. (2004). Plant sterol-fortified orange juice effectively lowers cholesterol levels in mildly hypercholesterolemic healthy individuals. Arterioscler Thromb Vasc Biol 24, e25–e28. 3. Devaraj S, Autret BC, Jialal I. (2006). Reduced-calorie orange juice beverage with plant sterols lowers C-reactive protein concentrations and improves the lipid profile in human volunteers. Am J Clin Nutr 84, 756–761. 4. Ridinger MHT. (2007). Nutraceuticals: miracle or meme? Clin Pharmacol Ther 82, 352–356. 5. Nielsen Global Survey. (2007). Word-of-mouth the most powerful selling tool: http:// www.nielsen.com/media/2007/pr_071001.html (accessed 22 October 2007). 6. Leibenstein H. (1950). Bandwagon, snob, and Veblen effects in the theory of consumers’ demand. Quart J Econ 64, 183–207. 7. Smith RN, Mann NJ, Braue A, Mäkeläinen H, Varigos GA. (2007). The effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris: a randomized, investigatormasked, controlled trial. J Am Acad Dermatol 57, 247–256. 8. Poulin Y, Bissonnette R, Juneau C, Cantin K, Drouin R, Poubelle PE. (2006). XP828L (Dermylex™) in the treatment of mild-to-moderate psoriasis: a randomized, double blind placebo-controlled study. J Cutan Med Surg 10, 241–248.

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Nutritional Supplements and Functional Foods: Functional Significance and Global Regulations

2

Osmo Hänninen1 and Chandan K. Sen2 1

Department of Physiology, University of Kuopio, Kuopio, Finland Davis Heart and Lung Research Institute, Department of Surgery, The Ohio State University Medical Center, Columbus, OH 43210, USA 2

Abstract Originally, foods that have the property to modulate the body function that contributes to the prevention of a disease were called ‘Functizonal Foods’. However, the term is now widely understood to mean foods that claim such biological effects beyond ordinary nutritional effects based on scientific validation. Today, we are eating food material of compromised nutritive value because of milling and processing. Furthermore, there is not enough time for a healthy balanced meal. Dietary supplements and functional foods are a prudent choice to offset these limitations in our daily lives. The terminology ‘physiologically functional foods’ or simply ‘functional foods’ was conceived in the context of nutrition during space travel. The modern concept of functional food for the general population was proposed by the Japanese academic society in the early 1980s and the legislation for functional foods was first implemented as FOSHU, which stands for ‘Foods for Specified Health Use’. Decisions and policies from global regulatory bodies have become increasingly influential for dietary supplement companies. Such bodies include Codex Alimentarius, the World Health Organization (WHO) and the Food and Agriculture Organization (FAO). The International Alliance of Dietary Food Supplement Associations (IADSA) works closely with these international bodies to ensure Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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12 Nutritional Supplements and Functional Foods

that the views of the dietary supplement industry are taken into account in the development of policy. The Dietary Supplement Health and Education Act of 1994 (DSHEA) was directed at ensuring that a dietary supplement is safe before it is marketed in the USA. In 1991, the Japanese Ministry of Health and Welfare (MHW) established the FOSHU labeling regulation. It was implemented by adding a new category of FOSHU to ‘Foods for Special Dietary Uses’ in the Nutrition Improvement Law. The momentum in Japan seems to be in the right direction providing the rest of the world with an opportune platform for further development.

Introduction Two hundred years ago, processed sugar was only available in drug-stores (1). Today, it is one of the most successfully marketed nutritional chemicals which addicts consumers from a time when they are very young. On one hand, we are eating food material of compromised nutritive value because of milling and processing (2). On the other hand, there is not enough time for a healthy balanced meal. To compensate for these losses, dietary supplements and functional foods are a must in today’s lifestyle (3–6). The search for functional foods or functional food ingredients, i.e. foods or food ingredients that can enhance health is beyond any doubt one of the leading trends in today’s food industry. Bread baked from the old varieties of wheat and rye, oats porridge, fish and fermented milk products, berries and fruits (some of which are also fermented like wines) as well as olive oil were the main items of daily diet in European countries. The present diets contain little or none of these, but much of refined carbohydrates (especially sucrose, which is almost of analytical grade) and in excess of n-6 series of fatty acids in vegetable oils. Similar trends dominate in the Americas and AsiaOceania. The previously necessary heavy dynamic work has also been replaced by sedentary occupations with significant persistent static muscle activation and lifestyle with elevated sympathetic tonus and an imbalanced endocrine status. The result is the incidence of metabolic syndrome on an epic scale. The metabolic syndrome, overweight and obesity, represents a major burden on the health care system in many countries (7). Glucotoxicity and lipotoxicity are more common than any other toxicities and harmful to the secretion of insulin, e.g. the key regulator our metabolism (8). Understanding the role of foods in the maintenance of health and cure of diseases has its roots in our ancient culture. Ancient documents of Indian ayurveda, Chinese scriptures, Judean and Christian Old Testament (Moses’ and Daniel’s books), Greek (Hippocrates), Islam (Koran) and also Finnish (Kalevala) cultures provide information on this understanding. Unfortunately, the rather recent developments of milling and other industrial refining methods of foods have obscured the old knowledge with the commercial trends in marketing. ‘White is beautiful’ is misleading in this context. The refined foods contain less and often only minuscule amounts of vitamins, minerals and other compounds which the plants provide for us. In nature, phytochemicals are present as a mixture. We are gradually realizing that such heterogeneous composition, which sharply departs from the ‘one active principle’ hypothesis, is of functional significance. Taken together these phytochemicals perform functions that are

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Introduction 13

often not reproduced by any single component or even a simple mixture of a few select components. Dietary phytochemicals play a major role in regulating human health and disease (9). As people can now easily compose their diets by avoiding the necessary and protective chemicals that nature provides, global epidemics of overweight and obesity in unprecedented scale are spreading not only in advanced and well-off nations (10) but also some economically privileged social layers in developing countries while other groups may be starving (11). Nutraceuticals are food or food ingredients that have defined physiological effects. They do not easily fall into the legal categories of food or drug and often inhabit a gray area between the two. These products in general terms cover health promotion, ‘optimal nutrition’, the concept of enhanced performance – both physically and mentally – and reduction of disease risk factors. The terminology ‘physiologically functional foods’ or simply ‘functional foods’ was conceived over three decades ago in the context of nutrition during space travel (12). The modern concept of functional food for the general population was proposed by Japanese academic society in the early 1980s and the legislation for functional foods was first implemented as FOSHU, which stands for ‘Foods for Specified Health Use’ (13,14). The goal of the Functional Food Science in Europe (FUFOSE) concerted action was to reach consensus on scientific concepts of functional foods in Europe by using the science base that supports evidence that specific nutrients positively affect physiological functions. The outcome proposed ‘a working definition’ of functional foods: foods can be regarded as functional if they can be satisfactorily demonstrated to affect beneficially one or more target functions in the body, beyond adequate nutritional effects, in a way relevant to an improved state of health and well-being and/or reduction of risk of disease. Functional foods must remain foods and they must achieve their effects in amounts normally consumed in a diet. Evidence from human studies, based on markers relating to biological response or on intermediate endpoint markers of disease, could provide a sound scientific basis for messages and claims about the functional food products. Two types of claims are proposed that relate directly to these two categories of markers: enhanced function claims (type A) and reduced risk of disease claims (type B). Next, a new EU Concerted Action undertook to build upon the principles defined within FUFOSE. The process for the assessment of scientific support for claims (PASSCLAIM) initiative was thus established (15–27). The European branch of the International Life Sciences Institute (ILSI; established in 1978, ILSI is a worldwide foundation that aims to help public health by advancing the understanding of scientific issues related to nutrition, food safety, toxicology and the environment. The Institute brings together scientists from academia, government, industry and the public sector to seek solutions for public health issues) (13,28) and the PASSCLAIM initiative are directed at assessing scientific support for claims on foods. The health promoting properties can be mentioned in marketing in some countries, but not the lessening of the disease risk. In Japan, FOSHU products are for sale under proper legislature as discussed later in this volume. FOSHU ranges over pharmacology, medicine and food and nutrition. Critiques have argued that even FOSHU contains highly purified or concentrated functional ingredients present in ordinary foods and thus, it is very important to take safety issues into consideration

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(29). FOSHU is the only type of food product (not ingredients) that can carry health claims and is composed of functional ingredients that affect the structure/function (physiological functions) of the body. These food products are intended to be consumed for the maintenance/promotion of health or special health uses by people who wish to control specified health conditions, such as gastrointestinal conditions and blood pressure. Therefore, FOSHU products target healthy people and people in a preliminary stage of a disease or a borderline condition. When the products are manufactured or distributed, permission or approval from the government is required after rigorous evaluation of the safety and effectiveness of proposed specified health uses(14). Functional foods are drawing more attention in public discussions and presumably soon there will be a standard global policy governing the sale and consumption of functional foods. Clearly, more research is needed to support that process. Research should also be carried out in different cultural settings, as the dietary habits are quite heterogeneous globally. Study outcomes are expected to be determined by the entire dietary matrix of which the functional food being tested would represent only a minor component. The aim of this chapter is to present an overview of the significance of traditional food items and their components as targets of research for functional foods and dietary supplements. A few select examples are discussed. Regulations in different countries that are directed at the sale and consumption of functional foods are concisely discussed.

Health Behaviors and Food Markets Health behaviors can be changed by appropriate interventions (30–32). A good example is eastern Finland where cardiovascular morbidity and mortality were the highest in the world according to statistics reported three decades ago. The North Karelia Project (33,34) has been successful in steadily minimizing cardiovascular morbidity and mortality in eastern Finland during the course of the last three decades (35). There are different theories about how the health behavior of people can be modified. As people are different and their willingness to adopt changes depends on their age and culture, different approaches must be run in parallel. Table 2.1 is a listing of those different approaches which may be used to change the health behaviors.

Possibilities to Promote Food Health Promoting Properties The better functionality of the foods can be promoted in different ways (13). There are many natural varieties of plants grown as part of agriculture. Better understanding of their nutritionally valuable components may revitalize their cultivation, as has taken place in the case of ancient wheat varieties. One can also introduce sets of genes to

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Fiber 15

Table 2.1 Health behaviors can be changed by emphasizing different aspects Health belief Consumer Behavioral intention Innovation diffusion

Communication persuasion Self-control Self-efficacy Problem behavior Social marketing Social learning

Change takes place as the person believes to be at risk and (s)he believes that the change will help Market, i.e. price, availability and presentation determine peoples’ choices Personal examples motivate others to change Novel ideas and practices gradually penetrate step by step first into a minority population and then eventually get adopted by the majority Change will take place if the information provided is understood and interesting People study themselves and take respective measures How determined the person is to change for personal reason Social immunization against poor food selections Social acceptability is the starting point in marketing Individual is both the subject and object of the change

Modified from (163)

plants as has been done by adding a carotene producing chain in rice. The opposite manipulation can also be done to lower or to remove an unhealthy component. Modification of foods and drinks can take place also by fortification as is done by adding vitamins and minerals. One can also remove components which are proven to be harmful as is done by removing cholesterol from eggs. In the production of the final food or drink, as in ancient times, fermentation has been used to increase digestibility and also to help storage. These bacteria have also been helpful by increasing the resistance to infection of the consumers. The biology of probiotics and prebiotics is well understood. Drinks can also be fortified with valuable chemicals as is done for products made for athletes and the fitness oriented general population.

Fiber The main components of natural plant foods are often different kinds of fiber (37–39). Fibers are valuable as distension of the stomach is one of the key regulatory signals contributing to satiety and termination of food intake. Dietary fiber also increases the volume of the gut contents. This is necessary for gut motility and functions including absorption and defecation. Dietary fiber components have many roles and this means that they are also perhaps the most important group of starting material in the development of functional foods and supplements (40). Dietary fiber consists of the remnants of edible plant cells, polysaccharides, lignin and associated substances resistant to (hydrolysis) digestion by the alimentary enzymes of humans. In Japan, the food tables list the dietary fiber content of animal as well as plant tissues, while many countries accept saccharides of less than DP-10 as dietary fiber (inulin, oligofructose,

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Fibersol-2, polydextrose, fructo-oligosaccharides, galacto-oligosaccharides etc.). These shorter chain oligosaccharides do not precipitate as dietary fiber in the standard Association of Official Analytical Chemists (AOAC) method, which is accepted by the US Food & Drug Administration, the US Department of Agriculture and the Food & Agriculture Organization of the World Health Organization for nutrition labeling purposes. In the UK, the term dietary fiber has been replaced in nutrition labeling by non-starch polysaccharides. Therefore, the American Association of Cereal Chemists (AACC) commissioned an ad hoc committee of scientists to evaluate continuing validity of the currently used definition and, if appropriate, to modify and update that definition. Dietary fiber can be considered a functional food when it imparts a special function to that food aside from the normal expected function and similarly when the dietary fiber is used as an additive to foods. For example, dietary fiber contributes to colonic health, bifidobacterial or lactobacillus stimulation in the gut, coronary artery health, cholesterol reduction, glucose metabolism, insulin response, blood lipids, cancer etc. Fibers also serve as substrates of numerous metabolic reactions in the gut microflora. Some of the components are short chain fatty acids. These fatty acids represent necessary energy sources for the colonic mucosal cells. They also contribute to metabolic regulation in the liver, e.g. in the endogenous synthesis of cholesterol (41). Fibers are starting materials of lignan production in gut microflora (42). Lignans are important regulators of the microflora itself and of mucosal cell renewal. Absorbed lignans contribute to the responses of metabolism of say steroid hormones and also check the propagation of hormone-related cancer cells (42). Lignans and other polyphenols are considered to have major beneficial effects on cardiovascular health (43,44). In particular, fiber seems to be highly valuable (43,45). In several central and north European countries, dark rye bread has been commonly used in all meals. Rye bread lowers the postprandial glucose response (45). In addition, rye bread decreases serum total and low-density lipoprotein (LDL) cholesterol in men with moderately elevated serum cholesterol (46). Rye is a good source of dietary fiber (36,47,48). We seem to have so much data on the benefits of rye that it could be confidently designated as a functional food item as in bread. Oat meal has traditionally been taken in regular breakfasts in several European countries and also in North America (49–51). The soluble fiber in the form of betaglucan is rich in oats (52–54). It can reduce or prevent the postprandial hyperglycemia and lipidemia, i.e. diminish glucotoxicity and lipotoxicity after a standard meal like breakfast. There are several studies on the effects of dietary beta-glucan isolated from oats on blood glucose and insulin levels (55–57). Oat-derived beta-glucan also reduces total blood and LDL cholesterol concentration in hyperchlosterolemic subjects (55,58). We have so much data on oat products that they could perhaps meet the requirements of nomination as functional foods (59). Probiotics, i.e. living microbial food supplements, and prebiotics, i.e. non-digestible food ingredients, are a subject of current attention. Both popular concepts target the gastrointestinal microbiota. While in the Western world the intake of probiotics has been recommended for a long time, prebiotics in general, and non-digestible oligosaccharides in particular, have only recently received attention (60–63).

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Antioxidants 17

Xylitol Trees use polymerized carbohydrates as their back bones. Actually, that reservoir has the clear potential of managing world famine significantly if taken into wider use. Unfortunately, the digestibility of cellulose is low in the human gut, but the cellulase technology is well known. Ruminants can use celluloses with the aid of their rumen bacteria. Some of the sugars of trees are widely used as food components. Birch trees contain a lot of pentose sugars. In Finland, the alcohol xylitol has been extensively studied for four decades. Xylitol, like other polyol sweeteners, is a naturally occurring sugar alcohol. Xylitol is sweet tasting, although the taste is a bit different from that of sucrose. When xylitol is added to candies and chewing gums instead of sucrose, bacterial growth in the mouth remains low compared to sucrosecontaining products. In this way, xylitol may effectively manage oral health (64–68). Although there are substantial data on the health benefits of xylitol, this natural sugar cannot be categorized as functional food. Xylitol traces in candies or chewing gums fall short of meeting the basic requirement of functional foods.

Polyphenols Seeds, berries and fruits as well as roots have protective polyphenols in addition to other valuable components (69,70). The Bible tells us about the balsam. Albeit anecdotally, the Finnish folk healing practices have benefited from the use of resins of pine and spruce in treating dermal wounds. Research on the effects of dietary polyphenols on human health has developed considerably in the past decade. In totality, the evidence supports a role for polyphenols in the prevention of degenerative diseases, particularly cardiovascular diseases and cancers. The antioxidant properties of polyphenols have been widely studied, but it has become clear that the mechanisms of action of polyphenols go beyond the modulation of oxidative stress (71). Whether pro-oxidant, antioxidant or any of the many other biological effects potentially exerted by polyphenols account for or contribute to the health benefits of diets rich in plant-derived foods and beverages remains to be definitively proven (72). Thus, the case for polyphenols as functional food is weak at present.

Antioxidants In the 1970s and 1980s, as the field of free radical biology was unfolding, there were hundreds of papers published demonstrating how oxygen derived free radicals could be damaging to human health (73–76). The field expanded so rapidly that it led to the establishment of dedicated journals such as Free Radical Biology & Medicine in the late 1980s. The academic community quickly turned towards solutions. The result has been a sharp rise in the study of agents that can protect against the detrimental effects of free radicals, i.e. antioxidants (77–80). An antioxidant is a substance that, when present at low concentrations compared to those of an oxidizable substrate, significantly delays or

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prevents oxidation of that substrate. Based on in vitro or biochemical studies, many substances have been suggested to act as antioxidants in vivo, but few have been proved to do so. Antioxidant therapy became the new buzzword of the mid-late 1980s and a quick glace at the literature would provide the impression that there was hardly any aspect of human disease that did not respond to antioxidant therapy in an experimental setting (81–90). While the basic scientists were trying to grasp the delicacies involved in free-radical antioxidant biology in vivo, quite a few clinical trials were launched to test the efficacy of antioxidants in a clinical setting (91). Meaningful clinical trials rely on a comprehensive understanding of the fundamental principles that underlie the practical hypothesis being tested. Clearly, this represented a major weakness in many of the trials testing the efficacy of antioxidants in a clinical setting. The first trial outcomes proved to be disappointing (92). Prospective epidemiological investigations suggested a reduction in cardiovascular risk associated with increased intake of antioxidant vitamins, particularly vitamin E. However, completed randomized trials did not support this finding (93). In general, antioxidants were regarded as being safe (94). That notion quickly changed with the reporting of large, randomized clinical trials testing beta-carotene in primary prevention – no beneficial effect and potential for harm associated with the use of beta-carotene. At the time, inconclusive and insufficient epidemiological and clinical trial data with regard to the role of vitamin C in cardiovascular protection was noted. Caution was issued against the wide-spread use of antioxidant vitamins in cardiovascular protection (95). The antioxidant paradox thus emerged (96). Two important lines of development in the mid-1990s supported the contention that free radical biology was more complex than most imagined. First, that an antioxidant can actually behave like a pro-oxidant depending on the local conditions (97–106). Second, that free radicals and their derivatives could actually serve beneficial physiological functions by acting as a cellular messenger (107,108). A new interdisciplinary field of redox signaling in mammals thus emerged (109–111). Oxidation–reduction (redox) based regulation of signal transduction and gene expression emerged as a fundamental regulatory mechanism in cell biology. Electron flow through side chain functional CH2-SH groups of conserved cysteinyl residues in proteins was noted to account for their redox-sensing properties (109). A new journal Antioxidants & Redox Signaling (www.liebertpub.com/ars) was established to support this novel interdisciplinary specialty. During the last decade over 3000 papers have been published in redox signaling. Although the search for the right antioxidant nutrients for the preservation of human health is still on, it is clear that regulation of tissue redox status may be effectively utilized for therapeutic purposes (112–116). The case for redox-active compounds, including antioxidants, as functional food is moderately strong. Antioxidants such as resveratrol (117,118), curcumin (119– 122) and tocotrienol (123–125) are sharply on the rise. In addition, edible berries show encouraging results (126–128).

Unsaturated Fatty Acids Fish has traditionally been available in regular meals in several Asian (like in Japan and coastal India), European (like in Finland and Norway) and Mediterranean countries

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Micronutrients 19

as also in Greenland and North American native populations. The low incidence of coronary heart diseases in Greenland Eskimos opened the eyes to see the benefits of fish diets and fish oils (129,130). Fish diet diminishes the cardiovascular risk as shown in numerous studies (131,132). n-3 Fatty acids are beneficial for cardiovascular health, reducing platelet aggregation, serum triglyceride levels and the risk of sudden death from myocardial infarction (131–133). Also fresh waster fish available in inland lakes and rivers contain n-3 fatty acids which, according to the current understanding, explain the beneficial effect of fish containing diets (134–136). n-3 Fatty acids from fish oils have been shown to attenuate postprandial hyperlipidemia (137). A combination of physical exercise and n-3 polyunsaturated fatty acids intake is potently helpful (138). n-3 Polyunsaturated fatty acids (PUFA) of marine origin diet limit induced obesity in mice by reducing cellularity of adipose tissue (139). Dietary long chain n-3 polyunsaturated fatty acids prevent sucrose-induced insulin resistance in rats (140). Current Western diet contains high amounts of n-6 polyunsaturated fatty acids which leads to a poor n-3 to n-6 PUFA ratio. Arachidonic acid effectively competes with eicosapentaenoic acid (141). n-3 Series fatty acids are found also in some plant, e.g. flax, lipids (142). Flax lipids represent an important source of -linolenic acid, which the body can use as starting material of eicosanoids, at least in adults. Fish oil capsules are marketed as dietary supplements to prevent cardiovascular diseases.

Micronutrients Micronutrients are nutrients needed for life in small quantities (143–152). They include chemical elements and chemical compounds such as minerals and vitamins. Microminerals or trace elements include at least iron, cobalt, chromium, copper, iodine, manganese, selenium, zinc and molybdenum. They are dietary minerals needed by the human body in very small quantities (generally less than 100 mg/day) as opposed to macrominerals which are required in larger quantities. Note that the use of the term ‘mineral’ here is distinct from the usage in the geological sciences. Vitamins are organic chemicals that a given living organism requires in trace quantities for good health, but which the organism cannot synthesize, and therefore must obtain from its diet. More than two billion people (i.e. one in three persons worldwide) suffer from micronutrient deficiency, a form of malnutrition (http://www.micronutrient.org). The most common deficiencies can have devastating consequences: 1. Vitamin A deficiency: nearly 3 million preschool children in developing countries are blind because of vitamin A deficit 2. Iron-deficiency anemia results in one out of four maternal deaths in the developing world. The cost of fortifying flour with iron is 20 cents (US) per person per year (World Bank estimate) 3. Iodine deficiency is the world’s leading cause of mental retardation – more than 2 billion children suffer from lowered IQ and retardation due to iodine deficiency. The costs of providing iodized salt are estimated at 10 cents per person per year 4. Vitamin E, zinc and manganese deficiencies are also serious causes for concern.

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Micronutrient malnutrition is practically unknown in developed countries owing to inexpensive interventions such as food fortification, supplementation and dietary diversification. South Asia and Sub-Saharan Africa are among the areas with the most affected people.

Plant Sterols High blood cholesterol levels indicate a risk of cardiovascular diseases. Blood cholesterol is either endogenous or exogenous by origin. Blood cholesterol levels are affected by diet and, in particular, by the type and amount of fat intake. Vegan foods are cholesterol free and may reduce the risk of cardiovascular diseases (153). In recent years, vegetable oil spreads containing plant sterols/stanols (as their fatty acid esters) have been developed. Numerous clinical trials on spreads with added plant sterols/ stanols have shown that they have much greater cholesterol-lowering properties than conventional vegetable oil spreads. Plant sterols decrease both dietary and biliary cholesterol absorption in the small intestine, with a consequential increase in excretion of cholesterol (154). Stanol-enriched plant margarines were first marketed in Finland, but they are now stable foods in several countries. In the USA, plant sterols have received GRAS status indicating that they are generally recognized as being safe.

Probiotics Fermented milk products have been used through the ages as staple foods by many nations. In India, cows have a special status in society for their contributions to human health. Previously, most of the milk consumed was fermented for practical reasons as storage possibilities were poor. Fermentation prevents the spoilage by harmful bacteria and prolongs shelf-life of milk products. Lactobacilli play a substantial role in food biotechnology and influence our quality of life by their fermentative and probiotic properties. The normal human microflora is a complex and usually stable ecosystem. The intestinal microflora is important to the host with regard to many metabolic functions and in resistance to bacterial infections. Administration of antimicrobial agents may disrupt the normal microflora, leading to a decrease in colonization resistance and alterations in metabolic activities of the intestinal bacteria. Antimicrobial therapy may also be accompanied by gastrointestinal disturbances and a reduction or elimination of lactobacilli in the intestinal microflora. Lactobacilli are part of the normal gram-positive anerobic microflora. Through the production of lactic and acetic acids, hydrogen peroxide and antimicrobial substances, these microorganisms possibly contribute to the maintenance of colonization resistance. Several studies have indicated a protective effect of lactobacilli against potential pathogens in the gastrointestinal tract. Also several other foods are used after fermentation. The traditional rye bread is a fermentation product. The effect of fermentation on oats and fish is less known, although again previously the fermentation was very common, but very little is known what really happens (155). Fermented fish is still a national tradition in Swedish cuisine.

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Research Needs: Safety and Efficacy 21

There are many research data on fermented foods, especially milk products. They can be also developed further and can be included in daily diets in amounts which probably make the title functional food justified. Tourists travelling to countries with poor hygienic standards are recommended to take lactobacillius preparations with them.

Research Needs: Safety and Efficacy First and foremost, safety, short-term as well as long-term, of dietary supplements and functional foods must be established in preclinical and clinical settings (156–160). In the USA, the Food and Drug Administration (FDA) regulates dietary supplements under a different set of regulations than those covering ‘conventional’ foods and drug products (prescription and over-the-counter). Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), the dietary supplement manufacturer is responsible for ensuring that a dietary supplement is safe before it is marketed. FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market. Generally, manufacturers do not need to register their products with the FDA nor get FDA approval before producing or selling dietary supplements. Manufacturers must make sure that product label information is truthful and not misleading. FDA’s post-marketing responsibilities include monitoring safety, e.g. voluntary dietary supplement adverse event reporting and product information, such as labeling, claims, package inserts and accompanying literature. The Federal Trade Commission regulates dietary supplement advertising. If award of functional food status to specific dietary components is to follow the same level of rigor that new medical drugs are subjected to, it is clear that a lot more appropriately controlled human studies are required. However, it is important to appreciate that double blind intervention trials are challenging to execute given their obvious differences in visual presentation. Epidemiological studies have shown that the Adventists have significantly lower health risks than the other Americans as a number of items of their diet are different (161). The duration of the studies must be long enough and also the populations large enough to power the study appropriately. The food must also contain the study component in such quantities that are relevant to real life, but also to given measurable effects in the markers selected. These studies should be conducted in different cultural settings as the chemical environments (matrixes) are important for dietary chemicals to reveal their properties. The studies should account for physical activity state of the subjects because dietary outcomes are clearly linked to such states. The background pathophysiology of the metabolic syndrome is probably due to glucotoxicity and lipotoxicity, i.e. the fluctuation of the blood levels which causes a strain to the endocrine system, especially on the secretion of insulin from the pancreas. Glucose and fatty acid metabolism are interlinked at several regulatory levels (8). Health claims of foods should be supported by appropriate and acceptable research results. There are opinions that this evidence should be as rigorous as in the case of drugs. This level may be difficult to achieve as foods are mixtures of known and unknown chemicals and all foods are eaten as a part of the wholeness, which is difficult to describe completely. The combination of traditional

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experiences and research results will lead to the development of healthy foods and new preventive and perhaps therapeutic approaches.

Dietary Supplement Health and Education Act (DSHEA) The Food and Drug Administration receives many questions about the labeling of dietary supplements. These questions are a consequence of the activity in this area over the past several years. Some of the important events relating to the labeling of dietary supplements include: 1. The Nutrition Labeling and Education Act of 1990 amended the Federal Food, Drug, and Cosmetic Act (the act) in a number of important ways. Notably, by requiring that most foods, including dietary supplements, bear nutrition labeling. 2. The Dietary Supplement Health and Education Act of 1994 (the DSHEA) amended the act, in part, by defining ‘dietary supplements’ adding specific labeling requirements for dietary supplements, and providing for optional labeling statements. 3. On September 23, 1997 (62 FR 49826), FDA implemented the DSHEA by publishing several key regulations on the statement of identity, nutrition labeling, ingredient labeling and nutrient content and health claims for dietary supplements. On June 5, 1998 (63 FR 30615), FDA amended the regulations pertaining to the nutrition labeling of extracts used in dietary supplements. 4. On January 15, 1997 (62 FR 2218), FDA published regulations that require a label warning statement on dietary supplements with added iron. These regulations also required the unit-dose packaging of supplements containing 30 milligrams or more, but this requirement has been eliminated as a result of a court challenge in January, 2003. 5. On July 11, 2003 (68 FR 41434), FDA published a final regulation that amended the labeling requirements for dietary supplements, as well as for conventional foods, that would make the declaration of trans fat mandatory in nutrition labeling. This regulation requires that, when present at 0.5 g or more, trans fat be listed in the Supplement Facts panel of dietary supplements on a separate line under the listing of saturated fat by January 1, 2006. FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word ‘should’ in agency guidances means that something is suggested or recommended, but not required. Americans spent $6.5 billion on dietary supplements in 1996, nearly doubling the 1990 total of $3.2 billion. This booming industry, which consists largely of natural health products, is attracting significant attention of the FDA and the medical community. The key questions that arise in this context are whether this is a legitimate

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Codex: Harmonizing Food and Supplement Rules Between all Nations of the World 23

effort by the FDA and the medical community to protect the health and safety of the public. Skeptics argue that this is a concerted effort by the FDA and medical community to protect the financial interests of the pharmaceutical drug industry and the medical community. Both sides have a point making this an interesting debate. Billions of dollars spent on supplements would otherwise be spent on drugs and doctors. The FDA is now considering changes to dietary supplement labeling for the purpose of ‘clarifying for manufacturers what types of claims they may and may not use on labels of dietary supplements under the Dietary Supplement Health and Education Act (DHSEA; Public Law 103–417, 103rd Congress; http://www.fda.gov/ opacom/laws/dshea.html) of 1994’ according to the FDA (April 27, 1998 fact sheet). The DHSEA established the framework for FDA regulation of supplements and it gave dietary supplement manufacturers more freedom to market products and provide information to consumers than they had previously. This freedom, in large part, is the reason that supplement sales have increased dramatically in the past few years.

Codex: Harmonizing Food and Supplement Rules Between all Nations of the World The biggest movement to develop harmonized or uniform health food standards is the Rome-based Codex Alimentarius (‘food code’) Commission (Codex), which was created in 1962 by two United Nations (UN) organizations, the Food and Agriculture Organization (FAO) and the World Health Organization (WHO). The goal was to design Codex as an ‘international mechanism for promoting the health and economic interests of consumers while encouraging fair international trade in food’, according to the US Codex Office. Codex is composed of more than 150 member countries and international organizations that meet and exchange information and ideas related to food safety and trade issues. Its members are also members of FAO and WHO and represent 98 percent of the world’s population, according to the FAO. Simply stated, the Codex Alimentarius is a collection of standards, codes of practice, guidelines and other recommendations. Some of these texts are very general and some are very specific. Some deal with detailed requirements related to a food or group of foods; others deal with the operation and management of production processes or the operation of government regulatory systems for food safety and consumer protection. The Codex Alimentarius, or the food code, has become the global reference point for consumers, food producers and processors, national food control agencies and the international food trade. The code has had an enormous impact on the thinking of food producers and processors as well as on the awareness of the end users – the consumers. Its influence extends to every continent and its contribution to the protection of public health and fair practices in the food trade is immeasurable. The Codex Alimentarius system presents a unique opportunity for all countries to join the international community in formulating and harmonizing food standards and ensuring their global implementation. It also allows them a role in the development of codes governing hygienic processing practices and recommendations relating to compliance with those standards. The significance of the food code for consumer

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health protection was underscored in 1985 by the United Nations Resolution 39/248, whereby guidelines were adopted for use in the elaboration and reinforcement of consumer protection policies. The guidelines advise that ‘When formulating national policies and plans with regard to food, Governments should take into account the need of all consumers for food security and should support and, as far as possible, adopt standards from the…Codex Alimentarius or, in their absence, other generally accepted international food standards’. Currently, Codex Alimentarius contains more than 200 standards, covering such issues as labeling, additives, methods of analysis and sampling, food import and export inspection and certification, pesticides in foods and contaminants. The code also deals with nutrition and foods for special dietary uses, which includes dietary supplements. The Commission for Nutrition and Foods for Special Dietary Uses (CNFSDU) of Codex, hosted by Germany, is charged with the following responsibilities: 1. to study specific nutritional problems assigned to it by the Commission and advise the Commission on general nutrition issues 2. to draft general provisions, as appropriate, concerning the nutritional aspects of all foods 3. to develop standards, guidelines or related texts for foods for special dietary uses, in cooperation with other committees where necessary; and, 4. to consider, amend if necessary, and endorse provisions on nutritional aspects proposed for inclusion Codex standards, guidelines and related texts. It does not address the broad category of dietary supplements, which includes herbals, amino acids, concentrates, metabolites and many other non-essential nutrients. In the early 1990s, the Codex Committee on Nutrition and Foods for Special Dietary Uses (CCNFSDU) began discussions on guidelines for vitamin and mineral supplements. At the 26th CCNFSDU session (Bonn, November 1–5, 2004), the Committee completed work on Draft Guidelines for Vitamin and Mineral Food Supplements and submitted them for adoption by the Codex Alimentarius Commission (CAC). The Guidelines were adopted at the 28th CAC Session that was held in Rome on July 4–9, 2005. The Guidelines apply only to supplements that contain vitamins and/or minerals, where these products are regulated as foods. The Guidelines address the composition of vitamin and mineral supplements, including the safety, purity and bioavailability of the sources of vitamins and minerals. The Guidelines do not specify upper limits for vitamins and minerals in supplements. Instead, they provide criteria for establishing maximum amounts of vitamins and minerals per daily portion of supplement consumed, as recommended by the manufacturer. The criteria specify that maximum amounts should be established by scientific risk assessment based on generally accepted scientific data and taking into consideration, as appropriate, the varying degrees of sensitivity of different consumer groups. The Guidelines also address the packaging and labeling of vitamin and mineral supplements. The US government has published its position (http://www.cfsan.fda.gov/~dms/dscodex.html). The USA supports consumer choice and access to dietary supplements that are safe and labeled in a truthful and non-misleading manner. The Dietary Supplement Health and Education

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International Alliance of Dietary Food Supplement Associations (IADSA) 25

Act of 1994 (DSHEA) ensures that a broad array of dietary supplements are available to US consumers. The Codex Guidelines for Vitamin and Mineral Food Supplements do not, in any way, affect the availability of supplement products to US consumers. On the contrary, the absence of science-based Codex guidelines could adversely affect the ability of US manufacturers to compete in the international marketplace. In its present form, it is clear that Codex Alimentarius falls much short of the global governance needed to regulate the marketing and consumption of dietary supplements. Individual countries such as Japan seem to be much ahead of the rest of the world. In 1991, the Japanese Ministry of Health and Welfare (MHW) established the FOSHU labeling regulation. It was implemented by adding a new category of FOSHU to ‘Foods for Special Dietary Uses’ in the Nutrition Improvement Law. The word ‘functional’, however, was not used since it appears in the definition of ‘pharmaceuticals’ where things intended to affect the structure or functions of the body are described as pharmaceuticals. FOSHU approval by the MHW is a permission system for labeling to claim that a food helps maintain or is suitable for a health condition, when the claim is substantiated based on medical and nutritional science. Therefore, scientific documents are required to obtain FOSHU approval, namely clinical and nutritional documentation demonstrating the health efficacy of the food or the ingredient, clinical and nutritional evidence on dietary intake, validation of safety and stability, and analytical methods and the results for identification. In the beginning not many industries were interested in FOSHU because of these burdens. But, in recent years, MHW took deregulation measures to encourage industries and so the FOSHU market has been expanding. From December 1999, the total number of approved FOSHU was 171. According to a survey, total FOSHU sales were around 130 billion yen in 1997, but it increased to 220 billion yen in 1999. Originally, foods that have the function to modulate the body function that contribute to the prevention of a disease were called ‘Functional Foods’. However, it is now widely understood to mean foods that claim such biological effects beyond ordinary nutritional effects based on scientific validation. In Japan, there are a variety of so-called health foods. Whether they are functional foods or not should be judged one by one from the above viewpoint. Among them, vitamins and minerals have been paid special attention as so-called dietary supplements. Although many scientific papers report on their functionality, there may be some controversy over whether they can be called functional foods when the form of the product is an important element of the definition of ‘functional foods’ because dietary supplements are usually recognized in the form of tablets or capsules. In 1999, the market size of health foods was approximately 750 billion yen. The momentum in Japan seems to be in the right direction providing the rest of the world with an opportune platform for further development.

International Alliance of Dietary Food Supplement Associations (IADSA) Since its creation in 1998, IADSA has developed into an alliance of more than 50 dietary supplement associations spread over 6 continents. There are at present more

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than 9500 companies who are part of the IADSA member associations. The efficacy of IADSA as an organization is based on its ability to communicate information and ideas around the globe to regulators, consumer organizations, scientific bodies and national associations and companies. The 2007 report on nutrition, healthy aging and public policy has been recently released (162). An IADSA workshop on International Perspectives on Dietary Supplements Regulation was held in Yokohama, Japan on April 17, 2007. Nearly 300 delegates, including regulators and government officials from the Association of South East Asian Nations (ASEAN), China, the European Union (EU), Japan, Mexico and the USA, scientific bodies, trade associations and industry attended the workshop. In the final session Dr Yozo Hayashi, Director General, The Japan Health Food & Nutrition Food Association and Dr Tohru Inoue from the Biological Safety Research Center of The Japanese National Institute of Health Sciences shared with delegates the conclusions they had drawn on the development of global regulation for food products and their vision of the future application and benefits of food supplements and functional foods. In his concluding remarks, IADSA Chairman Randy Dennin said that: ‘The Workshop demonstrated that while there continue to be many different approaches to regulating dietary supplements, the principles that form the basis of these are increasingly consistent throughout the world. IADSA will build on this global workshop with increased dialogue to encourage further detailed discussions at national levels’. The major activities of IADSA include: 1. providing a fast flow of regulatory and policy information on dietary supplements, ensuring that there is an awareness and understanding of new developments 2. coordinating strategy and action on global regulatory issues, particularly in relation to Codex Alimentarius initiatives on vitamin and mineral supplements, additives and health claims 3. widening and deepening the network of associations around the world by helping the establishment of new dietary supplement associations and supporting existing national associations; and 4. organizing global and regional events to promote dialogue on the scientific and regulatory issues underpinning the dietary supplement market. Decisions and policies from global regulatory bodies have become increasingly influential for dietary supplement companies. Such bodies include Codex Alimentarius, the World Health Organization (WHO) and the Food and Agriculture Organization (FAO). IADSA works closely with these international bodies to ensure that the views of the dietary supplement industry are taken into account in the development of policy.

Acknowledgment Supported in part by NIH grant NS42617 to CKS.

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References 27

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117. Athar M, Back JH, Tang X et al. (2007). Resveratrol: A review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol. 118. Holme AL, Pervaiz S. (2007). Resveratrol in cell fate decisions. J Bioenerg Biomembr. 119. Campbell FC, Collett GP. (2005). Chemopreventive properties of curcumin. Future Oncol 1, 405–414. 120. Maheshwari RK, Singh AK, Gaddipati J, Srimal RC. (2006). Multiple biological activities of curcumin: a short review. Life Sci 78, 2081–2087. 121. Singh S, Khar A. (2006). Biological effects of curcumin and its role in cancer chemoprevention and therapy. Anticancer Agents Med Chem 6, 259–270. 122. Thangapazham RL, Sharma A, Maheshwari RK. (2006). Multiple molecular targets in cancer chemoprevention by curcumin. Aaps J 8, E443–E449. 123. Packer L, Weber SU, Rimbach G. (2001). Molecular aspects of alpha-tocotrienol antioxidant action and cell signaling. J Nutr 131, 369S–373S. 124. Sen CK, Khanna S, Roy S. (2004). Tocotrienol: the natural vitamin E to defend the nervous system? Ann NY Acad Sci 1031, 127–142. 125. Theriault A, Chao JT, Wang Q, Gapor A, Adeli K. (1999). Tocotrienol: a review of its therapeutic potential. Clin Biochem 32, 309–319. 126. Erlund I, Freese R, Marniemi J, Hakala P, Alfthan G. (2006). Bioavailability of quercetin from berries and the diet. Nutr Cancer 54, 13–17. 127. Freese R. (2006). Markers of oxidative DNA damage in human interventions with fruit and berries. Nutr Cancer 54, 143–147. 128. Juranic Z, Zizak Z. (2005). Biological activities of berries: from antioxidant capacity to anti-cancer effects. Biofactors 23, 207–211. 129. Dyerberg J. (1989). Coronary heart disease in Greenland Inuit: a paradox. Implications for western diet patterns. Arctic Med Res 48, 47–54. 130. Jorgensen KA, Hoj Nielsen A, Dyerberg J. (1986). Hemostatic factors and renin in Greenland Eskimos on a high eicosapentaenoic acid intake. Results of the Fifth UmanaK Expedition. Acta Med Scand 219, 473–479. 131. Kris-Etherton PM, Harris WS, Appel LJ. (2003). Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol 23, E20–E30. 132. Wang C, Harris WS, Chung M et al. (2006). n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 84, 5–17. 133. Sands SA, Reid KJ, Windsor SL, Harris WS. (2005). The impact of age, body mass index, and fish intake on the EPA and DHA content of human erythrocytes. Lipids 40, 343–347. 134. Agren JJ, Hanninen OO. (1991). Effect of moderate freshwater fish diet on erythrocyte ghost phospholipid fatty acids. Ann Med 23, 261–263. 135. Sen CK, Atalay M, Agren J, Laaksonen DE, Roy S, Hanninen O. (1997). Fish oil and vitamin E supplementation in oxidative stress at rest and after physical exercise. J Appl Physiol 83, 189–195. 136. Vidgren HM, Agren JJ, Schwab U, Rissanen T, Hanninen O, Uusitupa MI. (1997). Incorporation of n-3 fatty acids into plasma lipid fractions, and erythrocyte

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membranes and platelets during dietary supplementation with fish, fish oil, and docosahexaenoic acid-rich oil among healthy young men. Lipids 32, 697–705. Agren JJ, Hanninen O, Julkunen A et al. (1996). Fish diet, fish oil and docosahexaenoic acid rich oil lower fasting and postprandial plasma lipid levels. Eur J Clin Nutr 50, 765–771. Smith BK, Sun GY, Donahue OM, Thomas TR. (2004). Exercise plus n-3 fatty acids: additive effect on postprandial lipemia. Metabolism 53, 1365–1371. Ruzickova J, Rossmeisl M, Prazak T et al. (2004). Omega-3 PUFA of marine origin limit diet-induced obesity in mice by reducing cellularity of adipose tissue. Lipids 39, 1177–1185. Ghafoorunissa, Ibrahim A, Rajkumar L, Acharya V. (2005). Dietary (n-3) long chain polyunsaturated fatty acids prevent sucrose-induced insulin resistance in rats. J Nutr 135, 2634–2638. Whelan J, Li B, Birdwell C. (1997). Dietary arachidonic acid increases eicosanoid production in the presence of equal amounts of dietary eicosapentaenoic acid. Adv Exp Med Biol 400B, 897–904. Schuman BE, Squires EJ, Leeson S. (2000). Effect of dietary flaxseed, flax oil and n-3 fatty acid supplement on hepatic and plasma characteristics relevant to fatty liver haemorrhagic syndrome in laying hens. Br Poult Sci 41, 465–472. Drain PK, Kupka R, Mugusi F, Fawzi WW. (2007). Micronutrients in HIV-positive persons receiving highly active antiretroviral therapy. Am J Clin Nutr 85, 333–345. Karp SM, Koch TR. (2006). Mechanisms of micronutrient deficiency. Dis Mon 52, 208–210. Neumann CG. (2007). Symposium: food-based approaches to combating micronutrient deficiencies in children of developing countries. Background. J Nutr 137, 1091–1092. Rennie KL, Livingstone MB. (2007a). Associations between dietary added sugar intake and micronutrient intake: a systematic review. Br J Nutr 97, 832–841. Rennie KL, Livingstone MB. (2007b). Systematic review: associations between dietary added sugar intake and micronutrient intake. Br J Nutr,, 1–10. Shenkin A. (2006). The key role of micronutrients. Clin Nutr 25, 1–13. Shenkin A. (2006). Micronutrients in health and disease. Postgrad Med J 82, 559–567. Visioli F, Hagen TM. (2007). Nutritional strategies for healthy cardiovascular aging: focus on micronutrients. Pharmacol Res 55, 199–206. Volpe SL. (2007). Micronutrient requirements for athletes. Clin Sports Med 26, 119–130. Webb P, Nishida C, Darnton-Hill I. (2007). Age and gender as factors in the distribution of global micronutrient deficiencies. Nutr Rev 65, 233–245. Key TJ, Appleby PN, Rosell MS. (2006). Health effects of vegetarian and vegan diets. Proc Nutr Soc 65, 35–41. John S, Sorokin AV, Thompson PD. (2007). Phytosterols and vascular disease. Curr Opin Lipidol 18, 35–40. Darbre A, Norris FW. (1956). Vitamins in germination; determination of free and combined inositol in germinating oats. Biochem J 64, 441–446.

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156. Gardiner P. (2005). Dietary supplement use in children: concerns of efficacy and safety. Am Fam Physician 71, 1068–1071. 157. Knight J. (2004). Safety concerns prompt US ban on dietary supplement. Nature 427, 90. 158. Morrow JD, Edeki TI, El Mouelhi M et al. (2005). American Society for Clinical Pharmacology and Therapeutics position statement on dietary supplement safety and regulation. Clin Pharmacol Ther 77, 113–122. 159. Yen PK. (2005). Food and supplement safety. Geriatr Nurs 26, 279–280. 160. Ziker D. (2005). What lies beneath: an examination of the underpinnings of dietary supplement safety regulation. Am J Law Med 31, 269–284. 161. Melby CL, Toohey ML, Cebrick J. (1994). Blood pressure and blood lipids among vegetarian, semivegetarian, and nonvegetarian African Americans. Am J Clin Nutr 59, 103–109. 162. Richardon DP, Group IS. (2007). Nutrition, health ageing and public policy. Brussels: International Alliance of Dietary Food Supplement Associations (IADSA), pp. 1–71. 163. Kauhanen J, Myllykangas M, Salonen JT, Nissinen A. (1998). Kansanterveystiede, 2nd edn. Porvoo: WSOY.

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Regulatory Hurdles for Marketing 3 New Dietary Ingredient Submissions: A Review of Past and Present 4 Marketing Dietary Supplements and Functional Foods in the USA: The Federal Trade Commission’s Advertising Substantiation Requirements

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PART

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New Dietary Ingredient Submissions: A Review of Past and Present

3

Chris Noonan MPH1 and W. Patrick Noonan J.D., RPH.2 1

Health Guidance LLC, Santa Monica, CA, USA

2

W. Patrick Noonan, A Professional Corporation, Woodland Hills, CA, USA

Abstract Anyone introducing a New Dietary Ingredient (NDI) into United States (US) commerce which has not been marketed in the US prior to October 15, 1994 must present to the Food and Drug Administration (FDA) a new dietary ingredient submission for safety 75 days prior to marketing. However, after almost fourteen years since this requirement became law, the percentage of New Dietary Ingredient (NDI) submissions admitted without further question is less than 30%. These dismal statistics can be attributed to both a failure of marketers and manufacturers to acknowledge the stringent requirements for safety and the FDA’s failure to clarify their definition of ‘a reasonable basis for safety’. This article reviews the common reasons for rejection and discusses some tactics to help improve the chances for a successful new dietary ingredient submission.

Introduction Almost fourteen years after the passage of the Dietary Supplement Health and Education Act (DSHEA), the dietary supplement industry has expanded beyond expectation. New products are introduced at a dizzying pace while new ingredients find their way into all kinds of product forms. Dietary ingredients are now within reach of most US consumers, eager to enjoy the health benefits afforded by the assortment of ‘functional’ foods lining retain shelves. With this expanding presence, the issue of safety has become more paramount. The Food and Drug Administration (FDA) has in place a safety review system for every new dietary ingredient before Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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40 New Dietary Ingredient Submissions: A Review of Past and Present

it enters the market, however, very few ingredients make it through the process successfully. There currently exists a fundamental disconnect between FDA and industry expectations on how to qualify safety for dietary ingredients. To ensure the continued safety for the consuming public, the question on how to fix this disconnect must be quickly addressed. Every new dietary ingredient introduced into US commerce after October 15, 1994 must comply with the requirements set forth in Section 413 of the Federal Food, Drug and Cosmetic Act (FDC Act) 21 U.S.C. 350 b(a) (FDA’s regulations at part 190, subpart B [21 CFR part 190, subpart B] implement these statutory provisions). These regulations were designed to assure the safety of new dietary ingredients by allowing FDA to review the basis on which a ‘manufacturer or distributor of a dietary supplement containing a new dietary ingredient… present the basis for their conclusion that said supplement or ingredient will reasonably be expected to be safe’ (Section 190.6(a)). On the surface, this requirement seems fairly straightforward, but the failure of most new dietary ingredient submissions is testament that the requirements are anything but transparent. Some would argue that the process requires too much evidence for safety. Others would contend that the process is a moving target, with FDA using ‘phantom’ criteria in order to evaluate safety. These and similar observations are understandable given the number of rejections that have occurred since 1994. It is readily apparent from the previous submissions that the process itself is not working according to the original intent when written into DSHEA. Instead of assessing new dietary ingredients for ‘a reasonable basis of safety’, FDA seems intent on creating a new standard equal to or surpassing the current GRAS (generally recognized as safe) food standard. While FDA disagrees with this assessment, not many who have been through the process would side with the agency.

New Dietary Ingredients (NDI) The procedural requirements for any new dietary ingredient submission can be found in 21 CFR 190.6. These are: 1. 2. 3. 4.

name and address of manufacturer or distributor of the new dietary ingredient name of the NDI description of the NDI including a full characterization of the ingredient level of NDI in dietary supplements which would include the amount included in dosage form products and expected daily consumption 5. conditions of use recommended in product labeling which includes the labeled suggested population for the ingredient and, most importantly 6. evidence proving the ingredient is safe. Since 1994, there have been roughly 430 new dietary ingredient submissions presented to the Food and Drug Administration1, based on a review of submissions to date (Tables 3.1–3.3). Some common reasons for refusal include: 1. Safety concerns 2. Incomplete

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New Dietary Ingredients 41

Table 3.1 All NDI’s submitted between Oct 1994–Oct 2007 Total New Dietary Submissions

443

100%

Accepted Rejected

130 313

29% 71%

Table 3.2 Botanical NDI’s submitted between Oct 1994–Oct 2007 NDI’s for Botonical

223

Accepted Rejected

51 172

23% 77%

Table 3.3 Non-Botanical NDI’s submitted between Oct 1994–Oct 2007 NDI’s for Non-Botanicals

220

Accepted Rejected

79 141

39% 61%

3. Significant safety concerns 4. Not a dietary supplement 5. Presence of an existing Investigational New Drug (IND). NOTE: Frequently, the FDA will refuse NDI’s on insufficient safety and also include other reasons why the NDI in question does not qualify.

Analysis Based on the last thirteen years of new dietary ingredient submissions, approximately 7 out of every 10 are refused. One would expect over time the number of submissions admitted without question would increase. Just the opposite has occurred. Since 2002, nearly 8 of every 10 submissions are refused indicating a downward trend for successful submissions. Both safety concerns and incomplete filings are the predominant reasons for rejection. In terms of safety, failure to adequately identify the ingredient, manufacturing process, or present data which supports safety of the ingredient at the dosage included in the submission are the predominant reasons for rejection. Many NDI’s are re-submitted after the FDA concerns are addressed, sometimes more than twice. This tactic has become increasingly common, including contacting FDA to discuss their various concerns and how best to address them. In many cases, NDI submissions will include complex analytical data which can be misinterpreted or overlooked by FDA personnel, particularly in the are a of analytical methods for producing the NDI in question. Getting through to the right FDA personnel has remained a significant obstacle for submitters. The most common reasons given by FDA for refusal of a NDI submission include: Failure to comply with the requirements of 190.6 (incomplete submission): there is simply no legitimate reason for failing to comply with the basic requirements of the

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NDI process. Littered in FDA’s database are submissions that were declared ‘incomplete’, rejected for reasons such as failing to include English translations of scientific literature, including ‘legible’ photostatic copies of original material used as evidence for the safety of the new ingredient, failing to submit an original plus two copies of the submission, or other careless missed procedural requirements. A careful review of your material prior to submission should address any procedural omissions that will result in rejection and a significant delay in obtaining FDA determination of the safety of the ingredient. Failure to define adequately your ingredient: it is imperative that the submitter recognize the level of detail expected by FDA in each submission. The ingredient included as part of the submission must be identified clearly; for a botanical, the proper Latin nomenclature must be included; for a nutrient (non-botanical), the correct (and complete) chemical description must be included. Failure to comply with this requirement will result in an ‘incomplete’ designation for the submission. Filing a submission for a product, not an ingredient: the requirements included as part of Section 413 of the FDC Act does not require product approval— only ingredient approval. Many refused NDI submissions have erroneously included product information for a product which contains many different ingredients. If the product includes more than one ingredient that is subject to the new dietary ingredient regulations, each ingredient should be treated as a ‘distinct’ submission. Given the scrutiny with which FDA analyzes each ingredient, including multiple ingredients as part of a product approval will certainly result in a rejection. Among those NDI submissions that followed the correct procedural format but were still refused, some not-so-common reasons are presented: Not a dietary ingredient: this has been a contentious issue in the last 3 years as many NDI submissions have included very novel ingredients. The legal definition of a dietary ingredient includes: 1. 2. 3. 4. 5.

a vitamin a mineral a herb or other botanical an amino acid a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or 6. a concentrate, metabolite, constituent, extract or combination of any ingredient described above (1). FDA has stated in informal guidance that dietary substance can be defined as ‘substances customarily used as human food or drink’(2). Ingredients more commonly rejected as not meeting the definition of a dietary substance include some extracts from trees, some amino acid derivatives, hormones and synthetic substances. In certain instances, FDA has responded with no question on the safety of the ingredient but contends the ingredient itself is not a dietary ingredient. In such cases, it is the decision of the submitter whether or not to proceed to market even though FDA has not granted its ‘no questions at this time’ acknowledgment.

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New Dietary Ingredients (NDI) 43

Inadequate characterization of ingredient: beyond the basic mistake of incorrectly labeling your ingredient, many submitters have been rejected because the ingredient included as part of the submission incorporated components that were not identified. In a submission posted in December of 2004 (3), the FDA rejected the submission because there was 1% of the composition not identified. In a recent submission for a well known ingredient, FDA raised objection to a subtle component of the ingredient, stating ‘it is unclear how the…components of your ingredient are qualitatively or quantitatively similar to the substances described in the safety information you relied on in your notification or how that information is relevant to evaluating the safe use of the substance included in this submission’ (4). According to informal guidance from FDA in various responses to NDI submissions, a notification must contain information on the actual preparation, composition, product specification, methods of analysis and purity of the ingredient when extracted from its source. Otherwise, FDA will consider the information inadequate to characterize and identify the specific new dietary ingredient included in the submission. Some submissions have omitted data necessary for sufficient characterization of safety because the submitter considered the data to be confidential. Any data submitted with an NDI submission can be kept confidential. Simply inform FDA of the content that is considered confidential and it will not be posted for public viewing. Existence of a published investigational new drug: the FDC Act definition of a dietary supplement, as a matter of law, excludes any dietary ingredient that was approved as a new drug before the marketing of an NDI ingredient (5). The presence of an FDAapproved IND application plus a published clinical study that occurred before marketing of the ingredient in question precludes that ingredient from being a dietary ingredient. This is sometimes referred to as the ‘race to market’ provision. FDA also asserts that it is not relevant in this determination if the IND is currently in force; only that it was filed and accepted by FDA at some time prior to the marketing of the NDI in question. Evidence for safety does not demonstrate safety of ingredient at the level to be used in US commerce: if clinical evidence is presented in support of the safety of the ingredient, ensure that safety measurements were included in the clinical study. A clinical trial without safety assessment does not fortify a submission. The ‘absence of side effects’ without measurement is not a qualification of safety for an ingredient. If safety data are included, all information must be verifiable by a biostatistician. If evidence is presented (e.g. epidemiological data) that shows a different dosage than included as part of the submission, FDA can object on the basis that the data demonstrate safety at a dosage much higher (or lower) than the dosage included in the NDI. Clinical trials can be great marketing tools but not necessarily sufficient for the NDI process unless a safety evaluation has been included in the trial and the trial was conducted on the same ingredient presented in the submission.

Preparation for Filing Despite the many details that must be in place in order to receive a favorable review, there are standard practices that can tip the odds in your favor before submitting an NDI.

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1. Conduct an audit of your ingredient prior to submission: identify any information about your new dietary ingredient that creates ambiguity and either clarify or eliminate it from the submission. Any questions you have about the data will certainly be raised by FDA. Omission of data that demonstrate your ingredient may be unsafe is against the law (6), but data that are included because they ‘may’ help support the safety profile is not a good idea. Many NDIs have been rejected because the data included to prove safety raised more questions than they answered. Another method is to prepare the entire submission and then submit to your legal counsel or other expert in the submission process. This will provide critical feedback that can significantly increase the chances of a successful filing. Having a third party or ‘editor’ review the submission helps identify weaknesses. 2. Clearly identify your new ingredient: identify the source of your ingredient clearly; it makes a difference whether the ingredient is from stems, roots, or leaves, (or other). For example, if a notification for a new botanical ingredient does not address the source of the plant material, parts of the plants used, harvesting, or handling of material prior to extraction, it will most likely be rejected. In addition, clearly describe every step of the manufacturing process from harvest (or extraction) to finished product. A description of the method of manufacture or process of obtaining an ingredient helps FDA clearly identify the ingredient and ensure it is the same as the ingredient you intend to market. It is imperative that you clearly identify all steps from harvest to finished product. If the ingredient in question is not a botanical, ensure that 100% of the ingredient is accounted for in the description and safety data. Even inert ingredients must be identified and explained. As previously mentioned, less than 1% of the ingredient left identified can be reason for rejection. 3. Establish a clear connection between any clinical or safety data and your ingredient: many objections are raised by FDA when the ingredient included as part of the submission cannot be clearly identified in the safety evidence included with the submission. The methods of any study should identify the ingredient(s) and dosage just as you have identified your ingredient. If there are differences, you must account for them. For example, if you submit a clinical study demonstrating safety, but the product used in the study is referred to by a different name (but is identical to your ingredient), you must establish the similarity. This may require written testimony from the author of the study that the ‘product X used in their study is identical to product Y included as part of this submission’. In other words, don’t consider any discrepancy as trivial – over explain the connection if in doubt. 4. If your NDI is identical to a previous NDI that was approved, you must prove it: every NDI submission is unique to the submitter, which requires one to convince FDA that the ingredient is safe based on the safety data included as part of the submission. One cannot rely on a previously successful submission as evidence of safety. FDA expects the submitter to qualify and quantify clearly the ingredient included as part of the submission and demonstrate how that ingredient is similar to the ingredient subject to a previously successful submission (if indeed your intention is to prove similarity).

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References 45

5. Again, the regulation at 21 CFR 190.6 is for a new ‘dietary ingredient’, not a new ‘dietary supplement product’. If you plan to submit an application for a multi-ingredient composition, you must qualify each dietary ingredient separately. For example, if your formula has three different ingredients, think of the submission as three separate submissions, one for each ingredient. In November 2004, the FDA published a guidance document (7) which announced the agency’s intention of enforcing the requirements for new dietary ingredients, including enforcement actions against companies marketing a dietary ingredient for which no NDI was filed. Since the public meeting held in October of 2004, no explicit actions have been taken on behalf of FDA. However, in April of 2008 FDA instructed US Marshalls to seize more than $1.3 million of dietary supplements on the grounds the supplements failed to comply with the requirements for new dietary ingredients. (11) The supplements seized contained possibly dangerous ingredients, but the FDA action is proof the agency can use the NDI provision as the basis for enforcement discretion at any time. In 2007, FDA stated its intention to issue guidance meant to clarify the submission process for NDI’s. This guidance document never materialized. To date, the best strategy for anyone interested in entering US commerce with a new dietary ingredient is to carefully evaluate the merits of your ingredient well before the submission is prepared and certainly before going to market.

Conclusion When the new dietary ingredient notification requirements were originally published as part of DSHEA, it was thought the process itself was little more than a simple safety review. The reality is the process is more akin to a certification rather than a notification. Submitters are asked to qualify every aspect of the new ingredient without leaving any ambiguity. Careful preparation is required. Reviewing past NDI submissions can provide some insight on how to avoid mistakes. (12) In many of the past NDI’s, FDA has provided some guidance on the criteria needed for qualifying safety. A careful evaluation of ingredient data strengths and weaknesses is also necessary to increase the odds for a favorable review. The process itself should not be considered as just a stepping stone on the way to market. Strategic evaluation of the ingredient well before entering the market can alert you to the short-comings of the data to support safety and provide the opportunity to address these issues well before entering the market. It is prohibited to market a new dietary ingredient in U.S. interstate commerce that has not been evaluated for safety by the FDA. (13) While the FDA has not taken significant steps to remove unapproved NDI’s from commerce, an unfavorable event occurring as a result of a safety issue for an unapproved ingredient would be catastrophic. Whether future FDA guidance provides better clarification on the NDI process is anybody’s guess, but given that almost all new dietary ingredients are now subject to the NDI process, a thorough understanding of the requirements should be part of any premarket strategy.

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Note 1

There were 443 NDI’s submitted as of 10/1/07 based on a review of all paper filings at FDA’s docket division in. After some early indecision, the FDA now designates each NDI submission with a ‘RPT’ plus numeral designation (except the first two). Some submissions are resubmissions and others should not have been granted a unique RPT number. Based on a lack of standardized recordkeeping system, there may be some variance of the true success/failure of NDI submissions.

References 1. 21 U.S.C. 350 b(a)(21 CFR part 190, Subpart B) implement these statutory provisions. 2. 21 CFR §190.6(a). 3. See Section 201(ff)(1) of the FDC Act. 4. FDA, Department of Health & Human Services, Warning Letter to Blue Light Inc, Ithaca, NY. December 18, 2000. 5. Letter from Susan J. Walker, M.D., Office of Nutritional Products, Labeling and Dietary Supplements addressed to Collier, Shannon, Scott PLLC, regarding NDI submission for ‘spermidine trihydrochloride’, April 15, 2005 (See RPT 269). 6. Letter from Linda S. Pellacore, PhD., Office of Nutritional Products, Labeling and Dietary Supplements addressed to Egil Nilsen, Natural ASA, regarding NDI submission for ‘Omega 3 Phospholipids’, Aug 4, 2006 (See RPT 354). 7. See Section 201ff(3)(b) of the FDC Act. 8. 62 Fed Reg. 49889 Sept 23, 1997. 9. CFSAN, Office of Nutritional Products, Labeling and Dietary Supplements, November 2004: available at http://www.cfsan.fda.gov/~dms/ds3strat.html 10. Information available at http://www.fda.gov/bbs/topics/NEWS/2008/NEW01815. html 11. www.fda.gov – NOTE: The FDA is no longer updating their website with new NDI submissions. The last NDI filing available for viewing was received by FDA on Aug 16, 2006. A fee-based service is available for viewing all NDI’s and relevant documents. See http://ndi.npicenter.com/ 12. 21 U.S.C. 331(a) and (v).

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Marketing Dietary Supplements and Functional Foods in the USA: The Federal Trade Commission’s Advertising Substantiation Requirements

4

Anne V. Maher Kleinfeld Kaplan & Becker, Washington, DC, USA

Abstract The Federal Trade Commission (FTC) has historically considered deceptive advertising for products purported to improve human health as one of its top law enforcement consumer protection priorities. In recent years, with the significant increase in marketing for dietary supplements and functional foods, the FTC has boosted its visibility with regard to these industries. This chapter describes the FTC’s legal authority, policies and enforcement priorities with regard to the advertising of dietary supplements and functional foods. The author discusses how the Commission identifies and interprets claims in advertising and what constitutes ‘false and Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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48 Marketing Dietary Supplements and Functional Foods in the USA

deceptive’ advertising. Also highlighted are the requirements that advertisers disclose information if it is material in light of representations made or suggested in an advertisement and how such disclosures should be clear and conspicuous in order to be effectively conveyed to consumers. Under FTC law, advertisers must have a reasonable basis for all express and implied claims conveyed by an advertisement. For claims regarding health, a reasonable basis consists of competent and reliable evidence. The author explains how the FTC evaluates the adequacy of scientific substantiation and provides numerous examples of how the FTC has applied the standard in law enforcement actions. Requirements regarding the use of consumer testimonials and expert endorsements are also discussed. The FTC has a wide range of remedies available to address deceptive advertising and the author sets out and explains these enforcement options in detail.

Overview of FTC’s Authority The Federal Trade Commission (FTC) has authority to take legal action against false and misleading claims for nearly every type of product and service, including products which are also regulated by the Food and Drug Administration (FDA), such as dietary supplements and functional foods. Over the past decade, the FTC has maintained an active role in policing promotional claims for these products and has brought over 230 enforcement actions challenging false and misleading health and safety claims for products ranging from weight-loss pills to products claiming disease treatment and prevention (1). In addition to bringing cases, the Commission has provided guidance on its food advertising enforcement policy and on dietary supplement advertising, and given countless presentations before industry groups explaining FTC law and policy (2). The FTC’s authority derives from Section 5 of the FTC Act which broadly prohibits ‘unfair and deceptive acts and practices in commerce’ (3) . In addition, dietary supplements and functional foods have traditionally been regulated under Section 12 and 15 which prohibit false advertisements for foods, drugs devices or cosmetics, defined as those that are ‘misleading in a material respect.’ (4). An advertisement is deceptive if it contains a misrepresentation or omission that is likely to mislead consumers acting reasonably under the circumstances to their detriment (5). Although deceptive claims are actionable only if they are material to consumers’ decisions to buy or use the product, the Commission will presume materiality for all claims regarding health and safety. Because of their overlapping authority, the FTC and FDA share jurisdiction over health-related products pursuant to a longstanding agreement (6). Under this agreement, the FTC has primary responsibility to oversee the advertising of over-the-counter drugs, food cosmetics and devices, while the FDA regulates the labeling of these products. The agreement, drafted years before the advent of the Internet, does not address whether Internet promotions are labeling or advertising, but both agencies have asserted jurisdiction over claims appearing on company websites. Moreover, in recent years, the agencies have conducted joint ‘surf days’, in which they search the Internet for dietary supplement claims that appear false and misleading or purport to treat disease and then notify the companies of their legal obligations (7). An important complement to the FTC’s authority to police deceptive advertising is the National Advertising Division of the Better Business Bureaus (NAD), a self-regulatory

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Determining AD Meaning 49

arm of the advertising industry. The NAD provides an independent forum for competitor advertising challenges. In addition, the NAD staff monitors national advertising and institutes its own challenges to advertising that appears unsubstantiated. Through a relatively informal process, which follows FTC and FDA laws and regulations, the NAD reviews company substantiation and issues written opinions which are available to subscribers. The NAD process provides a timelier and cost efficient means of dispute resolution than private litigation or government enforcement. While compliance is voluntary, nearly all companies cooperate with the NAD and abide by its decisions. Those few companies that refuse to comply are referred by NAD to the FTC, and the agency has committed to giving those referrals top priority. In recent years, the NAD has considered numerous advertising challenges involving dietary supplements and functional foods. In 2006, the Council for Responsible Nutrition, a leading trade association of dietary supplement manufacturers and ingredient suppliers, agreed to fund an attorney at the NAD dedicated to challenges to dietary supplement advertising. As a result, the NAD’s caseload with respect to dietary supplement advertising challenges will be increased. There are two basic principles under FTC law and policy that apply to advertising for all products and services, including dietary supplements and functional foods: 1. Advertising must be truthful and not misleading. 2. Objective claims must be substantiated before they are made. These principles are described in the FTC’s Deception Policy Statement and Advertising Substantiation Policy Statement (8). In addition, as highlighted below, FTC advertising cases have also established a large body of precedent in which these principles are applied. Under FTC law, all parties who participate directly or indirectly in the marketing of dietary supplements and functional foods may be held liable. The FTC has brought enforcement actions not only against manufacturers, but individuals, advertising agencies, distributors, retailers, catalogue companies, infomercial producers, call center operators and expert endorsers, as well as others involved in allegedly deceptive promotions.

Determining AD Meaning Identifying Express and Implied Claims Under FTC law, an advertiser is responsible for all express and implied claims that are reasonably conveyed by an advertisement (ad). Marketers are responsible for ensuring that whatever they say expressly in an ad is truthful, non-misleading and substantiated. More often, however, claims are implied or suggested in an ad. In determining whether reasonable consumers are likely to take an implied claim, the Commission looks at the net impression created by the ad as a whole (9). In determining the claims that an ad conveys, the Commission examines ‘the entire mosaic, rather than each tile separately’(10). When an ad lends itself to more than one reasonable interpretation, the advertiser is expected to have substantiation for each interpretation.

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When an implied claim is not clear enough to permit the Commission to determine its existence by examining the ad alone, extrinsic evidence may be required (11). In its proceedings, the Commission will consider methodologically sound advertising copy-tests to demonstrate the existence of implied claims, as well as testimony by marketing experts regarding principles derived from marketing research showing how consumers generally respond to ads presented in a particular way and evidence of the advertiser’s intent. The vast majority of FTC law enforcement actions are settled before trial and, in nearly all of those cases, the implied claims are clear enough from the ad itself, without extrinsic evidence. For the advertising cases that proceed to trial, however, ad meaning is almost always at issue and competing copy tests and expert testimony are under evaluation (12).

Disclosures in Ads Section 15 of the FTC Act requires advertisers to disclose information if it is material in light of representations made or suggested in an ad. Ads often contain fine-print disclosures or video superscripts that attempt to disclaim, limit, modify or explain claims made elsewhere in the ad. FTC law prohibits advertisers from using fine print to contradict other statements in an ad or to clear up misimpressions the ad would otherwise leave. Similarly, accurate information in a footnote or text is unlikely to remedy a false headline because reasonable consumers may glance only at the headline (13). To be effective, disclosures must be clear and conspicuous (14). In evaluating the effectiveness of disclosures, the Commission considers such factors as whether the qualifying information is prominent enough for consumers to see or hear; whether it is presented in understandable language that does not contradict other information in the ad; whether it is located in a place and in a format that consumers will understand; and, whether it is located in close proximity to the claim being qualified. In addition to its law enforcement cases, the Commission has convened workshops and issued policy statements to explain and illustrate the ‘clear and conspicuous’ standard (15). The Commission has acknowledged that it is a challenge for advertisers to explain complicated scientific concepts to consumers, especially, for example, where the advertiser wishes to promote the health benefits of a product when there is an emerging body of science supporting the benefit, but the evidence is insufficient to substantiate an unqualified claim. In those instances, the Commission has cautioned advertisers to ensure that consumers understand both the extent of the scientific support and the existence of any significant contrary information and has specifically noted that vague qualifying terms such as ‘may’ or ‘helps’ achieve the claimed benefit are unlikely to be adequate (16).

Advertising Substantiation The Competent and Reliable Scientific Evidence Standard Under FTC law, advertisers must have a reasonable basis for making objective product claims before the claims are disseminated. This doctrine was first announced in

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Advertising Substantiation 51

Pfizer, Inc., 81 F.T.C. 23 (1972) and has since been articulated in the Commission’s Advertising Substantiation Policy Statement. Advertisers must possess at least the level of substantiation expressly or impliedly claimed in an ad. For example, if an advertisement states that ‘clinical studies show’ that a substance causes a certain effect on the body, the advertiser must possess studies that experts in the field would consider of sufficient quality to demonstrate the effect. If no specific level of substantiation is claimed, what constitutes a reasonable basis is determined on a caseby-case basis by balancing and analyzing the following six ‘Pfizer factors’ set forth in Pfizer, Inc., supra, and subsequent FTC orders: 1. 2. 3. 4. 5. 6.

the type of product the type of claim the benefits of a truthful claim the ease and cost of developing substantiation for the claim the type of product, and, the level of substantiation experts in the field would agree is reasonable.

Thus, the FTC’s reasonable basis standard is flexible and depends on what claims are made, how they are presented in the entire ad and how they are qualified (17). For claims regarding consumer health and safety, the Commission has typically required a relatively high level of substantiation, usually ‘competent and reliable scientific evidence’ which has been described in countless FTC cases and guidances as: tests, analyses, research, studies, or other evidence based on the expertise of professionals in the relevant area, that have been conducted and evaluated in an objective manner by persons qualified to do so, using procedures generally accepted in the profession to yield accurate and reliable results (18).

Evaluating the Adequacy of Scientific Substantiation In making a determination about the adequacy of evidence as substantiation for a particular claim, a key question for the FTC is: What would experts in the field consider adequate under these circumstances? The Commission accords great deference to medical and other scientific experts, as well as to other authoritative bodies or government agencies which have set particular standards. For example, the FTC has stated that it will follow the FDA’s ‘significant scientific agreement standard’ for unqualified ‘health claims’, i.e., those claims that describe a relationship between a food, food component, or dietary supplement ingredient and reducing risk of a disease or health-related condition. The FTC will consider all types of competent and reliable scientific evidence when evaluating substantiation. Although it recognizes that well-controlled human clinical studies are the most reliable form of evidence, it will also consider animal and in vitro studies, as well as epidemiological evidence under certain circumstances. In addition, while independently conducted replication of studies adds to the weight of the evidence, more than one study is not always necessary to substantiate a health benefit claim for a dietary supplement or functional food, if the study is of high quality.

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In assessing substantiation, the FTC focuses on the internal validity of the tests or studies, examining the protocol, implementation, test results and test report. Among the indicia of reliability that add to the weight of the evidence are studies that are of longer duration, double-blinded, placebo controlled and with statistical and clinical significance (19). In addition, the FTC has made it clear that companies cannot rely on abstracts and informal summaries to substantiate claims, but must review the underlying studies themselves (20). In addition to the internal validity of scientific evidence, the Commission also looks to the surrounding context of the scientific evidence in evaluating substantiation. Studies, with outcomes that are inconsistent or contrary to those in the wider body of evidence, will not be accepted as adequate substantiation absent a compelling explanation for the different results (21). Another question central to the Commission’s evaluation of advertising substantiation is whether the scientific evidence is relevant to the advertised product and benefit being claimed. To that end, the FTC focuses on such issues as whether the researched product contains the same formulation, dose and method of administration as the marketed product, and whether the study population shares the characteristics and lifestyle of the population targeted by the ad (22). Similarly, the Commission examines whether the advertising claims match the results of studies, or whether the claims exaggerate the extent or nature of the results and the overall certainty of the science (23).

Consumer Testimonials and Expert Endorsements Consumer and celebrity testimonials are a staple of dietary supplement advertising, particularly in ads involving weight loss in which consumers are often depicted in ‘before and after’ dieting photos. Expert endorsements are also frequently featured in ads for products and services that claim health benefits. These advertising techniques have been challenged in numerous FTC cases. False or deceptive endorsements or testimonials are a violation of the FTC Act. The Commission has issued Guides Concerning the Use of Endorsements and Testimonials in Advertising (10) which are premised on the principle that, because consumers may rely on opinions of endorsers in making purchasing decisions, product endorsements must be truthful and substantiated. Endorsements must always reflect the honest opinions, findings, beliefs or experience of the endorser. Furthermore, they may not contain any representations which would be deceptive, or could not be substantiated if made directly by the advertiser (24). Endorsers represented directly or by implication to be experts must have qualifications sufficient to give them the represented expertise (25). An expert endorsement must be supported by an examination or testing of the product at least as extensive as experts in the field generally agree would be necessary to support the conclusions presented in the endorsement. Anecdotal evidence of a product’s effect, based solely on the experience of individuals, is insufficient to substantiate a claim. Advertisers are required to have competent and reliable scientific evidence to support any express and implied efficacy claims conveyed by the testimonials (26). In addition, any connection between the endorser

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Remedies for Violations of the FTC Act 53

and advertiser that would not reasonably be expected by a consumer and might materially affect the weight and credibility of the endorser must be disclosed (27). An advertisement using consumer testimonials will generally be interpreted to convey that the endorser’s experience is representative of what consumers will typically achieve with the product in actual use (28). If this is not the case, the advertiser must either clearly disclose the limited applicability of the endorser’s experience to what consumers may expect to achieve or must clearly disclose what performance consumers generally achieve (20). According to the FTC, the statement, ‘Not all consumers will get this result’ is insufficient to disclaim a representation that the endorser’s experience is representative of what a consumer will typically receive (29). In January 2007, as part of its systematic review of its guides and regulations, the FTC issued a notice requesting comments on its Endorsement and Testimonials Guides (30). In conjunction with the review, the FTC commissioned two consumer studies which examined whether advertisements with consumer testimonials conveyed to consumers that the products advertised would enable new users to achieve results similar to those portrayed by the testimonialists and would enable a substantial portion of new users to achieve results similar to those portrayed. The studies also examined whether certain disclosures affected the communication of those messages. The Commission also sought comments about any other available research concerning the messages conveyed by consumer testimonials. The Commission’s review is ongoing and should be completed in 2008.

Remedies for Violations of the FTC Act The Commission has a wide range of remedies available to redress cases of deceptive advertising. The basic administrative remedy is a cease-and-desist order which serves to enjoin the illegal conduct alleged in the complaint and to prevent future violations of the law (31). In preventing future violations, the Commission has broad ‘fencingin’ power to prevent future actions that are reasonably related to the challenged unlawful conduct (32). In addition to prohibiting future misrepresentations, the Commission may order corrective advertising to correct lingering misperceptions resulting from the prior misrepresentation (33), or may order companies to make accurate information available through disclosures, direct notification or consumer education (34). In recent years, the Commission has become more aggressive in seeking remedies to address the more egregious examples of deceptive dietary supplement advertising. The Commission has banned repeat offenders from involvement in certain businesses and ordered them to post bonds before engaging in certain business practices (35). Similarly, in recent years the FTC has been seeking and obtaining significantly larger amounts in consumer redress, disgorgement and other financial remedies. For example, in January 2007, the Commission announced settlements with the makers of four significant and high-profile weight-control and weight-loss products, Trimpsa, Cortislim, Xenadrine and One-a-Day WeightSmart (36). The marketers of these four products collectively surrendered total cash and assets worth more than $25 million. In 2000 and 2003, the Commission received $10 and up to $12 million from marketers of pills for weight loss and cellulite treatment, respectively (37). Given its commitment to vigorous

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law enforcement in the area of dietary supplement advertising, it is likely that the Commission will continue to seek substantial financial remedies from supplement marketers with widely disseminated national advertising campaigns.

Conclusion The FTC has historically considered deceptive advertising for products purported to improve human health as one of its top law enforcement consumer protection priorities. In recent years, with the significant increase in marketing for dietary supplements and functional foods, the FTC has boosted its visibility with regard to these industries. Accordingly, it has issued the Dietary Supplement Advertising Guide and engaged in industry outreach in order to explain the application of the ‘competent and reliable scientific evidence’ standard to dietary supplement advertising. In addition, it has significantly increased the numbers of actions it brings against supplement and food companies, particularly those targeted at weight loss and disease treatment or cure. Under their liaison agreement, the FTC and FDA have continued to strengthen their efforts with regard to the deceptive marketing of these products in order to leverage resources and achieve consistent outcomes. In addition, the FTC has noticeably sought and achieved more stringent remedies from dietary supplement manufacturers engaged in allegedly deceptive practices and this trend will most likely continue into the future.

References 1. Food for thought: the FTC and Market Influences on Consumer Health, Remarks of Deborah Platt Majoras, Chairman, Federal Trade Commission, 50th Annual FDLI & FDA Conference, April 12, 2007, available at http://www.ftc.gov/speeches/majoras/ 070412FDL_DK.pdf 2. Enforcement Policy Statement on Food Advertising, 59 Fed. Reg. 28388 (June 1, 1994); Dietary Supplements: An Advertising Guide for Industry (November 18, 1998) (‘DS Ad Guide’). These documents, as well as all other policy statements and most law enforcement actions cited herein are available at http://www.ftc.gov 3. 15 U.S.C. § 45. 4. 15 U.S.C §§ 52–55. 5. Deception Policy Statement, appended to Cliffdale Associates, Inc., 103 F.T.C. 110, 174), cited with approval in Kraft, Inc. v. FTC, 970 F.2d 314 (7th Cir. 1992) cert. denied, 507 U.S. 909 (1993). 6. Working Agreement Between the FTC and FDA, 4 Trade Reg. Rep (CCH) ¶ 9,859.01 (1971). 7. See FTC Press Release FTC and FDA Act Against Internet Vendors of Fraudulent Diabetes Cures and Treatment (Oct. 19, 2006) available at http://www.ftc.gov/opa/2006/10/diabetessweep.shtm 8. Deception Policy Statement, supra; Advertising Substantiation Policy Statement: Appended to Thompson Medical Co., 104 F.T.C. 648, 839 (1984), aff’d, 791 F.2d 189 (D.C. Cir. 1986), cert. denied, 479 U.S. 1086 (1987).

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9. Deception Policy Statement, 103 F.T.C. at 179 & n. 32; Stouffer Foods Corp., 118 F.T.C. 746, 799 (1994). 10. FTC v. Sterling Drug, 317 F2d 669, 674 (2d Cir. 1964). 11. Stouffer Foods Corp., 118 F.T.C. at 798-99. 12. See, e.g. In the Matter of Telebrands Corp, TV Savings LLC, and Ajit Khubani, Docket 9313 (September 25, 2005). 13. Deception Policy Statement, 103 F.T.C at 180–81. See also, Haagen-Dazs Co., 119 F.T.C. 762 (1994) (consent order) (challenging effectiveness of fine-print footnote qualifying claim that frozen yogurt was ‘98 fat free’); Stouffer Food Corp., 118 F.T.C. 746 (1994) (holding that sodium content claims for Lean Cuisine products were false and unsubstantiated and not cured by fine print footnote); Kraft, Inc. 114 F.T.C. at 124 (Initial Decision) (holding that complicated superscript – ‘one ¾ ounce slice has 70% of the calcium of five ounces of milk’ – does not cure deceptive calcium content claim for cheese slices). 14. E.g. Thompson Medical Co., 104 F.T.C at 842–43 (requiring simultaneous audio and visual disclosure of certain information; see also United States v. Bayer Corp., No. CV 00-132 (NHP) (D.N.J. Jan. 11, 2000) (consent decree) (requiring audio and visual disclosure of information when ads make certain representation about the benefits of aspirin in the prevention of heart attacks). 15. See, e.g. Disclosure Exposure: An FTC-NAD Workshop on Effective Disclosures in Advertising (May 22, 2001); Dot Com Disclosures: Information about Online Advertising (May 3, 2000). 16. DS Ad Guide at 7. 17. DS Ad Guide at 8. 18. See, e.g. Schering Corp., 118 F.T.C. 1030 (1994) (consent order) (requiring that tests and studies relied upon as reasonable basis must employ appropriate methodology and address specific claims made in ad); FTC v. Pantron I Corp., 33 F3rd 1088 (9th Cir. 1994), cert. denied, 514 U.S. 1083 (1995) (holding that consumer satisfaction surveys and studies demonstrating the placebo effect are insufficient to meet ‘competent and reliable scientific evidence’ standard); Thompson Medical Co., 104 F.T.C. 648 (1984) aff’d, 791 F.2d 1489 (1st Cir. 1989) (requiring two well-controlled clinical studies to substantiate certain drug claims). 19. For a discussion regarding the quality of evidence required to substantiate dietary supplement claims, see DS Ad Guide at p. 12–14. 20. FTC v. Sterling Drug, 317 F.2d at 678 (1964). 21. For a discussion on how the FTC views the totality of the evidence, see DS Ad Guide at 14–5. 22. United States v. Bayer Corp., No. 07-01(HAA) (D.N.J. Jan. 4 2007) (consent decree) ($3.2 million civil penalty case challenging claims for One-A-Day WeightSmart multivitamin where product contained only a fraction of the amount of the purported weight control ingredient used in a study). 23. Bertolli USA, Inc., 115 F.T.C. 774 (1992) (consent order) (challenging advertiser’s exaggeration of study’s conclusions that researchers had characterized as preliminary). 24. 6 C.F.R. § 255.1(a). 25. 16 C.F.R. § 255.3 (a); see FTC v. Lark Kendall, No. 00-09358-AHM (AIJx) (C.D. Cal. Aug. 31, 2000) (challenging as false the representation that person appearing on infomercial touting weight loss product was a nutritionist) (stipulated final order);

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26.

27.

28. 29. 30. 31. 32. 33.

34.

35.

36.

37.

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Synchronal Corp., 116 F.T.C. 1189 (1993) (consent order) (holding both advertiser and expert endorser liable for deceptive representations for baldness remedy and cellulite treatment); The Eskimo Pie Corp., 120 F.T.C. 1365 (1997) (consent order) (challenging deceptive claim that line of frozen desserts was approved or endorsed by the American Diabetes Association). See, e.g. Removatron, 111 F.T.C. at 302; Original Marketing, Inc., 120 F.T.C 278 (1995) (consent order) (challenging use of testimonials that did not represent typical experience of consumers who used weight loss product). 16 C.F.R. § 255.5. See Bodywise International, 116 F.T.C. 1078 (1995) (consent order) (challenging consumer endorser’s status as a distributor of the product to be a material connection that must be disclosed). 6 C.F.R. § 255.2(a); see Cliffdale Associates, 103 F.T.C. 110, 173 (1984). 6 C.F.R. § 255.2, Example 1. FTC Requests Public Comments on Endorsement Guides, January 16, 2007, available at http://www.ftc.gov/opa/2007/01/fyi0707.shtm. FTC v. Colgate-Palmolive Co., 380 U.S. 374 (1965) ITT Continental Baking Co. v FTC, 532 F.2 207 (2d. Cir. 1976) Novartis v. FTC, 223 F3d 783 (D.C. Cir. 2000) (upholding FTC order requiring marketer of Doan’s pills to run corrective advertising to remedy deceptive claim that product is superior to other analgesics for treating back pain). Panda Herbal Int’l, Inc., C-4018, and ForMor, Inc., C-4021 (Aug. 3, 2001) (consent orders) (requiring warnings in labeling and advertising that St John’s Wort can have potentially dangerous interactions for patients taking certain prescription drugs and for pregnant women); PhaseOut of America, Inc., 123 F.T.C. 395 (1997) (consent order) (requiring marketer of device advertised to reduce health risks of smoking to notify purchasers that product was not proven to reduce risk of smoking-related disease); Unites States v. Bayer Corp., No. CV 00-132 (NHP) (D.N.J. Jan. 11, 2000) (requiring $1 million education campaign warning consumers to discuss with their doctor before beginning aspirin therapy for prevention of heart attacks). FTC v Kevin Trudeau, No. 98-c-0168 and No. 03-C-904 (N.D. Ill. Sept. 3, 2004) (stipulated final order) (banning defendant for life from appearing in, producing or disseminating infomericals for any type of product, service or program); FTC v. American Urological Corp., No. 98-CVC-2199-JOD (N.D. Ga. Apr. 29, 1999) (final order for permanent injunction) (imposing $6 million bond on marketer of Vaegra, a dietary supplement purporting to treat impotence). Federal Trade Commission Reaches New Year’s Resolution with Four Major WeightControl Pill Marketers, (Jan. 4, 2007) available at http://www.ftc.gov/opa/2007/01/ weightloss.htm FTC V. Enforma Natural Products, Inc., No. 04376JSL(CWx) C.D. Cal. Apr. 26, 2000) (stipulated final order) ($10 million redress from marketer of purported weight loss products); FTC. V. Rexall Sundown, Inc., Civ. No. 00-706-CIV (S.D. Fla. Mar. 11, 2003) (stipulated final order) (up to $12 million redress for deceptive efficacy claims for Cellasene, a purported anti-cellulite dietary supplement).

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Manufacturing Compliance and Analytical Validation 5 Dietary Supplement GMP Regulations: The Impact on Industry, Regulatory and Consumer Confidence 6 Development and Validation of Analytical Methods to Ensure the Quality and Safety of Dietary Supplements

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PART

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Dietary Supplement GMP Regulations: The Impact on Industry, Regulatory and Consumer Confidence

5

Richard Crowley and Libby Harvey FitzGerald Covance Laboratories, Madison, WI, USA

Abstract The FDA estimates that US citizens spend more than $8.5 billion a year on dietary supplements and, worldwide, the market is estimated at more than $60 billion. However, although a majority of consumers express confidence in the safety of these products, 74% believe the government should be more involved in ensuring that these products are safe and efficacious. Recent regulatory initiatives, such as the adoption of current good manufacturing practices (cGMPs) for dietary supplements in the USA, implementation of cGMPs in Canada and the recent EU Dietary Supplement initiative, represent legislative and industry response to public clamor for more comprehensive oversight of dietary supplements. Regardless of mandated practices, the majority of dietary supplement manufacturers have done an excellent job of protecting the safety and quality of their products. The promulgation of these cGMPs will help ensure consumers that equal standards are followed throughout the industry. For some companies with established processes based on existing food or pharmaceutical cGMP regulations, the transition will be relatively painless while, for many, it will represent a significant increase in the level of documentation and testing. However, consumers deserve and demand that products meet standards for safety and quality and the implementation of cGMPs for these products are an important first step. Although the cGMPs are designed to ensure products are safe from a standpoint of identity, purity, quality, strength and composition, they do not address preclinical or clinical testing of ingredients for safety or efficacy. This would Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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60 Dietary Supplement GMP Regulations

involve ingredients meeting the requirements of generally recognized as safe (GRAS) status or going through the new dietary ingredient (NDI) process.

Introduction Consumer reliance on regulatory initiatives to ensure food safety dates back to landmark legislation such as England’s Adulteration of Food Acts of 1860 and 1972 which, for the first time, mandated the hiring of analysts and inspectors. In the USA, President Lincoln first appointed a chemist to the United States Department of Agriculture (USDA) in 1862 signaling what was to be the beginning of the Bureau of Chemistry and the eventual passage of the Food and Drug Act in 1906. Current good manufacturing practices (cGMP), whether they be for drugs, food products or dietary supplements are a key to consumer confidence, product safety and recognized standards. The potential physiological benefits of ingredients such as the antioxidant properties of polyphenolic compounds (e.g. catechins, trans-resveratrol, gallic acid) have accelerated the interest of consumers and health professionals in the role of these compounds in disease prevention. Although the dietary supplement boom of recent years has leveled off somewhat, the Food and Drug Administration (FDA) estimates that US citizens spend more than $8.5 billion a year on dietary supplements and, worldwide, the market is estimated at more than $60 billion (1). However, although a majority of consumers express confidence in the safety of these products, 74% believe the government should be more involved in ensuring that these products are safe and efficacious (2). Recent regulatory initiatives, such as the June 2007 adoption of cGMPs for dietary supplements in the USA, 2005 implementation of cGMPs in Canada and the recent EU Dietary Supplement initiative, represent legislative and industry response to public clamor for more comprehensive oversight of dietary supplements.

The Foundation is Laid The cGMPs for dietary supplements were first proposed under the auspices of the Dietary Supplement Health and Education Act (DSHEA) in 1994, which was enacted to ensure that consumers had access to safe dietary supplements (3). Specifically, the legislation recognized that ‘improving the health status of US citizens is national priority and that the use of dietary supplements may help prevent chronic diseases and maintain good health’ (2). Although DSHEA amended the Federal Food, Drug, and Cosmetic Act to allow the establishment of good manufacturing practices for dietary supplements, the foundation of the proposed cGMPs has had many building blocks. Primary among these is an outline for cGMPs submitted by representatives of the dietary supplement industry in 1995. These self-imposed industry recommendations have had a steady influence on increased consumer confidence. A survey commissioned by the Council for Responsible Nutrition (CRN) shows that 78% of consumers were either somewhat confident or very confident in the safety, quality and effectiveness of dietary supplements (Fig. 5.1). However, these numbers have increased only marginally from the

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The Foundation is Laid 61

60 53%

50%

50 41% 40 30

24% 20 10 0

Vitamins and minerals Very safe

Herbal products Somewhat safe

Figure 5.1 Perceived safety of vitamins, minerals and herbal products. Source: FDA (2).

800 700 600 500 400 300 200 100 0 FDA Benefits

CRN Benefits

FDA Annual costs

CRN Annual costs

FDA One time costs

CRN One time costs

Figure 5.2 FDA, CRN cost/benefit analysis associated with dietary supplement cGMPs ($ millions). Sources: (2,4).

74% reported in 2001 (4). As a result, CRN says industry needs ‘to continue to urge government and private funding for scientific research on the safety and effectiveness of supplements, as well as do a better job of communicating the kinds of things responsible companies do to ensure high quality products’ (Fig. 5.2). In the Federal Register of February 6 1997, an advance notice of proposed rulemaking was published soliciting comments on the need for, and content of, cGMP regulations for dietary ingredients and dietary supplements. In 2003, the FDA published its proposed rule on cGMPs for dietary supplements resulting in more than

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Table 5.1 Product quality concerns addressed by cGMPs ● ● ● ● ● ● ● ● ● ● ● ● ● ●

Foul odor Off taste Superpotent Subpotent Wrong ingredient Drug contaminants Other contaminants (e.g. pesticides) Disintegration time Color variation Tablet size or size variation Under-filled container Foreign material in a container Improper packaging Mislabeling

1600 pages of comments. This resulted in debate over some key issues such as the FDA’s authority to issue such expansive regulations that fall between conventional food and drug cGMPs, the amount of testing required for individual ingredients versus final products, as well as concerns about estimated financial impact (5,6). The final rules were published in the June 25 2007 Federal Register. Commenting on the rule, FDA commissioner Dr Andrew von Eschenback said, ‘This rule helps to ensure the quality of dietary supplements so that consumers can be confident that the products they purchase contain what is on the label’.

Primary Provisions The cGMPs for pharmaceutical and food products have been an integral facet of the successful status and continued growth of these industries. The regulations for dietary supplements and ingredients are patterned after those established for conventional food products and would establish the minimum requirements necessary to ensure that the manufacturing, packaging or holding of ingredients and supplements are done in a manner that prevents adulteration and misbranding of products. These include a wide variety of activities such as strict requirements for maintenance of the physical plant, equipment and utensils, and mandatory record keeping provisions. In addition, the production and process controls sections contain specific information on the levels of testing and quality control which would require manufacturers to evaluate the identity, purity, quality, strength and composition of ingredients and final products. Table 5.1 demonstrates the product quality concerns addressed by cGMPs. The regulations require manufacturers to establish specifications for the dietary ingredients and dietary supplements they produce. As a result, a dietary supplement with a particular ingredient listed on its label must contain that ingredient. The ingredient must also meet specifications the manufacturer establishes for purity, quality, strength and composition. These provisions are intended to ensure that a product contains what is listed on the label. If it does not, the dietary supplement would

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Personnel, Physical Plants and Equipment 63

not only be misbranded, but considered adulterated as well. In addition to requiring compliance with the provisions in Part III, the regulations specify other applicable statutes that may apply for some products. For example, a manufacturer whose product includes fish oil would also have to comply with Hazard Analysis and Critical Control Point (HAACP) rules. Table 5.2 exhibits the provisions of the cGMPs.

Personnel, Physical Plants and Equipment Well-trained and diligent personnel are critical to ensure the safety of any consumer product. The cGMPs include stipulations for prevention of microbial contamination as well as qualification and training of personnel. The rules specify the use of hygienic practices to the extent necessary to protect against contamination. In regard to the qualifications of staff, the cGMPs require that each person engaged in manufacturing, packaging or holding have the training and experience necessary to ensure they are competent to produce an unadulterated product. The extent and frequency of

Table 5.2 Provisions of proposed cGMPs Subpart A. General provisions Section 111.1: Who is subject to these Part III regulations? Section 111.2: What are these regulations intended to accomplish? Section 111.3: What definitions apply to this part? Section 111.5: Do other statutory provisions and regulations apply? Section 111.6: Exclusions Subpart B: Personnel Section 111.10: What microbial contamination and hygiene requirements apply? Section 111.12: What personnel qualification requirements apply? Section 111.13: What supervisor requirements apply? Subpart C: Physical plant Section 111.15: What sanitation requirements apply to your physical plant? Section 111.20: What design and construction requirements apply to your physical plant? Subpart D: Equipment and utensils Section 111.25: What requirements apply to the equipment and utensils you use? Section 111.30: What requirements apply to automatic, mechanical or electronic equipment? Subpart E. Production and process controls Section 111.35: What production and process controls must you use? Section 111.37: What requirements apply to quality control? Section 111.40: What requirements apply to components, dietary ingredients, dietary supplements, packaging and labels you receive? Section 111.45: What requirements apply to establishing a master manufacturing record? Section 111.50: What requirements apply to establishing a batch production record? Section 111.60: What requirements apply to laboratory operations? Section 111.65: What requirements apply to manufacturing operations? Section 111.70: What requirements apply to packaging and label operations? Section 111.74: What requirements apply to rejected components, dietary ingredients, dietary supplements, packaging and labels? (Continued)

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Table 5.2 Continued Subpart F: Holding and distributing Section 111.80: What requirements apply to holding components, dietary ingredients, dietary supplements, packaging and labels? Section 111.82: What requirements apply to holding in-process material? Section 111.83: What requirements apply to holding reserve samples of components, dietary ingredients and dietary supplements? Section 111.85: What requirements apply to returned dietary ingredients or dietary supplements? Section 111.90: What requirements apply to distributing dietary ingredients or dietary supplements? Subpart G Section 111.95: Consumer complaints – what requirements apply to consumer complaints? Subpart H Section 111.125: Records and recordkeeping – what requirements apply to recordkeeping?

the training is left to the discretion of the manufacturer. Consultants used for advice must be qualified by training and experience. The design and maintenance of the physical plant in which ingredients and products are manufactured and stored are critical to the safety and efficacy of supplements. The provisions for the design, construction and maintenance of the facilities include requirements for water quality, plumbing, ventilation systems and pest control. The regulations also include comprehensive requirements for ground maintenance, sanitation and the use or holding of toxic materials. Assignment of one or more employees to supervise sanitation would also be required. Unintentional contamination of food has always been a concern to consumers and manufacturers alike. In recent years, manufacturers have become more diligent about the maintenance and cleaning of equipment and utensils used in processing. As defined in the cGMP regulations, equipment and utensils would include, but not be limited to, equipment used to hold, convey or measure ingredients or final products. This includes equipment using compressed air or gas or used to carry out processes in closed pipes and vessels. Recognizing the growing reliance on automated systems, hardware and software are also cited for specific requirements.

Production and Process Controls From a scientific and testing standpoint, production and process controls are the cornerstone of regulatory compliance and consumer confidence. Table 5.3 shows the information required for batch production records. Although decisions about producing a dietary ingredient or supplement are left up to the manufacturer, the regulations recognize that standard measures designed to ensure that ingredients and supplements are manufactured in a safe manner are essential. Because even the most innocuous change in a formulation or preparation method or exposure to an unanticipated environmental condition could create a health hazard, monitoring of the physical and chemical characteristics is critical. Thus, a production and in-process control system, as well as the establishment of a quality control unit, are necessary to provide consistency in production.

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Laboratory Operations and Testing Requirements 65

Table 5.3 Information required for batch production record ● ●

● ● ●

● ●

●

●

● ● ●

● ●

Batch, lot or control number Documentation showing the date on which each step of the master manufacturing record was performed, the initials of the persons performing each step, including the person responsible for weighing or measuring each component used in the batch, and the person responsible for adding the components Identity of equipment and processing lines used The date and time of the maintenance, cleaning and sanitizing of the equipment and processing lines used The shipment lot unique identifier of each component, dietary ingredient, dietary supplement, packaging and label used The identity and weight or measure of each component The initials at the time of performance or at the completion of the batch of the person responsible for verifying the weight or measure of each component used in the batch The initials at the time of performance or at the completion of the batch of the person responsible for verifying the addition of components to the batch A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing Actual test results for any testing performed during production Documentation that the dietary ingredient and dietary supplement meets specifications Copies of all container labels used and the results of examinations conducted during the label operation to ensure that the containers have the correct label Any documented material review and disposition decision Signature of the quality control unit to document batch production record review and approval for reprocessing or repackaging

Quality Control and Assurance The regulations mandate that a quality control unit be established to ensure that dietary ingredients and supplements meet specifications for identity, purity, quality, strength and composition. It is recommended that all organizational units involved in critical formulation and manufacturing steps, such as production, engineering, research and regulatory affairs, be included in quality control functions. This unit has a broad range of compliance functions such as the review of all processes, documentation and production records. The quality group also has responsibility for the collection of representative samples for testing. These responsibilities are critical in the implementation of cGMP standards. The quality control unit must document the specifics of the review process. This documentation will include the time and date when the review, approval or rejection requirement was performed and the signature of the person performing the requirement.

Laboratory Operations and Testing Requirements Although analytical testing has long been a foundation of safe products, the popularity of television shows depicting science as the silver bullet for all problems has elevated the consumer’s view of the role of chemistry in our everyday lives. Analytical testing is performed to ensure that components, ingredients and supplements meet specifications throughout the manufacturing and distribution process as well as to determine that labeling reflects the true identity and amounts of ingredients. The establishment of standards

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Table 5.4 Provisions for laboratory operations mandated by the cGMPS ●

●

●

● ●

●

Section 111.60(b)(1): Establish and follow laboratory control processes approved by the quality control unit Section 111.60(b)(1)(iii): Laboratory control processes to include sampling plans for obtaining representative samples of: − Components, dietary ingredients and dietary supplements received − In-process materials during the batch manufacturing when testing or examination is required in the master manufacturing record − Each batch of dietary ingredient or dietary supplement manufactured to determine that the dietary ingredient or dietary supplement meets specifications − Packaging and labels received to determine that the materials meet specifications − Each batch of packaged and labeled dietary ingredients or dietary supplements to ensure that the label specified in the master manufacturing record has been applied Section 111.60(b)(iv) through (b)(vi): Require the laboratory control processes to include: − Use of criteria for selecting standard reference materials − Use of appropriate test method validations. − Use of test methods in accordance with established criteria Section 111.60(b)(2) and (b)(3): Documentation and recordkeeping for laboratory operations Section 111.60(c): Verification that the laboratory testing methodologies are appropriate for their intended use Section 111.60(d): Identify and use the appropriate validated testing method to use for each established specification for which testing is required

for laboratory operations requires that the appropriate reference materials, methods, instrumentation and personnel are used. It is also imperative that each of these factors is adequately documented. Table 5.4 details the requirements for laboratory operations mandated by the cGMPs. The regulations apply to all laboratory facilities used, not just those operated within a company. In other words, if a private laboratory or raw material supplier performs the actual tests, you must make sure that the testing laboratory’s facilities and processes are adequate and conform to cGMP regulations. A perceived skepticism by the public about the quality of dietary supplements has long been the bane of the industry and an assurance that a product is indeed what it purports will go a long way in improving the image of these products. The FDA specifies that at least one test or examination be done to verify that specifications for ‘Identity’ are met. In regard to other specifications, several trade associations have recommended that, under certain conditions, reliance on a raw material supplier’s certificate of analysis could be accepted in lieu of testing for ‘Other Specifications’ of components, ingredients or supplements. These conditions would include establishing the reliability of the supplier and confirming the supplier’s test results at appropriate intervals. The certificate of analysis provided should list a description of the appropriate test or examination methods used, test limits and test results. An ongoing audit or certification system to verify the reliability of suppliers is part of a well-documented quality control system. Scientists have been hampered in the analysis of certain products due to the lack of standard reference materials and, the truth is, that standard reference materials do not exist for many botanicals. Although the cGMPs allow the use of plant reference material authenticated by a qualified plant taxonomist as a standard reference in performing some

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Date of Expiration and Shelf-Life 67

organoleptic and microscopic examinations, a reference standard that is a highly purified and characterized compound must be used for quantitative chemical tests. Ideally, compendial reference standards are used whenever possible. If no compendial standard exists, appropriately characterized materials from representative lots may be used. Standards used in developing analytical methods include either reference standards that identify a single compound or entity and reference materials that represent a matrix of compounds. Although documentation of the reference materials is always important, extra diligence is required when non-compendial materials are used. The cGMPs require scientifically validated analytical methods. There is currently a gap between what a company might document as a method that is scientifically valid and Official Methods of Association of Official analytical Chemists (AOAC) International, which are considered the scientific gold standard and specified as the methods of choice in the Code of Federal Regulations for labeling purposes. The cGMPs would put the burden of deciding whether a method is valid squarely on the shoulders of individual FDA field inspectors. The proposed cGMP rule does not identify any specific analytical methods. As a result, evaluation of the most appropriate test for a component, ingredient or supplement is a decision left to the manufacturer. Test methodology must be specific for the component, ingredient or dietary supplement and meet established scientific specifications. The cGMPs recognize that requiring validated testing methods is not sufficient without documentation that those methods were actually used at the time the assay was conducted. Complete records must also be maintained for any testing of standards and reagents used. Furthermore, the regulations include provisions for calibration of laboratory instruments, apparatus, gauges and recording devices. Recognizing the need for development of additional analytical methods and reference materials, Congress has appropriated funds for the NIH Office of Dietary Supplements (ODS) to invest in these activities. ODS initially focused on safety issues by issuing a September 2001 contract with AOAC to validate various methods for ephedra and for aristolochic acid through the AOAC Official Methods process. ODS also contracted with AOAC in September 2002 to develop 20 new methods for commonly utilized dietary supplement ingredients, with a budget of $1 million over a 5-year period. As of January 2007, 18 methods have either completed or are undergoing the validation process.

Date of Expiration and Shelf-Life Consumers are very aware of food industry practices that incorporate expiration, best before and other dates on the product label to indicate freshness. The regulations specify requirements for the holding of components, ingredients and final product at all stages of the manufacturing and distribution process and require that ingredients and supplements be held under conditions that will protect against contamination and deterioration. Although the FDA’s proposed rule does not require testing to establish expiration or shelf-life dating on dietary supplements, the regulations require that a sample of each lot of ingredient and supplement received and each batch of

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finished product shipped must be retained for 3 years from the date of manufacture. These samples would be used in appropriate investigations including, but not limited to, consumer complaints. One trade association recommended the addition of specific expiration or shelf-life dating for all products while retaining samples for one year past the shelf-life date. Testing for degradation of each product and container could provide supporting data for written assessment of stability (e.g. breakdown of specific ingredients), change in physical characteristics (e.g. solubility) and safety (e.g. microbial contamination) up to the specified point in time.

Consumer Complaints and Recordkeeping It has long been recognized that consumer concerns about manufacturer claims and product safety were a driving force in the development of the cGMPs. The regulations would mandate the implementation of a formal, documented consumer complaint process. The rules consider a consumer complaint as a possible failure of an ingredient or supplement to meet the requirements of the cGMPs. The regulations would require that a written report be kept of every consumer complaint related to good manufacturing practices. The report should include all information necessary for the quality control unit to determine whether an investigation is necessary. Documentation is the key to a successful cGMP program and many of the provisions of the regulations hinge on accurate and comprehensive records. The regulations establish general recordkeeping requirements and set the minimum duration of time for which records must be kept. The rule would require that records be retained for 3 years beyond the date of manufacture of the last batch of the ingredients or dietary supplements associated with those records. The allowable format of the records includes original or true copies as well as electronic records. If reduction techniques (e.g. microfilming) are used, equipment must be available for inspections. If electronic records are used, compliance with 21 CFR Part II is required.

The Economic Impact The FDA recognizes there will be a significant financial impact and has estimated that the mean annual costs of the proposed cGMPs at $86 million with additional costs incurred in the first year the regulations are finalized. Industry trade associations have estimated the annual cost to be up to 10 to 15 times the FDA estimate. The worry, of course, is that many of these costs will be passed on to consumers in the form of higher prices. Estimating the costs involved in conducting the testing required for food and supplement products includes a breakdown of financial issues, such as the building and maintenance of laboratory facilities as well as investments in scientific expertise and method development. The FDA estimates of one-time costs for equipment and facilities are also considered conservative by industry groups. The

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The Conclusion: Good Practices Build Consumer Confidence 69

FDA projected just over $54 million in one-time costs, while industry places the cost at more than $600 million. The final rules could threaten the financial viability of some very fine small manufacturers and many believe that Congress did not intend such restrictive legislation and consequences when it enacted DSHEA in 1994. However, most dietary supplement manufacturers welcome the new cGMPs with enthusiasm, saying that the regulations will separate the pretenders from the manufacturers who are spending the time and money to produce compliant and safe products. If this forces these unqualified, low-quality manufacturers out of business, the cGMP regulations will be successful in their mission to improve overall quality and consumer confidence in the dietary supplement industry. It is clear that either industry itself and/or regulatory agencies must take action against disreputable companies that willfully ignore even self-regulation. Many industry experts have stated that, although there are some supplements that pose a significant risk to public health (e.g. Ephedra), most do not and thus controls that are similar to drugs are not justified. Recent high-profile safety issues with pharmaceuticals have helped to increase significantly consumer interest in dietary supplements and functional foods. What happens in regulation of dietary supplements will certainly impact the further development of functional foods. Are we seeing the beginning of a new herbal medicine drug category that mirrors the European model? As consumer trend toward alternative therapies continues to grow, most of these questions will be answered by the response and desires of the marketplace. Although the cGMPS do not address the safety and efficacy of ingredients (except where the cGMPs insist that the right ingredient or material is in the bottle and labeled as such), the FDA and Federal Trade Commission maintain broad mandates for the monitoring of products including imported goods and enforcing rules concerning adulteration, contamination, misleading claims and safety issues. These tools include seizure, warning letters and publication on the FDA website.

The Conclusion: Good Practices Build Consumer Confidence Regardless of mandated practices, the majority of dietary supplement manufacturers have done an excellent job of protecting the safety and quality of their products. Now, the promulgation of these cGMPs will help ensure consumers that equal standards are followed throughout the industry. For some companies with established processes based on existing food or pharmaceutical cGMP regulations, the transition will be relatively painless while, for many, it will represent a significant increase in the level of documentation and testing. However, consumers deserve and demand that products meet standards for safety and quality and the implementation of cGMPs for these products are an important first step. It should also be noted that both the FDA and industry consultants are eager to work with suppliers to resolve minor problems related to compliance with the new cGMPs.

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References 1. Nutrition Business Journal (2004), Global Nutrition Industry at $182 Billion: Supplements Top $60 Billion. Vol. IX, No. 10–11, Oct/Nov 2004. 2. Food and Drug Administration. (March 13, 2003). Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Ingredients and Dietary Supplements: Proposed Rule. Federal Register, 12157–12263. 3. Congress of the United States, The Dietary Supplement Health and Education Act of 1994, Public Law 103–417, 108 Statute 4325. October 25, 1994. 4. Council for Responsible Nutrition (2004), American confident in dietary supplements says new IPSOS-Public affairs survey. Press Release, Oct. 25, 2004. 5. American Herbal Products Association, Council for Responsible Nutrition, National Nutritional Foods Association (January 30, 2004), Joint Industry Submission Regarding the Food and Drug Administration’s Proposed Rule. 6. Council for Responsible Nutrition (Sept. 2003), Comments on Docket No. 96N-0417, Good Manufacturing Practices for Dietary Supplements. Topic: Economic Impact of the Proposed Rule.

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Development and Validation of Analytical Methods to Ensure the Quality and Safety of Dietary Supplements

6

Darryl Sullivan and Richard Crowley Covance Laboratories, Madison, WI, USA

Abstract The expanding use of innovative botanical ingredients in dietary supplements and foods has resulted in a flurry of research aimed at the development and validation of analytical methods for accurate measurement of active ingredients. The pressing need for these methods is being met through an expansive collaborative initiative involving industry, government and analytical organizations. This effort has resulted in the validation of several important assays as well as important advances in the method engineering procedures which have improved the efficiency of the process. The initiative has also allowed researchers to hurdle many of the barricades that have hindered accurate analysis, such as the lack of reference standards and comparative data. As the availability for nutraceutical products continues to increase, these methods will provide consumers and regulators with the scientific information needed to assure safety and dependable labeling.

Introduction The analysis of food and dietary supplements is constantly evolving in order to keep pace with new, innovative ingredients and products. The explosion in the use Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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72 Development and Validation of Analytical Methods

of botanical ingredients and nutraceutical products is perhaps one of the most challenging tasks to face the analytical community. The tremendous popularity of these products has resulted in increased scrutiny from consumers, health professionals and regulators about the quality and levels of active ingredients in these products. The need for dependable analytical methods has resulted in an unprecedented call to arms from industry, regulators and scientists to develop, validate and adopt standard assays for dietary supplements. Although some of the herbs and botanical derivatives marketed as dietary supplements have been consumed by humans for thousands of years, many of the ingredients have not been subject to comprehensive analysis. The importance of these methods cannot be overstated and it is a daunting task considering that hundreds of botanical ingredients are used in thousands of products. Development of these methods will help assure consumers that analytical data for all products are based on solid science and can be easily compared. From a regulatory standpoint, adoption of validated methods will make product monitoring more efficient, identification of adulterated products easier and, in some cases (e.g. ephedra, aristolochic acid), these methods are key in enforcing regulatory bans on specific compounds.

Unified Resources Both industry and the scientific community quickly recognized that the urgent need could only be met with a collaborative initiative. In response, a task group was formed in conjunction with the National Institutes of Health (NIH), the Food and Drug Administration (FDA) and Association of Official analytical Chemists (AOAC) International to identify dietary supplements for which validated methods are most urgently needed and facilitate the development and validation of these assays. This group is composed of many industry-leading scientists from around the globe with representatives from major manufacturers, trade associations and academia. The primary focus of the alliance is to address the issues that have hampered researchers, such as the identification of specific active ingredients, lack of validated reference standards and a dearth of collaborative data. The initial focus of the project was to identify and prioritize the substances to be included in the initiative. The screening process resulted in the identification of 14 supplements and ingredients to be included in Phase 1 of the initiative. Although the priority list initially included 20 ingredients, industry has indicated that at least five times this many could be immediately identified. Based on the contract with AOAC, the cost of developing fully validated methods for 100 ingredients could be in excess of $5 million. The decisions were based upon the depth of knowledge concerning the active ingredients, status of analytical methodology, potential for adverse effects and the consumer popularity of the supplement. Adverse incidents associated with the inappropriate or unmonitored use of dietary supplements (e.g. ephedra) provided the impetus for the support of regulatory groups.

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The Method Engineering Process 73

The ultimate goal is to address and overcome the challenges associated with the analysis of the products. Many of these hurdles are not encountered by other types of products in developing and validating analytical methods for dietary products. For example, in many cases, the active constituents are not known and appropriate marker substances must be selected. The natural variability of many of these products also complicates method development and validation. When instability of many of the active components and marker compounds after removal from the plant matrix is factored in, the need for agreement on a single, rugged, thoroughly validated analytical method becomes clear. Other issues to consider are the appropriateness of the marker compounds selected for the botanical and whether or not the method can be used for both raw materials and finished products. In many cases, matrix interferences result in the methods used for raw materials not being applicable for finished products. In addition, analytical standards are either extremely expensive to develop or non-existent. Effectively addressing all of these challenges requires adherence to a comprehensive and strictly defined method development process.

The Method Engineering Process The method engineering process establishes benchmarks for acceptance criteria and determines the validity of a method. The analysis of dietary supplements has generated many challenges for researchers. Primary among these was the lack of information for identifying and isolating the active ingredients in many of these materials and products. In general, the development of methods for a supplement is based on the identification of the known active ingredients, determination of the amount available in the source raw material and establishing a baseline of how much of the active ingredients should be included in the final product. From a good manufacturing practice (GMP) perspective the methods also allow analysis of the final product for quality control purposes. Although much work still needs to be done, researchers have now isolated known active ingredients in many of these products. To determine the amount of active ingredient available, the analyte of interest must be extracted from the raw material. To determine the accuracy of an extraction procedure, researchers must compare the results to known concentrations. This may be accomplished through standard addition, matrix fortification (i.e. spiking) or known reference standards. When analyzing raw materials, the standard addition and spiking methods are inadequate due to the lack of data on the true concentrations of many of the ingredients. Until recently, researchers have been hampered by the lack of known pure standards to use for comparison, both in validation of extraction process and in the separation and detection steps. The availability of such standards has accelerated method development for these products. A key to successful development of the supplement methods will be to identify the matrixes to be used and clarify the details of the type and quantities of the samples to be evaluated. Although a single-lab validation is a good indicator of the acceptability

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Table 6.1 Components of method validation ● ● ● ● ● ●

● ●

Accuracy (i.e. how closely the assay value represents the ‘true’ level of an analyte) Precision (i.e. comparison of repetitive measurements) Sensitivity (i.e. lowest analyte concentration) Selectivity/specificity (i.e. isolation of analyte of interest) Linearity (i.e. response function) Robustness, ruggedness and reproducibility (i.e. how well a method performs under different conditions of repeated use such as different analysts, laboratories or days) Range (i.e. interval between upper and lower levels) Limits of detection and quantitation (LOD, LOQ)

of an assay, the majority of recognized methods also undergo a stringent collaborative study process, which involves a team of scientific and statistical experts responsible for study direction, data review and analysis. Many of the methods are designated as ‘official’ by AOAC International and are considered as the gold standard and are preferred by the Code of Federal Regulations (21CFR2.19). All methods used to generate data for regulatory compliance must be validated (Table 6.1). However, the extent of validation required is dependent upon the status of the method. For a recently developed method, a full single-laboratory validation is conducted, which includes an evaluation of the precision, accuracy, linearity, selectivity, matrix effects, ruggedness, robustness, range and the limits of detection and quantification. In validation, both fortified solutions and the sample matrices designated in the protocol are used. Methods with official status that are being modified may undergo a less extensive validation process to measure assay performance compared with the original validation. This process can range from an ‘accuracy and precision’ study in a single laboratory to a nearly full collaborative validation. In some cases, these methods are developed in-house and only used by a single or limited number of laboratories. Although the method may be perfectly reliable, the data generated cannot be accurately compared to similar products that may be analyzed using methods that produce more apparently favorable numbers providing a competitive advantage. A limited validation is normally conducted when a method undergoes a ‘minor’ modification, such as a change in technique, site or instrumentation. A crossvalidation process is used when comparing results generated using different matrices. A cross-validation process compares results generated using matrices not within the scope of the original validation. This process helps ensure the validity of the results when applied across a broader range of sample types. Although a single-lab validation is a good indicator of the acceptability of an assay, the majority of the supplement analysis methods used also undergo a stringent AOAC collaborative study process (Fig. 6.1), which involves a team of scientific and statistical experts responsible for study direction, data review and analysis. An important advance in the method engineering process is the use of expert review panels to screen potential methods for specific compounds and identify the most promising methods. This eliminates wasted effort on assays with more limited scope or applicability. In the case of the dietary supplement initiative, this means the screening of literally hundreds of methods.

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The Method Engineering Process 75

Need for method identified by analytical community

Methods evaluated by Expert Review Panel

Method protocol(s) submitted

Most promising method selected by panel

Study director appointed

Study director writes protocol using standardized templates

Protocol reviewed by chair of the Methods Committee, two method experts, general referee, statistician, and safety advisor

Protocol revised and resubmitted

Revision requested

Methods Committee report sent to study director

Conduct collaborative study

Study director submits collaborative study manuscript

Study manuscript reviewed by general referee, statistician, and safety advisor Revision requested Comments sent to study director


Collaborative study manuscript reviewed by Methods Committee SD requests appeal to OMB

Collaborative study published in JAOAC

Revision requested

Rejected Committee comments sent to study director

Method approved as First Action by the Methods Committee


Method published in OMA

Method used in laboratories for a minimum of 2 years

Method approved as ‘Official Final Action’ by Methods Board

Figure 6.1 Flowchart of the collaborative study process

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The Collaborative Study Process A key to the establishment of official, recognized methods is a comprehensive, documented method validation process. For the purposes of this discussion, the primary focus will be the AOAC process, however, all well documented method engineering processes contain similar, if not identical, phases. Through the AOAC, analytical methods are collaboratively studied to ensure accuracy, precision (repeatability and reproducibility), sensitivity, range, specificity, ruggedness, limit of measurement and practicality under typical laboratory applications. Although the AOAC itself maintains no laboratories, the organization coordinates collaborative studies, evaluates the results and gives official sanction to methods that are found to be reliable. This process promotes uniformity and reliability in the reporting of results and the development of criteria for laboratory accreditation and analyst certification. The cornerstone of the AOAC process is the interlaboratory collaborative study. Using this process, methods are validated through independent testing in separate laboratories under specified conditions. The collaborative study is organized and directed by a study director designated by the AOAC. The study director must have experience and knowledge in the component, matrix and methods being evaluated. A primary responsibility of the study director is the generation of a detailed protocol that includes not only the specifics of the method, but also every aspect of the process including sample handling and preparation as well as reporting requirements. Valid data from a minimum of 8 laboratories are required for analytical methods. Furthermore, the number of laboratories used multiplied by the number of samples tested must equal at least 40. The purpose of the testing is to evaluate the method, not the analyst. For this reason, all analysts follow the method exactly as written. All results are compiled and evaluated by the study director who then prepares a comprehensive report, including rigorous statistical analysis, as well as comments and observations from the study participants. After a review of the data, the study director may choose to reject or recommend the method. If the method is recommended, it is passed on to a general referee who has recognized expertise in a given scientific discipline or product area. If, after reviewing the data, the general referee recommends the method, it is reviewed by the methods committee and, if approved, attains First Action status (1). At this time, the method will be used and commented on for a period of at least 2 years. After this period, the method can be recommended for official final action. Of the hundreds of methods developed, only a small percentage attains official status. Eight to 12 qualified laboratories are required for a collaborative study. Each must successfully analyze at least five sets of samples and standards according to an approved protocol. The results are then compiled and statistically evaluated. The data are reviewed and, if accepted, the method is used and further evaluated and modified in laboratories for a minimum of two years. After the trial period, adoption of a method as Official Final Action is determined by a vote of the Official Methods Board. The AOAC methods are recognized worldwide as an authoritative resource, and are written into the US Code of Federal Regulations, used to document product specifications, monitor quality control, relied on in legal proceedings and required as a basis of international trade. They are also adopted by national and international organizations

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Method Milestones 77

such as the International Standardization Organization, Codex Alimentarius Commission and American Association of Cereal Chemists. Methods which undergo this rigorous process can be used with confidence by regulatory agencies, industries, laboratories and academic institutions to determine compliance with government regulations, maintain product quality and develop analytical standards. Several of these have been adopted by the US Pharmacopeia (USP) which also has a set of compendial methods available for botanical analysis. Although some of these methods have not been subject to a complete collaborative study process, they have undergone stringent evaluation (2). In addition, several USP certified reference standards (e.g. ephedrine, chondroitin, Echinacea) are now available.

Method Milestones In recent years, researchers have developed and validated analytical methods for some of the more popular botanical compounds and there are currently more than 30 methods undergoing development and validation within the AOAC process. The methods being developed and validated primarily involve separation and determination of compounds using chromatographic techniques. Although the specific solvents and detection techniques may vary, analysis of most botanical products involves essentially the same steps (i.e. extraction, separation, detection). Before extraction, the product is ground to a powder and stored in airtight, light resistant containers. Using an appropriate solvent (e.g. methanol), the components of interest are extracted. A chromatographic process is then used for separation and detection. High performance liquid chromatography (HPLC) methods are the technique of choice for most products (Table 6.2). Without doubt, the highest priority has been the focus on ephedrine-type alkaloids which have been identified as being associated with a significant number of adverse incidents and have been banned by many countries including the USA. Originally, three methods were identified that could potentially meet the scientific and regulatory standards. The first method reviewed was developed by the FDA and uses liquid chromatography for separation and mass spectroscopy for detection (LC/MS). The method was modified to utilize a tandem stage MS (LC/MS-MS) system which facilitates optimum chromatographic parameters and a mode of detection that provides improved precision and accuracy as well as allows measurement of both the precursor and product (i.e. parent and daughter) ions for positive analyte identification (4). This method has completed the collaborative study process and is valid for the measurement amounts of ephedrine (EP), pseudoephedrine (PE), norephedrine (NE), norpseudoephedrine (NP), methylephedrine (ME) and methylpseudoephedrine (MP) in raw Ephedra sinica herb, ephedra extracts, ephedra tablets, complex dietary supplements containing ephedra, and a variety of other matrices. Aristolochic acid is found primarily in the plant Aristolochia but may also be present in other botanicals. Due to concerns about the potential for kidney damage from the use of supplements containing aristolochic acid, the FDA initiated a ban on the import of products containing this ingredient. Adoption of validated methods is

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Table 6.2 Current status of methods Method

Analyte(s)

Status

Aloe Aristolochic acid Carotenoids Chondroitin Chromium picolinate Coenzyme Q10 Cranberries

Glucomanans Aristolochic acid Beta-carotene Chondroitin sulfate

Single lab validation published Undergoing collaborative validation Approved standard Undergoing collaborative validation

Ubiquinone Anthocyanins Proanthocyanins Organic acids Six alkaloids Ginkgolides Flavonoid aglycones Glucosamine Triterpene glycosides Ginsenoside Allicin Alkamides Yohimbine Kavalactone Colostrum Glycyrrhizic acid Isoflavones

Approved standard Undergoing single lab validation

Ephedra alkaloids Ginkgo Ginkgo Glucosamine Black cohosh Ginseng Garlic Echinacea Yohimbe Kava IgG Licorice Isoflavones Soy isoflavones L-carnitine Lutein Lycopene Methocel MSM Omega 3 ORAC Phosphatidylserine Polyphenols SAMe Saw palmetto St John’s wort Vitamin E Pesticides

L-carnitine Lutein Lycopene Dietary fFiber Methyl sulfonyl methane DHA/ALA/EPA Antioxidants Phosphatidylserine Polyphenols Folin-ciocalteu S-adenosylmethionine Phytosterols Free fatty acids Hypericin Hyperforin Alpha-tocopherol Tocotrienol DDT, HCH,

Expert review panel Approved standard Undergoing single lab validation Approved standard Approved standard Call for methods Undergoing single lab validation Call for methods Expert review panel Call for methods Call for methods Undergoing single lab validation Call for methods Undergoing single lab validation Working group formed Undergoing single lab validation Undergoing single lab validation Undergoing single lab validation Method extension underway Undergoing single lab validation Working group formed Undergoing single lab validation Undergoing single lab validation Approved standard Single lab validation required Undergoing single lab validation Undergoing single lab validation Undergoing collaborative study

endosulfan, monochrotophos, ethion, chloropyrifos, phorate, 2,4-D, butachlor, isoproturon alachlor, atrazine, methyl parathion, malathion, aldrin, dieldrin Source: AOAC (3)

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Method Milestones 79

imperative because products that are suspected to contain aristolochic acid can only be allowed to enter the USA when adequate testing shows that the suspect ingredients are not present. An expert review panel recommended the evaluation of a twophase method. The method uses HPLC for separation and ultraviolet (UV) detection for an initial screen. If positive results are found, the sample is reinjected and MS is used for confirmation and quantiation. A single laboratory validation (SLV) study has been completed and plans for a full collaborative study are currently underway. The analysis of Ginkgo involves the use of two methods, one for quantitation of the aglycones and a second for determination of the terpene lactones. The flavonoids are hydrolyzed with acid to form aglycones. The three major aglycones are quantitated using HPLC with an ultraviolet (UV) detector. The terpene lactones are extracted in a mixture of methanol and ethyl acetate. Quantitation is done using HPLC and an evaporative light scattering detector. In ginseng, the six ginsenosides of interest are extracted in a mixture of acetonitrile and water. Quantitation is performed on an HPLC using an evaporative light scattering detector. Saw palmetto is the partially dried, ripe fruit of the American dwarf palm. It is analyzed for the content of several free fatty acids and specific plant sterols. Although campesterol, stigmasterol, and beta-sitosterol are phytosterols found in several plants, their presence is a good indicator of saw palmetto. Using gas chromatography, a cholesterol assay was modified to allow measurement of these compounds in saw palmetto raw materials and dietary supplements at concentrations of 1.00 mg/100 g. The lipid is saponified at high temperature with ethanolic potassium hydroxide solution. The unsaponifiable fraction containing the phytosterols and other sterols are extracted, the phytosterols are then derivatized to trimethylsilyl ethers and quantified by gas chromatography. This method has completed the SLV process and will undergo a collaborative study in the near future (5). The antioxidant properties of polyphenolic compounds, such as those found in Echinacea, have resulted in the need for the analytical methods to support product development and regulatory compliance. The compounds were isolated utilizing reversed-phase high-performance liquid chromatography and quantified using UV detection. The method has been used to quantify the major catechins found in teas, wine and a variety of foods and dietary supplements. Through the use of modified extractions and multiple detection systems, a variety of other compounds can also be analyzed including echinacea (i.e. caftaric acid, chlorogenic acid, cynarin, cichoric acid and echinoside), trans-resveratrol, caffeine and gallic acid. Chondroitin sulfate is a natural substance sometimes used for the treatment of arthritic conditions. The original method recommended by an expert review panel was modified so that it is capable of quantifying the di- and tri-sulfated derivatives. This modification was necessary because, during the original method development, the USP definition for chondroitin sulfate was used (i.e. chondroitin sulfate from bovine, porcine or avian sources) which does not contain the di- and tri-sulfated forms which are commonly found in marine cartilage. This modification was accomplished by making a minor change in the chromatography involving using a gradient of either the ion pairing agent concentration or organic concentration. The method development phase has been completed and an SLV is underway.

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Good Science is the Goal As a result of the increased use and visibility, questions have been raised about the level of testing and certifications necessary to ensure that an ingredient is what it purports to be, is not adulterated and is not contaminated with pesticide residues or other impurities. The dietary supplement industry has long recognized the need for validated methods and standard manufacturing processes. The collaborative development of methods is a significant proactive measure that will result in the availability of rigorous validated assays in advance of the data being mandated by regulators. These comprehensive tests are the key to quality data which, in turn, lead to enhanced consumer confidence and product success. Regardless of whether inhouse or outside resources are used, solid scientific practices and regulatory knowledge must be an integral part of any business plan.

References 1. Horwitz W, Latimer G. (2005). AOAC Official Methods, 18th edition. AOAC International. 2. United States Pharmacopeia. (2005). USP 28, NF 23. US Pharmacopeial Convention, Inc. 3. AOAC International. Status of Methods for Dietary Supplements. www.aoac.org/dietsupp6/Dietary-Supplement-web-site/DSHomePage2.html 4. Sullivan D, Wehrmann J, Schmitz J, Crowley R, Eberhard J. (2003). Determination of ephedra alkaloids by liquid chromatography/tandem mass spectrometry. J AOAC Int 86(3). 5. Sorenson W, Sullivan D. (2006). Single laboratory validation for the determination of campesterol, stigmasterol, and beta-sitosterol in saw palmetto raw materials and dietary supplements by gas chromatography. J AOAC Int 89(1).

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Importance of Safety Assessment 7 Breaking Down the Barriers to Functional Foods, Nutraceuticals and Claims 8 Nutraceutical/Drug/Anti-Terrorism Safety Assurance Through Traceability

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PART

4 83 109

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Breaking Down the Barriers to Functional Foods, Nutraceuticals and Claims

7

George A. Burdock1 and Ioana G. Carabin2 1

Burdock Group, Orlando, FL, USA

2

Woman in Science, Vero Beach, FL, USA

Abstract At a time when 150 million Americans spend over $20.5 billion on functional foods, nutraceuticals and dietary supplements, the Food and Drug Administration (FDA) is doing little to ensure that all the safe and efficacious products that could come to the market are allowed to do so. FDA has only responded slowly and reluctantly to Congressional action and to mandates from the Courts to implement the law. For example, FDA had set the bar too high for Health Claims and was forced by the Courts to implement a more reasonable standard, but the response, Qualified Health Claims, has failed to gain the confidence of the public because of the obtuse wording of claims demanded by FDA. Also, FDA-forced public disclosure of proprietary efficacy data assures few new products will be developed because there will be no return on investment for research performed by the manufacturer. Lastly, the 70% rejection rate of New Dietary Ingredient Notifications indicates FDA is not judging dietary supplements by the mandated standard of reasonable expectation of no harm, but enforcing the higher standard of reasonable certainty of no harm, the standard for food safety. This higher standard has forced manufacturers to take the safety decision making out of FDA’s hands by turning to the Generally Recognized As Safe process. The pressure on FDA and Congress for change is again building with increased public clamor for resolution on claims for functional foods. FDA needs to consolidate the claims into three categories – health claims for foods, claims for functional foods and claims for dietary supplements. FDA has the power and the duty to resolve the conflict and relieve the burden that has been created for industry, consumers and for itself. With the addition of the ‘functional food’ category, realistic distinctions between the categories, use of expert panels Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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84 Breaking Down the Barriers to Functional Foods, Nutraceuticals and Claims

and, maintenance of proprietary efficacy information – FDA can be seen as the champion of consumers and encouraging manufacturers to perform research to come up with new and better solutions for a demanding customer base. There is precedent for all of these suggested actions and compelling reasons to take the suggested route. The time for FDA to step up to the plate is now, before the credibility of the Agency is compromised.

Introduction Historically, food was something we ate as the result of its having taste, aroma or nutritive value. Today, however, most consumers recognize additional categories of foods, including added-value categories of ‘functional foods’ and ‘nutraceuticals’, located somewhere along a continuum of substances that have more benefit than simple foods and probably thought of as generally equivalent to “officially recognized” vitamins and minerals. The precise value a consumer might place on functional foods or nutraceuticals likely bears directly on the consumer’s self-image. That is, a hypothetical functional foods/nutraceuticals consumer might see himself/herself as normally performing within a range of 80–90% efficiency; a range in which he feels in equilibrium with his surroundings. Below 80% efficiency, there is no longer the ‘good feeling’ about oneself (i.e. no longer in equilibrium); and even lower, the status of feeling ‘sick’, prompting a need for some sort of therapeutic intervention (i.e. a drug). The upper end of this range, 90%, is the best one could expect to feel, given healthy lifestyle habits and ordinarily available foods. The goal is to maintain oneself in the 80–90% range, but given the conventional environment of only a limited food selection or restrictions on physical activity, staying within this optimal range can only be accomplished as the result of an exogenous influence and functional foods or nutraceuticals may put that goal within easier reach. There are likely a variety of other reasons for consuming these value added substances and may include a concern about the high cost of prescription drugs, a quest for more natural remedies or simply engaging in preventative measures (e.g. fiber), but there is no doubt that consumption of functional food and nutraceuticals is on the rise. According to a recent Bill in the US Congress1, over 158 000 000 Americans regularly consume these value added substances and consumer expenditures on dietary supplements (alone) reached a reported $20 500 000 000 in 2004, more than double the amount spent in 19942.

Table 7.1 Evolution of health care 2000 BC 850 AD 1000 AD 1940 AD 1985 AD 2007 AD

Here, eat this root That root is heathen; here, say this prayer That prayer is superstition; here, drink this potion That potion is snake oil; here, swallow this pill That pill is ineffective; here, take this antibiotic That antibiotic doesn’t work anymore; here, eat this root

Adapted from Rowe, 1999 (1)

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Terminology 85

Terminology To food formulators, functional foods and nutraceuticals have a slightly different meaning, as being those foods that contain some health-promoting component(s) beyond traditional nutrients. To the Food and Drug Administration (FDA), these terms have no meaning in regulation or the law and, in fact, are regarded as ‘fanciful’ (Table 7.2). This seeming inflexible posture by FDA is the result of the mandate to the Agency from Congress to protect the public from ‘snake oil’ salesmen and ‘health crusaders’ of the early 20th Century, with outlandish claims for healing foods3. That is, for foods, FDA must ensure that the substance does not touch upon the definition of a drug (so there is no potential to defraud the consumer), according to the definition of a drug in the Federal Food Drug and Cosmetic Act (FFDCA): … articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals [or] articles (other than food ) intended to affect the structure or any function of the body of man or other animals … (§201(g)(1)(B) FFDCA) Sometimes, however, when an article (food) is a nutrient, it can act like a drug when it prevents a disease (such as scurvy), cures or prevents (e.g. starvation) and treats a disease such as hypovitaminosis. Nutrients have regulations governing their use and all must be approved as such by the Food and Drug Administration (FDA)4, as well as any food substance for which a health claim (or qualified health claim) is to be made. Likewise, in the definition of a drug, there is a provision that a substance is not necessarily a drug simply because the label contains a health claim; this provides flexibility for certain foods, which may contain a health claim. Claims permitted for food are shown in Table 7.3. There are as well, ‘foods for special dietary use’5 and ‘medical foods’6; however, there are no efficacy standards for either of these categories nor is there a requirement for pre-market approval by FDA.

Table 7.2 Regulatory versus ‘fanciful*’ terms Regulatory terms

Other terms

Drug Food Food ingredient (food additive or GRAS) Food for special dietary use Medical food Nutrient supplement1 Dietary supplement Cosmetic

Nutraceutical Aquaceutical Functional food Herbal supplement Cosmeceutical Natural food

*‘… an arbitrary or fanciful name which is not false or misleading in any particular’2 1 21 CFR 170.3(o)(20) [substances] ‘that are necessary for the body’s nutritional and metabolic processes’. 2 21 CFR 133.148(e)(2) http://www.cfsan.fda.gov/~lrd/FCF133.html (site visited 19 Apr 08).

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Table 7.3 Five types of health-related statements or claims are allowed on food and dietary supplement labels 1. Nutrient content claims indicate the presence of a specific nutrient at a certain level 2. Structure and function claims describing the effect of dietary components on the normal structure or function of the body 3. Dietary guidance claims describing the health benefits of broad categories of foods 4. Qualified health claims conveying a developing relationship between components in the diet and risk of disease, as approved by the FDA and supported by the weight of credible scientific evidence available 5. Health claims confirming a relationship between components in the diet and risk of disease or health condition, as approved by FDA and supported by significant scientific agreement

Ef fic ac y

Fr ee

s es cc ra te ea Gr ty fe

Sa

sp ee ch

FDA

Consumer demand Industry

Consumer

Figure 7.1 The struggle: players and issues.

Recently, FDA has given voice to a possible new group of ‘bioactive’ food ingredients (3). Examples of this new category from the generally recognized as safe (GRAS) notification list include: vegetable oil sterol esters, phytostanol esters, lactoferrin, fructooligosaccharides, small planktivorous pelagic fish body, oil, fish oil concentrate, tuna oil, diacylglycerol and inulin (3). Another example of a bioactive food ingredient that received food additive approval several years ago is Olestra®, ‘the no-fat cooking oil with the full-fat flavor’7,8. However, is approval of Olestra® a genuine leap in creative application of the FFDCA or just progress in food technology? How can Olestra® be considered any more of a special category than oleomargarine (with no cholesterol) was over butter and the new ‘no trans-fats’ margarine over conventional margarine? FDA’s creative application of the law can resolve, as in the Olestra® example, the current conundrum of a definition and acceptance of claims for functional foods and nutraceuticals.

The Struggle: Players and Issues At this point, all stakeholders (i.e. consumers, industry and the FDA) have taken positions creating a tension with the other two (Fig. 7.1). Consumers are demanding greater access to products for which they see a benefit and industry is demanding that its right of free speech be not abridged by FDA. The push-back by FDA is fulfillment of its mandate to protect the consumer, ensuring the product is safe and to

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Ontogeny and Current Status of the Regulations 87

protect the consumer from fraud as the result of false claims on the label9. How did we get to this stalemate and how can it be resolved?

Ontogeny and Current Status of the Regulations A generation or two ago, an aging population accepted getting older, retiring to less active pursuits and ceded center stage to the next generation but, in the current youth oriented culture, the current aging generation (the baby boomers) are less willing to give in to the aging process and are seeking some palliative treatment. In addition, the shear number of aging Americans presents a forbidding burden to the heath care system, which is more geared to treatment than preventative measures10. The answer to both forces is to engage in prevention through healthier lifestyles and dietary choices before the inevitable onset of age-associated disease ‘… let food by thy medicine …’ (Hippocrates, 460–377 BC). The Japanese Ministry of Health Care recognized the size and gravity of the problem in the late 1980s and responded with FOSHU (Foods for Specialized Health Uses)11,12; the objective of which is to keep the aging population as healthy as possible for as long as possible (4). Similarly-intended legislation was passed by Congress with the National Labeling and Education Act (NLEA) in 1990 (allowing health claims for foods), which was followed, in 1997, by the Food and Drug Modernization Act (FADMA), (attempt by Congress to liberalize the FDA’s narrow interpretation of NLEA), and the Dietary Supplement Health and Education Act (DSHEA) in 199413. Each amendment to the Act permitted certain types of claims. As public interest increased and distinctions began to be made between products, the terms functional foods and nutraceuticals were coined. As indicated earlier, while neither term is supported by regulation or the law, each has a certain cachet that supports a persuasive concept. Another important regulatory milestone was the system of generally recognized as safe (GRAS), for review and approval of ingredients for addition to food, was included in the 1958 amendment to the FFDCA to provide an additional avenue for approval of food ingredients; a system parallel to the food additive petition process that is administered by FDA. A substance is GRAS, if there is agreement ‘… among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures (or, in the case as a substance used in food prior to January 1, 1958, through either scientific procedures or experience based on common use in food) to be safe under the conditions of its intended use’14. That is, a GRAS expert panel examines the data relevant to the safe use of a substance, including testing data and exposure (consumption) data, manufacturing information and specifications. Once found to be GRAS, a substance may be added to only those food categories at levels for which it was approved15. While not a requirement, some manufacturers choose to undergo the GRAS Notification process to determine if FDA is in agreement with the GRAS determination. To date, over 3000 ingredients have been approved by this method and represents a model of industry and regulator cooperation16 (5).

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Health Claims and the National Labeling and Education Act and the Food and Drug Modernization Act The NLEA (1990), which permitted health claims (HC) for food, had long been resisted by the FDA, with the idea that any health claim would render the product an unapproved drug. However, the degree of safety required for these substances for which health claims would be permitted was never in doubt because these substances would be added to food and, by default, must meet the food safety standard, reasonable certainty of no harm, embodied in the concept of generally recognized as safe (GRAS) or that of a food additive petition (FAP). Debate has centered on the ‘proof of efficacy,’ required for a health claim to meet the standard of Significant Scientific Agreement (SSA)17; importantly and, like drugs, only a government agency can determine if the standard was met. Further, a health claim required promulgation of a regulation by FDA (including a proposed rule, comment period and a final rule). In January of 1993, FDA adopted final regulations implementing NLEA health claims, but never established specific criteria for SSA, stating only that it would make case-by-case determinations. FDA also indicated that it would not permit disease (i.e. health) claims for which a difference of scientific opinion exists18. Because this standard was simply set too high, Congress passed the 1997 Food and Drug Modernization Act (FDMA), as an attempt to liberalize the interpretation FDA had required for health claims, by allowing the claims to be based on ‘authoritative statements’ of qualified scientific bodies much like judgments of safety could be made by expert panels for GRAS substances. In response, FDA met Congress half-way by allowing National Academy of Science or National Institutes of Health type statements such as those describing the benefits of fluoride in drinking water, low trans-fats in heart disease or the presence of choline in a particular food. However, these are not ‘health claims’, but ‘nutrient content claims’, which FDA calls ‘FDAMA claims’. However, FDA still maintains control, indicating that FDA must be notified of the claim and, if FDA does not act to prohibit or modify the claim, it may be used 120 after receipt of the notification by the Agency.19 In December of 1999, FDA made the pivotal decision that there must be significant scientific agreement about the substance/disease relationship rather than the actual claim being made20. While this decision pushed beyond what was required in the law (FFDCA 403(r)(3)(B)(i)) (which only required significant scientific agreement about the claim), it had the effect of forcing petitioners perilously close to the edge of a drug claim, leaving only a narrow gap for claims for a reduced incidence of disease in otherwise healthy populations. For example, because a claim based on reducing the symptoms of arthritis in arthritis-sufferers became a drug claim, manufacturers were forced to test the ability of the substance to decrease the incidence of arthritis in the general population – significantly, the population could not already have arthritis. This requirement to test in a general population resulted in a quantum leap in the cost of proving the claim, because it required a very large sample size, a much longer study duration and complex subject exclusion criteria (6,7). Further, FDA continues to cling to the weight of evidence concept, contrary to the urging from

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Qualified Health Claims 89

Single large clinical trial In vitro or animal (laboratory) data only

Supportive epidemiologic data Contradictory epidemiologic data Supportive laboratory data

Single small clinical trial

Contradictory laboratory data

Supportive laboratory data Small uncontrolled human studies

Multiple small clinical trials

Required Body of consistent, relevant evidence from well-designed clinical and/or epidemiologic and laboratory studies. Weight of evidence supportive

Consistent results with flawed designs Consistent results with good designs

Epidemiologic data: consistent results

Consistent results with good designs

Difficulty measuring substance Epidemiologic Epidemiologic data: data: contradictory consistent results results

Biologic plausibility and consistent laboratory data

Critical reviews by experts

Meta analyses Contradictory laboratory data Emerging evidence

Evidence accepted by federal scientific bodies or independent expert bodies as basis for public health recommendations NAS, NIH, CDC, AHA, ACS, etc.

Reviews by credible disinterested expert groups

Significant Scientific Agreement Consensus

Figure 7.2 Schematic for assessing strength and consistency of scientific evidence leading to significant scientific agreement (http://vm.cfsan.fda.gov/~dms/ssaguide.html).

the Courts that credible evidence be permitted as the basis of a claim. As illustrated above, the chances are slim for achieving SSA based on anything other than the ‘gold standard’ of an interventional, randomized, controlled clinical trial21 (Fig. 7.2). Although there are now 12 SSA claims, claims languished at the Agency until 1993, when the first claim (calcium and osteoporosis) was approved (Table 7.4). It would be fair to say that none of these claims were ‘tough calls’ and, for many, the claims were obviously valid even before new supporting data were generated in response to the requirement for SSA. Interestingly, while FDA maintained that the evidence supporting an SSA claim be nearly unshakable, the Agency, to it’s credit, has indicated that as the result of new evidence, it will review the evidence supporting the Health Claims for 21 CFR 101.73 (‘Dietary lipids and cancer’) and 21 CFR 101.82 (‘Soy protein and risk of coronary heart disease’). http://www.fda.gov/OHRMS/DOCKETS/98fr/cf0748. pdf (site accessed 19Apr2008). In comparison, the Japanese FOSHU list of foods or ingredients is lengthy (Table 7.5).

Qualified Health Claims The goal of an SSA/health claim regulation is rarely, or at best, slowly obtained by petitioners. This is because the very Agency that had resisted passage of the NLEA

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Table 7.4 Significant scientific agreement* 21 CFR

Substance and disease or health-related condition

101.72 101.73 101.74 101.75 101.76 101.77

Calcium and osteoporosis Dietary lipids and cancer**** Sodium and hypertension Dietary saturated fat and cholesterol and risk of coronary heart disease Fiber-containing grain products, fruits and vegetables and cancer Fruits, vegetables and grain products that contain fiber, particularly soluble fiber, and risk of coronary heart disease Fruits and vegetables and cancer Folate and neural tube defects Dietary non-cariogenic carbohydrate sweeteners and dental caries Soluble fiber from certain foods and risk of coronary heart disease Soy protein and risk of coronary heart disease**** Plant sterol/stanol esters and risk of coronary heart disease Whole grain foods and risk of heart disease and certain cancers Potassium and the risk of high blood pressure and stroke

101.78 101.79 101.80 101.81 101.82 101.83 Proposed** Proposed*** *

http://www.cfsan.fda.gov/~dms/flg-6c.html (site visited 19 Apr 08); Docket No. 99P-2209 (Claims Authorized Based on Authoritative Statements By Federal Scientific Bodies: a ‘FDAMA claims’.) *** Docket No. 00Q-1582. **** As the result of new information (Dec 07) these claims will be reviewed and may be rescinded. **

Table 7.5 FOSHU (foods for specialized health uses) Health claim Functional ingredients Food that improves gastrointestinal conditions Prebiotics: oligosaccharides, raffinose, lactulose, arabinose Probiotics: Lactobacillus, Bifidobacterium Dietary fiber Foods for those with high serum cholesterol Soy protein and peptide, alginate, chitosan, sitosterol ester Foods for those with high blood pressure Peptides

Number of products approved

Type of products in the market

336

Soft drinks, yogurt, cookies, table sugar, soybean curd, vinegar, chocolate, powdered soup, fermented milk, miso soup, cereal

28

Soft drinks, meat balls, sausage, soy milk, soup, cookies, margarine

42

Soft drinks, soup, drinkable products containing probiotic bacteria, soybean products

Foods for those with high serum triacylglycerol Diacylglycerol and sitosterol 9 Foods related to mineral absorption and transport Casein, calcium citrate, isoflavone 17 Non-cariogenic foods Mannitol, xylitol, paltinose Foods for hyperglycemics Wheat albumin, globulin digest, polyphenols

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Cooking oil Soft drinks, fermented soybean (natto), jelly

6

Chocolate, chewing gum

4

Candy, soup, soft drinks

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Qualified Health Claims 91

Table 7.6 Qualified health claims subject to enforcement discretion Cancer risk Tomatoes and/or tomato sauce and prostate, ovarian, gastric and pancreatic cancers Calcium and colon/rectal cancer and calcium and recurrent colon/rectal polyps Green tea and cancer Selenium and cancer* Antioxidant vitamins and cancer * As the result of new information (Dec 07) these claims will be reviewed and may be rescinded Cardiovascular disease risk Nuts and heart disease Walnuts and heart disease Omega-3 fatty acids and coronary heart disease B vitamins and vascular disease Monounsaturated fatty acids from olive oil and coronary heart disease Cognitive function Phosphatidylserine and cognitive dysfunction and dementia Diabetes Chromium picolinate and diabetes Hypertension Calcium and hypertension, pregnancy-induced hypertension and pre-eclampsia Neural tube birth defects 0.8 mg folic acid and neutral tube birth defects

health claim process was made the gatekeeper for approvals of the very claims it had resisted making before NLEA was passed. The bar for SSA status was simply set too high and, in response, a series of lawsuits were launched against FDA (i.e. Pearson versus Shalala and others) asserting the right of commercial free speech on food labels. As the result of decisions by the Court, FDA was forced to provide a mechanism accommodating free speech. In response, FDA unveiled Task Force Final Report: Consumer Health Information for Better Nutrition Initiative in July 2003, allowing for Qualified Health Claims (QHC), which were theoretically something less than an (unqualified) health claim under the rubric of ‘emergent’ evidence. For QHC, FDA has chosen not to officially approve any claims, but instead ‘exercise enforcement discretion’ relative to claims FDA has mandated using its qualifications. As the result of new information having emerged which may affect the basis of the claims for ‘selenium and cancer’ and ‘antioxidants vitamins and cancer’, FDA has announced that it will review the evidence supporting these claims. (http://www.fda.gov/OHRMS/DOCKETS/98fr/cf0748.pdf) (site accessed 19Apr08) At present, there are six categories for which the Agency has allowed claims, but the claims permitted have been worded by FDA to accommodate FDA’s estimate of the strength of the scientific evidence supporting the claims (Table 7.6). Needless to say, in an Agency as conservative as FDA, the claims are sometimes only those from which a competitor could benefit, as exemplified by the claim for green tea and cancer: Based on FDA’s review of the strength of the total body of publicly available scientific evidence for a claim about green tea and reduced risk of breast cancer, FDA

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ranks this evidence as the lowest level for a qualified health claim. For the reasons given above, FDA concludes that it is highly unlikely that green tea reduces the risk of breast cancer22. Based on FDA’s review of the strength of the total body of publicly available scientific evidence for a claim about green tea and reduced risk of prostate cancer, FDA ranks this evidence as the lowest level for a qualified health claim. For the reasons given above, FDA concludes that it is highly unlikely that green tea reduces the risk of prostate cancer23. Permission from the FDA to use claims, such as above, does not provide much encouragement to manufacturers to generate the quality and quantity of data apparently required to convince the Agency of the validity of a claim. At this point, the standard will continue to be set by SSA. Consumers are, as well, disappointed by the qualified health claims allowed by the Agency. Consumer survey information (8) has demonstrated that the use of a letter grade for claims, embedded disclaimers or point-counterpoint statements are often interpreted wrongly. Three categories of problems emerged: 1. some consumers felt that the claim reflected the quality of the product, rather than the strength of the evidence supporting the claim; 2. anything less than a ‘B’ grade was unacceptable and; 3. the statements had the paradoxical effect such that structure–function claims were looked upon more favorably than QHCs, presumably because of fewer ‘weasel-words’.

Dietary Supplement Health and Education Act – Structure Function Claims and a New Safety Standard A Closer Look at the Definition On a similar front, in the early 1980s, the use of dietary supplements began to proliferate, quickly followed by FDA attempts to curtail them through several measures, including a challenge that dietary supplements were actually unapproved food additives (9). Congress responded again to public demand by passage of DSHEA, which declared dietary supplements not to be food additives, but foods, for which structure/function claims (SFC) could be made. The rationale by which dietary supplements were actually foods, is evident from the list of examples provided by Congress (Table 7.7). Clearly, this list is one of substances that either should be or could be, a legitimate addition to the diet. Particularly insightful is the phrase ‘a dietary substance for use by man to supplement the diet by increasing the total dietary intake’ – this confirms that Congress viewed supplements as substances that should or could have been part of the diet in the first place but, importantly, did not require the substances to have established nutritive value. Implied by its omission is the requirement that the dietary

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Dietary Supplement Health and Education Act 93

supplement must be extracted from the actual food; that is, the supplement could be produced by synthetic means, just so it mimics the dietary supplement identified in food. The closeness of the mimicry has not generally been addressed in any guidelines promulgated by FDA, but persuasive logic would include an argument that if a substance were made more stable or more effective or without possible toxic ligands, this ‘improvement’ would be acceptable. Lastly, the supposition that the dietary supplement should or could have been part of the diet is reflected in the claims allowed. That is, DSHEA allows three types of ‘statements of nutritional support’ on labels without obtaining FDA’s approval (Table 7.8), with the caveats; that: 1. the statement is truthful, not misleading and can be documented; 2. a statement follows the claim relating to the fact that FDA does not endorse the claim and; 3. that the substance is not a drug (according to the definition of a drug)24. That is, only structure/function claims may be made (Table 7.8). These claims relate only to the maintenance of a physiologic function or structure (e.g. healthy bones or healthy urinary tract function), which falls short of a nutrient claim. DSHEA also requires that ‘the statement be truthful and not misleading’. Table 7.7 Definition of a dietary supplement (Federal Food Drug and Cosmetic Act (FFDCA)) Chapter II – Definitions SEC. 201 For the purposes of this chapter (ff) The term ‘dietary supplement’ – (1) means a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: (A) a vitamin; (B) a mineral; (C) a herb or other botanical; (D) an amino acid; (E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or (F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E)

Table 7.8 Supplement claims SEC. 403. [343] (r)(6) For purposes of paragraph (r)(1)(B), a statement for a dietary supplement may be made if: ● the statement claims a benefit related to a classical nutrient deficiency disease and discloses the prevalence of such disease in the United States, describes the role of a nutrient or dietary ingredient intended to affect the structure or function in humans ● [the statement] characterizes the documented mechanism by which a nutrient or dietary ingredient acts to maintain such structure or function [of the body], or ● [the statement] describes general well-being from consumption of a nutrient or dietary ingredient. However, these claims are allowed only if: ●

●

●

(B) the manufacturer of the dietary supplement has substantiation that such statement is truthful and not misleading, and (C) the statement contains, prominently displayed and in boldface type, the following: ‘This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.’ … the manufacturer shall notify the Secretary no later than 30 days after the first marketing of the dietary supplement with such statement that such a statement is being made.

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Until recently, foods per se were permitted to bear structure/function claims, but such claims were made on the basis of the nutrients they contain and for which a daily requirement (e.g. an RDA) has been established (10); for example, calcium in milk or potassium in orange juice. However, in an FDA Guidance Letter to industry dated January of 2007, FDA indicated a willingness to extend the use of structure function claims of foods25. That is, the agency expressed a willingness to go beyond the permitted ‘calcium builds strong bones’ type of claim and allow structure/function claims that characterize the means by which substances act to maintain such structure or function, for example, ‘fiber maintains bowel regularity’ or the claim may describe general well-being from consumption of a nutrient or dietary ingredient. In this notice, FDA also indicates it will allow structure/function claims to describe a benefit related to a nutrient deficiency disease (such as vitamin C and scurvy), ‘as long as the statement also tells how widespread such disease is in the US…. [and] such claims may not explicitly or implicitly link the relationship to a disease or health-related condition’. Further, the FDA insists that ‘the claims must derive from the nutritional value26 of the product’27, (albeit the fact that the few, even in the agency, would admit that fiber or probiotics are added for nutritional value). Howsoever, this statement, if read in the context of 21 CFR 172.5 (i.e. ‘The quantity of the substance added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food’) will likely be construed such that the structure/function claim must be achieved at the level at which provides the original effect (of taste, aroma or nutritive value; or any of the technical effects recited in 21 CFR 170.3(o). For example, if a flavor ingredient provided the needed flavor at 10 ppm, but supports a structure/function effect at a minimum of 50 ppm, but no change in flavor, is the manufacturer limited to only 10 ppm? Therefore, if an effective dose is higher, clearly, there will have to be a review of safety at this higher level (i.e. GRAS or food additive petition), but the manufacturer is still without an ‘approved’ effect.

The Exclusionary Clause Of particular interest to dietary supplement manufacturers should be the exclusionary clause of DHSEA (Table 7.9). This clause simply indicates that a dietary supplement cannot have had prior use as a drug or have been under investigation as a drug with clinical studies having been instituted. This provision theoretically prohibits the re-direction of substances once intended for use as drugs to the dietary supplement market or the marketing of a dietary supplement version of a drug (e.g. as a Table 7.9 Exclusionary clause (FFDCA 201(ff)(3)(B)) The definition of a dietary supplement does not include: (i) an article that is approved as a new drug, … certified as an antibiotic … or licensed as a biologic … or (ii) an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, which was not before such approval, certification, licensing, or authorization marketed as a dietary supplement or as a food …

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less potent form, such as might be used for an over-the-counter drug). A case in point was the marketing of red yeast rice (Cholestin®) which, although having been used as a food in China for centuries and in the USA for decades, was known to contain HMG-CoA reductase inhibitors (which lower blood cholesterol). It was maintained by the manufacturer that these inhibitors, although natural to the food, are indistinguishable from the synthetic lovastatin, the active ingredient in the prescription drug, Mevacor® by Merck. Based on this similarity and the fact that the manufacturer of Cholestin® had tweaked the manufacturing process to maximize the level of HMG-CoA reductase inhibitors, Cholestin® was determined a ‘drug’ by FDA and could not be marketed as a dietary supplement (12). The take home lessons here are three: 1. a manufacturer should not use a process designed to heighten the concentration of a constituent; 2. there should be no promotion of a particular constituent of a supplement, unless that constituent was previously marketed as a dietary supplement and; 3. the mere presence of a substance in the food supply may not be sufficient to meet the standard as having been previously marketed. In a case similar to the Cholestin®/lovastatin case, a citizen petition to FDA by BioStratum, Inc., states, among other things, that it is the manufacturer of Pyridorin® (pyridoxamine dihydrochloride), which is the subject of an investigational new drug (IND) that was filed with FDA in July 1999; that Pyridorin® was being tested for use as a potential therapeutic agent to slow or prevent the progression of diabetic nephropathy in patients with type 1 and type 2 diabetes. The petition further states that substantial clinical trials have been conducted for this drug and that the existence of those studies has been made public. In addition, the petition states that pyridoxamine was not marketed as a dietary supplement or as a food prior to Pyridorin’s® authorization for investigation as a new drug under an IND28. FDA is awaiting comments regarding the prior use of this substance as a dietary supplement before it makes a final decision. An ironic twist of fate may result if FDA determines that pyridoxamine is, in fact, covered by the exclusionary clause, and if BioStratum, Inc., decides not to market Pyridorin®, the end result may be a loss to the consumer because pyridoxamine would be forever precluded from being marketed as a dietary supplement.

The Standard for Safety A cause of controversy with DSHEA is the setting of a different standard for safety than that for food ingredients and, therefore, substances for which a health claim or qualified health claim can be made. The new standard is the concept of reasonable expectation of no harm, articulated in the FFDCA as [no] ‘significant or unreasonable risk of illness or injury’, above (Table 7.10)29. The basis for this rationale is that consumption of a dietary supplement is by choice, not involuntary as for a food and, because there is choice, there is an assumption of some risk on the part of the consumer. In many respects, DSHEA was a safety valve, venting consumer discontent with the high degree of restriction placed

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Table 7.10 Definition of an adulterated food SEC. 402. [342] A food shall be deemed to be adulterated – (f)(1) If it is a dietary supplement or contains a dietary ingredient that – (A) presents a significant or unreasonable risk* of illness or injury under – (i) conditions of use recommended or suggested in labeling, or (ii) if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use (B) is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury (C) the Secretary declares to pose an imminent hazard to public health or safety … *Importantly, this was changed from ‘significant and unreasonable risk’ in the original bill.

upon health claims. A tacit bargain between Congress and the consumers was struck, whereby Congress granted continued access by the public to dietary supplements by: 1. providing for a lower threshold of evidence for safety; 2. changing the role of FDA from gatekeeper to policeman (i.e. abandoning pre-market approval) and; 3. allowing a new type of claim (i.e. structure function claim, not health claim)29. The consumer’s concessions were that: 1. supplements could not be added to food (because of the lower threshold for safety for the supplement); 2. consumption will always remain the product of an overt, voluntary act on the part of the consumer (a dietary supplement can never be represented as a food) and; 3. because the recommended daily dose is presented on the supplement, the consumer will assume at least some risk30 from consumption (articulated by the standard of reasonable expectation of no harm (21 CFR 190.6(a)31). Because no system is perfect, Congress empowered the Secretary of Health and Human Services (not the Commissioner of FDA), to take action through the ‘imminent hazard’ clause of the regulation if the supplement is determined to be unsafe under the suggested conditions of use. Therefore, keys to a SFC are: 1. the substance must maintain a physiologic function and; 2. the standard of safety of reasonable expectation of no harm. The results so far on DSHEA are uneven. One provision of DSHEA was to allow continuation of the sale of dietary supplements marketed prior to October 1994; for substances not marketed prior to this date, a New Dietary Ingredient Notification (NDIN) to FDA was required. However, the exact criteria for what constitutes a marketing of a substance prior to October 1994 is unclear, especially as it relates to what sort of marketing is claimed and to whom. What is very clear is that FDA intends to use the NDIN provision as a mechanism for premarket notification of new dietary supplements. At this point in time, out of the substances submitted since November

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15 1999, 69% have been rejected32 but of the 45 substances submitted as NDINs in 2006, there was a 90% rejection rate (15). FDA has cited several reasons for objecting to these submissions, including: 1. mismatches between the marketed and tested ingredient; 2. use of therapeutic language, i.e. ingredient is represented for treatment or mitigation of a disease state; 3. use of food language, i.e. ingredient is represented as a traditional food; 4. clinical studies have been done via non-oral routes, but most often; 5. a lack of sufficient safety data and/or that the substance fails to meet the safety standard. FDA does not provide guidelines as to the type or amount of safety data it would find to be persuasive; it only indicates that safety must be demonstrated to the ‘reasonable expectation of no harm’ standard. This is not to say that some ‘objections’ by FDA are not well-founded. Some new dietary ingredient notifications have rightfully been faulted, as some submitters had the misguided assumption that a lower safety standard means no safety standard. However, an inspection of the rationale for rejection would seem to be an application of a higher standard than the threshold of ‘reasonable expectation’. This extraordinarily high ‘objection’ rate of rejection and application of a higher standard of safety, is essentially a form of paternalism and abrogates the bargain with the public; namely, a lower standard of safety for an assumption of risk, especially in light of the ‘reasonable consumer’ standard adopted by FDA (14). The core of the issue is simply that the regulatory Agency equates ‘expectation’ to ‘certainty’ thus, negating or at least diminishing the distinction between the two standards of safety. The Agency ‘expects’ the NDI notifier to be ‘certain’ of the safety of the ingredient, and this mind-set is not likely to change. In many ways, this attitude by the Agency is understandable, that the Agency likely feels it must err on the side of conservatism and recent episodes with legend drugs, such as Bextra® and Vioxx®, as well as adverse effects and publicity on kava kava and ephedra, lessen the chances that FDA will cede more safety decisions to the general public. Because of the high objection rate for NDINs, the predictable response from manufacturers will be to take control of the decision process, by opting out of the DSHEA program remove consideration of the new dietary ingredient by FDA and face near certain objection and, have the substance reviewed as a food ingredient through a GRAS determination. This route adds a potential increase in time and expense to generate safety data and prepare a safety dossier to the ‘reasonable certainty’ safety standard. However, this approach has the advantage of taking the decision of safety out of the hands of the FDA for an NDIN, especially when the GRAS acceptable daily intake includes consumption from use as a dietary supplement. It would be essential, however, to indicate in the NDIN, that the substance had been found GRAS (and undergone Notification), otherwise an intractable Gordian knot would be created if FDA decides that the data were insufficient to meet the reasonably expectation standard.

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The Immediate Future and the Path Forward The Immediate Future For the immediate future, without a comprehensive change in the statute or movement within the Agency, it is likely that (unqualified) health claims will remain as now positioned: approved under SSA in response to overwhelming evidence of health benefit and to distinguish a decision by the Agency from that promulgated by industry. However, qualified health claims (QHC) is the area where the greatest opportunity for change could occur.36 QHC will likely experience at least one more round in the Courts, addressing the issue of freedom of commercial speech with two significant changes: 1. an abandonment of the various grades of acceptance, settling on a binary system of ‘yes’ or ‘no’ for a claim, rather than leaving the public baffled with confusing statements and; 2. abandonment of the strictly ‘in-house’ review system (which currently includes various ‘evidence-based’ practice centers), leveling the playing field and including an option for review by independent panels of experts, much on the model of the GRAS system and similar to that employed by the Federal Trade Commission (i.e. ‘competent and reliable scientific evidence … based on the expertise of professionals in the relevant area’). The pressure for this change is mounting and will come rather soon, in response to new and different types of claims, many of which will be generated as the result of progress in nutrigenomics, proteomics and metabolomics. For example, for substances such as sulforanes (as detoxicants, promoting enzymes for type II detoxication reactions), sulfur compounds in garlic (which decrease gastric nitrosamine formation), proanthocyanins in cranberries and health claims for specific subpopulations (e.g. higher amounts of biotin are required by pregnant women of Mexican descent than women of Western European heritage, and for which precedent has been established by setting a standard for choline intake, a substance not required so much for women, as it is for men). These changes for QHC will also be a response to safeguard against a proliferation of inclusions into the ‘foods for special dietary use’ and ‘medical foods’ categories, two categories for which the framework for admission has not been well established. It is likely that future QHCs will be directed toward specific enhancements and specific population subsets, rather than addressing the general population. This will require re-thinking how clinical studies will be conducted and the general caveats that a substance will be safe for anyone to consume (within guidelines) and may instead have particular benefit for a specific population subset.

Four Things FDA Must Do to Resolve the Impasse Recalling Figure 7.1, there exists an impasse between the interested parties in functional foods, dietary supplements and the like, between FDA, industry and consumers. However, much of the foregoing text has described what amounts to failed attempts by FDA to respond to the situation. These palliative attempts have resulted

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The Immediate Future and the Path Forward 99

Table 7.11 Four things FDA must do to resolve the impasse 1. 2. 3. 4.

Create a new category of ‘functional’ claims Promote the use of independent expert determinations Initiate a notification system Provide a term of exclusivity and return on investment (ROI) for manufacturers

only in a stalemate that, as mentioned earlier, the Court or Congress may be forced to resolve, but the power of immediate resolution rests with FDA, with four actions, all of which are within the regulatory powers of the Agency (Table 7.11). Create a New Category of ‘Functional Claims’

Functional claims should be defined only as ‘providing a health benefit beyond basic nutrition’. FDA needs to make the switch in the mindset from ‘health’ claims to ‘functional’ claims. This category should be more relaxed in its requirements than those for health claims or qualified health claims – something that is more realistic and attainable. The More Obvious Have Been Identified At this point in time, we have already found the ‘no brainer’ nutrients, such as the vitamins and minerals, for which a deficiency was clinically obvious. Among these more obvious nutrients were vitamin C, a deficiency of which resulted in scurvy, thiamine (beri beri), iodine (goiter) and calcium (rickets). Likewise, we have also found those dietary elements whose absence (or excess) extracted a terrible cost to the public and, at great expense, have been incorporated in to regulation as health claims (e.g. calcium and osteoporosis, sodium and hypertension and dietary fiber and cancer (see Table 7.4)). As indicated earlier, the cost for clinical studies resulting in a health claim is prohibitive, thus requiring public funding for generation of most data. The cost for such studies basically shuts out most companies, especially when no return on investment can be expected. Moving Forward on a New Category To move forward with this new category of functional claims, FDA must (a) disconnect the health–disease relationship, (b) allow claims based on changes in biomarkers, (c) allow claims for specific population subsets and, (d) most of all, remain flexible. For FDA to make the ‘disconnect’ between substance and disease is essential and FDA must acknowledge that not all substances will have the same effect on all or even a majority of consumers. FDA must sever its mandated connection because the concept is intrinsically hobbled by three factors: (a) for something to be a ‘disease’, it must meet criteria which often require decades of debate and the debate is often distorted by political and economic interests; (b) the substance may only affect a ‘symptom’ or a biomarker which, when so affected, may be a desired outcome; and (c) not all or even a majority of people can be expected to experience the same effect from a substance. Agreement on what constitutes a disease is an arduous process. Many diseases are still unknown or undefined to the satisfaction of a consensus among mainstream scientists – such was the case with what we now recognize as a folate deficiency. What

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we may now judge to be the result of an aging process, an adverse bad reaction to a food or drug, an unexplained event or worse, wrongful attribution is all too often taking place. How long was ‘early-onset’ senility diagnosed before Alzheimer’s disease became known? How many died from unexplained cardiovascular and neurological deterioration in middle age before obstructive sleep apnea was agreed upon? How long was Crohn’s disease or gluten-sensitivity characterized as ‘indigestion of unknown origin’? Some ‘conditions’, if identified as diseases, may have undesirable political or economic outcomes. For example, recognizing a new disease may then require coverage by health, disability insurance or pension plans. Also, some charitable organizations and researchers have a vested interest in preserving unsolved problems and may find it difficult to make the transition to something else once the raison d’être no longer exists. For example, while the March of Dimes©33 has successfully made the transition from successfully combating polio to now ‘… preventing birth defects, premature birth, and infant mortality’34, many foundations might not be able to make such a successful transition. A change in a biomarker should be sufficient basis to make a claim. The second compelling reason for the ‘disconnect’ between a substance and a disease is that mitigation of a biomarker may be as important as mitigation of a disease. For example, while we know that abatement of hypertriglyceridemia or hypercholesterolemia has a statistically significant association in the reduction of risk of coronary heart disease, might there be other beneficial effects as well? Under the current system, the effect on each possible end disease would have to be tested (see also below). While the debate continues in the scientific community about the beneficial effects of decreased homocysteine levels, many educated consumers and clinical practitioners are already convinced of the need to lower these levels; further, because consumers and clinicians are convinced that the argument among scientists only has to do with efficacy and not safety, why not allow consumers a chance to decrease homocysteine blood level? Why not allow a truthful statement such as ‘Substance X will lower homocysteine blood levels’ as a claim? Consumers will rarely agree the Agency or mainstream science moves fast enough to respond to scientific developments, so if the association between the biomarker and the substance is demonstrated, then the consumer should be allowed to make the decision for him or herself. Not all consumers can be expected to benefit equally from a treatment. It has long been known that not all drugs will have the same quantitative or qualitative effects in all patients. For example FDA Center for Drug Evaluation and Research (CDER) does not approve drugs on the basis of imputed mechanism of action, but on empirical result, e.g. did the drug lower blood pressure? In the past few years we have learned that efficacy is not only controlled by availability of receptor sites and metabolism, but the ‘-omics’ of the individual (metabolomics, influencing the metabolism of the drug) and even ‘nutragenomics’ (when certain constituents of foods (or lack of these constituents), may have a profound response on the individual, e.g. tyramine in fish and monamine oxidase inhibitors) and/or the ability of the individual to ‘up-’ or ‘downregulate’ specific genes. Could it be that some of the several hundred ‘orphan diseases’ are actually as yet unidentified nutritional deficiencies in those victims with the disease? The Agency cannot expect that all subjects will respond equally or even

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The Immediate Future and the Path Forward 101

Confidential submission to agency

Dossier approved by independent experts (1) Safety and proposed claim (2) Supporting evidence

Decision by Agency

Criteria reviewed by agency Claim & supporting evidence (Limited review criteria)

Public notice by Agency

FDA Website No objection

Inadequate

(1) Experts qualified ‘…by training and experience…’ (2) Credibility of supporting data

‘Truthful statement’ (the claim) Product identity Manufacturer Safety data

No public notice Returned to submitter Figure 7.3 Notification system.

at all; the criterion for confirmation should be simply that the biomarker exhibited change in a susceptible population when treated with the substance. Now is the time to make the tough choices and allow claims for which a consensus may not exist, but for which persuasive clinical and mechanistic data do exist. Now is the time to allow changes in biomarkers and persuasive data from the new sciences of proteomics and metabolomics and to allow special subpopulations to experience a benefit. However, it should be clear that while a functional food may benefit only a small subset of the population, all functional foods must be safe for all consumers35. Promote the Use of Independent Expert Determinations

The second thing FDA must do is to accept input from independent expert panels, a concept for which there is ample precedent. These outside expert decisions include generally recognized as safe determinations for food ingredients; the now unused provision for experts determining drugs as generally recognized as safe and effective, but which has since morphed into the OTC drug reviews and the numerous FDA advisory panels. Use of independent expert panels could serve FDA for dietary supplements as well as claims for functional foods. Initiate a Notification System

Experts making claims for safety and efficacy will submit a confidential dossier on the substance, describing the safety, efficacy and rationale for both (Fig. 7.3). The agency can make a determination on the credibility of the experts and the credibility of the supporting data (i.e. ‘credible evidence’ as mandated by the court, not ‘weight of evidence’ as now observed by FDA). If the decision is that the dossier is not persuasive, the dossier will be returned to the submitter, without prejudice, for a possible re-submission. If, on the other hand, the document is found to be persuasive, FDA would inform consumers through a posting on the FDA website

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No ROI

$

X

Manufacturer

$

X Research & Development

Consumer demand

Manufacturing and Distribution

Safety testing

Marketing

Efficacy testing

$

‘Pirate’ FDA no objection Public release of efficacy data

Figure 7.4

with the product name, name of the manufacturer and the safety data. The efficacy data would remain confidential and placed in a food master file. While all safety data would be made public and could be relied upon by other submitters for their dossiers, any additional substances making a claim must submit their own efficacy data – there would be no piggy-backing on efficacy claims. This system would respond to demands for consumer empowerment, demands for commercial free speech and would relieve a potential log jam of petitions. Provide a Term of Exclusivity and Return on Investment (ROI) for Manufacturers

Keeping efficacy data proprietary is the essential fuel for driving research. Without the possibility for return on investment, there is no incentive for research. Making the efficacy data public has effectively killed the value that might otherwise have been derived from health claims or qualified health claims. Again, safety data should be made public, but efficacy data should remain secret, at least for some period in which the investment can be recaptured (Fig. 7.4). As depicted in Figure 7.4, the solid lines in the schematic illustrate the proposed method, i.e. manufacturers investing in research and upon a ‘no objection’ from the Agency, the manufacturing, marketing and distribution chains can be started up to serve the public and return profit to the manufacturer. However, if the ‘no objection’ notice by the Agency also reveals the efficacy data (see dashed lines), then pirates (for lack of a better term), can also start up their manufacturing, marketing and distribution chains and without the cost of research, can sell the product at a much lower price. This selling at a lower has the predictable effect of bleeding off profits for the return on the investment (ROI) needed to fuel more research and product innovation steps.

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Conclusion 103

Conclusion At a time when 150 million Americans spend over $20.5 billion on functional foods, nutraceuticals and dietary supplements, the Food and Drug Administration (FDA) is doing little to ensure that all the safe and efficacious products that could come to the market are allowed to do so. FDA has only responded slowly and reluctantly to Congressional action and to mandates from the Courts to implement the law. Additionally, FDA had set the bar too high for health claims and was forced by the Courts to implement a more reasonable standard, but the response, qualified health claims, has failed to gain the confidence of the public because of the confusing wording of the claims demanded by FDA. Further, disclosure of efficacy data has prevented ROI and development of new products. Congressional efforts to assure consumer access to dietary supplements have been met with similar resistance from FDA. The Dietary Supplement Health and Education Act (DSHEA) was the product of a compromise with a lower threshold for demonstration of safety (reasonable expectation of no harm) that would be met by consumer self-policing and assumption of some risk. FDA has thwarted this effort by raising the bar for New Dietary Ingredient Notifications (NDIN) to what appears to be the higher threshold for the safety of food ingredients (reasonable certainty of no harm) – FDA apparently sees these two safety thresholds as a distinction without a difference. As a result, increasing numbers of dietary supplement manufacturers, unwilling to gamble the future of their products to a system that provides little hope for the FDA’s response of ‘no objection’, have committed the additional resources necessary to obtain generally recognized as safe (GRAS) status for their supplements. The pressure on FDA and Congress for change is again building with increased dissatisfaction among consumers as the result of confusing labels and among manufacturers saddled with unreasonable requests for data with no expectation for return on their investment. While, if the confusion about health claims and the claims for dietary supplements were not enough, there is now public clamor for resolution on claims for functional foods. FDA has within its power to resolve the conundrum of so many claims borne of fine technical differences and presumptions of the ability of the consumer to distinguish the Byzantine wording of one type of claim or grade from another. FDA needs to consolidate the claims into three categories – health claims for foods, functional foods and dietary supplements. Health claims should remain the gold standard and require the highest level of proof of a health effect. The new category of functional foods would be those substances falling somewhat short of the threshold of a health claim and be substantiated by criteria such as biomarkers and mechanistic studies, not requiring the evidence of disease incidence reduction. Dietary supplements would remain relegated to structure function claims and not permitted to be added to food as they only satisfied the lower threshold of reasonable expectation of safety (Table 7.12). FDA has the power and the duty to resolve the conflict and relieve the burden that has been created for industry, consumers and for itself. With the addition of the ‘functional food’ category, use of expert panels and maintenance of proprietary

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Table 7.12 Resolution to the impasse Health claims

Functional food

Dietary supplements

Safety standard

Reasonable certainty

Reasonable certainty

Reasonable expectation

Addition to food

Yes

Yes

No

Type of claim

Health and disease reduction

Reduction of symptom, change in biomarker or clinical finding

Structure/functiona

Level of evidence supporting efficacy

Gold standard interventional studies

Meta-analysis of studies, biomarker change, epidemiological studies, mechanistic evidence, smaller clinical trialsb

One or more persuasive studies related to maintenance of healthy function or structure

Deciding body

As presently exists (FDA and regulation promulgated)

Expert panel with notification to FDA (no regulation promulgated)c

As presently exists

Public disclosure

Safety information, product identification and manufacturer. Efficacy information held in confidential master file for ⬎10 years

Safety information, As presently exists product identification and manufacturer. Efficacy information held in confidential master file for ⬎10 years

a

Structure/function claims are permitted for food ingredients. Generally considers two or more studies with consistent results within the more developed category shown in Figure 7.2 as ‘emerging evidence’. Discrepancies in data must be resolved to the satisfaction of the expert panel. c The agency notification review limited to (1) credibility of the experts (modeled on the description of experts in §201(s) of the FFDCA) and (2) credibility of submitted supporting evidence. b

information (on efficacy), FDA can be seen as the champion of consumers and encouraging industrial research to come up with new and better solutions for an aging and demanding customer base. There is precedent for all of these suggested actions and compelling reasons to take the suggested route. The public sees at least the food side of FDA as monolithic and all the good works on protection of the food supply from bioterrorism, spoiled goods, adulteration and mislabeling may be lost. The time for FDA to step up to the plate is now, before the credibility of the Agency is compromised.

Acknowledgments Portions of this article were previously published as ‘The Importance of GRAS to the Functional Food and Nutriceutical Industries’ in Toxicology 221, 12–27, 2006. The authors wish to thank Jim Griffiths for his editorial contribution.

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Notes 105

Notes 1

109th U.S. Congress (2005–2006); H.R. 2510 Dietary Supplement Regulatory Implementation Act of 2005. 2 H.R. 2510 (http://www.govtrack.us/congress/billtext.xpd?bill⫽h109-2510; site visited 03FEB07). 3 See: Worton JC (1982). Crusaders for Fitness. The History of American Health Reformers. Princeton University Press, Princeton, NJ. 4 21 U.S.C. 343(r)(4)). ‘According to the Nutrition Labeling and Education Act (NLEA, 1990), a nutrient must have an established amount that exerts a beneficial effect, such as a RDI. However, the food components being studied today for their beneficial effects [e.g. fiber or broccoli with high amounts of sulforanes] may not yet have recognized levels and therefore may not meet the NLEA standard for a nutrient’ (2). 5 21 CFR 105. 6 Medical foods are regarded as foods for the maintenance of a patient as opposed to a treatment. Further, medical foods are not those foods included within a healthy diet intended to decrease the risk of disease, such as reduced-fat foods or low-sodium foods, nor are they weight loss products (http://www.cfsan.lfda.gov/~dms/ds-medfd.html) (site visited 11Feb 07). 7 http://www.olean.com (site visited 11Feb07)8 8 Interestingly, Olestra® is not a ‘Food for Special Dietary Use’ (21 CFR 105.3) nor does it have a health claim. 9 FTC and FDA have complementary jurisdiction over the marketing of dietary supplements and similar products. Under the terms of a 1971 liaison agreement, the FTC has primary responsibility for regulating advertising and the FDA has primary responsibility for labeling (http://www.ftc.gov/opa/1998/08/fdaadvoc.htm) (site visited 19 Apr 08). 10 The 55–64 age group is expected to rise from 29 million Americans in 2004 to 40 million in 2014, Associated Press, December 8, 2005 (http://www.msnbc.msn.com/ id/10383942/) (site visited 11 Feb 07). 11 FOSHU are foods that are composed of functional ingredients that affect the structure/function of the body. These foods are used to maintain or regulate specific health conditions, such as gastrointestinal conditions, blood pressure and blood cholesterol level (4). 12 The FOSHU system is authorized by the Nutrition Improvement Law (Law No. 248, July 31, 1952, Amended by Law No. 101, May 24, 1995) and the Nutrition Improvement Law Enforcement Regulations (Ministerial Ordinance No. 41, July 1991, Amendment to Ministerial Ordinance No. 33, May 25, 1996). (http://www.nceff.com.au/pdf/Japan. pdf) (site visited 11 Feb 07). 13 The Federal Trade Commission (FTC) also has an interest in policing claims, but under the memorandum of understanding of 1971, FTC concerns itself with advertising instead of label claims. In this case, the standard set by FTC is ‘competent and reliable scientific evidence’, defined in FTC cases as ‘tests, analyses, research, studies, or other evidence based on the expertise of professionals in the relevant area, that have been conducted and evaluated in an objective manner by persons qualified to do so, using

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procedures generally accepted in the profession to yield accurate and reliable results’. The FTC does indicate, however, that it would defer to another agency (e.g. FDA), with expertise in the particular area. 14 FFDCA §201(s) (http://www.fda.gov/opacom/laws/fdcact/fdcact1.htm; site visited 03 Feb 07). 15 The specific nature of a GRAS determination was reinforced by FDA in 1974 with the following Federal Register announcement: ‘It has been too often assumed that the GRAS substance may be used in any food, at any level for any purpose. As a result, the uses of some GRAS food ingredients have proliferated to the point where the GRAS status was brought into serious question’ (Federal Register 39:34194–5, 1974). 16 Since the inauguration of the notification program in 1997, as of December 30, 2005, 184 substances have been submitted to FDA for review. The greatest source of GRAS determinations, the Flavor and Extract Manufacturers Association, does not submit Notifications. 17 The precise definition of which was not included in the law. 18 Federal Register 58:2501–02, 1993. 19 Guidance for Industry: Notification of a Health Claim or Nutrient Content Claim Based on an Authoritative Statement of a Scientific Body (June 11, 1998). 20 Guidance for Industry: Significant Scientific Agreement in the Review of Health Claims for Conventional Foods and Dietary Supplements (http://vm.cfsan.fda.gov/ ~dms/ssaguide.html) (site visited 03 Feb 07). 21 Ibid (http://vm.cfsan.fda.gov/~dms/ssaguide.html) (site visited 11Feb 07). 22 Letter responding to health claim petition dated January 27, 2004: Green tea and reduced risk of cancer health claim (Docket number 2004Q-0083). (http://www.cfsan. fda.gov/~dms/qhc-gtea.html) (Site visited 03 Feb 07). 23 Ibid. 24 This statement avoids the conundrum of ‘when is a food a drug’ (e.g. cure disease (such as starvation), mitigate or prevent a disease (such as a vitamin deficiency) and further; that, ‘[a] food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement is made in accordance with section 403(r)(6) of this title is not a drug … solely because the label or the labeling contains such a statement’. 25 http://www.cfsan.fda.gov/~dms/flguid.html (site visited 18 Feb 07). 26 Presumably, ‘nutritional value’ includes ‘taste’ and ‘aroma’ as per Nutrilab v. Schweiker. 713 F.2d 335 (CA 7, 1983); although according to 21 CFR 101.14(b)(3), a substance identified as the basis of a health claim, may be any of these three or ‘or any other technical effect listed in §170.3(o) of this chapter, to the food and must retain that attribute when consumed at levels that are necessary to justify a claim’. Because Hutt (11) asserts the limitation that a structure/function claim must directly relate to the nutritive value of the food has doubtful enforceability, FDA will likely extend this inclusion of technical effects to structure function claims as well. 27 Nutritive value means a value in sustaining human existence by such processes as promoting growth, replacing loss of essential nutrients or providing energy. (21 CFR 101.14(a)(3)). 28 Federal Register: November 18, 2005 (Volume 70, Number 222) page 69976–69977, Request for Comment on the Status of Pyridoxamine.

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References 107

29

Also articulated in the FFDCA (§413) as ‘reasonably be expected to be safe’. (http:// www.fda.gov/opacom/laws/fdcact/fdcact4.htm) (site visited 11 Feb 07). 30 FDA has stated that it would use a ‘reasonable consumer’ standard in determining whether a claim is misleading. The reasonable consumer standard replaced the standard of ‘the ignorant, the unthinking, and the credulous’ consumer, used by courts at the request of FDA in the past (13). 31 Referred in the FFDCA (§402(f)(1)(A)) as ‘significant or unreasonable risk of illness or injury’ (http://www.fda.gov/opacom/laws/fdcact/fdcact4.htm) (site visited 11 Feb 07). 32 §402 (f)(1) ‘If it is a dietary supplement or contains a dietary ingredient that (B) is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury …’ (http://www.fda.gov/opacom/laws/fdcact/fdcact4.htm) (site visited 11 Feb 07). 33 © 2007 March of Dimes Foundation. 34 Excerpted from the March of Dimes Foundation mission statement. (http://www. marchofdimes.com/; site visited 03 Feb 07). 35 Interestingly, this concept is very nearly already addressed in the regulations at 21 CFR 172.5(c) ‘The existence of any regulation prescribing safe conditions of use for a nutrient substance does not constitute a finding that the substance is useful or required as a supplement to the diet of humans. 36 In fact, change may come quickly, as in March of 2008, two US Senators (Durbin and Kennedy) and two US Representatives (DeLauro and Waxman), have written a letter to the FDA commissioner (von Eschenbach) asking FDA to make explicit its plans regarding a December 17, 2007 appropriations bill in which Congress “urged the FDA not to use funds provided in this bill to review requests for qualified health claims for conventional foods or to issue letters permitting such claims through exercises of enforcement discretion.”

References 1. Rowe SB. (1999). Round table forum, moderators comments. In What is a nutrient? Defining the food-drug continuum. Georgetown University. March 30. 2. Anonymous (1999). Executive Summary. In What is a nutrient? Defining the fooddrug continuum. Georgetown University, Center for Food and Nutrition Policy. Proceedings of a Symposium, Ceres Forum, March 30. 3. Rulis A. (2005). Food safety and nutritional risk. Bioactive food components. CSL/ JIFSAN Symposium on Food Safety and Nutrition. July. 4. Bailey R. (2005). Functional foods In Japan: FOSHU (foods for specific health uses) and foods with nutrient function claims. In Regulation of functional foods and nutraceuticals, Hasler. C. (ed.), pp. 247–261. Blackwell Publishing, Ames. 5. Burdock GA, Carabin IC. (2004). Generally recognized as safe (GRAS): history and description. Toxicol Lett 150, 3–18.

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6. Carabin IG. (2004). The clinical aspects of claim substantiation: clinical trial costs. FDLI Update 4, 39–43. 7. Carabin IG. (2004). The clinical aspects of claim substantiation: inclusion/exclusion criteria, screening and baseline evaluations in clinical trials. FDLI Update 5, 41–45. 8. International Food Information Council (IFIC) (2005). Qualified health claims consumer research project executive summary http://www.ific.org/research/qualhealthclaimsres.cfm (site visited 25 Dec 05). 9. Burdock GA. (2000). Dietary supplements and lessons to be learned from GRAS. J Regulat Toxicol Pharmacol 31, 68–76. 10. Council for Agricultural Science and Technology (CAST) (2003). Issue Paper No. 24, Nutraceuticals for health promotion and disease prevention. Camire, ME (chair). CAST, Ames, IA, 16 pages. 11. Hutt PB. (2000). U.S. Government regulations of food with claims for sepcial physiological value. In Essentials of functional foods, Schmidl K, Labuza T (eds), pp. 339–362. Aspen Publishers, Inc., Gaithersburg. 12. Kracov DA, Rubin PD, Dwyer LM. (2005). Dietary supplements and drug constituents: the Pharmanex v. Shalala case and implications for the pharmaceutical and dietary supplement industries. In Regulation of functional foods and nutraceuticals, Hasler C (ed.), pp. 137–148. Blackwell Publishing, Ames. 13. Walsh EM, Leitzan EK, Hutt PB. (2005). The importance of the court decision in Pearson v. Shalala to the marketing of conventional food and dietary supplements in the United States. In Regulation of functional foods and nutraceuticals, Hasler C (ed.), pp. 109–135. Blackwell Publishing, Ames. 14. Griffiths JC. (2005). The value of playing it safe. Function Foods Nutraceut Nov., 24–28. 15. Talati AR. (2007). New dietary Ingredient Notifications: A comprehensive Review and strategies for avoiding FDA objections. Food and Drug Law Journal, 62, 387–398.

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Nutraceutical/Drug/ Anti-Terrorism Safety Assurance Through Traceability

8

Paul A. Lachance The Nutraceutical Institute, The New Jersey Agricultural Experiment Station, New Brunswick, NJ, USA

Abstract Nutraceuticals are naturally occurring/derived bioactive compounds that are reported to have health benefits. The delivery systems for nutraceuticals are foods (functional foods), supplements or both. Drugs are designed to have medicinal properties for the prevention and treatment of identified diseases or signs and symptoms of disease. Counterfeit drugs contain placebo, materials not identified in the labeling or substandard or impure materials, which may produce untoward pharmacological or toxicological effects. In addition, the consumer has the right to microbiological safety and prevention from adverse exposure to hazardous chemical(s) and other adverse compounds. Nutraceutical/drug delivery systems are viewed as approaches to (a) enhanced consumer health, (b) decreased healthcare costs and (c) enhanced economic development. Therefore, the nutra/pharma/ceutical industry is reliant upon a strong underpinning of diversified research that addresses safety and assures chemical and biological efficacy. Significant safety through traceability can be assured by the coupling of the technologies of (a) global positioning (GPS); (b) bar/chip coding; and (c) hazard analysis critical control point (HACCP) management, coupled to rapid nanotechnology marker assays now under development.

Introduction The events of September 11, 2001 argue for the concept of traceability of all herbs and foods, nutraceuticals and ethical pharmaceuticals, not only for quality control Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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110 Nutraceutical/Drug/Anti-Terrorism Safety Assurance Through Traceability

and assurance but also to prevent the covert introduction of chemical and microbiological hazards as agents of terrorism or counterfeiting. The coupling of the three existing technologies described below and the sophistication of microbiological and chemical detection systems can simultaneously assure the intended quality of products per se and also assure against the introduction of counterfeit compounds and agents of terrorism. Safety through traceability (1) can be assured by the coupling of the existing technologies of (a) global positioning (GPS); (b) bar/chip coding; and (c) hazard analysis critical control point (HACCP) management, coupled to the on-going development of rapid (minutes and seconds) nanotechnology-based marker assays. The coupling of these technologies provides scientific underpinning, as well as global sourcing management, assuring standardization data for quality assurance of safety and efficacy, concurrently enhancing manufacturer accountability and making highly rapid and effective recalls possible. Safety is the agreed upon goal of all stakeholders and therefore it must be the foremost critical driver of food, nutraceutical and pharmaceutical marketing. Related goals, namely, standardization and efficacy are critical needs, but are viewed differently by the consumer, the regulators and the industry as the purveyor. Second only to safety is the goal of commercial viability and marketability (2).

Technologies Global Positioning of Agricultural Field of Crop or the Chemical Synthesis Manufacturing Plant The equipment for collecting GPS descriptors, which include latitude and longitude translatable into Arabic numbers, is compact. The equipment will fit into a small backpack and is accurate to a meter when three satellites are captured. The cost is less than $1000. For an example of the data describing a four-acre plot of high bush blueberry plants see Lachance and Saba (1). The first tier of safety requires that each food, nutraceutical or pharmaceutical per se (be it a known chemical entity or ingredient) and/or a herbal or functional food commodity (plant or animal) has a chemical identification and authentication. Thus, the ‘ceutical must have a pre-existing Chemical Abstracts Service (CAS) number, where the herbal or plant of the nutraceutical origin should have taxonomic identification, either by a systematic botanist and/or a DNA profile (genome). Iris identity in the case of farm animals is feasible. The toxicity history of the nutraceutical, functional food or herbal must be recognized to be low or nil. At this stage, the intelligent product delivery system for traceability begins with the GPS of the source (field or manufacturing site) (3).

Bar Coding Bar code technology is now practically universal for consumer products (http://www. taltech.com/TALtech_web/resources/intro_to_bc/bcbasics.htm). There are different degrees of bar coding sophistication, permitting the recording of considerable data and/or the recording of the location of files of data. This technology provides

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Standardization 111

accountability as well as data. Bar code readers sophisticated with chip technology are commercially available. With nanotechnology, the incorporation of chip capability within the consumer barcode is practically at hand. The bar code should include reference to the tier one technology files as well as the hazard analysis critical control point (HACCP) files that constitute tier three technology and thus, the concept of intelligent product delivery systems, as described by Lachance and Saba (1). Bar coding has become a universal method for identifying products and their manufacturer and bar coding is recognized by all consumers at the checkout counter. What the consumer overlooks is the connection to the mainframe, which provides the price of the article but also automatically provides a descriptor of the consumer and provides rapid inventory management. More advanced bar coding is available and is used to describe motor vehicles and their owner, drugs and dosage forms and to maintain inventories. These bar codes can be used to identify the source, various key dates, HACCP data and related files. Today, microchips with megabytes of information are available to replace bar coding.

Hazard Analysis Critical Control Points (HACCP) HACCP began at NASA to assure the microbiological safety and quality of flight food (4) and has been adapted to different degrees by regulators and the food industry. The system begins at the entry to the processing plant. Only state laws apply to commodities in transit. This is a major weak point in the system and opens up counterfeiting opportunities that are believed to lead to 100 000 deaths per year worldwide. Nanotechnology bar coding and global positioning at each transportation terminal needs to be sophisticated. If HACCP is in place, any suspicious lots should be identified and rejected upon entry (receiving) into the plant. HACCP permits the risk management of food or any chemical entity. The most critical HACCP parameter is microbiological, defined as freedom from food-borne pathogens, with microbiological tolerance limits allowed for non-processed food/herbal (e.g. spice) items. The goal can include the direct monitoring with rapid assay under development for Campylobacter, Staphylococcus, Salmonella, Listeria, 0157H7 Coli, Clostridium botulinum, viruses and bio-terrorism organisms such as the Centers for Diseases Control (CDC) designated Variola, Bacillus anthracis, Yersinia pestis, Francisella tularensis, Clostridium botulinum, Filovirus and Arenavirus. In addition, the third tier of safety includes a HACCP step that assures meeting the Environmental Protection Agency/ the Food and Drug Administration/US Department of Agriculture (EPA/FDA/USDA) standards for sorting out unacceptable particles and freedom from heavy metals (lead, cadmium, mercury etc.).

Standardization Standardization assumes that monitoring for safety is in place. Standardization addresses the assurance of product bioactivity and consistency achieved through measurements of chemical constituents or the conduct of biomarker assays. Variability in active ingredient(s) can be attributed to differences in genetics, environmental factors, age of the plant and the plant part in question, as well as seasonal and diurnal variations.

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112 Nutraceutical/Drug/Anti-Terrorism Safety Assurance Through Traceability

Information technology allows the delivery of greater product safety and value throughout the resource/product supply chain. This composite technology has been described as an Intelligent Product Delivery System (IPDS) (1).

Challenges Each IPDS technology is available but has not been fused. In addition, more smart devices and software are emerging. Meanwhile, the public is calling for safety, validation and accountability. Quantitative research is limited and unstructured, yet there is a need and a demand for standardization, particularly of nutraceuticals and other bioactives. Education is uneven and random. There is a regulatory ‘paranoia’. The consumer wants greater freedom of choice, but the regulator is conservative and sees a need to protect the consumer. Increased global sourcing of food/ingredients is resulting in greater actual and perceived safety issues. Health concerns of baby boomers are increasing. The industry is slow to adopt new technologies and gambles on the current system delivering greater and greater tonnage of domestic and imported, fresh and processed food. An increasing number of massive recalls of sufficient value to jeopardize profitability and/or continued business and/or filing for bankruptcy protection is telling and belies the facts. To realize the quality of life benefits from nutraceuticals, novel approaches to quality management are needed. The integration (IPDS) of the three technologies of global positioning, bar coding and HACCP can assure safety and overall product value. Furthermore, the Intelligent Product Delivery System can serve to assure protection from food-borne bio-terrorism.

Conclusion The coupling of three technologies, namely global positioning, bar coding and HACCP offer safety and protection of products in the food, nutraceutical and pharmaceutical industries from acts of terrorism through the synchrony of traceability, commencing with ingredient products from their origin, through processing and delivery to the consumer. A limiting factor is the development of very rapid assays for onsite monitoring through processing into final consumer packaging.

References 1. Lachance PA, Saba RG. (2002). Quality management of nutraceuticals, intelligent product delivery systems and safety through traceability. In Quality management of nutraceuticals, Ho C-T, Zheng Z (eds), pp. 2–9. American Chemical Society Series 803. 2. Childs NM, Lachance PA, Meaghe M. (2000). Advancing nutraceuticals opportunities: priorities for research. J Nutra Func Med Foods 2(3), 85–103. 3. Lockley AK, Bardsley RG. (2000). DNA-based methods for food authentication. Trends Food Sci Tech 11, 67–77. 4. Lachance PA. (1997). How HACCP started. Food Tech 51(5), letter.

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Regulations Around the World 9 10 11 12 13 14

15 16 17 18 19 20 21 22 23 24

FDA Perspective on Food Label Claims in the USA Health and Wellness Related Labeling Claims for Functional Foods and Dietary Supplements in the USA World Trade Organization and Food Regulation: Impact on the Food Supply Chain Emerging Policies and Practices Under the Canadian Natural Health Product Regulations European Legislation on Dietary Supplements and Functional Foods: Safety is Key Botanical Nutraceuticals (Food Supplements, Fortified and Functional Foods) in the European Union with Main Focus on Nutrition and Health Claims Regulation Regulations for Nutraceuticals and Functional Foods in Europe and the United Kingdom Complementary and Alternative Medicines in Australia and New Zealand: New Regulations Health Foods and Foods with Health Claims in Japan Regulations on Health/Functional Foods in Korea Chinese Approach on Regulating Food Additives, Novel Foods, Functional Foods and Dietary Supplements The Legislative Regulation of Biologically Active Food Supplements Circulation in the Russian Federation Regulations for Nutraceuticals and Functional Foods in the Indian Subcontinent Botanical Drugs, Nutraceuticals and Functional Foods: The Context of Africa Supplements and Functional Foods Legislation in Brazil Regulation of Functional Foods in Selected Asian Countries in the Pacific Rim

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FDA Perspectives on Food Label Claims in the USA

9

James E. Hoadley1 and J. Craig Rowlands2 1

FDA, Center for Food Safety and Applied Nutrition, College Park, MD, USA 2 The Dow Chemical Company, Toxicology and Environmental Research and Consulting, Midland, USA

Abstract Under the US laws that FDA enforces, food label claims generally fall into three categories: nutrient content claims, health claims and structure/function claims. Nutrient content claims are statements that characterize the level of a nutrient in a food. Nutrient content claims on food labels must be used in accordance with FDA authorizing regulations. Health claims describe a relationship of a food, food component or dietary supplement in reducing the risk of a disease or health-related condition. Health claims must be evaluated and authorized prior to their use in food labeling. There are three ways by which FDA exercises its oversight in determining which health claims may be used in food labeling. One way is the issuance of authorizing regulations based on FDA’s conclusion that there is significant scientific agreement that the available scientific evidence supports the relationship. A second way is through a notification to FDA of a health claim based on authoritative statements from a scientific body of the US government or the National Academy of Sciences that ensues from that scientific body’s deliberative review of scientific evidence on the substance/disease relationship. The third way provides for qualified health claims where the quality and strength of the scientific evidence falls below that required for FDA to issue an authorizing regulation. Structure/function claims are food label statements that describe the role of a nutrient or dietary supplement ingredient to affect normal structure or function in humans. Structure/function claims have historically appeared on the labels of conventional foods and dietary supplements. However, the Dietary Supplement Health and Education Act of 1994 established special regulatory procedures for the use of such statements on dietary supplement labels. Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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116 FDA Perspectives on Food Label Claims in the USA

Introduction Products, other than tobacco products and alcoholic beverages, marketed in the USA and intended for oral consumption are categorized for regulatory purposes as either foods or drugs. Within the context of the US Federal Food, Drug, and Cosmetic Act (FFD&C Act), dietary supplements are considered to be foods. Nutraceuticals and functional foods are food marketing concepts rather than regulatory categories and there are no US regulatory definitions to accommodate them separately from other foods. The US Food and Drug Administration (FDA) regulates the labeling of foods (other than US Department of Agriculture (USDA)-regulated meat products). The advertising of food falls under the jurisdiction of the Federal Trade Commission (FTC). Because the FDA and FTC enforce different laws, the regulations and policies pertaining to advertising and labeling of food differ. This chapter pertains to FDA regulation of food label claims and, as such, will not address advertising. Current US laws pertaining to food labeling are able, with some restrictions, to accommodate ‘functional foods’. The statutory definition of a ‘food’ in the FFD&C Act is: ‘an article used for food or drink for man or for other animals, chewing gum, and articles used for components of any such article’. The definition of a ‘drug’ in the FFD&C Act is, in part: ‘articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, and articles, other than food, intended to affect the structure or any function of the body of man or other animals’. Consistent with these definitions, the labeling1 of food may not include any information about the usefulness of a food to cure, mitigate, treat or prevent a disease, but food labels can present information about how a food may affect a structure or function of the body. The FFD&C Act also provides for the use of food label claims that describe how a food or food component may affect disease risk (i.e. health claims). The presence of an authorized health claim on a food label does not cause the intended use of the product to be a drug use. The statutory distinction between what is a food and what is a drug is based to a large extent on how the product is represented for intended use. It is possible for a substance to have both food and drug uses. An intended drug use does not necessarily preclude a product from also having a food use, or vice versa. Baking soda, for example, is useful both as an ingredient in baking (food use) and as a treatment of acid indigestion (drug use). A key phrase in the FFD&C Act drug definition is ‘intended for use’. Product labeling is one obvious way to show intended use of a product. A baking soda label stating that baking soda may be used for relief of acid indigestion shows that the product is intended to be used as a drug2. Any intended drug use must be in accordance with the premarket review and approval requirements for drugs, including efficacy and safety standards applicable to drugs. A product label claiming that the product is effective in the mitigation of a disease symptom (e.g. relief from osteoarthritis pain) shows the intended use of the product to be as a drug and therefore would be regulated as a drug, not as a food. A product labeled as a food may not bear a claim pertaining to use of the product as a drug (i.e. use in the cure, mitigation, treatment or prevention of any disease), irrespective of how good the evidence is to substantiate the effectiveness of the product for that particular use, unless the product has also been approved for use as a drug.

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Legal Basis for US Regulation of Food Label Claims 117

Legal Basis for US Regulation of Food Label Claims Most US laws pertaining to the labeling of food are contained within the FFD&C Act. FDA implements these laws through food labeling regulations found in title 21, Chapter 1, subchapter B, of the Code of Federal Regulations. The FFD&C Act has been amended by the US Congress several times in the 1990s to make significant changes in how food label claims are regulated. These amendments include: the 1990 Nutrition Labeling and Education Act (NLEA) (1), the 1994 Dietary Supplement Health and Education Act (DSHEA) (2) and the 1997 Food and Drug Administration Modernization Act (FDAMA) (3). NLEA amended the FFD&C Act in a number of important ways. Two chief aspects of the NLEA amendments to the FFD&C Act are that they established mandatory nutrition labeling for nearly all packaged foods sold in the USA and that they established FDA’s authority to regulate food label statements that characterize levels of nutrients in a food or that characterize relationships of food substances to a disease or healthrelated condition. In general, information provided by manufacturers on food labels is restricted only to the extent that the information may not be false or misleading. For nutrient content and health-related information, however, NLEA stipulated that statements characterizing the level of a nutrient in a food (nutrient content claims) and statements that characterize a relationship of a nutrient to a disease or health-related condition (health claims) may only be used in food labeling in accordance with relevant statutory provisions and FDA regulations. Although label statements such as ‘High Fiber’ (a nutrient content claim) and ‘Fiber May Reduce the Risk of Heart Disease’ (a health claim) may be perceived by many consumers as equivalent health messages, NLEA mandated that FDA regulate nutrient content claims and health claims as separate regulatory categories of food label statements. Although the FFD&C Act has always recognized that foods may be used to affect the structure or any function of the body, DSHEA added new provisions to the FFD&C Act defining and prescribing the use of structure/function claims in dietary supplement labeling. Structure/function claims describe a role of a nutrient or other dietary supplement ingredient in affecting the structure or function of the body (e.g. calcium builds strong bones). The process for substantiation and authorization of food label health claims in the USA has evolved from that initially established in 1990 under NLEA. The NLEA amendments require that FDA issue regulations authorizing use of a health claim about a substance/disease relationship only after having evaluated the scientific evidence for the substance/disease relationship and determining that the relationship is substantiated by an appropriate level of evidence. The validity requirement for the substantiation of health claims mandated by the NLEA amendments require an FDA assessment of ‘significant scientific agreement’ (SSA) among qualified experts that the totality of the scientific evidence supports the dietary substance/disease relationship. In 1997, FDAMA amended the FFD&C Act to provide an alternative to FDA’s process for SSA assessment and regulation of health claims. The FDAMA amendments provided for a process whereby the substantiation of a health claim is based on authoritative statements

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about a dietary substance/disease risk reduction relationship from any US federal scientific agency with official responsibility for public health protection or human nutrition research, or by the National Academy of Sciences or any of its subdivisions, rather than being based on an FDA review of the supporting scientific evidence. The FDAMA amendments also provided for the authorization of new authoritative statement-based nutrient content claims. The FDAMA provision for authoritative statement-based health claims and nutrient content claims was intended to expedite the process by which new claims are authorized. The basis for use of health claims further evolved following a series of court decisions which led to the 2003 FDA Consumer Health Information for Better Nutrition Initiative (4) under which certain ‘qualified health claims’ supported by credible, but not well established or conclusive scientific evidence, can be used in food labeling based on FDA’s exercise of regulatory discretion to allow the use of certain qualified health claims without an authorizing FDA regulation. FDA uses the term ‘qualified health claim’ to refer to health claims for which the scientific evidence does not meet the SSA standard; that include a disclaimer that explains (or qualifies) the level of scientific evidence supporting the claim; and that is the subject of a current FDA regulatory discretion enforcement decision.

Nutrient Content Claims A food label statement that directly or by implication characterizes the level of a nutrient in the food is a nutrient content claim. The NLEA amendments restrict the use of nutrient content claims to those statements made in accordance with FDA’s authorizing regulations for nutrient content claims. FDA’s nutrient content claim regulations define how descriptive terms can be used to characterize the level of a nutrient in a food. The level of a nutrient in a food may be characterized using descriptive terms such as free, high and low, or the level of a nutrient in one food may be compared to that in another food using descriptive terms such as more, reduced and lite. The requirements governing the use of nutrient content claims help ensure that descriptive terms are used consistently for all types of food products and are thus meaningful to consumers. Nutrient content claims include both explicit claims (e.g. low fat) and implied claims (e.g. healthy). With a few exceptions, only nutrients with an established daily value for nutrition labeling may be the subject of a nutrient content claim. The general principles for the use of nutrient content claims are listed in the Code of Federal Regulations, title 21 part 101, section 13 (21 CFR 101.13). Nutrient content claims have been defined only for situations where they will be nutritionally relevant. The terms good source (defined as 10 to 19 percent of daily value per reference amount customarily consumed (RACC)3), high (defined as at least 20 percent of daily value per RACC) and more (defined as at least 10 percent of daily value more than that in a reference food) have been defined for nutrients that have a daily value. The requirements for the use of good source, high and more content claims are listed in 21 CFR 101.54. The terms free, low and reduced have been defined for use only with calories, total fat, saturated fat, cholesterol, sodium

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Nutrient Content Claims

and, in some cases, sugars and salt. These descriptive terms are defined individually for each of the listed nutrients and there are a number of additional criteria that apply as well. For example, the criteria for sugar free include a sugar content limit (⬍0.5 g per RACC), a requirement that the label show the calorie profile (e.g. low calorie) and trigger levels for other nutrients (such as total fat) that require a disclosure statement. Consequently, the regulations governing these claims should be read carefully before using them on a food label. Authorized nutrient content claims for sugar include free, reduced and no added sugar; but a low sugar nutrient content claim is not permitted. Light (or lite) is a nutrient content claim that has been defined for certain foods reduced in fat and/or calories, or certain foods reduced in sodium content. The term light may also be used outside of a nutrient content claim context in describing organoleptic properties such as color, e.g. ‘light brown sugar’. Requirements for the use of light/lite nutrient content claims are found in 21 CFR 101.56. Requirements for the use of content claims about calories and sugar are found in 21 CFR 101.60. Requirements for the use of content claims about sodium and salt are found in 21 CFR 101.61. Requirements for the use of content claims about fat, saturated fat and cholesterol are found in 21 CFR 101.62. One exception to the rule that only nutrients with established daily values can be the subject of nutrient content claims is a provision that permits the use of quantitative statements (e.g. 100 mg of lycopene). A quantitative statement may be used in food labeling to describe the amount of a nutrient present in a food, whether or not a daily value has been established for the nutrient, provided that the statement does not use language that characterizes the amount. A statement such as ‘packed with 100 mg of lycopene’ characterizes the amount of lycopene in the food by suggesting this to be a significant amount of lycopene. Because there is not an established daily value for lycopene, the ‘packed with 100 mg of lycopene’ statement would not be permitted. The terms contains and provides are defined as nutrient content claim descriptors synonymous with good source. However, when contains or provides are used with a quantitative statement about a nutrient for which there is not an established daily value, the term is considered customary English usage, not a descriptive term nutrient content claim, thus ‘contains 100 mg lycopene’ may be used in the same manner as ‘100 mg lycopene’. When a quantitative statement is made about a nutrient for which there is an established daily value, the food must either meet the criteria of an appropriate nutrient content claim or carry a statement disclosing that the food does not comply with an authorized content claim. For example, ‘low sodium’ is defined as ⱕ140 mg sodium per RACC; therefore the quantitative statement ‘would need to be qualified such as: ‘only 200 mg sodium. Not low in sodium’. Nutrient content claims include both explicit claims and implied claims. Implied nutrient content claims describe a food or ingredient in a manner that suggests that a nutrient is either present in a certain amount, or is absent. For example, a food labeled ‘high in oat bran’, implies that the food is high in dietary fiber and therefore the food should contain at least 20 percent of the daily value per RACC of dietary fiber. The term ‘healthy’, and any derivation of healthy, when used in association with an explicit statement about a nutrient, e.g. ‘Healthy low sodium’, is considered to be an implied nutrient content claim characterizing the levels not only of the indicated

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nutrient, but also characterizing the amount of total fat, saturated fat, cholesterol and sodium in the food as all being at ‘healthy’ levels. FDA has set criteria to ensure that healthy is used consistently and in a meaningful way. There are five criteria to qualify as a healthy food. For most packaged foods these criteria are: 1. low in total fat 2. low in saturated fat 3. cholesterol content ⱕ60 mg per RACC and per 50 g of food if the RACC is under 30 g or 2 tablespoons 4. sodium content ⱕ480 mg per RACC and per 50 g of food if the RACC is under 30 g or 2 tablespoons, and 5. contain at least 10 percent of the daily value per RACC for one or more of vitamin A, vitamin C, calcium, iron, protein, or dietary fiber. The fifth criterion (occasionally called the jelly bean rule) is included to prevent foods with little intrinsic nutritional value (such as candy) from being characterized as ‘healthy’. There are some variations in these criteria depending upon whether the labeled food is a fruit or vegetable, a grain product, a seafood or game meat product, or meal-type product. The rules for labeling a food with a ‘healthy’ nutrient content claim are explained in the regulation 21 CFR 101.65(d). Two nutrient content claim regulations of potential relevance to ‘functional foods’ are regulations for the use of the terms ‘high potency’ and ‘antioxidant’. The level of vitamins and minerals in a food may be characterized as ‘high potency’ when the individual vitamins or minerals characterized by the claim are present at 100 percent or more of the daily value per RACC. A ‘high potency’ claim must identify the vitamin(s) and/or mineral(s) being characterized as ‘high potency’ unless the product is a single nutrient dietary supplement. Alternatively, a multivitamin/mineral product may be characterized as ‘high potency’ without specifying the individual nutrients when at least two-thirds of all the vitamins and minerals listed in the product’s nutrition information are present at 100 percent or more of the daily value. Nutrient content claims using the term ‘antioxidant’ may be used for nutrients that have an established daily value and that have recognized bioavailable antioxidant activity when ingested. The nutrients that meet both of these criteria are vitamin C, vitamin E and selenium. Beta-carotene may also be the subject of an ‘antioxidant’ nutrient content claim when the amount of vitamin A activity in the food, present as betacarotene, is sufficient to qualify for the claim. Vitamin A itself is not an antioxidant and the bioavailability of beta-carotene’s antioxidant potential is questionable (5). Nevertheless, under current nutrient content claim regulations, beta-carotene still may be the subject of an ‘antioxidant’ nutrient content claim. To use the claim ‘high in antioxidant beta-carotene’, the food would need to contain at least 1000 International Units (IU) of vitamin A activity per RACC from beta-carotene (20% of the vitamin A daily value is 1000 IU). At the time FDA’s nutrition labeling regulations were published, the accepted beta-carotene/vitamin A conversion factor was 1.8 ␮g of beta-carotene as equivalent to 1 IU of vitamin A activity. Thus, ‘high in antioxidant beta-carotene’ requires a minimum of 1.8 mg beta-carotene per RACC.

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A summary of the rules for the use of nutrient content claims can be found in A Food Labeling Guide (6); examples of authorized nutrient content claims are provided in Appendices A and B of this guide. FDA’s A Food Labeling Guide is on the Internet at: http://www.cfsan.fda.gov/~dms/flg-toc.html

Health Claims Validity Standard of Health Claims NLEA mandated that health claims may not be used in food labeling prior to FDA evaluation of supporting evidence and issuance of a regulation to authorize the health claim. NLEA allows FDA to authorize a health claim only after the agency has determined that there is ‘significant scientific agreement’ (SSA) among qualified scientific experts that the claim is supported by the totality of publicly available scientific evidence. The SSA standard for health claims has two components: 1. there is publicly available supporting scientific evidence from well-designed studies conducted in a manner consistent with generally recognized scientific procedures and principles, and 2. there is SSA among qualified experts that the substance/disease relationship is supported by the totality of the publicly available scientific evidence. An explanation of FDA’s use of the SSA standard to evaluate the supporting scientific evidence for a health claim is available on FDA’s Internet website (7). The SSA standard is intended to be a strong but flexible standard that provides a high level of confidence in the validity of a substance/disease relationship (7). NLEA did not require FDA to apply the SSA standard to dietary supplement health claims, rather the agency was given discretion to establish a validity standard it considered appropriate for dietary supplements. FDA considered a ‘level playing field’ approach to be preferable to multiple health claim standards and, therefore, FDA concluded that the same standard to which conventional food health claims were held (i.e. SSA) was also an appropriate standard for dietary supplement health claims.

General Health Claim Regulation The FDA ‘General Requirements for Health Claims’ regulation (21 CFR 101.14) sets out general requirements applicable to all food label health claims. FDA also issues specific authorizing regulations with additional criteria specific to each individual health claim meeting the SSA validity criteria. The general health claim regulation defines a health claim as a statement made on a food label that expressly or by implication, including ‘third party’ references, written statements (e.g. a brand name including a term such as ‘heart’), symbols (e.g. a heart symbol), or vignettes, characterizes the relationship of any substance to a disease or health-related condition. Implied health claims include any material presented in food labeling that suggests,

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within the context in which it is presented, that a relationship exists between a substance in the food and a disease or health-related condition. There are two components to a health claim: the substance and the disease or health-related condition. A food label statement that does not include, explicitly or implicitly, both components would not be a health claim. The FFD&C Act identifies the substance component of a health claim as any ‘nutrient which is of the type’ required to be listed in the food label nutrition information. However, in that the NLEA also included ‘dietary supplements of vitamins, minerals, herbs, or other similar nutritional substances’ as substances covered by the health claim provisions of the Act, it is clear that the substance of a health claim was not intended to be limited strictly to ‘nutrients’. The legislative history of NLEA shows that Congress intended that individual foods also could be the subject of health claims. The legislative history of NLEA also makes it clear that a health claim about a food must, at least by implication, be a claim about a substance in the food. When a consumer could reasonably interpret a claim about the relationship of a food to a disease or healthrelated condition to be an implied claim about a specific substance in the food, that claim would satisfy the ‘substance’ component of a health claim. FDA therefore has defined ‘substance’ as meaning any specific food or a component of a food (e.g. nutrients). Defining ‘substance’ broadly allows authorization of health claims for a wider variety of relationships (e.g. health claims for phytosterols) than would a narrower definition of ‘substance’ encompassing nutrients only. Health claims about consuming a substance at decreased levels (e.g. saturated fat, cholesterol and heart disease), however, are restricted to the nutrients that are required to be listed in the nutrition information on the food label. FDA’s general health claim regulation includes a requirement that the substance in a health claim must contribute taste, aroma, nutritive value or any other recognized technical effect of a food additive. This requirement impacts on the potential for use of health claims for food ingredients promoted for functional attributes other than the traditional food ingredient attributes of taste, aroma and nutrition. Because FDA recognizes that health benefits may be derived from food ingredients through a variety of processes, FDA has provided for flexibility in determining whether a food substance has nutritional value. ‘Nutritive value’ has been defined in FDA’s general health claim regulation as value in sustaining human existence by processes such as promoting growth, replacing loss of essential nutrients, providing energy and includes assisting in the efficient function of classical nutritional processes and of other metabolic processes necessary for normal maintenance of human existence. The second component of a health claim, the ‘disease or health-related condition’, means damage to an organ, part, structure, or system of the body such that it does not function properly (e.g. cardiovascular disease), or a state of health leading to such dysfunction (e.g. hypertension). The disease component of a health claim must be one for which the general US population, or an identified population subgroup (e.g. the elderly), is at risk. Diseases resulting from essential nutrient deficiencies (e.g. scurvy or pellagra) are excluded from the diseases that may be the subject of a health claim. As such, a food label statement about a nutrient deficiency disease would not be regulated as a health claim. A food label statement about a nutrient

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deficiency disease, however, should identify the prevalence of the nutrient deficiency disease in the USA so as not to be misleading. The nature of the substance/disease relationships addressed in health claims is that of disease risk reduction. Whenever the intended use of a product is to cure, mitigate, treat or prevent a disease, the product is considered to be a drug, rather than a food. Health claims cannot describe an effect of the substance to cure, mitigate, treat or prevent a disease because health claims apply only to foods. For example, a label statement about use of a food or dietary supplement for relief from arthritis pain (e.g. mitigation of a disease symptom) is not a health claim because it infers intent that the product be used as a drug. This principle was upheld in the 2004 Whitaker v. Thompson court decision (353 F.3d 947 (D.C. Cir), cert. denied, 125 S Ct. 310 (2004)), which held that it was constitutionally permissible for FDA to deny a health claim about use of saw palmetto extract dietary supplements for relief of urinary symptoms of benign prostatic hyperplasia on the basis that the claim constituted a drug use for the product. NLEA prohibited FDA from authorizing the use of health claims for foods that contain any nutrient in an amount that increases the risk of a diet-related disease. As such, the general health claim regulation has set threshold levels for several nutrients above which a food is disqualified from using health claims. The disqualifying nutrient levels for individual foods are 13 g of total fat, 4 g of saturated fat, 60 mg of cholesterol and 480 mg of sodium per RACC. Where the actual serving size of a food is greater than the RACC, the disqualifying nutrient levels are determined on the labeled serving size; and the disqualifying nutrient levels for foods with a small RACC (defined as 30 g or less or 2 tablespoons or less) are determined on a per 50 g of food basis. Any food that exceeds one or more nutrient disqualifying levels is prohibited from using any health claim, even though that food may otherwise meet other requirements of a specific health claim. FDA has authority to waive disqualifying nutrient levels in instances where the agency finds that allowing a health claim will assist consumers in maintaining healthy dietary practices in spite of a high level of a disqualifying nutrient, provided that the label contain a disclosure statement about the nutrient (e.g. ‘See nutrition information for fat content’). The general health claim regulation also restricts the use of health claims on labels of foods with minimal nutritional value. Except for dietary supplements, a food may not use a health claim unless the food contains at least 10 percent of the daily value for one or more of 6 core nutrients (dietary fiber, protein, vitamin A, vitamin C, calcium or iron) per RACC. The food must meet the 10 percent daily value minimum nutrient content requirement prior to any nutrient addition. This provision has come to be known as the ‘jelly bean rule’ because it was intended to restrict the use of health claims by foods with little inherent nutritional value, such as jelly beans. FDA has made exceptions to the ‘jelly bean rule’ in some health claims when a public health benefit warranted.

Authorized Health Claims FDA was directed initially to evaluate the available scientific evidence for 10 nutrient/disease relationships that Congress had considered to be probable health

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claim topics (Table 9.1). FDA concluded there was SSA on five of the initial 10 nutrient/disease relationships and health claims for these five substance/disease relationships were authorized. FDA concluded that the available evidence did not warrant authorizing claims for two other nutrient/disease relationships. FDA concluded that the evidence for the remaining three nutrient/disease relationships (i.e. dietary fiber and cardiovascular disease; dietary fiber and cancer; and antioxidant vitamins and cancer) was inconclusive but that there was SSA for a

Table 9.1 Authorized health claims from the 1990 Nutrition Labeling and Education Act Relationship

Initial 10 NLEA health claims

Calcium and osteoporosis

Foods/supplements that are high in calcium and reduced risk of osteoporosis among Caucasian and Asian women. 21 CFR 101.721

Lipids and cancer

Foods/supplements that are low in total fat2, or extra lean fish and game meat and reduced risk of cancer. 21 CFR 101.73

Sodium and hypertension

Foods/supplements that are low in sodium and reduced risk of high blood pressure. 21 CFR 101.74

Lipids and cardiovascular disease

Foods/supplements that are low in total saturated fat and cholesterol2, or extra lean fish and game meat and reduced risk of coronary heart disease. 21 CFR 101.75

Dietary fiber and cancer

Fruit, vegetable or grain products that are low fat and are a good source of dietary fiber and reduced risk of cancer. 21 CFR 101.76

Dietary fiber and cardiovascular disease

Fruit, vegetable or grain products that are low in total fat, saturated fat and cholesterol and that contain soluble dietary fiber and reduced risk of coronary heart disease. 21 CFR 101.77

Antioxidant vitamins and cancer

Fruits or vegetables that are low fat and a good source vitamin A, vitamin C or dietary fiber and reduced risk of cancer. 21 CFR 101.78

Folic acid and neural tube birth defects

Foods/supplements that are a good source of folate and reduced risk of neural tube birth defects3. 21 CFR 101.79

Zinc and immune function in the elderly

No authorized claim

Omega-3 fatty acids and heart disease

No authorized claim4

1

Food labeling regulations are codified in Title 21 of the Code of Federal Regulations (CFR), Part 101. The regulation authorizing the health claim about the relationship of dietary calcium and osteoporosis risk is in section 72 of this part, i.e. 21 CFR 101.72. 2 Although dietary supplements are not explicitly excluded from use of these claims, these claims are not available for many dietary supplement products because the ‘low’ nutrient content claims for total fat, saturated fat and cholesterol are not defined for ‘low calorie’/‘calorie-free’ dietary supplements that are. 3 Authorization of the folate health claim was delayed until 1996 pending resolution of safety questions. 4 Although there was insufficient scientific evidence to support an authorizing regulation, there is a qualified health claim for omega-3 fatty acids and heart disease.

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relationship between diets characterized by the types of foods that are rich sources of these nutrients (i.e. fruits, vegetables and grain products) and reduced disease risk. FDA therefore authorized three alternative health claims for fruits, vegetables and grain products that are rich in antioxidant vitamins or in soluble fiber (see Table 9.1). The NLEA amendments directed FDA to establish a petition procedure through which interested parties could request FDA to authorize additional health claims. The NLEA amendments permitted FDA to authorize a petitioned health claim only when the agency has determined that the claim meets general requirements for health claims established by the agency and that the SSA standard has been satisfied. NLEA specified that health claim authorizing regulations issued by the FDA shall: 1. describe the substance/disease relationship of the health claim and the significance of the substance in affecting the disease 2. require that the claim be stated in a manner that is an accurate representation of the substance/disease relationship and 3. require that the claim be stated in a manner that enables the public to understand the information provided in the claim and to understand the relative significance of such information in the context of a total daily diet. FDA has authorized new health claims in response to a number of health claim petitions over the past decade (Table 9.2). The health claims that have been authorized as the result of health claim petitions include claims about sugar substitutes and

Table 9.2 Authorized health claims from health claim petitions Relationship

Authorized health claim

Non-cariogenic carbohydrate sweeteners and dental caries

Sugar-free foods sweetened with certain sugar alcohols and other sugar substitutes – xylitol, sorbitol, mannitol, maltitol, isomalt, lactitol, hydrogenated starch hydrolysates, hydrogenated glucose syrups, erythritol, D-tagatose and sucralose. 21 CFR 101.80

Soluble fiber from certain foods and coronary heart disease

Foods low in total fat, saturated fat and cholesterol and that contain barley grain or a whole oat ingredient (oat bran, oatmeal, whole oat flour or oatrim) providing at least 0.75 g beta-glucan fiber per serving Foods low in total fat, saturated fat and cholesterol and that contain psyllium seed husk providing at least 1.7 g soluble fiber per serving. 21 CFR 101.81

Soy protein and coronary heart disease

Foods low in total fat, saturated fat and cholesterol and that contain at least 6.25 g soy protein per serving. 21 CFR 101.82

Plant sterol/stanol esters and coronary heart disease

Foods/supplements that are low in saturated fat and cholesterol and that contain at least 400 mg per serving of plant sterols or stanols 21 CFR 101.83

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dental caries; whole oat and barley beta-glucan fiber and heart disease; psyllium husk fiber and heart disease; soy protein and heart disease; and plant sterol/stanol esters and heart disease (see Table 9.2). The health claim authorization procedure established by NLEA involves FDA evaluation of supporting scientific evidence and, upon a determination that there is SSA that the substance/disease relationship is substantiated by the available scientific evidence, FDA follows ‘notice and comment’ rulemaking to issue an authorizing regulation. The FDAMA provision for authoritative statement-based health claims serves as an alternative to the health claim petition and FDA rulemaking process. Substantiation of an authoritative statement-based health claim derives from a review of scientific evidence conducted by any US federal scientific agency with official responsibility for public health protection or human nutrition research or by the National Academy of Sciences or any of its subdivisions, where the result of such review is published as an authoritative statement of that agency about a dietary substance/disease risk reduction relationship. The same SSA validity standard applies in both processes, but they differ in where the deliberative review of the scientific evidence occurs. The process leading to authorization of an authoritative statement-based health claim begins with submission to FDA of a notice that includes the exact wording to be used in the health claim, the authoritative statement that is the source of the claim and a balanced representation of the scientific literature relating to the substance/ disease relationship to which the claim refers. The new health claim that is the subject of an authoritative statement health claim notification becomes authorized by law 120 days after receipt of the notification by FDA provided FDA has taken no regulatory action during that period to prohibit or modify the claim. FDA uses the 120-day period to determine whether both the notification and the claim meet the requirements established by FDAMA. FDA may issue regulations to prohibit, or to modify, authoritative statement-based health or nutrient content claims. FDA guidelines on the procedure for notifying FDA of intent to use health claims based on an authoritative statement from a scientific body is available on the Internet (8). Table 9.3 lists the authorized health claims which are based on authoritative statement health claim notifications.

Qualified Health Claims In 1999, the US Court of Appeals for the DC Circuit issued its decision in Pearson v. Shalala (164 F.3d 650, D.C. Cir. 1999) (Pearson). The Pearson plaintiffs had challenged FDA’s decision to apply the SSA standard to dietary supplement health claims and FDA’s decision not to authorize health claims for four specific substance/disease relationships: dietary fiber and colorectal cancer; antioxidant vitamins and cancer; omega-3 fatty acids and coronary heart disease; and the claim that 0.8 mg of folic acid in dietary supplement form is more effective in reducing the risk of neural tube birth defects than a lower amount in conventional food form. FDA had previously denied these four claims after it concluded that supporting evidence for these claims did not meet the SSA standard and the claims would therefore be misleading to consumers. The court held in Pearson that the Constitutional protection of free speech does not permit FDA to reject health claims that the agency determines to be potentially misleading unless the agency

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Table 9.3 Authorized health claims based on an authoritative statement Relationship

Authorized health claim

Whole grains and heart disease and cancer

Foods with 51% or more whole grain ingredients; dietary fiber content is the measurable marker of whole grains. Multiple notifications specifying three variations of claim wording: Diets rich in whole grain foods and other plant foods and low in total fat, saturated fat and cholesterol may reduce the risk of heart disease and some cancers. Diets rich in whole grain foods and other plant foods and low in saturated fat and cholesterol may reduce the risk of heart disease. FDA Docket no. 1999P-2209, 2003Q-0547

Potassium and high blood pressure and stroke

Foods which are good sources of potassium in addition to being low in total fat, saturated fat, cholesterol and sodium. Diets containing foods that are a good source of potassium and that are low in sodium may reduce the risk of high blood pressure and stroke. FDA Docket no. 2000Q-1582

Fluoridated water and dental caries

Fluoridated bottled water, except those specifically marketed for use by infants. Drinking fluoridated water may reduce the risk of dental caries [or tooth decay]. 006Q-0416

Dietary fats and heart disease

Foods which are low in saturated fat and cholesterol, moderate in fat content and contain less than 0.5 g/RACC trans fat. Diets low in saturated fat and cholesterol and as low as possible in trans fat may reduce the risk of heart disease. 2006Q-0458

can also reasonably determine that no disclaimer would eliminate the potential deception. The court stated in Pearson that the potential for claims that do not meet the SSA validity standard to mislead the consumer could be remedied by including ‘qualifying’ language in the claim which would disclose the level of scientific support for the claim (i.e. disclosure of more information is preferential to suppressing information). FDA interpreted the Pearson court opinion to suggest that where there was more scientific evidence against a specific claim than there was evidence in support of the claim, the claim would be inherently misleading (rather than merely potentially misleading) and could be prohibited. FDA initially applied a ‘weight of the evidence’ standard, as an alternative to the SSA standard, in evaluating one of the first health claim topics to be re-evaluated under Pearson (a claim for antioxidant vitamin supplements and cancer risk). FDA concluded that there was more scientific evidence against the validity of this claim than there was to support the claim, thus FDA would not permit a qualified health claim for antioxidant vitamins and cancer risk because the weight of available scientific evidence did not support this substance/disease relationship (9). FDA’s interpretation of

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Pearson in the decision to deny a qualified health claim for antioxidant vitamin supplements and cancer was challenged in another lawsuit (Whitaker v. Thompson, 248 F. Supp 2d 1 (D.D.C. 2002)) (Whitaker). The court’s opinion in Whitaker was that FDA’s ‘weight of the evidence’ standard misinterpreted Pearson and that qualified health claims must be permitted if there is any credible scientific evidence in support of a claim. Consistent with Whitaker, FDA now considers exercising its regulatory discretion to permit qualified health claims where there is any credible scientific evidence to support the claim. To develop a framework to help consumers obtain accurate, up-to-date and science-based information about conventional foods and dietary supplements, the FDA convened the ‘Consumer Health Information for Better Nutrition Initiative’ Task Force with the mission of establishing goals and guidelines for health claims that do not meet the SSA standard (4). In July 2003, this FDA Task Force released an interim guideline for the evaluation and labeling of qualified health claims for both conventional foods and dietary supplements as part of the Task Force Report (10). To provide for the use of qualified health claims as directed by Pearson, FDA uses regulatory discretion in enforcing the requirement that the use of health claims on food labels must be in accordance with authorizing regulations. FDA’s qualified health claim enforcement discretion decisions are posted on the FDA Internet website rather than codifying the decisions in a regulation. The agency letters announcing an enforcement discretion decision include an explanation of the rationale for the decision and specify the conditions under which the agency will consider the exercise of its enforcement discretion (e.g. the exact wording of the qualifying language). The enforcement discretion decision letters caution that since the qualified health claim topics are areas where the evidence for the claim is incomplete and subject to change, FDA intends to evaluate new information as it becomes available to determine whether the new evidence necessitates a change in the decision. Table 9.4 presents a listing of qualified health claims that have been evaluated by FDA.

Structure/Function Claims Food labels may use claims about effects of the food on structures or functions of the body. The FFD&C Act recognizes explicitly that foods, as well as drugs, can be used to affect the structure or any function of the body4. Provisions of the DSHEA amendments further clarified distinctions between the regulation of health claims and of structure/function claims made for dietary supplement products. FDA uses the phrase ‘structure/function claim’ to refer to food label statements that describe the role of a nutrient or other dietary supplement ingredient in maintaining normal structure or function in humans (e.g. calcium builds strong bones) or to promote general wellbeing. Structure/function claims can also characterize the means by which a nutrient or other dietary ingredient acts to maintain a body structure or function (e.g. antioxidants maintain cell integrity or fiber maintains bowel regularity). Health claims and structure/function claims differ in that there are two elements of a health claim: the substance and the disease or health-related condition, whereas, structure/function claims have the first element (a substance) but cannot state or imply any relationship

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Table 9.4 Qualified health claims considered under FDA’s exercise of enforcement discretion Enforcement discretion considered1

Qualified claim petitions denied

Tomatoes and prostate, ovarian, gastric and pancreatic cancers Calcium and colorectal cancer Green tea and breast and prostate cancers Selenium and cancer Antioxidant vitamins and cancer B vitamins and vascular disease Walnuts and CHD Nuts and CHD Omega-3 fatty acids and CHD Unsaturated fatty acids from canola oil and CHD Monounsaturated fatty acids from olive oil and CHD Phosphatidylserine and cognitive dysfunction Chromium picolinate and type 2 diabetes Folic acid and neural tube birth defects

Lycopene and various cancers Calcium breast and prostate cancers Green tea and various cancers Dietary fiber and colorectal cancer Green tea and cardiovascular disease Omega-3 enriched eggs and CHD Vitamin E and CHD Chromium picolinate and cardiovascular disease, retinopathy and kidney diseaseLutein and zeaxanthin and macular degeneration and cataract Hydrolyzed whey protein and infant food allergy Calcium and urinary stones Calcium and menstrual disorders Glucosamine/chondroitin sulfate and osteoarthritis Chondroitin sulfate and osteoarthritis

1 The enforcement discretion letters describe the specific conditions under which the claim can be used, including the qualifying language which characterizes the strength of the scientific evidence behind the claim. A current listing of qualified health claim petitions considered by FDA is posted at: http://www.cfsan. fda.gov/~dms/lab-qhc.html CHD: coronary heart disease

of the substance to a disease or health-related condition. The context of a statement within the entire label is considered in determining whether a label statement implies a relationship to a disease or a health-related condition. For example, a statement such as ‘supports the cardiovascular system’ does not of itself imply a disease connection. However, this same statement on the label of a product called ‘CardioCure’ would constitute a disease claim within the context of the entire label. A food label statement that makes, or implies, a relationship with a disease or health-related condition is either a health claim or a drug claim, not a structure/function claim. An exception to the prohibition of structure/function claims from referencing a disease is that structure/ function claims may describe a benefit related to a classical nutrient deficiency disease (e.g. vitamin C and scurvy), as long as the statement also tells how widespread such a disease is in the USA. The distinction between a disease claim and a dietary supplement structure/function claim is described in 21 CFR 101.93(g). Structure/function claims, like all food labeling statements, must be truthful and not misleading. Unlike health claims and nutrient content claims, there are no FFD&C Act provisions that provide for FDA’s prior review or approval of structure/function claims before their use. Although structure/function claims are not regulated by FDA to the extent that health claims and nutrient content claims are, the DSHEA amendments to the FFD&C Act established three conditions for the use of structure/function claims in the labeling of dietary supplements. The first condition is that the manufacturer of a dietary supplement making a structure/function claim has substantiation that the claim is truthful and not misleading. The second condition is that the following statement must be

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displayed prominently and in boldface type on the label with the structure/function claim: ‘This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease’. The third condition is that the dietary supplement manufacturer notify FDA, within 30 days of first marketing a dietary supplement label bearing a structure/ function claim, that the statement is being made. FDA examines the dietary supplement structure/function claim notifications to determine that the claims are actually structure/ function claims and not claims to reduce the risk of, prevent or treat a disease. DSHEA’s structure/function claim conditions apply specifically to dietary supplement labeling. All structure/function claims, whether used on conventional food labels or dietary supplement labels, need to be adequately substantiated to satisfy the ‘not false or misleading’ criterion that applies to all label information. However, there are no provisions in the FFD&C Act requiring manufacturers using structure/function claims on conventional food labels either to include the disclaimer statement or to notify FDA of their structure/function claims. Unlike dietary supplements, structure/function claims made for conventional foods must be about effects that derive from the taste, aroma or nutritive value of the food or food ingredient that is the subject of the claim. This limitation on use of structure/function claims for conventional foods is based on a federal court ruling that structure/function claims on a conventional food label cause the product to be a drug if the claim promotes the product for an effect that is unrelated to the product’s ‘food attributes’ of taste, aroma and nutritive value (Nutrilab v. Schweiker, 713 F. 2d 335 (7th Cir. 1983)). Table 9.5 compares regulatory differences between health claims and structure/function claims used on conventional foods and dietary supplements.

Table 9.5 Requirements for health claims and structure/function claims

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Health claims – conventional food and dietary supplements

Structure/ function claims – dietary supplements

Structure/ function claims – conventional food

Petition FDA for new claims Requires prior FDA review and approval

Yes Yes

No No

No No

Cannot be false or misleading

Yes

Yes

Yes

Notify FDA within 30 days of marketing product labeled with the claim

No

Yes

No

Include a disclaimer stating the claim has not been evaluated by FDA

No

Yes

No

Each manufacture using the claim must possess substantiating evidence for the claim

No

Yes

Yes

Product subject to disqualifying nutrient levels and minimum nutrient levels

Yes

No

No

Substance must have food attributes such as nutritive value

Yes

No

Yes

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References 131

Because structure/function claims for dietary supplements must be truthful and not misleading, FDA recommends that manufacturers possess adequate substantiation for all reasonable interpretations of the claims made. FDA recommends applying a standard that is consistent with the Federal Trade Commission standard of ‘competent and reliable scientific evidence’ to substantiate a claim (11). FDA considers the following factors important to establish whether information would constitute ‘competent and reliable scientific evidence’: ● ●

●

●

Does each study or piece of evidence bear a relationship to the specific claim? What are the individual study’s or evidence’s strengths and weaknesses? Consider the type of study, the design of the study, analysis of the results and peer review. If multiple studies exist, do the studies that have the most reliable methodologies suggest a particular outcome? If multiple studies exist, what do most studies suggest or find? Does the totality of the evidence agree with the claims?

FDA has recently provided guidelines on the amount, type and quality of evidence that FDA recommends a manufacturer have to substantiate a structure/function claim (12).

Notes 1

There is a legal distinction between the ‘label’ (on the immediate product container) and ‘labeling’ (material accompanying the product). In this chapter, we use the terms ‘label’ and ‘labeling’ interchangeably to describe the written, printed or graphic matter on any food, its containers or wrappers or other material accompanying the food. 2 Bicarbonate ion-containing active ingredients, such as sodium bicarbonate (baking soda) are an approved antacid over-the-counter drug for relief of heartburn and acid indigestion (21 CFR 331). There are brands of baking soda marketed in the USA with the labeling required for intended use both as a food and as a drug. 3 Reference Amounts Customarily Consumed per Eating Occasion (RACC) are used as a reference point for determining the serving sizes used for nutrition labeling and as a uniform reference amount for basing nutrient content claims. RACCs for 139 food product categories are listed in 21 CFR 101.12. 4 Drugs are defined, in part, as ‘… articles (other than food) intended to affect the structure or any function of the body of man …’ FFD&C Act section 201(g)(1)(C).

References 1. Nutrition Labeling and Education Act of 1990. Public Law 101–535. November 8, 1990. Summary available at http://thomas.loc.gov/cgi-bin/bdquery/z?d101: HR03562:@@@D&summ1&|TOM:/bss/d101query.html

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2. Dietary Supplement Health and Education Act of 1994. Public Law 103–417. October 25, 1994. Available at http://www.fda.gov/opacom/laws/dshea.html 3. Food and Drug Administration Modernization Act of 1997. Public Law 105–115. November 21, 1997. Available at http://www.fda.gov/oc/fdama/ 4. Food and Drug Administration. Consumer Health Information for Better Nutrition Initiative. Task Force Final Report. July 2003. Available at http://www.cfsan.fda.gov/ ~dms/nuttftoc.html 5. Food and Nutrition Board, Institute of Medicine. (2001). Vitamin A. In Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, nickel, silicon, vanadium, and zinc. The National Academy Press, Washington, DC. 6. Food and Drug Administration. A Food Labeling Guide. September 1994. Available at http://www.cfsan.fda.gov/~dms/flg-toc.html 7. Food and Drug Administration. Guidance for Industry: Significant Scientific Agreement in the Review of Health Claims for Conventional Foods and Dietary Supplements. December 1999. Available at http://www.cfsan.fda.gov/~dms/ssaguide.html 8. Food and Drug Administration. Guidance for Industry: Notification of a Health Claim or a Nutrient Content Claim Based on an Authoritative Statement of a Scientific Body, June 1998. Available at http://www.cfsan.fda.gov/~dms/hclmguid.html 9. Letter to Jonathan Emord (Emord & Associates) from Christine Lewis (FDA, CFSAN). Re: Petition for Health Claim: Antioxidants and Cancer (Docket No. 91N-0101). May 4, 2001. 10. Food and Drug Administration. Guidance for Industry and FDA: Interim EvidenceBased Ranking System for Scientific Data. July 10, 2003. Available at http://www. cfsan.fda.gov/~dms/hclmgui4.html 11. Bureau of Consumer Protection, Federal Trade Commission. Dietary Supplements: An Advertising Guide for Industry. April 2001. Available at http://www.ftc.gov/bcp/ conline/pubs/buspubs/dietsupp.html 12. Food and Drug Administration. Guidance for Industry: Substantiation for Dietary Supplement Claims Made Under Section 403(r)(6) of the Federal Food Drug, and Cosmetic Act, November 2004. Available at: http://www.cfsan.fda.gov/~dms/ dsclmgui.html

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Health and Wellness Related Labeling Claims for Functional Foods and Dietary Supplements in the USA

10

Sanjiv Agarwal1, Stein Hordvik2 and Sandra Morar3 1

Sara Lee Food & Beverage, Downers Grove, IL, USA Hordvik’s Consulting , Elkhorn, NE, USA 3 McGrath North Mullin & Kratz PC LLO, Omaha, NE, USA 2

Abstract Food and supplement labels are an important educational tool to assist consumers in making healthier choices. In addition to mandatory nutritional labeling information, manufacturers have a variety of options on the food/supplement packages to communicate the nutrition/ health benefits of their products. This chapter describes the different types of claims that can be made for foods and dietary supplements.

Introduction A diet and health relationship was initially proposed in the fourth century BC by Hippocrates. Although, there is significant scientific agreement that diet plays an important role in health, only about 12% of Americans are eating healthy and many Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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134 Health and Wellness Related Labeling Claims

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ion educt h claim ase risk r rosis’ lt a e H ise po le in d osteo nt’s ro the risk of ie r t u n ribes educe Desc ium may r lc a ‘C

ance claim ction h mainten n u F / ealt ture s’ Struc ’s role in h ong bone nt str ie d r t il u u n elps b ribes ium h Desc ‘Calc nt t claim onten l of nutrie c t n e ie v r t le ’ u N the ium izing e of calc c acter Char ood sour ‘G

Figure 10.1 Different types of labeling claims for functional foods and dietary supplements.

are not meeting the dietary guidelines recommendations and not consuming enough nutrients including vitamins and minerals from foods (1,2). Food labels are important tools to educate consumers about the healthfulness of specific foods and the benefits of following a nutritious diet. In addition to the mandatory nutrition labeling information (Nutrition Facts or Supplement Facts), current Food and Drug Administration (FDA) regulations (3) provide several provisions to communicate the healthfulness of the food products to the consumers (Fig. 10.1).

Nutrient Content Claims Nutrient content claims are regulated by the FDA under the Nutrition Labeling and Education Act (4). They explicitly or implicitly characterize the level of a nutrient in a food. These claims are made to describe the nutrient levels using such terms as ‘free’, ‘low’ and ‘high’ as well as to compare the nutrient levels using terms ‘more’, ‘reduced’ and ‘light’: 1. Characterizing the nutrient levels ● Free – identifies food that contains a nutrient at inconsequential levels. ● Low – identifies food that is distinctly low in a nutrient compared to a daily value (DV). ● Good source/excellent source – identifies foods that contain higher levels and contribute significantly toward the DV. 2. Comparing the nutrient levels ● Reduced, more or light – identifies nutritionally meaningful differences from a reference product. 3. Implied nutrient claim

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Nutrient Content Claims 135

Table 10.1 Currently permitted nutrient content claims (numbers are rounded) as of March 2007 Nutrients

Claims

CFR reference

Calories

Free – less than five calories per reference amount (RACC) and serving Low – 40 calories or less per RACC or per 50 g if RACC is 30 g or less. 120 calories or less for meals and main dishes Reduced or less – at least 25% fewer calories per RACC than an appropriate reference food Free – less than 0.5 g fat per RACC and serving Low – 3 g or less fat per RACC or per 50 g if RACC is 30 g or less. 3 g or less fat per 100 g and not more than 30% calories from fat for meals and main dishes Reduced or less – at least 25% less fat per RACC than an appropriate reference food Free – less than 0.5 g saturated fat and less than 0.5 g trans fat per RACC and serving Low – 1–g or less saturated fat per RACC and less than 15% calories from saturated fat. 1 g or less fat per 100 g and not more than 10% calories from fat for meals and main dishes Reduced or less – at least 25% less saturated fat per RACC than an appropriate reference food Free – less than 2 mg cholesterol per RACC and serving or per serving for meals and main dishes and 2 g or less saturated fat per RACC or per serving for meals and main dishes Low – 20 mg or less cholesterol per RACC or per 50 g if RACC is 30 g or less. 20 mg or less cholesterol per 100 g for meals and main dishes. 2 g or less saturated fat per RACC or per serving for meals and main dishes Reduced or less – at least 25% less cholesterol per RACC than an appropriate reference food Free – less than 5 mg sodium per RACC and serving or per serving for meals and main dishes Low – 140 mg or less sodium per RACC or per 50 g if RACC is 30 g or less. 140 mg or less sodium per 100 g for meals and main dishes Reduced or less – at least 25% less sodium per RACC than an appropriate reference food Free – less than 0.5 g sugar per RACC and serving or per serving for meals and main dishes Low – claim is not defined and therefore not permitted Reduced or less – at least 25% less sugar per RACC than an appropriate reference food Good source – 10–19% DV per RACC Excellent source – 20% or more DV per RACC

101.60

Total fat

Saturated fat

Cholesterol

Sodium

Sugar

Vitamins, minerals, fiber and protein

101.62

101.62

101.62

101.61

101.60

101.54

CFR: Code of Federal Regulations

Implied nutrient content claims are claims about a food or an ingredient in a food suggesting that a nutrient or ingredient is present in certain amounts. ● ●

Healthy is an implied nutrient content claim. Lean and Extra Lean are terms that can be used to describe the fat content of meat, poultry, seafood and game meats.

Table 10.1 provides a list of nutrient content claims and their specific requirements (as of March 2007). These claims are, by and large, allowed for those nutrients for

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Table 10.2 Implied nutrient content claims as of March 2007 Claim

Requirements

CFR reference

Healthy

‘Low fat’, ‘Low saturated fat’, Cholesterol below 60 mg (90 mg for meals and main dishes) and Sodium below 480 mg (600 mg for meals/main dishes). At least 10% of the DV for one (individual foods), two (main dishes) or three (meals) of the six nutrients (Vitamin A, Vitamin C, iron, calcium, protein or fiber) Less than 10 g total fat, 4.5 g saturated fat and 95 mg of cholesterol per reference amount and labeled serving (per 100 g and per serving for meals/main dishes) Less than 5 g total fat, 2 g saturated fat and 95 mg of cholesterol per reference amount and labeled serving (per 100 g and per serving for meals/main dishes)

101.65

Lean

Extra Lean

101.62

101.62


which the FDA has established a daily value. Nutrient content claims are currently permitted for calories, fat, saturated fat, cholesterol, sodium, sugar, vitamins, minerals, fiber and protein. Nutrient content claims for total carbohydrate (except for sugar and fiber) are currently not defined by the FDA and therefore are prohibited. A number of food manufacturers and trade organizations, in 2004, petitioned the FDA to allow nutrient content claims for carbohydrates and to define ‘free’, ‘low’, ‘good source’ and ‘excellent source’ claims for total carbohydrates. The FDA is currently reviewing the petitions. For nutrients/food components, which do not have a daily value, a factual statement specifying the nutrient quantity present in the food, e.g. ‘… mg of … per serving’ can be used on a food label. However, statements that characterize the amount of the nutrient as being high or low, e.g. ‘only … mg of … per serving’ are not permissible and would be considered to be implied nutrient content claims. Also, quantitative statements must include the unit of measure. The general principles for making these claims are provided in 21 CFR § 101.13, 101.54–101.69 (6). Additional requirements for nutrient content claims are: (a) for foods with a RACC less than 30 g, nutrient content claims must be determined as if there were 50 g of product; and (b) a disclosure statement, ‘See nutrition information for … content’, is also required as part of the claim when levels of fat, saturated fat, cholesterol and/or sodium exceed 13 g, 4 g, 60 mg, 480 mg, respectively, to call the consumer’s attention to one or more nutrients in the food that may increase the risk of a disease or health-related condition that is diet related. Table 10.2 provides a list of implied nutrient content claims and their requirements (as of March 2007).

Structure/Function Claims Structure/function claims describe the role of a nutrient or a substance in food or a food supplement in affecting the normal structure or function in the body. These also refer to a change in, the support of, maintenance or functions of the body and may

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Health Claims 137

Table 10.3 Common structure/function claims currently in the marketplace Structure/function claims

Nutrient

Calcium is important for both men and women to help build strong bones Fiber promotes digestive health Protein for muscle strength Grape juice may promote healthy arteries

Calcium Fiber Protein Flavonoids

Antioxidant Vitamins A, C and E help the body’s natural defenses

Vitamin A, C and E

Antioxidants may help protect against the damaging effects of free radicals Antioxidants help provide support for your body’s natural defenses

Lycopene, Vitamin A, C and E, selenium, flavonoids Lycopene, Vitamin A, C and E, selenium, flavonoids Lutein, Vitamin A

For healthy eyes

also describe the mechanism of action. These, however, do not relate to a disease or a health-related condition. For example, ‘calcium helps build strong bones’ is a structure/function claim, whereas ‘calcium reduces the risk of osteoporosis’ is a health claim (see Fig. 10.1). The key components of structure/function claims are safety, scientific basis and the nutritive value. Table 10.3 provides some examples of structure/function claims used in the market. Some of these claims may not have strong scientific support and therefore the regulatory agencies may consider them as ‘misleading to consumers’. Premarket approval for structure/function claims is not required. The FDA requires that these claims be truthful, non-misleading and substantiated by the appropriate scientific data and the food/supplement manufacturer must ensure their accuracy and truthfulness. In the case of dietary supplements, these claims are accompanied by a disclaimer stating that ‘the FDA has not evaluated this claim and this product is not intended to diagnose, treat, cure or prevent any disease’. Moreover, the FDA has to be notified about the claim, including the text, within 30 days of marketing a dietary supplement bearing a new structure/function claim. The FDA has provided a guidance document to distinguish between structure/function claims and disease claims (5).

Health Claims Health claims describe the relationship between a substance (food, food component or dietary supplement) and a disease or a health-related condition (see Fig. 10.1). There are two important constituents of a health claim: a substance and a disease or health-related condition. Claims relating to a dietary pattern instead of a substance are not considered as health claims. Unlike structure/function claims, health claims must be pre-approved by the FDA. The FDA conducts an evidence-based review to ascertain the scientific validity of the claim. FDA reviews and authorizes the health claims by three means (6): 1. Claims based on significant scientific agreement: The Nutrition Labeling and Education Act 1990 (NLEA) and the Dietary Supplement Health and

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Table 10.4 Approved NLEA health claims with significant scientific agreement as of March 2007 Health claim

CFR reference

Calcium and osteoporosis Dietary lipids (fat) and cancer Sodium and hypertension Dietary saturated fat and cholesterol and risk of coronary heart disease Fiber-containing grain products, fruits and vegetables and cancer Fruits, vegetables and grain products that contain fiber, particularly soluble fiber and risk of coronary heart disease Fruits and vegetables and cancer Folic acid and neural tube defects Dietary carbohydrate sweeteners and dental caries Soluble fiber from certain foods and risk of coronary heart disease Soy protein and risk of coronary heart disease Stanols/sterols and risk of coronary heart disease

21 CFR 101.72 21 CFR 101.73 21 CFR 101.74 21 CFR 101.75 21 CFR 101.76 21 CFR 101.77 21 CFR 101.78 21 CFR 101.79 21 CFR 101.80 21 CFR 101.81 21 CFR 101.82 21 CFR 101.83


Table 10.5 Currently authorized FDAMA health claims as of March 2007 Health claim

Docket reference

Whole grain foods and the risk of heart disease and certain cancers Potassium and the risk of high blood pressure and stroke Nutrient content claim (good source) of choline Fluoridated water and the risk of dental caries or tooth decay Saturated fat, cholesterol and trans fat and the risk of heart disease

99P-2209 and 03Q-0547 00Q-1582 01Q-0352 2006Q-0418 2006Q-0458

Education Act (DSHEA) of 1994 allow health claims on food or supplement labels describing the role of a substance in disease risk reduction. The FDA authorizes these claims based on the totality of publicly available scientific evidence and using significant scientific agreement (SSA) criteria to determine the validity of the substance/disease relationship. A list of current (as of March 2007) FDA approved SSA health claims are presented in Table 10.4. 2. Claims based on authoritative statement: The FDA Modernization Act (FDAMA) of 1997 also allows health claims based on an authoritative statement issued by a scientific body of the US Government bearing a public health protection responsibility, such as The National Institutes of Health (NIH), The Centers for Disease Control (CDC) or The National Academy of Science (NAS). However, FDAMA claims are not available for dietary supplements. Table 10.5 lists the health claims that are currently (as of March 2007) approved under the FDAMA process. 3. Qualified health claims: Consumer Health Information for Better Nutrition Initiative of FDA (2003) provides the use of health claims (qualified health claims (QHC)) for foods or dietary supplements where the scientific evidence to support a substance/disease relationship is still emerging and has not developed enough to meet the SSA standard. These claims have to include qualifying

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Dietary Guidance Statements 139

Table 10.6 Qualified health claims as of March 2007 Permitted qualified health claims

Docket reference

0.8 mg folic acid and the risk of neural tube birth defects* B Vitamins (B6, B12 and folic acid) and the risk of vascular disease* Selenium and the risk of cancer* Phosphatidylserine and the risk of cognitive dysfunction and dementia* Antioxidant vitamins (Vitamin C and E) and the risk of cancer* Nuts and the risk of heart disease Walnuts and the risk of heart disease Omega-3 fatty acids (EPA and DHA) and the risk of coronary heart disease Monounsaturated fatty acids from olive oil and the risk of coronary heart disease Green tea and the risk of cancer Calcium and the risk of colorectal cancer* Calcium and the risk of hypertension* Chromium picolinate and the risk of insulin resistance or type II diabetes* Tomatoes and/or tomato sauce and the risk of prostate, ovarian, gastric and pancreatic cancer Unsaturated fatty acids from canola oil and the risk of coronary heart disease Corn oil and corn oil-containing products and a reduced risk of heart disease

91N-100H 99P-3029 02P-0457 02P-0413 91N-0101 02P-0505 02P-0292 2004Q-0401 2003Q-0559 2004Q-0083 2004Q-0097 2004Q-0098 2004Q-0144 2004Q-0201 2006Q-0091 2006P-0243

*Approved only for the dietary supplements

language as part of the claim indicating that the evidence supporting the claim is limited. In July 2003, the FDA provided interim guidelines outlining the petition process and the evidence-based ranking system to evaluate the scientific data concerning the claim. Since July 2003, the FDA has authorized several qualified health xlaims for foods and dietary supplements. Table 10.6 shows all the approved qualified health claims to date (as of March 2007). Health claims in general relate to disease risk reduction, but do not quantify the degree of risk reduction. Health claims language always uses ‘may’or ‘might’ to express the substance and disease relationship. All FDA approved health claims are generic and not for the exclusive use of the petitioner. These claims are available to any conventional food or dietary supplement product that meets the SSA or FDAMA claims criteria or the QHC enforcement discretion conditions specified by the FDA. Additionally, the foods bearing the health claims must contain 10% or more of the DV for one or more of the six nutrients (vitamin A, vitamin C, iron, calcium, protein or fiber) without fortification. Dietary supplements are exempt from this requirement. Foods bearing the health claims must also contain less than the 13 g, 4 g, 60 mg, 480 mg of fat, saturated fat, cholesterol and sodium, respectively, the disqualifying nutrients 21 CFR § 101.14 (6).

Dietary Guidance Statements The FDA also allowed dietary guidance statements on food labels to encourage good nutrition among consumers as a part of the Consumer Health Information for Better Nutrition Initiative (7). These statements address the role of dietary patterns

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or of general categories of foods (e.g. fruits and vegetables) in health and are not considered health claims. Although dietary guidance statements are not subject to FDA review and authorization, these must be truthful and non-misleading. The FDA recently offered a dietary guidance statement for fruits and vegetables: ‘Diets rich in fruits and vegetables may reduce the risk of some types of cancer and other chronic diseases’ (8).

Factual Statements There are several other claims/factual statements that are often used by the manufacturers. Some of the common examples are provided below. Many of these may not have strong scientific support or regulatory guidance and therefore the regulatory agencies may view them as misleading to consumers. Legal counsel should be consulted prior to making any claims not clearly defined in the regulations. 1. Net carbs: Net carbs is a way of representing the amount of carbohydrate not contributing significantly towards energy or blood sugar. The net carbs number is often calculated by subtracting fiber and/or sugar alcohol from total carbohydrate. The net carbs calculation is generally presented next to the claim. The FDA has not provided any guidance on how to calculate or make net carb claims. 2. ‘Zero’ g trans fat or 0 g trans fat: This is a factual statement. In absence of any guidance from the FDA about ‘trans fat free’, this statement is becoming a common claim of expressing that the product does not have any significant amount of trans fat. 3. Whole grain goodness: This is a statement indicating that the product contains whole grain and therefore may provide the health benefits that are associated with whole grain. 4. Loaded with nutrition/complete nutritious food: It suggests that the product contains nutrients. 5. Glycemic index (GI): This is measured as a rise in the blood sugar following ingestion of a food and is representative of the quality of carbohydrate in the food. Usually foods with a glycemic index of 55 or less are considered as low GI foods. 6. Other common factual statements are: ‘as much calcium as a glass of milk’, ‘contains same amount of vitamin C as a glass of orange juice’ and ‘as much fiber as in an apple’.

Nutritional Claims Display on Packages Manufacturers use a variety of ways to communicate the nutritional attributes and health advantages of their products: 1. Attribute on the principle display panel as a burst. 2. List of attributes in a check box style on the side panel. 3. Goodness corner to highlight the attributes.

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References 141

4. Complete back panel to display the nutritional attributes and their associated functional/health benefits. 5. Company/brand’s website. 6. Sales literature and other materials available at the point of purchase (grocery store/health food store). According to a Food Label Package Survey conducted by the FDA (9), 49.7% of the FDA regulated products sold during 2000–2001 had nutrient content claims, 6.2% had structure/function claims and 4.4% had health claims on food labels.

References 1. Frazao E. (1995). The American diet: health and economic consequences. USDA/ ERS, AIB-711. 2. Moshfegh A, Goldman J, Cleveland L. (2005). What we eat in America, NHANES 2001–2002: usual nutrient intakes from food compared to dietary reference intakes. USDA, ARS. 3. FDA. (2004). Code of Federal Regulation, Title 21, Part 101 Food Labeling, http://www.access.gpo.gov/nara/cfr/waisidx04/21cfr10104.html 4. Nutrition Labeling and Education Act of 1990. (1990). Public Law 101–535, 1990. 5. FDA. (2002). Guidance for Industry, Structure Function Claims – Small Entity Compliance Guide, http://www.cfsan.fda.gov/~dms/sclmguid.html 6. CFSAN. (2003). Claims that can be made for conventional foods and dietary supplements, http://www.cfsan.fda.gov/~dms/hclaims.html 7. FDA. (2003). Consumer Health Information for Better Nutrition Initiative, http:// www.cfsan.fda.gov/~dms/nuttftoc.html 8. CFSAN. (2003). Dietary guidance message about fruits and vegetables, http://www. cfsan.fda.gov/~dms/lab-dg.html 9. LeGault L, Brandt MB, McCabe N, Adler C, Brown A-M, Brecher S. (2004). 2000– 2001 Food label and package survey: an update on prevalence of nutrition labeling and claims on processed, packaged foods. J Am Diet Assoc 104, 952–958. 10. Dietary Supplement Health and Education Act of 1994. (1994). Public Law 103–417. 11. FDA Modernization Act of 1997. (1997). http://www.cfsan.fda.gov/~dms/labfdama. html

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World Trade Organization and Food Regulation: Impact on the Food Supply Chain

11

Okezie I. Aruoma Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, NY, USA

Abstract Consumers nowadays are faced with food or food ingredients that may derive from distant countries or continents and with a less transparent food supply. Safety concerns must cover the range of different food chains relevant to a certain food product or product group, including all relevant producers, manufacturing sites and food service establishments within a country as well as those importing into the country. Food regulation in the main is aimed at protecting the consumer’s health, increasing economic viability, harmonizing well-being and engendering fair trade on foods within and between nations. Hazard analysis at critical control points (HACCP), good manufacturing practice (GMP) and good hygiene practice (GHP) are major components of the safety management systems in the food supply chain. Principally, ‘a hazard’ is a biological, chemical or physical agent in, or condition of, food that has the potential to cause an adverse health effect. The likelihood of occurrence and severity of the same is important for the assessment of the risk presented by the hazard to the food supply chain. The Government’s regulatory mechanisms in accordance with the World Trade Organization (WTO) agreements (HACCPs, sanitary and phytosanitary (SPS) measures etc.) oversee the analyses of public health problems and their association to the food supply. Under the WTO SPS Agreements and the codes of practices issued by the Codex Alimentarius Commission there now exists a benchmark for international harmonization that guarantees the trade of safe food. In parallel with this is the adage of the standard food security definition which observes that the modern retailer-driven food supply chain has generally provided consumers with sustained ‘physical and economic access to sufficient, safe and nutritious food’. Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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144 World Trade Organization and Food Regulation

Food Regulation, Supply Chain and the World Trade Organization (WTO)

Preparing portioning packaging

Food processor

Further processing mixing, assembly

Portioning packaging branding

Consumers

Extended storage and transport

Retailer

Food commodities (Farming’ fishing)

Fresh produce

Wholesaler

Food regulation in the main is aimed at protecting the consumer’s health, increasing economic viability, harmonizing well-being and engendering fair trade on foods within and between nations. Many factors that affect the food systems include the climate, available arable land, technology (from the standpoint of production, preservation, processing and storage). A modern food control program centers at all stages of the food supply chain, from farm to consumers (Fig. 11.1). There is a need to balance the benefits of increased food supplies through technological processes against associated health and economic risks, a need that is of increasing importance given the rising trend in world population, the opening up of boundaries, migration, urbanization and, with these, changing food habits. Agricultural mechanization and industrial food processing advocated in Figure 11.1 embrace that foods produced and presented to the markets have to meet standards that are universally acceptable. Thus, food legislation assures a safe supply of commodities and aspires to eliminate fraudulent practices. This is important given the diverse and changing trend of food commodities. Perishable food products, such as meats, fish and vegetables (processed and packaged and ready to eat foods), are finding their way across international boundaries and meeting competition with indigenous manufacturers. Given this, agricultural selfsufficiency ignores the relevance of the whole food chain and how the food chain itself might enhance or weaken food security. Using the standard food security definition, it is clear that the modern retailer-driven food supply chain has generally provided consumers with sustained ‘physical and economic access to sufficient, safe and nutritious food’. Modern supply chains have vulnerabilities, but are not necessarily more risky than alternative, or historic, supply chain systems (the intricacy of this can be read by the various contributors to the segments in Figure 11.1). There may, however, be a degree of trade-off between resilience and efficiency in the issue of redundant

Storage Ingredients producer

Figure 11.1 The food supply chain. This has seen a continued trend in technological innovations from foods leaving the farm and their handling up until reaching the end user the consumer. Public concern about food safety is placing increasing pressure on government agencies to be more prescriptive and proactive in their regulation of the food industry. There is increased emphasis to optimize the logistics of delivering fresh produce, chilled products, dry groceries and frozen products to retail outlets and to caterers.

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Food Regulation, Supply Chain and the World Trade Organization (WTO) 145

physical capacity. The competitiveness of markets, domestically and internationally, are of great importance. Many consumers worldwide worry that food derived from genetically modified organisms (GMOs) may be unhealthy and hence regulation on GMO authorizations and labeling have become more stringent. Nowadays, there is a higher demand for non-GM products and these products could be differentiated from GM products using the identity preservation system (IP) that could apply throughout the grain processing system. IP is the creation of a transparent communication system that encompasses hazard analysis at critical control points (HACCP), traceability and related systems in the supply chain. This process guarantees that certain characteristics of the lots of food (non-GM origin) are maintained ‘from farm to fork’. In pursuance of the risk assessment governing GMOs, manufacturers should be able to supply evidence to satisfy the competent authorities that they have taken appropriate steps to avoid the presence of adventitious or technically unavoidable materials. There may be a case to tolerate presence of organisms that is inherent because of the nature and geographical origin of the crop, the current structure of the supply chain, current industrial practices and premises, as far as the regulatory thresholds are met. The appropriate steps taken to avoid adventitious or technically unavoidable presence of GM material will depend on, inter alia, the origin, nature and composition of the food or food ingredient. Briefings on the regulations may be found from the following websites of the European Union: http://europa.eu.int/comm/research/quality-oflife/gmo/index.html and http://europa.eu.int/comm/research/fp5/eaggmo.html. Risk analysis has become important to assess conditions and take decisions on control procedures on their consideration of prerequisites in the evaluation of GM food (1). The World Trade Organization (WTO), formed in 1995, is the only global international organization dealing with the rules of trade between nations. At its heart are the WTO agreements, negotiated and signed by the bulk of the world’s trading nations and ratified in their parliaments. The goal is to help producers of goods and services, exporters and importers conduct their business (Fig. 11.2). These agreements are the legal ground-rules for international commerce. Essentially, the agreements are contracts that guarantee member countries important trade rights. The instruments also bind governments to keep their trade policies within agreed limits to everybody’s benefit. The agreements were negotiated and signed by governments. But their purpose is to help producers of goods and services, exporters and importers conduct their business. Although the Government’s regulatory mechanisms oversee the analyses of public health problems and their association to the food supply, food safety is still mainly the responsibility of the consumer, they nevertheless need to be well informed. The activities of the WTO can be summarized as follows: ● ● ● ● ●

●

Administering trade agreements Acting as a forum for trade negotiations Settling trade disputes Reviewing national trade policies Assisting developing countries in trade policy issues through technical assistance and training Cooperating with other international organizations.

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The World Trade Organization (WTO) is the only international organization dealing with the rules of trade between nations. WTO agreements are negotiated and signed by the bulk of the world’s trading nations and ratified in their parliaments

The agreements are legal ground rules for international commerce that aims to guarantee member countries trading rights. In the same vein, trade policies are kept within an agreed limits to mutual benefits

The WTO’s overriding objective is to help trade flow smoothly, freely, fairly and predictably. By lowering trade barriers, the WTO’s system breaks down other barriers between peoples and nations

Agreements are intended to help producers of goods, exporters and importers conduct their business

Figure 11.2 The role of the WTO and international trade. The liberalization that has been achieved through GATT/WTO negotiations is especially noteworthy in light of the fact that negotiations occur through time between the governments of various countries. This feature raises the possibility that the market access implied by existing tariff commitments may be altered by tariff commitments made at some point in the future.

While it is clear that developed countries monitor their food systems with the expected outcome in providing a consistent and constant supply of safe and wholesome food, many developing countries battle with an unsafe and inadequate food supply. This leads to heavy economic losses (particularly scarce foreign exchange) and health hazards ranging from malnutrition to food-borne illnesses. Interestingly, while economic globalization can easily equate with the expansion of international trade, it is clear that some developing countries continue to struggle to become fully integrated into the world trading system. It is critical therefore to improve awareness, simplify rules, improve skills and infrastructure, adapt food safety monitoring to local conditions and help formulating risk management systems for niche products from developing countries (2–7). As argued by Henson et al. (5): there are concerns about power relations through the supply chain, supermarket demand for high-value fresh produce can provide opportunities for the enhancement of small-scale producer livelihoods and, at the same time, attention has focused on the processes through which small-scale producers are integrated into, or excluded from, supermarket supply chains and the associated impact of stricter food safety and quality standards and logistics requirements. Resilience itself is increasingly a commercial issue. Many of the risks involved are in firms’ interests to guard against since this directly affects their business or reputation.

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Food Regulation, Supply Chain and the World Trade Organization (WTO) 147

Business continuity planning has grown in recent years, but there is potential for further improvement. Contingency planning by Government, and the need to work closely with the food industry, remains important to overcome any infrastructure, information and coordination failures. The confusion between quality and safety, over regulation, selective enforcement, lack of integration of food laws and regulations in the overall legislative system, the multiplicity of responsible agencies, and the mismatch between the required standards are among the major issues that the World Bank have come to realize. So poor economics, poor infrastructure and lagging skills have negative impact on trade for the developing countries. Improving food safety along the standards of the developed economies, however, may carry considerable costs and price food out of reach of the poor. Indeed, improving awareness, simplifying rules, improving skills and infrastructure, adapting food safety monitoring to local conditions and help in formulating management systems, e.g. HACCPs, for niche products for developing countries are within the context of seeking harmonization in world trade. Yapp and Fairman (8) have reviewed the factors affecting food safety compliance within small and medium-sized enterprises (SMEs) and the implications for regulatory and enforcement strategies in the UK. The findings were quite remarkable. Among the identified factors were: lack of money (where SMEs focus on immediate survival rather than potential benefits derived over the long term) and lack of time. Time has tended to prevent the identification and interpretation of regulations, thereby preventing further action being taken by SMEs. More interesting, however, the realization is that food sector SMEs do not see these steps as part of their business operation. This was viewed as the duty of the external agencies such as the Environmental Health Practitioners (EHPs) who inspect food businesses according to criteria contained within Code of Practice issued under section 40 of the Act UK’s Food Standards Agency. Yapp and Fairman argued that it is this reactive attitude rather than a lack of time that prevents identification and interpretation of regulations by SMEs. Lack of experience, lack of access to information (seen as a problem with overprovision of information resulting in confusion about relevance), lack of support (where SMEs perceive that support is biased towards larger companies), lack of interest (where SMEs focus upon business survival rather than compliance with regulations) and lack of knowledge (where SMEs have poor awareness of the relevance of legislation) were noted. Quoting the work of Reiss (1984), Yapp and Fairman brought attention to the view that: The principal objective of a compliance law enforcement system is to secure conformity with the law by means of insuring compliance or by taking action to prevent potential law violations without the necessity to detect, process and penalize violators. The principal objective of deterrence law enforcement systems is to secure conformity with law by detecting violations of law, determining who is responsible for their violation, and penalizing violators to deter violations in the future. It is clear that these considerations are not dissimilar from the experience of other SME in the world market.

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The intent of the Global Agreement on Tariffs and Trade (GATT) has been one of streamlining international trade. In the early phases of GATT, most attention was given to trade and trade conflicts between large trading blocks and markets such as the USA, European Community, Japan etc. and too little to the interests of smaller developing countries. So the developing countries (or the less developed countries) have been left to adopt the rules that were specifically created for these large markets and given little time to adjust their institutions to assure that export products are in compliance with, to them exotic, food safety rules. Thus, the introduction and application of food safety tools and rules need to be affordable and build on local food management customs rather than simply imposing standards that are expensive to monitor (3,5,9–11). Such an application has its benefit as Baker (12) observed: a HACCP based food safety system that was integrated with restaurant policies, operations, documentation and communication strategies could have avoided the costly exercise of removing a highly profitable menu item, the associated loss of market momentum, heightened regulatory scrutiny and the potential to raise questions of consumer confidence. The WTO SPS Agreement relates to three main issues: food safety, animal health and plant health. In each case, the Agreement identifies an international body as providing the basic standards against which disputes over national regulations would be judged. Under the WTO, SPS Agreements and the codes of practices issued by the Codex Alimentarius Commission constitute the benchmark for international harmonization that guarantee the trade of safe food (7,13). These need to be enacted and enforced in each country’s food legislation. The market access agenda in industrial countries extends to trade-impeding regulations such as environmental and health standards and restrictive rules of origin, as well as restrictions and regulations that limit the ability of developing countries to sell services abroad, especially through the temporary movement of workers (14). It is clear that trade liberalization needs to be complemented by a number of other policies such as sound macroeconomic management, effective regulation (e.g. financial services) and improved customs and tax administration. This needs to embrace the policies and institutions to support social objectives and safeguard the interests of the poorest in society. Further, global trade rules need to be defined from a developmental perspective if they are to serve as tools for poverty reduction. In this context, capacity building measures should include bolstering the ability of stakeholders in developing countries to participate in the development and implementation of traderelated policies and global trading rules. Compliance with the decision of the WTO remains an area of concern given the tendency of developed and powerful countries continuing to threaten the survival of the WTO system through lengthy and costly legal interpretations and appeals of dispute settlements without serious efforts by all parties to find win-win solutions. The most flagrant trade violations have been eliminated as a result of improved transparency in the process. Consumers are in general better off, since they have greater diversity and increased safety in what they can buy. The guidelines of the World Bank in

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its 2002 handbook on the magnitude of border barriers and trade liberalization, upon which the foregoing comments were based, can be summarized as seeking to foster: ●

●

●

●

●

Effective market access that has a wider dimension than border restrictions on goods Reciprocal liberalization for developing countries that achieves improved access to markets abroad and greater openness at home, but there are major political economy constraints to be overcome Trade liberalization to form only a small part of the comprehensive domestic reforms that are needed to deliver poverty-reducing growth Better analysis of the costs and benefits of global trade rules for developing countries Integrating developing countries more effectively into the global economy.

Sanitary and Phytosanitary Agreements Global harmonization of food safety regulations will undoubtedly help to ensure fair competition among countries in terms of trade and, at the same time, it will enable all populations enjoy the same degree of food safety. This was one of the ideas behind the Uruguay Round of Multilateral Trade Negotiations, which resulted in the creation of the WTO in 1995, including a number of agreements, e.g. the Agreement on the application of SPS and the Agreement on Technical Barriers to Trade (TBT). The Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement) came into force with the formation of the World Trade Organization (WTO) 1995. The SPS Agreement was aimed at controlling issues affecting food safety measures. Although some constraints had been applied by the original General Agreement on Tariffs and Trade (GATT) in 1947, it was believed that various countries were using food safety concerns to justify maintaining or erecting food regulations against imported foods which were a barrier to trade. One major qualification is contained in Article 3(3) of the SPS Agreement which states that: Members may introduce or maintain sanitary or phytosanitary measures which result in a higher level of sanitary or phytosanitary protection than would be achieved by measures based on the relevant international standards, guidelines or recommendations if there is a scientific justification, or as a consequence of the level of sanitary or phytosanitary protection a Member determines to be appropriate in accordance with the relevant provisions … To help with interpretation, the term ‘scientific justification’ was further defined as follows: There is a scientific justification if, on the basis of an examination and evaluation of available scientific information in conformity with the relevant provisions of this Agreement, a member determines that the relevant international standards,

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guidelines or recommendations are not sufficient to achieve its appropriate level of sanitary or phytosanitary protection. The term ‘sanitary or phytosanitary measure’ is defined as: ‘any measure applied to protect human, animal, or plant life or health from certain risks, including risks arising from: (i) the spread of pests, diseases, disease-carrying organisms or diseasecausing organisms, (ii) the presence of additives, contaminants, toxins or diseasecausing organisms in foods, beverages or feeds and (iii) diseases carried by animals, plants or products thereof ’. The SPS Agreement, therefore, includes a broad scope of activities related to food safety as well as the protection of animal and plant health. As such, the SPS Agreement applies to all sanitary and phytosanitary measures that may affect international trade. Exporters must meet the quality and safety demanded by import market consumers. For this reason, international trading rules are in place in order to ensure that public standards are applied fairly and equally to domestic and imported products. WTO members supported the following SPS principles: ● ● ● ● ● ● ●

Transparency Equivalence Harmonization Science-based measures Regionalization National sovereignty Dispute resolution.

Hence, nations are required to publish their regulations and provide a mechanism for answering questions from trading partners. Member nations must accept that SPS measures of another country are equivalent if they result in the same level of public health protection, even if the measures themselves differ. The same level of health protection should apply to both domestic and imported products. Regulations should be such that they cannot impose requirements that do not have a scientific basis for reducing risk. The concept of pest- or disease-free areas within an exporting country is recognized. Exports can be allowed from such areas, even if other areas of an exporting country still have the disease or pest. Countries may choose a risk standard that differs from the international standard. This recognizes that individual nations are unwilling to subscribe to uniform international standards for all hazards. There is a clearly defined mechanism for resolving disputes between countries in a timely manner. The dispute settlement panel is expected only to state whether the SPS measures under question have a scientific basis and are consistently applied. Further, member nations recognize the desirability of common SPS measures. Three international organizations are recognized as sources of internationally agreed-upon standards: 1. The Codex Alimentarius Commission (Codex) 2. The International Office of Epizootics (OIE) 3. The International Plant Protection Convention (IPPC). Brief comments on the first of these follow. The Codex Alimentarius develops food safety standards which serve as a reference for international food trade. This was set

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up in the 1960s as a joint instrument of the UN FAO and the WHO with the primary mission to protect the health of consumers and ensure fair practices in international food trade. Thus, Codex Alimentarius Commission adopts standards for commodities, codes of practice and maximum limits for additives, contaminants, pesticides residues and veterinary drugs. Following the conclusion of the Uruguay Round in 1994, the role of Codex Alimentarius Standards was strengthened. The WTO Agreement on SPS measures considers that WTO members applying the Codex Alimentarius standards meet their obligations under this Agreement. Additional information and updates can be obtained from http://www.wto.org. Traditional trade protection has been reduced by the 1994 GATT agreement, which means that SPS measures assume greater importance in determining market access (4,7,15–17). The challenges and issues food safety standards for export across trade barriers includes: 1. the importance of fresh food product trade by region and the kinds of issues that arise from those products 2. the role of farm to table approaches and HACCP (Fig. 11.3) in ensuring safety 3. the role of the public sector in WTO member countries and the less developed countries in facilitating trade and 4. the potential role of the SPS Agreement in resolving disputes and determining equivalency of standards between high and low income countries.

CAPACITY and COMPETENCY Implementation of HACCP must embrace existing constraint of an organisation in the context of time and resources [3] Set valid critical limits for safe management of critical control points

[1] Hazard analysis and validation of such hazards ofsuchhazards [2] Identification of critical control points (CCPs) Application of the 7 principles of HACCP

[6] Verification of HACCP plan which can be periodic testing of samples, auditing of HACCP plan, evaluation of consumer complaints and review of CCP monitoring

[4] Establish and/or formulate a viable monitoring procedures

[7] Keep records to include CCP monitors, CCP record reviewers, verification activities and record of amendment to system with the justification

[5] Aim to establish a corrective action

Figure 11.3 Application of the principles of HACCP. Food supply chain management systems in assuring safety and quality are interfaced by a prerequisite requirement (e.g. good manufacturing practice, (GMP), good hygiene practice (GHP)), food safety assurance plan (e.g. HACCP plan), a quality system and a cultural/managerial approach (e.g. ISO 9000, TQM etc).

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Hazard Analysis at Critical Control Points (HACCP) The health status of a population can be evaluated by use of the microbiological risk assessment (MRA) for a product or product group to which a pathogen is associated. On a population basis, a calculation of risk can predict the expected number of specific illnesses or deaths per 100 000 population per year attributable to the pathogen/ food in question, or risk can be defined as the probability of a specific adverse outcome per exposure to the food. An MRA can give an absolute or a relative indication of the health status, i.e. provide an absolute numerical expression of the risk at population level respectively a relative or benchmarked expressing (e.g. a ranking). This applies whether the food product originates from one country or is imported into it. Applicable definitions in risk analysis based food control are presented in Figure 11.4. The food industry is not only responsible for producing safe food but also for demonstrating in a transparent manner how food safety has been planned. For example, hazards which have been considered in production and the measures that have been

Risk analysis based on food control Food safety objectives (FSO) Appropriate level of protection (ALOP)

Performance objectives (PO) Governmental and operational control levels for food safety

Control measures (CM)

Performance criterion (PC)

Food safety controls and food safety management. Government’s regulatory mechanisms oversees the analyses of public health problems and their association to the food supply chain Figure 11.4 Risk assessment criteria. Appropriate level of protection (ALOP), level of protection deemed appropriate by the member (country) establishing a sanitary or phytosanitary measure to protect human, animal or plant life or health within its territory; Food safety objective (FSO), this refers to the maximum frequency and/or concentration of a hazard in a food at the time of consumption that provides or contributes to the ALOP. FSO is just one of the options to give guidance to food safety management the expected management of risks. Performance objective (PO), the maximum frequency and/or concentration of a hazard in a food at a specified step in the food chain before the time of consumption that provides or contributes to an FSO or ALOP, as applicable; performance criterion (PC), the effect in frequency and/ or concentration of a hazard in a food that must be achieved by the application of one or more control measures to provide or contribute to a PO or an FSO; control measure (CM), any action and activity that can be used to prevent or eliminate a food safety hazard or to reduce it to an acceptable level (it can be microbiological specifications, guidelines on pathogen control, hygiene codes, microbiological criteria, specific information (e.g. labeling), training, education, and others).

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put in place to ensure the safety of products. This is done through the development of HACCP studies and HACCP plans as part of the food safety assurance system. HACCP is a straightforward and logical system of control based on the prevention of problems – a common sense approach to food safety management. HACCP merits in food safety management can be realized only if the people charged with its implementation have the knowledge and expertise to apply it effectively. This could be a combination of horizontal and vertical partnerships, as in the poultry industry. The resulting network involved all kinds of parties in the industry from breeding farms down to the packing stations, along with feed producers, veterinarians and a quality service organization. The need is to guarantee the quality of poultry products to the consumer and to provide information for associated transparency. Seminal discussions on the workings of HACCP and application to several food sectors are widely reviewed in the literature to which the reader is referred (e.g. 18–25, http://www.codexalimentarius.net; http://www.wto.org.; http://www.fao.org). ‘Hazard’ is ‘a biological, chemical or physical agent in, or condition of, food with the potential to cause an adverse health effect’ (19). Hazard analysis, therefore, requires that both the likelihood of occurrence and severity of that hazard are considered, in effect an assessment of risk. Validation of the hazard analysis is an important element and, probably, the key principle in the whole HACCP system and the one which many find difficult to apply. CCPs can be designated a prerequisite so as not to undermine the whole process. For example, failure to wash hands if not designated as a prerequisite hygiene program can create problems if regarded as a CCP and it is not adhered to. It is no accident that HACCP evolved at the food processing step of the farm to table supply chain (see Fig. 11.1). It is at this step that effective controls, such as cooking, drying, acidification or refining are available to eliminate significant hazards. Two typical examples are pasteurized dairy products and in canned foods. Here food safety is assured by process control, not by finished product testing. HACCP is of critical importance to the food service sector as it helps to ensure that the whole production line of the food chain is acceptable and which is necessary to improve public health. For HACCP to be effective when targeting the specific needs of the retail food establishment, it must be compatible with the products sold, the clients served and the facilities and equipment used during food production. As argued by Sperber (23): HACCP cannot provide greater transparency in the food supply chain in the context of this type of opaque regulatory environment. Rather, greater transparency, and improved public health protection, must be realized through the development of voluntary science based systems, especially involving the food processing industry, where the very idea of HACCP was conceived and implemented. Regulatory action is an appropriate response when food markets fail to deliver the level of safety required to satisfy social public health goals. In the field of food safety economics, social welfare analysis of policies focuses on the regulation of markets to increase social welfare (i.e. improvements in public health) in situations where markets fail, while the political economy (private) approach focuses on the position of interest groups in the process of regulation (26).

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Hazard Identification

Description of food safety problem and context

What agents are present in the food and capable of causing adverse health effects?

Hazard characterization Exposure assessment

What is the nature of adverse effects?

What is the likely frequency and level of consumption?

Dose-response assessment

Risk estimate Probability and severity of illness attributable to the food/pathogen source; e.g. no. of illnesses per year, or per 100 K population. Uncertainty: What important data or knowledge are missing?

Risk characterization Integration of exposure assessment and hazard characterization

Variability: What variable factors influence the magnitude of the risk? Figure 11.5 Risk assessment is a science-based investigation consisting of four steps: hazard identification, exposure assessment, hazard characterization and risk characterization in accordance with the framework adopted by the Codex Alimentarius Commission. (From Lammerding AM, Fazil A. (2002). Hazard identification and exposure assessment for microbial food safety risk assessment. Intl J Food Microbiol 58, 147–157.)

Food safety management as in GMP, GHP and HACCP provisions, are specific to the available facility, the processing line and the exact product composition and processing. So, for a specific food product, microbiological risk assessment considers all foods consumed in a country, whether produced in that country or imported; it involves all different production facilities, a multitude of production lines and product compositions and processing. MRA takes a generic, population level view on the overall production and marketing of a food product. Risk assessment is a science-based investigation consisting of four steps: hazard identification, exposure assessment, hazard characterization and risk characterization as outlined in Figure 11.5, itself based on the framework adopted by the Codex Alimentarius Commission (27).

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References 155

Hazard identification identifies the issues of concern and provides the focus of the risk assessment. The exposure assessment generates estimates of the likelihood and magnitude of exposure to the hazard, setting the stage for the next two steps of the assessment, hazard characterization and risk characterization, in which the exposure outputs are translated into a measure of risk (27). Although policy-makers may argue that the primary responsibility for food safety lies with the private sector, whereas the definition of basic standards, monitoring and policing is the responsibility of the public sector. It is clear that the heightened concern for food safety has meant that both public and private regulations and activities are jointly instrumental to the delivery of a safer food supply. Governmental risk managers may choose to implement specific risk management measures (standards, microbiological criteria, hygiene code, labeling, education, etc.) in addition to a food safety objective (FSO). Such measures may be relevant to all or the majority of supply chain so they should be included in all cases. Alternatively, such measures may be essential additions to the target without which the appropriate level of protection (ALOP) may not be met. FSO is just one of the options to give guidance to food safety management the expected management of risks. As there are often many links in a food supply chain (see Fig. 11.1), it is clear that establishing and/or defining several operational targets along the chain will help ensure that the chain as a whole operates to meet the FSO at consumption. HACCP is a major contributor to overall quality assurance system (ISO 9000) in international food trade.

Acknowledgment Adapted from a review article: Aruoma OI. (2006). The impact of food regulation on the food supply chain. Toxicology 221, 119–127.

References 1. Zepeda C, Salman M, Ruppanner R. (2001). International trade, animal health and veterinary epidemiology: challenges and opportunities. Prev Vet Med 48, 261–271. 2. Anyanwu RC, Jukes J. (1991). Food systems and food control in Nigeria. Food Pol 16, 112–126. 3. Brown CG, Longworth JW, Waldron S. (2002). Food safety and development of the beef industry in China. Food Pol 27, 269–284. 4. Henson S, Loader R. (2001). Barriers to agricultural exports from developing countries: the role of sanitary and phytosanitary requirements. World Dev 29, 85–102. 5. Henson S, Masakure O, Boselie D. (2005). Private food safety and quality standards for fresh produce exporters: The case of Hortico Agrisystems, Zimbabwe. Food Pol 30, 371–384. 6. Juke D. (1988). Developing a food control system. The Tanzanian experience. Food Pol 13, 298–304.

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7. Jukes D. (2000). The role of science in international food standards. Food Control 11, 181–194. 8. Yapp C, Fairman R. (2006). Factors affecting food safety compliance within small and medium-sized enterprises: implications for regulatory and enforcement strategies. Food Control 17, 42–51. 9. Chen J. (2004). Challenges to developing countries after joining WTO: risk assessment of chemicals in food. Toxicology 198, 3–7. 10. Key N, Runsten D. (1999). Contract farming, smallholders and rural development in Latin America: the organization of agro-processing firms and the scale of out-grower production. World Dev 27, 381–401. 11. Nguz K. (2007). Assessing food safety system in sub-Saharan countries: an overview of key issues. Food Control 18, 131–134. 12. Baker DA. (2002). Use of food safety objectives to satisfy the intent of food safety law. Food Control 13, 371–376. 13. Boutrif E. (2003). The new role of Codex Alimentarius in the context of WTO/SPS agreement. Food Control 14, 81–88. 14. World Bank. (2002). Development, trade and the WTO. A handbook. The World Bank, Washington, DC. 15. Kastner JJ, Pawsey RK. (2002). Harmonising sanitary measures and resolving trade disputes through the WTO-SPS framework. Part I: a case study of the US-EU hormone-treated beef dispute. Food Control 13, 49–55. 16. Kastner JJ, Pawsey RK. (2002). Harmonising sanitary measures and resolving trade disputes through the WTO-SPS framework. Part II: a case study of the US-Australia determination of equivalence in meat inspection. Food Control 13, 57–60. 17. Unnevehr LJ. (2000). Food safety issues and fresh food product exports from LDCs. Agric Econ 23, 231–240. 18. Azanza MPV. (2006). HACCP certification of food services in Philippine. interisland passenger vessel. Food Control 17, 93–101. 19. Codex Alimentarius Commission (1997). Hazard analysis and critical control point (HACCP) system and guideline for its application, Annex to CAC/RCP 1-1969, Rev 3. 20. Jeng H-YJ, Fang TJ. (2003). Food safety control system in Taiwan. The example of food service sector. Food Control 14, 317–322. 21. Mortimore S. (2001). How to make HACCP really work in practice. Food Control 12, 209–215. 22. Sperber WH. (1998). Auditing and verification of food safety and HACCP. Food Control 9, 157–162. 23. Sperber WH. (2005). HACCP and transparency. Food Control 16, 505–509. 24. Sperber WH. (2005). HACCP does not work from farm to table. Food Control 16, 511–514. 25. Sun Y-M, Ockerman HW. (2005). A review of the needs and current applications of hazard analysis and critical control point (HACCP) system in foodservice areas. Food Control 16, 325–332. 26. Martinez MG, Fearne A, Caswell JA, Henson S. (2007). Co-regulation as a possible model for food safety governance: opportunities for public–private partnerships. Food Pol 32, 299–314.

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27. Lammerding AM, Fazil A. (2000). Hazard identification and exposure assessment for microbial food safety risk assessment. Int J Food Microb 58, 147–157. 28. Jukes D. (1993). Regulation and enforcement of food safety in the UK. Food Pol 18, 131–142. 29. Varzakas TH, Chryssochoidis G, Argyropoulos D. (2007). Approaches in the risk assessment of genetically modified foods by the Hellenic Food Safety Authority. Food Chem Toxicol 45, 530–542. 30. WTO. (1995). Agreement on the Application of Sanitary and Phytosanitary Measures. World Trade Organization. www.wto.org 31. WTO. (1999). Review of operation and implementation of the Agreement on the Application of sanitary and Phytosanitary Issues. World Trade Organization. www. wto.org

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Emerging Policies and Practices Under the Canadian Natural Health Product Regulations

12

Stephanie Martyres, Melody Harwood and Earle R. Nestmann Cantox Health Sciences International, Mississauga, ON, Canada

Abstract The popularity of traditional or alternative medicines is evidenced by the volume of such products available around the world. In Canada, the Natural Health Product Regulations, promulgated in 2004, categorized such products as natural health products and outlined requirements for their premarket assessment of safety, efficacy and quality. With a new regulatory framework for over 40 000 products on the Canadian market, the Natural Health Products Directorate (NHPD) has faced numerous challenges in its goal to license all products. As such, the policies and practices of the NHPD and other related regulatory agencies within Health Canada are constantly changing in order to address these issues. The basic principles of the Regulations and examples of major issues faced by the NHPD are discussed.

Introduction The use of traditional or alternative medicines has been well documented for centuries in various cultures. Today, the widespread use of such therapies is evidenced by the wide variety and large volume of supplement products on markets around the world. The World Health Organization (1) reported that the use of traditional Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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160 Emerging Policies and Practices Under the Canadian Natural Health Product Regulations

medicines, which include plant-, animal- and mineral-based medicines, spiritual therapies and manual techniques and exercises, has increased in popularity in industrialized countries, while its popularity among developing nations has been maintained. Between 1990 and 1997 in the USA, the use of alternative medicines was reported to increase from 33.8 to 46.3%, and visits to alternative medicine practitioners increased by 46.3% (2). More recently, Timbo et al. (3) reported a prevalence rate of 73% among participants (n ⫽ 2743) of the US Food and Drug Administration (FDA) 2002 Health and Diet Survey. A recent survey in Canada indicated that 71% of Canadians had used a natural product at least once, while 38% of those that have used such products do so on a daily basis (4). The increasing use of traditional medicines has raised concerns about the safety and quality of the available products, with some ingredients having been demonstrated to possess pharmacological properties that may pose a risk to human health, while others may have contaminants, such as heavy metals, that are not controlled (1,5). Public perception that ‘natural’ ingredients are safe also may prompt consumers to use traditional or alternative medicines without taking into account other factors, such as concurrent medications or recommended conditions of use. One-half of Canadians surveyed agreed that natural health products may be safe because they are made using natural ingredients, while 37% agreed that natural products available for sale to the public were safe (4). With concerns over safety, efficacy and quality, the Canadian government established a new regulatory framework for the over 40 000 supplement products and traditional and alternative medicines on the Canadian market by creating the Natural Health Product Regulations (the NHP Regulations) and establishing a category for such products as natural health products (NHP). Developed with the intent of providing Canadian consumers with ready access to NHP that are safe, effective and of high quality, the NHP Regulations, promulgated in 2004, are applicable to the sale, manufacture, packaging, labeling, importation, distribution and storage of NHP and are administered by the recently formed Natural Health Products Directorate (NHPD) within Health Canada. This chapter briefly outlines the general provisions of the NHP Regulations as well as the challenges faced by, and emerging issues and policies developed by, the NHPD as they work toward evaluating all products currently in the Canadian marketplace. The regulations and regulatory practices governing NHP in Canada were described in a previous publication (6), so the following sections provide only a brief overview of the regulations and focus more on issues that have arisen and on policies that are developing in response.

NHP Regulations In Canada, products that now fall under the definition of an NHP previously were regulated either as foods or as drugs under the Food and Drugs Act and Regulations, with drugs requiring premarket approval and the issuance of a Drug Identification Number (DIN). Although encompassed under the Food and Drugs Act (the Act), the

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NHP Regulations are essentially independent of the Food and Drug Regulations and provide for a unique regulatory regime for these products as sold in Canada. As NHP are not defined in the Food and Drugs Act, in order to be incorporated under the Act, NHP are regulated as a subset of drugs and several provisions from the Food and Drug Regulations were integrated to allow for proper administration of the NHP Regulations.

Definition of NHP Under the NHP Regulations, the definition for NHP involves two elements: a substance component and a function component. The substance component incorporates various substances permitted for sale as NHP, either singly or in combination, and includes herbal remedies, traditional and homeopathic medicines (HM) and a schedule of express inclusions comprising the following: materials derived from plants, algae, bacteria, fungi or non-human animal material; amino acids; essential fatty acids; probiotics; minerals; several vitamins; and synthetic duplicates of these natural ingredients, where applicable. Excluded from the definition of NHP are antibiotics, substances administered by puncturing the dermis, substances regulated under the Tobacco Act and several substances regulated under the Food and Drug Regulations, such as radiopharmaceuticals, biologics and drugs. The function component of the NHP definition includes those permitted substances sold or represented for human use without a prescription: 1. for the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state or its symptoms 2. for restoring or correcting organic functions or 3. for otherwise modifying organic functions in a manner that maintains or promotes health.

Transition Period With over 40 000 products on the market when the NHP Regulations took effect, the NHPD established a 6-year transition period for the licensing of NHP, and product licenses would be granted following the successful review of a Product License Application (PLA) submitted by the manufacturer, distributor, packager, labeler or importer of the product. NHP were categorized according to risk, with products perceived to be of higher risk given a higher priority compliance deadline by which a PLA would need to be submitted. Products with a DIN, having already undergone a review of safety and quality, were determined to be low risk and would have a full 6 years by which they would need to be licensed. The original priority categories and deadlines by which PLAs must be submitted are presented in Table 12.1. NHPD has extended the deadlines for some categories based on the volume of applications anticipated, current backlog and changes in risk criteria, as also noted in Table 12.1. Compliance action can be and has been taken against products on the market that are not the subject of a PLA submitted by the compliance deadline.

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Table 12.1 Risk-based priority groups Priority

Date

NHP category a

1

1 June 2004

2

1 January 2005b

3 4

1 June 2005 1 June 2006c

5 6

1 January 2007d 1 June 2007e

NHPs on TPDs Listing of Drugs Currently Regulated as New Drugs, Revised April 1999 (e.g. plant sterols, co-enzyme Q) Isolates, amino acids, fatty acids, concentrated volatile (essential) oils indicated for internal use and extracts others than those prepared by traditional methods Algal, bacterial, probiotic, fungal and non-human animal materials Plants, plant materials, extracts prepared by traditional methods and volatile (essential) oils other than those that are concentrated and indicated for internal use Vitamins and minerals Homeopathic medicines

Adapted from NHPD (7); TPD ⫽ Therapeutic Drugs Directorate. a Date was extended to 30 June 2004; b Date was extended to 31 January 2005; c Date was extended to 1 June 2007; d Date was extended to 1 January 2008; e Date was extended to 1 June 2008.

Regulatory Components The NHP Regulations apply to the sale, manufacture, packaging, labeling, importation for sale, distribution and storage of NHP. Provisions for conducting clinical trials also are outlined in the Regulations. The Regulations consist of five parts, which detail how these activities are to be regulated: product licensing, site licensing, good manufacturing practice (GMP), clinical trials and labeling and packaging. Product Licensing and Adverse Reaction Reporting

Under the Regulations, all NHP are required to undergo premarket review to obtain a product license and a corresponding Natural Product Number (NPN) or, in the case of homeopathic medicines, a DIN-HM. Generally, the PLA must contain information to allow the Directorate to evaluate the safety, efficacy and quality of the NHP, as well as the proposed label text(s), however, the extent of the required information depends on the submission type. Compendial PLAs, for ingredients monographed in NHPD’s Compendium of Monographs, do not require supporting evidence of safety and efficacy provided that the intended conditions of use for the medicinal ingredient are in line with those outlined in its monograph. Non-compendial PLAs, which include traditional use and non-traditional use claims, require a full review of all data. Other types of applications include those for transitional products (NHP already holding a DIN) and for HM. Over 6000 PLAs have been approved as of March 2008, with an approximately even split between compendial and noncompendial applications. Once a product is issued an NPN, the licensee is required to keep records containing a list of all ingredients and enough information to issue a lot or batch recall, if required, for at least one year after the expiry date of the NHP. Additionally, each licensee is required to implement and maintain a system for adverse reaction (AR)

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reporting for each of their licensed NHP on the market. Licensees are required to prepare, maintain and submit case reports for certain serious ARs and annual summary reports and interim summary reports for all ARs reported. Annual and interim summary reports must include a concise and critical analysis of the ARs reported and whether any significant safety issues have been identified with their use. Licensees also must monitor and report ARs resulting from new studies, such as clinical trials, using the licensed product. A discussion of the terminology, reporting guidelines and timelines for reporting is presented in NHPD’s Adverse Reaction Reporting Guidance Document (8). Site Licensing

In addition to providing data on the safety, efficacy and quality of NHP ingredients, each applicant must provide information regarding the site(s) of manufacture, packaging, labeling, distribution and importation, if applicable. All Canadian sites involved in these activities, with the exception of the distribution of NHP, must hold a site license, acquired through the submission of a site license application (SLA). A Canadian importer is required for NHP that are manufactured, packaged and labeled outside of Canada and all foreign sites must be listed on the importer’s site license. The goal of site licensing is to ensure that all NHP are manufactured, packaged, labeled, distributed and imported in accordance with NHP GMP requirements in order to ensure the safety and quality of the finished product. Applicants must demonstrate compliance with NHP GMP requirements before being issued a site license through the completion of a Quality Assurance Report (QAR) Form, which details all of the procedures concerning the production of NHP in place at each site. In order to ensure that licensed manufacturers, packagers, labelers and importers continue to operate under GMP, site licenses are subject to expiry dates and must be renewed every year for the first 3 years, every 2 years for years 4 to 9, then every 3 years if the license has been held for 9 years or more. To renew a site license, updated QAR forms must be submitted in the fourth and ninth years, and every 3 years thereafter. At other renewal periods, a summary of net changes and the appropriate records are all that are required to be submitted. Similar to the transition period for product licensing outlined above, a 2-year transition period was established for site licensing. All sites involved in the manufacture, packaging, labeling or importation of NHP on the Canadian market were given until December 31, 2005 to obtain site licenses. Any individuals or business operating without a valid site license beyond this date will be subject to compliance action, which may involve the cessation of all operations until a valid site license is issued. Good Manufacturing Practice (GMP)

NHP GMP requirements are outlined in the NHP Regulations as well as the NHPD’s GMP Guidance Document (9). The requirements are divided into four categories: places, people, processes and products. Within each category are requirements that must be met in order to ensure that the premises and equipment are suitable for the

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production of NHP (places), to ensure that the personnel involved with the production of NHP have suitable education, qualifications and training (people), to ensure that there are suitable sanitation, health and hygiene programs in place, as well as proper standard operating procedures (processes) and to ensure that products meet their established specification and are stable, and that proper sample retention and recordkeeping procedures are in place (product). Recall reporting procedures also are outlined under the GMP requirements. Clinical Trials

As discussed above, information supporting the safety and efficacy of the NHP must be submitted for certain PLAs. In cases where no human data exist, a clinical trial may be required to provide supportive evidence of efficacy and/or safety. The NHP Regulations outline the requirements for the conduct of a clinical trial, with the goal of ensuring the safety of clinical trial subjects, compliance with good clinical practice and the safety, efficacy and quality of the clinical trial protocol and the investigational product and placebo/comparator. A clinical trial application (CTA) must be submitted to NHPD to obtain approval for conduct of the trial. The CTA submission package must include details of the clinical trial, including the clinical trial protocol, investigator’s brochure, informed consent documents and clinical trial site information forms, details of the chemistry and manufacturing of the medicinal ingredient(s) and quality data, including specifications and certificates of analysis. The NHP Regulations also outline the requirements for recordkeeping, amendment of the clinical trial protocol and discontinuation of the protocol, which also are detailed in the Clinical Trials for Natural Health Products Guidance Document (10). Labeling and Packaging

All NHP sold in Canada must be labeled and packaged in accordance with the requirements outlined in the NHP Regulations. A printed version of the proposed label text, which includes all regulatory information, must be submitted with all PLAs. NHP must be labeled with information related to the proper use of the product (dosage form, recommended dose, directions, route of administration), recommended use or purpose of the product, list of all medicinal and non-medicinal ingredients, quantity of all medicinal ingredients, risk information, storage conditions, lot number, expiry date and name and address of the product license holder and importer, if applicable. The NPN assigned to the product upon approval also must appear on the label. Requirements also are outlined for the labeling of HM, NHP containing medicinal ingredients of certain standards or grades (e.g. United States Pharmacopoeia standard), NHP in enteric-coated tablet form, organic products and irradiated products. NHP also are required to be packaged in security packages, which offer consumers reasonable assurance that the product has not been opened or tampered with. Security packages may include seals, transparent wrappers, cotton swab inserts and lids that are sealed until opened. The proposed label must identify the security features of the product if it is not evident in the product packaging.

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Health Claims As discussed above, the definition for NHP involves a function component, which includes the purpose of the product (i.e. the health claim). Prior to the implementation of the NHP Regulations, NHP were previously regulated in Canada under the Food and Drug Regulations as food products, which could not bear health claims, or as drugs with authorized claims and directions for use. Under the NHP Regulations, various types and categories of product claims can be made based on the credibility, strength and quality of the evidence used to support the claim. The Directorate defines a claim as ‘a statement that indicates the intended beneficial effect of an NHP when used in accordance with the recommended conditions of use’ (11). Claims permitted for NHP fall into one of three types: treatment claims, risk reduction claims and structure/function claims. A description of each type of claim and an applicable example are provided in Table 12.2. Within these types of claims, there are two categories that are evaluated by the NHPD: traditional use and non-traditional use claims, each with differing levels of supportive evidence. Traditional use claims refer to the practices based on the experience of indigenous or different cultures used in the maintenance of health or the prevention, diagnosis or treatment of physical and/or mental illness for at least 50 consecutive years. Traditional use claims must be supported by at least two independent references. Non-traditional use claims must be supported by scientific evidence, meaning the requirements are more stringent than for traditional use claims. The strength of evidence for non-traditional claims is graded by level of evidence from human studies, with well-designed randomized, controlled trials bearing the greatest amount of strength, and claims to treat more serious health conditions requiring support by the strongest level of evidence, as outlined in Table 12.3.

Table 12.2 Description and examples of permitted health claims for NHPs Claim type

Description

Example

Treatment

Relates to the diagnosis, treatment and mitigation or prevention of a disease, disorder or abnormal physical state or its symptoms in humans

Effective in reducing joint pain

Risk reduction

Based on the relationship between a Use of [product xyz] is associated medicinal ingredient and the reduction in the with a decreased risk of risk of developing a certain disease, possibly osteoporosis by the alteration of a major risk factor or other contributing factor involved in the development of disease

Structure/function

Relates to the effect or support of an NHP ingredient on the structure or anatomical, physiological or mental function in the human body

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Table 12.3 Strength of evidence supporting health claims Level

Description

I II III IV

Well-designed randomized controlled clinical trials Clinical trials without randomization or control groups Descriptive and observational studies Expert opinion reports, published articles (peer-reviewed), conclusions of other reputable regulatory agencies and previous marketing experience References to traditional uses

V see (11)

Emerging Issues and Policies With a new regulatory framework for over 40 000 products on the Canadian market, the NHPD has faced numerous challenges in its goal to license all products within 6 years. NHPD is constantly holding consultations with industry stakeholders as it develops new policies and provides clarification and continuous guidance on a number of issues that have emerged. The following sections highlight some of the major issues and new policies that have arisen since the NHP Regulations took effect in 2004.

NHP in Food Forms In Canada, permitted forms of NHP are not expressly defined in the Regulations, however, the Directorate recognizes the commonly sold forms of these products, such as capsules, pills, tablets, powders or liquids and also considers certain other forms, including bars and gums, as acceptable forms, without excluding other food items, such as wafers or beverages, provided that such product forms are not intended to be primary sources of nutrition (12). NHP in Canada also include dermal products such as lotions, toothpastes, etc., but do not include substances administered by injection. When the NHP Regulations were promulgated, the NHPD acknowledged that ‘hybrid’ NHP products, containing a food, a cosmetic, or a medical device component in addition to the NHP ingredients, may be subject to the Food and Drug Regulations, Cosmetic Regulations, or Medical Devices Regulations, as applicable, in addition to the NHP Regulations (12). The NHPD indicated that each product would need to be reviewed on a case-by-case basis. Given the absence of any restriction on dosage forms, and in the absence of functional food regulations in Canada, numerous applications have been submitted to the NHPD for NHP in food forms, such as juices, drinks, cakes, yogurts and butters. In October 2007, Health Canada announced that PLAs for NHP in food forms would be reviewed by the Food Directorate in collaboration with NHPD (13). In addition to the NHPD guidance documents, the Food Directorate also would consider the standards of evidence for health claims on NHP-food products in accordance with the Interim Guidance Document–Preparing a Submission for Foods with Health Claims: Incorporating Standards of Evidence for Evaluating Foods with Health Claims. The

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availability of NHP in food forms has raised concerns within Health Canada that such products may cause confusion to the public and the industry, and may pose a risk to consumer health, as individuals accustomed to freely consuming certain food products may not take into consideration the recommended conditions of use and potential risks of these types of NHP. Health Canada is expected to consider a regulatory amendment that would change the regulatory status of NHP in food forms to be considered foods rather than NHP; however, no such amendment has been drafted to date (12). Concerns about risk to consumer health also prompted the NHPD to announce that they would process applications for NHP in food forms that are fortified with vitamins and minerals only if they were in accordance with the limitations, requirements and guidelines outlined in Health Canada’s proposed food fortification policy (14). The proposed policy, Addition of Vitamins and Minerals to Foods 2005: Health Canada’s Proposed Policy and Implementation Plans released in 2005, outlines which foods may be fortified, which vitamins and minerals may be added to these foods and the levels of fortification. Although the policy has not been fully adopted by Health Canada, it is NHPD’s view that it would be appropriate to adopt this policy for its assessment of NHP products in food form that are fortified with vitamins and minerals given that the proposed policy was developed following thorough risk assessment and extensive consultation.

Safety of Natural Ingredients As discussed above, many consumers have the perception that natural ingredients are safe. The intent of the NHP Regulations and the requirement for the premarket review of the safety and efficacy of all NHP products and ingredients are to ensure consumer safety and informed choice. As discussed above, an AR monitoring and reporting system must be put in place for all approved NHP as a post-marketing surveillance tool. In addition, new scientific data on NHP ingredients are constantly being generated and are monitored by Health Canada. As such, Health Canada issues advisories against the use of approved NHP ingredients that may pose a risk to human health. In May 2006, one such advisory was issued against the use of L-arginine in patients who had previously had a heart attack (15). The ingredient, consumed to promote and sustain healthy heart function, was the subject of a study by Schulman et al. (16) following which, the investigators recommended that L-arginine not be consumed in patients with a history of heart attack due to a higher than expected mortality rate and a significantly higher incidence of death in patients taking L-arginine relative to a placebo group. Although questions about the cause of mortality have been raised (17) and there have been no scientific data to support the findings of Schulman et al. (16), Health Canada, in its advisory (15), cited the Schulman et al. (16) study and required all products containing L-arginine to be labeled with a warning that reflects the results of the study. As a result, a stop-sale and recall order was issued for all products containing L-arginine that did not have the appropriate labeling. A number of case reports linking black cohosh and liver damage internationally and in Canada prompted Health Canada to issue an advisory against the use of this ingredient (18). Health Canada acknowledged that the link between the herb and liver toxicity

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was not clear and that it was taking a precautionary approach in its advisory. Although a stop-sale and recall order was not issued in this advisory, precautions, including possible symptoms that may be indicative of liver toxicity, were outlined. Upon review of the adverse reaction case reports by Health Canada, the European Medicines Agency, and the Australian Therapeutic Goods Administration, it was determined that of the cases that were determined to be probably or certainly related to liver damage, there was insufficient evidence that the products involved contained authentic black cohosh (19). Despite the lack of evidence, Health Canada deemed it appropriate to revise the NHPD monograph for black cohosh to include the cautionary statement ‘Consult a health care practitioner prior to use if you have a liver disorder or if you develop symptoms of liver trouble’ (20). Another challenge for Health Canada and the NHPD is to keep abreast of unapproved products penetrating the Canadian market. Health Canada has issued numerous advisories against the use of several unapproved foreign products that are on the market illegally, have claims that they can treat serious diseases and/or have been found to contain prescription drugs or high levels of contaminants. The infiltration of such adulterated products onto the Canadian market highlights the need to have strict quality control procedures in place in order to ensure public safety.

Classification of Ingredients Numerous drugs are derived from natural sources, however, prescription drugs currently fall outside the definition for NHP, as they are listed without qualifiers on Schedule F of the Food and Drug Regulations, which lists drugs with prescription status. Since the NHP Regulations entered into force, the status of certain prescription drugs has come under review by Health Canada either to clarify their status or to change their status to NHP. A number of examples of such ingredients exist, including vitamin K, ‘gotu kola’, carnitine and tryptophan. With respect to vitamin K, a review of the available safety data and the practices in other regulatory jurisdictions prompted the adoption of a regulatory amendment in October 2005, which de-scheduled vitamin K1 and vitamin K2 in oral dose formulations providing 120 micrograms/day or less and all preparations intended for external use from prescription drugs status (21). The maximum oral dose of 120 micrograms/day was determined to be within the range of other international jurisdictions that did not require a prescription (40 to 130 micrograms/day) (21). The amendment also modified the NHP Regulations to add Vitamin K1 and K2 to the list of vitamins on the inclusion list of NHP substances. Other substances, such as ‘gotu kola’, derived from Centella asiatica, required clarification. Centella asiatica extract and its active principles currently have prescription drug status, however, in February 2006, following extensive internal discussion and consultation with industry stakeholders, the NHPD announced that while the extract and its active principles would continue to be regulated as prescription drugs, the crude herb and parts of the herb would be classified as NHP (22). Although in principle the crude herb and its parts contain the extract and its active principles, it was determined that the original prescription drug status listing was intended to include only the extract and its active principles and not the herb itself.

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Other ingredients are currently under review, such as carnitine and tryptophan. Although amino acids are on the list of permitted NHP substances, both carnitine and tryptophan are currently on Schedule F without qualifiers for their prescription drug status. In 2004, representatives from the Canadian Health Food Association met with the NHPD and recommended that both amino acids be moved from prescriptiononly status to allow for their use in NHP (23). Although these ingredients are under review, a timeframe for any proposed regulatory amendments to de-schedule them from prescription drug status has not been identified, nor it is certain what conditions of use, if any, will be outlined.

Permitted Health Claims As discussed above, a number of types of claims are permitted for NHP, which include claims related to the diagnosis, treatment and mitigation or prevention of a disease, disorder or abnormal physical state or its symptoms in humans. However, the Food and Drugs Act expressly states that no drug, food, cosmetic or device may be represented as a treatment, preventative or cure for any of the diseases, disorders or abnormal physical states listed on Schedule A of the Act. Schedule A contains a list of over 40 diseases, including arthritis, cancer, diabetes, hypertension and obesity, among many others. In November 2005, a proposed regulatory amendment to permit the labeling and advertising of non-prescription drugs and NHP with treatment and preventative claims for Schedule A diseases, disorders and abnormal physical states was published (24). The original purpose in prohibiting such claims for these diseases was to prevent fraud in advertising and labeling and to prohibit the sale and advertising of products intended for self-care for serious diseases or to treat conditions where no treatment was known to medical science. With the premarket review of the safety and efficacy of both non-prescription drugs and NHP as well as pre-approved claims, it is Health Canada’s view that consumers would be adequately protected and would be empowered to make informed choices about self-care products that might contain claims related to Schedule A diseases. There is no known timeframe for the adoption of this amendment. In the interim, the NHPD has noted that provided sufficient evidence to support the safety and efficacy of the product has been submitted in a PLA, a product license will be issued for NHP that make Schedule A health claims; however, the Schedule A claim may not appear on the product label or in any product advertising until the regulatory amendment has been adopted (25).

Backlog Reduction Measures Since the promulgation of the NHP Regulations in January 2004, which required all marketed NHP to be licensed over a 6-year transition period, the NHPD has received thousands of PLAs. At the outset, the NHPD was committed to providing guidance and flexibility to applicants under this new regulatory framework by helping to ensure that all applications were complete. To achieve this, the NHPD accepted all applications, regardless of their completeness and, in turn, contacted applicants to inform them of

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what documentation was missing, as applicable. It was NHPD’s goal to provide this guidance for a 1-year period and, in April 2006, having provided assistance to applicants for over 2 years, and with a backlog of over 10 000 PLAs, the NHPD released a statement that in order to reduce the backlog and implement new performance standards, they would no longer accept incomplete PLAs (26). In April and May 2006, the NHPD also removed approximately 1900 applications that were deemed incomplete but were previously accepted into the processing queue (26,27). By September 2006, the NHPD reported that there was a backlog of 6578 PLAs that were all in the third of four stages of processing, a significant improvement from the beginning of the year, when over 7300 applications were only in the initial screening phases of processing (28). The focus for NHPD is to implement a standard operating procedure for the assessment of PLAs, which will include an Evidence Decision Making Framework for the timely and consistent assessment of applications. As of March 2008, a total of 6303 product licenses had been granted since the NHP Regulations took effect (29). The NHPD has adopted a similar approach to reduce the backlog of SLAs. With approximately 47% of a total of 330 SLAs stalled in the processing queue due to a lack of response by applicants to NHPD’s requests for additional information, the NHPD announced in October 2006 that they would be removing these applications from the processing queue (30). As of March 2008, a total of 662 site licenses had been granted since the NHP Regulations took effect (29).

Other Issues and Policies Health Canada and the NHPD are constantly developing new policies and clarifying issues as they arise as far as NHP are concerned. Consultations with industry stakeholders are commonplace prior to implementation of new policies and guidelines. In October 2006, a guidance document on the advertising of marketed health products, including non-prescription drugs and NHP, was released. The new guidance document, which supersedes previous guidelines published in 1990, clearly indicates that advertising guidelines for NHP will follow those established for non-prescription drugs. A new draft guidance document for the AR reporting of marketed health products also has been released for comment. The final guidance document is intended to supersede previous guidance, published in 1996, and includes the AR reporting requirements for NHP outlined in the NHP Regulations.

Conclusions The NHP Regulations were designed with the goal of providing consumers the ability to make informed choices about self-care products that are safe, efficacious and produced under good manufacturing practices. Contrary to the previous situation in Canada, the NHPD Regulations provide an even playing field for manufacturers and distributors of NHP by implementing a unique regulatory category for natural products and developing consistent requirements for the positioning of NHP for sale in Canada. With over 40 000 products falling under the definition of an NHP and a defined transition period by which these products must be licensed, the NHPD has

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References 171

already faced numerous challenges. As such, the policies and practices of the NHPD and other related regulatory agencies within Health Canada are constantly changing in order to address various issues. With less than 2 years left in the transition period, the constant introduction of new products, and the generation of new scientific data, it is anticipated that many more changes will occur in the near future and beyond as the NHPD strives to keep up with the ever-evolving NHP industry.

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16. Schulman SP, Becker LC, Kass DA et al. (2006). L-arginine therapy in acute myocardial infarction: the vascular interaction with age in myocardial infarction (VINTAGE MI) randomized clinical trial. J Am Med Assoc 295(1), 58–64. 17. Abumrad NN, Barbul A. (2006). Arginine therapy for acute myocardial infarction. J Am Med Assoc 295, 2138–2139. 18. Health Canada. (2006). Health Canada is advising consumers about a possible link between black cohosh and liver damage. Advisory Issued August 18, 2006, http:// www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2006/2006_72_e.html 19. Health Canada. (2007). Black Cohosh. Health Canada Fact Sheet. March 28, 2007. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/monograph/ cohosh-grappes_fact-fiche_e.html 20. NHPD. (2007). Black Cohosh Monograph. March 29, 2007. Natural Health Products Directorate. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/monograph/mono_cohosh-grappes_e.html 21. Canada Gazette. (2005). Regulations amending the Food and Drug Regulations (1385-Vitamin K) [SOR/2005-307]. C an Gaz II 139(21), 2386–2390. Available from: http://www.canadagazette.gc.ca/partII/2005/20051019/html/sor307-e.html 22. NHPD. (2006). NHPD February 2006 monthly communique. Natural Health Products Directorate. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/bulletins/communiques/ communique_feb06_e.html#1_3 23. NHPD. (2004). Record of decision from meeting with the Canadian Health Food Association. July 16, 2004. Natural Health Products Directorate. http://www.hcsc. gc.ca/dhp-mps/prodnatur/activit/assoc/chfa-acas_meet-reunion_06-16-04_e.html. 24. Canada Gazette. (2005). Regulations amending certain regulations made under the Food and Drugs Act. C an Gaz I 139(47), 3828–3836. Available from: http://canadagazette.gc.ca/partI/2005/20051119/html/regle1-e.html 25. NHPD. (2007). Fact Sheet: Schedule A health claims for natural health products. May 9, 2007. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/bulletins/scha_annea_fact_ fiche_e.html 26. NHPD. (2006). Information on the NHPD’s backlog reduction measures. Natural Health Products Directorate electronic bulletin. April 25, 2006. http://www.hc-sc.gc. ca/dhp-mps/prodnatur/bulletins/backlog_level1_arriere_niveau1_e.html 27. NHPD. (2006). Incomplete product licence applications will be removed from level 2 of the NHPD’s processing queue. Natural Health Products Directorate electronic bulletin. May 2, 2006. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/bulletins/avis_ important_ notice_e.html 28. NHPD. (2006). NHPD status of submissions report. Natural Health Products Directorate. September 2006. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/report-rapport/sub-report_ pres-rapport_sept06_e.html 29. NHPD. (2008). NHPD status of submissions report. Natural Health ProductsDirectorate. March 2008. http://www.hc-sc.gc.ca/dhp-mps/prodnatur/reportrapport/ sub-report_ pres-rapport_mar08_e.html 30. NHPD. (2006). Information on site license application backlog reduction measures. Natural Health Products Directorate electronic bulletin. October 25, 2006. http:// www.hc-sc.gc.ca/dhp-mps/prodnatur/bulletins/sl_refus_le_e.html

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European Legislation on Dietary Supplements and Functional Foods: Safety is Key

13

Patrick Coppens, Miguel Fernandes da Silva and Simon Pettman European Advisory Services (EAS) – Strategic Advice on Nutritional Products, Brussels, Belgium

Abstract In the late 1990s, research into functional ingredients was showing promising prospects for their use in foodstuffs. Following safety concerns, the European Commission 2000 White Paper on Food Safety announced some 80 proposals for new legislation in this field and more than 90% of those proposals have been implemented since. However, there is not, as such, a regulatory framework for ‘functional foods’ or ‘nutraceuticals’ in EU food law. The applicable rules are numerous and depend on the nature of the foodstuff. The provisions of the general food law Regulation are applicable to all foods. In addition, legislation on dietetic foods, on food supplements or on novel foods may also be applicable to functional foods depending on the nature of the product or on its use. Finally, the regulations on nutrition and health claims and on the addition of nutrients to foods also have a considerable impact on the marketing of ‘nutraceuticals’ in Europe. Decisions by the EU legislator are based on the risk analysis model, in which scientific risk assessment is performed by the European Food Safety Authority (EFSA) and risk management is performed by the European Commission, the Member States and the European Parliament in certain cases. In the risk management phase, both the precautionary principle and other legitimate factors may be considered in choosing the best way to deal with an issue. The process of having ‘functional foods’ approved in the EU is costly and time-consuming but it may also be worth it in terms of market success and improved consumer health. Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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174 European Legislation on Dietary Supplements and Functional Foods

Introduction In the late 1990s, many publications in lay and specialized press were devoted to so-called ‘functional foods’ or ‘nutraceuticals’. Research into functional ingredients was showing promising prospects for the use of such ingredients in food products, thereby creating added value for manufacturers and benefits for consumer health. There was an urgent call for legislation, which would help create a viable framework for this new array of foods. This chapter aims to present the various rules that may be of importance in the marketing of functional foods, the way in which they came into being and some practical examples of the consequences this complex framework has in the market place. It will take the reader through the basic principles of EU food law as applied through the General Food Law Regulation (EC) No 178/2002 (1) and the practical aspects of the complex procedures. It will also cover the most recently adopted legislation and make specific reference to ‘functional foods’, i.e. Directive 46/2002/EC on Food Supplements (2) and the regulations on nutrition and health claims made on foods (3) and on the addition of vitamins and minerals and of certain other substances to foods (4).

The Basic EU Legal Framework Based on Risk Analysis The 1997 Green Paper on Food Law (5), preceding the major food scares of the late 1990s, gave a new impetus to the foundation of European Food Law. It laid down for discussion a number of important principles for the revision of EU Food Law and was followed by the 2000 White Paper on Food Safety (6) announcing more than 80 proposals for new and improved legislation in this field. In particular, it foresaw the establishment of a general food law regulation, laying down the principles of food law and the creation of an independent Food Authority, endowed with the task of giving scientific advice on issues with clearly separated responsibilities for risk assessment, risk management and risk communication.

General Food Law Regulation The ‘General Food Law Regulation’ or, as it is officially called, Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 (1), laying down the general principles and requirements of food law, establishing the European Food Safety Authority (EFSA) and laying down procedures in matters of food safety (OJ L 31, 1.2.2002, p. 1), contains the foundation of European Food law. Its aim was to: provide the basis for the assurance of a high level of protection of human health and consumer interest in relation to food, taking into account in particular the diversity in the supply of food including traditional products, whilst ensuring

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the effective functioning of the internal market. It establishes common principles and responsibilities, the means to provide a strong science base, efficient organisational arrangements and procedures to underpin decision-making in matters of food and feed safety. As the Regulation applies to all foodstuffs, its general principles also cover foods with added functional properties (e.g. ‘functional foods’, ‘nutraceuticals’, dietetic foods and food supplements). A number of aspects of general food law are especially relevant for these types of foods. In this section, a short overview will be given of these aspects: the definition of foodstuffs, the process of risk analysis, the creation of the European Food Safety Authority and the responsibilities of food business operators, including the duty to notify a product to the authorities at the time of marketing.

Definition of Foodstuffs Regulation (EC) No 178/2002 (1) defines ‘food’ (or ‘foodstuff ’) as: any substance or product, whether processed, partially processed or unprocessed, intended to be, or reasonably expected to be ingested by humans. ‘Food’ includes drink, chewing gum and any substance, including water, intentionally incorporated into the food during its manufacture, preparation or treatment. It includes water after the point of compliance as defined in Article 6 of Directive 98/83/ EC and without prejudice to the requirements of Directives 80/778/EEC and 98/83/EC. ‘Food’ shall not include: feed; live animals unless they are prepared for placing on the market for human consumption; plants prior to harvesting; medicinal products within the meaning of Council Directives 65/65/EEC and 92/73/EEC; cosmetics within the meaning of Council Directive 76/768/EEC; tobacco and tobacco products within the meaning of Council Directive 89/622/ EEC; narcotic or psychotropic substances within the meaning of the United Nations Single Convention on Narcotic Drugs, 1961, and the United Nations Convention on Psychotropic Substances, 1971; residues and contaminants. The fact that this definition excludes medicinal products means that the decisive step to judge whether medicinal law or food law applies to a specific product will have to be sought in medicinal law. This is not a theoretical issue as products with added health functions may resemble closely medicinal products given their composition, claims and presentation. Medicinal products are defined by Directive 2004/27/EC (7) amending Directive 2001/83/EC (8) on the Community code relating to medicinal products for human use, as: Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or any substance or combination of substance which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

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Furthermore, Article 2.2 of the said Directive also states that in cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a ‘medicinal product’ and within the definition of a product covered by other Community legislation the provisions of this Directive shall apply. This provision basically puts into legal text the jurisprudence that has been established over the years by the European Court of Justice on borderline cases. It falls out of the scope of this chaper to elaborate in detail on the differentiation between medicinal products and foods, but suffice to say that both food and medicinal law contain a number of indications of what can fall under food law, so in practice the number of problems is not so important and most classification problems exist not because of the composition of the product but because of its presentation.

Risk Analysis Article 6 of Regulation (EC) No 178/2002 (1) firmly establishes scientific risk analysis at the basis of the decision-making process in matters of food law. It defines this process through a number of definitions and lays down the responsibilities for each of the respective stages of the risk analysis process. The following definitions are established: ●

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Hazard: means a biological, chemical or physical agent in, or condition of, food or feed with the potential to cause an adverse health effect Risk: means a function of the probability of an adverse health effect and the severity of that effect, consequential to a hazard Risk analysis: means a process consisting of three interconnected components: risk assessment, risk management and risk communication Risk assessment: means a scientifically based process consisting of four steps: hazard identification, hazard characterization, exposure assessment and risk characterization. Risk assessment is to be based on the available scientific evidence and undertaken in an independent, objective and transparent manner. The responsibility for risk assessment lays with the EFSA (see further). Risk management: means the process, distinct from risk assessment, of weighing policy alternatives in consultation with interested parties, considering risk assessment and other legitimate factors and, if need be, selecting appropriate prevention and control options. Risk management is to take into account the results of the risk assessment and, in particular, the opinions of the EFSA, other factors legitimate to the matter under consideration and the precautionary principle. The responsibility of risk management lies with the European Commission (EC), the Council and the European Parliament (EP). Risk communication: means the interactive exchange of information and opinions throughout the risk analysis process as regards hazards and risks, risk-related factors and risk perceptions, among risk assessors, risk managers, consumers, feed and food businesses, the academic community and other interested parties, including the explanation of risk assessment findings and

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the basis of risk management decisions. It is to be noted that the task of Risk Communication is shared between EFSA and European Commission, with EFSA having autonomy in communication about the risk assessment results and the EC about the ensuing risk management measures taken. One piece of legislation where the risk assessment/risk management process is well developed is the Food Supplements Directive 2002/46/EC (2).

Food Supplements Directive The regulatory framework on food supplements is fairly recent. Such products remained under national law until 2002, subject of course to the principle of mutual recognition that proved rather ineffective to ensure free movement of such products across the EU. The principle of mutual recognition, as embedded in Article 28 of the Treaty, was taken as the basis for a new Food Law approach by the 1985 White Paper on the Completion of the Internal Market. Harmonization would only be undertaken for the elements that are essential to protect consumer health and provide correct information. The principle says that a product, lawfully manufactured in one Member State should be able to move within the European Community without restrictions. The only exceptions to this principle are those justified by Article 30 of the Treaty on grounds of public morality, public policy or public security; the protection of health and life of humans, animals or plants; the protection of national treasures possessing artistic, historic or archaeological value; or the protection of industrial and commercial property. Such prohibitions or restrictions must not constitute a means of arbitrary discrimination or a disguised restriction on trade between Member States. Unfortunately, in spite of numerous court cases, the reason for the protection of public health has been used in many instances by national Member States to restrict the marketing of certain products with added health benefits, including food supplements and foods with added nutrients. Thus, an initial decision to harmonize food supplement legislation across the EU was taken in the late 1980s but it was many years before the text was finally drafted and adopted. In Article 2 of Directive 2002/46/EC on food supplements (2), food supplements are defined as: foodstuffs the purpose of which is to supplement the normal diet and which are concentrated sources of nutrients or other substances with a nutritional or physiological effect, alone or in combination, marketed in dose form, namely forms such as capsules, pastilles, tablets, pills and other similar forms, sachets of powder, ampoules of liquids, drop dispensing bottles, and other similar forms of liquids and powders designed to be taken in measured small unit quantities. A number of elements from that definition are important to ascertain the products that fall under the scope. An important element is that food supplements are considered as foodstuffs. This means that regulations that cover foodstuffs are applicable to food supplements except where specifically provided for in the food supplements

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legislation itself. This does not completely resolve the issue of the borderline between medicinal products and food supplements, given that specific compositional provisions are still missing, but it does indicate that when they are in line with the definition, such products should follow food law. A second important element is that food supplements may contain substances with a nutritional or physiological effect. Until that point it was not legally recognized that substances possessing physiological, but non-medicinal properties could be regulated outside medicinal law, although this was the practical reality in most Member States. The third element is the fact that in order to fall under the food supplements law, the product must be a concentrated form, presented to be taken in measured small unit quantities. The Directive represents a first step in the harmonization process as it focuses only on vitamins and minerals. For the range of other substances used in food supplements, the Commission is required to submit to the European Parliament and the Council a report on the advisability of establishing specific rules, including, where appropriate, positive lists, on categories of nutrients or of substances with a nutritional or physiological effect, accompanied by any proposals for amendment to this Directive which the Commission deems necessary. Officially, this report should be issued not later than 12 July 2007 but, in practice, this is unlikely to appear before fall 2007. Furthermore, the Directive foresees that maximum amounts of vitamins and minerals present in food supplements shall be set, taking into account the upper safe levels of vitamins and minerals established by scientific risk assessment based on generally accepted scientific data, taking into account, as appropriate, the varying degrees of sensitivity of different consumer groups; and intake of vitamins and minerals from other dietary sources. It also specifies that when the maximum levels are set, due account should also be taken of reference intakes of vitamins and minerals for the population. This is a good example of the application of the Risk Analysis process. In a first phase, the Upper Tolerable Safe Intake Levels (UL) of the vitamins and minerals are set by the Scientific Committee on Food (SCF), continued, after its creation, by the relevant European Food Safety Authority scientific panel. The UL is the intake level that can be consumed daily over a lifetime without being likely to pose any risk to health according to available evidence. It guides the Risk Assessor in characterizing the risk associated with each individual vitamin and mineral. In a second phase, the risk manager considers the risk assessment. He will have to determine what maximum levels will be established for the use in food supplements based on the established UL and the intake of the vitamins and minerals from other food sources including water. The European Responsible Nutrition Alliance (ERNA) has developed a risk management model as an example of how such maximum levels can be set, taking into consideration the risk characterization of the vitamins and nutrients and European intake data, based on the population safety index (PSI) of each individual nutrient (9). The International Life Sciences Institute (ILSI) developed a similar model for determining the maximum amounts of vitamins and minerals for addition to regular foods (10). Another example in the Food Supplements Directive for managing risk through scientific risk assessment is the establishment of a positive list of nutritional substances

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that are allowed in food supplements. The list, initially included in the proposed text, was the list of Directive 2001/15/EC (11) on substances that may be added for specific nutritional purposes in foods for particular nutritional uses. The argumentation was that the substances included in that Directive had been evaluated by the SCF and thereby had been considered safe and appropriate for use in dietetic foods. The Directive foresaw an authorization procedure for those sources of vitamins and minerals currently in use after a favorable EFSA opinion and a period during which Member States can grant derogations to those substances that were lawfully marketed in the European Union until EFSA gives a favorable opinion. However, this aspect has been very much criticized. In fact, in the UK, the High Court of Justice of England and Wales brought it before the European Court of Justice for a preliminary ruling concerning the validity of the Food Supplements Directive. The Court Decision of 12/07/05, however, rejected the action and judged that the approach chosen, including the establishment of positive lists and subsequent authorization procedure in this case, was rightful and not disproportionate for regulating vitamin and mineral substances to be used as sources of nutrients in food supplements.

Addition of Nutrients Regulation A last example of the application of the risk analysis principle can be found in Regulation (EC) No 1925/2006 (4) on the addition of vitamins and minerals and certain other substances to foods which was adopted in December 2006 and became applicable on the first of July 2007. Of special relevance for ‘functional foods’ or ‘nutraceuticals’ is Chapter 3 of the said Regulation. It deals with the concern Member States have with regard to substances that are added to foods or used in the manufacture of foods at conditions that are likely to result in the ingestion of amounts of this substance greatly exceeding those reasonably expected to be ingested under normal conditions of consumption in a balanced and varied diet. The Regulation establishes two possibilities for dealing with such a risk: ●

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In the case that, following an assessment of available information by EFSA, a harmful effect on health resulting from such use has been identified, the use of the substance and/or the ingredient containing the substance, shall either be prohibited or only be allowed under specific conditions In the case that, following an assessment of available information by EFSA, the possibility of harmful effects on health resulting from such use is identified but scientific uncertainty persists, the substance shall be placed on a specific list. Food business operators, or any other interested parties, may at any time submit for evaluation to EFSA, a file containing the scientific data demonstrating the safety of a substance listed on that list, under the conditions of its use in a food or in a category of foods and explaining the purpose of that use. Within four years from the date a substance has been listed, a decision shall be taken, taking into account the opinion of the Authority on any files submitted for evaluation

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to generally allow the use of a substance, prohibit it or only allow it under specific conditions. In all cases, the decision is taken by the Commission, on the basis of a scientific risk assessment opinion by EFSA, and in accordance with the new regulatory procedure with scrutiny (comitology) – according to which the Commission can only adopt a final decision with the approval of both the Council and the European Parliament. This legislation can have considerable consequences for those substances already in use today, when used at higher levels. In such cases, the burden of proof is reversed. It is no longer the enforcing authority that must prove the harmfulness of the substances. It is the Food Business Operator that must prove its safety. Although liability law and general food law impose the safety criterion to foodstuffs, in this case scientific proof of safety will be required.

The Precautionary Principle Following the unfortunate developments of the bovine spongiform encephalitis (BSE) crisis where uncertainty was a constant factor in the scientific assessment of risks and consequences, Regulation (EC) No 178/2002 (1) introduced a new principle for the European Union in the risk management process in food law. Originally applied in environmental issues, the precautionary principle tries to deal with those circumstances where, following an assessment of available information, the possibility of harmful effects on health is identified but scientific uncertainty persists. In such situations, provisional risk management measures necessary to ensure the high level of health protection chosen in the Community may be adopted, pending further scientific information for a more comprehensive risk assessment. Since such measures may have a vast array of consequences, the European legislator builds in a number of conditions when the precautionary principle is applied, including the requirement for such measures to be proportionate and no more restrictive of trade than is required to achieve the high level of health protection chosen, with consideration being given to technical and economic feasibility and other factors regarded as legitimate in the matter under consideration. The measures shall be reviewed within a reasonable period of time, depending on the nature of the risk to life or health identified and the type of scientific information needed to clarify the scientific uncertainty and to conduct a more comprehensive risk assessment. A more comprehensive view on the precautionary principle is given in the 2000 Communication of the European Commission on the Precautionary Principle (6). It addresses the issue of when and how to use the precautionary principle and the dilemma of balancing the freedom and rights of individuals, industry and organizations with the need to reduce the risk of adverse effects to the environment, human, animal or plant health. ‘Therefore, finding the correct balance so that the proportionate, non-discriminatory, transparent and coherent actions can be taken, requires a structured decision-making process with detailed scientific and other objective information’.

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The Communication’s fourfold aim is to: ● ● ●

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outline the Commission’s approach to using the precautionary principle establish Commission guidelines for applying it build a common understanding of how to assess, appraise, manage and communicate risks that science is not yet able to evaluate fully, and avoid unwarranted recourse to the precautionary principle, as a disguised form of protectionism.

The precautionary principle, which is essentially used by decision-makers in the management of risk, should not be confused with the element of caution that scientists apply in their assessment of scientific data.

Application of the Precautionary Principle in the SEM Issue An example of the application of the precautionary principle is seen in the risk management of SEM, semicarbazide, a compound that was discovered to migrate from the plastic gaskets of the metal lids of sterilized products packed in glass jars. It was especially important since many baby foods are sold in exactly this sort of packaging. SEM was found to be formed by the heat treatment in the plastic gaskets that are foamed using the chemical blowing agent, azodicarbonamide and migrate into the food. The application of the precautionary principle in this case was, as it should be, started with a scientific evaluation during which a certain uncertainty was identified. In its first statement on 28/07/2003, EFSA concluded that the toxicological data available were very limited: only two studies had indicated that it may cause cancer in one sex of one species of animal. There also was some indication that semicarbazide is genotoxic but the data are insufficient to draw any firm conclusion. ‘In view of the uncertainties in both the analytical and toxicological aspects it is not possible at present to give scientifically based risk assessment advice on the possible occurrence of semicarbazide in foods in contact with food packaging gaskets’. In the meantime, the food industry had joined forces with the packaging manufacturers to initiate new investigations to identify a replacement chemical that was safer and equally effective to assure the closure of the lids. In its 01/10/2003 opinion, the EFSA concluded that considerable uncertainties about semicarbazide still remain, not only about the extent of human exposure via foods that have been in contact with foamed gaskets but also concerning possible effects in vivo. But it added that taking into account the information available to date, on the levels in food, intake and toxicology, the risks to consumers eating products containing semicarbazide is likely to be very small. On the situation for baby foods, EFSA stated that highest concentrations of semicarbazide have been reported to be in baby foods packaged in glass jars and bottles. Due to their food consumption patterns and small body weight, the highest intakes of semicarbazide are likely to be in infants of 6–12 months consuming such foods regularly. Given the present uncertainties in the science, the presence of semicarbazide in baby foods is undesirable.

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Since EFSA was aware that industry was working intensely on technological means to achieve reduction and/or elimination of semicarbazide, it urged, in the light of the continuing uncertainties in the toxicological data, that industry progress with maximum speed in these efforts to achieve the goal of reduction of semicarbazide in baby foods and ultimately in other foods. EFSA also noted that glass jars and bottles with secure seals offer very good protection against microbial risks and this should be taken into account in any risk management decisions that may be made. After a discussion within an expert group, EFSA issued an additional second opinion on 09/10/2003 to confirm among others that there is no risk of immediate illness to adults, children or infants from consumption of foods containing semicarbazide and that the long-term risk, if any, was judged to be very small, both for infants and adult consumers. It was emphasized that jars of baby food have an excellent microbiological safety record since the airtight seal maintains microbiological stability and ensures a long shelf-life, prevents contamination with microorganisms, dirt or insects, during storage and protects the nutritional integrity of the product. If alternative technologies are going to be used to reduce or eliminate semicarbazide from baby foods, it is crucial that the same rigorous microbiological standards are upheld. The European Union, in accordance with the precautionary principle, referred to in Article 7 of Regulation (EC) No 178/2002 (1), issued legislation (Directive 2004/1/EC) (12) to suspend the use of azodicarbonamide as from 02/08/05, giving industry sufficient time to look for alternatives. In its final opinion (21/06/05), the EFSA concluded that the issue of carcinogenicity is not of concern for human health at the concentrations of SEM encountered in food because a large margin of at least 5 orders of magnitude exists between the dose causing tumors in experimental animals and human exposure, including that of infants. Although the legislation specified that suspension of azodicarbonamide from the incomplete list of additives fully harmonized at EU level should apply while the EU seeks more complete information from any source to clarify the gaps in the present state of knowledge of SEM, the ban on SEM is still there and it remains to be seen if this substance will be allowed to be used again. Fortunately, the joint industry effort in the meantime has developed an acceptable alternative to SEM and safe products can continue to be put on the market.

Other Legitimate Factors Risk Perception Risk management requires a thorough knowledge and analysis of the actual risk that is present for the population or, in case the precautionary principle is applied, of the exact degree of uncertainty that exists. An important element that often impacts decisions taken in case of risk management is risk perception. Risk is the result of combining the hazard with its exposure level. A hazard may be present but that does not necessarily mean that this hazard becomes a risk of danger for the population. For example, a toxic compound may be

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present in a raw material, such as cyanide in manioc, but it may be removed completely by processing therefore not exposing the population to that hazard. In the case of manioc, the toxic substance present is a very serious hazard but the risk run is very low. On the other hand, a weak hazard may become a substantial risk if exposure of the population is high. This is for instance the case with heavy metals or certain pesticide residues. Risk perception, however, follows a completely different set of rules. It is the feeling of being at risk that determines the insistence of the call for strict measures. And often risk perception is very weakly linked with the actual risk run. A number of factors play an important role in the perception of a certain risk. These factors include the feeling of being in control and media coverage. For example, most people will overestimate the risk of aviation and underestimate that of road travel. According to air traffic statistics (www.planecrashinfo.com), the number of air crash fatalities in recent years is roughly between 700 and 1400 worldwide. This is less than the number of yearly traffic deaths in Belgian alone (www.bivv.be). Nevertheless, people will feel much more secure in their car than in an airplane because of the feeling of control they perceive they have. When considering measures to contain a food-linked risk in order to preserve the highest level of consumer protection, risk managers have to balance the consequences of their decision with the impact on society. In the case of SEM, the risk management measure could have been to take all products from the shelves. However, this would not only have resulted in considerable losses for the economic actors involved, but could have lead to a situation where, when carefully controlled baby food jars would no longer be available and the public would then have had no choice other than to use regular foods. This would oblige consumers to prepare their own baby foods, which might result in inadequate nutritional intake (which was considered as a potential counterbalancing risk in the EFSA opinion). However, such decisions are difficult to communicate to the public, especially when the media are covering the issue. In the case of the SEM, after the reassuring EFSA opinions, headlines in the newspapers ran as; ‘Jars of baby foods with toxin to stay on sales’; ‘Baby food firms told to replace packaging toxin linked to cancer’; ‘Mother told “make your own baby food” in cancer alert’; ‘Toxin found in baby food’; ‘Jars of baby foods in cancer alert’; ‘Food industry in turmoil over poison jars alert’. None of this reassured the population that the risk, if any, is very small. Consumers only think in absolute terms: either there is a risk, or there isn’t. The fact that a non-risk environment is non-existent and that scientific risk assessment is precisely the scientific discipline to assess the magnitude of a certain risk makes the life of the risk manager rather difficult.

Risk Management Options and Impact Assessment Balancing the effects of restrictive measures against the benefits is not an easy task. Application of legislation can have expected or even unexpected side effects if the consequences have not been properly investigated. It must be said that the European Union has a bad record when it comes to performing impact assessment on new

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measures in the food field. The most recent proposals do include some rudimentary form of impact assessment and only first proposal that will be underpinned by a serious impact assessment will be the upcoming revision of the nutritional labeling Directive (13). Public confidence in food safety reached an absolute low after the food scares of the late 1990s, such as BSE and dioxin. It led to the reorganization of the European Commission structure, the establishment of the EFSA and a number of legislative initiatives including the setting of very strict limits as regards contaminants and residues in foodstuffs, where the principle of ALARA (as low as reasonably achievable) was gradually replaced by the principle of ALAAMCD (as low as analytical methods can detect). Limits have currently been established for maximum residue levels of many plant protection agents and for contaminants such as nitrates, a number of mycotoxins, heavy metals and certain environmental pollutants. And a monitoring system is in place, under the supervision of the European Food and Veterinary Office in Dublin. The result is a burden put on industrial operators for containing risks of a different order than the ones the consumer is normally exposed to. As to the highest risks that are linked to food consumption, microbiological food-borne pathogens resulting in food poisoning are still by far the number one risk. A cigarette after a copious meal may not exactly be in line with the high level of consumer protection the European Union has in mind and the risks run by inappropriate frying of foodstuffs or barbecuing are higher than the polynuclear aromatic hydrocarbons (PAH) threshold limits currently under discussion. Risk managers have a wide range of possible measures or initiatives in case they have to act over specific risks. Such measures range from legally binding measures such as prohibitions, restrictions, imposing authorization procedures, establishing mandatory conditions for use, purity criteria or labeling requirements, such as warnings or instructions of use to less ingressive measures such as giving recommendations, fostering voluntary approaches and identifying and supporting of further research. The approach would need to be chosen from among the risk management options that minimizes burden on the civil society, while still achieving its purpose of providing a high level of protection. It is, of course, tempting when pressured by public opinion to go directly for very strict measures, but it should be the actual risk that determines the measure taken. The European Court of Justice (ECJ) has established this principle in a number of court cases (e.g. European Commission v. Austria (C150/00), European Commission v. Germany (C387/99)). The legislator should recognize that by implementing certain measures, he will unleash a chain of consequences driven by social opinion that may be desirable or not. And the best way to assess these consequences is to perform a proper impact assessment. Next to the scientific risk assessment results the general food law Regulation also foresees that other legitimate factors relevant for the health protection of consumers and for the promotion of fair practices in food trade can be taken into consideration when considering appropriate risk management measures. The definition of the scope of such legitimate factors is presently being studied at international level (particularly in Codex Alimentarius). Examples are environmental considerations, animal welfare, sustainable agriculture, consumers’ expectation regarding product

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quality, fair information and definition of the essential characteristics of products and their process and production methods.

Nutrition and Health Claims Regulation An example that illustrates the above is the Regulation on nutrition and health claims that entered into force in January 2007 and became applicable on the first of July 2007 (3). The legislative attitude to regulating the use of nutrition and health claims is, to say the least, restrictive, the possibility to make reduction of disease risk claims excepted. The EU legislator could have chosen for a situation where the use of health claims could be based upon guidelines and notification, as is currently the case in a few Member States. Instead, it has opted for a system of premarketing approval and prohibition, which has not existed up until now in Member States. The impact assessment that accompanied the original proposal dismissed the consequences of this legislation for industry as being negligible. It argued that it is voluntary to make health claims, so the rules only apply if you choose them to apply. And, furthermore, it put forward the advantage for manufacturers that will now have access to a whole European market place. What it did not admit was, of course, that this legislation will apply to a vast number of companies already making claims and that only those companies interested in the pan-European market will profit from the benefits of the harmonized market. The scope of the Regulation is broad, since it not only covers the labeling of foodstuffs but also the presentation and advertising of the food. Not in the initial proposal, but introduced in the course of the discussions by the Council and European Parliament, is the fact that it will even apply to trade marks and brand names that could be understood as a claim. The Regulation also covers all possible claims relating to health. It covers nutrition claims – claims which state, suggest or imply that a food has particular nutrition properties due to the energy (calorific value) it provides, provides at a reduced or increased rate, or does not provide, and/or the nutrients or other substances it contains, contains in reduced or increased proportions, or does not contain; health claims – claims that state, suggest or imply that a relationship exists between a food category, a food or one of its constituents and health; and reduction of disease risk claims – claims that state, suggest or imply that the consumption of a food category, a food or one of its constituents significantly reduces a risk factor in the development of a human disease. The way the legislator has chosen to regulate claims is through authorization prior to marketing. Furthermore, a number of conditions, restrictions and prohibitions are included in the text. It is this approach that has met with great opposition, especially in the European Parliament because it is judged disproportionate with regard to the intended purpose. It has nothing to do with safety but with the provision of correct information to the consumer and assuring equal conditions for fair competition. It is also argued that it is the first case where Community agencies will determine what can be said and what cannot in the labeling of food products. Although not related to risk, it is nevertheless important to note that the basis for making nutrition and health claims should be sound science. It was surprising to see, therefore, during

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the negotiating stages of the text that the legislator, supported by consumer associations, proposed to prohibit without exception a number of claims arguing that such claims would be misleading anyhow and not scientifically supportable. However, this prohibition has been modified in the text finally adopted. Another highly criticized aspect is the so-called concept of nutrient profiles. This was included at a very late stage, after the public consultation on the text and became the political focus of much of the discussions. Article 4 foresees that nutrient profiles will be set for foods or categories of foods, based on their nutritional composition and, more specifically, the content of fat, saturated fatty acids, trans-fatty acids, sugars and salt. The main argument in favor of this profiling system is that it would not be appropriate to allow nutrition and/or health claims on foodstuffs with an ‘unfavorable’ nutrient profile since the consumption of such products should not be encouraged by giving them a positive health image. The main criticism of the concept is that it will be very difficult to determine in an objective scientific matter the nutrient profiles for foods, since their effect is not determined so much by their composition but rather by their use. The European Parliament, representing the civil society, chose in its first reading to delete nutrient profiles from the proposed legislation. However, the Council approved them unanimously which made it very difficult for the Parliament to reject them again in its second reading (it normally takes two readings to adopt a legislative text in co-decision). After a long and tense political struggle, the profiles were finally adopted. The Regulation establishes different procedures to authorize different kinds of claims: ●

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Nutrition claims will only be possible if they are included in the Annex to the Regulation. Only the nutrition claims included in the Annex will be allowed and only if the products bearing those claims fulfil the specific conditions indicated therein for each claim. The annex as adopted is considered to be too restrictive (e.g. Omega–3 fatty acids are not included). Health claims based on generally accepted scientific data will only be allowed if included on a positive list – the ‘Community list’. It is feared that Member States will considerably limit the number of claims to be included in this list, especially those regarding other substances and botanicals. Health claims based on newly developed science and/or requesting the protection of proprietary data will also need to be included in the Community list, but this will be done via a specific authorization procedure. Reduction of disease risk claims and claims referring to children’s development and health will only be allowed after being authorized through a specific procedure involving EFSA, the Commission, the Standing Committee on the Food Chain as well as the Council and the European Parliament (as a result of the introduction of the new regulatory procedure with scrutiny). It is feared that the requirements for such files and the conditions for their approval will only be possible for multinational companies with substantial financial and other resources.

It is feared that some of these authorization procedures will suffer the same disadvantages as the Novel Foods procedure (see next section), i.e. time consuming,

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expensive, unpredictable, inaccessible for small and medium enterprises and will make illegal many of the claims currently lawfully made in many Member States. That is why it is often questioned whether the chosen risk management option of requesting a premarketing authorization is really the only, most proportionate, least invasive way of achieving the desired objective of consumer protection. And, if so, have the consequences for economic operators, public authorities and other stakeholders been properly studied by appropriate impact assessments?

The Application of Other Legitimate Factors in GMO Legislation GMO (genetically modified organisms) legislation is another good example of the application of other legitimate factors in the risk management and decision-making process. The use and application of genetic modification techniques have long been submitted to authorization procedures (contained use: Directive 90/219/EC, deliberate release: Directive 90/220/EC (14)). In 1997, use of GMOs in food applications became regulated as part of the Novel Food and Novel Food Ingredients Regulation (EC) No 258/97 (15). It specified that foods and food ingredients containing or consisting of genetically modified organisms within the meaning of Directive 90/220/EEC (16) and foods and food ingredients produced from, but not containing, genetically modified organisms would need to be approved through the authorization procedure established by the Regulation. Article 8 of the Regulation also specifies the labeling requirements for Novel Foods and additional labeling requirements can be established in the authorization decision. Two genetically modified products (soya bean Glycine max L. cv A5403, line (40-3-2) (Commission Decision 96/281/EC) and maize Zea mays L. line (CG 00256-176) (Commission Decision 97/98/EC)) had been on the market before the Novel Foods regulation came into application, would not need to go through the authorization procedure and, as a consequence, would not need to be labeled as obtained by genetic engineering. This launched a storm of protest by environmental groups and organizations demanding proper information on food products containing derivatives of such ingredients. Since the safety of these two varieties of GMOs had been assessed by the Scientific Committee on Food (1995–96) and judged as being equivalent to their conventional counterparts, this would mean that the information to the public would serve only to identify the origin of the ingredient and enable the public to make an informed choice. It must be said that, in this case, the reassuring voices of scientists and authorities based on scientific risk assessment were no match for the vigorous media attention and debate on the so-called ‘Frankenstein Foods’. It is doubtful that under such conditions consumers could be objectively informed to make such objective informed choice. But it is clear that, when presented with the choice, chances are that consumers will choose for certainty rather than for doubt. So, when under public pressure, the European Union initiated its proposal for labeling of these two varieties of products, it was in fact well aware that this would not serve to increase public trust and confidence in GMOs but that it put at the public disposal a tool to decide on the future of GMO use and research in Europe. So, in this case, the requirement of informing objectively the public was a factor taken into the risk management process.

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Although scientific risk assessment did not show risks associated, the risk manager decided to give people the tool to decide for themselves if they would want or not to use such products. And the information was indeed objective. Because the only difference between a derivative of the traditional variety compared to the genetically modified one was the presence of the foreign DNA introduced in the plant and the resulting protein, the first approach was to indicate on the label of foods the GMO origin only in case of analytical detectability. Thus, ingredients such as soy protein, soy lecithin, maize starch, would have to be labeled because they contain the foreign protein, while derivatives such as refined soy oil and glucose derived from maize are so purified that they cannot be analytically distinguished from their traditional counterpart. Such was established Regulation (EC) No 1139/98 concerning the compulsory indication of the labeling of certain foodstuffs produced from genetically modified organisms as amended by Regulation (EC) No 49/2000 (17). Public criticism then turned precisely to those ingredients. In view of the new framework on GMOs announced in the White Paper on Food Safety and since then completed by Regulation (EC) No 1829/2003 (18) on genetically modified food and feed and Regulation EC (No) 1830/2003 (19) on labeling and traceability of GMO, the request was voiced stronger and stronger for labeling of those ingredients that were derived from GMOs but were indistinguishable from their traditional counterparts. The European legislator therefore chose to abandon the analytical basis in favor of a traceability approach. In that way, labeling of all derivatives became possible and enforcement was based on a paper trail. Such an approach, although far more vulnerable to fraud than analytical verification, was believed also to reduce the costs for industry by not requiring costly analysis of all batches. However, the approach led to a further corroboration of a market place exempt from GM derivatives, since companies now turned to look for traditional alternatives for a vast number of ingredients where before this had not been necessary. Furthermore, because of the fact that control authorities continue to rely in great part on analytical controls, analytical analysis remains the basis for verification, so the burden of the analytical cost has not really gone down. On the other hand, the approach of the European legislator was nevertheless balanced by not imposing the same labeling requirement for foodstuffs produced from animals that are fed by GMOs. This became the next target of public criticism since it was argued that the consumer had the right to know that the animal of which they wished to eat the meat had not been fed with feed ingredients derived from GMOs. In this case, the legislator chose not to impose labeling requirements given that this would be going too far, thereby preventing a situation that would have put the EU economic operators in a very disadvantageous position. Nevertheless, the result of the application of other legitimate factors in the measures on GMOs has led to a virtual standstill of research in the field in Europe and remains a matter of debate at the international level.

European Authorization Procedures The way in which the risk analysis is applied in authorization procedures can be illustrated by an example that may be relevant in the case of nutraceuticals or

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functional foods, namely the Novel Foods Regulation. The authorization procedure as contained in the nutrition and health claims Regulation is similar. Regulation (EC) No 258/97 of the European Parliament and of the Council of 27 January 1997 (15) concerning novel foods and novel food ingredients lays down an authorization procedure for a number of foods or food ingredients that have not been consumed to a significant degree in the European Union. In order to protect public health, it was deemed necessary to ensure that such novel foods and novel food ingredients are subject to a safety assessment through a Community procedure before they are placed on the market. This procedure is, in essence, a procedure managed by the Member States. But, in cases where concern is raised by Member States because of public health or food safety concern (which is rather the rule than the exception), the Community procedure of risk analysis comes into play. Products defined as Novel Foods may be: ●

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foods and food ingredients with a new or intentionally modified primary molecular structure foods and food ingredients consisting of or isolated from microorganisms, fungi or algae foods and food ingredients consisting of or isolated from plants and food ingredients isolated from animals, except for foods and food ingredients obtained by traditional propagating or breeding practices and having a history of safe food use foods and food ingredients to which has been applied a production process not currently used, where that process gives rise to significant changes in the composition or structure of the foods or food ingredients which affect their nutritional value, metabolism or level of undesirable substances.

Initially, foods and food ingredients containing or consisting of genetically modified organisms within the meaning of Directive 90/220/EEC (16) and foods and food ingredients produced from, but not containing, genetically modified organisms were also part of the scope of Regulation (EC) No 258/1997 (15), but with Regulation (EC) No 1829/2003 (18) there is a specific authorization procedure for these products. If a food or food ingredient falls within one or more of the abovementioned food categories, the decisive factor on whether it will be regarded as novel is whether it has already been sold under food law on the EU market before 1997. The EU Novel Foods Regulation stipulates that a food/food ingredient is novel if it has not been used to a significant degree for human consumption in the EU before May 15, 1997. In order to prove the non-novel food status of your food/food ingredient, proof is required of ‘significant’ EU sale under food law before May 1997. The key aspects that need to be considered and complications that may arise to provide such proof is described elsewhere (20). The Novel Foods Regulation provides two different procedures for authorization: 1. The simplified procedure is based on a notification system and can only be followed if the applicant can provide evidence that the novel food/food ingredient is substantially equivalent to an existing food ingredient as regards to composition, nutritional value, metabolism, intended use, level of undesirable substances

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and that the food/food ingredient consists of or is isolated from microorganisms, fungi or algae or consists of or is isolated from plants, or food ingredients isolated from animals, except for food ingredients obtained by traditional propagating or breeding practices and having a history of safe food use. When placing a substantially equivalent food/food ingredient on the EU market, a dossier providing evidence of its substantial equivalence needs to be submitted to the European Commission. The Novel Foods Regulation foresees two different routes to proving substantial equivalence, namely on the basis of generally recognized scientific evidence or on the basis of an opinion of a competent food assessment body in the Member States. As the Novel Foods Regulation does not provide an indication to what is meant by generally recognized scientific evidence, all notifications made so far have relied upon opinions of the competent food assessment bodies of the Member States. After submission of the dossier, the European Commission will within 3 months forward a copy of the dossier to the Member States. If the evidence of substantial equivalence is accepted by the Commission, the novel food/food ingredient is approved. In case the evidence is regarded as insufficient by the Commission or objections/doubts are raised by certain Member States, the Commission will ask a competent Member State food assessment body of its own choice to provide an opinion on the product. If this opinion is positive, the novel food/food ingredient is approved. If this is negative, the novel food/food ingredient then needs to be approved by the full authorization procedure. 2. The full authorization procedure applies if no evidence of substantial equivalence can be provided and, in any case, for foods and food ingredients with a new or intentionally modified primary molecular structure and foods and food ingredients to which has been applied a production process not currently used, where that process gives rise to significant changes in the composition or structure of the foods or food ingredients which affect their nutritional value, metabolism or level of undesirable substances. A request for marketing approval together with a dossier needs to be submitted to one of the 27 EU Member State authorities of the applicant’s own choice for initial assessment. This Member State authority will then check the administrative completeness of the documentation and appoint an assessment body that will provide its opinion on the application in an assessment report within 3 months. If the national assessment body gives a positive opinion, the European Commission forwards the assessment report to the other 26 Member States who have 60 days to object to the opinion provided by the assessment body. In practice, there has always been at least one Member State objecting, which therefore has triggered the need for a so-called Community Decision. Objections to a positive opinion of the assessment body can be raised by a Member State on the grounds of public health or safety concerns. Where an objection is raised, the European Commission will undertake an additional assessment. Before the General Food Law Regulation came into force, the risk assessment was performed by the Scientific Committee on Food

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(SCF) within the European Commission. With the creation of the EFSA, the risk analysis process was taken out of the risk management body and became a separate entity. When the relevant EFSA scientific panel delivers its opinion on the application file the European Commission will then present the opinion to the Standing Committee on the Food Chain and Animal Health, which is composed of Member States’ experts that assist the European Commission in the risk management process and which are endowed with the powers to decide on measures. If the Standing Committee approves the novel food or novel food ingredient, it can be placed on the EU market. If on a particular issue, no qualified majority can be reached in the Standing Committee to support the authorization, the decision is transferred to the Council that has to reject or adopt the Commission proposal to authorize the Novel Food within 3 months. If not, the European Commission can apply the decision. This has been the case recently with the approval of a number of genetically modified organisms. All in all, the novel food procedure is not a very clear and transparent one. If an application is successful, it may offer a certain number of advantages, including marketing approval across the 27 EU Member States, which provides legal clarity and avoidance of any potential risk of challenge, which may be especially important in borderline cases. And it may also grant some form of exclusivity for the applicant, such as in the example of the use of phytosterol-esters in different type of food products. When the company introducing the first application received the novel foods approval for the use of phytosterol-esters in yellow fat spreads in 2000, the Standing Committee on Foods pointed out that this approval was only given for this specific application. Over the two following years, a number of other companies have handed in their own novel foods dossiers for the use of phytosterol-esters in other products such as sausages, cheeses and yoghurts. But the procedure also has some major disadvantages. Time and cost implications are significant. Not only does the compilation of a safety dossier require considerable financial resources, the time estimate for the actual regulatory process of 9–12 months has proven to be very optimistic. In practice, approvals have taken as long as 2–3 years. For companies, having invested years in the research of an innovative product or ingredient and hundreds of thousands of Euros, having to wait several years before being allowed to enter the market, without being sure of a favorable decision, is a risky operation. Furthermore, in the meantime, their competitors, well aware of the dossier under investigation, have ample time to catch up. In addition, once a novel food or novel food ingredient has been approved, it offers a possibility for competitors to apply for approval under the substantial equivalence procedure, thereby avoiding the heavy burden of research investments. Another hampering factor is that dossier requirements are very extensive. The extensive scientific data that are required for a successful authorization will be out of the league of many applicants, given also the risk of having the file rejected because it is incomplete or does not meet the scientific requirements or because some EU Member States raise objections. This may either cause a considerable delay in the approval process for revising and completing the dossier through the submission of

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additional data or even result in a complete ban in the sales of the product (e.g. the rejection of the EU novel foods application due to a lack of safety data for Stevia rebaudiana and Nangai nuts). It has been said sometimes that if products such as coffee and potatoes were introduced today in the EU market and had to undergo the novel food procedure, these products would never be allowed because of their composition. A final problem is the uncertainty about communication. In many cases, the standing Committee will impose additional labeling provisions or warnings that may necessitate the revision of the marketing of the entire product. And, in most cases, when the health claim is submitted in the dossier, it is not considered, which means that Member States may even object to the product, if approved as a novel food, because of the claims made. Given that since 1997 only around 70 applications for authorization have been received, of which around 25 were approved, this may perhaps hint to the fact that the novel foods procedure lacks a certain maturity rather than that the European food industry lacks innovative potential. For a number of reasons, the European Commission is currently planning to revise and update the Novel Foods Regulation and has already submitted a discussion paper. Nevertheless, the way in which the Standing Committee has recently argued on what is and what is not considered ‘significant use’, may hint to the fact that we are not progressing to a simpler and more easy to apply procedure but rather to a more broad application of the authorization procedure. Instead of a Novel Food Regulation we appear to be ending up with a ‘novel use regulation’.

Foods for Particular Nutritional Purposes or Dietetic Foods European legislation does not consider ‘functional foods’ or ‘nutraceuticals’ as specific food categories. In the above, a number of legislative texts that may be of importance to such foods have already been elaborated, including the general food Regulation, the food Supplements Directive, the Novel Food Regulation and the regulations on nutrition and health claims and on the addition of vitamins and minerals and other substances to foods. But there is one category of products that has a firmly established legal framework, which is ‘foods for particular nutritional uses’ (also called PARNUTS or dietetic foods). It offers a good example of a legislation that balances scientific risk assessment, consumer protection, manufacturer responsibility and market innovation in a rather proportionate way. Harmonization efforts in this field were among the first within the European Union but, given the complexity and diversity of these products, it may come as no surprise that this exercise has not yet been finalized. The current applicable legal text dates back to 1989. The so-called PARNUTS framework Directive 89/398/EEC (21) defines the scope of PARNUTS and creates the framework for a number of vertical Directives with specific provisions for a number of PARNUTS categories. Originally, the

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European Legislator foresaw nine categories of PARNUTS foods that would become subject of a specific Directive. Today, five of them have been finalized: ●

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Infant formulas and follow-on formulas (Directive 91/321/EEC) (22) (originally two different Directives were foreseen) Processed cereal-based foods and baby foods for infants and young children (Directive 96/5/EC) (23) Foods intended for use in energy-restricted diets for weight reduction (Directive 96/8/EC) (24) Foods for Special Medical Purposes (Directive 1999/21/EC) (25).

A specific piece of legislation for foods intended to meet the expenditure of intense muscular effort, especially for sportsmen is under discussion but not yet proposed. The necessity of a Directive for foods for persons suffering from carbohydrate-metabolism disorders (diabetes) is still being investigated and it is not sure whether this will ultimately lead to a harmonization in this field. Foods with modified sodium content and gluten-free foodstuffs will be dealt with by labeling requirements, still to be developed. For products not falling under any of these categories but, nevertheless, considered PARNUTS, Article 9 of Directive 89/398/EEC foresees a procedure to be followed when putting such products on the market. This PARNUTS legislation is applicable to some ‘functional foods’ or ‘nutraceuticals’ if such foods are intended for particular nutritional uses. According to Directive 89/398/EEC, this basically means that such foods must have a special composition or manufacturing process, must be clearly distinguishable from foodstuffs for normal consumption, must be suitable for their claimed nutritional purposes and marketed in such a way as to indicate such suitability. With ‘particular nutritional use’ is understood that the product must fulfil the particular nutritional requirements of certain categories of persons whose digestive processes or metabolism are disturbed; or of certain categories of persons who are in a special physiological condition and who are therefore able to obtain special benefit from controlled consumption of certain substances in foodstuffs. Given these requirements, it is clear that only products that are destined to be used in small target populations suffering from disturbed metabolism or digestion could fall under this legislation. Products destined for the normal general population would clearly not fall under this. However, some differences in interpretation are seen between Member States as to products specifically destined for e.g. pregnant and lactating women and even low fat polyunsaturated fat spreads. One category of PARNUTS of particular relevance because of their functional properties are foods for special medical purposes. Directive 1999/21/EC (25) defines such products as a category of PARNUTS specially processed or formulated and intended for the dietary management of patients and to be used under medical supervision. They are intended for the exclusive or partial feeding of patients with a limited, impaired or disturbed capacity to take, digest, absorb, metabolize or excrete ordinary foodstuffs or certain nutrients contained therein or metabolites, or with other medically-determined nutrient requirements, whose dietary management cannot be achieved only by modification of the normal diet, by other foods for particular nutritional uses, or by a

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combination of the two. Such products have to bear the statement ‘For the dietary management of (diseases, disorders or medical conditions for which the product is intended)’ and a description of the properties and/or characteristics that make the product useful in particular, as the case may be, relating to the nutrients which have been increased, reduced, eliminated or otherwise modified and the rationale of the use of the product. The procedure to put such products on the market is a notification procedure, which means that the manufacturer must notify the competent authority of the Member States of the placing on the market of the product. The manufacturers should have at hand the necessary documentation to demonstrate that the product indeed is suitable for its intended use as food for special medical purposes. Member States may request evidence for verification. Together with the General Food Law requirements that put primary responsibility of food safety with the food business operator, they require them to have in place a system for traceability of the foodstuff and adequate procedures to withdraw the foodstuff from the market they consider or have reason to believe that it is not in compliance with the food safety requirements. They also impose a notification duty, i.e. immediately to inform the competent authorities if they consider or have reason to believe that a food which they have placed on the market may be injurious to human health. This would seem to be a balanced way of creating a regulatory framework that fosters both consumer protection and quick innovation as a result of scientific developments.

Conclusion There is not, as such, a regulatory framework for ‘functional foods’ or ‘nutraceuticals’ in EU food law. The rules to be applied are numerous and depend on the nature of the foodstuff. The rules of the general food law Regulation, including responsibility for food safety, traceability, recall and notification, are applicable to all foods. The regulatory frameworks of PARNUTS or dietetic foods and of food supplements may be applicable to some ‘functional foods’. The novel foods Regulation will be applicable to ‘new’ ‘functional foods’ depending on whether they have been used to a significant degree in the EU before 15 May 1997. The nutrition and health claims Regulation as well as the Regulation on the addition of vitamins and minerals and certain other substances to foods will also be an important factor in the future marketing of ‘functional foods’ in Europe. Finally, in case procedures have to be followed and decisions have to be taken by the EU legislator, these should be based on the risk analysis model, where scientific risk assessment is performed by the European Food Safety Authority and risk management is performed by the European Commission, the Member States as well as the European Parliament in certain cases. In the risk management phase, both the precautionary principle and other legitimate factors may be considered in choosing the best way of dealing with an issue. That the process of having ‘functional foods’ approved may be a costly, tedious and time-consuming task is clear from the example of the phytosterol containing fat spread product that went

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References 195

through the novel food procedure. But it also proves that it was worth it, given the market success it achieved afterwards.

References 1. Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety. Official Journal L 031, 01/02/2002 P. 0001–0024. 2. Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002 on the approximation of the laws of the Member States relating to food supplements. Official Journal L 183, 12/07/2002 P. 0051–0057. 3. Regulation (EC) No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. Official Journal L12, 18/01/2007, pp. 0003–0018 (Corrigendum). 4. Regulation (EC) No 1925/2006 of the European Parliament and of the Council of 20 December 2006 on the addition of vitamins and minerals and of certain other substances to foods. Official Journal L440, 30/12/2006, pp. 0026–0038. 5. European Commission (1997). The General Principles of Food Law in the European Union. Commission Green Paper COM(97) 176. 6. European Commission (2000). White paper on Food Safety. COM(1999) 719. 7. Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. Official Journal L 136, 30/04/2004 P. 0034–0057. 8. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Official Journal L311, 28/11/2001, pp. 0067–0128. 9. European Responsible Nutrition Alliance-ERNA (2004). Vitamin and mineral supplements: a risk management model. 10. Flynn A, Moreiras O, Stehle P, Fletcher RJ, Muller DJ, Rolland V. (2003). Vitamins and minerals: a model for safe addition to foods. Eur J Nutr 42, 118–130. 11. Commission Directive 2001/15/EC of 15 February 2001 on substances that may be added for specific nutritional purposes in foods for particular nutritional uses. Official Journal L 052, 22/02/2001 P. 0019–0025. 12. Commission Directive 2004/1/EC of 6 January 2004 amending Directive 2002/72/ EC as regards the suspension of the use of azodicarbonamide as blowing agent. Official Journal L007, 13/01/2004, pp. 0045–0046. 13. European Advisory Services – EAS (2004) The Introduction of Mandatory Nutrition Labelling in the European Union – Impact assessment undertaken for DG SANCO, European Commission. 14. Council Directive 90/219/EEC of 23 April 1990 on the contained use of genetically modified micro-organisms. Official Journal L 117, 08/05/1990 P. 0001–0014. 15. Regulation (EC) No 258/97 of the European Parliament and of the Council of 27 January 1997 concerning novel foods and novel food ingredients. Official Journal L 043, 14/02/1997 P. 0001–0006.

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16. Council Directive 90/220/EEC of 23 April 1990 on the deliberate release into the environment of genetically modified organisms. Official Journal L 117, 08/05/1990 P. 0015–0027. 17. Commission Regulation (EC) No 49/2000 of 10 January 2000 amending Council Regulation (EC) No 1139/98 concerning the compulsory indication on the labelling of certain foodstuffs produced from genetically modified organisms of particulars other than those provided for in Directive 79/112/EEC. Official Journal L 006, 11/01/2000 P. 0013–0014. 18. Regulation (EC) No 1829/2003 of the European Parliament and of the Council of 22 September 2003 on genetically modified food and feed. Official Journal L 268, 18/10/2003 P. 0001–0023. 19. Regulation (EC) No 1830/2003 of the European Parliament and of the Council of 22 September 2003 concerning the traceability and labelling of genetically modified organisms and the traceability of food and feed products produced from genetically modified organisms and amending Directive 2001/18/EC. Official Journal L 268, 18/10/2003 P. 0024–0028. 20. European Advisory Services-EAS (2003) Novel Foods in the European Union: Developing Regulatory Strategies. 21. Council Directive 89/398/EEC of 3 May 1989 on the approximation of the laws of the Member States relating to foodstuffs intended for particular nutritional uses. Official Journal L 186, 30/06/1989 P. 0027–0032. 22. Commission Directive 91/321/EEC of 14 May 1991 on infant formulae and followon formulae. Official Journal L 175, 04/07/1991 P. 0035–0049. 23. Commission Directive 96/5/EC, Euratom of 16 February 1996 on processed cerealbased foods and baby foods for infants and young children. Official Journal L 049, 28/02/1996 P. 0017–0028. 24. Commission Directive 96/8/EC of 26 February 1996 on foods intended for use in energy-restricted diets for weight reduction. Official Journal L 055, 06/03/1996 P. 0022–0026. 25. Commission Directive 1999/21/EC of 25 March 1999 on dietary foods for special medical purposes. Official Journal L 091, 07/04/1999 P. 0029–0036. 26. Communication from the Commission on the precautionary principle-COM(2000) 1. 27. Commission Directive 65/65/EC of 26 January 1965 on the approximation of provisions laid down by Law, Regulation or Administrative Action relating to proprietary medicinal products. Official Journal P022, 09/02/1965, pp. 0369–0373. 28. Council Directive 76/768/EEC of 27 July 1976 on the approximation of the laws of the Member States relating to cosmetic products. Official Journal L262, 27/09/1976, pp. 0169–0200. 29. Council Directive 80/778/EEC of 15 July 1980 relating to the quality of water intended for human consumption. Official Journal L229, 30/08/1980, pp. 0011–0029. 30. Council Directive 89/622/EEC of 13 November 1989 on the approximation of the laws, regulations and administrative provisions of the Member States concerning the labelling of tobacco products. Official Journal L359, 08/12/1989, pp. 0001–0004.

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31. Council Directive 92/73/EEC of 22 September 1992 widening the scope of Directives 65/65/EEC and 75/319/EEC on the approximation of provisions laid down by Law, Regulation or Administrative Action relating to medicinal products and laying down additional provisions on homeopathic medicinal products. Official Journal L297, 13/10/1992, pp. 0008–0011. 32. Council Directive 98/83/EC of 3 November 1998 on the quality of water intended for human consumption. Official Journal L330, 05/12/1998, pp. 0032–0054. 33. European Advisory Services-EAS (2005) Marketing Food Supplements, Fortified & Functional Foods in Europe. 34. Proposal for a Regulation of the European Parliament and of the Council on nutrition and health claims made on foods. COM(2003) 424 final. 35. Richardson D. (2005). The scientific substantiation of health claims with particular reference to the grading of evidence. Eur J Nutr 44, 319–324.

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Botanical Nutraceuticals (Food Supplements, Fortified and Functional Foods) in the European Union with Main Focus on Nutrition and Health Claims Regulation

14

Om P. Gulati1 and Peter Berry Ottaway2 1

Scientific & Regulatory Affairs, Horphag Research Management SA, Geneva, Switzerland 2 Berry Ottaway & Associates Limited, Hereford, UK

Abstract Botanical nutraceuticals that have defined nutritional or physiological effects can be found in food supplements, fortified foods and functional foods. They do not fall easily into the legal categories of food or drug and often inhabit a gray area between the two. These products in general terms cover health promotion, ‘optimal nutrition’, the concept of enhanced performance and reduction of disease risk factors. Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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200 Botanical Nutraceuticals

In this chapter, the focus is mainly on the legislative instruments governing food supplements, fortified and functional foods and the nutrition and health claims regulation. The regulatory status of botanical nutraceuticals in a European context as food ingredients, food supplements, functional and fortified foods, foods for particular nutritional use and novel foods, in the diversified, complex and ever changing European regulatory environment is discussed. Botanicals present additional problems because of their complex nature and composition, particularly on quality aspects, which in turn affect safety parameters and overall efficacy of the products. Quality and safety issues are briefly discussed. Two European Union Regulations came into force in early 2007, one controls nutrition and health claims and the other the fortification of foods with vitamins, minerals and ‘other substances’ including botanicals. The consequences of this new legislation are considered. Emphasis is given to the nutrition and health claims legislation, the types of claims and criteria of substantiation in light of the new adopted Nutrition and Health Claims Regulation. Procedures to obtain generic and product specific health claims are described. The role of the European Commission and the European Food Safety Authority during the evaluation process, preparation of opinions and the decision-making procedures are described. The process for assessment of scientific support for claims (PASSCLAIM) initiative is discussed in the light of ongoing discussions within Europe. The concept of grading of evidence to substantiate different claims and to establish standards, which should not be revoked or reversed by emerging science at a later stage, has also been considered.

Introduction The term ‘Nutraceutical’ was originally used by Defelice (1) in 1995 with the definition: ‘Food or parts of food that provide medical or health benefits, including the prevention and treatment of disease’ (1). As they have defined physiological effects, nutraceuticals do not easily fall into the legal categories of food or drug but inhabit a gray area between the two (2). Nutraceuticals are currently receiving international recognition as having potentially beneficial effects on health when consumed as part of a varied diet on a regular basis and at effective levels (3). The legal categorization of a nutraceutical is, in general, made on the basis of its accepted effects on the body. Thus, if the substance contributes only to the maintenance of healthy tissues and organs, it may be considered to be a food ingredient. If, however, it can be shown to have a modifying effect on one or more of the body’s physiological processes, it is likely to be considered as a medicinal substance. Nutraceuticals in a broad sense can be found in functional and fortified foods and food supplements (4). Functional and fortified foods are those with a similar appearance to their traditional counterparts, while food supplements are components that are mostly consumed in unit dose forms such as tablets, capsules or liquids and are commonly known as food/dietary supplements. Botanicals represent a large segment of the nutraceuticals category and present additional problems relating to the complex nature and composition of botanical ingredients. Botanicals in this context represent whole, fragmented or cut plants, algae, fungi, lichens and botanical preparations from these materials involving extraction, distillation,

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Legislation on Botanicals as Medicines or Foods 201

expression, fractionation, purification, concentration and fermentation. Botanical substances are defined by the botanical name of the plant according to the binomial system (genus, species, variety and author) and the part used (e.g. leaf, root and fruit). The challenges ahead, particularly for botanical nutraceuticals, relate to quality, safety and claims. In many cases, there are still a number of unknowns, such as the identification of specific active components, their absorption and metabolism in the human body and the effects of processing on the products containing them. In this chapter, the focus will mainly be on legislation governing enrichment of foods and health claims made on botanical-sourced, functional and fortified foods and food supplements in the European Union (EU).

Nutraceutical Concept in the European Union Much of the early development of the nutraceutical concept and products was driven from the USA where, since its introduction in 1994, the Dietary Supplement and Health Education Act (DSHEA, 1994) has allowed considerable flexibility and blurred the boundaries between foods and medicines found in other parts of the world (5). Under DSHEA, a dietary supplement may contain ‘a herb or other botanical’ or ‘a concentrate, metabolite, constituent, extract or combination of any ingredient from the other categories’. This is subject to very little qualification and, as a consequence, a wide variety of botanicals and other substances have been sold as dietary supplement ingredients, including many that are considered to be medicinal substances under most regulatory regimes in EU countries.

Legislation on Botanicals as Medicines or Foods There is currently no consistency in the legal status of some botanicals across the EU. In some EU countries, botanical products are sold as foods, food supplements or incorporated in functional/fortified foods, meaning that no medicinal claims are made, whereas in other EU countries, these preparations are seen as herbal medicines registered by full or simplified registration procedures. In some countries, the medicinal product status is automatically linked to pharmacy-only status. 1. Although the definition of a medicine is given in EU legislation (Directive 2001/83/EC, formerly 65/65/EC) as amended by Directive 2004/27/EC, it has been interpreted differently by member states in the context of products containing botanicals (6–8). As stated above, the definition is in two parts and a product falling into the scope of either part is considered a medicinal product under law. It is the precise interpretation of the term ‘pharmacological function’ in the second part that has led to the inconsistencies of interpretation between member states. 2. If medicinal claims are made based on its traditional use as defined in Directive 2004/24/EC on Traditional Herbal Medicinal Products (9), or the herb is considered medicinal by function, the product may be categorized as a ‘Traditional

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3.

4.

5.

6.

7.

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Herbal Medicinal Product’, provided the time-related criteria are met (i.e. 30 years usage in the EU). The General Food Law Regulation (EC) No 178/2002 defines food and lays down the general principles and requirements of food law, establishes the European Food Safety Authority (EFSA) and lays down procedures in matters of food safety (10). Its aim was to ‘provide the basis for the assurance of a high level of protection of human health’. The Regulation applies to all food stuffs; its general principles also cover foods with added functional properties (e.g. ‘functional foods’, ‘nutraceuticals’, dietetic foods and food supplements). ‘Food’ (or ‘foodstuff ’) is defined as ‘any substance or product, whether processed, partially processed or unprocessed, intended to be, or reasonably expected to be ingested by humans’. ‘Food’ includes drink, chewing gum and any substance, including water, intentionally incorporated into the food during its manufacture, preparation or treatment. The fact that this definition excludes medicinal products means that the decisive step to judge whether medicinal law or food law applies to a specific product will have to be sought in medicinal law. This is not a theoretical issue as products with added functions with regard to health may closely resemble medicinal products given their composition, claims and presentation. Article 2.2. of Directive 2004/27/EC states that in cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a ‘medicinal product’ and within the definition of a product covered by other Community legislation, the provisions of this Directive shall apply. This provision basically puts into legal text the jurisprudence that has been established over the years by the European Court of Justice on borderline cases. If a botanical is categorized as Food or Food ingredient as per Article 2 of Regulation (EC) No 178/2002, it must be characterized and further defined as per the following categories of foods. Novel Food Regulation (EC) No 258/97 defines a ‘novel food’ as foods or food ingredients, which have not been used to a significant degree for human consumption in the EU before 15 May, 1997 (e.g. Noni juice). A comprehensive safety evaluation is required before approval for use in foods is given (11). Directive 89/398/EEC defines ‘foods for particular nutritional use’ (PARNUTS) as foods, ‘which, owing to their special composition or manufacturing process are clearly distinguishable from foodstuffs for normal consumption, which are suitable for claimed nutritional purposes, and which are marketed in such a way as to indicate such suitability’. This category covers the dietetic foods (12). Examples are infant formulas, baby foods for infants and young children, slimming foods, foods for special medical uses, sports foods, food for diabetics etc. Directive 89/107/EEC defines ‘food additives’ as substances that are intentionally added to foods to perform certain technological functions such as to color or to preserve. Processing aids are not, as yet, regulated as food additives and flavorings are the subject of specific legislation (13). Directive 2002/46/EC defines ‘food supplements’ as ‘foodstuffs the purpose of which is to supplement the normal diet and which are concentrated sources of

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Regulatory Status and Positioning of Botanicals 203

nutrients or other substances with a nutritional or physiological effect, alone or in combination, marketed in dose form namely forms such as capsules, pastilles, tablets, pills and other similar forms, sachets of powder, ampoules of liquids, drops dispensing bottles and other similar forms of liquids and powders designed to be taken in measured small unit quantities’ (14). 8. A Regulation on Nutrition and Health Claims on foods (15) was adopted on 12 October 2006 and came into force in early 2007. This will control all nutrition and health claims and only those claims put on an approved lists will be allowed. This is discussed in detail later in this chapter. 9. A Regulation on food fortification (16) with the formal title of ‘The addition of Vitamins, Minerals and certain other Substances to Foods’ was adopted in October 2006 as Regulation (EC) No 1925/2006 and came into force on 19 January 2007. This Regulation applies controls to the use of vitamins, minerals and other substances including botanicals in foods. Chapter 3 of this Regulation covers the control of substances, including botanicals, in foods including food supplements. There will be an annex containing a list of prohibited ingredients, one with a list of ingredients subject to controls on levels or other requirements such as labeling and a third, contentious, list of ‘substances under scrutiny’. This third list is intended to contain substances for which safety concerns have been raised and which are required to be evaluated for safety by the European Food Safety Authority. 10. Directive 76/768/EEC on use as a cosmetic agent can put some herbal products into the cosmetic category, as defined in the legislation (17).

Regulatory Status and Positioning of Botanicals as Food Supplements, Fortified and Functional Foods Food Supplement Directive Article 2a of Directive 2002/46/EC defines a Food Supplement, as described earlier in section 3, para 7. As stated in paragraph 6 of the Recitals, Directive 2002/46/EC at present only covers vitamins and minerals, however, in the next year the scope will be extended to include other ingredients that are present in food supplements including amino acids, essential fatty acids, fibers and various plants and herbal extracts (14). The Food Supplement Definition specifically makes mention of substances with nutritional or physiological effects such as plant extracts. The Food Supplement Directive 2002/46/EC, which came into force in August 2005, has been implemented in the amended legislations of different states of the EU. Botanicals are already covered at national levels in Austria, Belgium, the Czech Republic, Finland, France, Greece, Italy and Slovenia in their respective legislation adopting the Food Supplement Directive.

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Traditional Herbal Medicinal Products Directive Directive 2004/24/EC on ‘Traditional Herbal Medicinal Products’ introduces a simplified registration procedure, based on ‘traditional use’ ensuring quality and safety, without the need to prove efficacy of the product. Community lists are being prepared for traditional medicinal herbs (9). A large number of botanical materials find their way onto the food supplement market. From the view point of legislation as discussed earlier, the herbal food supplement category has to be separately identified by carefully interpreting the data on physiological versus pharmacological and health versus disease conditions on dose/concentration basis, taking into consideration Directive 2002/46/EC on Food Supplements (14) and Directives 2004/27/EC and 2004/24/EC on medicinal products (8) and traditional herbal medicinal products (9) respectively. The problem of borderline botanical-sourced products is still not resolved and will remain unresolved, unless there is a clear distinction between products defined as herbal/traditional herbal medicinal products (according to Directives 2001/83/EC and 2004/27/EC) and food supplements (according to Directive 2002/46/EC).

Botanicals for Enrichment of Foods and Functional Foods When considering the use of botanical ingredients to be added in foods in the EU, there are a number of issues in addition to those already discussed. The two most important are the Novel Food status and whether the ingredient could be deemed to be ‘medicinal by function’. Although the Regulation on Novel Foods and Novel Ingredients came into force in early 1997, it was almost 7 years later that the European Commission introduced a change in the interpretation of the Regulation. This change was ratified by the EU Standing Committee on the Food Chain and Animal Health in February 2005 (18). The result of this change is that the pre-1997 use in food supplements only does not confer exemption from the Regulation for use in other food categories. This means that if an ingredient can only be demonstrated to have been used in supplements in the EU before May 1997, any intention to use it in a drink, for example, would require a novel foods application and official approval. The application must include a comprehensive range of toxicity studies. If the ingredient was in use in supplements only before 1997, there is a high probability that extra data will be required to sustain an application for food use. In addition to the Novel Food status of an ingredient intended for use in a food, it is important that the type of ingredient and levels of anticipated consumption do not classify it as being ‘medicinal by function’. Such a classification would preclude its use in foods. If the product falls into the classification of a dietetic food (10) further controls may apply. Functional Foods

The concept of foods for specified health use (FOSHU) was established (19) in Japan in 1991.

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Foods that are expected to have certain health benefits, and have been licensed to bear a label claiming that a person using them for a specified health use may expect to obtain the health use through the consumption thereof. According to the Japanese Ministry of Health and Welfare, FOSHU are: ●

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Foods that are expected to have a specific health effect due to relevant constituents, or foods from which allergens have been removed, and Foods where the effect of such addition or removal has been scientifically evaluated and permission is granted to make claims regarding their specific beneficial effects on health.

According to the working definition adopted in a European Consensus document: A food can be regarded as ‘functional’ if it satisfactorily demonstrated to affect beneficially one or more target functions in the body, beyond adequate nutritional effects, in a way that is relevant to either an improved state of health and well-being and/or reduction of risk of diseases. Functional foods must remain foods and they must demonstrate their effects in amounts that can normally be expected to be consumed in the diet: they are not pills or capsules, but part of a normal food pattern (20). It is in that general context that the European Commission’s concerted action on Functional Food Science in Europe (FUFOSE), actively involving a large number of the most prominent European experts in nutrition and related sciences, was engaged by the International Life Science Institute (ILSI) in Europe (20). In this context, ‘target function’ refers to genomic, biochemical, physiological, psychological or behavioral functions that are relevant to the maintenance of a state of well-being and health or to the reduction of the risk of a disease. Modulation of these functions should be quantitatively/objectively evaluated by measuring the biochemical markers (e.g. metabolite, specific proteins, hormone, enzyme, etc.) or physiological parameters (e.g. blood pressure, heart rate, gastrointestinal transit time, etc.) or changes in physical and intellectual performance using objective parameters. EU Legislation and Functional Foods Current EU legislation does not recognize functional foods as a distinct category of foods, as for example in Japan. This means that functional products must comply with all relevant food legislation with respect to composition, labelling, claims etc. There is no legal definition for functional foods in Europe (4). Functional foods must comply with the requirements of the Regulation on Nutrition and Health Claims and there are no special concessions for this product category. In 1995, the UK Ministry of Agriculture, Fisheries and Food (MAFF now DEFRA) developed a working definition, which is ‘a food that has had a component incorporated into it to give a specific medical or physiological benefit, other than a purely nutritional effect’. This definition distinguishes functional foods from those that are fortified with vitamins and minerals and from food supplements (21).

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According to the International Life Sciences Institute (ILSI) (22), functional food is defined, ‘as a food which by virtue of physiologically active food components, provides health benefits beyond basic nutrition’. Functional food embraces a wide range of botanical products containing bioactive food components such as soy beans (isofavones), tomatoes (lycopene), garlic (allicin) and tea (polyphenols, catechins). Food law always lags behind innovation and developments, sometimes by more than a decade. This is particularly true in the case of functional food, which is still in a state of taking shape in the framework of European legislation. Within Europe there has been increasing recognition of functional foods by national health authorities, particularly in the area of health claims (discussed later under Nutrition and Health Claim Regulation). According to Art.2 of the European Food Labelling Directive (2000/13/EC) (23): it is prohibited to ‘attribute to any food stuff the property of preventing treating or curing a human disease, or refer to such properties’. This rule applies to the presentation of the foodstuffs and, in particular, their shape, appearance or packaging, the packaging materials used, the way in which they are arranged and the setting in which they are displayed. As the food labeling legislation is in the form of a Directive and not a Regulation, there have been some nuances in the interpretation of certain aspects but, in general, it has provided consistency between member states. In January 2008, the European Commission has adopted a proposal on the provision of food information to consumers (24). This proposal combines consolidating Directive 2000/13/EC and Directive 90/496/EEC on Nutrition Labeling presentation and advertising of foodstuffs into one instrument. In addition, the proposal simplifies the structure of the horizontal food labeling legislation in Directive 2000/13/EC, by recasting and replacing provisions already in place under this Directive. Labeling requirements Labeling requirements include: ●

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Declaration of all ingredients (including subcomponents) in descending order of weight Quantitative declaration of claimed ingredients Open expiry date and storage conditions Generic description Name of manufacturer, packer, importer, distributor (whichever is applicable) established within the EU Specified warning statement (e.g. aspartame and polyols etc.) Format and calculation of nutrition labeling (if applicable) Specified labeling of genetically modified organisms (GMO) content (if applicable).

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EU Legislations and Fortified Foods

Regulation on ‘The Addition of Vitamins, Minerals and Certain other Substances to Foods’: Regulation (EC) No 1925/2006 Regulation The aim of the regulation is to harmonize divergent national rules concerning the addition of vitamins and minerals and of certain other substances to foods in order to ensure a high level of consumer protection and the free circulation of goods within the Community. The main focus is on vitamins and minerals, however, the Regulation includes botanicals as ‘other substances’. In the Regulation, ‘other substances’ are defined as ‘a substance other than a vitamin or a mineral that has a nutritional or physiological effect’. The Regulation has been closely linked to the Nutrition and Health Claims Regulation to be described later in this chapter. The Regulation will not affect: ●

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The provisions in national legislation that require the addition of vitamins, minerals or other substances to particular foods (e.g. in the UK white and brown bread must contain certain specified quantities of various nutrients). The provisions of the Food Supplement Directive already in force.

The Regulation sets out a positive listing of vitamins and minerals and their sources, a prohibited list of other substances, a controlled usage list (with specified conditions) and a scrutiny list. The positive list will be established within 2 years of the Regulation’s entry into force (i.e. 2009). Any vitamins or minerals or their sources not on the first list will not be allowed to be added to foods. This list may be amended from time to time. The Regulation also requires that maximum levels are assigned for each of the vitamins and minerals, taking into account:

● ● ● ●

A scientific risk assessment based on generally acceptable scientific data Intakes of vitamins, minerals or other substance from other dietary sources The contribution of individual foods to the overall diet of the population Any nutrient profile established for the particular food in accordance with the Nutrition and Health Claims Regulation.

The Regulation imposes labeling requirements for any fortified foods and requires a fortified product to display the total amounts of vitamins, minerals or other substance in that food. The Nutrition and Health Claims Regulation, which requires various conditions to be met before any nutrition or health claim may be made, is also relevant. The Regulation gives powers to the European Food Safety Authority (EFSA) to scrutinize substances other than vitamins and minerals in due course. If necessary, use of such substances may be restricted or forbidden in the future. The Regulation prohibits the addition of vitamins, minerals or other substance to unprocessed foodstuffs (including fruit, vegetables, meat, poultry and fish) and alcoholic drinks, other than fortified tonic wine.

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The Regulation provides transition periods, including a transition period for vitamins and minerals not on the approved list which may continue to be added to foods for 7 years following the date of entry into force of the Regulation (20 days after publication in the Official Journal of the EU), provided that each of the following conditions is fulfilled: ●

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the substance has been used for addition to foods prior to the entry into force of the Regulation and a dossier supporting use of the substance is submitted to the Commission within three years of the Regulation coming into force, and EFSA has not given an unfavorable opinion in respect of the use of that substance.

A Community-wide register will be opened to contain: ●

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The lists of permitted vitamins, minerals or other substances. (The list of permitted vitamins and minerals is given in Annex 1 of the Regulation.) The list of the permitted sources of those vitamins and minerals. The Regulation sets out a positive list of over 100 substances which are sources of vitamins and minerals that can be added to foods (Annex 2 of the Regulation) The Commission must submit, within 2 years of the Regulation’s entry into force, a proposal on maximum levels of vitamins, minerals and other substances that can be added to foods A list of any substances for which a dossier has been submitted under the transitional provisions described above Information on national provisions on the mandatory addition of vitamins, minerals or other substances Details of the foodstuffs to which vitamins and minerals may not be added Details of any other substances whose use is prohibited or restricted.

EU Legislation and Foods for Particular Nutritional Uses (PARNUTS)

The EU PARNUTS Directive 89/398/EEC was introduced to control products that meet the particular nutritional requirements of certain categories of populations (dietetic foods). The definition of PARNUTS Foods has been stated earlier (12). There are six categories of PARNUTS foods: 1. Infant formulas and follow-on formulas are governed by Directive 91/321/EEC (25) 2. Processed cereal-based foods and baby foods for infants and young children. This category of PARNUTS foods is governed by Directive 96/5/EC (26) 3. Foods for energy-restricted diets (slimming foods) are governed by Directive 96/8/EC (27) 4. Dietary foods for special medical uses (medical foods) are governed by Directive 99/21/EC (28)

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5. Sports foods: directive is in development phase 6. Diabetic foods: directive is in development phase. The list of permitted PARNUTS nutritional ingredients is attached as Annex 2 of Directive 2001/15/EC (29). These are: vitamins, minerals, amino acids, carnitine and taurine, nucleotides, choline and inositol. Applications can be made for additions to the list but they have to be supported by a comprehensive safety dossier which is assessed by the European Food Safety Authority (EFSA). Substances belonging to non-existent ingredient categories, such as fatty acids and botanical products, are not listed. There are no harmonized EU rules for these substances. The permitted use as a PARNUTS food containing other ingredients is decided at national level. PARNUTS foods have to comply with the general labeling provisions (23) in Directive 2000/13/EC and, in addition, those requirements specified in the Directives relating to different categories of PARNUTS foods. There are well-defined PARNUTS authorization procedures. EU Legislation and Novel Foods

In 1997, the European Commission introduced Regulation (EC) No 258/97 concerning novel foods and novel food ingredients (11). For the definition of a novel food or ingredient see point 4 of the Regulatory Framework above. A novel food or ingredient is one which has not been used for human consumption in the EU to a significant degree before 15 May 1997. There were six categories of foods or food ingredients that fell within the scope of the original Regulation: 1. 2. 3. 4.

Containing or consisting of genetically modified organisms (GMOs) Produced from (but not containing) GMOs Consisting of or isolated from microorganisms, fungi or algae Consisting of or isolated from plants and ingredients isolated from animals except those obtained by traditional propagating or breeding practices and having history of safe food use 5. Having a new or intentionally modified primary molecular structure 6. Having been subject to a new production process resulting in significant changes in the composition or structure of foods/food ingredient, which affects the nutritional value, metabolism or level of undesirable substances.

From 1 May 2004, the first two categories were transferred to Regulation (EC) No 1829/2003 on Genetically Modified Foods (30), leaving 3–6 in the Novel Foods Regulation. The Novel Food Regulations have well-defined authorization procedures leading to marketing authorization on a Pan-European basis.

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The European Commission, on 14 January 2008, adopted a proposal to revise the Novel Foods Regulation with a view to improving the access of new and innovative foods to the EU market, while still maintaining a high level of consumer protection. Under the draft Regulation, novel foods would be subject to a simpler and more efficient authorization procedure, which should enable safe, innovative foods to reach the EU market faster. Moreover, special provisions are made for foods which have not been traditionally sold in the EU but which have a safe history of use in third countries (31).

Quality Aspects The botanical product should be well identified and characterized. Identification, standardization and specification are of paramount importance in considering the safety of botanicals (32,33). A few points to consider for reference are: the botanical source, growth conditions, raw material, manufacturing process, botanical preparation and end product. These are described in detail in the authors’ earlier publication (2). The variability of the plant material is due to different climatic conditions, harvesting and drying and storage conditions. Standardized conditions of cultivation in the form of good agriculture practice (GAP) are essential.

Safety Aspects In Vitro Safety Data These include isolated cells, microorganisms, subcellular components (enzymes, receptors and DNA). These models are rapid, less expensive and reveal mechanisms of actions. The guiding principle is that the in vitro study data can serve as signals of potential harmful effects in humans, but not as independent indicators of risk unless an ingredient causes an effect that has been associated with harmful effects in animals or humans and there is evidence that the ingredient or its metabolites are present in physiological sites where they could cause harm. On its own, an in vitro study should serve only as a hypothesis generator and indicator of possible mechanisms of harm when the totality of the data from different key factors is considered.

In Vivo Animal Safety Data Animal studies serve as important signal generators and, in some cases, may stand alone as indicators of unreasonable risks. These include acute, subchronic, chronic toxicity, reproduction toxicity, in vivo genotoxicity and safety pharmacology studies. Knowledge of an ingredient’s pharmacokinetics and in vivo metabolism will allow the most appropriate interpretation of relevancy of the dose used in the in vitro tests. All cells react differently to its unique biochemical pathways. The guiding principle of animal data is that even with the absence of human adverse events, evidence of abnormalities from laboratory animal studies can be indicative of potential harm to humans. This indication may assume greater importance if the route

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Efficacy Aspects 211

of exposure/administration is similar (e.g. oral), the formulation is similar and more than one species show the same toxicity.

Clinical Safety Data Vulnerable subpopulations can be defined as groups of individuals who are more likely to experience an adverse event related to the use of a food, food supplement or ingredient or an individual in whom such events are more likely to be serious in comparison with the general population. Characteristics of such vulnerability may be: ●

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Physiological (e.g. capacity of digestion, metabolism and excretion), for example in the elderly population, children, age-related changes, pregnancy Reactions to specific allergens Disease related (e.g. hepatitis, renal disease may alter xenophobic clearance, hypertension, diabetes) Therapeutic intervention (e.g. AIDS patients on drug combinations, which may alter cytochrome P450 activity) Drug/food supplements interactions (e.g. vitamin E with statin drugs).

The guiding principle of clinical data is, when data indicate that an identifiable subpopulation may be especially sensitive to adverse effects from certain food or supplement ingredients, then this higher level of concern should be taken into account when screening the food, food supplement or ingredient. European Food Safety Authority (EFSA) has published a draft guidance document (34) for public consultation on the procedures to be adopted for safety assessment of botanicals and botanical preparations intended for use as food supplements, which is at present in the consultation phase up to 15 February, 2008.

Efficacy Aspects Nutrition and Health Claims Regulation The Regulation was adopted on the 12 October 2006 and published in the Official Journal of the EU on 30 December 2006. The regulation complements the general principles laid down in Directive 2000/13/EC (23) and lays down specific provisions concerning the use of nutrition and health claims (15). The basic principle of the Regulation is the harmonization of provisions laid down by law, regulation or administrative action relating to nutrition and health claims in the EU member states in labeling, presentation and advertising of food and related categories of nutraceuticals. This Regulation takes into account the definitions of food provided in Food Regulation No. 178/2002 (10) and food supplements in Directive 2002/46/EC (14). For definitions on ‘Nutrition labeling’ Directive 90/496 /EEC and for labeling Directive 2000/13/EC shall apply. Provision is made in the Regulation to support small and medium enterprises (SMEs) to comply with the Regulation.

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Nutrient Profiles

The key precept of the Regulation is that there should be clear definitions for claims such as ‘low energy’, ‘low fat’, ‘high fiber’ or even ‘reduces cholesterol’. A producer can make a claim concerning one of the three ingredients (fat, sugar and salt) if the other two ingredients also comply with the regulation or if it is clearly stated that the product has a ‘high content’ of these ingredients According to Article 4 on nutritional profiles, the appropriate ratios of salt, sugar and fat in any given product will be laid down by the Commission in consultation with the food industry and consumer bodies on the basis of information provided by the EFSA. The conformance with nutrient profiles is mandatory wherever applicable for the use of nutrition and health claims. These take into account the quantity of certain nutrients and other substances contained in the food such as saturated fatty acids, trans fatty acids, sugars and salt; their role, importance and contribution to the diet of population in general and risk groups including children and the overall nutritional composition of the foods and presence of nutrients that have been recognized as having an effect on health. The nutrient profiles are based on scientific knowledge about diet and nutrition and their relation to health. Nutrient profiles have to be established within 2 years of the Regulation coming into force The Conditions and General Principles for Claims

According to Article 5 of the Regulation, the conditions are: the presence of the active ingredient in sufficient quantity to produce the nutritional or physiological effect claimed, as established by generally accepted scientific evidence. The wording of claims should be understood by the average consumer and should not be misleading in any sense. In the case of food supplements, the nutrition information must be provided in accordance with Article 8 of Directive 2002/46/EC. Special conditions stated in Article 10 prevail, stating the importance of a varied and balanced diet. Appropriate warnings (such as for vitamin A) are to be provided for products likely to present a health risk, if consumed in excess. Article 6 sets out the general principles for substantiation of claims. Health claims will therefore only be approved for use on labeling, presentation and advertising of foods in the EU market after a scientific evaluation of the highest possible standard. Fresh food such as fruit, vegetables and bread are excluded from the regulation. National rules will apply until (and if) Community standards are adopted. Types of Claims

Nutrition Claims Nutrition claims will be banned on products containing alcohol at more than 1.2% v/v, except if these claims refer to reduction in alcohol or calories. In the absence of specific Community rules regarding nutrition claims referring to ‘low alcohol levels’ or ‘the reduction or absence of alcohol’ or ‘energy content’, relevant national rules may apply. Generic Health Claims According to Article 13, generic health claims have to go through the Member States who were required to prepare lists of claims for the Commission within 12 months

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of the Regulations entry into force. The Commission will adopt a community list of claims accompanied by conditions applying to them. There are rules on newly developed scientific evidence and/or request for the protection of proprietary data. Claims referring to children’s development and health are specifically controlled under Article 14. The list provided by member states for claims already approved at their national level is to be established within 3 years, i.e. by the end of January 2010. Product Specific/Other Health Claims Article 14 includes the criteria for authorization of reduction of disease risk claims and claims referring to children’s development and health. Disclaimer statements apply to the reduction of disease risk claims. ‘The disease to which a claim refers has multiple risk factors and altering one of those risk factors may or may not have a beneficial effect’. The use of a new health claim/product specific claim, or disease reduction claim, or claims referring to children’s development and health will require specific authorization by the Commission.

Procedures for Authorization of Claims

Application The procedures for the application for the authorization of a claim, other than those covered by Article 13 are given in detail in the Regulation. The review of the scientific evidence will be carried out by EFSA who will give their opinion to the Commission. The final authorization will come from the Commission. EFSA, on the request of European Commission, has published a document (35), ‘Scientific and technical guidance for the preparation and presentation of the application for authorisation of health claim’, which was adopted on 6 July 2007. b. Community Register (Article 20) The salient points are: 1. The Register shall include nutrition and health claims and any restrictions adopted; the authorized claims and the conditions applying to them and a list of rejected health claims and the reasons for their rejection. This will allow manufacturers who wish to introduce a product with a particular health claim simply to consult the register in order to know what conditions are to be observed and the wording of the claim without having to go through the authorization process itself. 2. Health claims authorized on the basis of proprietary data shall be recorded in a separate Annex to the Register together with the following information: ● the date the Commission authorized the health claim and the name of the original applicant that was granted authorization ● the fact that the Commission authorized the health claim on the basis of proprietary data

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the fact that the health claim is restricted for use, unless a subsequent applicant obtains authorization for the claim without reference to the proprietary data of the original applicant 3. The Register shall be made available to the public. ●

Data Protection According to Article 21, the scientific data and other information may not be used for the benefit of a subsequent applicant for a period of 5 years from the date of authorization, unless agreed upon by the prior applicant or until the Commission takes the decision whether a claim could be or could have been included in the list provided for in Article 14 or where applicable Article 13 without the submission of these data. The conditions which apply are: ●

●

●

The scientific data and other information have been designated as proprietary data (PD) by the prior applicant at the time of his application The prior applicant had exclusive rights of reference to these PD at the time of application The health claim could not have been authorized without the submission of the PD.

Safeguard Measures Where a Member State has serious grounds for considering that a claim does not comply with the Regulation, or the scientific substantiation provided is insufficient, the Member State may temporarily suspend the use of that claim within its territory. It shall inform other Member States and the Commission giving the reasons. A decision shall be taken by the Commission after obtaining an opinion from EFSA. The suspension may be maintained until the Member State is notified of the decision. Implementation and Enforcement The Regulation came into force on the 19 January 2007, 20 days after publication in the Official Journal on 30 December 2006. The first provisions of the Regulation applied 6 months from entry into force. Nutrient profiles will be established within 2 years of the Regulation coming into force. Transitional Measures and Periods 1. Foods with non-compliant labels placed on the market before the Regulation came into force or within 6 months of it coming into force may stay on the market until their expiry date but not later than 30 months after its coming into force, e.g. 31 July 2009. 2. Products bearing trade marks or brand names giving a message expressed or implied relating to a nutrition or health claim existing before 1 January 2005 which do not comply with the Regulation may stay for 15 years after enforcement of the Regulation, until 19 January 2022. Derogations will apply to generic descriptors (e.g. digestives) 3. Health claims as referred to in Article 13.1(a) may stay under the food business operator’s responsibility until they are adopted in the community list, provided

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4.

5.

6.

7.

they comply with the requirements of the Regulation and with existing national provisions in a particular Member State. Health claims that are not included on the final list will be prohibited following publication of the list. Health claims other than those in Articles 13.1(a) and 14, which complied with national provisions before enforcement of this Regulation, and which had been the subject of an evaluation and authorization in a Member State, had to be communicated to the Commission by 31 January 2008. Such claims had to be accompanied by their assessment report. The Commission will consult EFSA and adopt a decision on such claims. Health claims not authorized under this procedure may continue to be used for 6 months following the adoption of a decision. Health claims other than those in Articles 13.1(a) and 14, which complied with national provisions before enforcement of this Regulation but which had not been the subject of an evaluation and authorization in a Member State, may continue, provided an application was made before 19 January 2008. The Commission will consult EFSA and adopt a decision on such claims. Those health claims not authorized under this procedure may continue to be used for 6 months after a decision is taken. Nutrition claims which had been in use within a particular Member State before 1 January 2006 in compliance with national provisions and which are not included in the Annex to the Regulation, may continue to be used under the responsibility of the food business operators until 19 January 2010. Nutrition claims in the form of pictorial, graphic or symbolic representation which comply with the general principles of the Regulation and are used in compliance with national provisions, but which are not included in the Annex, had to be communicated to the Commission by 31 January 2008, accompanied by scientific data in support of the conditions and criteria for use. The Commission will consult EFSA and adopt a decision on such claims. Nutrition claims not authorized under this procedure may continue to be used for 12 months following the adoption of a decision.

Passclaim Initiative The International Life Science Institute (ILSI Europe) initiated the concerted action supported by the European Commission on ‘Process for the Assessment of Scientific Support for Claims (PASSCLAIM)’. PASSCLAIM is built on a concerted action by Functional Food Science in Europe (FUFOSE), which suggested claims for ‘enhanced function’ and ‘reduced risk of disease’ should be based on sound scientific evidence, using appropriate validated biomarkers (36). The FUFOSE consensus document was published in the British Journal of Nutrition (20).

Process for Scientific Validation and Substantiation of Health Claims

The objectives were to identify common new ideas, definitions, best practice and methodology to underpin current and future regulatory developments (37).

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Criteria for Scientific Substantiation ●

●

●

●

●

●

The food or food component, including the botanical product/ingredient to which the claim is attributed should be well characterized. Substantiation of a claim should be based on human data, primarily from well-designed intervention studies taking into consideration target population, appropriate controls, adequate duration of exposure and a follow-up, to demonstrate the intended effect. Generally accepted scientific data must be systematic and objective, balanced and unbiased, strong, consistent and reproducible, with appropriate statistical analysis. The data should be based on validated and predicted biomarkers for: ● Enhanced function ● Disease risk reduction. The claim must be evaluated on the totality of the scientific evidence (i.e. both positive and negative evidence). The overall assessment should be based on the application of scientific judgment and critical interpretation of the data as a whole.

The claims on the positive list (generic claims) must be based on and substantiated by ‘generally accepted scientific evidence’ and the person or company placing the product on the market may be required to produce all relevant elements and data establishing the science behind the claim.

Authorizing Bodies and Qualified Levels of Health Claims

The preamble of the EU legislation states that health claims should only be authorized by EFSA after scientific assessment of the highest possible standard. There is no dispute about this, but the major concern is how to accommodate the emerging science in an appropriate grading system. The World Health Organization (WHO) and the World Cancer Research Fund (WCRF) have established four grades of evidence: ‘convincing’, ‘probable’, ‘possible’ and ‘insufficient’. These correspond to the four levels of qualified health claims proposed in the USA. The first level, ‘convincing’, means convincing scientific evidence. The second level, ‘probable’, means that although there is scientific evidence supporting the claim, the evidence is not conclusive. The third level, ‘possible’, means ‘some scientific evidence may support the claim, however, the evidence is limited and not conclusive’. The fourth level, ‘insufficient’, means ‘very limited and preliminary scientific research suggests there is little scientific evidence to support the claim’. The EU has not yet considered the concept of grades of evidence, but it is crucial to support scientific initiatives to find an approach where the term ‘generally accepted scientific data’ includes not only generic or well-established linkage between food and food components and health benefits, and to establish standards which should not be revoked or reversed by emerging science at a later stage. The concept of ‘grades of evidence’ had not been adopted by EFSA at the end of 2007 and the review of the scientific substantiation of claims by EFSA is expected to start

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References 217

in May 2008. A significant number of claims for botanicals have been submitted via a number of Member States. Efforts are in progress to explore and develop different wordings on the level of certainty of the scientific evidence, which is of paramount importance.

Conclusions The addition of botanically-sourced nutraceuticals to food supplements and functional foods encompasses a number of issues. The predominant one is the status of the food or ingredient in relation to EU legislation covering both medicines and foods, as many of the ingredients are very close to the borderline between the two classifications. Although new legislation covering traditional herbal medicines is now in force, the work on the control of botanically derived substances, in particular herbs, in food supplements and other foods has barely started and controls of these ingredients in food supplements are now unlikely to be in place before 2012. In the meantime, companies wishing to market products in the EU will have to continue to assess their regulatory status in each Member State. The Nutrition and Health Claims Regulation and the ‘Fortified Foods’ Regulation came into force in early 2007. These will facilitate the market potential of botanically sourced nutraceuticals, however, for food business operators, it will become hard to position their products in the right category of foods with appropriate claims or no claims, depending upon the quality of scientific evidence available to support their products.

References 1. Defelice SL. (1995). The nutraceutical revolution, its impact on food industry research and development. Trends Food Sci Technol 6, 59–61. 2. Gulati OP, Berry Ottaway P. (2006). Legislation relating to nutraceuticals in European Union with a particular focus on botanical-sourced products. Toxicology 221, 75–87. 3. Mandel S, Packer L, Youdim MBH, Weinreb O. (2005). Reviews: current topics. Proceeding from the Third International Conference on Mechanism of action of nutraceuticals. J Nutr Biochem 16, 513–520. 4. Richardson DP. (1996). Functional foods – shades of grey: an industry perspective. Nutr Rev 54(11), S174–S185. 5. Dietary Supplement Health Education Act (DSHEA) of 1994, Public Law 103–417 available at FDA Website: http://www.fda.gov 6. Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by Law, Regulation or Administrative Action relating to proprietary medicinal products. Official Journal 022, 09/02/1965, pp. 0369–0373. 7. Directive 2001/83/EC of the European Parliament and of the Council of 6th November, 2001 on the community code relating to medicinal products for human use. Official Journal L-311, 28/11/2004, pp. 0067–0128.

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8. Directive 2004/27/EC of the European Parliament and of the Council of 31st March 2004 Directive 2001/83/EC of the European Parliament and of the Council of 6th November, 2001 on the community code relating to medicinal products for human use Official Journal 136, 30/04/2004, pp. 0034–0057. 9. Directive 2004/24/EC of the European Parliament and of the Council of 31st March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/ EC on the Community code relating to medicinal products for human use Official Journal L 136, 30/04/2004, pp. 0085–0907. 10. Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28th January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety. Official Journal L 31, 01/02/2002, pp. 0001–0024. 11. Regulation (EC) No 258/97 of the European Parliament and of the Council of 27th January 1997 concerning novel and novel ingredients. Official Journal L 043, 14/02/1997, pp. 0001–0007. 12. Directive 89/398/EEC of the European Parliament and of the Council of 3rd May 1989 on the approximation of the laws of Member States relating to foodstuffs intended for particular nutritional uses. Official Journal L 186, 30/06/1989, pp. 0027–0032. 13. Directive 89/107/EEC of the European Parliament and of the Council of 21st December 1988 on the approximation of the laws of Member States concerning food stuffs intended for human consumption. Official Journal L 40, 11/02/1989, pp. 0027–0032. 14. Directive 2002/46/EC of the European Parliament and of the Council of 10th June 2002 on the approximation of the laws of Member States relating to food supplements. Official Journal L 183, 12/07/2002, pp. 0051–0057. 15. Regulation (EC) No 1924/2006 Regulation of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. Official Journal L 404, 30/12/2006, pp. 0009–0025. 16. Regulation (EC) No 1925/2006 Regulation of the European Parliament and of the Council of 20 December 2006 on the addition of vitamins and minerals and of certain other substances to foods. Official Journal L 404, 30/12/2006, pp. 0026–0038. 17. Directive 76/768/EEC of the European Parliament and of the Council of 27th July 1976 on the approximation of the laws of Member States relating to cosmetic products. Official Journal L 262, 27/09/1976, Articles 1–15. 18. Standing Committee on the Food chain and animal health (2005), Proceedings of the committee meeting (Section of Toxicological Safety and section on General Food Law) of 14th February 2005, p.6. 19. The FOSHU system (1991) Nutrition Improvement Law Enforcement Regulations (Ministerial Ordinance No. 41, July 1991. 20. Diplock AT, Aggett PJ, Ashwell M, Bornet F, Fern EB, Roberfroid MB. (1999). Scientific concepts of functional foods in Europe – consensus document. Br J Nutr 81(Suppl 1), S1–S27. 21. Ministry of Agriculture, Fisheries and Food (MAFF). (1995). Food standards and labelling division discussion paper on functional foods and health claims. MAFF Publications August 1995. 22. Milner JA. (2002). Functional foods and health: a US perspective. Br J Nutr 88(Suppl 2), S151–S158.

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23. Directive 2000/13/EC of the European Parliament and of the Council of 20th March 2000 on the approximation of laws of the member states related to labeling, presentation and advertising of food stuffs. Official Journal L 109, 06/05/2000:29. 24. European Commission, (2008), Proposal for a Regulation of the European Parliament and of the Council on the Provision of Food Information to Consumers. COM (2008), Brussels of 30.01.08, 2008/028 (COD). 25. Directive 91/321/EEC of the European Parliament and of the Council of 14.05.1991 on infant formulae and follow-on formulae. Official Journal L 175, 04.07.1991. 0035–0049. 26. Directive 96/5/EC of 16 February 1996 on processed cereal-based foods and baby foods for infants and young children. Official Journal L 049, 28.02.1996. 0023–0038. 27. Directive 96/8/EC of 26 February 1996 on foods for use in energy restricted diets for weight reduction. Official Journal L 055, 06.03.1996. 0022–0026. 28. Directive 1999/21/EC of 25 March 1999 on dietary foods for special medical purposes Official Journal L 091, 07.04.1999. 0029–0037. 29. Directive 2001/15/EC of 15 February 2001 on substances that may be added for specific nutritional purposes in foods for particular nutritional uses. Official Journal L 052, 22.02.01. 0019–0025. 30. Regulation (EC) No 1829/2003 of the European Parliament and of the Council of 22nd September 2003 on genetically modified food and feed. Official Journal L 268, 18/10/2003. 0001–0023. 31. European Commission. (2008). Proposal for a Regulation of the European Parliament and of the Council on Novel food amending Regulation EC (Common Procedure) COM (2007), 872 Final, Brussels, of 14.01.08, 2008/028 (COD). 32. Shilter B, Andersson C, Anton A et al. (2003). Guidance for the safety assessment of botanicals and botanical preparations for use in food and food supplements. Food Chem Toxicol 41, 1625–1649. 33. Coppens P, Delmule L, Gulati O et al. (2006). Use of botanicals in food supplements – regulatory scope, scientific risk assessment and claim substantiation. Ann Nutr Metab 50, 538–554. 34. European Food Safety Authority (EFSA) (2007). Safety assessment of botanical and botanical preparations intended for use as food supplements. Draft Guidance Document of the Scientific Committee (Question No EFSA –Q-2005-233). 35. European Food Safety Authority (EFSA) (2007). Scientific and technical guidance for the preparation and presentation of the application for authorization of a health claim. EFSA J 530, 1–44. 36. Bellisle F, Diplock AT, Hornstra G et al. (1998). Functional food science in Europe. Br J Nutr 80(Suppl.1), S1–S193. 37. Richardson DP, Affertsholt T, Asp N-G et al. (2003). PASSCLAIM – Synthesis and review of existing processes. Eur J Nutr 42(1), 96–111.

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Regulations for Nutraceuticals and Functional Foods in Europe and the United Kingdom

15

Stephen A. Ruckman Huntingdon Life Sciences, Alconbury, Cambridgeshire, UK

Abstract The history of European food law is rooted within the body of legislation created originally by its individual Member States. Today’s body of legislation has also been influenced by a number of safety crises arising during the last twenty years. The European Union (EU) operates in principle with a single internal market, through harmonization and mutual recognition. The European Food Safety Authority (EFSA) is responsible for risk management and communication. EFSA will also have the task of evaluating health claims under the new nutrition and health claims regulation. Under the new regulation, a positive list of generic claims will be compiled within three years. After that time, claims will have to pass a full authorization procedure. For the first time in European Union law it will be possible to make a health claim for a food ingredient which asserts a reduced risk for a disease condition. All forms of evidence to support the claims will be considered, but the gold standard will be properly controlled clinical trials in European subjects. The safety and approval of vitamin and mineral products is controlled by the food supplements directive and the fortified foods regulation. Other supplements and health food ingredients fall under the auspices of the Novel Foods Regulation. This legislation applies to all food ingredients not consumed to a significant degree in the EU prior to 1997. If considered novel, then an ingredient should be the subject of an application to the competent authority of a Member State: either a simplified application claiming substantial equivalence to an existing Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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222 Regulations for Nutraceuticals and Functional Foods in Europe and the United Kingdom

EU food on the basis of composition, nutritional value, metabolism, intended use, and impurities, or a full application containing supporting safety data. Human safety data should be included and the potential for allergenicity should be addressed. The novel foods regulation is being reappraised with a view to make it less restrictive.

Introduction In the developed nations, the standard of living has steadily increased since the 1950s. In Europe and Japan, as well as in the USA, people have more disposable income and a longer life expectancy than ever before. There exists a post-modern trend away from synthetic, manufactured products towards a more natural way of life and eating, giving rise to a greater demand for more healthy food, organic foods, herbal remedies and dietary supplements. The average age of the population is increasing and more people are seeking to buy key nutrients in concentrate or supplemental form. The USA, Europe and Japan all regulate in a broadly similar manner the permitted claims for these products, to distinguish them from medicines, inasmuch as claims for the prevention, treatment or curing of disease are not allowed. The regulation of food supplements and health food ingredients in Europe is totally contained within the framework of food law. Europe recently introduced a dietary supplements directive, which currently applies to vitamins and minerals only but may be expanded in the future. Unlike the USA, which has the Nutrition Labeling and Education Act of 1993, health claims for food ingredients have hitherto not been permitted in the European Union. However, a new nutrition and health claim regulation permits properly substantiated claims, even as far as advertising a reduced disease risk. Proof of efficacy will be required; the gold standard being well-designed clinical studies. With respect to safety, the same degree of relaxation of regulatory control represented by the USA’s Dietary Supplement and Health Education Act, compared with that for food additives, does not apply to Europe. Whereas herbals may be sold as dietary supplements in the USA, in Europe they are generally regulated as medicines, typically under the Traditional Herbal Medicinal Products Directive (1), and are not the subject of this chapter. In Europe, the Novel Foods Regulation applies to any food product which has not been consumed to a significant degree within the community prior to 1997. This regulation also defines specific toxicology tests. This chapter will provide an understanding of European and UK food laws and how they apply specifically to nutraceuticals and functional foods.

Background The food and drink industries generate an annual turnover of more than £400 billion and provide 2.7 million jobs. UK food and drink imports and exports are £20.9 billion and £9.8 billion respectively and most of this trade is within the European Union (EU). The food and drink industry has received continual media attention for many years, owing to several well-known safety concerns, such as bovine spongiform encephalopathy, Salmonella and the dioxin and Sudan 1 contaminations. There is a

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Background 223

high degree of sensitivity to anything new, seen particularly with the attempted introduction of genetically modified foods. More recently, there is increasing interest in the links between food and health, the WHO-recommended five portions per day of fruit and vegetables, the increasing focus upon foods which are high in fat, salt or sugar and the widespread marketing of foods and supplements rich in omega-3 fatty acids and calcium, to name but two. The food industry is responding by developing new products aimed at health-conscious consumers with ever more comprehensive labeling. Food law is high on the regulatory agenda in Europe and the UK. The food sector is the subject of laws, regulations, codes of practice and guidance relating to all aspects of the food chain ‘from farm to fork’. The plethora of regulations affecting functional foods and food supplements can be bewildering (Fig. 15.1). Today, European food law determines most UK food law and the two are inseparable. European regulations are directly effective in the UK and European directives have to be implemented in the UK within a short time. Additional national legislation may supplement the EU directives and regulations but they should not conflict with them. National legislation may insert extra detail or may determine how the laws should be enforced. To understand the laws affecting the regulation of nutraceuticals and functional foods, we need to consider the background to food law making in the European Union.

CLAIMS Prohibited claims nutrient profiles List of established claims/wording Substantiation/ authorization

FOOD SUPPLEMENT DIRECTIVE Extension of positive lists

ADDITIVES AND CONTAMINANTS

List of banned substances

Setting max levels

Beeswax

Setting max levels

Extension to other ingredients

PAHs

FORTIFIED FOOD DIRECTIVE Foods to which substances added

Dioxins & PCBs

LABELING Allergen 25% rule

FUNCTIONAL FOODS and FOOD SUPPLEMENTS

Processing aids

Parnuts

Revision of novel foods regulations GMOS Authorization labeling - trace

Lead/heavy metals

Mycotoxins

Nutrition labeling

NOVEL FOODS

Shellac

CODE OF MEDICINES

TRADITIONAL HERBAL PRODUCTIONS

Definitions

Safety

Registration

Scope

Quality

Positive list

Figure 15.1 Overview of key EU legislation affecting functional foods and food supplements (adapted from a diagram by the European Advisory Service).

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History of EU Food Law The European Union consists of 27 countries or Member States, soon to rise still further. On joining, Member States relinquish some of their sovereignty to the EU institutions of the European Parliament, the European Commission and the Council of Ministers, who are responsible for proposing and adopting EU legislation. Member States do retain their laws but must also adopt all of the European legislation. If national laws conflict with EU laws, then EU law prevails. EU law materializes in three ways: primary legislation, in the form of international treaties laying down basic policies, structures, procedures and powers; secondary legislation, in the form of regulations, directives and decisions; and case law, produced by the European Court of Justice to resolve disputes in interpretation and application of EU law. In this chapter, we are considering certain elements of secondary legislation, such as the Novel Foods Regulation (EC 258/97) (2) or the Food Supplements Directive (2002/46/EC) (3). Regulations are directly applicable in all Member States from the date they enter force, directives do not apply until implemented in national law, which can take from 1 to 3 years. Most EU food legislation is the result of a co-decision process by the Parliament, the Council of Ministers and the Commission, in which the European Commission proposes the new legislation and the Parliament and Council act as co-legislators to pass the law (Fig. 15.2). This generally involves two readings by the Parliament and Council, although legislation can be passed in one reading if the Council and Parliament are able to agree, otherwise it is put before a conciliation committee. Once adopted, the legislation is published in the Official Journal of the EU. At the core of the EU is the concept of a single internal market. In theory, at least, all products meeting EU requirements should be able to move freely throughout the union. The tools which aid this process are those of harmonization and mutual recognition. The harmonization process, during which Member States adopt the same laws, employs vertical and horizontal legislation. Horizontal legislation

Parliament

Council

Commission (Directorates Générales)

EFSA

Figure15.2 EU legislative process.

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UK Law 225

consists of the basic requirements and principles that apply to all foods, such as labeling, additives and hygiene and vertical legislation regulates the composition and labeling of specific products, for example coffee, although the latter has decreased in emphasis to promote diversity in taste. Mutual recognition is the principle whereby one Member State cannot prohibit the sale of products which are lawfully produced and marketed in another Member State, even if the standards of production are different. The European Court of Justice has ruled on a number of cases relating to the free movement of goods under the principle of mutual recognition.

EU Food Safety Numerous food safety crises in the 1980s and 1990s exposed weaknesses in the legislation. The EU analyzed the existing body of legislation and proposed a legal structure that was intended to create the most effective food safety regime in the world, to restore consumer confidence in the food industry. The Commission believed that it was necessary to improve risk assessment, risk management and risk communication. A new regulation (EC 178/2002) (4) established the European Food Safety Authority (EFSA), now based in Parma, Italy. It comprises a management board, an executive director and staff, an advisory forum, a scientific committee and various scientific panels for different aspects affecting food safety. It is funded from the EU budget but operates independently to maintain openness and transparency. EFSA’s key responsibilities fall within the areas of risk management and communication: ● ● ● ●

providing independent advice on all matters relating to food and feed safety communicating risk and outlining measures to be taken by risk managers raising awareness and explaining advice managing the rapid alert system for food and feed.

The rapid alert system is for the notification of any risk to human health through the network of Member States, the Commission and EFSA. Member States must notify the Commission of any measure they adopt regarding a particular product, or any recommendation reached with operators to manage the risk, or any rejection of food or feed by a Member State’s authority or an EU border post. The Commission transmits this information to other Member States and to EFSA and EFSA may supplement with scientific or technical informationz to aid the risk management by other Member States. Generally, this information will be available to the general public, unless confidential.

UK Law The UK joined the European Economic Community in 1973 and, in so doing, agreed to adopt all EEC legislation and to harmonize UK food law with EEC food law.

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UK food law was already comprehensive and the integration with EEC did not change things substantially and, in addition, the UK was in a strong position to influence European law after 1973. UK law centers around three acts: ● ● ●

the Food Safety Act 1990 the Food and Environment Protection Act 1985 the Food Standards Act 1999, which established the Food Standards Agency: which was a model for the design of EFSA, to come later.

So today, EU law determines most UK law. There are other UK regulations impacting upon food which do not warrant direct mention here, except perhaps the Trade Descriptions Act of 1968, which certainly affects claims made for health food ingredients, but has been overtaken by the introduction of the EU-wide health claims legislation.

Health and Nutrition Claims It is not permitted to make claims for foods implying that the ingredients can diagnose, cure, treat, mitigate or prevent a disease, such would clearly be medical or drug claims. However, it has long been recognized that certain food ingredients possess properties beyond the normal bounds of nutrition. Regulating the claims that can be made for such ingredients has differed widely within EU countries, according to traditional uses and has been further complicated by national legislation relating to herbal remedies, which also straddle the food–medicine boundary. EU-wide legislation for the labeling of health food ingredients has been scant. An obvious example is the PARNUTS Directive (Foods for Particular Nutritional Uses: 89/398/EEC) (5). This category can perhaps best be compared with the ‘medical foods’ category in the USA, which can only be used under auspices of a physician. Examples of PARNUTS foods are those intended for individuals with particular metabolic disorders or digestive limitations, infant formulas or energy-restricted diets. Claims for foods in the PARNUTS categories are strictly nutritional in nature. The national laws in individual EU countries largely cover the claims that can be made. For example, the UK laws determine that a claim that a food is suitable for a particular nutritional purpose can only feature where the claim is true and product labeling indicates the components that allow the product to make that claim. All claims must be capable of substantiation. The manufacturer would be expected to hold scientific data to vouchsafe such a claim. Other EU countries have similar protections.

The Nutrition and Health Claims Regulation (6) On 16 July 2003, the European Commission published a proposal for a regulation on nutrition and health claims. The aim was to ensure that consumers were better

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Health and Nutrition Claims 227

informed and to replace the different national provisions relating to such claims. In actual fact, there is quite a long history to the development of claims legislation: 1970s: Work started on drafting in late 1970s 1980: Proposal circulated and adoption expected in 1982 and to come into force in 1984 1990: Working document to amend labeling (6) Directive on QUID and claims. Claims then omitted 1992: Working document on claims, followed by draft Directive 1994: No agreement among Member States on draft, simplified version circulated in November 1994 1995: Still disagreement and text withdrawn 2001: Discussion paper on nutrition and functional claims 2002: Draft proposal released end 2002 2003: Proposal adopted by Commission 16 July 2003. The new regulation will cover any nutrition claim or health claim made on food labeling.

Nutrition Claims

A nutrition claim is any claim which states, suggests or implies that a food has particular nutritional properties due to the energy it provides or does not provide or provides at a reduced or increased rate and/or the other substances it contains or does not contain, or contains in a reduced or increased proportion. Annex I of the regulation will contain the criteria a product should meet in order for its labeling to carry particular claims, such as ‘sugar-free’ or ‘low fat’. Criteria contained in the annex can be updated to reflect the latest scientific advances. Comparative claims can be permitted to compare the energy and nutrient levels of a food with other foods of the same category.

Health Claims

A health claim, on the other hand, is any claim that states, suggests or implies that a relationship exists between a food category, or a food or one of its constituents and health, for example: ‘Ingredient X is good for your bones’. Certain long-established health claims will be permitted without requiring full authorization, provided they are on a list being assembled by EFSA, which then will be adopted by the Commission. Submissions for inclusion in the list had to be made by January 2008. After this time, all health claims have to undergo the full authorization procedure. An EU positive list will be created within 3 years. Based upon generally accepted scientific data, generic health claims need to be well understood by the consumer. The regulation will permit enhanced function claims, for example for minerals or vitamins which may have a different range of benefits at higher doses than the traditional recommended daily allowance.

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Perhaps most importantly of all, a reduction of risk of disease claim will be allowed. This is defined as a health claim that states, suggests or implies that the consumption of a food category, a food, or one of its constituents significantly reduces a risk factor in the development of a human disease. This comes as close to being a prevention claim (i.e. a drug type claim) as it is possible to be without actually being one. In addition, children’s development and health claims will be a separate category.

Labeling

Where a health or nutrition claim is made, nutrition labeling will be mandatory. For a nutrition claim, energy value, protein, carbohydrates and fat content are required. For a health claim, additional information is required: sugars, saturates, fiber and sodium content. Where a claim is made in relation to a substance that does not appear in the nutrition labeling, the amount of this substance would also need to be indicated. Additional specific labeling requirements are: ● ● ● ●

a statement indicating the importance of a balanced diet and healthy lifestyle the quantity of food and consumption pattern needed to receive the benefit an indication of who should avoid the food where appropriate, a warning on maximum consumption level.

For a reduction of disease risk claim, a statement is needed that diseases have multiple risk factors and that altering just one factor may not have the desired benefit. Points of Procedure

In the latter stages of ratification, the main obstacles to agreement between the EU Parliament and the Council were on notification versus authorization (a) and on nutrient profiling for products making claims (b): (a) The EU Parliament had proposed that a notification process would be simpler for all concerned: the manufacturer would notify EFSA when the product was first placed on the market; EFSA would then inform the Member States and the European Commission; if the Commission had any doubts it would ask EFSA for an opinion within 4 months; if EFSA confirmed the doubts, the Commission could propose the claim be prohibited. Instead, we have a formal approval process for health claims (Fig. 15.3). An application has to be made to the Commission, which it passes to EFSA for an opinion. The application must include scientific substantiation as well as details of the claims. A summary of the dossier will be made available to the public. EFSA may have further questions for the manufacturer before reverting with a final opinion to the Commission. If the opinion is favorable, the Commission will make a positive recommendation to the Member State Committee, which will take a vote on whether to include the claim in the Community Register.

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Health and Nutrition Claims 229

Application to Commission

•

Proposed wording substantiated

•

Claim complies with all criteria

•

Claim is understandable and meaningful to consumer

•

Recommended wording in all EU languages

5 Months (+2) EFSA Opinion 2 Months Commission 3 Months MS Committee

Community Register

Figure 15.3 Health claim approval process.

The total process could take a year, assuming that the manufacturer does not have to generate any further data to substantiate the claim. The advantage for the producer of investing in the substantiation of health claim is the allowance in the regulation for data confidentiality for 7 years, providing the data are proprietary and exclusive to the producer and that the proprietary data were necessary for the substantiation of the claim being made. (b) The Commission proposed that a procedure be introduced for establishing nutrient profiles that foods would need to respect in order to carry a health or nutrition claim. The Parliament was against this. In the end, a compromise was reached. Nutrition and health claims on beverages containing more than 1.2% alcohol would be banned, except for nutrition claims referring to a reduction in alcohol or energy content. With regard to sugar, fat and salt, the compromise is that a claim can be made providing no more than one out of the three exceeds the limit but the product must carry a label warning, e.g. ‘High in Salt’! Other restrictions on claims are: ● ● ● ●

The regulation should include ‘on-pack’ and ‘off-pack’ claims No claims suggesting not consuming the food is harmful No claims referring to the rate or amount of weight loss No claims referring to recommendations of individual doctors or other health professionals.

Under the new regulation, the EU Commission will establish and maintain a register of permitted nutrition and health claims and the conditions under which they

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can be made, as well as a list of rejected health claims. The register will be a public document. There are some transitional provisions for products already on the market, which may allow products to continue on the market which are not in compliance with the regulation for a period after it comes into force. Currently, it is felt that EFSA does not have the resources necessary for evaluation yet and there will have to be some changes made. However, consumer understanding and the market advantage afforded by any label claims will be the big issue for the producer, as it has been in the USA. This has been complicated already by some European companies taking a unilateral approach to color-coded nutrient labeling. Companies will also need to watch for published deadlines to ensure they do not lose the right to current claims.

UK Health and Nutrition Claims In the UK, the borderline between medicines and foods is patrolled by the Medicines and Health Products Regulatory Agency (MHRA). The agency will determine whether or not a product can legitimately be sold as a food or supplement, taking into account the presentation to the consumer, the ingredients, whether any stated claim for benefit could be taken to imply a diagnosis, cure, treatment, mitigation or prevention of a disease, or whether the active component(s) could modify a physiological function through the exertion of a pharmacological, immunological or metabolic action. In addition to specific nutrition claims covered under the Food Labelling Regulations (1996), the Food Standards Agency (FSA) has produced guidance on how nutritional claims including the words such as ‘low’, ‘increased’, ‘free’ and others should be used. Many of the conditions in the guidance differ from those in the new EU regulation, so the FSA will need to update the guidance to reflect the new law. Joint Health Claims Initiative

In the absence of EU-wide health claims legislation, the UK Joint Health Claims Initiative (JHCI) operated for a number of years as a voluntary system for approving health claims but ceased to operate on 31 March 2007. The JHCI was a tripartite joint venture between consumer organizations, industry and the regulatory authorities in the UK. The JHCI adopted a code of practice to apply to claims that a food provides a specific health benefit. The main purpose was to provide a manufacturer with some defense should there be a challenge to the claim, although a JHCI approval cannot be stated on the product. Secondly, the JHCI process ensured that health claims on foods are scientifically substantiated, legal and not misleading to consumers. In order to substantiate a claim, a producer submitted a dossier of scientific evidence to support it, in the context of a typical UK diet, and demonstrated how the claim would be used in advertising the product. The JHCI process normally took approximately 6 months. Claims already approved under the JHCI process had an obvious advantage when the new EU legislation came into force. JHCI distinguishes between generic claims, based upon well-established, generally accepted knowledge, and innovative health claims requiring specific substantiation.

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The Novel Foods Regulation (EC) 258/97 231

Some generic claims approved under JHCI: 12/10/01: ‘Decreasing dietary saturates (saturated fat) can help lower blood cholesterol.’ 4/2/02: ‘People with a healthy heart tend to eat more wholegrain foods as part of a healthy lifestyle.’ 29/7/02: ‘The inclusion of at least 25 g soya protein per day as part of a diet low in saturated fat can help reduce blood cholesterol.’ 6/5/04: ‘The inclusion of oats as part of a diet low in saturated fat and a healthy lifestyle can help reduce blood cholesterol.’ 11/2/05: ‘Eating 3 g weekly, or 0.45 g daily, long chain omega-3 polyunsaturated fatty acids, as part of a healthy lifestyle, helps maintain heart health.’ The process used in the assessment of claims, both for JHCI and for the new EU regulation, was developed by ILSI (the International Life Sciences Institute) and is called PASSCLAIM (the Process for the Assessment of Health Claims) and follows the following criteria: 1. The food or component with the effect should be characterized 2. Substantiation of the claim should be based mainly on human data, primarily from clinical studies including consideration of: (a) (b) (c) (d) (e) (f) (g) (h)

subjects representative of the target population appropriate controls adequate duration of exposure and observation characterization of background diet and lifestyle daily consumption properly reflects intended use influence of the food matrix and dietary context on the functional effect monitoring subject compliance statistical power

3. Biomarkers should be used as a substitute when the true endpoint cannot be measured directly 4. Biomarkers should be biologically and methodologically valid 5. The degree of change in the target variable should be both statistically and biologically significant for the target group 6. The total weight of evidence will be considered in the substantiation of the claim. The emphasis is on human data with in vitro data and animal studies used as supporting evidence only. The gold standard evidence is a properly controlled, randomized, double-blind clinical trial.

The Novel Foods Regulation (EC) 258/97 The safety of novel functional foods and nutraceuticals to the consumer in the EU is governed by the Novel Foods Regulation (1). This regulation has nothing

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to do with the health claim or intended physiological function of the food ingredient, but is concerned entirely with the protection of the consumer from adverse health events. It lays out the general principles and detailed rules for the authorization of novel foods and food ingredients. Novel foods and ingredients are those which have not been used for human consumption to a significant degree within the EU before 15 May 1997. The definition of ‘significant degree’ has always been a moot point and is subject to various considerations, including ethnic, cultural and dietary differences in the various countries of the union. When the details of the regulation were conceived, the focus included foods containing, consisting of, or produced from genetically modified organisms, which might be considered ‘substantially equivalent’ to the unmodified variety, and so assessment of substantial equivalence to a traditional EU reference food is integral to the process. Although genetically modified foods are regulated under separate legislation nowadays, the principle of substantial equivalence is still applied under the Novel Foods Regulation. There may be some doubt over whether a food or ingredient is novel or not. For example, it may be intended to market it in a different form to that already sold in the EU – in a capsule or as a pill rather than as part of a conventional food – or it may be derived from a closely related organism, or there may have been a slight change of production process which has altered the level of certain impurities. A change of production process confers novelty upon the food under the regulation because of the change in impurity profile and this is a separate category requiring an application for approval. If the applicant considers their product is not novel, a formal enquiry can be made to the competent authority of the Member State where the product is intended for first marketing. The objective is to receive a ‘not novel’ letter in return. If the food is considered to be novel, then an assessment of substantial equivalence to a suitable traditional reference food should be made: For any food not consumed to significant degree within the European community prior to May 1997:

●

●

●

Foods substantially equivalent in composition, nutritional value, metabolism, intended use, and impurities, to a reference food – no further testing Foods that are substantially equivalent to a traditional reference food except for a single or a few traits – toxicology testing on those traits only Foods that are neither wholly nor partially equivalent to a traditional reference food – combined nutritional/toxicology assessment.

If the food is substantially equivalent to a traditional reference counterpart, then a simplified application can be made to a competent authority; if not, then a full application, including the results of safety studies, is required. The amount of safety testing depends upon the degree and extent of the intended exposure in humans. As of February 2007, there have been 79 simplified and 75 full applications to regulatory authorities of EU Member States.

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In applications, novel foods are classified according to the following scheme: Class 1 Pure chemicals or simple mixtures 1.1 1.2

the source has a history of food use in EU the source has no history of food use in EU

these are single substances or mixtures of single substances. Previous examples: phytosterol esters, d-tagatose. Class 2 Complex novel foods 2.1 2.2

the source has a history of food use in EU the source has no history of food use in EU

these may be intact plants, animals or microorganisms or complex food components. Previous examples: saskatoon berries, mushroom extracts, docosahexaenoic acid (DHA), echium oil. Class 6 Foods produced using a novel process resulting in a changed chemical composition or structure affecting purity, nutritional value or metabolism previous examples: trehalose, lycopene The content of the application is outlined below: 1. Specification of the novel food: origin/species and composition from a safety/nutritional viewpoint; 2. Effect of the production process: what is novel in the process? what is the impact upon nutritional and toxicological factors? address any organic or inorganic residues; 3. History of the source organism: if a new species to EU, full information on past and present use in other parts of the world, conversion to raw material, transport/storage, role in diet outside the European community; 4. Anticipated intake and extent of use: based upon intended use, is it replacing or supplementing another EU food?; 5. Previous human exposure to the food or source: history of use outside the EU not a guarantee of safety within EU. Include traditional handling and preparation to prevent adverse health effect; 6. Nutritional information: review of composition, preparation and role to show substantial equivalence; if not equivalent, then conduct nutritional/toxicological studies in animals and studies in humans representative of target consumer groups, at normal and maximum consumption levels, taking storage and preparation into consideration; vulnerable groups should be considered: children, pregnant/lactating women, elderly, metabolically compromised; post-marketing surveillance may be needed;

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7. Microbiological information: if the source organism is microbiological, it must be non-pathogenic or toxicogenic and should not be adverse to gut microflora; the microorganisms and the metabolites should be characterized; 8. Toxicological information: if substantial equivalence cannot be established, safety assessment must consider possible toxicity of chemical components; toxicity studies in vitro and in vivo, including mutagenicity, reproduction, long-term feeding studies and allergenicity, on a case-by-case basis; microconstituents follow a conventional toxicological approach but for macroconstituents mutagenicity and feeding studies should take account of any potential nutritional imbalance. The best approach for the submission and approval of a novel foods application should be to follow a close consultation with the competent authority of the Member State to which the application is intended to be made, selecting either a country with an agency that has reviewed similar products or the country where it is first intended to market the product. If a full application is being made, then the strategy of supporting studies should be agreed in advance with the reviewing scientific body. The process for approval of novel foods follows a rapporteur system, under which one Member State makes an initial assessment on behalf of the whole union (Fig. 15.4). After a maximum period of 90 days, the authority decides upon whether an additional assessment is required and passes its initial decision to the EU Commission which circulates the assessment to the other Member States. After a further 60 days, the Commission either approves the novel food, which can then be placed on the market immediately, or takes an authorization decision with the assistance of the Standing Committee for

Submission to MS 90 days MS decides if additional assessment required

MS assessment forwarded to EU Commission and all other MS

MS gives opinion on equivalence

60 days EU Commission either approves or takes an authorization decision

EU Commission informs applicant of decision

If favorable, applicant notifies EU Commission

Figure 15.4 Novel foods: the complete process.

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Foodstuffs. An authorization decision covers the scope of applications of the product, conditions of use, designation of the food or ingredient, specification and labeling requirements. Any decision which may have an effect on public health is also referred to EFSA. The authorization decision is published in the EU Official Journal. Examples of applications under the Novel Foods Regulation

Astaxanthin A rich carotenoid oleoresin extracted from the alga Haematococcus pluvialis. Health benefits: antioxidant, gastric health, immune enhancement. A submission was made in March 2004, under the simplified procedure, claiming substantial equivalence to the algal meal product already marketed in Sweden. The application stated Class 2.1 but was evaluated as Class 2.2 (the source has no history of food use in the EU). It was accepted as substantially equivalent on the basis of composition, nutritional value, metabolism, intended use and levels of undesirable substances. Noni Juice A juice from a Pacific island berry (Morinda citrifolia) originating in south-east Asia. A company submitted an application to UK FSA in September 2004; which was authorized in November 2004. The company had been the sole supplier of Noni juice to another company, which had received approval in June 2003, and now wished to market directly in EU. Although approvals apply to the applicant company only, substantial equivalence of an identical product can be claimed in the usual way (via a Member State). Saskatoon berries A North American purple berry fruit similar to blueberries, grown commercially since the late 1960s but not grown commercially in Europe significantly prior to 1997. Health benefit: antioxidant, immune modulator. The application was submitted in May 2004 to the UK Food Standards Agency (Class 2.2) under the simplified procedure, claiming substantial equivalence to blueberries. It was rejected in June 2004 at a meeting of the ACNFP (Advisory Committee on Novel Foods and Processes) on the grounds that the two species are different. Although the nutritional profiles were similar, the phytochemical compositions were different. A full pre-market safety assessment was therefore required. Docosahexaenoic acid DHA is a rich omega-3 oil produced by algal fermentation using wild type (not recombinant DNA) microalgae from the genus Schizochytrium. Health benefit: CNS and cardiovascular A full application for a particular brand was submitted to the UK Food Standards Agency (Class 2.2) in February 2001. Some components were already present in the food chain. It was authorized in June 2003. The positive aspects of the submission included a good product specification, no nutritional concerns (already part of human diet), there was good toxicology and safety data including a human trial, Schizochytrium were generally recognized as safe (GRAS) approved in the USA and

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there was low protein content (low allergenicity risk). Safety studies were conducted on the originating algal organism (reproductive studies and mutagenicity studies) and on the oil itself (Ames test and an acute feeding study in mice). In addition, tolerance studies in target livestock were conducted to cover use in animal feed products. Echium oil Echium oil is a natural vegetable oil from Echium plantagineum, rich in omega-3 and omega-6 fatty acids, intended as an alternative to blackcurrant seed oil or evening primrose oil and to be marketed as a dietary supplement or in nutritional bars. A full application was submitted to the UK Food Standards Agency (Class 2.2) in October 2000 but was withdrawn in March 2002. The specification was not adequately supported by analytical data (no maximum limit for cyclopropenoid and epoxy fatty acids), there was insufficient information on characterization and analytical data (data on total protein and cytochrome C allergen), there were insufficient safety data (particularly related to the pharmacological action on skin) and insufficient human exposure data. Trehalose Trehalose is known as a potent preservative in desert plants; a naturally occurring disaccharide of glucose, which can be used as a food ingredient to replace the technological properties of sucrose where lower sweetness is required. A full application was submitted to the UK Food Standards Agency in May 2000. It was submitted as Class 6 owing to a novel fermentation process. Two of the enzymes had no history of food use. To be addressed were the safety of the enzymes, potential toxins from the fermentation organism, quality control of the enzyme preparation and consistent production purity of the trehalose. It was approved in September 2001. Positive aspects of the submission included good quality control mechanisms in production and post production, good toxicological data to support safety and no nutritional or microbiological concerns. Safety studies included single dose studies, repeat dose and reproductive studies in rodents and non-rodents, metabolic studies in four species and mutagenicity studies. Separate limited safety data were generated on the isoamylase enzyme preparation. Phytosterol esters Phytosterol esters have been produced from a number of sources and can be used to reduce cholesterol absorption. A full application was submitted to the Netherlands authority in May 1998 and approved in July 2000. A condition of approval was that the submitter should conduct a post-marketing survey, the first of its kind. The reason was the concern that -carotene absorption might be impaired. The outcome was favorable to the product. Two points should be made about the safety assessment of novel foods. The first is that if substantial equivalence cannot be established, a full nutritional assessment needs to be done in human subjects. The reasons are that if predicted human intake levels are likely to be high, the safety margin provided by conventional toxicology studies may be too low and that traditional metabolic and pharmacokinetic studies are not directly applicable to complex chemical mixtures like foods. Human safety studies should be based on well-defined hypotheses, with clear nutritional and metabolic outcomes relevant to the novel food, its dietary context and the

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The Food Supplements Directive (2002/46/EC) 237

anticipated consumer group. Human safety assessment can be conducted as part of a trial to establish a health claim for the ingredient. The second is that some statement should be made about the potential for allergenicity, particularly for protein components. In general, individuals who react to the traditional counterpart or its source should be tested in vitro and in vivo for immunogenicity. Evaluations to consider are: sequence homology to known allergens; heat stability; resistance to digestion; animal models can be used but are of limited relevance to idiosyncratic hypersensitivity reactions in humans; in vitro radioallergosorbent test (RAST) or western blotting using specific or targeted serum screening from sensitized individuals; skin prick tests or double-blind placebo-controlled trials. The Novel Foods Regulation is undergoing review. To some extent, during its short lifetime, it has been seen as a barrier to trade with non-EU countries and too restrictive against foods which have a long history of human consumption outside the EU. Additionally, authorization decisions are only addressed to the applicant. Another change which may be under consideration is to permit multiple-use applications to cover use as food additives, flavorings and extraction solvents. The advantage here would be one application and one risk assessment, so that, for example, a plant pigment might be submitted for use as a color and as an antioxidant.

The Food Supplements Directive (2002/46/EC) This directive has been in force since July 2002 and applies only to vitamins and minerals, although the scope may later be expanded. It was implemented by Member States from August 2003. Annex I is the positive list of permitted vitamin and mineral supplements and Annex II is the list of final forms in which they may be marketed to the consumer. Unapproved and undefended products were banned from August 2005. Defended products for which a safety dossier was submitted before August 2005 can continue to be marketed until 2009. One major criticism of the directive has been that the list of approved forms has excluded many modern natural product forms in favor of some of the older synthetic forms with lower bioavailability. More than half of 420 forms in 5000 products in the UK may be lost. There has been disagreement within the union over how to set maximum permitted levels for vitamins and minerals. Some Member States, such as the UK and the Netherlands, have favored a maximum dose set by reference to a risk assessment; others, such as Germany, preferred a recommended daily allowance. An issue not easy to resolve is whether maximum levels should be set separately for supplements and fortified foods. The consumer will encounter vitamins and minerals in a variety of forms during a typical day’s consumption, with different bio-availabilities. Should different population subgroups also be considered separately?

Fortified Foods Regulation This regulation is in draft form but is nearing approval at the time of writing. It applies to the same vitamins and minerals as the food supplements directive. Three

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reasons for fortification are allowed: restoration to the original levels prior to manufacture, handling or storage; substitution for other foods; or enrichment owing to a proven health benefit or nutrient deficiency in the population. Foods not in compliance can continue on the market for 3 years after the regulation comes into force, provided they were already on the EU market. A 7-year transition period is allowed for vitamins and minerals not on the list if they were already in use prior to the regulation and if supporting dossiers are submitted within 3 years.

Conclusion European Union food law hitherto has been a maze of international and national instruments which together comprise a possibly daunting set of hurdles for the uninitiated producer wishing to market a food ingredient. The European Food Safety Authority (EFSA), modelled to a large extent on the UK’s Food Standards Agency, is still relatively young and the roles and responsibilities within are still being discussed. As this body takes on a greater level of influence and importance so the individual national competent authorities increasingly will defer to it for decisions and authorizations. In addition, the many pieces of food legislation are being rationalized. The centralization of the legislative and approval processes should gradually permit a more accessible and simpler route to the EU consumer for the producer of functional food ingredients. The market for functional foods in the EU is growing. As the average age of the European consumer increases so does the concern to maintain health and wellness. In addition, as more countries join the union, so the list of ingredients that would not be considered novel also increases. The revision of the Novel Foods Regulation and the advent of the new Nutrition and Health Claims Regulation will present new opportunities for the producer to reach such an important market for health and wellness nutrition. The Global Harmonisation Initiative will gradually remove trade barriers presented by differing international standards in food safety. Taken together, these changes represent an exciting time for the producer.

References 1. Directive 2004/24/EC of the European Parliament and of the Council, Official Journal of the European Communities L 136/85–90, 30.4.2004. 2. Regulation (EC) No 258/97 of the European Parliament and of the Council, Official Journal of the European Communities L 43/1–8, 14.2.1997. 3. Directive 2002/46/EC of the European Parliament and of the Council, Official Journal of the European Communities L 183/51–57, 12.7.2002. 4. Regulation (EC) No 178/2002 of the European Parliament and of the Council, Official Journal of the European Communities L 31/1–24, 1.2.2002. 5. Council Directive 89/398/EEC, Official Journal of the European Communities L 186/27–32, 30.6.89. 6. Regulation (EC) No 1924/2006 of the European Parliament and of the Council, Official Journal of the European Union L 12/3-18, 18.1.2007.

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Complementary and Alternative Medicines in Australia and New Zealand: New Regulations

16

Dilip Ghosh1, Lynnette R. Ferguson2 and Margot A. Skinner3 1

Regulatory Affairs, National Centre of Excellence in Functional Foods, University of Wollongong, NSW, Australia 2 Department of Nutrition/ACSRC, The University of Auckland, Auckland, New Zealand 3 Health and Food, The Horticulture and Food Research Institute of New Zealand Ltd, Auckland, New Zealand

Abstract Currently, the regulation of complementary and alternative medicines and related health claims in Australia and New Zealand is managed in a number of ways. Complementary medicines, including herbal medicines, minerals, nutritional/dietary supplements, aromatherapy oils and homeopathic medicines are regulated under therapeutic goods/products legislation. The Therapeutic Goods Administration (TGA), a division of the Commonwealth Department of Health and Ageing is responsible for administering the provisions of the legislation in Australia. The New Zealand Medicines and Medical Devices Safety Authority (Medsafe) administers the provision of legislation in New Zealand. In December 2003, the Australian and New Zealand governments signed a treaty to establish a single, bi-national agency to regulate therapeutic products, including medical devices and prescription, over-the-counter and complementary medicines. The role of the newly formed agency in 2006 (The Australia New Zealand Therapeutic Products Authority, ANZTPA) Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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240 Complementary and Alternative Medicines in Australia and New Zealand

will be to safeguard public health through regulation of the quality, safety and efficacy or performance of therapeutic products in both Australia and New Zealand. The ANZTPA will gradually replace the Australian TGA and the New Zealand Medsafe phase wise in the future. The major activities of the new ANZTPA are in product licensing, specifying labeling standards and setting the advertising scheme together with determining the risk classes of medicines and creating an expanded list of ingredients permitted in Class I medicines. A new, expanded definition of complementary medicines is proposed and this definition is currently under consultation. Related Australian and New Zealand legislation is being developed to implement the joint scheme. Once this legislation is passed, the Treaty will come into force and the new joint regulatory scheme will begin.

Introduction A range of complementary and alternative medicine practices is being increasingly used by the Australian and New Zealand public (1–4). An industry survey indicated that 77% of Australians use complementary medicines, supplied by a growing $1 billion industry comprising small, medium and large companies (www.medsafe.govt.nz/ hot/fact.htm). A good example is for Crohn’s disease (CD), which mainly affects people in affluent developed countries, with approximately 500 000 sufferers in the USA and a similar number in Europe. A recent New Zealand survey showed that a large percentage of CD patients utilize complementary or alternative therapies, with 72% finding dietary adjustment to be useful (www.nutrigenomics.org.nz). Complementary medicines, including herbal, mineral and nutritional/dietary supplements, aromatherapy oils and homeopathic medicines are regulated under therapeutic goods/products legislation. These products are readily available from supermarkets, health food shops, pharmacies, by mail order or direct selling, and supplied by various types of practitioners. The Therapeutic Goods Act 1989 (5) came into effect in 1991. The Therapeutic Goods Administration (TGA) (www.tga.gov.au), a division of the Commonwealth Department of Health and Ageing (www.health.gov.au/), is responsible for administering the provisions of the Act in Australia. On the other side of the Tasman Sea, Medsafe (www. medsafe.govt.nz) is New Zealand’s Medicines and Medical Devices Safety Authority. It is a business unit of the Ministry of Health and is the authority responsible for the regulation of therapeutic products in New Zealand. These products include medicines and related products, herbal medicines, medical devices and controlled drugs used as medicines. The regulation is via the Medicines Act 1981 and Regulations 1984 and parts of the Misuse of Drugs Act 1975 and Regulations 1977. The overall objective of these Acts is to ensure the quality, safety and efficacy of therapeutic goods, including medicines and medical devices, available to the Australian and New Zealand public.

Regulation of Complementary Medicines Under the Joint Regulatory Scheme The Australian and New Zealand Governments have agreed to harmonize the regulatory arrangements for therapeutic products between both countries. They signed a treaty

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The Current Regulatory Framework for Therapeutic Goods in Australia 241

in Wellington, New Zealand, in December 2003 to establish a single, bi-national agency to regulate therapeutic products, including medical devices and prescription medicine, and over-the-counter, complementary and alternative medicines. The newly formed agency, The Australia New Zealand Therapeutic Products Authority (ANZTPA), which will replace the Australian Therapeutic Goods Administration (TGA) and the New Zealand Medsafe, will be accountable to both Australian and New Zealand Governments and have a fully functional office in both countries (http://www.anztpa.org). Under the ANZTPA, products represented as being for therapeutic use are to be regulated as therapeutic products. These include complementary medicines such as herbal substances, homoeopathic and related medicines, as well as vitamin and mineral supplements, other nutritional supplements, traditional medicines and aromatherapy oils (6). The new regulatory activities would draw on the best features of New Zealand, Australian and international approaches. It is anticipated that the ANZTPA will enhance the future regulatory capacity in both countries, will avoid costly duplication of effect, will maintain a voice internationally on therapeutic product regulation and will also minimize barriers to trade. Extensive phase 2 public and industry consultation has occurred followed by release of a discussion document prepared by New Zealand and Australian officials to facilitate informed debate about the details of the scheme. Phase 3 consultation will commence in March 2007. Article 1 of the Treaty defines ‘therapeutic product’ for the purposes of the joint scheme. This definition includes prescription medicines, over-the-counter medicines, complementary medicines, human blood and blood components, medical devices, cell and tissue therapies and other products meeting the definition of therapeutic products. The related Australian and New Zealand legislation is currently being developed to implement the joint scheme. Once this legislation is passed, the Treaty will come into force and the new joint regulatory scheme will begin.

The Current Regulatory Framework for Therapeutic Goods in Australia Australia is a federation of states with a Commonwealth (Federal) Government and six State and two Territory Governments. While the Therapeutic Goods Act provides a substantially uniform national system of controls over therapeutic goods, other Commonwealth and separate State and Territory legislation may apply to certain therapeutic goods. In fulfilling its responsibilities under this Act, the TGA is required by the Australian Government to recover its operating costs through fees and charges. The Australian Register of Therapeutic Goods (ARTG) is a database maintained by the TGA. It includes details of all therapeutic goods that are imported into, supplied in, or exported from Australia. It is a legal requirement that, unless specifically exempt or excluded, all therapeutic goods must be included in the ARTG prior to their supply. Some aromatherapy oils and homoeopathic medicines are exempt from this requirement. The TGA, in consultation with the key Australian complementary

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medicines industry bodies, the Australian Self-Medication Industry and the Complementary Healthcare Council of Australia, have developed the Australian Regulatory Guidelines for Complementary Medicines (ARGCM, www.tga.gov.au/ docs/html/argcm.htm). The ARGCM details TGA regulatory processes and indicates the minimum requirements to support the quality, safety and efficacy of registered and listed complementary medicines. In addition, eight adjunct guidelines have been developed to supplement the ARGCM to provide specific advice on: ● ● ● ●

● ● ●

●

The use of the term ‘quantified by input’1 for complementary medicines Stability testing of listed complementary medicines The identification of herbal materials and extracts Levels and kinds of evidence to support indications and claims for nonregistrable medicines, including complementary medicines and other listable medicines Coloring permitted in medicines for oral use Product changes in the Electronic Listing Facility (ELF 3) Interpretation of the Australian Code of Good Manufacturing Practice for Medicinal Products (16 August 2002) applicable to the manufacture of complementary medicines Supplementary requirements for therapeutic goods for minimizing the risk of transmitting transmissible spongiform encephalopathies (TSEs).

There are a number of expert committees that provide advice to the TGA, including the Complementary Medicines Evaluation Committee (CMEC). The evaluations or assessments undertaken vary depending on the therapeutic product and its indications and claims. The Australian Adverse Drug Reactions Advisory Committee (ADRAC) provides advice on all areas of drug safety to the TGA including prescription medicines, vaccines, over-the-counter medicines and complementary medicines (7).

Complementary Medicine Regulation Australia has a regulatory system for complementary medicines and other therapeutic goods, the latest developments of which were based on a regulatory reform package introduced into legislation in 1999. Complementary medicine substances are defined in section 52F of the Therapeutic Goods Act 1989. Essentially, if the substance is a designated active ingredient that has an established identity and tradition of use, it is a complementary substance. A number of new substances (e.g. activated charcoal, bovine colostrum powder, lutein) approved for inclusion in Listed medicines are now included in the latest consolidation of Schedule 4 of the Therapeutic Goods Regulations 1990. Indications and claims can be based on evidence of traditional use of a substance or product and/or on scientific evidence. Indications/claims and evidence are categorized as being ‘general’, ‘medium’ or ‘high’ level.

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The Current Regulatory Framework for Therapeutic Goods in Australia 243

Indications/Claims Based on Evidence of Traditional Use

To make an indication or claim based on evidence of traditional use, sponsors must first assess the level of the evidence and hold one of the following sources of evidence: ● ● ●

●

TGA-approved pharmacopeia TGA-approved monograph Three independent written histories of use in the classical or traditional medical literature Availability through any country’s government public dispensaries for the indication claimed.

If one of the above sources of evidence is held, a general level evidence is held. If two of the above sources of evidence are held, medium level evidence is held. High level indications and claims are not permitted based on evidence of traditional use. If general level evidence is held, general level indications and claims can be made relating to: ● ● ●

Health maintenance, including nutritional support Vitamin or mineral supplementation Relief of symptoms (not related to a named disease, disorder or condition).

The following kinds of indications and claims are permitted for medium level evidence: ● ● ● ●

●

Health enhancement Reduction of risk of a disease/disorder/condition Reduction in frequency of a discrete event Aiding/assisting in the management of a named symptom/disease/disorder/ condition Relief of symptoms of a named disease/disorder/condition.

Indications/Claims Based on Scientific Evidence

General level evidence includes: ● ● ●

Descriptive studies, case series or reports of relevant expert committees Texts, such as TGA-approved pharmacopeias or monographs Other evidence-based reference texts.

The following kinds of evidence constitute medium level evidence: ● ●

●

Evidence obtained from well-designed controlled trials without randomization Evidence obtained from well-designed analytical studies, preferably from more than one center or research group, including epidemiological cohort and casecontrol studies Evidence obtained from multiple time series with or without intervention, including within-country and between-country population studies.

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Table 16.1 Designated or kind of ingredients permitted in complementary medicines A choline salt A homeopathic preparation A microorganism, whole or extracted, except a vaccine A mineral, including a mineral salt and a naturally occurring mineral A mucopolysaccharide A lipid, including an essential fatty acid or phospholipid A substance produced by or obtained from bees, including royal jelly, bee pollen and propolis A sugar, polysaccharide or carbohydrate A vitamin or provitamin An amino acid Non-human animal material (or a synthetically produced substitute for material of that kind), including dried material, bone and cartilage, fats and oils and other extracts or concentrates Plant or herbal materials (or a synthetically produced substitute for material of that kind), including plant fibers, enzymes, algae, fungi, cellulose and derivatives of cellulose and chlorophyll

The levels of indications/claims for general and medium evidence are the same as required for evidence of traditional use. High level evidence relates to diseases or disorders and includes: ● ● ●

Treatment, cure or management of any disease/disorder/condition Prevention of any disease, disorder or condition Treatment of a specific named vitamin or mineral deficiency disease.

High level indications/claims require scientific evidence obtained from: ●

●

A systematic review of all relevant randomized, controlled trials. The trials must be without significant variations in the directions and degrees of results or At least one properly designed randomized controlled (preferably multicenter) double blind trial. It is preferable to have data from at least two trials independent of each other but, in some cases, one large well-conducted trial may suffice.

It is only possible to make high level indications/claims for Registrable medicines. Listable medicines cannot carry high level indications and claims. Listed medicines are considered to be of lower risk than Registered medicines. Most, but not all, complementary medicines are Listed rather than Registered in the ARTG. Listed goods or Registered goods can be identified by the inclusion on the product label of a unique number preceded by either AUST L or AUST R, respectively. The ingredients or kind of ingredients permitted to be included in complementary medicines are shown in Table 16.1 (8,9). If a new substance is proposed for use in a Listed complementary medicine, it must first be evaluated. Only when accepted as low risk, will it be permitted for use as a Listed medicine. Only certain claims and indications may be made for Listed medicines, regardless of whether they contain only low risk ingredients (see later). If a complementary medicine ingredient is not considered suitable for use in a Listed medicine, it may, following evaluation, be suitable for inclusion in Registered complementary medicines.

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The Current Regulatory Framework in New Zealand 245

All indications/claims must be true, valid and not misleading, and not lead to unsafe or inappropriate use of the products. Evidence must relate to the whole product or the same active constituent(s) with similar dosage regimen, dose form and route of administration to the product/ingredient for which a claim is being made. Sponsors must hold evidence in line with these guidelines before claiming an intended use or indication for a product.

The Current Regulatory Framework in New Zealand Medsafe is New Zealand’s Medicines and Medical Devices Safety Authority. It is a business unit of the Ministry of Health and is the authority responsible for the regulation of therapeutic products in New Zealand. These include medicines and related products defined as a product that is primarily a food, dentifrice or cosmetic but has a secondary therapeutic use; herbal medicines; medical devices, and controlled drugs used as medicines. The mission of Medsafe is to enhance the health of New Zealanders by regulating therapeutic products to maximize safety and benefit. Medsafe operates out of four regional offices, with centralized administrative functions, product approval and standard setting based at its head office in Wellington. In carrying out its functions, Medsafe is accountable to the Ministry of Health, and through the Ministry to the Minister of Health. It is also accountable to the pharmaceutical industry for those activities that are funded by fees collected from the industry. Medsafe is responsible for administering the Medicines Act 1981 and Regulations 1984, and parts of the Misuse of Drugs Act 1975 and Regulations 1977. As of February 2007, Medsafe does not regulate dietary supplements. These are regulated by the Dietary Supplements Regulations 1985 under the Food Act, administered by the New Zealand Food Safety Authority (NZFSA, www.nzfsa.govt.nz). Medsafe does regulate those products that make therapeutic claims and therefore are medicines. For example, when a herbal capsule claims to help or cure a disease state (e.g. psoriasis or heart disease), the product is a medicine and requires approval through the route administered by Medsafe. The objective of the medicine legislation is to manage the risk of avoidable harm associated with the use of medicines. The legislation is designed to ensure that: ● ●

●

Medicines meet acceptable standards of safety, quality and efficacy Personnel, premises and practices used to manufacture, store and distribute medicines comply with requirements designed to ensure that products meet acceptable standards right up until they are delivered to the end-user Information about the selection and safe use of medicines is provided to health professionals and consumers.

Medsafe is responsible for applying a framework of controls designed to ensure that the therapeutic products available in New Zealand are those that can be expected

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to have greater benefits than risks if used appropriately. This is achieved through premarketing approval of products and post-marketing surveillance. The interface between therapeutic-type and food-type dietary supplements is subject to consultation between the NZFSA and Medsafe. Premarketing approval must be obtained for new and changed medicines. New medicines cannot be marketed in New Zealand without the consent of the Minister of Health (or his/her delegate). Medicines to which changes have been made cannot be marketed without the consent of the Director-General of Health (or delegate). Data that satisfactorily established the quality, safety and efficacy of the product, for the purposes for which it is to be used, must be submitted for evaluation before consent can be granted. The premarket approval system for medicines is managed by Medsafe. Post-marketing surveillance monitors the safety of medicines and medical devices in use. Products shown to be unsafe are removed from use and prescribers are advised about new safety information for products. Post-marketing surveillance is achieved through activities such as: ●

● ● ●

Monitoring adverse reactions to medicines used in New Zealand and monitoring the international literature and other information sources Testing marketed medicines against product quality standards Handling complaints and investigations Auditing of good manufacturing practice (GMP).

Transition for Complementary Medicines During the finite period of transition (from an independent to a joint Australian/New Zealand authority), the aims are to reduce duplication and to allow both agencies to make more effective use of their resources while maintaining the high level of consumer and professional confidence in the safety of medicines in Australia and New Zealand. Transitional arrangements are required to give suppliers and manufacturers of complementary medicines in Australia and New Zealand time to achieve compliance with regulatory requirements under the joint scheme. These arrangements will be based on the principles set out in the Treaty. Applications meeting the specified criteria will be identified and separated out during the evaluation process and assigned to a technical secretariat for evaluation of key elements. For new applications and those in progress, the product details will be entered onto an interim register through the Complementary Medicines Transition (COMET) database (http://www.medsafe.govt.nz/CompMedPage.htm). The product will receive an interim product license (PL) for New Zealand only, which will be valid for the 3-year transition period. It will be necessary to apply for a joint agency PL during the transition period. For low risk medicines or related products, which include mouthwashes, shampoos and toothpastes, applications will be submitted in the usual way. Until new legislation is passed, however, Medsafe will continue to evaluate medicines and dietary supplements sold under the old legislation.

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Conclusion 247

Conclusion The establishment in 2006 of a single, bi-national agency (The Australia New Zealand Therapeutic Products Authority) to regulate therapeutic products including complementary medicines in New Zealand and Australia has opened an unprecedented level of trans-Tasman cooperation and collaboration in medical therapeutics between the two countries. This initiative supports the Closer Economic Relations (CER) Agreement-1983 and the Trans Tasman Mutual Recognition Arrangement (TTMRA)-1998. Very recently, the Australian Government has backed the recommendations contained in a high level review by the Expert Committee on Complementary Medicines in the Health System aimed at enhancing the public’s confidence in the Australian alternative medicines sector. The public in both countries will be the main beneficiaries of a new, world-class regulatory system in complementary and alternative medicine areas. Currently, an Interim Ministerial Council is operational and related Australian and New Zealand legislation is being developed to implement the joint scheme. The overarching principles to apply to the transitional arrangements are outlined in Article 21 of the Treaty, i.e.: on and after the commencement date, the manufacture, supply, import, export or promotion of a therapeutic product that was lawful in the territory of one party immediately before the commencement date continues to be lawful in the territory of that party for a specified period by virtue of the deemed grant of a transitional approval under the scheme on the terms and conditions (if any) that applied in respect of the manufacture, supply, import, export or promotion of a therapeutic product before the commencement date. The major activities of the joint Australia New Zealand therapeutic products agency will be concerned with product licensing, labeling standards and advertising schemes, risk classes of medicines and the expanded list of ingredients permitted in Class I medicines. A new, expanded definition of complementary medicines is proposed and this definition is currently under consultation. The proposed definition includes more objective criteria for determining the eligibility of a medicinal product or ingredient to be regulated as a complementary medicine. Although most will be classified as Class I medicines, it allows for inclusion into Class II medicines. Class I complementary medicines are low risk medicines. All other complementary medicines are higher risk Class II complementary medicines for which a product license can only be granted following evaluation of the safety, quality and efficacy of the medicines. It is important to note that even if a medicinal product or ingredient is determined not to be a complementary medicine, it may still be eligible for regulation as a Class I medicine. The new proposed regulatory definition would allow for traditional methods of manufacture of complementary medicines, but also permit the use of more modern methods in their manufacture provided they meet the required standards. The ANZTPA will regulate products through wholesale/retail systems and production by manufacturers for commercial supply. They will not regulate Rongoa (the Maori term for medicines that are produced from native plants in New Zealand), traditional healers, cultivation of plants and personal imports. In addition,

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the joint scheme will not affect the Wai 262 claim (Treaty of Waitangi claim, especially on flora and fauna), intellectual property rights and Te Tiriti o Waitangi (Treaty of Waitangi). In conclusion, although complementary and alternative medicines are currently regulated by different agencies in Australia and New Zealand, the new joint agency, ANZTPA will regulate this type of product in the future.

Acknowledgment Some portions of this article are reprinted from Ghosh et al., Toxicology 221, 88–94, 2006 with permission from Elsevier.

Note 1

The term ‘quantified by input’ refers to the practice of justifying some situations where the assay of an active ingredient in every batch of finished product is not necessary.

References 1. MacLennan AH, Myers SP, Taylor AW. (2004). The escalating cost and prevalence of alternative medicine. Prev Med 35, 166–173. 2. MacLennan AH, Wilson DH, Taylor AW. (2002). The continuing use of complementary and alternative medicine in South Australia: costs and beliefs in 2004. Med J Aus 35, 166–173. 3. McCabe P. (2005). Complementary and alternative medicine in Australia: a contemporary overview. Complement Ther Clin Practice 11, 28–31. 4. Robson T. (2003). An introduction to complementary medicine. Allen and Unwin, Australia. NZ Med J 5. Commonwealth of Australia. (2001). Therapeutic Goods Act 1989 as amended. 6. Ghosh DK, Skinner M, Ferguson L. (2006). The role of the Therapeutic Goods Administration and the Medicine and Medical Devices Safety Authority in evaluating complementary and alternative medicines in Australia and New Zealand. Toxicology 221, 88–94. 7. Boyd IW. (2002). The role of the Australian Adverse Drug Reactions Advisory Committee (ADRAC) in monitoring drug safety. Toxicology 181–182, 99–102. 8. Briggs DR. (2002). The regulation of herbal medicines in Australia. Toxicology 181–182), 565–570. 9. Commonwealth of Australia. (2001). Schedule 14, Therapeutic Goods Regulations as amended.

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Health Foods and Foods with Health Claims in Japan

17

Hirobumi Ohama1, Hideko Ikeda1 and Hiroyoshi Moriyama2 1

Biohealth Research Ltd, Bunkyo-ku, Tokyo, Japan Laboratory of Pharmacotherpeutics, Showa Pharmaceutical University, Machida, Tokyo, Japan

2

Abstract The term ‘health foods’ (HF) is commonly used in Japan to describe what may be called ‘functional foods’ (FF) or ‘dietary or food supplements’ in the USA and other countries. This chapter serves to enhance understanding of HF in relation to various regulatory systems and safety concerns in consumers. The ‘Foods with Specified Health Uses’ (FOSHU) concept is described as it evolved from FF which was first developed and published for the health benefits of foods in our country in 1984. In 1991, the Ministry of Health and Welfare (MHW), now known as the Ministry of Health, Labor and Welfare (MHLW), officially presented the FOSHU system as a basis for making the functional claims of ‘foods’(FD) with reference to the increase in the occurrence of lifestyle-related diseases (LSRD) that include diabetes mellitus, high blood pressure, cerebro- and cardiovascular diseases and cancer. In 2001, a new regulatory system, ‘Foods with Health Claims’ (FHC) was established and consisted of a new concept of ‘Foods with Nutrient Function Claims’ (FNFC) and innovated FOSHU. In 2005, the MHLW additionally changed the existing FOSHU system. Such change includes the new subsystems of FOSHU: (1) standardized FOSHU, (2) qualified FOSHU and (3) disease risk reduction claims. Lastly, issues directed to the safety and quality of raw materials and HF products are also discussed with the focus on two guidelines that require good manufacturing practice (GMP) and self-investigating systems for safety of raw materials.

Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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250 Health Foods and Foods with Health Claims in Japan

Introduction Japanese food is healthy to begin with. The presence of the four distinct seasons with appropriate temperature and humidity in Japan surrounded by sea fostered the Japanese food eating habit and created a distinctive Japanese food culture. Moreover, the availability of agricultural crops, such as soybean, mushroom, rice, wheat, tea, marine products which comprise seaweed, algae, bonito, bream, etc. enriched the food resources to establish the Japanese traditional food. The art of fermentation also contributed to constitute Japanese traditional foods, such as ‘natto’ (fermented soybean with Bacillus subtilis var. natto), ‘miso’ (fermented soybean paste), ‘katsuobushi’ (fermented bonito) and so on, utilized not only for preservation of food, but also for adding taste and health benefits. However, after World War II, the lifestyle of Japanese people has drastically been changed along with rapid economic growth. Dietary patterns of Japanese people have also diversified it being said that Japanese people live in ‘rich food style’ or ‘the age of overabundance’. At around this time, the word ‘westernization’ was introduced into the food style among a wide range of age groups and provided the formation of the westernized modern dietary custom in Japan. The changes gradually gave rise to the positioning of foods not only for a function as nutrition, but also functions for sensory satisfaction and health benefits (1). From the viewpoint of sensory satisfaction, in particular, foods based on meats, eggs, milk, butter, etc. of animal origins and processed foods such as those so-called ‘fast food’ and ‘instant food’ were prevalent while, in recent years, public health concerns involved excess or insufficient nutritional intake, such as excessive intake of fat or imbalanced diets and also so-called ‘skipped meals’, spreading over the broad array of Japanese people from school children to working people and even the elderly. Such derogatory dietary habits are, in part, responsible for the induction of ‘lifestyle-related diseases’ (LSRD) such as obesity, diabetes mellitus, high blood pressure, cerebrovascular and cardiovascular diseases and cancer, which have remarkably increased in recent years (2). Although causes of LSRD are multifactorial and complex, other social and cultural factors which might have affected the increase in the incidence of LSRD are various stresses including anxiety and mental exhaustion, habitual alcohol drinking and smoking, and the lack of exercise and/or sedentary lifestyle. It is obvious that genetic factors play a pivotal role. More recently, the term ‘metabolic syndrome’(MS) is popularly and synonymously used as a specific part of LSRD among marketers and consumers, whereas MS is intensively defined as abdominal obesity or excessive fat tissue in and around the abdomen with signs or complications of two or more of hyperglycemia, hyperlipidimia, and hypertension in Japan. At the same time, the demographic trend of ‘shrinking and graying’ has progressively become notable and now is becoming an unprecedented population crisis, which generates economic and social impacts such as financial pressure to the Government on medical or health care costs for the elderly and a decline in the working population. Under the circumstances, life expectancy continues to increase in Japan; for example, men and women will live up to 78.53 and 85.49 years old, respectively (http://mhlw.go.jp/english/index.html). In 1980, the population of people

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Historical Development of ‘Functional Foods’ 251

aged over 65 represented 9.1% of the total population, while the same population accounted for about 17.3% and 20.0% in 2000 and 2005, respectively (http://www. stat.go.jp/english/index.htm). Ironically, the expansion of the aging population has also elevated the occurrence of age-related LSRD. Furthermore, an increase in LSRD has profoundly affected the mortality rate of the Japanese people. In fact, while cancer is the number one cause of death in Japan, mortality caused by cancer and vascular diseases is continuing to increase (2). According to Sugimura (3), a dietary factor is one of the main causes of cancers, suggesting as an example, that the ‘westernization’ of food consumption may have some negative effect on the balance of nutritional intake in Japanese people. In this chapter, we describe the historical development of ‘functional foods’ (FF) in Japan for health benefits of Japanese people and how ‘foods’ (FD), including ‘health foods’ (HF), ‘so-called health foods’ (SCHF) and ‘foods with health claims’ (FHC) are regulated by multiple laws to protect consumers from misuses of the FD. Moreover, newly established systems for FD help consumers, including elderly people, to live healthier. We also attempt to explain safety challenges for HF which are related to safety of raw materials formulated into products as well as the good manufacturing practice (GMP) guidelines for the products. Much of the information and data in the chapter are referred to and based on the previous work of Ohama et al. (2) with modifications and updates.

Historical Development of ‘Functional Foods’ In the 1980s, Japanese consumers began to realize the importance of maintaining and improving their health as prompted by a gradual increase in the occurrence of LSRD. Concomitantly, intensive studies were performed on the physiological effects of various foods and their ingredients on the so-called ‘tertiary function of foods’ as described by Arai (1). In brief, the ‘tertiary function of foods’ is defined and understood as to be directly involved in the modulation of the human physiological systems such as the immune, endocrine, nerve, circulatory as well as digestive systems, while the primary and secondary functions are related to nutrition and sensory satisfaction, respectively. In 1984, the term FF was first assigned in the project initiated by the Ministry of Education (presently The Ministry of Education, Culture, Sports, Science and Technology), thus crediting Japan for the creation of the term FF. The concept of FF evidently attracted the HF industry and health-conscious consumers. The Government, however, prohibited the use of the word FF because the word might imply drug-like effects which could mislead consumers with the expectation of prevention or even cure. Nevertheless, the term HF was extensively used and recognized by consumers, thereby replacing the term FF. In 1991, in the attempt to replace FF, the concept of FF was integrated into the ‘Foods with Specified Health Use’ (FOSHU) system (4). More specifically, in 1984, studies on functional foods were initially led by the Special Study Group on the Systematic Analysis and Development of Food Function

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under the Ministry of Education, as a part of the specified project for the investigation of functional foods controlling the physiological functions of a living body. The project was carried out for 3 years and was continued for an additional 3 years in 1988 (1). In 1996, the American Chamber of Commerce of Japan (ACCJ) requested the deregulation of an HF system in Japan to remove an important trade barrier of dietary supplements between the USA and Japan. The regulatory system of HF, which is generally known as dietary supplements in Japan, is unique and rigid to products imported from overseas countries. As an example, orally taken drugs in the form of small round tablets and capsules were prohibited from distribution as HF under the regulation. Therefore, the petition was accepted by the Government and the deregulation was discussed by the special investigative committees on dietary supplements for the following 4 years. Based on the conclusion made by the committees, the Ministry of Health, Labor and Welfare (MHLW) decided to frame a new regulatory system of HF called FHC and enforced the new system in April 2001. The new system of HF was amalgamated with the innovated FOSHU and another new category, Foods with Nutrient Function Claims (FNFC). In the FOSHU prior to 2001, only the form of conventional foods was permitted while other forms such as tablets or capsules were not allowed. Although the regulatory system of HF was successfully introduced, HF that was not regulated by the new system grew and occupied the largest segment of the HF market, accounting for more than 65% of the total market in Japan. The MHLW decided to reconsider the regulatory system of HF with the request of the Liberal Democratic Party, in 2003. As a result of the discussion from the special investigative committee for the reconsideration, the FOSHU system was relaxed by proposing subcategories such as the qualified FOSHU and standardized FOSHU systems to the existing FOSHU. Concurrently, the disease risk reduction claims were allowed for FOSHU products containing specified nutrients. Two nutrients, calcium and folic acid, are presently allowed for the disease risk reduction claims. It must be emphasized that there is no category or no term for supplements (dietary or food) according to the regulatory or legal understanding in Japan. While foods having intake forms or shapes such as tablets or capsules are included in the category of HF, discrimination between conventional food and supplement is not legally accepted. Even in the FOSHU system, most of the products, about 700, are in the form of conventional foods, whereas a very few FOSHU products in tablet forms are available on the market. The aforementioned situation may often make it difficult to comprehend the Japanese regulatory system of HF for the food industry in foreign countries.

HF It is necessary briefly to summarize the market, definition and necessity of regulatory systems for HF products in the Japanese marketplace, before reviewing various regulations on the HF.

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HF 253

HF and FOSHU Markets With the introduction of the FHC system in 2001, drugs and foods were categorized according to the outline of food–drug classification as defined by the Pharmaceutical Affairs Law (Fig. 17.1). Since then, the market size of FOSHU rapidly augmented and reached about $3.8 billion US dollars in 2001 (2). It reached about $6.1 billion US dollars in 2006 with a predicted growth rate of 160% in the next 5 years. In spite of the drastic increase in the number of FOSHU products on the market, SCHF products still represent the largest market share. However, in 2006 a decline in the SCHF market size was observed even though it was perceived as a temporary downward trend of the market. The downsizing of the market was caused by: 1. the statement of the MHLW regarding Agaricus (Agaricus blazei Murrill) as a cancer promoter and 2. safety concern regarding ingestible form of Q10 (CoQ10) and soybean isoflavones as FD.

Implications of Defining HF According to the proposed definition of HF by the MHLW, the category of HF is the sum of two categories, i.e. FHC and SCHF as follows: HF FHC SCHF Although the proposed definition remained ambiguous, HF has been used by consumers and the HF industry with the implication of the foods that are good for health benefits. SCHF comprises a wide range of food products which include products in tablet or capsule forms and other intake forms. However, SCHF are prohibited to make any health claims, thus generating a risk of overdose, resulting in adverse reactions in this category.

Drugs (DR) (including quasi-drugs)

Foods with nutrient function claims (FNFC) Foods with health claims (FHC)

Product taken orally

Foods for specified health uses* (FOSHU)

Foods (FD) including Health foods (HF)

The Pharmaceutical Affairs Law and the Food Sanitation Law

General foods including ‘so-called health foods’ (SCHF)

* Individual approval FOSHU, Standardized FOSHU, Qualified FOSHU and FOSHU with disease risk reduction claims are included.

Figure 17.1 Positioning and classification of ‘drugs’ (DR) and ‘foods’ (FD) ‘so-called health foods’(SCHF) and FHC (FOSHU and FNFC).

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Necessity of Regulation for HF Consequently, the MHLW held a new special investigative committee meeting on the revision of the regulatory system for SCHF as requested by the Liberal Democratic Party. After discussion by the committee for more than one year, the MHLW announced the implementations of new systems into the previous framework of the FOSHU system. The main objective was to allow FOSHU to offer better opportunities to the food industry for accepting SCHF as FOSHU under the new categories such as ‘Qualified FOSHU’ and ‘Standardized FOSHU’.

Labeling and Laws Various laws regulate labeling of HF, such as Pharmaceutical Affairs Law, Food Sanitation Law and Japan Agricultural Standards Law (Fig. 17.2), among which the Pharmaceutical Affairs Law plays an essential role in controlling functional and/or efficacy claims on FD. Functional and/or efficacy claims are not allowed in principle for HF except for FHC because these claims or indications are interpreted as drug-related. The claims, however, with expressions such as to maintain or promote the health condition of a healthy individual are acceptable for HF. Claims such as: 1. for diagnosis, cure or prevention of disease in human or animal 2. items which are intended to affect the structure or functions of the body of human or animal, 3. ‘hints’ for drug efficacy violate the Pharmaceutical Affairs Law. The ‘hints’ for drug efficacy include: (a) product naming or promotional statements or phrases suggesting drugs (b) description of pharmaceutical ingredients (c) description of manufacturing process suggesting drugs (d) description of origin or history suggesting drugs (e) reference to articles from newspapers and scientific journals or quotations from interviewing medical doctors or scientists.

Use and Dosage Directions for HF Products Use and dosage directions of HF products must not be stated as those of drugs, for example: 1. 2. 3. 4. 5. 6.

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before meals, after meals or during meals 2–3 times daily 1–2 tablets per dose, twice a day adult 3–6 tablets a day – adjust according to condition 1–2 tablets before and after meals and 1–2 capsules before bedtime.

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HF 255

General

Assurance of food safety

Basic Safety Food Law

1. Food Sanitation Law 2. Food Manufacture etc. Regulatory Ordinance

Manufacture

Formulation of drug constituents Pharmaceutical Affairs Law Dosage forms (tablets, etc.) Inclusion of toxic substances and/or foreign particles Quality Microbial contamination Food Sanitation Law Use of food additives not in the positive list Specification standards of foods/food additives Basic labeling items

Drug efficacy Label and advertisement

1. Food Sanitation Law 2. Japan Agricultural Standards Law Pharmaceutical Affairs Law

False/exaggerated statements or expressions

1. Act against Unjustifiable Premium and Misleading Presentation 2. Health Promotion Law 3. Food Sanitation Law

Proper information offer

1. Health Promotion Law 2. Japan Agricultural Standards Law

Mail-order selling

Door-to-door selling

Telemarketing Marketing and distribution

Multilevel marketing/ Direct selling

Act on Specified Commercial Transaction

Retail selling

Others

Figure 17.2 Regulations for ‘health foods’ (HF) as products (source: Tokyo Metropolitan Health Bureau and Tokyo Metropolitan Life Culture Bureau, 2005. Health Food Handling Manual. 4th edn, Yakuji-Nipposha, Tokyo. p.6 (in Japanese)).

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Dosage Forms of HF Products Dosage forms or shapes such as tablets, capsules, etc. used for HF products have been deregulated, although several special delivery forms used in drugs are still forbidden. The examples of these special delivery forms are ampoules, sublingual tablets, the product absorbed from mucous membranes and spray type product into the oral cavity. On the other hand, the forms allowed for food uses include hard gelatin capsules, soft gelatin capsules, tablets, powder, liquid or granules.

Regulatory Systems on HF It is preferred to have a unified law to regulate HF and FHC as categorized under the FD in safety, quality, manufacturing, labeling, efficacy, advertisement, sales, etc. Therefore, the presence of diverse laws that belong to different ministries may result in the lack of lateral communication and comprehensive control. For example, a label of an HF product carrying a drug-like effect primarily violates the Pharmaceutical Affairs Law which is under the MHLW. If the same product promoted claims in any of the printed materials without scientific substantiations, it is subject to violation ruled by the Fair Trade Commission of the Minister’s Cabinet Office. However, each law has its own penalty systems. Consequently, it is important to enhance the understanding of each law bound to HF and the claims made by HF to protect consumers from being misled by HF products. The laws related to the FD category affecting the consumers and the HF industries are briefly explained. Some of the regulatory systems have been previously described (2).

Basic Food Safety Law The main objective of this law is to ensure safety of foods for consumers by implementing and following: 1. basic principles for the measurements of consumer health protection 2. taking appropriate actions on stages of the food supplying process (food chain) 3. anticipating potential health hazard causing factors based on accessible scientific evidence. The others include statements concerning responsibility of individuals and local authority, responsibility of food industry and establishing the Food Safety Commission. The law also states that consumers are recommended to enhance understanding on food safety and to express their opinions regarding policies to ensure food safety. The Food Safety Commission (FSC) plays a key role in achieving the objectives of the law, for example, by conducting risk assessments in response to the concerns raised by the minister, even though the FSC was established within the Cabinet Office (http://www.cao.go.jp/index-e.html).

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Regulatory Systems on HF 257

Pharmaceutical Affairs Law According to the Food Sanitation Law, any substance ingested orally is defined either as FD or ‘drugs’ (DR) (see Fig. 17.1). DR are strictly specified by the Pharmaceutical Affairs Law according to: 1. items recognized in the Japanese Pharmacopeia 2. items (other than quasi-drugs) that are intended for use in the diagnosis, cure or prevention of disease in man and animal, and that are not equipment or instruments 3. items (other than quasi-drugs and cosmetics) that are intended to affect the structure or functions of the body of man or animal and that are not equipment or instruments. Based on the Pharmaceutical Affairs Law, two lists are issued by the MHLW for identifying DR and non-DR. Such lists are: 1. list of ingredients (raw materials) used as exclusively as DR (DR List) and 2. list of ingredients (raw materials) used as materials not judged as DR, as long as no DR efficacy claim is made (non-DR List). These lists are further classified into three subcategories as: 1. substances originated in plants 2. substances originated in animals 3. other substances such as chemicals, minerals and other synthesized or highly purified substances obtained from natural substances (Fig. 17.3). Thus, the substances listed as non-DR may be used mainly as FD including HF, whereas the substances included in the third subcategory (e.g. chemicals) are included in food additives. When substances or raw materials on the non-DR List are to be processed further to obtain specific ingredient(s) by means of extraction with solvents, excluding water and ethanol (and probably carbon dioxide used in supercritical fluid extraction method), the ingredient(s) so obtained shall be reinvestigated in the light of the criteria described below to determine if it should be included in the DR List. This suggests that the solvents excluding water and ethanol are prohibited in the manufacturing of such ingredient(s). The criteria for identifying substances to be included in the DR List that are established by the MHLW are briefly summarized below: 1. Substances actually used exclusively as DR (e.g. antipyretic, analgesic, antiinflammatory agents, hormones, antibiotics and digestive and other enzymes) 2. Substances such as those of plant or animal origin (including extracts) and synthetic chemicals such as poisons or powerful DR (e.g. highly toxic alkaloids

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Plant origin

Drugs (DR)a

Animal origin Others (such as chemicals, etc.)

Ingredients (raw materials) Plant origin Non-drugs (non-DR) as long as no drug efficacy claim is madeb Criteria for distinction

Animal origin Others (such as chemicals, etc.)

Figure 17.3 Distinction between ‘drugs’ (DR) and ‘non-drugs’ (non-DR). aList of ingredients (raw materials) used as exclusively as drugs. bList of ingredients (raw materials) used as materials not judged as drugs (‘non-drugs’) as long as drug efficacy claim is not made (2).

or toxic proteins), narcotic, psychotropic DR or stimulants having DR-like action, and substances that are designated as DR from the standpoint of public health. However, substances that are generally consumed by eating or drinking as FD are excluded from the DR List. Substances such as vitamins, minerals and 23 amino acids including 4-hydroxyproline and hydroxylysine are excluded from the DR category. To apply for a new ingredient (raw material) not in the aforementioned two lists for distinction with the intention to be categorized as FD, manufacturers or importers may request its evaluation by submitting data and documents to the Compliance and Narcotics Division, Pharmaceutical and Medical Safety Bureau, and the MHLW. The data required for investigation include scientific names of the ingredients (raw materials) expressed in Latin, site of use, pharmacological and/or physiological action, any narcotic, psychotropic DR or stimulant DR-like action, any previous examples of approval as a DR in Japan or overseas and target consumers (Table 17.1). Historical uses as edible materials and consumers play a key role in the evaluation. Data and information submitted are reviewed by assigned pharmaceutical and medical authorities of the MHLW. Furthermore, reclassifying ingredient(s) in the DR List to the non-DR List is possible. The petition of the reclassification of ingredient(s) is accepted by the aforementioned divisions of the MHLW and allowed after being reviewed by an assigned panel of pharmaceutical and medical authorities. For example, three prominent ingredients have been reclassified from the category of DR to the non-DR List. They are CoQ10 in March 2001, L-carnitine and its

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Table 17.1 Documentation and evaluations for new ingredients (raw materials) 1 2 3 4 5

General name and family Latin name Site of use Active components or contents Toxicological data

6 Narcotic, psychotropic drug or stimulant druglike action 7 Examples of approvals as a drug a. Previous examples of approvals as a drug in Japan or overseas b. Traditional or historical use as a drug 8 Eating custom in Japan 9 Eating custom overseas

LD50 (p.o., etc.)(mg/kg) Other chronic toxicological data: Yes, No Yes, No Yes, No If Yes: country Efficacy statement Yes, No Product form: eat raw, cooked Yes, No. If Yes: country Product form: eat raw, supplements

10 Refer to herbs, animals or ingredients in the nondrug list and drug list Note: (1) List of such ingredients shall be periodically published (once a year). (2) It will be insufficient if the eating custom is limited to supplements (2)

organic salts in November 2002, and -lipoic acid (thioctic acid) in March 2004. It is apparent that some discrepancy arises in the daily doses (Table 17.2). The issue concerning the daily dose as an HF product that exceeds the dose as designated for DR was under dispute in the FSC of the Cabinet Office. For example, recently, the FSC and MHLW came to a conclusion on the dosage issue of CoQ10, i.e. the maximum limit is not determined, however, marketing companies are required to perform postmarketing surveillance on adverse reactions to the products. The other aspect of the law is to prohibit FD products from making any drug statements as defined above. The law applies to labeling and advertising such as package label, inserts, printed materials such as brochures, leaflets, books and booklets and mass media such as TV, radio, newspaper, magazines and the Internet. The law is also extended to direct marketing such as door-to-door, mail order and telemarketing, which represent about 75% of the total HF market. Furthermore, the law restricts the formulation or adulteration of any chemicals or natural substances including herbs in the list of DR. A representative example related to this law that developed into a social issue occurred in 1999 and the early 2000s when HF for body weight control imported from China contained DR such as fenfluramine, N-nitroso-fenfluramine and thyroid hormone in different concentrations, causing hepatic dysfunction and a detrimental effect on the thyroid or, in some cases, death of the consumers by ingesting the HF. Since then, the HF for weight control has been under the control of the MHLW. The other DR used in the weight control products were mainly sennosides (A and B) as laxative from senna (Cassia angustifolia Vahl and Cassia acutifolia Delile) leaves. The other DR detected and causing adverse reactions were norephedrine and ephedrine in the 1990s and sibutramine hydrochloride monohydrate.

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Table 17.2 Examples of reclassifying from ‘drugs’ (DR) to ‘non-drug’ (non-DR) Substance (date reclassified as food)

Drug

Fooda

Coenzyme Q10 (March 2001)

Dosage: 30 mg/day p.o. Indication: mild or moderate congestive cardiac failure Dosage: 30–60 mg/kg/day p.o. (as levocarnitine chloride) Indication: L-carnitine deficiency in patients with propionic acidemia or methylmalonic academia Dosage: 10–25 mg/kg/day i.v., i.m., s.c. Indication: (1) supplementation of thioctic acid when highly needed (by hard physical labor); (2) Leigh syndrome; (3) poisoning deafness, noiseinduced deafness

Generally 100–200 mg/day

L-Carnitine (November 2002)

-Lipoic acid (thioctic acid) (March 2004)

Generally not more than 20 mg/kg/ dayb or 1000 mg/dayc

Generally 100–200 mg/day

a

No upper limit has been decided by the MHLW. Maximum dose determined by the USA. These daily doses are suggested by the MHLW as the maximum doses in Japan. c Maximum dose determined by Switzerland. These daily doses are suggested by the MHLW as the maximum doses in Japan (2) b

Health Promotion Law In 2003, the Health Promotion Law replaced the Nutrition Improvement Law under the control of the MHLW, the aim of which is interpreted as ‘to improve the health of consumers according to established principles that support and fulfill the necessities including the nutrition improvement from the viewpoint of promoting human wellbeing’. The law considers the rapidly growing awareness of the aging population and LSRD in particular. The law also governs the making of regulations with respect to the approval, labeling, quality assurance, ingredients, etc. of ‘Foods for Special Dietary Uses’ (FSDU) and FHC products. Moreover, under the law, labeling of such product carries nutrition facts, such as energy, protein, fat, carbohydrate, sodium and other nutrients, if required, with proper units and per serving amount in accordance with the nutrition facts standards. The law prohibits any false, exaggerated and/or any misleading statements on the product label, advertisement and other means of communication to consumers such as catalogs.

Food Sanitation Law The objective of the Food Sanitation Law is to secure the safety of FD by controlling the risk of health hazards caused by ingestion of FD. The law establishes the responsibilities of the Government, local authorities and FD industry.

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The law also serves diversified roles in HF as a most crucial regulatory system to ensure the safety of FD. The law prohibits any product that may contain poisonous or carcinogenic substances, non-healthy and health-hazardous substances, additives which possess high risk factors for consumer’s health to be manufactured, imported, sold, used, displayed, etc. Examples are: 1. deteriorated or microbial contaminated FD 2. toxins from fungi and others, alkaloids of plant origins 3. foreign particles such as pieces of glass, metals, etc. The restrictions on distributing, selling or using ‘food additives’ as excipients are determined by the law. The law as Ministerial Notice enables the establishment of the standards for manufacture, preservation, use of FD, including genetically recombinant FD or food additives, and specifications. The other function of the law is to monitor whether package labeling of HF products is correctly stated and/or whether any statements are missing from the labels. For example, label statements must include: 1. 2. 3. 4. 5. 6.

designation of the product food additives used preservation method expiration (consumption or quality limit) date manufacturer and address statements of genetically modified organism-containing FD and allergenic FD.

The law also controls any false or misleading statements on the labels and advertising as specified by the Pharmaceutical Affairs and Health Promotion Laws. The labeling for FHC products is also controlled under the Food Sanitation Law in addition to the applicable regulations governed by the Health Promotion Law. Moreover, the law has provisions for risk communication with consumers, positive list on pesticides remaining in FD, etc. and surveillance systems for imported FD.

Japanese Agricultural Standards Law The Japanese Agricultural Standards (JAS) follows the Law Concerning Standardization and Proper Labeling of Agricultural and Forestry products, stipulating product information requirements such as processed FD and others. Labeling of HF, as of processed FD, is to carry information such as designation of product, list of raw materials and food additives (FA) used, preservation method, manufacturer or importer name and the address, content (weight), expiration date and statements for genetically modified organism-containing FD or organic FD, if applicable, and the country of origin in the case of imported FD products. If the HF products are made from organic materials, the organic JAS symbol is allowed on the labels. The Law is under the control of the Ministry of Agriculture, Forestry and Fisheries or MAFF (http://www.maff.go. jp/eindex.html).

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Act Against Unjustifiable Premiums and Misleading Presentation and Other Laws The other laws concerning FD products include: 1. Act against Unjustifiable Premiums and Misleading Presentation 2. Act on Specified Commercial Transaction. Both laws protect consumers from the standpoint of sale, while (1) is governed under the Cabinet Office (http://www.cao.go.jp/index-e.html and http://www. jftc.go.jp/e-page/index.html) and (2) is under the Ministry of Economy, Trade and Industry or METI (http://www.meti.go.jp/english.html). The laws extend not only to FD products, but also to other products and services that consumers can purchase from various distribution channels in order to protect consumers from misled or misinterpreted purchase motivations, created by sellers of products and services, resulting in financial loss or any kind of damage. For example, false and/or exaggerated promotional statements on health benefits of HF products without any clear evidence directed to the products are strictly regulated by: 1. products are excluded from the marketplace unless any rational evidence is presented within 15 days 2. involves mostly methods or ways of selling products, for example, by door-todoor, mail order, direct-marketing, telemarketing, etc. Any violation of (1) and/or The Act on Specific Commercial Transaction evokes serious social concerns. Furthermore, illegal methods of selling often result in negative perception of HF by the consumers, thereby ultimately affecting the entire HF industry. Therefore (1) and (2) play a pivotal role in the control of conveying correct information and data on HF products.

Food Additives In Japan, the Food Sanitation Law basically regulates uses of FA which must be approved by the MHLW for following purposes: 1. to maintain the nutritional quality of FD 2. to provide certain ingredients in FD for consumers who require special diets not intended for prevention or treatments of certain diseases 3. to enhance the preserved quality and/or stability of FD or to improve the organoleptic properties without altering the nature, characteristics or quality of the FD for the benefit of consumer 4. to support the manufacture, processing, preparation, treatment, packing, transport, or storage of FD without generating any effects in the use of labile raw materials or of undesired practice or technique.

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FHC 263

The FA are required to be rigorously tested for effectiveness, safety and physicochemical characteristics and specifications. The effectiveness studies required for FA such as antimicrobial, flavoring, coloring, stabilizing agents, etc. include: 1. effectiveness and comparison in the effect(s) with other similar FA 2. effects on nutrients of FD. Information/data or studies required to demonstrate safety of FA are: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

LD50 (single administration study) 28-day toxicity study 90-day toxicity study one-year toxicity reproduction study teratogenicity study carcinogenicity study combined one-year toxicity/carcinogenicity study antigenicity study mutagenicity study general pharmacological studies information concerning metabolism and pharmacokinetic data the daily intake of the FA information concerning safety in humans.

In addition, information on the physicochemical characteristics and specifications of FA generally required are name, formulas, assay, manufacturing methods, identification and purity tests, stability, etc. Moreover, according to the Food Sanitation Law as described above, FA used to prepare HF, regardless of administration forms such as tablet and capsule or of conventional food forms, must be stated on package labels.

FHC Conventional FD such as yogurt, cooking oil and lactic acid drink were originally in the FOSHU category, but intake forms such as tablets or capsules had not been recognized. In 2001, criteria for FOSHU were integrated into the FHC system and then revised to include capsules, tablets or other administration forms commonly used in supplements. The FOSHU are allowed to make structural and functional claims on the human body with the approval of the Minister of the MHLW. Consequently, health benefits are permissible to be included on the labels of the products. The domain of claims are limited to the contents: 1. indicating the benefits for maintaining or improving healthy condition that are clearly observed and measured (e.g. to help maintain normal blood pressure)

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2. indicating that the FD product aids to maintain or improve healthy physical condition or tissue functions (e.g. to help maintain the bowel movement) 3. indicating that the FD product improves temporarily the physical condition, provided that it will not provide continuous or long-term effects and the expectation of such effects (e.g. appropriate to one who feels tiredness) and disease risk reduction claims (Fig. 17.4).

FDSU FDSU regulations were established after the enactment of the Food Sanitation Law in 1947 for fulfilling the needs of the Japanese people by improving the unsatisfactory nutritional conditions after the World War II. FDSU have since been developed and diversified into various diets for subjects meeting the requirements of their physical

Drugs (DR) (including quasi-drugs) (Pharmaceutical Affairs Law)

Such as medicinal ingredients, efficacy and pharmaceutical effects, shape, dosage forms and administration methods

Foods for patients

Orally taken substances

– Standardized type – Single product Low sodium food, low protein food, low calorie food, allergen free food, etc. – Assorted products for diabetes, liver diseases, etc.

Foods (milk powder) for pregnant and lactating women

Individually approval type

Foods (milk powder) for infants

Easy edible foods for the elderly people having difficulties of swallowing and/or mastication

FDSU (Health Promotion Law, (Food Sanitation)

Foods (FD) (Food Sanitation Law, Health Promotion Law)

Other foods provided by the ordinance of the Ministry of Health, Labor and Welfare

Foods for lactating women

FOSHU FHC (Health Promotion Law, Food Sanitation Law)

FNFC

General foods including SCHF (Food Sanitation Law) Figure 17.4 Positioning of DR and FD including FDSU, FHC (FOSHU and FNFC) and SCHF in accordance with the Pharmaceutical Affairs Law, the Food Sanitation Law and the Health Promotion Law (see text for the symbols).

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FOSHU 265

conditions. Now FDSU are classified based on the approvals of MHLW under the Health Promotion Law. FDSU were categorized as: 1. FD for the patients such as low sodium FD, low protein FD, low calorie FD, FD for allergic diseases, assorted FD for diabetes and so on 2. FD (milk powder) for pregnant and lactating women 3. FD (milk powder) for infants 4. FD for children 5. easily edible FD for the elderly 6. FOSHU (see Fig. 17.4).

FOSHU FOSHU is a subcategory of FHC as well as of FDSU, and FNFC belongs to the other subcategory of FHC. FOSHU is separately approved by the MHLW on the basis of the conclusion drawn from deliberations in the Pharmaceutical Affairs and Food Sanitation Council of the MHLW, while FNFC is a new system established in 2001 under the regulations of HF restricted to the specified nutrients (vitamins and minerals) whose nutritional function claims are established on the basis of well-confirmed scientific evidence (see Fig. 17.4)

Approval System for FOSHU

To obtain approvals for FOSHU products, identification of the key ingredient and elucidation of the mechanistic action of the ingredient are essential. Before a FOSHU product is ready to acquire approval, the following requirements must be taken into consideration: 1. Improvement to dietary habits and contribution to maintaining and enhancing the state of health is expected 2. The decisive ingredient of FD related to the claim for health-related uses should be clearly based on the medical and nutritional evidence demonstrated scientifically from clinical studies 3. Appropriate doses of FD or the decisive ingredient can be established on the basis of the medical and nutritional evidence 4. Safety of FD or the decisive ingredient can be confirmed by referring published scientific papers that are peer-reviewed 5. The decisive ingredient of FD should be identified by employing the following methods: a. the physical, chemical and biological characteristics must be clearly identified and the test methods for characterization must be established b. quantitative and qualitative analytical methods must be established However, the above is exempted if reasonable rationale(s) are presented

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6. It must be confirmed that the decisive ingredient dose does not interfere with the composition of other nutritional ingredients in FD or in the same kind of FD 7. The ingredient needs to be included in commonly used FD 8. FD or the decisive ingredient should not be included in the DR list. Effectiveness or efficacy is substantiated by elucidating the mechanism of action, establishing the dosage level, performing tests in animal and human subjects conducted under the double-blind, placebo-controlled, randomized clinical trial, and assessing the findings with appropriate statistical analyses. Safety is confirmed by demonstrating the historical diet usages in both Japan and foreign countries, conducting in vitro and in vivo toxicity tests that include acute toxicity, 28-day and 90-day toxicities and mutagenecity as minimum requirements to ensure safety intake levels. Safety must also be clinically proven by carrying out overdose (usually 3- to 5-fold of the established dosage level) administration study. Reproduction, chronic toxicity, antigenicity, carcinogenicity or teratogenicity, or general pharmacology studies may be required based on the outcomes of the toxicity studies or if the product contains a new key ingredient previously not found in the list of the approved FOSHU products. Physiochemical properties of the decisive ingredient as well as the stability of the product formulated with the decisive ingredient and ingredient itself must be evaluated in terms of quality. All toxicity tests should be performed on the basis of good laboratory practice (GLP), whereas clinical studies must be approved by a committee on ethical consideration pertaining to the protection of human rights in accordance with the spirit of the Helsinki Declaration and be carried out on the basis of good clinical practice (GCP). Furthermore, the clinical studies should be conducted as randomized placebo-controlled double blind trials and the results must show statistical significance against the control at a P-value less than 0.05. The subjects for the clinical trial should be healthy subjects or subjects who are on the borderline of being healthy as judged by health diagnosis such as blood cholesterol, triglycerides and glucose and blood pressure (Table 17.3). The findings from clinical studies conducted for the product are crucial in the determination of an approval for the product as FOSHU. Accurate determination of an active constituent is essential as part of the requirements for FOSHU approval. An established manufacturing procedure for a FOSHU product is required. Labeling, shelf-life, formulation, dosage, nutritional information, precautions, etc. of the intended product for obtaining FOSHU status should be clearly stated. Number of FOSHU

As of April 18, 2007, 681 products have been approved as FOSHU. As shown in Table 17.4, decisive or functional ingredients of FOSHU products are listed according to the categories of health claims. About 41% of FOSHU products claim that they are ‘maintaining gastrointestinal condition’. Oligosaccharides, Lactobacillus, Bifidobacterium and dietary fibers are major ingredients for the activities in this category. The other category, representing 21% of FOSHU products, makes health claims that they are ‘good for those concerned about high serum cholesterol/triglycerides’ and ‘good for those concerned about body fat’. Chitosan, soybean protein, phytosterol, dietary fibers, diacylglycerol, EPA and DHA, etc. are the major active ingredients in this category.

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FOSHU 267

Table 17.3 Health conditions and basic criteria for clinical studies required for FOSHU as a general rule Clinical study

Health conditions and basic criteria

Cholesterol-related

To perform trial for more than 12 weeks with subjects having total blood cholesterol level ranges 200–240 mg/dl and/or LDL cholesterol level ranges 120–160 mg/dl To perform trial with subjects having slightly higher TG level. (120–200 mg/dl) than normal upper level To perform trial for more than 12 weeks when the effectiveness of lowering TG level at fast is studied To perform trial for more than 12 weeks with subjects with high within normal blood pressure levels and/or patients having low to moderate risk of mild hypertension To perform trial for more than 12 weeks with subjects having fasting blood glucose level at threshold levels or by glucose tolerance test according to the standards of Japan Diabetes Society To perform trial for more than 12 weeks with subjects having obesity level 1(25 BMI 30) in accordance with the standards of Japan Society for the Study of Obesity or subjects having comparatively high BMI values within normal range. To perform the above trials with subjects stratified by sex and age

Triglyceride(TG)-related

Blood pressure-related

Blood glucose-related

Body fat-related

Qualified FOSHU and Standardized FOSHU

With the recent relaxation of the FHC system in February 2005, the qualified and the standardized FOSHU systems were introduced into the framework of the previous FOSHU systems, making it easier for applicants to obtain approvals for distributing FOSHU products in the marketplace. Concomitantly, the ‘disease risk reduction claims’ were added to the existing items approved for FOSHU, reflecting the Codex decision. The schematic illustration of the new FHC system is exhibited in Table 17.5 and differences between the existing FOSHU and qualified FOSHU systems are shown in Table 17.6. The major differences are: 1. requirement for elucidating the mechanism of a key ingredient and 2. acceptance of P-values for statistical analysis. The elucidation of the mechanism in the action of the key ingredient is not always required for the qualified FOSHU. For the statistical analysis of the data from clinical studies, significant difference against the control may be acceptable with P-value less than 0.1 and the randomized controlled study is not essential for the qualified FOSHU products. Other data and documents are necessary for the approvals of the qualified FOSHU products in accordance with the existing FOSHU system, such as clinical studies using higher dosages for confirming adverse effects in the case of overdosing. The standardized FOSHU system was also enforced, allowing for claims such as ‘maintaining good gastrointestinal condition’. Such functional ingredients include: 1. 2. 3. 4.

indigestible dextrin (3–8 g/day) polydextrose (7–8 g/day) xylo-oligosaccharide (1–3 g/day) fructo-oligosaccharide (3–8 g/day)

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Table 17.4 FOSHU products (681 products approved as of April 18, 2007) Target

Specified health claims

Intestinal Condition

Maintain intestinal condition by improving balance of enterobacteria and/or promoting regular bowel movement Improve bowel movement by improving balance of enterobacteria Good for those concerned about serum cholesterol

Cholesterol/ triglycerides/ body fat

No. of products (%) 279 (40.97)

Oligosaccharides, lactobacillus, Bifidobacterium, Psyllium husk, indigestible dextrin, wheat bran, low molecular sodium alginate, partially hydrolyzed guar gum

72

Chitosan, phytosterol, soybean protein, low molecular sodium alginate, CSPHP

31

Psyllium husk

Good for those having relatively high serum cholesterol Reduce cholesterol absorption and maintain intestinal condition

Good for those having relatively high 4 serum cholesterol and triglycerides with mild obesity Good for those having relatively high 19 serum triglycerides Help to improve dietary life rich in fat Good for those concerned about body fat

17

Blood glucose

Good for those concerned about blood glucose level

89 (13.07)

Blood pressure Teeth

Good for those having relatively high 82 (12.04) blood pressure Maintain strong and healthy teeth 47 (6.90)

Bone

Help maintain calcium in bones

30 (4.41)

Make bones strong by efficient calcium absorption. Good for those who are short of calcium intake Good for those who are susceptible to anemia

11 (1.61)

Total

681 (100)

Mineral absorption

Main decisive ingredients or source mateials

5. 6. 7. 8. 9.

143 (21.00)

Diacylglycerol phytosterol

EPA, DHA, degradation products of globin protein, Oolong tea polymerized polyphenols, diacylglycerol Manno oligo-saccharides from coffee beans, green tea catechin, middle chain fatty acid Indigestible dextrin, L-arabinose, wheat albumin, guava leaves polyphenols, Touchi (fermented soybeans) extract GABA, casein dodecapeptide, sardine peptide, lacto-tripeptide Xylitol, maltitol, paratinose, calcium phosphate, Colpomenia sinuosa extract, green tea polyphenols, CPP-ACP Vitamin K2, flacto-oligosaccharides, soy isoflavone

Fructo-oligosaccharides, CCM, CPP, heme iron

soybean oligosaccharide (2–6 g/day) isomalto -oligosaccharide (10 g/day) lacto-fructo-oligosaccharide (2–8 g/day) galacto-oligosaccharide (2–5 g/day) partially hydrolyzed guar gum (5–12 g/day).

Most of the FD (totaling more than 100 products) containing the aforementioned ingredients, having sufficient scientific evidence to support their claims, were

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FOSHU 269

Table 17.5 Revision of FHC in February 2005 FHC FNFC

FOSHU

Type of system

Standardized

Functional component(s) Claims

Nutrients (12 vitamins and 5 minerals) Nutrient function claims (structure and function claims)

Ranking of scientific evidences

A

Individual approval FOSHU Standardized FOSHU Nutrients and other food ingredients Specified health claims (structure and function claims) Disease risk reduction claims A, B

Qualified FOSHU

Nutrients and other food ingredients Specified health claims (structure and function claims)

C

Ranking of scientific evidences is defined as follows: (A) evidences are both medically and nutritionally established from the scientific point of view; (B) evidences are confirmed at the level previously required for the approval of existing FOSHU; (C) evidences are not established but the efficacy is suggested (2)

Table 17.6 Differences in criteria between the existing and qualified FOSHUs Randomized controlled trial (RCT≤)

Clinical study

Mechanism of action

Clear Unclear

P 0.05

0.05 ≤ P ≤ 0.10

Existing FOSHU Qualified FOSHU

Qualified FOSHU Qualified FOSHU

Non-randomized controlled trial Qualified FOSHU

Note: Control, placebo; subjects, healthy subjects; compliance with Helsinki Declaration (2)

approved as FOSHU products in the 1990s. Thus, clinical studies except for those evaluating the safety are not required for approval. In fact, to classify the present FOSHU claims to the standardized FOSHU, requires the following criteria: 1. over 100 kinds of FOSHU products with same decisive ingredients are sold in the market 2. such FOSHU products need to be in the market for at least 6 years and more than two companies are to be distributing the products that belong to the same claim category. FOSHU and the Japanese Traditional Diets

Some of the FOSHU products were based on FD materials used in the Japanese traditional diet. For example, fermented soybean (‘natto’) containing vitamin K2 (menaquinone-7) that helps the absorption of calcium was approved as a FOSHU product (5,6). Soybean is a traditionally natural crop used as source for fermentation to yield ‘miso’, soy sauce and ‘natto’. Soybean isoflavone was shown to be effective in the improvement of mineral absorption (8). Soy protein as the decisive ingredient proved to control the serum cholesterol level (8,9).

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More recently, two soybean isoflavone products in non-conventional form were approved as FOSHU. The issue of UL (maximum upper intake level), concerning safety, however, was raised and discussed at FSC. As a result, an intake of 75 mg of aglycone a day was established as upper limit that was safe on the basis of total intake of isoflavone from daily meals. Thus, 30 mg a day was determined as safe for upper limit intake of aglycone for FOSHU and SCHF products in dosage forms such as tablets and capsules. The other Japanese traditional food called ‘katsuobushi’ or fermented bonito containing peptides shown to lower blood pressure (10), made the health claim of ‘good for those having relatively high blood pressure’. Tea polyphenols are also decisive ingredients for ‘helping to maintain strong and healthy teeth’ (11). We expect additional claims to be adopted as FOSHU products based on the Japanese traditional diets.

FOSHU and Botanicals

A few botanical products have been hitherto approved as FOSHU products. These products include leaves of guava (Psidium guajava L.) with polyphenols as the decisive ingredient claiming it as ‘good for those concerned about blood glucose level’ and green tea (Camellia sinensis L.) with catechin as the key ingredient claiming it as ‘good for those concerned about body fat’. The other botanical species approved for FOSHU is the leaves of Gutta-percha tree (Eucommia ulmoids Oliv.) containing geniposide as the key ingredient claiming it as ‘good for those concerned with relatively high blood pressure’. The aforementioned FOSHU products are in the form of tea. We expect FOSHU botanical-based products to be listed in the non-DR and confirmed safety and effectiveness will become more available to consumers for maximizing the FOSHU system. Disease Risk Reduction Claims

According to the decision by Codex Alimentarius committee under WHO/FAO, the MHLW introduced the disease risk reduction claims to the existing FOSHU system. The disease risk reduction claims are currently limited to two ingredients, calcium and folic acid, specifying the minimum and maximum limits of daily intakes. The selection of ingredients for the disease risk reduction claims should be entirely based upon concrete scientific evidence which is comprehensively accepted by scientists. When disease risk reduction claims are expressed on a package label, the disclaimers should also be stated on the same label. Calcium Daily intake of calcium from the FOSHU products should be in the range of 300– 700 mg. Labeling should include the following: the product contains adequate calcium and intake of a proper amount of calcium contained in healthy meals with appropriate exercise may support the health of the bones of young women and reduce the risk of osteoporosis in the aged.

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FNFC 271

Folic Acid Daily intake of folic acid from the FOSHU products should be between 400 and 1000 g. Labeling includes the following: the product contains adequate folic acid and healthy meals containing an appropriate amount of folic acid may help women bear healthy babies with reduction in the risk of neural tube defects, such as spondyloschisis.

FNFC FNFC allows for the nutrient function claims that were enforced by the MHLW and authorized by the Minister of the MHLW, according to the fundamental and decisive scientific evidence. The claims are standardized according to the conclusion derived from the authorities of the MHLW. Nutrients acceptable as FNFC must be essential for fundamental activity of human life, which are supported by scientific evidence and extensively acknowledged medically and nutritionally. To make claims about FNFC, the minimum and maximum daily intakes of individual nutrients are determined as the standard of daily dosage by the MHLW. Disclaimers are also required to be placed on the label according to the individual ingredients. This category was enforced since April 1, 2001. Twelve vitamins and -carotene and 5 minerals are adopted in this category where an individual nutrient function claim is determined. Table 17.7 summarizes these vitamins and minerals. Specified dosage levels of the vitamins and minerals of FNFC and the claims allowed are listed in Tables 17.8–17.11. The labels of FNFC contain statements, such as ‘Intake of excessive quantities of this product does not heal the illness or improve health. You must follow the dosage as directed’. Furthermore, it is stated, ‘This product was not investigated individually by the Minister of the MHLW unlike FOSHU’.

Safety Safety is of the utmost importance for HF consumers and manufacturers. The manufacturers, in particular, are expected to take careful actions in accordance with the various established regulations and guidelines coupled with upcoming regulations in Table 17.7 Vitamins and minerals permitted and not permitted as FNFC Permitted (17)

Not permitted (8)

12 Vitamins

5 Minerals No deficiency in Japan Data not available for the calculation of nutritional parameters based on the national nutritional survey

A and -carotene, B1, B2, B6, B12, pantothenic acid, biotin, nicotinic acid/ nicotinamide, folic acid, C, D, E Iron, calcium, copper, zinc, magnesium Vitamin K, phosphorus, potassium Iodine, manganese, selenium, chromium, molybdenum

Claims are determined by the MHLW for individual nutrients based on the Significant Scientific Agreement. Disclaimers are required for description (2)

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Table 17.8 Standards of daily dosage of FNFC (revised in July 2005) Vitamins Niacin (mg) Maximum limit 60 Minimum limit 3.3 Vitamin B1 (mg) Maximum limit 25 0.3 Minimum limit Vitamin C (mg) Maximum limit 1000 Minimum limit 24

Pantothenic acid (mg)

Biotina (μg)

Vitamin Ab

30 1.65

500 14

600 g g 2000 IU 135 g g 450 IU

Vitamin B2 (mg)

Vitamin B6 (mg) Vitamin B12 (μg)

12 0.33

10 0.3

60 0.6

Vitamin D

Vitamin E (mg)

Folic acid (μg)

5.0 g (200 IU) 1.50 g g 60 IU

150 2.4

200 60

a

Biotin is permitted only for FHC. -Carotene as the precursor of Vitamin A can be approved as the FNFC of Vitamin A source. In that case, the maximum limit is set at 7200 gg the minimum limit is set at 1620 g (2)

b

Table 17.9 Standards of daily dosage of FNFC (revised in July 2005) Minerals Calcium (mg) Maximum limit Minimum limit

Iron (mg)

600 210

10 2.25

Zinca

Coppera

Magnesiuma

Maximum limit

15 mg (ULb minus maximum amount of intake from conventional foods)

6 mg (UL minus maximum amount of intake from conventional foods)

300 mg (calculated by modifying the UL set by the USA comparing the weight difference of the average American and Japanese)

Minimum limit

2.10 mg (30% of NRV)c

0.18 mg (30% of NRV)

75 mg (30% of NRV)

a

Zinc, copper and magnesium were added in 2004. UL, tolerable upper intake level. c NRV, nutrient reference value (2) b

order to secure the safety of HF products. Consequently, the industry is fully responsible to make every effort and contribution to the health benefits of the consumers. Risk Analysis by the Food Safety Committee

The occurrence of BSE (bovine spongiform encephalopathy) in Japan was a major determinant for the establishment of the Food Safety Commission based on the Basic Safety Food Law (http://www.fsc.go.jp/english/index.html). To combat food hazards, the Food Safety Commission is responsible for risk assessment and risk analysis, and for adopting systems which are implemented independently from risk management, while the MHLW and MAFF are in charge of risk management. Furthermore, the

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FNFC 273

Table 17.10 Nutrient function claims of vitamins Vitamin

Nutrient function claims

Niacin Pantothenic acid

Niacin is a helpful nutrient for the healthy maintenance of the skin and mucosa Pantothenic acid is a helpful nutrient for the healthy maintenance of the skin and mucosa Biotin is a helpful nutrient for the healthy maintenance of the skin and mucosa Vitamin A is a helpful nutrient for the maintenance of eyesight at night Vitamin A is a helpful nutrient for the healthy maintenance of the skin and mucosa Vitamin B1 is a helpful nutrient for producing energy from carbohydrate and the healthy maintenance of the skin and mucosa Vitamin B2 is a helpful nutrient for the healthy maintenance of the skin and mucosa Vitamin B6 is a helpful nutrient for producing energy from protein and the health maintenance of the skin and mucosa Vitamin B12 is a helpful nutrient for the formation of red blood cells Vitamin C is a helpful nutrient for the healthy maintenance of the skin and mucosa and with the process of antioxidation. Vitamin D is a nutrient for accelerating the absorption of calcium in the bowel and helping the formation of bones Vitamin E is a nutrient for preventing internal lipids from oxidizing by the process of antioxidation and helping the health maintenance of cells Folic acid is a helpful nutrient for the formation of red blood cells Folic acid is nutrient for contributing to the healthy growth of the embryo

Biotin Vitamin Aa Vitamin B1 Vitamin B2 Vitamin B6 Vitamin B12 Vitamin C Vitamin D Vitamin E Folic acid

-Carotene as the precursor of vitamin A can be approved as the FNFC of vitamin A source. In that case the maximum limit is set at 3600 g, the minimum limit is set at 1080 g (2) a

Table 17.11 Nutrient function claims of minerals Mineral

Nutrient function claims

Calcium Iron Zinc

Calcium is a necessary nutrient for the formation of bones and teeth Iron is a necessary nutrient for the genesis of red blood cells Zinc is a necessary nutrient for keeping the normal condition of degustation Zinc is a helpful nutrient for the healthy maintenance of the skin and mucosa Zinc is a necessary nutrient for maintaining the normal vital activity participating in the metabolism of proteins and nucleic acids Copper is a helpful nutrient for the formation of red blood cells Copper is a helpful nutrient for the normalization of the function of various endogenous enzymes and for the formation of bones Magnesium is a necessary nutrient for the formation of bones and teeth Magnesium is a necessary nutrient for the normalization of the function of various endogenous enzymes, for helping energy generation and for the normalization of the blood circulation

Copper

Magnesium

See (2)

Food Safety Commission evaluates all filed documents related to safety of FOSHU. Also, the Commission performs analysis on hazards induced by FD in the market. General Foods and Safety Concern

SCHF is included in the category of the general FD (see Fig. 17.1). FD, having the forms or shapes of tablets, capsules and others generally used in the category of supplements in the overseas countries, are included in the categories of FNFC and SCHF in Japan. Most

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of the herbal or botanical products are included in the SCHF and a very few are now found in the FOSHU category. Only statements on the nutritional content are accepted on the labels of the products in the general food category and any functional claim is prohibited. As stated before, SCHF is regulated by various and independent laws, which are not included in the framework of the specific laws. Moreover, most of the HF products having dosage forms of tablets or capsules included in the category of SCHF may increase the risks of overdose, resulting in adverse reactions, due to the presence of highly concentrated active ingredients. In fact, some accidental events such as liver disorders have occurred in the past, which were thought to be caused by the intake of SCHF products. Therefore, efficient countermeasures are required to prevent these accidents from occurring. On the other hand, for example, cases of potent adverse reactions have been reported in which DR ingredients, etc. were intentionally formulated into FD materials to enhance efficacy. In such cases, products with the confirmed presence of DR ingredients are no longer called and sold as SCHF, but are named, instead, as ‘nonapproved and/or non-permitted DR’. Moreover, such product names and DR ingredients are made available to the public. The reported cases often involve personally imported products, including appetite suppressant, tonic adulterated with sildenafil as DR ingredient etc. In 2005, the MHLW announced two guidelines to ensure safety and to guarantee the quality of HF products with dosage forms of tablets, capsules and related forms: 1. good manufacturing practice (GMP) guideline and 2. guideline for the self-investigation of safety of raw materials included in HF products in capsules, tablets or other forms. Consequently, such guidelines which control the requirements for raw materials used in GMP and safety assurance may be practiced in other countries. GMP Guideline for HF Products

GMP guideline has been established by the MHLW based on that for DR. The GMP being introduced in HF according to the governmental guideline should be performed voluntarily. However, the Government strongly recommends practicing the GMP system in the product manufacturing lines for HF. The guideline requires that GMP is used not only for finished products, but also for raw materials, including imported raw materials and finished products. Recently, two organizations, the Japan Health and Nutrition Food Association (JHNFA) and the Japanese Institute for Health Food Standards (JIHFS), have established their own GMP regulatory and introduced a certifying system for manufacturing facilities. JIHFS will confer the products manufactured in the facility certified by the GMP audit with a GMP certification mark on the product. Guideline for Self-Investigation of the Safety of Raw Materials

Raw materials used for manufacturing HF are required to be investigated for safety according to the guidelines established by the MHLW. FD products with dosage

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Discussion 275

forms like tablet, capsule, powder or liquid are subjected to ‘self-investigation’ of the safety of raw materials, in particular, when raw materials are processed by using the methods of extraction, fractionation, purification and chemical reaction. Raw material manufacturers as well as distributors of finished products are required to evaluate the safety on the basis of the self-investigation system of the raw materials. The ‘self-investigation’ of the safety of materials is accomplished according to the following steps established by the MHLW as a model system: Step 1 To identify all raw materials in a finished product Step 2 To define raw materials according to the DR or non-DR List Step 3 To confirm the identity of an individual raw material by employing reasonable techniques such as profiling and DNA analyses and morphologic characterization or to confirm if cultivation of raw material is carried out under voluntary GAP (good agricultural practice) system, etc. Step 4 To confirm if it is equivalent to the existing materials used as ingredients in the conventional FD generally distributed Step 5 To study information regarding safety data of the raw materials obtained from Chemical Abstract, PubMed and RTECS if reliable data regarding safety, toxicology, and epidemiology are obtainable Step 6 To identify undesirable substances (e.g. alkaloids, toxins, hormones, neurotropic, carcinogenic, teratogenic, genotoxic and other toxic substances, and substances having closely related chemical structures to those of the aforementioned undesirable substances) from the published papers. If sufficient information regarding the above-mentioned substances is not available, then the raw materials should be analyzed to confirm if undesirable substances are present Step 7 To perform toxicity studies such as 90 days repeated subchronic toxicity study and in vitro genotoxic studies that are required, although this step is applicable only when safety cannot be confirmed by Step 6 Step 8 To conclude by certifying the absence of impurities such as heavy metals and microorganisms is required and the manufacturing process is preferably controlled under a proper GMP system.

Discussion After the USA, Japan possesses the second largest health foods market in the world, which is almost equivalent to the EU market. In fact, the market of HF without FOSHU reached about US$12.1 billion in 2006 (Fig. 17.5) and the total market achieved about US$17.1 billion in 2006. The FOSHU market represents about 36% of the total HF market (Fig. 17.6). The growth of the HF market has accelerated remarkably since 2001, which was presumably reflected by the deregulations that the Japanese government implemented (see Fig. 17.5). Therefore, Japan is one of the few countries in the world to attain a large health food market. On the other hand, the systems that the Government developed for HF differ from the systems in Europe, the

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14

12

Billion (US$)

10

8

6

4

2

0

1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Year

Deregulation

Permitted structure and Introduced 13 Vitamins were approved as foods function claims for FHC new FOSHU About 100 herbs were approved as foods system 13 Minerals were approved as foods The shape regulation was removed

Figure 17.5 The changes in retail-sales based market size of ‘health foods’ (HF) without FOSHU in Japan (source: personal communication from the Health Industry News, CMP Japan Co., Ltd).

7

6

Billion (US$)

5

4

3

2 Data are not available

1

Data are not available

0 1997

1998

1999

2000

2001 2002 Year

2003

2004

2005

2006

Figure 17.6 The changes in retail-sales based market size of FOSHU products in Japan (source: personal communication from the Health Industry News, CMP Japan Co., Ltd).

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Discussion 277

USA and various Asian countries. The most remarkable difference is that the positioning of supplements is not legally defined as a system. The systems of FHC and SCHF are recognized in Japan as frameworks used to classify and determine the labeling of functional claims. Furthermore, both FOSHU and FNFC are allowed for specific functional claims that are approved by the Minister of the MHLW and recognized as an exceptional case of the Pharmaceutical Affairs Law. While SCHF is solely positioned as general FD and is distributed in the marketplace, the products are strictly under the control of the Pharmaceutical Affairs Law and are never allowed any functional claims to be placed on the labels. HF is classified into FHC and SCHF by the approval of functional claims. Thus, the ingredients which are occasionally missing from conventional FD or whose physiological and nutritional functions are not expected from general FD are provided as supplements in dosage forms such as tablets or capsules. By maximizing the use of these supplements, the needed ingredients become available regularly, quantitatively and continuously for the health benefits of consumers. Unfortunately, the concept or system that distinguishes HF by dosage form is absent in the regulatory system in Japan. While the majority of foreign countries have attempted or are in the process of establishing a system for supplements, some countries have already completed the system. The establishment of such systems will be crucial for the manufacturing of supplements with respect to evidence-based efficacy, safety and quality assurance. Although the advanced approval system for FHC and FOSHU is present in Japan, the law that specifically regulates SCHF is totally absent. Thus, the regulations are dependent on various laws. Because of the non-specific regulatory system for the category of SCHF, the products under the category are not allowed to make any efficacy statements on the labels; rather, they are required to handle the issues of safety and quality comprehensively. Furthermore, the HF industry is forced to market SCHF products without mentioning the functions of active ingredients on the labels as well as any advertisement directed to the products since functional statements are prohibited in this category. In addition, the concerns being raised under such circumstances are that, although the majority of products in tablet and capsule forms are distributed as SCHF products, they are infrequently sold as in FOSHU products. Since SCHF differs from FOSHU due to the rigorous approval systems, SCHF products that satisfy the legal requirements, such as the Pharmaceutical Affairs Law, Food Sanitation Law, Health Promotion Law and Act against Unjustifiable Premiums and Misleading Presentation, based on voluntary judgments, may be freely available without acquiring any approvals from the Government. With the distribution of HF products in the forms of tablets and capsules, specifically in SCHF, overdosing is a major risk that causes crucial problems such as adverse reactions. In addition, exaggerated and false advertising, contamination with toxic substances and drug interactions are possibly found in the SCHF products that result in legal and often social problems. Serious HF-related health hazards that have occurred among Japanese consumers have been attributed to SCHF products. This problem suggests the need for the establishment of a more stringent law regulating supplements as practiced in many overseas countries. The MHLW has shown a strong concern and presented countermeasures. Paying much attention to HF products in the form of tablets or capsules, the MHLW has

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recently introduced two guidelines for the management of the manufacturing process with respect to GMP and the ‘self-investigation’ of the safety of raw materials for HF industry, requiring industries who are responsible for assuring the safety and quality to resolve aggressively the issues. The two guidelines are controlled under the Food Sanitation Law. Although following the guidelines is voluntary for manufacturers, the basis is in accordance with the Food Sanitation Law. GMP as a standard for managing the manufacturing process is demanded not only for finished products, but also for raw materials and for imported raw materials and finished products. The two guidelines are considered to be unique and important from the global point of view. Also, the guideline for assuring the safety of raw materials is like a ‘decision tree’, which is a highly sophisticated scheme and highly regarded internationally. As explained earlier in this chapter, the absence of a regulatory system for supplements implies that the system is not accepted in Japan even though the significance of supplements has been well recognized globally. On the other hand, the Government has begun to direct attention to the important issue of the products in the form of tablets, capsules, etc. Also, we anticipate that the necessity of supplemental products to be dealt with and managed by an independent legal system. Although the Japanese government is presently promoting the systemization of HF from an independent standpoint, apart from the global movement of supplement, we ought to plan to establish an exclusive regulatory system for supplements in light of international sharing of information and data for efficacy and safety, global harmonization of the methodology for quality management, and promotion of international trade. It is important to recognize that Japan is required to show an aggressive position toward the establishment of the regulatory system for supplements to enhance the understandings of roles that supplements play in the midst of the global harmonization, resolving various health concerns such as promoting health and reducing disease risks as well as improving welfare of all mankind. We also think that the roles that Japan plays are significant as proven in developing the concept of the functionalities of FD and presently proposing the new guidelines for safety and quality management by employing an advanced method. The newly introduced system added the qualified and standardized FOSHU. Such ‘deregulations’ are intended to resolve various issues, including the decrease in the number of illegal labeling, advertising and products with poor quality by bringing HF products under the FOSHU system. Since regulatory systems for HF in Japan have become rather complex compared to the systems in other countries, the MHLW strongly recommends consumer education concerning roles that HF products play and fostering supplement advisers, in view of safety and efficacy. As mentioned above, the MHLW is concerned about consumer overdosing on HF products on the market and is enforcing HF companies to perform a series of safety tests on their products to ensure the consumer health benefits. However, from the viewpoint of the HF industry, small and medium-sized companies may suffer a heavy cost burden for conducting safety and relevant tests to ensure the safety of the products, as well as introducing the GMP regulating standards. As a result, we anticipate that some of the companies may have to withdraw from the HF market, while large food or pharmaceutical companies will have opportunities to enter and expand the

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Discussion 279

businesses in the HF market. In fact, most of the FOSHU products approved are of the major companies with good research and development. To surmount such competition is obviously vital. Thus, various organizations including universities/scientific institutes, local commercial organizations and the Government vigorously collaborate with the small and medium HF companies, particularly in the area of safety and proper marketing of HF, which will ultimately benefit the consumers and industry and prevent consumers from buying unsafe HF products. As a basic rule, not all FD listed in the non-DR are safe. To reduce any health hazards to consumers, the effort of manufacturers alone is not sufficient. Of course, consumers need to have accurate information on the FD or HF products that they ingest, although sellers and mass media such as TV, newspaper, magazines, books, etc., ought to provide them with proper information and data. In particular, healthoriented TV programs which play a critical role; for example, the recent incidence of a popular TV program which took place in January 2007 caused a social concern and questioned morals of mass media by faking scientific evidence for health benefits of FD (12). In this case, audience ratings were the priority, while accurate information on FD was not conveyed to the audience including HF users. To provide reliable data on effects and safety of HF ingredients to consumers and any updated issues including HF related to health hazards on HF, National Institute of Health and Nutrition (http://www.nih.go.jp/eiken/english/index.html) and Tokyo Metropolitan Health Bureau and Life Culture Bureau (http://www.metro.tokyo.jp/ENGLISH/index. htm) should therefore play important roles. It is a challenge to make consumers aware of the presence of such websites and resources of information and data on HF. Appropriate usage and safety of such HF products should be explained by the sellers to consumers who are also required to read the label statements carefully and to obtain product information/data. If this cannot be accomplished, a system to support consumer awareness of HF safety and usage should be performed by educating and/ or training the consumers by health professionals, for example, certified FD specialist, nutritionist, pharmacist and/or even physician by employing all communication means available such as radio, TV, drugstore, clinics, etc. Additional concern is abuse or false information and data from websites on HF, which should be strictly monitored by the Government; hence, the Government supports the establishment of websites offering accurate information and data to consumers for their health benefits and risks, capitalizing on the aforementioned organizations. More recently, diversified HF products have been reported by health organizations for the interaction of HF product(s) with OTC and/or prescribed DR that consumers ingest. Since HF products are considered as FD, no clear dosage direction (unlike DR) is stated on labels, as discussed before. Thus, overdosing, concentrated ingredients and simultaneous intake of DR causing health hazards are distinctly controlled by regulations based on the accumulation of scientifically substantiated data on negative HF and DR interaction. The other measure to protect health benefits of consumers is post-surveillance of FD that includes SCHF and FHC. Although the MHLW has recently initiated to develop methodology for the post-surveillance of FD, an effective method is not yet under investigation. Also, the MHWL recognizes that procurement and accumulation of information and data on health hazards including FD-DR interaction are urgently

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required. The present situation thereby is to respond to reports on adverse reactions generated by medical centers and institutes and to handle each case by releasing the reported cases to the public, leading to prohibition of selling these products. It is our hope that all consumers enjoy health benefits from proper and well-regulated HF products and go on with their daily living being protected from various diseases, which will also help to reduce medical costs incurred to the Government.

Acknowledgments We thank Mr J. Makino of CMP Japan Co., Ltd. for providing us with invaluable information and advice. We are also grateful to Mr S. Ando of Biohealth Research Ltd. for collecting information of regulation on HF.

References 1. Arai S. (1996). Studies on functional foods in Japan. Biosci Biotechnol Biochem 60, 9–15. 2. Ohama H, Ikeda H, Moriyama H. (2006). Health foods and foods with health claims. Toxicology 221, 95–111. 3. Sugimura T. (2002). Food and cancer. Toxicology 181–182, 17–21. 4. Hosoya N. (1998). Health claims in Japan-foods for specified health uses and functional foods. J Nutr Food 1, 1–11. 5. Tsukamoto Y, Ichise H, Yamaguchi M. (2000). Prolonged intake of dietary fermented soybeans (natto) with reinforced vitamin K2 (menaquinone-7) enhances circulatory -carboxylated osteocalcium concentration in normal individuals. J Hlth Sci 46, 317–321 (abstract in English). 6. Yamaguchi M, Taguchi H, Gao YH, Igarashi A, Tsukamoto Y. (1999). Effect of vitamin K2 (menaquinone-7) in fermented soybean (natto) on bone loss in ovariectomized rats. Bone Min Metab 17, 23–29. 7. Fujikura K, Chiba Y, Yano H, Kobayashi C. (2003). Effect of soft drink containing soy isoflavone on urinary bone resorption marker (deoxypyridinoline) in middle aged women. J Nutr Food 6, 69–79. 8. Ishikawa T, Jun CJ, Fukushima Y et al. (2002). Effect of soy protein drink on serum lipids in subjects with high and normal cholesterol level. J Nutr Food 5, 29–40 (abstract in English). 9. Anderson JW, Johnstone BM, Cook-Newell ME. (1995). Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 333, 276–282. 10. Sakanaka S, Aizawa M, Kim M, Yamamoto T. (1992). Preventive effect of green tea polyphenols against dental caries in conventional rats. Biosci Biotech Biochem 56, 593–594. 11. Fujita H, Yamagami T, Ohshima K. (2001). Effects of an ace-inhibitory agent, katsuobushi oligopeptide in the spontaneous hypertensive rat and in borderline and mild hypertensive subjects. Nutr Res 21, 1149–1158. 12. Cyranoski D. (2007). Japanese TV show admits faking science. Nature 445, 804–805.

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Regulations on Health/ Functional Foods in Korea

18

Ji Yeon Kim1, Dai Byung Kim1 and Hyong Joo Lee2 1

Program in Food Science and Biotechnology, School of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, South Korea 2 Nutrition and Functional Food Headquarters, Korea Food and Drug Administration, Seoul, South Korea

Abstract The term ‘health/functional food’ (HFF) refers to food supplements containing nutrients or other substances (in a concentrated form) that have a nutritional or physiological effect whose purpose is to supplement the normal diet. The Korean Health/Functional Food Act that came into effect in 2004 requires these products to be marketed in measured doses, such as in pills, tablets, capsules and liquids. HFFs are of two types: generic and product-specific. There are 37 ingredients listed in the act for generic HFFs and, if an HFF contains a new active ingredient that is not included in the generic 37 products, it is considered a product-specific HFF. The standardization, safety and efficacy of a new active ingredient are reviewed by the Korean Food and Drug Administration in order to receive approval as a product-specific HFF. Conforming with international standards and protecting public health requires constant upgrading of the Health/Functional Food Act.

Introduction The rapid increase in the elderly population is expected to increase the prevalence of chronic diseases such as diabetes, cardiovascular disease and cancer. These trends have compelled scientists to identify physiologically active components in food, and Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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282 Regulations on Health/Functional Foods in Korea

more and more media output is dedicated to the relationship between diet and health. The increasing amount of public information available regarding the health benefits of foods has resulted in a consumer’s interest in health issues becoming a leading factor in purchasing decisions. Therefore, labeling and advertising should be clear and correct and avoid any misunderstanding or exaggeration. The requirement to protect consumers and ensure their right to accurate information on food functionality has led to the introduction of regulations about functional food and dietary supplements in many nations since the 1990s, including the USA, Japan and the EU. The Health/Functional Food Act (HFFA) introduced in Korea in 2002 (1) defined only supplement forms of HFF under food. This chapter reports on the scope of functional foods, the strength of the evidence required for their efficacy, safety considerations and future perspectives in Korea.

Health/Functional Food Act The Korean Health and Welfare Committee of National Assembly proposed the HFFA in November 2000. In August 2002, the HFFA was enacted as a new regulatory framework for the safety, efficacy and labeling of health/functional foods (HFFs) and it came into effect in January 2004. The ultimate goal of this act is to enhance public health by ensuring the safety of new active ingredients. From a regulatory perspective, the law defined HFFs as food supplements containing nutrients or other substances (in a concentrated form) that have a nutritional or physiological effect whose purpose is to supplement the normal diet. The act requires these products to be marketed in measured doses (e.g. as in pills, tablets, capsules and liquids) so as to ensure good manufacturing practice. Before the HFF was signed into law, there were a few categories in which health benefit advertisements could be made without premarket approval: nutrient supplement, health supplement, ginseng and its products, and foods for patients. These were regulated like other conventional foods under the Food Hygiene Act and were not subject to any evaluation system. As a result, the market was confusing and it was very difficult legally to introduce new active ingredients. However, the HFFA made HFFs a new category that was separated from conventional foods. HFFs are divided into generic and product-specific HFFs. The generic HFFs contain products that had health benefit claims under the Food Hygiene Act, such as nutrient supplements and ginseng and its products, and health supplements, as listed in Table 18.1. All new ingredients that are not generic HFFs are subjected to efficacy evaluation before marketing on the basis of their ingredients or physiologically active components to ensure the accuracy of the health claims. Authorization is granted on a productby-product basis by issuing a certificate without regulatory amendments. The HFFA does not define what constitutes ‘substantiation’ for a claim made for an HFF. Instead, it gives the Korean Food and Drug Administration (KFDA) the exclusive authority to evaluate the safety and efficacy of HFFs prior to their introduction to the market and also makes manufacturers or distributors responsible for providing all evidence backing up the claims of their products by developing substantiation for claims or relying on existing information.

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Generic Health/Functional Foods 283

Table 18.1 Generic health/functional foods Nutritional supplement Ginseng product Red ginseng product Eel oil product EPA/DHA-containing product Royal jelly product Yeast product Pollen product Squalene-containing product Yeast-containing product Probiotics-containing product Chlorella product Spirulina product Gamma-linolenic-acid-containing product Embryo bud oil product Embryo bud product Lecithin product Octacosanol-containing product Alkoxy-glycerol-containing product

Grape seed oil product Fermented vegetable-extract product Mucopolysaccharide product Chlorophyll-containing product Mushrooms product Aloe product Japanese apricot-extract product Soft-shelled-turtle product Beta-carotene product Chitosan-containing product Chito-oligosaccharide-containing product Glucosamine-containing product Propolis-extract product Green-tea-extract product Soy-protein-containing product Phytosterol-containing product Fructooligosaccharide-containing product Red yeast rice product

Under the HFFA, claims about nutrient functions, other functions and reductions of disease risk that are compatible with those adopted by the Codex Alimentarius Commission in 2004 (2) can be used for labeling and advertising HFFs. Each type of claim is defined as follows: – Nutrient-function claims: these claims describe the physiological role of the nutrient in the growth, development and normal functions of the body. Such claims should be applied to the nutrients, which have their own recommended daily amounts (RDAs) and be based on current, university-level nutrition texts as a possible source of evidence – Other-function claims: these claims concern specific beneficial effects of HFFs in the context of the total diet on normal functions or biological activities of the body. Such claims relate to a positive contribution to health, to the improvement of a function, or to modifying or preserving health – Reduction-of-disease-risk claims: these claims describe the relationship between the consumption of HFFs (in the context of the total diet) and the reduced risk of developing a disease or health-related condition – Claims about the use of HFFs to prevent or cure specific diseases are not permissible. The KFDA intends to develop a more focused definition for such disease-related claims.

Generic Health/Functional Foods There are 37 products in the HFFA for generic HFFs (3), among which the major ones are 13 vitamins, 11 minerals, essential amino acids, proteins, dietary fiber and essential fatty acids (Fig. 18.1).

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Chito oligosaccharide containing product 2% Propolis extract product Others 3% 17%

Nutritional supplement 29%

Chlorella product 3% EPA/DHA containing product 3% Gamma-linolenic acid containing product 3% Yeast product

Red ginseng product 10%

3% Probiotics containing product 9%

Aloe product 4%

Glucosamine containing product 9%

Ginseng product 5% (a)

Propolis extract product 2%

Others 19% Nutritional supplement 41%

Chlorella product 5% EPA/DHA containing product 8%

Gammalinolenic acid containing product 3%

Yeast product 3%

Ginseng product 2%

Aloe product 6%

Glucosamine containing product 8% Probiotics containing product 3%

(b)

Figure 18.1 Market status of health/function food in Korea (as at October 2005) (a) Produced in Korea; (b) imported into Korea.

Nutrient-function claims should be only made for vitamin and mineral supplements, which have their own RDAs. They are well-established health claims describing the physiological role of the nutrient in the growth, development and normal functions of the body. The amount of vitamin/mineral supplements should be between designated upper and lower limits. The lower limit was set as 30% of the recommended daily amount for Koreans and the upper limit was determined as that at which adverse effects occur; the upper limits are now being amended based on nutrient risk analysis. Dietary fiber supplement is included in the nutritional supplements with claims related to weight management and maintaining good gastrointestinal

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conditions. However, because the functionality and characteristics of dietary fiber are very diverse, they are supposed to be separated from nutritional supplements and divided into each product. Among generic HFFs, green tea extract (antioxidant), soy protein (cholesterol lowering), red yeast rice (cholesterol lowering), fructo-oligosaccharide (maintaining good gastrointestinal conditions) and phytosterol (cholesterol lowering) were most recently added after the HFFA was enacted. The safety and efficacy of these HFFs were evaluated by the KFDA. Also, KFDA will expand the numbers of generic HHFs, continuously. Others include docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA), glucosamine, chitosan/chito-oligosaccharide, octacosanol, mucopolysaccharide, aloe, probiotics, gamma-linolenic acid and lecithin, some of which exert only a tonic effect. Therefore, the efficacies of generic HFFs have been re-evaluated since 2004 and this will be complete by 2007.

Product-Specific Health/Functional Foods If manufacturers or distributors want to make HFFs that are not included in the list of generic HFFs, they have to apply for approval as a product-specific (4). First, if a functional dietary ingredient in the product is not in the list of generic HFFs (and hence is regarded as new), manufacturers or distributors have to provide the KFDA with evidence of the standardization, safety and efficacy of the product. The KFDA must perform a premarket review within 120 days of receiving the application focused on the origin and nature of the ingredients, contents of functional component (or index components), processing methods, information on the methods and validation for analysis of functional components, data on the stability, and purity (in terms of the content of microbial, heavy metals, pesticides, etc), and scientific evidence of the safety and efficacy of the HFFs. The evaluation by the KFDA begins once the applicant has submitted the relevant documents. The KFDA first determines if the standardization has been performed adequately and then evaluates the safety, efficacy and specification. If the ingredient meets the required standard, its efficacy is formally designated as such.

Standardization The applicant has to submit data on the special characteristics of the functional ingredient (or, in the case of an unclear functional ingredient, an index ingredient) and state the yield and change in content of the functional component (or index component) resulting from the main manufacturing processes. The KFDA then evaluates the adequacy of these data.

Safety Evaluation The safety of the active ingredient is assessed by the KFDA reviewing submitted data, including that on the history of use, manufacturing processes, amount to be consumed, results of toxicity tests, results of human study and results of nutritional evaluation and bioavailability. The safety of the active ingredient should be validated

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A

Yes Is the ingredient registered according to regulations related to materials ‘not permitted in the use of HFFs’? No Has the material of animals, plant, algae, or m/o origin been used before without further process?

No Yes Are there any serious side effects?

No

Has the material been processed before?

Yes

Yes

No Is there any change in the exposure level? Yes

B C

C

Yes

Is a physical modification of simple extraction method involving water or fermented alcohol?

No

D

No Is it a synthesized ingredient? No

Yes

Is it approved as a food/food additive?

Yes

No Is there any change in the exposure level? Yes

B D

No Is it same as any single substances existing in nature?

Yes

D

No

A

Others

D

[Scope of data on safety to be submitted] A

B

C

D

Data on its history of safe use

V

V

V

Results on database searches on side effects and toxicity

V

V

V

Results on evaluating the intake

V

V

V

V

V

Cannot be used as a raw ingredient for a health/functional food

Results on nutritional evaluation Results on toxicological data, and other data that support its safety

V

V

Figure 18.2 Decision tree for the preparation of safety data.

scientifically with reference to a decision tree (4) (Fig. 18.2). We divide the preparation of safety data into four categories: 1. cannot be used as a raw ingredient for an HFF 2. scientific data or historical use describing its manufacturing process, usage and the amount of intake, database searches of the side effects and toxicity, evaluating the amount to be consumed

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3. scientific data or historical use, database searches of the side effects and toxicity, evaluating the amount to be consumed and evaluating the nutritional effects 4. database searches of the side effects and toxicity, evaluating the amount to be consumed, evaluating the nutritional effects, toxicity data and other data possible to prove its safety.

Efficacy Evaluation The evaluation of efficacy of HFFs should differ from those of medicines, since the targets of HFFs are either healthy individuals or individuals in a preliminary stage of a disease or borderline condition in an at-risk group. Therefore, the effectiveness might be less distinct for these individuals using HFFs than for patients with a particular condition taking medicine. No formula exists for how many or what types of studies are needed to substantiate a claim regarding HFFs and so the KFDA applies a standard of ‘competent and reliable scientific evidence’, not only to provide manufacturers or distributors flexibility in the precise amount and type of evidence, but also to maintain consumer confidence in HFFs. In order to evaluate whether the supplied information constitutes ‘competent and reliable scientific evidence’, each study is reviewed independently, followed by considering the strength of the total body of evidence, as follows: ●

●

Reviewing individual studies: first, the design type of each study is characterized. Competent and reliable scientific evidence adequate to substantiate a claim would generally consist of information derived primarily from human studies. In particular, a randomized, double-blind, parallel-group, placebocontrolled intervention study is considered the gold standard. Other types of scientific evidence such as that from animal studies, in vitro studies, anecdotal evidence, meta-analysis and review articles would generally be considered background information, but alone may not be adequate to substantiate a claim unless there are sufficient animal studies and in vitro studies to explain the biochemical and physiological mechanisms for the beneficial effect on health or to show dose–response relationships. Second, the scientific quality of each study is reviewed based on several factors including the study design and implementation, the study population, data collection, outcome measures, statistical analysis and confounding variables. A scientific study that adequately addresses most of the above factors would be considered to be of sufficiently high quality. Reviewing the totality of studies: although the type and quality of the individual studies are important, each piece of data therefrom should be considered in the context of all available information. The strength of the entire body of scientific evidence can be considered based on several criteria, including quantity, consistency and relevance. The collection of a larger amount of data from independently conducted studies makes the evidence more persuasive. It is ideal if the evidence used to substantiate a claim agrees with the background information, whereas conflicting or inconsistent results question whether a particular claim is substantiated. Relevant biomarkers may be used as indicators or

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Table 18.2 Appropriate statements for describing health/functional foods according to scientific evidence Type of claim

Level of scientific evidence

Appropriate statement

Reduction of disease risk

Significant scientific agreement

Other function (I)

Convincing

Other function (II)

Probable

Other function (III)

Insufficient

‘Can help to reduce the risk of … (disease)’ ‘Can have a beneficial effect on …’ ‘May improve …’ ‘May increase (decrease) …’ ‘May improve …, but this requires verification’ ‘May improve …, but the scientific evidence is insufficient’

predictors of the proposed relationship between an ingredient or a component and a health endpoint. There are concerns that consumer information on the health benefits of foods may be too limited if only claims that reach the standard required for scientific proof are allowed in the labeling and advertising of HFFs. The KFDA therefore introduced an evidencebased rating system, where the rank is determined taking into account the type and quality of individual studies and the quantity, consistency and relevance of the aggregated studies. Claims related to the reduction of disease require the highest level of evidence, primarily based on well-designed human intervention studies having a valid design for showing a persistent effect of an HFF. Also, it should be validated by the consensus of a significant scientific agreement among experts qualified with the appropriate scientific training and experience to evaluate them. However, a wider range of scientific evidence can be used for other-function claims. Although human intervention studies are preferred, animal and in vitro studies alone may be sufficient to demonstrate other-function claims of HFFs, especially if they are relevant to or sufficiently close representations of human metabolism. The KFDA defined the following three levels of other-function claims based on these variations in scientific evidence: ‘convincing’, ‘probable’ and ‘insufficient’ (Table 18.2). The evidence-based ranking system links the ranking of scientific evidence to the wording of relevant claims, where different levels of evidence will result in different appropriate statements (see Table 18.2). The KFDA intends to conduct consumer research in order to develop new statements or graphic formats to improve the understanding among consumers.

Specification The applicant should also submit samples of the product with documentation on the method used to analyze the functional component to the KFDA, which validates the method, determines the contents of the functional component and, if the decision is made to grant approval for the product as an HFF, confirms the period of conformity and hygiene specifications.

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Advisory Committees 289

Table 18.3 Types of efficacy of product-specific health/functional food Type of claim

Efficacy category

Reduction of disease risk Other function

Reduction of dental caries Reduction of blood pressure Reduction of cholesterol Reduction of body fat Maintenance of good health Modulation of blood glucose level Modulation of postprandial glucose level Keeping good gastrointestinal condition Antioxidative effect Improvement of memory function Improvement of cognitive function

No. of approved product-specific HHF

25

20

15

10

5

0 Reduction of Other function Other function Other function claim I disease risk claim II claim III Figure 18.3 Number of approved product-specific health/functional foods (as at October 2005).

Claims Approved in the Product-Specific Health/ Functional Food As at October 2005, 23 active ingredients and 27 product-specific HFFs have been approved by the KFDA. Most of the statements of Korean HFFs are for other-function claims, with claims for the reduction of disease risk only approved for the reduction in dental caries associated with the use of xylitol (Table 18.3, Fig. 18.3).

Advisory Committees The KFDA has advisory committees for HFFs comprising 80 experts with backgrounds in nutrition, food science, medicines and consumer unions. The committees comprise

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six subcommittees that advise the KFDA about regulation, good manufacturing practice, importing and exporting, new active ingredients, standards and specifications and labeling and advertisements.

Future Perspectives The ability to determine whether a claim does not mislead consumers is important in establishing a reliable process for health claims. In order to ensure a successful program for accurate and understandable health claims, it is essential to identify the appropriate words and phrases to convey to consumers in an understandable manner the different levels of scientific evidence underlying different claims. Our recent survey suggests that the present expressions are inadequate for informing consumers about the scientific evidence underlying other-function claims. Moreover, consumers consider that the present expressions do not describe the efficacy in an easily understandable manner. They consider that it would be more appropriate to explain the claims rather than provide a conclusive expression. The KFDA therefore needs both to develop statements of health claims that consumers can understand easily and provide consumer education to ensure that consumers make correct choices about HFFs. The labeling of health-related foods should always be based on scientific evidence that is consistent with international standards. Recent guidelines being developed by Codex (5) also suggest that health claims should be based on scientific evidence, especially human data. Korea has established a new regulatory system for food function claims, especially on the forms of supplements. However, the application of claims related to the reduction of disease risk to supplements is limited, because emphasizing the use of a supplement is likely to be misunderstood by consumers about the need for a balanced diet. Our opinion is that health claims and the associated regulation of supplements or functional foods should be based on the protection of public health. We therefore hope that Korean regulations developed for both HFFs and conventional foods will aim to protect public health and be consistent with international standards.

References 1. HFFA (2004). Health/Functional Food Act, 2004. Ministry of Health and Welfare, Korea. 2. CCFL (2004). Codex guidelines for use of nutritional and health claims, 2004. ALINORM 04/27/41. Codex Committee on Food Labeling. 3. HFFC (2004). Health/functional food code, 2004. No. 2004-14. Regulation of the Korea Food and Drug Administration, Korea. 4. RHFF (2006). Regulations on the premarket approvals of functional ingredient of product-specific health/functional food, 2006. No. 2006-36. Korea Food and Drug Administration, Korea. 5. CCNFSDU (2004). Proposed draft recommendations on the scientific basis of health claims at step 3, 2005. CX/NFSDU 05/29/9. Codex Committee on Nutrition and Foods For Special Dietary Uses.

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Chinese Approach on Regulating Food Additives, Novel Foods, Functional Foods and Dietary Supplements

19

Ashley Roberts and Rebecca Rogerson Cantox Health Sciences International, Mississauga, ON, Canada

Abstract As a result of increasing interest within the Chinese market among food and supplement industries, the Chinese Authorities have the responsibility of ensuring that any new food or food ingredient imported into or produced in China meets the safety standards established by the government. By adhering to these standards, the government establishes a decreased risk of food contamination and safety issues within their food supply. In China, the Food Hygiene Law (1995) establishes the general principles for food hygiene regarding foods, food additives, containers, packages, utensils and equipment used for foods. As the Food Hygiene Law (1995) establishes only the basic requirements for food hygiene, supplementary regulations regarding food additives, novel foods, functional foods and dietary supplements provide specific safety requirements. This chapter discusses the regulations of the above-mentioned products, providing the requirements for regulatory approval within the Chinese market.

Introduction The Chinese marketplace, having over a billion potential customers, is becoming of increasing interest to the multinational food and food ingredient industry wishing to Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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292 Chinese Approach on Regulating Food Supplements

market their products in this rapidly developing economy. The food and supplement industries are looking at China as a major business expansion opportunity for their products. Further interest has resulted because the changing economic climate of China has led to a change in the diet of many urban Chinese. The diet of the Chinese people is becoming increasingly ‘Westernized’ with the outcome that there is increasing evidence of rising obesity rates in children and adults. As a result of these dietary changes, the Chinese government has the responsibility of ensuring that any new food or food ingredient imported into China or produced in China meets the established safety standards and that there is a decreased risk of food contamination. The latest round of changes to the Chinese regulatory system provides the Chinese public with potential increased food choices. The Chinese regulatory system for food products could be classified as being unique within the world of fully established systems such as those developed in the USA, Europe and Australia/New Zealand. The purpose of this chapter is therefore to provide an overview of the regulations currently governing food additives, novel foods, functional foods and dietary supplements in China and how regulatory clearance is obtained for these products.

History of Food Regulations in China Food inspection and execution of food laws were established by the People’s Central Government Ministry of Public Health or Ministry of Health (MOH) soon after the commencement of the People’s Republic of China on October 1, 1949 (1). Subsequently, the State Council, which comprises various ministries including the MOH, was established in 1954. By 1965, the State Council had promulgated its prototype for food safety laws, named the Regulation for Food Sanitation Control for Trial Implementation, however, due to the Cultural Revolution from 1966 to 1976, this trial Regulation was not implemented owing to the collapse of the legal system (1,2). It was not until 1979 that new food hygiene laws were established under the Regulations on the Administration of Food Hygiene. As the Chinese economy grew, the laws regarding food hygiene were adapted to reflect the need to ensure food safety for the Chinese public. In 1982, regulations were formulated to establish the requirements for the sanitization of imported foods and food hygiene supervision and, on July 1 1983, these regulations were developed into the Food Hygiene Law of the People’s Republic of China (trial implementation). A finalized version of the Food Hygiene Law of the People’s Republic of China (Food Hygiene Law) was promulgated and implemented on October 30 1995, which provided revisions to the 1983 trial implementation to reflect the current economic position of the People’s Republic of China and remains today the most current version of the Food Hygiene Law in China.

Food Hygiene Law of the People’s Republic of China The purpose of the Food Hygiene Law (1995) is to ensure food hygiene, prevent food contamination or harmful substances from injuring human health, safeguard

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the health of the people, and improve physical fitness. This law consists of 9 chapters and 57 articles that provide the standards of hygiene for all foods, food additives, containers, packages, utensils and equipment used for foods. Standards for detergents, disinfectants, premises, facilities and establishments associated with food production or marketing are likewise established within this law, however, while general standards are established, the Food Hygiene Law (1995) does not establish specific limits for food production or marketing, sensory properties or safety. Instead, specific limits are established within supplementary regulations to the Food Hygiene Law (1995). While the majority of the hygiene standards for food and anything associated with food are controlled by the State Council and associated national agencies, the Food Hygiene Law (1995) allows provincial and municipal governments and interested parties to set hygiene standards where national standards are lacking. This law allows the responsibility of food hygiene control to be shared throughout all levels of government within the People’s Republic of China, with the overall control existing with the national authorities. The Food Hygiene Law (1995) provides definitions for foods, food additives, food fortifiers, containers and packages used for food, food production or marketing and producers or marketers of food, however, the control of farming industries, such as the crop and extensive livestock industry, is excluded from this law. This law also provides a rudimentary outline of administrative procedures for hygiene, outlining the basic approval process for domestic and imported or exported foods, as well as providing general labeling requirements. Since the Food Hygiene Law (1995) establishes general standards for food hygiene, this law is intended to be supported through the use of regulations that specifically outline the requirements for foods, food additives and all things associated with food. For example, the basic regulatory requirements for food additives, novel foods, functional foods and dietary supplements are established within this law, but greater detail regarding the regulatory procedure of these products is provided in the regulations discussed below.

Food Additive Regulations Food additives are regulated and approved by the Ministry of Health of the People’s Republic of China (MOH). This is the department of the State Council that is directly responsible for all health related issues within China. Health administrative departments within the provinces, autonomous regions and municipalities also are involved in the regulation of food additives by reviewing domestic food additive applications before they are forwarded to the MOH. The China Food Additive Association (CFAA), established in 1993, assists the Chinese government in making regulations and policies regarding industrial standards, quality supervision and market entry by collecting domestic and foreign opinions on behalf of the industries and presenting the opinions to the MOH. The CFAA also expands the application of any newly developed technology and products and is the only nationwide food additive and ingredients industry organization approved

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by the government. The purpose of the CFAA is to contribute to the sound development of the food and food additive industries, as well as to the safety and health of consumers. Food additives, as defined by the Food Hygiene Law (1995), are synthetic chemicals or natural materials added to food for the purpose of improving quality, color, flavor or taste. Food additives also may be added to food for the purposes of preservation from decay and for processing technology. While the Food Hygiene Law (1995) does set hygiene standards for food additives, the regulatory requirements for food additives are established in two documents promulgated by the MOH. The Administrative Measures for Food Additive Hygiene (Ministry of Health Decree No. 26) defines the regulatory process for obtaining approval from the MOH for new food additives or changes in uses and use levels of previously approved additives, whereas the Food Additive Hygiene Standard (GB 2760-2007) provides a list of approved food additives.

Administrative Measures for Food Additive Hygiene (Ministry of Health Decree No. 26) On July 1 2002, the Administrative Measures for Food Additive Hygiene (Ministry of Health Decree No. 26) became effective, replacing the previous version, dated March 15 1993. The 2002 version of the Administrative Measures (Decree No. 26) provided updates to the 1993 version so as to reflect the changing Chinese economy and to accelerate administration regarding the hygiene of food additives, prevention of food contamination and to protect the health of consumers. Gaining regulatory approval for food additives is a two-step process. The first step is to obtain approval from the MOH for the food additive by proving safety, whereas the second step is for the manufacturer to obtain a hygiene license before producing, marketing or using the food additive. Both of these steps are explained in further detail below. Approval from the Ministry of Health

All food additives permitted for use in food at defined use levels are published within the Food Additive Hygiene Standard. Any new food additives or previously approved food additives with an increase in the application scope or use level are required to obtain regulatory approval from the MOH before it can be imported, produced or marketed. Food additives are evaluated on the basis of their safety. The standard of safety for food additives is established by providing documents that explain the production techniques, the source of the material along with the physical and chemical properties, the testing methodologies, the product quality standards and the regulatory status of the food additive in foreign markets. Safety of the additive is further supported through toxicity studies. A prior favorable Joint FAO/WHO Expert Committee on Food Additives (JECFA) evaluation also is taken into consideration and provides further supporting evidence of the safety of the material. In the absence of a JECFA

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safety opinion or listing by Codex Alimentarius (Codex), a food additive normally requires approval in two or more major countries before acceptance is granted by the MOH. Before a new food additive application is made to the provincial health administrative departments or the MOH, a sample of the food additive should be sent to a testing agency accredited by the provincial health administrative department. The testing agency will perform toxicity tests, if required, as well as hygiene tests on three consecutive batches of the product. After the completion of the tests, the testing agency will provide a report to the manufacturer or importer that must be included in the application documents to the provincial health administrative department or the MOH. Also, if microorganisms are used to produce the food additive, the approved testing agency will provide appraisal reports on the bacteria strain and safety assessments. Domestic Food Additive Application Should a manufacturer wish to produce, market or use a new food additive variety or increase the application scope or use level of a previously approved food additive, an application for approval must be made to the local health administrative department at the provincial level. The provincial health administrative department will conduct a preliminary review of the food additive application, to verify if the application is complete, legitimate and consistent. Should the province accept the application, they will submit a preliminary opinion to the MOH. The MOH convenes an expert panel of toxicological, nutritional, medical, pharmaceutical and other technical personnel once every 2 months to undertake a technical review of all food additive applications collected during that time period and prepare opinions on the acceptability of the food additives. Imported Food Additive Application An importer wishing to market or use a new food additive variety or increase the application scope or use level of a previously approved food additive must submit an application for approval to the MOH. The MOH convenes an expert panel of toxicological, nutritional, medical, pharmaceutical, and other technical personnel once every 2 months to undertake a technical review of all food additive applications collected during that time period and prepare opinions on the acceptability of the food additives. If the food additive is manufactured overseas and is intended to be sold in China, the application also must include certificates from the government of the exporting country demonstrating that the food additive has been approved for production and marketing. Accreditation documents of the manufacturer produced by the regulated agency or organization from the country of origin must be provided. It is recommended by the Chinese Authorities that overseas applicants have the registration of new food additives handled by a representative officer or authorized agent in China. Hygiene License

Once the applicant has obtained approval from the MOH regarding the safety of the food additive, the manufacturer must obtain a hygiene license before producing,

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marketing or using the food additive. To obtain a hygiene license, the manufacturer must submit an application and documents to support the hygiene of the manufacturing facility, which should include information regarding production conditions and techniques, equipment, quality guarantee system and quality standards.

The Food Additive Hygiene Standard The Food Additive Hygiene Standard lists permitted food additives for use in food in China. The original version of this Standard (GB 2760-1996) published December 29 1996 and implemented February 1 1997. Since its implementation, many new food additives or alterations in food additive uses have been approved by the MOH and subsequently published in circular reports from the MOH. On August 22, 2007, a new version of the Food Additive Hygiene Standard (GB 27602007) was issued and became effective June 1, 2008. The new Standard references the format and provisions of CODEX STAN 192 General Standard for Food Additives of codex Alimentarius Commission. Furthermore, this Standard replaces GB 2760-1996 as well as GB/T 12493-1990 (Classification and Coding of Food Additives). The Food Additive Hygiene Standard (GB 2760-2007) (provides categorized lists of food additives based on their use in food and further explains the scope of the application of the food additive and the maximum allowable levels to be used in food. The Standard also includes a list of permitted natural and synthetic flavorings, tentatively permitted flavorings, gum-based substances and ingredients permitted in chewing gum and processing aids recommended for food industry use.

Novel Food Regulations In China, novel foods are known as new resource foods. On July 28, 1990, the Hygiene Administration Regulation for New Resource Foods became effective, establishing the regulatory process and supporting documents required for the regulatory approval and labeling of the new resource foods. In 2007, these Regulations underwent a substantial review and new regulations for new resource foods were drafted February 21, 2007. The Regulations, now named Administrative Measures on New Resource Foods (Order of the Ministry of Health No. 56) defined new resource foods as raw food materials or food ingredients which do not have a significant history of consumption in China, meaning that the regulatory process will apply to novel food ingredients and not final novel food products. Furthermore, new resource foods are separated into the following 4 categories: (1) animals, plants and microorganisms that are not traditionally consumed in China; (2) raw food materials that are derived from animals, plants, and microorganisms and are not traditionally consumed in China; (3) new varieties of microorganisms that are used during food processing; or (4) raw food materials, the original composition or structures of which are significantly changed by the adoption of new techniques during production. This definition, however, does not include transgenic foods, which are regulated by the Ministry of Agriculture and are outside the scope of this discussion.

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Administrative Measures on New Resource Foods On December 1 2007, the Administrative Measures for New Resource Foods became effective, establishing the regulatory process and supporting documents required for the regulatory approval and labeling of new resource foods. Under these Measures, applicants wishing to obtain regulatory approval for a new resource food must submit an application for registration to the MOH along with documentation supporting the safety of the new resource food. As the Administrative Measures for New Resource Foods (Order No. 56) establishes the regulatory approval process for new resource foods based on the safety of the food and not efficacy, new resource foods are not permitted to make health claims. The regulatory process for approval of new resource foods is described in detail below. Approval from the Ministry of Health

New resource foods are evaluated on the basis of their safety or, if applicable, the basis of substantial equivalence to other approved new resource foods. Materials required for the new resource food application and assessment include the name of the new resource food, source of the material, production techniques and processes, testing methodologies, product quality standards, food hygiene quality analysis data, composition analysis data, estimated intake, toxicological data, regulatory status of the new resource food in foreign markets, new resource food labels, purpose and scope of use of the new resource food biological traits of strains, genetic stability, pathogenicity, virulence, etc. of microorganism products, and a sample of the new resource food. Should a manufacturer or importer wish to produce or market a new resource food, an application for approval must be made to the MOH by sending the New Resource Food Registration Application Form along with all required materials listed within the Measures. A preliminary review of the new resource food application package will be conducted by an Assessment Committee consisting of toxicological, nutritional, medical, pharmaceutical, and other technical personnel to determine if the application is complete, legitimate and consistent. After the preliminary technical review, the Assessment Committee will determine the required safety testing, test sample batches, test methods, and test institution approved by the MOH. The cost of the testing conducted by the MOH approved institution will be the responsibility of the applicant. The Assessment Committee also will determine whether to conduct on-site examinations and collections of sealed samples and will inform the applicant. If it is determined that on-site examinations and collections of sealed samples are required following the preliminary technical assessment, the provincial health administration authority will organize the examinations and collections. Based on the Assessment Committee’s conclusions following the technical review and the results of the testing agency and on-site examination, the MOH will conduct an administrative review to decide whether to accept the registration of the new resource food and inform the applicant of the decision. After the MOH has decided to accept the registration of the new resource food, a list of approved new resource foods will be published on the MOH website, which will include the

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name, source, specification, usage scope, and purpose of the approved new resource food. Furthermore, any new resource food substantially equivalent to resource foods previously approved by the MOH can be directly sold in the Chinese market without approval by the MOH. It is recommended by the Chinese Authorities that overseas applicants have the registration of new resource foods handled by a representative officer or authorized agent in China.

Functional Food and Dietary Supplement Regulations As a result of government restructuring in 1998, the MOH’s Department of Drug Administration merged with the State Pharmaceutical Administration of China to become the State Drug Administration (SDA). The SDA was responsible for all drug manufacturing, trade and registration, whereas the responsibility of food manufacturing, trade and registration remained with the MOH. In 2003, however, the SDA was reorganized to become the State Food and Drug Administration (SFDA). The SFDA is based on the US Food and Drug Administration (US FDA), providing a centralized governmental organization that controls and regulates the safety management of foods, health foods and medicines. Interestingly, however, the regulations guiding food additives and new resource foods remained under the control of the MOH. As a result of the formation of the SFDA, new interim regulations regarding health foods were drafted and accepted by the State Council in 2005. The Administration Regulation for Health Food, promulgated June 1 1996 by the MOH, was revised in 2005 by the SFDA and became the Interim Administrative Measures for Health Food Registration (Decree of the State Food and Drug Administration No. 19). The Interim Measures (2005) expand on the original definition of a health food as defined by the MOH. While the basic definition of a health food remained the same, such as regulating bodily functions for a specific population and not being permitted for the treatment of diseases, the SFDA expanded the definition to include vitamin or mineral fortified or enriched foods and further established that a health food is not to produce any harmful effects. The SFDA also published 27 accepted functions of health foods, such as regulating the immune system, delaying senility, memory enhancement, growth enhancement, anti-mutation and tumor inhibition, blood lipid regulation, libido enhancement, blood sugar regulation, etc. As before, the new definition did not provide any distinction between functional foods and dietary supplements. The definition retained that functional foods and dietary supplements are to be considered under the same regulation. The Interim Measures (2005) also expand on the requirements for approval, providing outlines for the application process for new or changes in the composition of approved health foods and for transferring the manufacturing of the health food from one manufacturer to another. Furthermore, the measures differentiate between application processes for health foods that are manufactured in China (domestic health foods) and those that are manufactured overseas (imported health foods).

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These measures further explain and define raw materials and supplementary materials used in the manufacture of health foods and the required standards that they must meet, as well as specifications for labels, testing, re-registration, re-examination, legal liabilities and supplementary provisions for health foods. While the Interim Measures (2005) provide much greater detail regarding application requirements in comparison to the former, the Interim Measures (2005) are not meant to be used alone. The SFDA has published seven other Interim documents stating specific requirements beyond those established in the Interim Measures (2005) for the application of health foods containing fungi, probiotic microflora, nucleic acids, wild plants, animal products and amino acid chelates, as well as nutritional supplements and health foods applying macro reticular resin separation and purification techniques. Furthermore, five other health food-related documents have been published by the SFDA outlining the supplementary requirements, requirements for application items and formats for applications, license and registration related notifications. The basic approval process for health foods did not change between the MOH version of the Administrative Measures and the SFDA’s version, with the exception that the SFDA now assumes the responsibility for health foods rather than the MOH.

Approval of Health Foods The process for domestic and imported health food regulatory approval is similar, with the exception of where the application is originally sent. In the case of imported health foods, the use of a local Chinese agent to help with the application process is recommended by the SFDA as the agent will have access to notarized translators to translate any foreign documents into Chinese and will be able to advise the applicant of any requirements beyond the basic requirements presented in this chapter. Before the application for a health food is sent to the local food and drug administration department or the SFDA, the applicant must send samples of the health food to testing agencies approved by the SFDA for testing and examination. Along with the health food sample, the applicant should prepare a product research and development report if the functions of the health food are within the specified functions of health foods published by the SFDA. A product research and development report should include information on the basic concept of the research and development of the health food, function screening process and expected effects. If the functions of the health food are outside the 27 functions recognized and published by the SFDA, the applicant should conduct animal and human trials as well as provide a function research and development report to the testing agency. The function research and development report includes information on the name of the function, the reason for application, function testing, evaluation methods and test results. If the applicant is unable to conduct animal and human trials, a reason should be supplied in writing with the sample and the function research and development report to the testing agency. The testing agency will conduct the animal and/or human trial at a fee to the applicant. The testing agency will conduct safety toxicology tests, function tests on the effective or main ingredients, hygiene tests and stability tests

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on the health food and provide a report of the results to the applicant that is to be included with the application to the SFDA or local food and drug administrative departments. Domestic Health Food Application A health food that is manufactured and sold within China must gain regulatory approval though the SFDA. Applicants must send the Domestic Health Food Registration Application Form along with all required materials listed in the Interim Administrative Measures for Health Food Registration (2005), as well as any other relevant SFDA published requirements and samples of health food, to the food and drug administrative departments in the provinces, autonomous regions or municipalities. The food and drug administrative departments will review the application to see if the application documents are standard and complete. If the application is accepted, the food and drug administrative departments also are responsible for checking the testing and sample production sites for compliance with good manufacturing practices. During the application process, the approved testing agency is to carry out the examination of the sample and re-examination provided from the food and drug administrative department within 50 days and produces a test report. The test report is to be sent to the SFDA as well as to the food and drug administrative departments of the province, autonomous region and municipality and the applicant. Upon receipt of the test and examination report from the testing agency and samples from the food and drug administrative departments, the SFDA will form an expert panel of food, nutritional, medical, pharmaceutical and other technical personnel to review the application dossiers and form an opinion accepting or rejecting the registration of the health food. This expert panel meets once a month to discuss the registration of new health food products. As stipulated within the Interim Administrative Measures for Health Food Registration (2005), the application process should take about 150 days from time of application to receipt of approval or rejection notification; however, depending on the quality of the submitted dossier and product, this process could take more than a year. Should the SFDA decide to accept the registration of the health food, the applicants will be issued a Domestic Health Food Registration Certificate. Imported Health Food Application An imported health food refers to a health food that is manufactured and sold overseas for more than a year that is intended to be sold within the territory of China. The registration process for an imported health food follows a similar examination process as a domestic health food, with a few exceptions. The applicant must submit an Imported Health Food Registration application form along with application materials and product samples to the SFDA directly, rather than through the food and drug administrative departments of the provinces, autonomous regions or municipalities. As a result, the SFDA will examine the application materials for compliance with the standard format and completeness. If the application is accepted for further examination, the SFDA will send a test notification and product samples to the approved testing agencies, which will carry out the examination

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Conclusions 301

of the sample and produce a test report. The SFDA may decide to examine the manufacturing site and experimental site to ensure compliance with good manufacturing practices. Upon receipt of the test report from the approved testing agency, the SFDA will assemble an expert panel of similar members as in the Domestic Health Food Registration process once a month to review the application dossiers and decide on approval or rejection of the health food registration. The entire application process should take approximately 140 days as stipulated within the Interim Administrative Measure for Health Food Registration (2005). This amount of time is less than the domestic registration as the application is sent directly to the SFDA and does not have to go through the food and drug administrative departments of the provinces, autonomous regions or municipalitie, however, depending on the quality of the dossier and product submitted for approval, this process could take longer than a year. If the health food is approved for registration, the SFDA will send notification along with an Imported Health Food Approval Certificate, which is valid for 5 years, effective after issuance.

Conclusions In China, food additives are considered materials that are added to foods in an effort to improve quality, color, flavor, taste and for the purpose of preservation or the required processing techniques. Food additives not listed in the Food Additive Hygiene Standard or other official published sources must be approved by the Ministry of Health (MOH) before import and marketing. An application should be made to the local health administrative department at the provincial level or directly to the MOH. Prior to making an application, a sample of the food additive should be sent to a testing agency accredited by the provincial health administrative department. The testing agency will perform toxicity tests, if required, as well as hygiene tests. After the completion of the tests, the testing agency will provide a report to the manufacturer or importer that must be included in the application documents to the provincial health administration or MOH. The MOH shall arrange an expert meeting once every 2 months to decide if the applications for food additives gathered during that period shall be approved. Once approval has been granted, the manufacturer must obtain a hygiene license before producing or marketing the food additive. Overseas applicants are requested to have the registration of new food additives handled by a representative officer or authorized agent in China. Novel foods in China are called new resource foods and are currently defined as raw food materials or food ingredients which do not have a significant history of consumption in China, meaning that the regulatory process will apply to novel food ingredients and not final novel food products. Furthermore, new resource foods are separated into 4 distinct categories. Similar to new food additives, new resource foods require regulatory approval from the MOH prior to being available for sale within the Chinese market. The approval process likewise includes the submission of an application to the MOH who will convene an Assessment Committee to decide the necessary product testing to be conducted by a testing agency approved

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by the MOH and to decide whether on-site examinations and sample collections are required. Based on the conclusions of the Assessment Committee, the MOH will conduct an administrative review of the new resource food. The MOH will publish a list of approved new resource foods on the MOH website, which will include the name, source, specification, usage scope, and purpose of the approved new resource food. Furthermore, any new resource food substantially equivalent to resource foods previously approed by the MOH can be directly sold in the Chinese market without approval by the MOH. Overseas applicants also are requested to have the registration of new resource foods handled by a representative officer or authorized agent in China. In contrast, functional foods and dietary supplements in China are considered a ‘health food’ and require registration with the State Food and Drug Administration (SFDA) in order to be permitted for import and sale. Health foods are permitted to be marketed with a health claim. However, before the application for registration will be accepted, testing of samples, including toxicity, efficacy, active ingredient, hygiene and stability tests, must be conducted by designated testing agencies. Health foods are permitted to make reference to health benefits or altered bodily functions, but may not make reference to the treatment or cure of disease. Imported health foods are required to be manufactured overseas for more than one year. An application for approval of a health food requires a list of health claims, concentrations and testing methods for the functional ingredients, manufacturing process information, product quality specifications, test certificates from a suitable test facility for toxicology, efficacy, formulation, contaminants, stability, sample product packaging, documents demonstrating the product is approved for sale in the country of origin, a sample of the product, evidence the product has been produced and marketed in the country of origin for more than 1 year, and standards from the country of origin. Application materials are required to be prepared in Chinese and translations should be notarized by a domestic notary to ensure consistency with the original. To facilitate the Chinese regulatory process, foreign applicants are advised to have the registration of health foods handled by a representative officer or authorized agent in China. Once the application for health food registration is received, the SFDA will provide a letter of acceptance or rejection, which is dependent upon receipt of the required application materials. If registration is granted, an Imported Health Food Approval Certificate is issued to the applicant. The unique regulatory system established by the Chinese Authorities and presented in this chapter allows interested manufacturers and importers of this greatly expanding economy to easily comply with the regulations, while clearly establishing a safe food supply for the Chinese population.

References 1. Pan D. (1997). Food and drug regulation of the People’s Republic of China: a comprehensive analysis of the PRC food and drug regulatory structures and laws. Available from: http://www.leda.law.harvard.edu/leda/data/168/dpan.pdf

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2. Yongmin B. (2004). The challenges for food safety in China: current legislation is unable to protect consumers from the consequences of unscrupulous food production. China. Perspectives no 53, May–June, 2004, p. 4. Available from: http://www.cefc. com.hk/uk/pc/articles/art_ligne.php?num_art_ligne ⫽ 5301

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The Legislative Regulation of Biologically Active Food Supplements Circulation in the Russian Federation

20

Victor A. Tutelyan and Boris P. Sukhanov RAMS Institute of Nutrition, Moscow, Russia

Abstract Biologically active food supplements (BAFS) have become a dynamically growing market in economically developed countries such as Russia. The Russian Federation (RF) defines BAFS as nutritive substances and minor food components used to ameliorate deficiencies, decrease risk of debilitating diseases and improve life quality. The RF plays an important role in regulating nutraceutical and functional foods through health and safety legislation, general requirements of BAFS and label content requirements. This chapter gives an account of the principles of estimating food supplement quality, safety and efficacy as well as of the legislative base, regulating the registration process and control over food supplement turnover in the Russian Federation. In addition, the positive and negative components that form or eliminate, respectively, a food substance as a BAFS are discussed.

Introduction In recent years, the production and circulation of biologically active food supplements (BAFS) are becoming one of the most dynamically developing branches of economics, Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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306 The Legislative Regulation of Biologically Active Food Supplements Circulation

trade and the means of population life quality improvement in all economically developed countries. In Russia, this market has been developing since 1990. After the State registration, these products were referred to the group of (Russian) as the English term ‘Food additives’ implies. Several years later, a new term ‘biologically active food supplements’ was introduced in Russia (1), which resulted in a clear-cut differentiation between these two quite different groups of products. According to the experts (2), there was practically no BAFS market in Russia in 1990 and this market did not emerge until 2005. At that time, there were more than 3000 BAFS produced by more than 600 businesses. In 2005, the Russian BAFS market capacity (allowing for all kinds of sales) was about 1.1 billion US dollars. It should be pointed out that nowadays more than half of BAFS present in the Russian market is produced in Russia. In view of the importance and necessity for the control of micronutrients and the deficiency prevalence among the population of vitamins, minerals and biologically active substances, dietary fiber, polyunsaturated fatty acids and others, the Russian Federation (RF) government approved in 1998 the ‘State Policy in Healthy Nutrition of the Population of the Russian Federation by the year 2005’ (3). It is for the first time in the RF in this document that BAFS are defined as the means for the rapid elimination of deficiency of nutritive substances and minor food components in the diet and are characterized as the most acceptable at present products contributing to nutrition and life quality improvement as well as to the decrease of the risk of many widespread human diseases. A goal of active escalation of domestic production of BASF was set. The results of large-scale epidemiologic studies and achievements in biochemistry, physiology of nutrition, chemistry, pharmacognosy, genomics, proteomics, metabolomics and other sciences, obtained during the last 15–20 years in various countries including the Russian Federation, became the fundamental scientific basis for the development of this new trend in nutriciology. It was established that structure, nutrition quality of the population of economically developed countries and its energy consumption had markedly changed by the end of the 20th century. It was also established that scientific and technical revolution resulted in the energy consumption decrease from 3000–3500 kcal/day in the middle of the last century to 1900–2100 kcal/day at the present time. Such dramatic energy consumption decrease has brought about drastic reduction of the role of food as the only source of energy, micronutrients and biologically active compounds. Food product industrialization has greatly contributed to the change of food quality. At the same time, the needs of individuals for essential nutritive and biologically active substances have changed insignificantly since it is determined by the evolution of human development and is genetically secured. Food ration strength, i.e. its richness in dietary and biologically active substances has not changed, however. If we consider human nutrition from the evolution point of view, we can easily see that the formation of dietary links has occurred in such a way that bulks of food for human energy consumption at the level of 2800–3500 kcal/day provided the main dietary substances, micronutrients and minor food components. At the same time, smaller bulks of consumed food could not provide people with adequate amounts of micronutrients and minor food components. The resulting discrepancy is the objective that prevents modern people from getting necessary amounts of micronutrients

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and biologically active substances from ordinary natural products with adequate energy content. As a result, the population experiences shortage of essential dietary substances, in particular micronutrients and biologically active minor components in their diet. Therefore, it is necessary to find alternative sources of such compounds and to develop ways for their use in everyday diets. Another matter explaining keen interest of the population in BAFS is the active introduction of ‘chemistry’ in all spheres of human life including nutrition. It causes opposing reaction in part of the population and attraction of people to natural and historically traditional nutrition. The development of the pharmaceutical industry, biotechnology, chemistry, the introduction of super state-of-the-art technologies of vegetable and other raw materials treatment to obtain highly pure biologically active compounds and their complexes made it possible to produce adequate bioactives and minor components of food in unlimited quantities. It remained to be decided which forms are the most suitable for administration. Pharmaceutical dosage forms such as pills, capsules, powders, dragée and others turned out to be optimal. By using biologically active substances in these forms, one could stick to a strict dosage depending on a person’s need, gender, age, health, occupation and other factors. On the one hand, the combination of these components was crucial for arousing the interest of people in natural biologically active substances and the need to use them for the improvement of nutrition and life quality and prevention of many diseases. It also opened up new prospects and opportunities for their production in necessary amounts and their practical use. The scientific component necessitating an additional use of biologically active and minor food components as pharmaceutical forms was, on the one hand, proof of their important role in ensuring vital activity and, on the other hand, their deficiency in the diet of modern man. Currently, due to the above-mentioned causes, the majority of the population of economically developed countries, as well as of Russia, experience deficiency of polyunsaturated fatty acids (omega-3 and omega-6), soluble and insoluble dietary fiber (pectin, gums, mucilage, cellulose and others), vitamins (B group, E and others), a wide specter of vitamin-like natural substances (L-carnitin, ubiquinone, choline, methylmethioninesulfone, lipoic acid and others), macroelements (calcium and others) and microelements (iodine, iron, selenium, zinc and others) in their diet (4). Evidence-based medicine principles helped to obtain new data concerning the biological role of natural minor biologically active substances in the human organism. First of all it relates to such compounds as: ●

●

●

●

various groups of flavonoids (flavonols and their glycosides – quercetin, kaempferol, rutin and others; flavons – luteolin, apigenin and others; flavonons naringenin, hesperidin and others; dehydroflavanols, proanthocyanidins, catechins and others) the physiological functions of which are extremely diverse and important in decreasing the risk of many widespread diseases including cardiovascular and oncological diseases indoles which regulate the activity of enzymes at the first and second stages of metabolism and render foreign substances harmless exogenous peptides and certain amino acids and their mixtures. Their role in the regulation of organs and systems function was proved by numerous studies

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(peptides, for example, provide a specific intermolecular interaction with promotor parts of genes, their fragments are ingredients of a number of polypeptides – interleukins, cytostatin, thyroglobulin and others). The important role of organic acids, fenolic compounds, beta-sitosterols, isoflavons, isotiocyanates, glucomannans, polyfrutanes, inulin, chlorophyll, caffeine, hipericin, glucosamines, chondriotisulfate, chitosan and many others as components of nutrition has been proven. Biologically active compound deficiency in a diet leads to a myriad of adverse consequences, such as decreased resistance of the organism to unfavorable environmental factors (maladaptation), development of immunodeficiency states, disturbance of antioxidant systems function, chronic diseases, a higher risk of disease development, worsening life quality and inadequate effectiveness of treatment. Thus, today there is a general agreement endorsing the importance of micronutrients and minor components of food as essential elements of nutrition. We have discovered more than 120 biologically active compounds (‘Recommended levels of nutritive and biologically active substances consumption’, MR 2.3.1. 1915-04) of plant, animal and biotechnological origin relating to minor components of food. Decoding the mechanism of their action made it possible to use them as BAFS components for individualized nutrition, replenishment of their deficiency in the diet and decrease of the risk of many diseases. Medicinal plants, seafood traditionally not used for nutrition, biotechnological and less often chemically synthesized products and other natural sources (bee-keeping products, mumiyo) can be used as the sources of such similar food compounds. The use of such sources is quite justifiable both from economic and scientific points of view since the content of their biologically active substances exceeds that of traditional foodstuffs tens and hundreds-fold. The legal part of BAFS circulation is regulated by the Russian Federation Laws ‘Sanitary and epidemiological well-being of the population’ (No 52 March 30, 1999, the first version of the Law was adopted in 1991), ‘Quality and safety of food stuffs’ (No 29 January 02.02. 2000), ‘Consumer rights protection’ (No 196 December 30, 2001), ‘Advertisement’ (No 38 March 13, 2006), by RF Government Resolutions, Russian Federation National standard ‘Food stuffs. Information for consumer. General requirements’ (State Standard P No 51074-2003) as well as by a number of other Federal level documents including Sanitary regulations and norms (SanRaN), methodical instructions (MI) and methodical recommendations (MR) concerning various aspects of turnover control, quality ensuring, safety and effectiveness of this new kind of product for the country. Health Ministry, ‘Rospotrebnadzor’ Orders, Resolutions of RF Chief State sanitary doctor and other documents play an important role in the system of BAFS turnover control. These RF Laws require that the manufacturers bear responsibility for their quality, safety, effectiveness, authenticity and completeness of information on the products. Legislative, normative and methodical base guaranteeing the safe use of BAFS have been created in the Russian Federation by the present time. It is much stricter than that in Europe, USA or Asia. The first stage of this base creation dated back to 1997 when the first document concerning BAFS turnover regulation in Russia was issued. It was in 1997 that the Health Ministry of Russia passed the order ‘Expert examination and hygienic certification procedure of biologically active dietary supplements’. According to RF Sanitary legislation,

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BAFS in Russia is subject to State registration, carried out by ‘Rospotrebnadzor’ on the Federal level. BAFS State registration is the confirmation of BAFS quality and safety in accordance with RF sanitary legislation in a given area. BAFS State registration data are introduced in the BAFS Federal list, which is available at the Russia Rospotrebnadzor site. RF Law ‘On quality and safety of foodstuffs’ puts BAFS in the group of foodstuffs and gives them the following definition: BAFS are ‘natural (identical to natural) biologically active substances meant to be consumed along with food or to be incorporated into foodstuffs’. Thus, BAFS in food are not medicines meant to treat and diagnose human diseases. As a part of foodstuffs, they are an additional source of essential scarce dietary (amino acids, vitamins, macro- and microelements, polyunsaturated fatty acids, vitamin-like and other compounds) substances and the source of biologically active substances. State sanitary-epidemiological surveillance (Rospotrebnadzor) exercises control over their production and turnover. According to Russian Federation sanitary legislation, BAFS in food can be produced as various pharmaceutical forms in conformity with technical documents. BAFS are the source of the components of animal, plant and mineral origin mainly relating to essential nutrition factors. They can include both components of natural origin and compounds produced by means of biotechnological and chemical methods. Compounds to be synthesized by the latter technologies must obtain a special permission prior to their production. Unlike medicines, which include biologically active substances with curative aim and in curative doses which exceed the physiological need of a healthy person ten-fold and hundred-fold and are administered both per os and parenterally, BAFS are used to replenish deficiency in the diet. Their daily dose does not exceed the physiological need and they are administered only per os with food. As a rule, BAFS exert their effect by stimulating universal mechanisms of adaptation-adjustment response of the body to various external and internal factors. At the same time, quantitative changes of parameters of body system functioning are within their physiological boundaries. BAFS may only be used in various diseases in combination with specific medicines and as an element of curative diet (dietetic or curative nutrition), but they must never be used as medicines alone since they are not medicines by definition. BAFS help to shorten disease duration, accelerate convalescence processes, avoid certain complications and chronic disease, cut down the doses of specific chemotherapy and reduce terms of patients’ stay in hospitals. To avoid a possible mutual negative effect one must take into consideration the compatibility of BAFS and medicine composition during their combined use. According to the sanitary legislation of Russia, BAFS may be considered an additional source of proteins, fats and carbohydrates only if their number in a single BAFS portion is at the level which is not lower than 2% of recommended daily intake of these components. The level of vitamins, macro- and microelements and biologically active substances must not be lower than 10%. At the same time, according to international practice, the content of vitamins in a daily dose of BAFS must not exceed the recommended daily intake (an adequate level of daily intake) more than threefold (the uppermost permissible level of consumption) for vitamins A, D, K, B1, B2, B6, B12, niacin, folic and pantothenic acids, biotin and more than 10-fold for vitamins E and C. If a manufacturer recommends a vitamin dose exceeding the adequate level, proof must be accompanied with the recommendation. Such proof can be given both on the basis of analysis and generalized literature

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data and on the basis of specific experimental or clinical studies. These documents are submitted to the process of BAFS State registration in Russia. The number of mineral substances (macro- and microelements) in BAFS should be at the level not exceeding twice the daily (adequate) requirement (the uppermost permissible level). Recommendations for a higher level of mineral substances (more than 100% of the adequate level) as well as vitamin consumption must be convincingly substantiated by documents. Vitamins and mineral salts content in BAFS daily dose must be 10–100% of the recommended daily (adequate) consumption level. The extensive use of medicinal plants in the make-up of BAFS necessitated the development of a normative-methodical base providing an effective control of safety and quality of this kind of product. According to generally accepted international practice, parameters such as toxic elements, pesticides, mycotoxins, sanitary-significant microorganisms, radioactive nuclides and so on, safety problems of such products have already been solved both abroad and in Russia; however, the problem of BAFS safety after incorporation of medicinal plants and their extracts (in methodological and methodical respect) had not been solved until 2004, not only in Russia but also in other countries as well (quality control of pharmacologically active substances and the establishment of their admissible level in BAFS make-up, values of BAFS components authenticity). While solving this problem, it was very important to preserve the ‘golden mean’. When, on the one hand, the product containing medicinal plants would be the source of biologically active substances and, on the other hand, would remain in the group of foodstuffs (BAFS). Having started solving this problem, we paid attention to the fact that many biologically active substances of medicinal plants are included in foodstuffs of plant origin. For example, anthrachiones are both a part of such commonly used dietary plants as rhubarb, dock, legumes and such herbs as Cassia tora, Aloe vera, Polygonum bistoria; isoflavons are included in legumes as well as in such herbs as Trifolium pretense and Sophora japonica. Being administered with food in small quantities, pharmacologically active substances regulate functional activity of human systems and organs within physiological boundaries of their activity. In bigger doses, these substances produce a more marked impact on human organs and systems beyond the parameters of physiological boundaries of human organs and systems functional activity. In this latter instance, sources of biologically active substances should be related to medicinal means of natural origin and used according to doctors’ prescription and under their control. Bearing in mind the importance of biologically active and minor compounds in supporting functional activity of human systems and organs and their deficiency in population’s ration due to limited, monotonous and refined nutrition as well as inability to get them with traditional food, we tried at first to isolate the most common biologically active substances from medicinal plants most commonly used in BAFS sold in the Russian market. Then we tried to find nutritive plants containing these biologically active substances. By analyzing literature data, generalizing our own experience as well as by considering this problem with pharmacologists, clinicians, toxicologists, pharmacodiagnostitians and other specialists, by taking into account population nutrition structure and calculating the feasible content of certain biologically active substances in the daily ration, we examined the data on certain biologically active compounds intake with daily ration and thus acquired recommended values of their daily consumption. The

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results of this work have become a scientific basis for the use of herbs incorporated in BAFS as the sources of biologically active compounds important for human nutrition. Unfortunately, this method is time consuming, complicated and very costly. The second method of calculating the permissible amount of medicinal plants in BAFS, which we used, is much simpler and accessible. Together with the above mentioned group of specialists, we did the following calculation: if we use a medicinal plant as a curative means, the content of pharmacologically active compounds of a medicinal plant in a daily dose of BAFS should not exceed 50–60% of a single therapeutic dose. The lower margin of these compounds’ content in BAFS should not be lower than 10% of a single therapeutic dose. Such a method, on the one hand, ensured the presence of essential for life compounds in a BAFS, on the other hand, did not characterize this BAFS as possessing curative properties and guaranteed safety according to the criterion of specific pharmacologically active components content. This criterion is the most important reference point in solving the problem of a certain biologically active substance dose in a BAFS. This work helped to identify traditional and alternative sources of nutritive and biologically active substances which can be used in BAFS production, to name the values of adequate and the highest permissible levels of more than 120 biologically active substances consumption and to develop ‘Recommended levels of nutritive and biologically active substances consumption’ (MP 2.3.1. 1915-04) (see Appendix 20.1). Traditional sources of nutritive and biologically active substances are the sources of nutritive and biologically active compounds of animal, plant and microbiological (biotechnological) origin undoubtedly and traditionally relating to nutritive (food) raw material and nutritive products. Alternative, identical to natural, sources of nutritive and biologically active substances are the sources permitted for nutritive and medical use in accordance with established procedure, not undoubtedly relating to traditional nutritive raw material and nutritive products (medicinal plants, substances obtained as the result of biotechnological or chemical synthesis, natural mineral raw materials, bee-keeping products, mumiyo and others). BAFS safety in the process of their market turnover must be ensured by reliable methods of checking the content of active substances in them and confirming the authenticity of claimed components in product composition. These are the criteria of control for BAFS quality and effectiveness. A methodical base helping to carry out quantitative identification of more than 120 active components in the composition of a given product has been developed in RF (Manual P 4.1.1672-03 ‘Manual on the methods of quality and safety control of biologically active dietary supplements’). In 2000, a positive list of components which can be used in the process of BAFS production was approved in Russia (SanRaN 2.3.2.1078-01 ‘Hygienic claims on safety and nutritive value of food products’). The list includes more than 190 names (see Appendix 20.2). This document also contains a negative list (forbidden components). It starts with the components containing potent, narcotic, psychotropic and poisonous substances. According to this list, BAFS in RF must not contain: ● ●

substances alien to food, nutritive and medicinal plants not natural synthetic substances – analogues of active elements of medicinal plants (which are not essential factors of nutrition)

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● ● ●

● ● ●

●

antibiotics hormones potentially dangerous tissues of animals, their extracts and products of their processing including materials capable of transmitting agents of prion diseases (bovine spongiform encephalopathy, BSE): skull, including brain and eyes, palatal tonsils, spinal cord and vertebral column of cows (bulls) older than 12 months, goats, sheep (rams) older than 12 months or having molar incisors erupting through gums; spleen of sheep (rams) and goats; when it becomes known that in the process of production of imported to RF BAFS raw material of animal origin was used, the epidemiological situation with BSE in the country of the company producing these components must be taken into account; this point is included on the basis of EU Commission Decision ‘EU Commission Decision of July 30, 1997 (97/534/EU) 75/320/EEU on prohibition of the use of material presenting risk of transmitting spongiform encephalopathies’ human tissue and organs spores-forming microorganisms (Bacillus subtilis, B. licheniformis and others) species of genera and kinds of microorganisms including opportunistic variations of microorganisms (Enterococcus faecalis, E. faecium, Escherichia, Candida and others) live yeast; the validity of this stand is due to the fact that Saccharomyces cerevisiae is often isolated in patients with disseminated infection as well as due to their strong antagonism to normal microflora of the human gastrointestinal tract.

Later the following microorganisms were added to the negative list: ●

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all kinds of microscopic fungi belonging to Aspergillus, Alternaria, Candida, Chaetomium, Cladosporum, Fusarium, Geotrichum, Penicillium, Pseudollescheria genera; 48 species causing human diseases (mycoses) were identified among them species of genera and kind of bacteria containing varieties causing human diseases or capable of acting as vectors of antibiotic resistance genes Spore-forming aerobic microorganisms – species of Bacillus genus: B. polymyxa, B. cereus, B. megatherium, B. thuringiensis, B. coagulans (Lactobacillus coagulans is its obsolete name) and other species of this genus lactobacilli and other species of sporeless microorganisms, isolated from animal and avian organisms and unusual to normal protective human microflora.

Besides, such objects of animal origin as Scorpiones L. (the whole body), all kinds of Lytta spp. (the whole body), Coccinella septempunctata L. (the whole body) are prohibited to be used in BAFS. Sanitary-epidemiological expert evaluation of BAFS precedes its State registration and is carried out by organizations authorized by Rospotrebnadzor to ascertain the quality and safety correspondence of products to operating legislative acts and normative requirements. It includes the following procedures (Methodical instructions ‘Definition of safety and effectiveness of biologically active dietary supplements’, Russia Health Ministry, M. 1999, p. 88): ●

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primary expert evaluation of the application, documents and materials characterizing a given product

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●

●

determination of the need and extent of necessary BAFS investigations carrying out a complex of necessary sanitary-chemical, sanitary-microbiological and other kinds of investigations and evaluation of their results to confirm safety, formula components and the quantity of active ingredient authenticity experimental studies of toxic, physiological and metabolic effects to confirm BAFS safety and claimed effectiveness (if necessary) clinical evaluation (if necessary) the evaluation of experimental and clinical studies results (if they were not carried out) evaluation of the results of the studies determining the content of the main ingredients and BAFS authenticity preparation and drawing up of the opinion of the commission of experts, including the draft of the product’s label; their approval by the organization carrying out sanitary-epidemiological expert evaluation followed by the submission of the opinion of the commission of experts and the draft of the label to ‘Rospotrebnadzor’ for drawing up of a registration document in an established order.

All documents for carrying out sanitary-epidemiological expert evaluation are submitted in the original form and/or as notarized copies and with the translation into Russian. All kinds of BAFS investigations are carried out at institutions and laboratories accredited for definite kinds of work in an established order. BAFS for children of various age groups occupy a substantial part of this group of products. As a rule, such BAFS are the source of micronutrients (vitamins, mineral substances, certain kinds of polyunsaturated fatty acids and others). There are no objections to using products with such composition in pediatric practice, since children of all age groups very often reveal a deficiency of these components. However, recently, the manufacturers of these products started to include in BAFS various medicinal plants including unofficial ones with a marked pharmacological effect. Is it well-grounded and necessary? Children under 14 are especially sensitive to non-traditional and, in particular, to nutritive effects. Their metabolic systems are not completely formed and are not always capable of effective resistance and adequate response to increased load. At the same time, BAFS are administered without a doctor’s prescription, which is a highly potential threat to the health of children. Thus, in Russia, BAFS for children under 14 may include a very limited number of nutritive, spicy and medicinal plants (see Appendix 20.3). Vitamins and mineral substances are included in accordance with the positive list published in SanRaN 2.3.3. 1940-05 ‘Arrangement of pediatric nutrition’ (see Appendix 20.4). Components with pre- and probiotic effect may be used in this group of products. Components used in BAFS for children must conform to special hygienic safety and nutritive value standards, established by sanitary-epidemiological rules and standards (SanRaN 2.3.2.1078-01 ‘Hygienic requirements for safety and nutritive value of food products’). It is postulated in SanRaN 2.3.2.1293-03 (‘Hygienic requirements on the use of food supplements’) that fragrances, dyes, stabilizers, preservatives, dietary supplements with the exception of pediatric nutrition products allowed for manufacture must not be included in BAFS and herbal teas for children under 3. The use of artificial sweeteners (sugar substitutes) is also prohibited.

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The problem of including information in the column ‘Contraindications’ on the label is extremely important in the process of State registration. According to RF legislation (SanRaN 2.3.2.1290-03 ‘Hygienic requirements to the arrangement of production and turnover of biologically active food supplements (BASF)’, this column should solely contain information on the substances included in the given BAFS. If these substances are nutritive substances and micronutrients, it is pointed out that BAFS is an additional source of particular vitamins or mineral substances; if a BAFS contains only herbal components, it is pointed out that it is the source, for example, of arbutin, quercetin, ubiquinone and so on. It is prohibited to include information concerning any medical effects of BAFS in this column. In 2006, Rospotrebnadzor introduced a non-governmental system of voluntary BAFS certification entitled to create its own voluntary BAFS certification registration document after the consideration of the results of BAFS clinical trials. The column ‘Recommendations for use’ of this document may include expected medical effects of the BAFS. RF sanitary legislation (SanRaN 2.3.2.1290-03 ‘Hygienic requirements for the arrangement of production and turnover of biologically active food supplements (BASF)’ allows the following wording concerning BAFS effectiveness: for optimization of carbohydrate, fat vitamin and other kinds of metabolism in various functional conditions; for normalization and/or improvement of the functional state of human body organs and systems, including agents producing general tonic, mild sedative of other effects in various functional states; for decreasing morbidity risk; for normalization of gastrointestinal tract microflora; as enterosorbents. Other claims on BAFS labels are prohibited. These claims mainly coincide with BAFS labeling practice adopted in many countries. It should be pointed out that this problem has not been completely solved and is being continually discussed both on the international level and on the level of individual countries. BAFS marketing cannot be realized without meeting other requirements for their labels content (SanRaN 2.3.2.1290-03 ‘Hygienic requirements to the arrangement of production and turnover of biologically active food supplements (BASF)’). Requirements for BAFS labels content: ●

●

●

●

●

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the name of BAFS. The name must not disclose the expected effectiveness of the product, or the manufacturer must give convincing proof of such effectiveness a complete BAFS composition. The ingredients should be named in the order corresponding to the decrease of their weight and percent content without indicating the quantity of each component; after naming the main BAFS ingredients, the manufacturer must name all auxiliary substances included in BAFS in the order corresponding to the decrease of their weight and percent content information on BAFS weight and volume in a single consumer package and weight or volume of a product unit recommendations for the use (requirements are given above), dose and the route of administration information on contraindications

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Introduction 315

● ● ● ● ●

●

notification that the product ‘Is not a medicine’ notification ‘Consult a doctor before the use’ manufacture data, guaranteed shelf-life or the expiry date of the product storage conditions information on BAFS state registration, naming the number and the date of registration the whereabouts, the name of manufacturer; the whereabouts and the telephone of the organization authorized by the manufacturer (distributor) to receive complaints from consumers.

The use of the term ‘Ecologically clean product’ in the name and in the information on a BAFS label, as well as the use of other terms having no legislative and scientific justifications is prohibited. BAS package must guarantee its safety and quality at all stages of its circulation. Materials used for BAFS packaging must be those allowed in established order to be in contact with nutritive products or medicines. BAFS may be sold in RF in pharmacies, pharmacy stores, pharmacy kiosks, specialized stores selling dietary products and specialized departments in supermarkets. BAFS must not be sold: if they have not passed state registration; without quality and safety certification; if they do not meet sanitary requirements and standards of quality and safety; with expired shelf-life; in the absence of adequate conditions of sale; if it is impossible to identify them; without labels as well as when the information on the label does not conform with that agreed upon during state registration; if the information stipulated by the requirements of an operating legislation is not written on the label. BAFS re-registration is carried out in the following situations: ● ●

● ●

at the expiration of the period of validity of the existing registration certificate upon the change of name, BAFS dispense form, spheres and recommendations of use, contraindications and limitations of its use upon change of requirements included in BAFS hygienic characteristic upon change of trade mark of a BAFS manufacturing firm or the change of manufacturing place (enterprise-manufacturer).

BAFS advertising must not contradict data agreed upon during state registration; BAFS which have not passed state registration must not be advertised; it must not be advertised as a unique and the most effective and safe remedy having no side effects; advertisements must not delude consumers concerning BAFS composition and effectiveness; advertisements must not produce the impression that natural origin of the raw material used in BAFS is a guarantee of its safety; advertisements must not undermine consumers’ faith in the effectiveness of other remedies; advertisements must not produce the impression of the uselessness of a physician’s role in BAFS use, especially in BAFS of herbal origin. In conclusion, observance of all requirements for BAFS in accordance with the modern legislative and normative base is an important condition for providing the population with safe and quality BAFS essential for nutrition optimization and human health.

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References 1. Tutelyan V. (1996). Food supplements: past, present and future. Problems Nutr 6, 3–11. 2. Khoudova D, Melik-Gusseinov. (2006). Food supplements market in Russia. Pharmaceut Bull 10, 20 March. 3. On State Policy in Healthy Nutrition of The Population of the Russian Federation by the year 2005. Government decree No. 917 of 10 August 1998. 4. Policy of Healthy Diet. Federal and regional levels. (2002). Siberian University Press, Novosibirsk.

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Traditional nutritive products and food raw materials of animal and plant origin

Alternative sources of identical to traditional sources of nutritive and biologically active substances

Cranberry, pear

Arbutin

Arctostaphylos uva-ursi, shoots, leaves; Chimaphila umbellata, plant (over ground part); pear, leaves; Plantago major, leaf and seeds; Bergenia crassifolia, leaves; Vaccinium myrtillus L. leaf; Vaccinium vitisidaea, leaf

Onobrychis meschetica, root; pear, leaves; Arctostaphylos uva-ursi, leaves; Bergenia crassifolia, leaves 8 mg

5 mg

Adequate level of consumption (measurement un.: mkg, mg, g, CFU /day)

Source: Recommended levels of nutritive and biologically active substances consumption (MR 2.3.1. 1915-04)

Blueberry, anise, pear, cow berry

Hydroquinone

Simple phenols

Phenol compounds

Biologically active substances of natural origin. Minor food components

Nutritive and biologically active components of food

25 mg

15 mg

The upper permissible level of consumption (measurement un.: mkg, mg, g, CFU /day)

Recommended values of nutritive and biologically active substances daily intake for adults included in dietary (curative and prophylactic) nutrition products and BAFS to food (a fragment)

Appendix 20.1

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Appendix 20.2 Biologically Active Substances, Food Components and Their Sources, Producing no Harmful Effect on Human Health, used for Producing BAS to Food Nutritive Substances

Proteins and their derivatives (of animal, plant, microbial and other origin): isolates, concentrates, hydrolysates, amino acids and their derivatives Fats, fat-like substances and their derivatives Vegetable oils sources of essential polyunsaturated fatty acids, phytosterins, phospholipids, fat-soluble vitamins Fish and sea animal oil – sources of polyunsaturated fatty acids, phospholipids and fat-soluble vitamins Individual polyunsaturated fatty acids isolated from food sources: linoleic, linolenic, arachidonic, eicosapentaenoic, docosahexaenoic and other fatty acids Sterins isolated from nutritive raw material Midchain triglycerides Phospholipids and their precursors including lecitin, cephalin, choline, ethanolamine Carbohydrates and products of their processing Dietary fiber (cellulose, hemicellulose, pectin, lignin, gums and others) Polyglucosamines (chitosan, chondriotin sulfate, glycosaminoglycanes, glucosamine and others) Starch and products of its hydrolysis Inulin and other polyfructosanes Glucose, fructose, lactose, ribose, xylose, arabinose Vitamins, vitamin-like substances and co-enzymes; vitamin C (ascorbic acid, its salts and ethers), vitamin B1 (thiamin), vitamin B2 (riboflavin, flavin mononucleotide), vitamin B6 (pyridoxine, pyridixal, pyridoxamine and their phosphates), vitamin PP (nicotinamide, nicotinic acid, salts of nicotinic acid), folic acid, vitamin B12 (cyanocobalamin, methylcobalamin, pantothenic acid (salts of pantothenic acid), biotin, vitamin A (retinol and its ethers), carotenoids (beta-carotene, lycopene, lutein and others), vitamin E (tocopherols, tocotrienols and their ethers), vitamin D and its active forms, vitamin K, p-aminobenzoic acid, lipoic acid, orotic acid, inositol, methylmethioninesulfone, carnitin, pangamic acid Mineral substances (macro- and micro elements): calcium, phosphorus, magnesium, potassium, sodium, iron, iodine, zinc, boron, chromium, copper, sulfur, manganese, molybdenum, selenium, silicon, vanadium, fluorine, germanium, cobalt;

Minor Components of Food Enzymes (of plant origin or obtained by biotechnological methods on the basis of microbial synthesis)

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Appendix 20.2 319

Polyphenolic compounds including those with the marked antioxidant activity, namely, flavonoids, anthocyanins, catechins and others Natural metabolites: succinic acid, alpha-ketoacids, ubiquinone, citric acid, fumaric acid, tartaric acid, ornitin, citrulin, creatin, betain, glutathione, taurine, hydroxycitric acid, indoles, isothiocyanates, octacasanol, chlorophyll, terpenoids, iridoids, resverathrol, steviosides.

Probiotics (In Monocultures and in Associations) and Prebiotics Bifidobacteria including species infantis, bifidum, longum, breve, adolescentis Lactobacilli including species acidophilus, fermentii, casei, plantarum, bulgaricus and others; Lactococcus; Streptococcus thermophilus; Propionibacterium and others Various classes of oligo- and polysaccharides (fructo-oligosaccharides, galacto-oligosaccharides of natural origin, microbial synthesis and others) Biologically active substances – immune proteins and enzymes, glycopaptides, lysozyme, lactoferrin, lactoperoxidase, bacteriocines of lacto-microorganisms excluding specimens obtained from human tissues and liquids.

Plants (Nutritive and Medicinal), Sea, River, Lake Products Reptiles, arthropoda, mineralo-organic and mineral natural substances (dry, powdered, tabletic, incapsulated, as aqueous, alcoholic, fatty, dry and liquid extracts, decoctions, syrups, concentrated balms): mumiyo, spirulina, chlorella, inactivated yeast and their hydrolysates, zeolites and others

Bee-Keeping Products Queen-bee milk, propolis, wax, bee pollen, bee-bread Source: SanRaN 2.3.2.1078-01 ‘Hygienic requirements for safety and nutritive value of food products’.

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Appendix 20.3 Vitamins and Mineral Salts to be Used in the Production of Pediatric Nutrition Products Including BAFS for Children under 14 Name

Form

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Vitamin A Vitamin D Vitamin E Vitamin B1 Vitamin B2 Vitamin PP Vitamin B6 Pantothenic acid Vitamin B12 Folic acid Vitamin C

12. 13. 14. 15. 16. 17.

Vitamin K Biotin Choline Inositol Carnitine Calcium

Retinolacetate; retinolpalmitate; beta carotene D2- ergo-calciferol; D3- chole-calciferol D-tocopherol; DL –alpha-tocopherol Thiamine hydrochloride; thiamine bromide; thiamine mononitrate; thiamine chloride Riboflavin; riboflavin-5-phosphate Nicotinamide; niacin Pyridoxine hydrochloride; pyridoxine-5-phosphate; pyridoxine dipalmitate Calcium D-pantothenate; sodium D-pantothenate; dexpantenol Cyanocobalamin; hydroxocobalamin Folic acid L-ascorbic acid; sodium L-ascorbate; calcium L- ascorbate; 6-palmitil-L-ascorbic acid (ascorbilpalmitate); potassium ascorbate Phylloquinone (phytomenadion) D-biotin Choline chloride; choline citrate; choline bitartrate Inositol L-carnitine; L-carnitine chloride Calcium carbonate (E 170); calcium citrate trisubstituted (E 333); calcium gluconate (E 578); calcium glycerophosphate (E 383); calcium lactate (E 327); calcium salt of orthophosphoric acid (E 341) Sodium citrate; sodium chloride (E 331) Magnesium gluconate (E 580); magnesium salts of orthophosphoric acid (E 343) Magnesium sulfate (E 518); magnesium lactate (E 329) Potassium citrate (E 332); potassium lactate (E 326); potassium phosphoric diphosphate (GOST 2493) Iron gluconate (11) (E 579); ferric sulfate 7-aqueous (11) (GOST 4148); iron lactate (11) (E 585) Iron fumarate (11); iron diphosphate (pyrophosphate) (11); elementary iron Copper carbonate; copper citrate; copper gluconate; copper sulfate (E 519) Zinc acetate; zinc sulfate; zinc chloride Manganese carbonate; manganese chloride; manganese citrate; manganese gluconate; manganese sulfate Potassium iodide; potassium iodate

18. Sodium 19. Magnesium 20. Potassium 21. Iron 22. 23. 24. 25.

Copper Zinc Manganese Iodine

Source: SanRaN 2.3.2. 1940-05 ‘Arrangement of pediatric nutrition’

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Appendix 20.4 321

Appendix 20.4 Types of Medicinal, Nutritive and Spicy Plants to be Included in BAFS for Children under 14 Years No

Latin name of a plant

The part used in BAFS

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

Anisum vulgare Gaerth Fam. Umbelliferae Althaea officinalis Fam. Malvacea Betula verrucosa Ehrh. Fam. Betulaceae Betula pendula Fam. Betulaceae Hibiscus sabdariffa L. Fam. Malvacea Hibiscus sabdariffa L. Fam. Malvacea Origanum vulgare Fam. Lamiaceae Fragaria Fam. Rosaceae Calendula officinalis L. Fam. Composite Urtica dioica L. Fam. Urticaceae Lavandula angu Millstifolia Fam. Lamiaceae Tilia cordata Mill Fam. Tiliaceae Rubus ideaus L. Fam. Rosaceae Malva sylvestris L.(syn. Malva mMauritiana) Fam. Malvaceae Malva sylvestris L. (syn. Malva mauritiana) Fam. Malvaceae Melissa officinalis Fam. Lamiaceae Melissa officinalis Fam. Lamiaceae Mentha piperita Fam. Lamiaceae Hippophae rhamnoides L. Fam. Elaeagnaceae Plantago major L. Fam. Plantaginaceae Plantago media L. Fam. Plantaginaceae Plantago lanceolate L. Fam. Plantaginaceae Citrus aurantium Fam. Rutaceae Matricaria recutita L. (syn. Chamomilla L.) Fam. Chamomilla Ribes nigrum L. Fam. Saxifragaceae Thymus vulgaris L. (Thymus marschallianus) Fam. Lamiaceae Thymus serpyllum Fam. Lamiaceae Thymus serpyllum Fam. Lamiaceae Carum carvi Fam. Umbellifere Foeniculum vulgare Mill Fam. Umbellifere Foeniculum vulgare Mill Fam. Umbellifere Bidens tripartite L. Fam. Composite Vaccinium myrtillus L. Fam. Vacciniaceae Rosa Fam. Rosaceae Vaccinium vitis-idaea L. Fam. Vacciniaceae

Anisi fructus Althaeae radix Betulae folium Betulae folium Hibisci flos Hibisci flos Origani herba Fragariae folium Calendulae flos Urticae folium Lavandulae flos Tiliae flos Rubi idaei folium Malvae flos Malvae flos Melissae folium Melissae folium Menthae piperitae folium Hippophaes folium Plantaginis herba Plantaginis herba Plantaginis herba Peel of the fruit Chamomillae flos Ribi nigri folium Thymi herba Thymi herba Thymi herba Cari carvi fructus Foeniculi fructus Foeniculi fructus Bidentis herba Myrtilli fructus Rosae fructus Vaccini fructus

Source: SanRaN 2.3.2.1940-05 ‘Arrangement of pediatric nutrition’

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Regulations for Nutraceuticals and Functional Foods in the Indian Subcontinent

21

Kantha Shelke1 and Christopher Hewes2 1

Principal, Corvus Blue LLC, Chicago, IL, USA; Ingredients Editor, Food Processing and Wellness Foods magazines 2

Principal, Corvus Blue LLC, Chicago, IL, USA

Abstract The regulatory environment of a country is a fair indicator of the sustainability and competitive strength of its food industry. India, the second largest producer of foods (next only to China), has a biodiversity with a plethora of nutritive and therapeutic compounds whose value is yet to be realized in the modern marketplace. The Indian population has consumed such products for millennia and is comfortable with their demonstrated safety. Historically, multiple laws/regulations prescribed varied standards regarding food and food additives, contaminants, food colors, preservatives and labeling. India recently passed The Food Safety and Standards Act (the Act) – a modern, integrated food law to serve as a single reference point in relation to the regulation of food products including nutraceuticals, dietary supplements and functional foods. The Food Safety and Standards Act still needs to be made considerably substantive with infrastructure and appropriate stewardship for it to match the international standards set in Europe and the USA. Significant augmentation is necessary for the Act to have the magnitude of impact on the Indian nutraceutical and functional food industry like the Dietary Supplement Health and Education Act of 1994 (DSHEA) has had on the dietary supplement industry in the USA. The passing of the Indian Act is a significant first step; a lot more has to happen to eliminate the confusing overlap with the old laws and regulations. Relevant guidelines, processes and protocols are required to gain momentum for effective implementation across the nation. If substantiated and enforced effectively, the Food Safety and Standards Act Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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324 Regulations for Nutraceuticals and Functional Foods

has the potential to open up tremendous opportunities for nutraceuticals, dietary supplements and functional food businesses. In India, nutraceuticals, dietary supplements and functional foods are not conceptualized in terms of segments, regulations, manufacturing, marketing and exports and imports like they are defined in the USA, Europe and other developed countries. These products are not recognized as separate segments by government regulations; instead the Food Safety and Standards Act includes them with the other food categories. The governance is still in a state of flux being shared between the Ministry of Health and Family Welfare and the Ministry of Food Processing Industries and will likely continue until the critical infrastructure is set in place. Starting with an in-depth narration of the historical background of the mandates that led to the Food Safety and Standards Act that governs nutraceuticals and functional foods, the chapter includes scope, definitions and elements of importance, followed by regulatory challenges. The chapter concludes with an outlook for the industry in the context of current and evolving regulations.

Introduction India is without a doubt one of the most promising markets for nutraceuticals and functional foods manufacturing and retailing in both domestic and international sectors. The country has many obvious benefits: a 1.1 billion population; the tenthlargest economy with an annual growth rate of 8 percent; an increasingly liberalized trade environment; growing affluence and a burgeoning middle class; an informal food supply chain still open for development by commercial food companies; and a population that has been comfortable with the concept of nutraceuticals and functional foods for thousands of years (1,2). The Indian nutraceutical and functional food industry, by forging commercial plans out of innovative ideas that reflect local Indian practices and customs, has fostered a retail segment that is growing at 13 percent annually (compound annual growth rate). The retail segment (annual turnover) of the Indian food industry, estimated at US$91.66 bn by the Confederation of Indian Industries, is a veritable commercial gold mine for ingredient and branded product manufacturers (3). Sophisticated advertisements proclaim better quality and production standards of manufactured packaged food items than unpackaged commodity sales and Indian consumers are increasingly buying packaged food items. Promotion campaigns are successfully establishing many new food brand names and particularly local and imported nutraceuticals and functional foods. As regards production and marketing of nutraceuticals and functional foods in India, the law continues to be cumbersome and bureaucratic. The modernization of Indian law to allow for transparency and minimization of bureaucratic paper work is a work in progress and there are considerable legal and cultural intricacies to overcome. The nation has moved from multiple laws/regulations to an integrated law governing all food products including nutraceuticals and functional foods. The food laws in India are enforced by the Director General of Health Services, Ministry of Health and Family Welfare, Government of India (GOI). According to market research leader Frost & Sullivan, nutraceuticals and dietary supplements are governed by the food law, whereas their licensing is taken care of by the Ministry of Health and Family Welfare (2).

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Historical Background 325

Historical Background India has a rich tradition in complementary and alternative medicine which has served its functional foods and nutraceuticals industry very well. The current surge in the marketplace is a reflection of growing consumer interest in health and wellness. Herbal preparations, tonics, elixirs and nutritional supplements, however, are not new to the local diet. Since very early times Indians have consumed similar products from – Ayurvedic, Siddha, Unani and Homeopathy – traditional medicines that are an integral part of their heritage and food habits. Naturally, the Indian population has maintained a culturally favorable outlook towards functional foods and nutraceuticals as part of their health and wellness regimen (4). With the changes brought about by contemporary lifestyles in the nation’s food habits, Indians are relying more and more on processed foods or foods prepared outside the home (5). Subsequently, they are increasingly relying on nutraceuticals and functional foods for additional nutrition and health benefits, thus contributing to exponential growth in the industry. Globalization has further contributed to their awareness of nutraceuticals popular elsewhere in the world and Indian consumers are rapidly adopting these products and brands into their lives. Until recently, however, consumers in India were unsure about the quality and scientific validity of functional foods and nutraceuticals manufactured domestically and imported from other countries. Several of these products were being produced without proper legislation or guidance regarding their production and labeling. The absence of a proper definition for the terms ‘nutraceutical’ and ‘functional foods’ and regulations further confounded issues for manufacturers and retailers (6). Indian constitution makers had initially left it to the individual states to regulate the food industry and afford protection for its citizens. A number of states in India legislated laws for the prevention of adulteration of foodstuffs but, as these mandates were issued at different times and without mutual consultation with other states, they lacked uniformity and were largely incompatible across the nation. In 1954, the Indian government passed the Prevention of Food Adulteration Act for uniformity across the nation and the Food Safety and Standards Act was amended several times to address the evolving needs of the industry and consumers. In 1988, the Ministry of Food Processing Industries was established to help develop the food processing industry and to create increased employment in the rural sector. The Ministry, headed by a Minister of State with independent charge, served to enable farmers with modern technologies and helped create surplus for exports and stimulate demand for processed food in the nation. The primary functions of the Ministry are to provide policy support for all aspects of the food processing sector, enhance the sector with advanced technologies and create the appropriate regulatory environment to support and promote the food processing sector effectively. Subsequent advances in scientific research and food manufacturing practices in conjunction with the growing complexity in the socioeconomic life of the citizens and the globalization of trade and commerce led to a variety of legislations to provide quicker and customized relief for unique situations. Over time, procedural laws became entwined with the substantive regulations and overlaps created loopholes and redundancies which spawned additional issues instead of solutions in some instances.

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The multiplicity of food regulations, policy makers and enforcement agencies prevailing in different sectors of the food industry contributed to considerable confusion among consumers, producers, manufacturers, retailers and businesses and, as such, were detrimental to the growth of the nutraceutical and functional food industry. By the mid-1990s, the food processing sector was framed in a veritable grid of regulations including a multitude of state laws as well as the following national laws: ● ● ● ● ●

● ● ● ● ●

● ●

● ● ●

Export (Quality Control and Inspection) Act, 1963 Solvent Extracted Oils Control (SEO) Order, 1967 The Insecticide Act, 1968 Meat Food Products Order (MFPO), 1973 Prevention of Food Adulteration Act (PFA), 1954 and Rules (Ministry of Health and Family Welfare & Family Welfare) with the last amendment in 1986 Bureau of Indian Standards (BIS) Act, 1986 Environment Protection Act, 1986 Pollution Control Act, 1986 (Ministry of Environment and Forests) Milk and Milk Products Order, 1992 The Infant Milk Substitutes, Feeding Bottles and Infant Foods (Regulation of Production, Supply and Distribution) Act, 1992 and Rules 1993 Fruit Products Order (FPO), 1995 Agriculture Produce (Grading & Marking) Act (Ministry of Rural Development) Essential Commodities Act, 1955 (Ministry of Food & Consumer Affairs) Industrial Licenses Vegetable Oil Product Control (VOP) Order, 1998.

In 1998, the Prime Minister’s Council on Trade and Industry appointed a Subject Group on Food and Agro Industries which recommended a comprehensively unified legislation under a single Food Regulatory Authority. Public health experts and the Standing Committee of Parliament on Agriculture encouraged the convergence of current food laws with a single regulatory authority accountable for public health and food safety in India. The Member-Secretary, Law Commission of India, further proposed integrating all Acts and Orders relating to foods and eliminating multilevel and multidepartmental controls. Special emphasis was given to include nutraceuticals and functional foods – a poorly-defined segment with growing potential and implications on the health of consumers. In 2002, a national non-profit association emerged with the objective of representing the interest of health foods, dietary supplements, nutraceuticals and the healthcare industry in general which comprised of manufacturers and suppliers of vitamins, minerals, botanical products, sports nutrition products and herbs. The group aimed to support a science based environment to ensure responsible marketing of health foods, dietary supplements and nutraceuticals and to promote and defend a regulatory environment conducive to the industry in general as well as consumer protection. The organization aimed to prevent and eradicate malpractices that could hurt the industry and to establish a code of ethics for observance by its members in line with the prevailing regulations.

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The organization originated as the Indian Health Foods and Dietary Supplements Association (INHADSA, www.iadsa.org) (7) and changed its name to Health Foods and Dietary Supplements Association (HADSA, www.hadsa.org) (8) in April 2004. A member of the International Alliance of Dietary/Food Supplement Associations (IADSA, www.iadsa.org), it dedicated its first two years (2002–2004) actively to educate the industry and representatives of the Ministry of Health and Family Welfare, the Ministry of Food Processing Industries and state Food and Drug agencies in India to help raise their awareness and comprehension of nutraceutical products and their growing potential in the marketplace. HADSA played a pivotal role in educating and bringing together various ministries of the Indian government, regulatory agencies, industry, research and development organizations like the Council of Scientific and Industrial Research (CSIR, www.csir.res.in) (9) and Central Food Technology and Research Institute (CFTRI, www.cftri.com) (10) to a common platform through a series of meetings and technical summits in India. With the support of IADSA and Natural Products Association (formerly the National Nutritional Foods Association, www.naturalproductsassoc.org), HADSA helped increase among consumers, the health care industry and regulatory agencies awareness of and support for the creation of a separate, well recognized, regulated market for dietary supplements and nutraceuticals within India (11). Additionally, HADSA helped with the organization of the Food Safety and Standards Authority of India with representatives from various relevant ministries, state governments, the food industry, consumer organizations and even farmers’ agricultural organizations. The scientific committees and panels were charged with establishing standards and testing protocols and regulating the limits on the usage of food additives, crop contaminants, pesticide residues and heavy metals, processing aids, mycotoxins, antibiotics and pharmacologically active substances. The Central Advisory Committee was charged with prioritizing the work. In 2004, HADSA drafted the Food Safety and Standards Bill in accordance with legislations and guidelines from global regulatory bodies including Codex Alimentarius Commission (CAC, www.codexalimentarius.net), the World Health Organization (WHO, www.who.int) (12) and the Food and Agriculture Organization (FAO, www.fao.org), and incorporated the salient provisions of the 1954 Prevention of Food Adulteration (PFA) Act of India (7,13–15). In addition to regulating nutraceuticals and dietary supplements, the Food Safety and Standards Bill formulated mechanisms and guidelines for the accreditation of bodies engaged in the certification of a food safety management system for the nutraceutical and functional food industries. It also set up food labeling standards including health claims. The Food Safety and Standards Bill identified the current deficiencies in monitoring and provided suitable, relevant and meaningful regulations for nutraceuticals, dietary supplements and functional foods. In essence, the Food Safety and Standards Bill recognized a special category besides foods and drugs in India for ‘Dietary Supplements/Nutraceuticals/Functional Foods/Foods for special dietary application’. Additionally, the Food Safety and Standards Bill recommended the establishment of a Food Safety Appellate Tribunal to hear the appeals of disputing parties (16). The Bill responded to the demands of the food processing industry that all the cases pending in

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various courts and tribunals all over India under the Prevention of Food Adulteration Act, 1954, shift under the new Food Safety Appellate Tribunal that was to be constituted immediately after the enactment of the Food Safety and Standards Act, 2006. The Food Safety and Standards Bill was ratified by parliamentarians in both the upper (Raj Sabha) and lower house (Lok Sabha) in August 2006 (17) and ultimately endorsed by the President of India in January 2007. The Food Safety and Standards Act, 2006 stands to revitalize the industry and increase foreign trade by simply acknowledging the category of dietary supplements, nutraceuticals, functional foods and foods for special dietary applications. The new rule establishes what kind of health/nutritional claims can be made for these products and encourages manufacturers to perform testing and clinical studies and form structure/function claims based on the results (6,18–21).

The Food Safety and Standards Act – Scope and Definitions The main objectives of the Food Safety and Standards Act, 2006 (22,23) are to introduce a single statute relating to food and to science-based development of the food processing industry. The Food Safety and Standards Act integrates the laws governing the food sector by repealing eight existing laws related to food safety in the country. By moving from multilevel, multidepartmental control to a single line of command, the Act essentially aims to establish a single reference point for all matters relating to food safety and standards. It establishes the Food Safety and Standards Authority (FSSA) to regulate the food sector and aims systematically and scientifically to develop the food (including the nutraceutical and functional food) processing industries (24). Food Safety and Standards Authority has several scientific panels and a central advisory committee to help lay the foundation of standards for food safety. The efforts started by HADSA, CFTRI, CSIR and the Ministry of Food Processing Industries in 2004 finally received government funding in December 2007 and efforts are underway to identify appropriate resources and personnel to establish the necessary standards for food safety. These standards include specifications for ingredients, contaminants, pesticide residue, biological hazards and labels. At the time of this writing, the government is in the process of selecting the Chief Executive Officer, Food Safety and Standards Authority of India. Salient points of the Food Safety and Standards Act are highlighted below. ●

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According to the Act, State Commissioners of Food Safety and other local level Food Safety Officers are to help enforce the law. Although the Ministry of Health and Family Welfare has been entrusted with the responsibility of establishing the FSSA, ambiguity continues about who will ultimately control the Commissioners and the local officials – the industry relevant Ministry of Food Processing Industries or the incumbent Ministry of Health and Family Welfare appointed by the President of India. The preparatory activities for establishing Food Safety and Standards Authority have begun in full swing. Drafting of rules and regulations is a mammoth task and will follow as soon as the FSSA has been established.

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The Food Safety and Standards Act – Scope and Definitions 329

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Every entity in the food sector is required to get a license or a registration issued by local authorities. Nutraceuticals and dietary supplements fall under the food law but have to seek licensing from the Ministry of Health and Welfare Services. Every distributor is required to be able to identify any food article by its manufacturer and every seller is required to be able to identify any food article by its distributor. Any entity in the sector is bound to initiate recall procedures if it finds that the food sold has violated specified standards. The significance of the Act is that it intends to establish ‘science-based standards for articles of food and regulation of their manufacture, storage, distribution, sale and import’ and deals with all packaged and processed food.

The Food and Safety Standards Act 2006 consists of 12 chapters. Chapter IV, article 22 of the Act addresses nutraceuticals, functional foods and dietary supplements and the need to regulate these products, such that anybody can manufacture, distribute, sell or import these products. These products can fall under any of the following categories, novel food, genetically modified articles of food, irradiated foods, organic foods, foods for special dietary uses, functional foods, nutraceuticals, health supplements and proprietary foods. The following definitions are verbatim. The Food Safety and Standards Act defines these products as ‘foods for special dietary uses or functional foods or nutraceuticals or health supplements’ and mandates that these products will be regulated as per the following definitions. 1. ‘Foods for special dietary uses or functional foods or nutraceuticals or health supplements’ means: (a) Foods which are specially processed or formulated to satisfy particular dietary requirements which exist because of a particular physical or physiological condition or specific diseases and disorders and which are presented as such wherein the composition of these foodstuffs must differ significantly from the composition of ordinary foods of comparable nature, if such ordinary foods exist, and may contain one or more of the following ingredients, namely: i. plants or botanicals or their parts in the form of powder, concentrate or extract in water, ethyl alcohol or hydro alcoholic extract, single or combination ii. minerals or vitamins or proteins or metals or their compounds or amino acids (in amounts not exceeding the Recommended Daily Allowance for Indians) or enzymes (within permissible limits) iii. substances from animal origin iv. a dietary substance for use by human beings to supplement the diet by increasing the total dietary intake (b) (i) a product that is labeled as a ‘Food for special dietary uses or functional foods or nutraceuticals or health supplements or similar such foods’ which is not represented for use as a conventional food and whereby

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such products may be formulated in the form of powders, granules, tablets, capsules, liquids, jelly and other dosage forms but not parenterals, and are meant for oral administration (ii) such product does not include a drug as defined in clause (b) and Ayurvedic, Siddha and Unani drugs as defined in clauses (a) and (h) of section 3 of the Drugs and Cosmetic Act, 1940 (23 of 1940) and rules made thereunder (iii) does not claim to cure or mitigate any specific disease, disorder or condition (except for certain health benefit or such promotion claims) as may be permitted by the rules made under this Act (iv) does not include a narcotic drug or a psychotropic substance as defined in the Schedule of the Narcotic Drugs and Psychotropic Substances Act, 1985 and rules made there under and substances listed in Schedules E and E1 of the Drugs and Cosmetic Rules, 1945 2. ‘Genetically engineered or modified food’ means food and food ingredients composed of or containing genetically modified or engineered organisms obtained through modern biotechnology, or food and food ingredients produced from but not containing genetically modified or engineered organisms obtained through modern biotechnology 3. ‘Organic food’ means food products that have been produced in accordance with specified organic production standards 4. ‘Proprietary and novel foods’ means an article of food for which standards have not been specified but is not unsafe. Provided that such food does not contain any of the foods and ingredients prohibited under this Act and regulations made thereunder. In essence, this section provides that no person shall manufacture, process or sell genetically modified articles of foods, irradiated food, organic foods, functional foods, nutraceuticals, health supplements, proprietary foods and similar foods except in accordance with the provisions contained in the Act and its rules and regulations. The inclusion of genetically modified articles of food, irradiated foods and organic foods in this group is rather unusual as one does not regard these items as functional, supplemental, or -ceutical, but as foods specially bred or processed. Regardless, the Act groups these products together without specific regulations per se and instead mandates them to adhere to the general safety norms and standards of processed and packaged foods. Additionally, the government is still in the process of developing standards such as the Organic Specifications for crop production and manufacture. Chapter IV, Article 23 of the Food Safety and Standards Act addresses the Packing and Labeling of Food Articles for foods including nutraceuticals and functional foods as follows: 1. No person shall manufacture, distribute, sell or expose for sale or dispatch or deliver to any agent or broker for the purpose of sale, any packaged food products which are not marked and labeled in the manner as may be specified by regulations. Provided that the labels shall not contain any statement, claim,

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design or device which is false or misleading in any particular concerning the food products contained in the package or concerning the quantity or the nutritive value implying medicinal or therapeutic claims or in relation to the place of origin of the said food products. 2. Every food business operator shall ensure that the labeling and presentation of food, including their shape, appearance or packaging, the packaging materials used, the manner in which they are arranged and the setting in which they are displayed, and the information which is made available about them through whatever medium, does not mislead consumers. This section provides that no person shall manufacture, distribute, sell, expose for sale, dispatch or deliver to any agent or broker for the purpose of selling, any packaged food products which are not marked and labeled per regulations. The label must not misrepresent origin, content, amount and nutritive value of the product and not imply medicinal or therapeutic effects. Every food business operator shall ensure that the labeling and presentation of food does not mislead consumers. The next section – Chapter IV, Article 24 – addresses the restriction of advertisement and the prohibition of unfair trade practice. 1. No advertisement shall be made of any food which is misleading or contravenes the provisions of this Act, the rules and regulations made thereunder. 2. No person shall engage himself in any unfair trade practice for purpose of promoting the sale, supply, use and consumption of articles of food or adopt any unfair or deceptive practice including the practice of making any statement, whether orally or in writing or by visible representation which (a) falsely represents that the foods are of a particular standard, quality, quantity or grade-composition (b) makes a false or misleading representation concerning the need for, or the usefulness (c) gives to the public any guarantee of the efficacy that is not based on an adequate or scientific justification thereof: Provided that where a defense is raised to the effect that such guarantee is based on adequate or scientific justification, the burden of proof of such defense shall lie on the person raising such defense. The Food Safety and Standards Act restricts advertisement that is misleading or in contravention of the provisions of the Act and its rules and regulations. It also prohibits any unfair trade practice for the purpose of promoting sale, supply, use and consumption of articles of food or adoptions or any unfair or deceptive practice to mislead the public regarding the standards, quality, quantity, usefulness or giving of any guarantee of the efficacy that is not based on an adequate or scientific justification thereof. The Act does not, however, provide any sampling or testing protocols nor does it provide a system for ensuring the validity of these tests. The key sections of the Food Safety and Standards Act directed towards foods and which are also applicable to functional foods and nutraceuticals are described below.

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1 Prescription of Standards for Food Articles The Food Safety and Standards Act prohibits the use of food additives, processing aid, contaminants, heavy metals, insecticides, pesticides, veterinary drugs residue, antibiotic residues, or solvent residues unless they are in accordance with specified regulations (that are yet to be developed). Functional foods, nutraceuticals and health supplements, like irradiated food, genetically modified food, organic food, foods for special dietary uses and proprietary food, cannot be manufactured, processed or sold without adhering to the regulations governing foods. India does not have the framework of say, DSHEA or good manufacturing practices as established by the Food and Drug Administration in the USA.

2 Identification of the Product The Food Safety and Standards Act makes it mandatory for the distributor of a food article to identify the manufacturer and the seller to identify either the manufacturer or the distributor of a food item. Every packaged functional food, nutraceuticals and health supplement product has to be labeled as per regulations in the Act. The packaging and labeling of a food product should not mislead consumers about its quality, quantity or usefulness. India does not, however, have a formal system for nutrition labeling, nutrient claims or an established framework for statement of identity, net contents declaration, (US Code of Federal Regulations, 21 CFR 101.105), ingredient list, name and place of manufacturer or distributor like that mandated by the Nutrition Labeling and Education Act of 1990 (NLEA) in the USA. The Indian Act offers the opportunity for the government to create a viable system along the lines of the NLEA, but such a system’s implementation is not defined within the current wording of the Act.

3 Regulatory Authority The Food Safety and Standards Authority of India (Food Authority) is responsible for creating scientific standards of food safety and ensuring safe and wholesome food. Once the Central Advisory Committee, a Scientific Committee and a number of Scientific Panels are established, they will embark on specifying standards. The standards would be enforced by the Commissioner of Food Safety of each state through Designated Officers and Food Safety Officers. The Food Safety and Standards Authority would consist of a Chairperson and 22 members. The Chairperson would be either an eminent food scientist or a civil servant not below the rank of Secretary. Seven of the members would be ex-officio, not below the post of Joint Secretary, from various ministries. Five members would be appointed by rotation every 3 years from the states and Union Territories. The Food Authority would have two representatives each from the food industry and consumer organizations, one food technologist and one member from a farmers’ organization. The Indian government authorized funding for the hiring of personnel of Food Safety and Standards Authority in December 2007 and much of this effort is underway at this time.

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4 Enforcement Every food business operator is required to have a license in order to operate a food business. Petty manufacturers who make their own food, hawkers, vendors or temporary stallholders do not require a license. Instead, they need to get their businesses registered with the local municipality. The Food Safety and Standards Act empowers Food Safety and Standards Authority and State Food Safety Authorities to monitor and regulate food business operators. The Commissioner of Food Safety of each state appoints a Designated Officer (DO) whose duties include issuing or canceling licenses, preventing sale of food articles that violate specified standards (yet to be set), receiving reports and samples of food articles from Food Safety Officers and analyzing them (via protocols yet to be established). The DO has the power to serve an ‘improvement notice’ to any food operator and to suspend the license in the event of non-compliance. The DO also investigates any complaint made in writing against Food Safety Officers. Food Safety Officers are appointed for a specified local area and their duties include sampling, seizing articles of suspect quality and inspecting facilities where food articles are manufactured or stored. The State Commissioner, on the recommendation of the DO, decides whether a case of violation would be referred to a court of ordinary jurisdiction or to a Special Court. Cases relating to grievous injury or death for which a prison term of more than 3 years is prescribed are tried in Special Courts. The recourse decision is left to the discretion of the State Commissioner.

5 Penalties The Act provides for a graded penalty structure where the punishment depends on the severity of the violation. Offences such as manufacturing, selling, storing or importing substandard or misbranded food could incur a fine. Offences such as manufacturing, distributing, selling or importing unsafe food, which result in injury, could incur a prison sentence. The sentence could extend to life imprisonment in case the violation causes death. Petty manufacturers who make their own food, hawkers, vendors or temporary stallholders could be fined for violating specified standards. In order to judge cases related to breach of specified regulations, the state government has the power to appoint an Adjudicating Officer, not below the rank of Additional District Magistrate. Any person not satisfied by the decision of an Adjudicating Officer has the right to appeal to the Food Safety Appellate Tribunal (or to the State Commissioner until the Tribunal is constituted). The Tribunal enjoys the same powers as a civil court and decides the penalty in case of non-compliance with the provisions of the Act (25).

6 Food Recall Procedures The Food Safety and Standards Act has special provisions for food recall procedures. A food business operator with concern that a processed, manufactured or distributed food item is not in compliance with the specified standards, should initiate procedures

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to withdraw the food in question and inform the competent authorities about it. The Food Safety and Standards Authority has, however, yet to specify the guidelines for food recall procedures which are not defined in the Act itself.

Regulatory Challenges The Food Safety and Standards Act aims to establish science-based standards for articles of food including nutraceuticals, functional foods and dietary supplements and the regulation of their manufacture, storage, distribution, sale and import. The Act provides nutraceuticals, dietary supplements and functional foods a clear status – for the first time in India (25). The law effectively precludes arbitrary and uneven declarations attempted recently by some Indian States that dietary supplements are drugs merely because of their physical format, e.g. capsules and tablets. Manufacturers can apply for fresh licenses without jeopardizing licenses issued under the Prevention of Food Adulteration Act. Because the Food Safety and Standards Act is still in its nascent stage, manufacturers and retailers have to alternate between it and the Prevention of Food Adulteration Act for different elements of the law (26). This calls for a very complex landscape of ill-defined and overlapping laws at the current time (27). The situation opens up the opportunity for members of the industry to adopt proven and viable methods and frameworks from other nations and guide the Food Safety and Standards Authority The Food Safety and Standards Act collectively addresses genetically modified articles of foods, irradiated food, organic foods, functional foods, nutraceuticals, health supplements, proprietary foods and similar foods as a single category, but does not distinguish them from foods in the remainder of the thesis. The individual products, however, require considerable attention to ensure that both the industry and consumers are served well (26). The Food Safety and Standards Act, while a good first step, is a far cry from the purposefully differentiated and tailored regulatory mechanisms established in Europe and the USA. Indian consumers and the industry will be best served if the authorities model their system on the sophisticated regulatory systems of Europe and the advanced and proven regulatory systems of the USA. The Food Safety and Standards Act, once it is in place, will likely benefit the organized manufacturing sector and spur sales of branded products. The unorganized sector – as the fragmented cottage industry comprised largely of petty manufacturers, hawkers and vendors is called – although more numerous in number than those in the organized sector, will surely feel the brunt of the paperwork and legislated requirements and get slowly edged out of existence because of its inability to comply (28,29). At this time, the Food Safety and Standards Act does not distinguish between the organized and the unorganized food sectors and mandates compulsory registration for every operator in the organized and unorganized sectors, the latter including food retailers, hawkers, itinerant vendors and temporary stallholders (30). The Food Safety and Standards Authority, however, has one representative from the small-scale industry and none from the unorganized class. One law for all food systems regardless

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Regulatory Challenges 335

of the size of the operator is a law that privileges large-scale industrial commercial establishments and discriminates and penalizes the small, local and the diverse unorganized sector. The penalty depends largely on the nature of the offence and has the potential to close the unorganized sector very rapidly. The biggest issue for the industry is really that of implementation. Since its enactment, the ownership of the Food Safety and Standards Act remains a question. The Act is entrusted with the Ministry of Health and Family Welfare which received funding in December 2007 to hire personnel to start the work. The Ministry of Food Processing Industries, however, has more industry relevant expertise and is likely more suitable for the task. Strangely, the Food Safety and Standards Act does not have the rich industry relevant involvement that the Food Safety and Standards Bill had. The absence of primary processors along with their knowledge and infrastructure of relevant departments and ministries can seriously hinder the substantiation and subsequent implementation of the Act for both general foods and the more specialized nutraceutical and functional food sectors (18). Without the involvement of expert practitioners and relevant industry knowledge it will be difficult for the Food Safety and Standards Committee to develop specific regulations and a framework that food and nutraceutical companies can adhere to with ease (31). The composition of the Food Safety and Standards Authority of India is still to be finalized with appropriate industry representation having relevant knowledge and skills. The government has yet to populate the various committees and panels with the right competency for establishing standards and testing protocols and selecting the optimum from the existing regulations on food additives, crop contaminants, pesticide residues and heavy metals, processing aids, mycotoxins, antibiotics and pharmacologically active substances. The government appears to have recognized the need for additional resources and training to get these elements in place and remove ambiguity between the Food Safety and Standards Act and the pre-existing Acts and Orders (32,33). At the time of this writing, the government of India approved the funding for the Food Safety Authority and the appointment of its Chief Executive Officer along with the appointment of key personnel of the Food Safety Appellate Tribunal and those responsible for the enforcement of the Food Safety and Standards Act, i.e. the Commissioner of Food Safety, Designated Officer, Food Safety Officer, Food analyst, and Adjudicating Officer. The Food Safety and Standards Authority of India is in the process of being established by the Central Government as a corporate body, having perpetual succession, a common seal and with a head office in Delhi. At this time, the State governments have yet to appoint their Commissioner of Food Safety for efficient implementation of food safety and standards (34). Other challenges include the disparity in how the law is administered at different levels of the government. The power to suspend the license of any food operator is given to a local level officer opening scope for harassment and corruption with unbridled power for inspectors and uncertainty for vendors, hawkers and small manufacturers. Without any formal training, the way the law is interpreted or administered is the issue and can be detrimental not only for domestic processors and retailers but also for those importing into India.

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A glaring issue is the absence of viable guidelines for anyone in the industry wanting to do things correctly. The Article dealing with Packaging and Labeling stresses that food products, including nutraceuticals and functional foods, should not make any false claims or support any false advertising. The law also mandates every packaged nutraceutical and functional food product to be labeled as per regulations in the Food Safety and Standards Act which mandates that the packaging and labeling should not mislead consumers about its quality, quantity or health benefits. At this time in India, however, there is no nationally accredited testing system to validate any product claims ranging from structure-function, health, to nutritional. The nation is in the process of recognizing the need for a government approved food safety testing laboratory (16,33). Additionally, the ‘validity’ of any test is the responsibility of the Indian court. It appears then, that any ‘scientific justification’ provided by the defense is not required to meet any pre-existing or defined standard but is only required to convince the courts. This has the potential for powerful entities to establish their ‘scientific justification’ by influencing the court. The Food Safety and Standards Act introduces two new consumer friendly clauses into the Indian Jurisprudence – traceability and food recall procedure. The Act ensures traceability by making it mandatory for the distributor of a food article to identify the manufacturer and the seller to identify either the manufacturer or the distributor of a food item. There is an opportunity for the installation of supply chain tools to manage traceability for small and large businesses in India. The food recall procedure is simplistic at best. The law implies that if a food business operator believes that a nutraceutical or functional food product it has processed, manufactured or distributed is not compliant with any provision of the Act, it shall immediately initiate procedures to withdraw the food in question. The Act does not, however, define any withdrawal procedures. There is also no requirement that the food business operator inform consumers about a product recall, especially if some of the products have already been sold, nor is there any system in place to document and report any adverse events. The government does not appear to have publicly assessed the technical foundation and upgraded manpower required to meet and monitor the intended objectives. Transparency in such planning can help the government attract proven players from around the world and accelerate the pace of change within its jurisprudence. Clarity of regulation and a reliable support and reliable system are very important factors influencing foreign players seeking new business opportunities in India (5). The ideal would be for the Food Safety and Standards Authority to be transparent during its organization development phase and to engage the industry in open dialogues during the identification and establishment of various regulations. Although the new integrated food law promises availability of safe food, its effective implementation will remain the key. The Food Safety and Standards Act attempts to level the playing field by treating all types of food as the same (35). In reality, however, natural organically processed nutraceuticals and functional foods are not the same as their chemically processed counterparts which, in turn, can be significantly different from genetically engineered food products. Different foods have different safety risks and require different safety laws and different systems of management.

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Conclusion and Outlook 337

Not having appropriate risk assessment and management systems in place can set some segments of the nutraceutical and functional foods at a huge disadvantage and unfairly grant a leg up to others. This disparity has the potential to affect consumer health and well-being in the long run. In the end, it is the host nation that will likely suffer from the ill effects of the disadvantage. To be commercially successful, nutraceutical products – functional foods and dietary supplements – need to be standardized. Scientific validation to ensure safety and efficacy can enhance confidence among customers to reach out to them not merely as an alternative medicine, but also as a part of a well-defined daily regimen for health and wellness. The Food Safety and Standards Act recognizes that scientific validation of health claims can significantly help advance the industry and is, in fact, the need of the hour (26,36). It also opens up an opportunity for companies to step in and establish precedence with the potential to become the de facto standard for the industry and the nation. The Indian regulatory environment is evolving and does not have the formal system for the registration and approval of nutraceutical and functional food products one encounters in the USA and Europe. The government appears to recognize uncertainty and lack of clarity in regulation as some of the biggest obstacles for the development of the industry in India. Although the Food Safety and Standards Act appears to have integrated the multiplicity of food laws, the next frontier for the government is the integration and/or the elimination of the involvement of at least 3–4 regulatory bodies that are still involved in the launch and growth of any nutraceutical and functional food business in India (34). Not having proper regulations and clear controls in place have the potential to create confusion and uncertainty in the outcome of any business initiative. There is an opportunity to install rapidly a single national authority and empower it with the appropriate expertise and infrastructure. Additionally, the government aims to establish credible testing facilities for accurate and reliable safety tests done to help the participants and the enforcers of the law become more efficient. The Food Safety and Standards Act does not differentiate between nutraceuticals, dietary supplements and functional foods and, instead, classifies all these products as ‘foods for special dietary applications’. This allows for functional foods and food supplements with therapeutic claims to be sold alongside food and without declaration of nutraceutical content, clinical trials and health studies. The fact that the Act does not mandate the inclusion of safety, toxicity and efficacy data from manufacturers of nutraceuticals and functional foods is a serious disservice to consumers and to the industry at large. Unanticipated adverse events have the potential to mar the reputation of the industry and create distrust among consumers, who otherwise are willing to trust established brands and brands with prominent advertising.

Conclusion and Outlook In addition to utilizing nutraceutical products to ensure general health and well-being among its population, India has the potential to become a leader in this field with its

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historical expertise as well as richness in biodiversity. While the Food Safety and Standards Act has taken the first step to recognizing nutraceuticals and dietary supplements and classifying them with foods, the future is fertile with opportunities to assess and adopt proven systems and frameworks from the more mature regulatory environments of developed markets in North America and Europe. The time is right for entrepreneurs and businesses from around the world to take advantage of the situation and establish protocols and services with the potential to become a de facto standard in the Indian regulatory network. The piloting of the Foods Safety and Standards Bill in 2006 by HADSA, CFTRI, CSIR and the Ministry of Food Processing Industries marked a pivotal moment for the food processing industry in India and consumers at large (34). The Food Safety and Standards Act endorsed by the President in January 2007, when implemented, will change the regulatory scenario for food processors and retailers in India. Optimists expect the formation of one single regulatory system to bring synergy in technical and regulatory matters and substantially reduce the transaction costs imposed on the food processing industry at large including nutraceuticals and functional foods. Pragmatists question whether the Ministry of Health and Family Welfare, embarking on the preparatory activities for the establishment of the FSSA and regulations, will have the industry relevant insight and wherewithal of the Ministry of Food Processing Industries to create a regulatory environment viable for the industry and meaningful to consumers.

References 1. Centers for Disease Control and Prevention. (1982). International notes follow up on epidemic pneumonia with progression to neuro-muscular illness Spain. Morbid Mortal Wkly Rep 31(8), 93–95. 2. Frost & Sullivan (2007). Executive Summary of Indian Nutraceuticals and Dietary Supplement Markets, December. 3. Confederation of Indian Industries, New Delhi, India. www.ciionline.org. 4. Amit A. (2005). Research and development in the herbal sector. Food Bev News January 20. 5. Verma R. (2007). Branded foods in India – forecasts to 2015: 2008 edition: Introduction. Just-Food, Bromsgrove. Nov 2007. 6. India Together. http://www.indiatogether.org/2006/feb/law-foodsafe.htm#hilite 7. Indian food safety and standards bill 2005 signed into law. NPIcenter. October 12, 2006. http://www.npicenter.com/anm/templates/newsATemp.aspx?articleid⫽ 16796& zoneid⫽18 8. Health Foods and Dietary Supplements Association, New Delhi, India. (www.hadsa.com). 9. Council of Scientific and Industrial Research, New Delhi, India. www.csir.res.in 10. Central Food Technological Research Institute, Mysore, India. www.cftri.com 11. International Alliance of Dietary Food Supplement Associations, Brussels, Belgium. www.iadsa.org

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References 339

12. World Health Organization. (2002). Health Situation in the South East Asia Region 1998–2000. Office for the South East Asia Region. p. 259 13. Food Safety and Standards Bill (2005). http://www.pfndai.com/food_safety.pdf 14. Food and Agriculture Organization, Rome, Italy. www.fao.org/docrep/W3699T/ w3699t06.htm 15. India passes bill to create new regulatory category for dietary supplements. (2007). HerbalGram 74,17. 16. Regulatory norms for nutraceuticals-India. www.neeman-medical.com/Resources/ Regulatory%20Norms%20for%20Nutraceuticals%20in%20India.pdf 17. Karnik B. (2006). India: challenges and opportunities. Nat Prod Insider February. http://www.naturalproductsinsider.com/articles/477/477_621intlfocus01. html?cntwelcome⫽1 18. Hariharan V. (2006). India – the nutraceutical sprinter to watch. Food Bev News November 18. 19. Indian food bill with supplements category becomes law. NutraIngredients.com. October 16, 2006. Available at: http://www.nutraingredients-usa.com/news-by-product/news.asp?id⫽71292&idCat⫽53&k⫽indian-food-bill 20. Karnik B. (2007). Indian regulations on nutraceuticals and functional foods. Personal Communication from Dr Bhushan Karnik, Trustee-Health Foods and Dietary Supplements Association of India, HADSA, New Delhi, India. 21. The Food Safety and Standards Bill (2005). Bill 123 of 2005. August 25. Available at: http://mofpi.nic.in/foodsfty.pdf. 22. Das PK. (2006). Universal’s handbook on The Food Safety & Standards Act, 2006. Universal Law Publishing Co., New Delhi. 23. Kothekar SC, Waghmare JT, Momin SA. (2005). Nutraceuticals: the Indian scenario. Int News Fats Oils Relat Mater 16(9), 548. 24. Kumar’s Commentaries on Food Safety & Standards act, 2006, 2nd edn. Law Publishers Pvt. Ltd., New Delhi. 25. Nutraingredients.com. Progress for Indian food bill that embraces supplements. Staff reporter. http://www.nutraingredients.com/news/ng.asp?id⫽69648-gci-nutrients-india 26. Phani Raj YV. (2006). USP India to issue certificates after ingredient verification programme. Food Bev News May 06. 27. Consumer Online Foundation. Food Safety and Standards Act, 2006 – Is it a landmark consumer friendly legislation? http://www.consumeronline.org/guest/focus/ linkdetails.asp?ID⫽food_focus1 28. Down to Earth: Science and Technology Online. Laws are modified to suit MNCs. http:// www.downtoearth.org.in/interview1.asp?foldername⫽20050630&filename⫽news& sec _id⫽14&sid⫽4 29. Express Pharma Online. Pharma treads the nutra path. http://www.expresspharmaonline.com/20060715/market03.shtml 30. Bhowmik SK. (2005). Street vendors in Asia: a review. Econom Polit Wkly May 28June 4, 2259–2260. http://www.wiego.org/papers/2005/unifem/4_Bhowmik_Asian_ Hawkers_EPW.pdf 31. Food and Beverage News. (2007). Sahai spells out agenda for FP. November 17. http://www.fnbnews.com/article/print.asp?articleid⫽22078

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32. Rao R. (2006). Clarity in regulations can strengthen nutraceutical sector in India. Pharmabiz.com. August, 2006. http://www.pharmabiz.com/article/detnews. asp?Arch⫽a&articleid⫽34784§ionid⫽19 33. Regulations for nutraceuticals and functional foods in the Indian subcontinent. Food and Beverage News. http://www.efenbeonline.com/view_story.asp?type⫽Story&id⫽880 34. Torcato R. (2007). Need to address industry’s agenda on food regulation. Food Bev News October 20. 35. Vision, Strategy and Action Plan for Food Processing Industries in India Vol.1, pp. 73–74, Prepared by Rabo India Finance Pvt. Ltd. for Ministry of Food Processing Industries, GOI, April 2005. http://mofpi.nic.in/visdoc/volume1.pdf 36. Food majors welcome Food Safety Act. (2007). Food Bev News September 15.

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Botanical Drugs, Nutraceuticals and Functional Foods: The Context of Africa

22

Theeshan Bahorun1, Vidushi S. Neergheen1 and Okezie I. Aruoma2 1

Department of Biosciences, Faculty of Science, University of Mauritius, Réduit, Republic of Mauritius 2 Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, USA

Abstract The involvement of developing countries in international food trade has transcended ideology from the traditional production of cash crops and raw materials to producing processed or semiprocessed food products. The African continent is endowed with a great variety of plant species and their use for the purpose of achieving nutritional and therapeutic effects is strongly anchored in African culture. There is need for pharmacological, toxicological studies which complement the strict regulatory framework governing the sale, manufacture, packaging, labeling, importation, distribution and storage of natural health products. For the products (botanical drugs, nutraceuticals and functional foods) emanating from the endemic plants, these important determinants anchor the supply chain and regulation of botanical drugs, nutraceuticals and functional foods.

Introduction The food supply chain needs to embrace an efficient food safety system aimed at minimizing food losses, increasing health protection, consumer satisfaction, product competition and poverty alleviation (1–5). The various factors that determine the supply of Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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342 Botanical Drugs, Nutraceuticals and Functional Foods: The Context of Africa

botanical drugs and functional nutraceuticals include bioprospecting for new products, low cost sources of existing products, standards that govern the introduction of new products and enhancement of the acceptance of existing products, differentiating products based on the physicochemical properties of the products, product innovation (e.g. new additives to foods, drinks and/or cosmetics). Bioactive molecules and their precursors (largely visualized as being at the very high end of the chemical products value spectrum) in food plants and traditional medicinal plants are widely used in pharmaceutical and nutraceutical formulations. Functional foods have generally been defined to include products that influence specific functions in the body (thereby offering benefits for health, well-being or performance). Functional foods result from technological innovation (e.g. cholesterol lowering products, sweeteners in chewing gums, fermentation products and genetically modified products). For genetically modified foods, however, it is notable that the food aid fears led to some African governments requiring food-aid grain to be milled before it is distributed. Namibia for example, cut off all corn trade with South Africa in 2004 because the latter grows genetically modified (GM) corn. It would then seem clear that exchanging of technical information about GM products, training African scientists, creating a public awareness of biotechnology issues and helping African nations develop their own policies to guide regulatory, legal and technology transfer issues would represent inward measures for sustainable integration. Future sources of food production and agricultural growth in Africa need to embrace measures to lift the declining yield in cash crops possibly residing in the use of agricultural extension agents, conventional plant breeding or biotechnology-driven crop improvement to lift cereal yields (3). Stewart and Knight (6) observed that: ‘international trade concerns and recent crises played out in front of the public have the potential to not only stifle support for these products, but also lead to their being discarded if they are perceived by producers and retailers as too much of a risk. With many nations following the lead of Europe by not accepting goods derived from GM plants into their markets, or demanding their labeling, consumers will not have an opportunity to purchase these products, as these markets will remain closed. In countries that are willing to embrace genetic engineering plants, like the United States, if consumers are unwilling to buy these products and the public is unwilling to accept the risk of GM plants being grown, it is unlikely that GM crops will survive as part of the agricultural system. The reviews of Eicher et al. (3) and Bodulovic (2) on ‘crop biotechnology and the African farmer’ and ‘the effects of attitude toward GM products and African development’ respectively present a very interesting case. Both papers deduce that: The origins of African policy makers’ concern over biotechnology are partially a spillover from concerns in Europe about food safety, the environment and generalized public mistrust of multinational seed companies as being manipulative and unscrupulous. It was further observed that the transplanting of European consumer concerns coincided with a regional drought in Southern Africa in the years 2002–2004 necessitating a large amount of food aid. The main supplier of food aid was the United States, which did not have ‘identity-preserved supply chains’ for most of the GM and non-GM maize. Hence African governments

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Herbal Medicine on the African Continent 343

become concerned about the potential health, environmental and trade effects of importing food aid. The lack of biosafety regulations and the capacity to evaluate GM and non-GM maize was heightened by the slowness of international organizations to come out and say that GM maize food aid was safe. In the absence of authoritative information, the debate over technical issues turned into sovereignty issues and become a fertile ground for anti-GM activists to fuel the fears of policy makers and general public. Zambia’s experience captures the GM debate in Southern Africa. The government of Zambia rejected GM food aid from the United States even as the country was facing drought in 2002 while intense debate ensued over whether the food aid was GM grain and whether it contained possible health, environment and trade concerns (2,3).

Herbal Medicine on the African Continent Traditional medicine practice that is unequivocally entrenched in the culture of African people resides with numerous varieties of herbal extracts and teas with long professed medicinal values (Table 22.1). A wide number of plant species from the Alliaceae, Anacardiaceae, Apiaceae, Apocynaceae, Asteraceae, Bignoniaceae, Bombaceae, Cactaceae, Caesalpinaceae, Celastraceae, Clusiaceae, Erythroxylaceae, Euphorbiaceae, Hymenocardiaceae, Lamiaceae, Myrtaceae, Meliaceae, Oxalidaceae, Ebenaceae, Rubiaceae, Urticaceae families contribute to the management of diseases in the African countries (see Table 22.1). The demand on natural products will escalate with the emergence of new diseases and this will be further heightened since imported medicine is unsustainable in several African countries under the current economic realities. The traditional, complementary and alternative medicines contain toxic and potentially lethal constituents including aristolochic acids, pyrrolizidine alkaloids, benzophenanthrine alkaloids, lectins, viscotoxins, saponins, diterpenes, cyanogenetic glycosides and furanocoumarins (19). In addition, adulteration and misidentification of plant samples in traditionally prepared herbal medicines has given rise to toxicological concerns (20). Cases of nephropathy involving substitution of Aristolochia fangchi and Stephania tetrandra, and substitution of Aristolochia manshuriensis stem for the stem of Clematis and Akebia species (4) have been reported. A case of poisoning following administration of red pepper in the form of a red powder was lethal to an 8-month old child (21). In addition, a number of traditional remedies are taken for gynecological disorders and concerns on the safety of their use remain (13). Among the alkaloids are Asclepias fruticosa from Asclepiadaceae, Gloriosa virescens from Colchicaceae which lead to respiratory disorders and weak heartbeat while Catharanthus roseus from Apocynaceae, Callilepsis laureola from Asteraceae and Adenia gummifera from Passifloraceae results in hypoglycemia (13,16,18). Given the wealth of information on traditional uses of plants, investigation on their bioefficacy is still warranted (17,22). However, as with other pharmaceutical agents useful for disease prevention, pharmacoeconomic analysis of a therapeutic formulation would need to be considered and the composition of the formulation should be judged to have improved over time.

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Table 22.1 Traditionally based botanical drugs in use in some African countries for the management of primary health care Therapeutic indications

Plant species

Family

Plant part used

Country

Reference

Anti-fungal

Diospyros usambarensis Hymenidictyon parvifolium Vernonia oligocephala Vernonia colarata Catharanthus roseus

Ebenaceae Rubiaceae Asteraceae

Roots

Tanzania

(7)

Roots Twigs Leaves

South Africa

(8)

South Africa

(9)

Cassia obtusifolia ⫹ Newbouldia laevis Phyllanthus muelverianus Plectranthus madagascariensis Vitex doniana ⫹ Psidium guajava Adansonia digitata Ayapana triplinervis Anacardium occidentale Azadirachta indica Acanthus montanus Mangifera indica Cassine orientalis Averrhoa bilimbi Ageratum conyzoides Allium cepa Allium sativum

Eaesalpiniaceae Bignoniaceae Euphorbiaceae Lamiaceae Verbenaceae Myrtaceae Bombaceae Asteraceae Anacardiaceae Meliaceae Acanthaceae Anacardiaceae Celastraceae Oxalidaceae Compositae Alliaceae

Leaves Stem/Leaves

Nigeria Nigeria

(10) (11)

Leaves Leaves

Mauritius Nigeria

(12) (11)

Leaves

Mauritius

(12)

Leaves Leaves Leaves

Nigeria Mauritius Nigeria

(11) (12) (11)

Mauritius

(12)

Nigeria

(11) (13)

Vangueria apiculata Cassia occidentalis Anthocleista vogelii Cassia fistula Leonotis leonuris

Rubiaceae Caesalpinaceae Loganiaceae Caesalpinaceae Lamiaceae

Pentanisia prunelloides Barleria randii Xylopia parviflora

Rubiaceae Acanthaceae Annonaceae

Anti-malarial Breast and Uterine Cancer Cough

Diarrhoea

Diabetes Hypertension and cardiac dysfunctions HIV/AIDS Induce labour

Laxative

Treatment of wounds Gynaecological problems

Apocynaceae

Whole plant Stem bulb, leaves, Root tuber Root Root bark Root Pods Twigs, Leaves, Flowers Roots Roots/Leaves Roots

Uganda

Nigeria

(14,15)

Mauritius South Africa

(6) (16)

South Africa

(17,18)

African Traditional Medicinal Plants: Source of Bioactive Ingredients Although the benefits of the rich plant biodiversity have long been recognized through indigenous knowledge, the plants are also exploited and used for various purposes (Table 22.2). Since over 50% of all modern clinical drugs are of natural product origin (23), considerable attention has been focused on identifying the naturally occurring components in medicinal plants. Characterization and isolation of the active compounds is of significant interest to the pharmaceutical industry and is essential to ensure a comprehensive understanding of their overall synergistic action in a complex extract. Alkaloids, terpenoids and polyphenolics are classes of plant secondary metabolites that have gained significant recognition as therapeutic compounds. The alkaloids vincristine and vinblastine, isolated from Catharathus roseus, are among the most

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African Traditional Medicinal Plants: Source of Bioactive Ingredients 345

Table 22.2 African medicinal plants exported for their active ingredients Plant species

Parts used

Active ingredients

Source area

Allanblackia floribunda Ancistrocladus abbreviatus Corynanthe pachyceras

Fruit Plant Bark

Côte D’Ivoire Cameroon, Ghana Ghana

Dennetia tripetala Griffonia simplicifolia

Fruit Seed

Fat Michaelamine A and B Yohimbine, corynanthine,corynanthidine Essential oil BS11 lectin

Harpagophytum procumbens; Harpagophytum zeyheri

Root

Glucoiridoids

Hunteria eburnea Jateorhiza palmata

Bark Root

Pausinystalia johimbe Pentadesma butryacea Physostigma venenosum Prunus africana

Bark Fruit Fruit Bark

Rauvolfia vomitoria

Root

Eburine Palmatine, jateorhizine, colombamine Yohimbine Fat Physostigmine Sterols, triterpenes, n-decosanol Reserpine, yohimbine

Strophanthus spp Voacanga africana

Fruit Seed

Ouabain Voacamine

Ghana Ghana, Côte D’Ivoire, Cameroon Namibia

Ghana Tanzania Cameroon Côte D’Ivoire Ghana, Côte D’Ivoire Madagascar, Cameroon, Kenya Zaire, Rwanda, Mozambique West Africa Cameroon, Côte D’Ivoire, Ghana

potent anti-leukemic drugs in use, while several other alkaloids including quinine (from Cinchona succirubra) and atropine (from Atropa belladonna) have established medical applications (24). The terpenoids also comprise some of the very important naturally occurring pharmaceuticals: artemisinin (antimalarial), taxol (anticancer), Digitalis sterol glycosides (prescribed for congestive heart diseases) and steroidal saponins from yam (precursors for the synthesis of progesterone-like compounds for birth control pills) (25). Table 22.2 gives an account of the African medicinal plants exported for their active ingredients. The restricted technological advances in several of these developing countries hinder extraction, processing and commercialization of these bioactive constituents. The review of Nwaka (26) alluded to the set of Millennium Development Goals (MDGs) of the United Nations aimed at alleviating extreme poverty in developing countries (which pledged to halt and begin to reverse the incidence of HIV/AIDS, malaria and other major diseases by 2015). The expected collaboration with pharmaceutical companies will provide access to affordable essential drugs in developing countries and can ultimately lead to increased proportion of populations in the developing countries being able to have access to affordable essential drugs on a sustainable basis. Several factors affect access to pharmaceuticals. The drug supply chain is eminently reviewed in Figure 22.1 (26) with the following paragraph being seminal: One of the factors of course is availability – the drug must be developed and manufactured. This requires that basic research is properly managed to interface with drug discovery and development. The second major determinant is the accessibility of the new drug in disease-endemic countries. This requires

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Upstream

Discovery

I RF AC E

RF AC E

Translation research

PPRs Discovery and Development Activities

DEC regulatory approval

NT E

I NT E

Knowledge drug demand/supply

Supportive policies

CE FA

BASIC RESEARCH Dec research capacity

Downstream

R TE IN

CE FA

Knowledge disease burden

R TE IN

Long-term funding

Development

PHARMACOVIG. Public/private distribution

Trained providers/ Infromed customers

Health Impact Accessibility Availability Acceptability Affordability Rational use Quality assurance

Align R&D to access

Donors/sustainable financing and DEC’s engagement

Figure 22.1 The drug discovery supply chain. In the context of this framework, some African based initiatives for R&D, biotechnology, manufacturing and regulatory development are also being discussed and incubated by various groups. Specific examples include the Product Research and Development in Africa initiative (PRADA) and the initiative for pharmaceutical technology transfer as well as other biotechnology, science and technology initiatives (from Nwaka (26)).

(i) better regulatory systems in developing countries to assess the quality of drugs, (ii) effective distribution systems, (iii) affordability, (iv) sustainable financing, (v) trained healthcare workers and (vi) informed consumers. It is vital to align basic research with translational research in order to produce leads that feed into the drug development pipeline (Fig. 22.1). Basic research needs access to screening facilities and chemical libraries as well as other expertise including focused medicinal chemistry efforts if ideas are to be translated into drug leads (26).

Regulatory Status on Botanical Drugs, Nutraceuticals and Functional Food in the African Continent Traditional medicine represents utilization of whole, fragmented or cut plants, algae, fungi, lichens and botanical preparations from these materials involving extraction, distillation, expression, fractionation, purification, concentration and fermentation. However, the manufacturing process, use of solvents/additives, purification and drying techniques, and storage conditions may play a major role in the occurrence of significant amount of contaminants, pesticides, microorganisms, heavy metals, toxic chemicals or solvent residues in the samples. Thus it is of utmost importance to define and implement rigorous, standardized manufacturing stages/procedures, quality assurance and quality control techniques. The Dietary Supplement Health and Education act (DSHEA), introduced in 1984 in the USA provided consumers ready access to dietary supplements that are safe, effective and of high quality. Several other countries have adopted and amended this act for regulating supplement products. Thus, in Canada, Natural Health Products regulations have been introduced in 2004 to regulate the sale, manufacture, packaging, labeling, importation, distribution and storage of

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References 347

the nutraceuticals (27). Similar legislation relating to nutraceuticals in the European Union is strictly applied, although there seems to be no consistency in the legal status of some botanicals across the European countries. For instance, many functional foods or food-derived ingredients are sold as foods, whereas in other European countries these are considered as herbal medicines registered by full and simplified registration procedures (9). Similar cases can be recorded across the African continent since there is currently no common regulatory framework to assess these natural health products. Medicinal and food plants contain a reservoir of untapped bioactive components that have potential therapeutic effects on health. The concepts of plant-made pharmaceuticals and the latest advances in the genetic engineering of plants can hold much promise for the production of medicines that are inexpensive and yet abundant by using a range of different plants as factories to express active medicinal ingredients. Ultimately, how the benefits and risks of plant made pharmaceuticals (hence the botanical drugs and nutraceuticals) are addressed by the respective government’s regulation and how this will affect the products that make it to the marketplace and their ultimate success are of great concern to consumers, farmers to health and food production industries.

References 1. Aruoma OI. (2006). The impact of food regulation on the food supply chain. Toxicology 221, 119–127. 2. Bodulovic G. (2005). Is the European attitude to GM products suffocating African development? Functional Plant Biol 32, 1069–1075. 3. Eicher CK, Mariddia K, Sithole-Niang I. (2006). Crop biotechnology and the African farmer. Food Pol 31, 504–527. 4. EMEA (2001). Herbal Medicinal Products Working Party. Position paper on the risks associated with the use of herbal products containing Aristolochia species. EMEA web-site:www.eudra.org/emea.html 5. Otusuki T, Wilson JS, Sewadeh M. (2001). Saving two in a billion: quantifying the trade effect of European food safety standards on African exports. Food Pol 26, 495–514. 6. Stewart P, Knight AJ. (2005). Trends affecting the next generation of U.S. agricultural biotechnology: politics, policy, and plant-made pharmaceuticals. Technol Forecast Social Change 72, 521–534. 7. Hamza OJ, van den Bout-van den Beukel CJ, Matee MI et al. (2006). Antifungal activity of some Tanzanian plants used traditionally for the treatment of fungal infections. J Enthnopharmacol 108, 124–132. 8. Clarkson C, Maharaj VJ, Crough NR et al. (2004). In vitro antiplasmodial activity of medicinal plants native to or naturalized in South Africa. J Ethnopharmacol 92, 177–191. 9. Gulati OP, Ottaway PB. (2006). Legislation relating to nutraceuticals in the European Union with a particular focus on botanical-sourced products. Toxicology 221, 75–87. 10. Guo HZ, Chang ZZ, Yang RJ, Guo D, Zheng JH. (1998). Anthraquinones from hairy root cultures of Cassia obtusifolia. Phythochemistry 49, 1623–1625. 11. Adjanahoun E, Ahyi MRA, Ake-Assi L et al. (1991). Traditional medicine and pharmacopoeia. Contribution to ethnobotanical floristic studies in Western Nigeria. Organization of African Unity, Scientific Technical and Research Commission Lagos, Nigeria.

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12. Gurib-Fakim, A. Guého, J. (1996). Plantes médicinales de Maurice, Tome 2. Editions de L’Océan Indien. 13. Steenkamp V. (2003). Traditional herbal remedies used by South African women for gynaecological complaints. J Ethnopharmacol 86, 97–108. 14. Igoli JO, Igwue IC, Igoli NP. (2003). Traditional medicinal practices amongst the Igede people of Nigeria. J Herbs, Spices Med Plants 10, 1–10. 15. Okorie DO. (1976). A new phthalide and xanthones from Anthocleista djalonensis and Anthocleista vogelli. Phytochemistry 15, 1799–1800. 16. Van Wyk B-E, Gericke N. (2000). People’s plants. a guide to useful plants of Southern Africa. Briza Publications, Pretoria. 17. Gurib-Fakim A. (2007). Medicinal plants: traditions of yesterday and drugs of tomorrow. Mol Asp Med 27, 1–93. 18. Van Wyk B-E, Van Oudtshoorn B, Gericke N. (1997). Medicinal plants of South Africa. Briza Publications, Pretoria. 19. Adewunmi CO, Ojewole JAO. (2004). Safety of traditional medicines, complementary and alternative medicines in Africa. Afr J Trad CAM 1, 1–3. 20. Fennell CW, Lindsey KL, McGaw LJ et al. (2004). Assessing African medicinal plants for efficacy and safety: pharmacological screening and toxicology. J Ethnopharmacol 94, 205–217. 21. Snyman T, Stewart MJ, Steenkamp V. (2001). A fatal case of pepper poisoning. Forensic Sci Internl 124, 43–46. 22. Neergheen VS, Soobrattee MA, Bahorun T, Aruoma OI. (2006). Characterization of the phenolic constituents in Mauritian endemic plants as determinants of their antioxidant activities in vitro. J Plant Physiol 163, 787–799. 23. Farombi EO. (2003). African indigenous plants with chemotherapeutic potentials and biotechnological approach to the production of bioactive prophylactic agents. Afr J Biotechnol 82, 662–671. 24. Leveque D, Wihlm J, Jehl F. (1996). Pharmacologie des Catharanthus alcaloïdes. Bull Cancer 83, 171–186. 25. Calixto JB, Beirith A, Ferreira J, Santos ARS, Filho VC, Yunes RA. (2000). Naturally occurring antinociceptive substances from plants. Phytother Res 14, 401–418. 26. Nwaka S. (2005). Drug discovery and beyond: the role of public-private partnerships in improving access to new malaria medicines. Trans Royal Soc Trop Med Hyg 99S, S20–S29. 27. Nestmann ER, Harwood M, Martyres S. (2006). An innovative model for regulating supplement products: natural health products in Canada. Toxicology 221, 50–58. 28. Arnold H-J, Gulumian M. (1984). Pharmacopoeia of traditional medicine in Venda. J Ethnopharmacol 12, 35–74. 29. Bahorun T, Neergheen VS, Aruoma OI. (2005). Phytochemical constituents of Cassia fistul. Afr J Biotech 4, 1530–1540. 30. Grierson DS, Afolayan JH. (1999). An ethnobotanical study of plants used for the treatment of wounds in the Eastern Cape, South Africa. J Ethnopharmacol 67, 327–332. 31. Kamatenesi-Mugisha M, Oryem-origa H. (2007). Medicinal plants used to induce labour during childbirth in western Uganda. J Ethnopharmacol 109, 1–9. 32. Nguz K. (2007). Assessing food safety system in sub-Saharan countries: an overview of key issues. Food Control 18, 131–134.

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Supplements and Functional Foods Legislation in Brazil

23

Maria Cecília de Figueiredo Toledo1 and Franco M Lajolo2 1

Departamento de Ciência de Alimentos, Faculdade de Engenharia de Alimentos – Universidade Estadual de Campinas, Campinas-SP, Brasil 2 Departamento de Alimentos e Nutrição Experimenta Faculdade de Ciências Farmacêuticas Universidade de São Paulo, São Paulo-SP, Brasil

Abstract The Brazilian regulatory framework for functional and health claims for either nutrient or nonnutrient components has been developed based on safety and efficacy and lays down the concept that functional foods are foods and not drugs. The legal requirements for the risk assessment and registering of novel foods and ingredients and for proving the efficacy of a function or health claim are contained in four regulations which came into effect in 1999. Foods and drugs are clearly distinguished by their intended use and form of presentation. The term ‘supplement’ applies only to minerals or vitamins or a combination of both. A specific regulation on bioactive substances and probiotics was created later on in 2002 to address products inhabiting a gray line between food and drugs. The Brazilian regulatory agency responsible for the assessment of functional foods is the National Health Surveillance Agency (ANVISA), which has approved claims on a case-by-case basis with the scientific advice of the Technical and Scientific Committee on Functional Food and Novel Ingredients (CTCAF). This chapter describes the legislation that is relevant in the marketing of supplements and functional foods in Brazil. It also contains a list of horizontal function and health claims that have been approved in the last years.

Introduction Brazil is the only country in Latin America to have a well-defined legislation for functional and health claims for either nutrient or non-nutrient components and Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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350 Supplements and Functional Foods Legislation in Brazil

also for the demonstration of safety and efficacy. Although there is no official definition of functional foods in Brazil, the norms are based on the concept that functional foods are foods and not drugs and, as such, they are part of a normal diet and may claim to have health-related benefits. Foods and drugs are clearly distinguished by their intended use and presentation as well as by their target population. Products inhabiting a gray line between food and drugs are legally classified as bioactive substances and are subject to a specific regulation. Terms as ‘nutraceuticals’ and ‘pharma-food’ are avoided by the scientific community and by regulatory agencies (1,2). The food categories dietary supplements or food supplements do not exist as such. According to the present regulatory understanding (3), the term ‘supplement’ applies only to minerals or vitamins or a combination of both. Mixtures of foods and food components with herbals that have pharmacological action are considered drugs or phytotherapeutical agents, being subject to medicinal laws. The regulatory system, enacted in April 1999, was based on internationally accepted principles and can be considered updated (4–7). Legislation essentially rules on demonstration of safety and efficacy of novel foods and ingredients and productspecific health/functional claims. All of these products need a premarket register and approval by the regulatory health authorities. Safety demonstration is a priority and should be based on risk analysis. Efficacy of claims should be based on scientific evidence obtained from the literature or by new research and must represent scientific consensus. Both function and health claims are defined and allowed. As for health claims, only health maintenance and disease risk reduction claims are allowed, with both prevention and cure allegations being prohibited. In this case, the product is considered a drug and assessed as such. Nutrient content claims were authorized many years ago in Brazil (8). Minerals and vitamins were freely added to food and beverage till then, when the addition of those nutrients was restricted to the limit of 100% of the recommended daily allowance (RDA). The Brazilian regulatory agency responsible for the assessment of functional foods is the National Health Surveillance Agency (ANVISA), which is linked to the Ministry of Health (9). This agency has approved claims on a case-by-case basis and is still in the process of developing function and health claims provided there is adequate scientific validation. The approval of claims has been based on an extensive review of existing scientific literature and on locally conducted research requested to support product efficacy for the Brazilian population. Function and health claims should be true, clearly understandable by consumers and not misleading. When necessary and appropriate, information on the limitation of efficacy and restriction of use by specific groups or individuals should be provided. In any case, the claim should be in accordance with public health policies. This chapter describes the legislation that is relevant in the marketing of supplements and functional foods in Brazil, how it was developed and some of its particularities.

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Historical Background In the early 1990s, numerous petitions involving a variety of products, many of which not usually recognized as food, were submitted to the Brazilian health authorities for registering as foods. In the following years, not only the number and diversity of petitions increased, but also the advertisement of these products in the media (10). Based on the precautionary principle, the regulatory authorities were not favorable to the approval and use of these products as foods; nevertheless, a large number of products were already available on the market in pharmaceutical forms, many bearing unproven preventive and curative claims. They were sold either as dietary supplements, natural products or botanicals, some consisting of complex mixtures of herbs extracts containing very active pharmacological compounds such as amphetamines (ephedrine) and alkaloids. At the same time, new products made with novel ingredients such as omega-3 fatty acids, phytosterols, fibers and oligosaccharides carrying non-authorized claims were being introduced into the market at lightning speed (1,2). Only after 1998, following more than one year of scientific discussion with the participation of representatives from government, academia and industry, ANVISA approved and published a regulatory framework for the analysis of novel foods and novel ingredients, including foods with function and or health claims (4–7). In developing health claim legislation, Brazil has adopted various concepts and made assumptions, as described below: 1. functional foods would not to be legally defined as a new food category but considered as conventional foods with claims 2. foods with claims should provide health-related benefits and not oppose the national nutrition and health policy 3. product safety and efficacy should be proved through a science-based process 4. claims should be true, not misleading and written in language understandable by consumers. The approved regulations lay down legal requirements for the risk assessment and registering of novel foods and ingredients (4,6,7) and for proving the efficacy of a function or heath claim (5). They were built taking into consideration the existing regulation in several countries all over the world, seeking a consistent and balanced position. With this new approach, which incorporated scientific risk analysis in the decisionmaking process, a scientific commission was established to support ANVISA in the assessments. The creation of the Technical Scientific Commission on Functional Foods and Novel Foods (CTCAF) (11) was the first act after the publication of the technical regulations on functional foods, thus guaranteeing scientific-based evaluations. The nominated members of the CTCAF (available at http://www.anvisa.gov.br/ alimentos/comissoes/tecno_assessoramento.htm) come from academia and research

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institutes and have expertise in areas such as food science, nutrition and toxicology. When necessary, experts from specific areas are invited to participate in the Commission’s meetings, which have occurred every one to two months, depending on the number of processes to be evaluated. According to internal established principles, the recommendations made by the CTCAF on the safety and efficacy of ingredients or products should be based on current scientific knowledge, be conducted on a case-by-case basis and be in accordance with national health policies. Previous decisions may be reviewed whenever new scientific evidences are available or by request of the manufacturer. Claims should be easily understandable by consumers and not refer to disease prevention, treatment or cure. By applying the enacted legislation, CTCAF first evaluated approximately 2000 already existing products with regard to their safety and/or the efficacy and adequacy of claims. Of these, most were rejected on the grounds that the data presented to establish safety were not adequate. A number of products, many imported and marketed as dietary supplements, were either prohibited or registered as drugs, mostly as phytotherapeuticals, and others were forced to undergo review as part of the submission process. Following previously established principles, herbal extracts and foods containing isolated compounds or herbals with pharmacological activity were considered drugs and therefore submitted to pharmaceutical regulations. As mentioned before, although functional foods are not officially defined in Brazil, the common understanding is that they are foods, in most cases similar to conventional foods, consumed as part of a usual diet, capable of producing physiological or metabol ic effects, useful to maintain good health and reduce the risk of non-transmissible chronic disorders, beyond their basic nutritional properties (1,2,10). Products containing bioactive substances with added functions having dosage forms or presented in tablets or capsules, which closely resemble medicinal products given their composition, claims and presentations, were not considered either foods or drugs. Such products, usually referred to as ‘nutraceuticals’ in other regions, were placed in a gray borderline while internal discussions were undertaken to develop an adequate regulatory framework to cover this wide range of products. In many countries, nutraceuticals have a slightly different meaning, as being those foods that contain some health-promoting components beyond traditional nutrients. To ANVISA, this term has no meaning in the current regulation. In practice, most classification problems existed not because of the composition of the product but because of the form of presentation. The understanding of the Brazilian regulatory authorities is that pharmaceutical forms are not characteristic of foods. As a result of the discussions and taking into consideration the variety of bioactive substances that were then the object of the petitions, a new regulation was issued in January 2002, covering the register and market of bioactive substances and probiotics (12). In a continuous and dynamic process of updating the legislation, after 5 years of joint work with the CTCAF, the Brazilian regulatory authorities decided to review the previously approved health and functional claims. The bases for the review were the availability of new scientific data and information on the difficulty encountered by consumers in understanding the meaning of the wording used in the labeled claim

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Regulatory Framework for Supplements 353

of some products. Moreover, it was noticed that several claims originally allowed were misused, i.e. the statements on the label were far beyond what was approved based on the existing scientific data. The review resulted in various products losing the permission to use claims and others had their claims modified. Additionally, a positive list of approved horizontal claims linked to specific substances and probiotics was developed (Table 23.1) and should be used whenever a product containing the functional ingredient makes a claim. No change in the wording of the approved claim is allowed. The reader should keep in mind that this list is only valid at this point in time and that a process of revision and update of this list has been on going since June 2007, which means that in the near future it may be different. As it is voluntary to make claims, the rules only apply if the manufacturer or distributor chooses them to apply. Taking into consideration that, in some circumstances, the food matrix may interfere with the bioavailability of the functional ingredient, additional data on the efficacy of the ingredient in the context of use may be requested before a decision is taken. An example is the addition of phytosterols to orange juice, for which controlled clinical studies involving the exposure to the intended product were requested in order to confirm the efficacy of phytosterols in this beverage (the claim had been previously approved for spreads). For certain novel ingredients, post-marketing surveillance may also be required, as it was for olestra, quitosane and fat spreads with phytosterols.

Regulatory Framework for Supplements In Brazil, different from other legislations, the term ‘supplement’ applies only to products containing vitamins or minerals or a combination of both, which are regulated by a specific norm (3). Article 3 of this norm defines mineral or vitamin supplements as ‘foods intended to supplement with vitamins and or minerals the daily diet of a healthy individual, whenever the intake of these nutrients from a regular diet is insufficient or in cases where a supplementation is required’. Supplements should contain in the recommended daily serving at least 25% and at most 100% of the recommended daily intake of vitamins and minerals for Brazilians (13). They should not substitute any conventional food item or be eaten as a sole item of a meal or of the diet. According to this regulation, supplements are classified as: 1. 2. 3. 4.

vitamins isolated or in combination minerals, isolated or in combination mixtures of vitamins and minerals and products that are natural sources of vitamins and or minerals and that are regulated by a specific Standard of Quality and Identity.

The products may be commercialized in solid, semi-solid, liquid or spray forms. The only permitted claims in supplements are those referring to normal scientifically proven functions of vitamins and minerals, including the description of the

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Functional ingredients Powered resistant dextrin

Partially hydrolyzed guar gum

Fatty acids of the omega-3 family

Functional or health claim

Dietary fibers help the intestines to function normally. They should be consumed in association with a balanced diet and healthy living habits


The consumption of omega-3 fatty acids helps maintaining healthy levels of triglycerides, provided it is associated with a balanced diet and healthy living habits

1. This claim must only be used for long-chain omega-3 fatty acids coming from fish oils (EPA – eicosapentaenoic acid and DHA – docosahexaenoic acid) 2. This claim may be used provided the daily serving or 100 g or 100 ml of the product ready for consumption, as is the case, contains at least 0.1 g EPA and/or DHA 3. The above requirements apply to the recommended daily portion of the product when presented in capsules, tablets, pills and the like 4. The nutritional information table must declare saturated fats, monounsaturated and polyunsaturated fats, with the quantity of omega-3 fatty acid declared below the polyunsaturated fats 5. The following warning phrase, highlighted and in bold letters, must be included on the label of the product ‘People with illness or presenting any physiological alteration, pregnant women or nursing mothers should consult their doctor before using this product’

1. This claim may be used provided the daily serving of the product ready for consumption contains at least 3 g of partially hydrolyzed guar gum (solid food) or 1.5 g partially hydrolyzed guar gum (liquid food) 2. The above requirement applies to the recommended daily portion of the product when it is presented in capsules, tablets, pills and the like 3. This claim is approved only for partially hydrolyzed guar gum obtained from the vegetable species Cyamoposis tetragonolobus-Indian cluster bean 4. The amount of partially hydrolyzed guar gum must be declared below dietary fibers 5. The minimum quantity of water needed to dissolve the product must be informed on the label when commercialized as isolated fiber 6. The following warning phrase highlighted and in bold letters, must be inlcuded on the label of the isolated fibers, when presented in capsules, tablets, pills, powders and the like: ‘This product must be consumed along with the intake of liquids’

1. This claim may be used provided the daily serving of the product ready for consumption contains at least 3 g of resistant dextrin (solid food) or 1.5 g resistant dextrin (liquid food) 2. The above requirement applies to the recommended daily portion of the product when presented in capsules, tablets, pills and the like 3. The use of the ingredient must not exceed 30 g in the daily serving of the product ready for consumption 4. The amount of powdered resistant dextrin must be declared as soluble fiber, below dietary fibers 5. The following warning phrase highlighted and in bold letters, must be included on the label of the isolated fibers, when presented in capsules, tablets, pills, powders and the like: ‘This product must be consumed along with the intake of liquids’

Specific requirements

Table 23.1 Function and health claims permitted in Brazil (updated in April 2008)


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Functional ingredients Lycopene Lutein Zeaxantin

Dietary fibers

Polydextrose

Beta-glucan

Fructooligosaccharides (FOS)


Lycopene (lutein, zeaxantin) has antioxidant properties that protect cells against free radicals. It should be consumed in association with a balanced diet and healthy living habits



Beta-glucan (dietary fiber) helps in reducing the absorption of cholesterol. It should be consumed in association with a balanced diet and healthy living habits

Fructo-oligosaccharides (FOS) contribute to the equilibrium of the intestinal flora. They should be consumed in association with a balanced diet and healthy living habits

Table 23.1 Continued

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(Continued )

1. This claim may be used provided the daily serving of the product ready for consumption contains at least 3 g FOS (solid food) or 1.5 g FOS (liquid food) 2. The amount of fructo-oligosaccharides must be declared in the nutritional information table, below dietary fibers 3. The following warning phrase highlighted and in bold letters, must be included on the label of the isolated fibers when presented in capsules, tablets, pills, powders and the like: ‘This product must be consumed along with the intake of liquids’

1. The daily serving of the product ready for consumption must contain a minimum of 3 g beta-glucan (solid food) or 1.5 g beta-glucan (liquid food) 2. The claim is approved only for beta glucan from oat 3. The amount of beta-glucan must be declared in the nutritional information table, below dietary fibers 4. The following warning phrase highlighted and in bold letters, must be included on the label of the isolated fibers when presented in capsules, tablets, pills, powders and the like: ‘This product must be consumed along with the intake of liquids’

1. This claim may be used provided the daily serving of the product ready for consumption contains at least 3 g polydextrose (solid food) or 1.5 g polydextrose (liquid food) 2. The above requirement applies to the recommended daily portion of the product when presented in capsules, tablets, pills and the like 3. The amount of polydextrose must be declared as soluble fiber, below dietary fibers 4. The following warning phrase highlighted and in bold letters, must be included on the label of the isolated fibers, when presented in capsules, tablets, pills, powders and the like: ‘This product must be consumed along with the intake of liquids

1. This claim may be used provided the daily serving of the product ready for consumption contains at least 3 g fibers (solid food) or 1.5 fibers (liquid food) 2. The amount of dietary fibers must be declared in the nutritional information table 3. The above requirement applies to the recommended daily portion of the product when presented in capsules, tablets, pills and the like 4. The following warning phrase highlighted and in bold letters, must be included on the label of the isolated fibers, when presented in capsules, tablets, pills, powders and the like: ‘This product must be consumed along with the intake of liquids’

1. The amount of lycopene (lutein, zeaxantin) contained in the daily serving of the product ready for consumption must be declared on the label, next to the claim 2. The amount of lycopene (lutein, zeaxantin) contained in the daily recommended portion of the product must be declared when the isolated product is presented in capsules, tablets, pills and the like 3. A detailed description of the process of production and standardization of the substance, including the use of solvents and other chemicals should be provided 4. Analytical data on the residual level of solvents and on the purity of the product should be provided



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1. This claim may be used provided the daily serving of the product ready for consumption contains at least 3 g psiillium (solid food) or 1.5 g psiillium (liquid food) 2. The above requirement applies to the recommended daily portion of the product when presented in capsules, tablets, pills and the like 3. The only species already evaluated is Plantago ovata. Any other species must be evaluated as to the safety of its use. 4. The amount of psyllium fiber must be declared in the nutritional information table, below dietary fibers5. The following warning phrase highlighted and in bold letters, must be included on the label of the isolated fibers when presented in capsules, tablets, pills, powders and the like: ‘This product must be consumed along with the intake of liquids’ 1. This claim may be used provided the daily serving of the product ready for consumption contains at least 3 g quitosane (solid food) or 1.5 g quitosane (liquid food) 2. The above requirement applies to the recommended daily portion of the product when presented in capsules, tablets, pills and the like 3. The petition must contain analytical data on the levels of the inorganic contaminants arsenic, cadmium, lead and mercury. (Decree no 55871, of March 26, 1965 (DOU 09/04/65), should be taken as reference for tolerable levels of contaminants in food category: other foodstuffs) 4. Analytical data on the physico-chemical composition, including the amount of fiber and ash, should be presented 5. The amount of quitosane must be declared in the nutritional information table, below dietary fibers 6. The following warning phrase highlighted and in bold letters, must be included in the label: ‘People allergic to fish and shellfish must avoid eating this product’ 7. The following warning phrase, highlighted and in bold letters, must be included on the label of the isolated fibers when presented in capsules, tablets, pills, powders and the like: ‘This product must be consumed along with the intake of liquids

Lactulose

Psiillium or psyllium

Quitosane

Lactulose helps the intestines to function. It should be consumed in association with a balanced diet and healthy living habits

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Psiillium (dietary fiber) helps in reducing the absorption of fat. It should be consumed in association with a balanced diet and healthy living habits

Quitosane helps in reducing the absorption of fat and cholesterol. It should be consumed in association with a balanced diet and healthy living habits

1. This claim may be used provided the daily serving of the product ready for consumption contains at least 3 g lactulose (solid food) or 1.5 g lactulose (liquid food) 2. The above requirement applies to the recommended daily portion of the product when presented in capsules, tablets, pills and the like 3. The amount of lactulose as dietary fibers must be declared in the nutritional information table 4. The following warning phrase highlighted and in bold letters, must be included on the label of the isolated fibers when presented in capsules, tablets, pills, powders and the like: ‘This product must be consumed along with the intake of liquids’

1. This claim may be used provided the daily serving of the product ready for consumption contains at least 3 g inulin (solid food) or 1.5 g inulin (liquid food) 2. The above requirement applies to the recommended daily portion of the product when it is presented in capsules, tablets, pills and the like 3. The amount of inulin must be declared in the nutritional information table, below dietary fibers 4. The use of the ingredient must not exceed 30 g in the daily serving of the proudct ready for consumption 5. The following warning phrase highlighted and in bold letters, must be included in the label of the isolated fiber when presented in capsules, tablets, pills, powders and the like: ‘This product must be consumed along with the intake of liquids’

Inulin

Inulin contributes to the equilibrium of the intestinal flora. It should be consumed in association with a balanced diet and healthy living habits


Functional ingredients




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Phytosterols

Mannitol Xylitol Sorbitol

Probiotics Lactobacillus acidophilus Lactobacillus casei shirota Lactobacillus casei, variety rhammosus Lactobacillus casei, variety defensis Lactobacillus paracasei Lactobacillus lactis Bifidobacterium bifidum Bifidobacterium animallis, (including the subspecies B. Lactis) Bifidobacterium longum Enterococcus faecium Soy protein

Phytosterols help in reducing the absorption of cholesterol. They should be consumed in association with a balanced diet and healthy living habits

Mannitol (xylitol, sorbitol) does not form acids that damage the teeth. The consumption of the product does not replace adequate dietary and mouth hygiene habits

The (probiotic) contributes in maintaining the equilibrium of the intestinal flora. It should be consumed in association with a balanced diet and healthy living habits

The daily consumption of at least 25 g of soy protein may help to reduce cholesterol. It should be consumed in association with a balanced diet and healthy living habits

1. The amount of soy protein contained in the daily serving of the product ready for consumption must be informed on the label, next to the claim 2. The amount of soy protein contained in the recommended daily portion of the product ready for consumption must be declared when presented in capsules, tablets, pills and the like 3. Soybean based products may not contain in their labels or in advertising material any reference to the content of isoflavove or to any functional or health or therapeutic (prevention, treatment or cure of diseases) claim associated to isoflavone.

1. The minimum amount of live probiotic in colony forming units (CFU) contained in the daily serving of the product ready for consumption must be in the range 108 to 109 per day. Lower values may be accepted once the efficacy is proved 2. The manufacturer must submit analytical data to assure the quantity of the live microorganisms until the shelf-life of the product 3. Data on bile tolerance and resistance to acids must be provided 4. The amount of probiotic in colony forming units (CFU), contained in the daily serving of the product ready for consumption, must be informed on the label, next to the claim

This claim is approved for use in chewing gums only

1. The amount of free phytosterols contained in the daily serving of the product must not be less than 0.8 g 2. The recommended daily serving of the product (1–3 portions per day) must guarantee a daily intake of 1 to 3 g phytosterols 3. The information “with phytosterols” must be included on the label 4. The amount of phytosterol contained in the daily serving of the product ready for consumption must be informed on the label, next to the claim 5. Phytosterols include both free and esterified sterols and stanols 6. A detailed description of the process of production and standardization of the substance, including the use of solvents and other chemicals must be provided 7. Analytical data on the residual level of solvents must be provided 8. Analytical data on the purity of the product and characterization of the phytosterols must be provided 9. The following warning phrases highlighted and in bold letters, must be included on the label: ‘People with high levels of cholesterol should seek medical guidance’, ‘Phytosterols do not provide additional benefits when consumed in amounts above 3 g per day’, ‘The product should not be consumed by children below 5 years old, pregnant old, pregnant women and nursing mothers


Source: Brasil. Ministério da Saúde. Agência Nacional de Vigilância Sanitária. Available at http://www.anvisa.gov.br/alimentos/comissoes/tecno_lista_alega.htm

Functional ingredients



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physiological role of these nutrients in the growth, development and normal functions of the body. Claims that make reference to prevention, mitigation or cure of diseases or to any alteration in physiological conditions are prohibited. The following warning statement in the label is required: ‘Pregnant and lactating women and children up to 3 years should only consume this product under medical supervision’.

Regulation on Function and Health Claims On 30 April 1999, the National Health Surveillance Agency of the Minister of Health enacted four regulations covering the register and safety of novel food and ingredients, the efficacy of claims and the register of foods bearing claims (4–7). Later on, in 2002, in view of the need to clarify the differences between functional foods and bioactive compounds (nutraceuticals), the latter usually sold in pharmaceutical forms, containing mostly herbs and other botanicals, a new regulation was added to the already existing regulatory framework, covering at this time ‘Isolated bioactive substances and probiotics with health or functional claims’ (12). Brazil was the first country in Latin America to issue legislation for functional food and function/health claims and today about nine different claims associated to 19 functional ingredients and one claim associated to 10 probiotics are allowed (see Table 23.1). Foods per se are also permitted to bear function or health claims, but such claims must be made on the basis of an ingredient or nutrient they contain and for which the efficacy in the food has been established. Procedures for the registration of novel foods and/or new ingredients are specified in RDC 16 (4), where novel foods or ingredients are defined as ‘foods or substances without a record of consumption in the country or foods with substances already consumed, that are added or begin to be used at levels much higher than those currently observed in foods used in a regular diet’. Manufacturers or distributors are responsible for submitting all evidence to assure safety and substantiate the claims for their products. A technical scientific report, written in Portuguese, is an essential part of the dossier and should contain the following information: name of the product/substance; purpose of use, conditions of use recommended in product labeling which includes the labeled suggested population for the ingredient; description of the origin of the ingredients and of the manufacture process; specification of the mineral or botanical species or animal source from where the product/novel ingredient originates (if applicable); chemical composition and molecular characterization (when appropriate) and or formulation of the product, with description of the analytical methodology for the evaluation of the food or ingredient that is object of the petition, certificate of analysis of contaminants such as heavy metals, mycotoxins, pesticide and veterinary drugs residues, depending on the origin of the product. Applicable scientific evidences, as appropriate to prove safety of use, should be part of the dossier. Scientific evidences on the safety of the food or substance should include data on: 1. nutritional and or physiological and or toxicological studies in experimental animals

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Regulation on Function and Health Claims 359

2. 3. 4. 5.

biochemical assays epidemiological studies statistically valid clinical studies information on historical use by humans, without harm, when available.

The report should also contain information about the status of approval of the product or substance in other countries as well as other recommendations from international, regional or national regulatory agencies or committees with regard to safety issues. Products are assessed case-by-case and all documents referred to in the report as scientific evidence for safety should be annexed. Only articles/papers published in peer review journals are accepted. Publications such as articles from weekly magazines and the Internet, as well as book chapters, are not considered as evidences. Scientific papers written in English or Spanish do not need to be translated. Papers in other languages should be translated into Portuguese. Foods that start to be commercialized in pharmaceutical forms and have no claim (e.g. dehydrated beetroot), a statement that ‘the Ministry of Health warns: There is no proven scientific evidence that this product prevent, treat or cure diseases’ should be included on the label. Additionally, the regulation states that any information or functional or health claim of a food or ingredient advertised by any media to promote the product cannot differ in meaning from that approved to be displayed on the label. Basic guidelines for the risk and safety assessment of foods in general are contained in a separate Regulation (7), where references are made to the fact that proof of safety shall be conducted taking into account information on the purpose and conditions of use of the food or ingredient and on risk evaluation based on one or more scientific evidences, according to the circumstances. It is also mentioned that the risk evaluation must be conducted case-by-case by the CTCAF on the basis of existing scientific information and taking into account the nature of the material being assessed. From the Brazilian regulatory perspective, functional claim is legally defined as that related to the metabolic or physiological role that a nutrient or a non-nutrient plays in the growth, development and maintenance and other normal functions of the human organism, while health claims are those that imply, suggest or state the existence of a relation between the food or ingredient and a disease or a condition related to health (7). Both functional and health claims are optional and may refer to the maintenance of health, to the physiological role of nutrients and non-nutrients and to the reduction of risk to diseases. Claims referring to prevention or cure of diseases are not permitted. Furthermore, paragraph 3 of Article 3 of the said Regulation states that function and content claims are permitted for both nutrient and non-nutrients whenever their physiological role on the growing, development and normal body functions are described and assured. This paragraph continues with: ‘For nutrients with functions widely recognized by the scientific community the demonstration or analysis of efficacy is not necessary for functional claim on the label’. Because an apparent ambiguity was detected, the meaning of this last sentence was further subject

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of a document developed by ANVISA to help clarify this item thus giving a better background to those involved in the analysis of the claim as well as transparency to the interested parties. The need for the document was identified after the occurrence of situations in which products complying with this item were opposing principles of public health policies, thus bringing confusion to consumers. The understanding of ANVISA was that the use of claims in foods that are not part of the regular diet of the Brazilian population or in foods which consumption should not be stimulated should be restricted. To accomplish this goal, in 2004, ANVISA published on its website a guidance document entitled ‘Guidelines for the use, in labels of food, of claims for nutrients with functions widely recognized by the scientific community’ (14), in which they announced criteria with which the claims should comply. The first one was that the claim must be related to nutrients that are naturally present in the product, at levels at least equivalent to the quantity established for the attributed source, as specified in the appropriate regulation (15). The second criterion requires the claim to be specific to the function of the nutrient object of the claim and the third specifies that the claim must be associated to foods that are part of the dietary habit of the population and not of occasional consumption and that the food should not be presented in capsules, pills, tablets or other pharmaceutical forms. Additionally, the document states that any information published by the media should not differ from those approved for the label and should be truthful and not misleading. When these criteria are fulfilled, there is no need for further information or to conduct a technical analysis. It should be stressed that nutrient or non-nutrient when associated to botanical substances recognized as phytoterapeuticals or used in popular medicine are not considered foods, independently of the concentration of the nutrient or non-nutrient. ANVISA guidance document of 2004 (14) is clearly intended to reinforce that the requirements for marketing foods with added nutrients bearing functional claims must be followed and will be evaluated case-by-case. Besides demonstrating safety and efficacy, claims must inform the consumer that the claimed effect is to be observed in the context of a normal diet. The message on the label should reflect scientific agreement and not conflict with the nutrition and health policy of the country. The extent of demonstration, type and number of studies depends on the claim. The presence of a single study, published in scientific literature, may either qualify or disqualify a claim. In all assessments, CTCAF is responsible for the risk assessment and ANVISA, for the risk management. Final decision on the approval or prohibition of the product and or claim has been taken based on the CTCAF recommendations and the current public health policies. Dialog with the industry and request for additional information may be necessary before a decision is taken. The time taken between the submission of the petition and the final decision depends on the weight of credible scientific evidence provided. Although there is no definition of what constitutes substantiation for a claim, it is expected that reliable scientific evidence consists primarily of information obtained from well-designed human intervention studies.

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Regulation on Bioactive Substances and Probiotics 361

Regulation on Bioactive Substances and Probiotics In January 2002, a specific resolution (12) was issued to regulate the register, marketing and safety assessment of ‘Isolated bioactive substances and probiotics with health and or functional claims’, a group of products which the Brazilian health authorities found necessary to distinguish from functional food. According to paragraph 2.1.4 of the said regulation, bioactive substances are defined as ‘nutrients and those non-nutrients having a specific metabolic or physiological activity’. The term isolated is further clarified as meaning that the substance was extracted from its original source. These substances are classified in seven different chemical groups: carotenoids, phytosterols, flavonoids, phospholipids, organosulfur compounds, polyphenols and probiotics. Probiotics are defined as ‘live microorganisms having the ability to improve the microbial intestinal equilibrium and thus produce beneficial effects to the individuals’ health’. They were included in this regulation because they are available to the consumer in non-food forms. Similarly to functional foods, bioactive substances and probiotics must be approved and registered before being launched into the market. Because many of the commercial products are concentrates of bioactive components, safety is an issue and should be assured. The products should be safe for human consumption without medical prescription, unless they are recommended for specific population groups. Medical or therapeutical prescriptions are not allowed. Vitamins and or minerals may be added when the recommended daily intake of the product does not exceed 100% of the RDA and does not interfere in the bioavailability of other components. Accepted forms of presentations include tablets, pills, powders, capsules, granules, solutions or suspensions. Bioactive substances and probiotics must carry a function or health claim explaining how they act and the related health benefits. Probiotics must warrant that the physiological property alleged is maintained during the shelf-life informed on the label. It is important to stress that different from novel foods and ingredients, it is mandatory that bioactive or probiotic products carry an approved claim on their labels and authorization is granted on a product-by-product basis. Products containing amino acids and peptides such as creatine, taurine, arginine and carnitine, although very popular in the US market, are not covered by this regulation. Although these substances are usually used to increase muscular mass and to improve performance, the Brazilian health authorities have great concern on the safety of some of these compounds for which there is a lack of data on the effects of long-term ingestion. Foods and beverages made from soybean and those added of soybean proteins in different forms or obtained through different technologies are available in the Brazilian market and are gaining increasing popularity due to the publicity on the health properties of isoflavones. Despite this, soybean-based products may not contain on their labels or in advertising materials any reference to the content of isoflavones or to any functional or health or therapeutic claim associated to isoflavone.

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Isoflavones in capsules are also available in the market, but as drugs and not as functional food or bioactive substances. This is because the interested parties did not present sufficient evidence to substantiate the requested claims, which were associated to cancer treatment, osteoporosis reduction, efficacy in hormone replacement therapy and/or heart protection. At present, isolated isoflavones may be registered in Brazil as phytotherapeutical drugs and should be used under medical supervision. Accepted prescriptions include the reduction of symptoms of menopause and as auxiliary to reducing the levels of cholesterol (information available at http://www.anvisa.gov.br/ faqdinamica/index.asp?Secao ⫽ Usuario&usersecoes ⫽ 28&userassunto ⫽ 43). As mentioned earlier plant parts, plant extracts, botanicals or herbals are ruled under the medicinal regulations and are not allowed to be sold in supermarkets but only in pharmacies, which is an important difference between Brazil and other countries (10). Dietary fibers have also been an issue of discussion since the creation of CTCAF and an increasing number of fibers products and fiber-added foods have been marketed in Brazil in the last years carrying several types of claims. However, because of differences in functionality and characteristics, the regulatory authorities have faced some legal problems with regard to which fibers are eligible for claims and what should be the correct claim for each type of fiber. Several products have, for instance, undigested polysaccharides that behave physiologically like fiber but legally are not defined as such. The legal definition of fiber in Brazil is ‘any eatable material not hydrolyzed by the endogenous enzymes of human digestive tract’ (16) which was adopted in the scope of the South Market (Mercosur) harmonization process. Because of a lack of consensus on the most adequate definition for fiber and since not all types of fibers have the capacity for lowering cholesterol or reducing blood glucose levels or be fermented to produce short chain fatty acids, they have been analyzed case-by-case and each product is required to present a proper characterization of the fiber it contains, according to the claim made. Even the statement that a product is ‘rich’ or a ‘good source of fiber’ depends on the definition of what is considered fiber.

Future Perspectives The evolution of food science and technology and the recognition of the close relationship between nutrition and health have driven scientists and health professionals to a continuous search for substances/foods that can effectively play a beneficial role in human health. Although extensive studies have been conducted in attempting to assure safety and efficacy, the extent of demonstration, type and number of studies as well as the need of a real consensus is still a matter of debate among regulators, academia and industry. The Brazilian legislation on functional foods has focused on safety and efficacy and has been constantly updated to keep up with science development and national health policies. It is believed that developing and enacting sound regulations on functional

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References 363

foods will create opportunities for manufacturers to develop effectively and market safe and efficacious products (10). At present, a number of scientifically substantiated function and health claims are legally permitted in Brazil and have been used in different types of products in the market. Understanding the legal distinction between food, bioactive substance and drug is imperative for any company that wishes to market a health product in the Brazilian marketplace. Health authorities, academia and industry all over the world have jointly organized scientific meetings to discuss functional food and supplements and international forums have been fomented to exchange information and to set the standard for worldwide legislation. It is expected that, in the near future, the use of genomics and proteomics in demonstrating safety and efficacy will promote renewed research that can foster the development of functional foods. Moreover, as both scientists and regulators are gaining more experience and scientific understanding of health and nutrition and new methods of assessment are made available, the possibility for functional foods development will increase.

References 1. Lajolo FM. (2004). Alimentos funcionais, genômica e biotecnologia. In Genômica, L Mir (ed.), v1, pp. 785–799. Atheneu, São Paulo. 2. Lajolo FM. (2005). Functional food legislation in Brazil. In Regulation of functional foods and nutraceuticals, CM Hasler (ed.), pp. 367–376. Blackwell Publishing, Iowa. 3. Brasil. Regulamento Técnico para Suplementos Vitamínicos e ou de Minerais, Portaria no 32, de 13 de janeiro de 1998; Ministério da Saúde, Secretaria da Vigilância Sanitária: Brasília, Diário Oficial da União, Poder Executivo, de 15 de janeiro de 1998. 4. Brasil. Regulamento Técnico de Procedimentos para o Registro de Alimentos e ou Novos Ingredientes, Resolução no 16, de 30 de abril de 1999; Agência Nacional de Vigilância Sanitária: Brasília; Diário Oficial da União, Poder Executivo, de 03 de dezembro de 1999. Available in English at ANVISA website: http://www.anvisa.gov. br/eng/legis/resol/16_99_e.htm 5. Brasil. Regulamento Técnico para Procedimento de Registro de Alimento com Alegações de Propriedades Funcionais e ou de Saúde em Sua Rotulagem, Resolução no 19, de 30 de abril de 1999; Agência Nacional de Vigilância Sanitária: Brasília, Diário Oficial da União, Poder Executivo, de 10 de dezembro de 1999. Available in English at ANVISA website: http://www.anvisa.gov.br/eng/legis/resol/19_99_e.htm 6. Brasil. Regulamento Técnico que Estabelece as Diretrizes Básicas para Avaliação de Risco e Segurança dos Alimentos, Resolução no 17, de 30 de abril de 1999; Agência Nacional de Vigilância Sanitária: Brasília, Diário Oficial da União, Poder Executivo, de 03 de dezembro de 1999. Available in English at ANVISA website: http://www. anvisa.gov.br/eng/legis/resol/17_99_e.htm 7. Brasil. Regulamento Técnico que Estabelece as Diretrizes Básicas para Análise e Comprovação de Propriedades Funcionais e ou de Saúde Alegadas em Rotulagem de Alimentos, Resolução no 18, de 30 de abril de 1999; Agência Nacional de

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8.

9.

10. 11.

12.

13.

14.

15.

16.

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Vigilância Sanitária: Brasília, Diário Oficial da União, Poder Executivo, de 03 de dezembro de 1999. Available in English at ANVISA website: http://www.anvisa.gov. br/eng/legis/resol/18_99_e.htm Brasil. Regulamento Técnico de Alimentos Adicionados de Nutrientes Essenciais, Portaria no 31, de 13 de janeiro de 1998; Ministério da Saúde, Secretaria da Vigilância Sanitária: Brasília, Diário Oficial da União, Poder Executivo, de 16 de janeiro de 1998. Brasil. Define o Sistema Nacional de Vigilância Sanitária, cria a Agência Nacional de Vigilância Sanitária e dá outras providências, Lei no 9.782, de 26 de janeiro de 1999; Congresso Nacional: Brasília, Diário Oficial da União, Poder Executivo, de 27 de janeiro de 1999. Lajolo FM. (2002). Functional foods: Latin American perspectives. Br J Nutr 88(52), S45–S150. Brasil. Institui a Comissão de Assessoramento Técnico–-científico em Alimentos Funcionais e Novos Alimentos, Portaria no 15, de 30 de abril de 1999; Agência Nacional de Vigilância Sanitária: Brasília, Diário Oficial da União, Poder Executivo, de 03 de maio de 1999. Brasil. Regulamento Técnico de Substâncias Bioativas e Probióticos Isolados com Alegação de Propriedade Funcional e ou de Saúde, Resolução RDC no 2, de 7 de janeiro de 2002; Agência Nacional de Vigilância Sanitária: Brasília, Diário Oficial da União, Poder Executivo, de 09 de janeiro de 2002. Brasil. Adota valores como níveis de IDR para as vitaminas, minerais e proteínas Portaria no 33, de 13 de janeiro de 1998; Ministério da Saúde, Secretaria da Vigilância Sanitária: Brasília, Diário Oficial da União, Poder Executivo, de 16 de janeiro de 1998. Brasil. Informe Técnico no 9, de 21 de maio de 2004 Orientação para utilização, em rótulos de alimentos, de alegações de propriedades funcionais de nutrientes com funções plenamente reconhecidas pela comunidade científica (Item 3.3 da Resolução ANVS/MS N°18/99). Available at ANVISA website : http://www.anvisa.gov.br/alimentos/informes/index.htm Brasil. Regulamento Técnico referente à Informação Nutricional Complementar (declarações relacionadas ao conteúdo de nutrientes), constantes do anexo desta Portaria , Portaria no 27, de 13 de janeiro de 1998; Ministério da Saúde, Secretaria da Vigilância Sanitária: Brasília, Diário Oficial da União, Poder Executivo, de 16 de janeiro de 1998. Brasil. Regulamento Técnico sobre Rotulagem Nutricional de Alimentos Embalados, Resolução RDC no 360, de 23 de dezembro de 2003; Agância Nacional de Vigilância Sanitária: Brasília, Diário Oficial da União, Poder Executivo, de 26 de dezembro de 2003. Available in portuguese at http://www.anvisa.gov.br/alimentos/ comissoes/tecno_lista_alega.htm

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Regulation of Functional Foods in Selected Asian Countries in the Pacific Rim

24

Jerzy Zawistowski University of British Columbia, Vancouver, BC, Canada

Abstract The diet-related chronic diseases, such as coronary heart disease and diabetes, have been on the rise in the Asian countries in the Pacific Rim. This is especially pronounced among the urban communities due to the adoption of Western-style diet and pace of living. To combat chronic diseases, the nutritional trends have changed dramatically during the last two decades. There has been greater focus on the preventive role of nutrition and food with health benefits, such as functional foods. In response to consumer trends, the industry increased efforts to produce foods which possess ‘specific health care abilities’. Functional foods were also imported from other countries such as China, Japan and Europe. To control production and movement of this food category, many Asian jurisdictions in the Pacific Rim, including South Korea, Taiwan and Malaysia, have succeeded in developing regulations for the production and use of nutraceuticals and functional foods. Some other countries either utilized the existing global regulations or still have been working on the development of a new system. Although most of the countries in the region adopted the Codex Alimentarius definition, functional foods may have divergent meaning in various countries. The term ‘functional foods’ may include health and functional health foods, foods that are fortified with minerals and vitamins, dietary supplements or even traditional Chinese medicine. The purpose of this chapter is to review a regulatory system for functional foods in the eight countries of the Pacific Rim: Taiwan, Hong Kong, South Korea, Malaysia, Indonesia, Singapore, Philippines and Thailand. Diverse acts, regulations and guidelines that may govern this type of foods, as well as labeling and possible health claims are also discussed. Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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366 Regulation of Functional Foods in Selected Asian Countries in the Pacific Rim

Introduction Asia is a pioneer in recognizing foods with health benefits, known today as functional foods. In China and other Asian countries, foods have always been considered to be critical for human health and often used in the prevention and even treatment of diseases. Although most of the foods with disease-prevention attributes were lacking scientific support, some foods, such as tea, have been the subject of intensive research. Tea research performed during the Tang Dynasty (618–907) provided the initial impetus to establish ten main functions of tea (1). This historical event could be considered the very first set of health claims for functional foods described by modern standards. The ancient Chinese claim ‘tea is beneficial to health and relieves fatigue’ (1) is a very similar statement to the current Health Canada’s Natural Health Products Directorate health claim that states: ‘tea is accredited for the maintenance of good health and increasing alertness’. The modern concept of functional foods was also born in Asia. In 1980, the Japanese government sponsored a national research program on ‘systematic analysis and development of functions of food’ (1984–1986) and ‘analysis of functions for adjusting physical conditions of the human body with food’ (1988–1990). This research effort led to the identification of the tertiary function of foods. Unlike the conventional (primary – nutrition and secondary – taste/sensory) functions of food, the tertiary function is directly involved in the modulation of human physiological systems, such as the immune and digestive (2), which can improve or maintain health. It has become clear that food can be designed not only to satisfy primary functions, but also for adjusting conditions of the human body’s homeostasis that will regulate health and wellness. This new concept of physiologically functional foods (functional foods) consequently led to the creation of the Japanese regulatory system for this category of foods. In 1993, the Ministry of Health and Welfare established a policy to regulate ‘Food for Specified Health Use (FOSHU)’ or ‘Tokuho’ in its Japanese abbreviation. Under this system, the use of health claims for some selected functional foods is legally permitted (3). Today, Japan has the well-defined and established regulatory system and vibrant market with over 600 FOSHU products. Following the Japanese example, many global jurisdictions including Asia have succeeded in developing regulations for the production and use of nutraceuticals and functional foods. The regulation of this particular recent food segment is very critical, since it is the fastest growing food market in the world, resulting in billions of dollars in global sales.

Taiwan Preamble Taiwan has one of the highest gross national products per capita in Asia and, with a sufficiently large population and a fondness for anything that is novel, this country represents an excellent market for functional foods and dietary supplements (4).

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Taiwan 367

In addition, a well-established regulatory environment for food products, including health foods, currently exists in Taiwan. The Executive Yuan, Department of Health (DOH), which is Taiwan’s highest authority on health, is responsible for health administration, the guidance, supervision and coordination of local health agencies. In January 1999, DOH issued the Health Food Control Act (HFCA) which was initiated in February and implemented in August 1999. The HFCA has been amended several times including last amendments made in May 2006 (5). The act governs all matters relating to health foods, such as health food permits, manufacturing, importing, management of safety and sanitation, labeling and advertising, inspection of food facilities, manufacturers and vendors practices, as well as enforcement and sanction. Although this act defines only health foods, dietary supplements and medicine, functional foods match very well the definition of health foods. HFCA defines ‘health food’ as food products that possess ‘special nutritious elements’ (bioactive components) or ‘specific health care abilities’ to improve health, and/or reduce the risk of disease. This type of food is not intended to use for mitigation, curing and/or treating human diseases. Any food product that is labeled or advertised as food matching the definition specified in HFCA, is governed by the Health Food Control Law, regardless whether it is named health foods or functional foods. Subsequently, any foods with health-care abilities, including functional foods, must be registered within Department of Health. To qualify for a health food permit, a food product has to comply with the following conditions (5): ●

●

●

Food should contain clearly identified bioactive components that exert a health benefit within reasonable consumption. The health benefit effect must be supported by scientific proof. If it is not possible to identify specific ingredient(s) that are contributing to the health effect, the beneficial effects should be listed and supporting literature should be provided to the central health authority for evaluation and verification Food must be safe and the health beneficial effect(s) must be harmless to humans with typical consumption as assessed by toxicological techniques The central health authority must approve all methodology that is used to assess efficacy and safety of foods and associated bioactive constituents.

Health foods are permitted to carry seven DOH-approved maintenance claims (5): 1. 2. 3. 4. 5. 6. 7.

regulating blood lipids regulating the gastrointestinal tract regulating the immune system preventing osteoporosis maintaining dental health regulating blood sugar protecting the liver from chemical damage.

The health claim can be made for foods if it is supported by scientific assessments and approved by the Department of Health. The authorized health claims describe

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a type of health maintenance that foods may provide in a relationship to disease or health-related conditions (e.g. preventing disease). In contrast to the USA and some European regulations, the HFCA does not permit a link between a food bioactive ingredient and a disease. Please note that in Taiwanese regulations there are no specific requirements regarding the maximum level of adverse nutrients such as fat, saturated fat, salt, sugar or cholesterol to qualify food to carry a health claim. This prompted some Taiwanese institutions such as a non-governmental organization (NGO) to request that the HFCA be amended. The NGO suggests that a health food product should be evaluated as a whole and the use of excessive amounts of adverse nutrients in the food formulation should be restricted (6). This type of ruling is implemented in the USA under the Nutrition Labeling and Education Act as a prerequisite for food to carry a health claim on a label (7). This approach makes sense, since not only specific bioactive(s) but also all consumed food constituents play an important role in maintaining the health status of consumers.

Selling Health (Functional) Foods in Taiwan In order to sell domestic or imported health food products, the manufacturer or importer has to register a food product and then obtain a health food permit from DOH. The registration process is required to submit an application for review by the Health Authority. A dossier should contain all relevant information including (5,8): ● ●

●

● ●

● ● ●

A list of ingredients and their specifications Efficacy assessment of the food product as relating to the health maintenance claim Assessment of ingredients involved in the efficacy of food. This information should comprise function and its effects relating to the health maintenance claim, ingredient specifications and methods of analyses. Any research data and literature relevant to efficacy of ingredients should be included Assessment of safety of the food product A summary of manufacturing process along with supporting documents indicating that food is manufactured in accordance with good manufacturing practices (GMP). The central competent authorities must certify the GMP standards. Imported health foods must conform to GMP of the country of origin A food product label indicating the nutritional content A sample of the food product Application fees, including a permit fee along with review and testing fees are required.

The approval process consists of five steps as described in Table 24.1 (9). Once all documents are submitted, DOH conducts an assessment of the dossier and, if review is successful, the manufacturer or importer is granted a permit valid for 5 years to sell the health product. The permit may be extended for another 5 years by applying for renewal within 3 months prior to the expiration of the issued permit. DOH has the right to revoke the permit if scientific support of product efficacy is in doubt, when the bioactive ingredients, formulation, or method of manufacturing is changed and when safety of product is in doubt during its validity period.

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Taiwan 369

Table 24.1 Approval process for health functional foods in Taiwan Step1 Submission of a dossier to DOH for examination and registration Step 2 DOH conducts an initial assessment of the dossier Step 3 The Health Food Evaluation Committee appointed by DOH conducts further examination of the dossier to ensure that the efficacy and safety of the product are met Step 4 If the application is successfully reviewed, DOH approved the health food product and a permit is granted for 5 years to market the product

1

2

3

Figure 24.1 Example of Taiwanese health (functional) food product; sterols-containing milk drink for the risk reduction of coronary heart disease. (1) Logo for ‘health food’ with the reference number of the permit; (2) name of product ‘Plant sterols milk’; (3) approved health claim, ‘An animal study shows that consumption of this product may help lower blood total cholesterol’.

Under the current Taiwan’s regulations, relatively few products have received approval to market as health foods. During the first 4 years since implementation of the HFCA, 28 products obtained health food certificates (10). As of today, only 88 products have been approved. This falls far behind the number of products approved in Japan (over 600) and China (over 3000) (9). An example of a health (functional) food product that was introduced to the Taiwanese market in 2007 by Uni President is shown in Figures 24.1 and 24.2.

Labeling In Taiwan, regulations of food labeling are promulgated under a number of laws. Food products, domestic or imported, must conform to the national standards. These

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1

4 5

3

6 7

2 3 Figure 24.2 A label of Taiwanese health (functional) food product – sterols-containing milk drink for the risk reduction of coronary heart disease. (1) Logo for ‘health food’ with the reference number of the permit; (2) name of product ‘Plant sterols milk’; (3) approved health claim ‘An animal study shows that consumption of this product may help lower blood total cholesterol’ in Chinese and English; (4) nutritional information; (5) information on plant sterols; (6) instructions for use; (7) warning ‘pregnant and breast feeding women should consult their doctor before drinking this product’.

standards are similar to international standards for food labeling. This is because Taiwan, as a member of the World Trade Organization (WTO), is making a conscious effort to comply with international laws and regulations. Functional foods that are approved as health foods must be labeled according to the standards promulgated under regulations for food labeling of Food Administration Act (FAA) (11) and HFCA. The FAA regulations apply to conventional foods sold at Taiwanese market, while HFCA describes specific instruction for health foods. In general, food products must be labeled in Chinese, conspicuously displaying the product name, contents of ingredients and their origin, net weight or volume of the contents, date of production, the expiration date, telephone number, address and name of the manufacturer. For foods that are imported, a label should contain the name of country of origin, telephone number, address and name of the importer. In addition to general labeling standards, health food products must contain the following information on the label: ● ● ●

● ●

The approved health benefit effects (health claim) Reference number of the permit, the legend of ‘health food’ and standard logo Amount of intake (serving size) and important message for consumption of the health food and other necessary warnings Nutritional information In the case of a health food which is a blend of two or more ingredients, the ingredients shall be separately labeled.

The specifics of food labeling are described in the Regulations for Food Labelling (11).

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Hong Kong 371

Hong Kong Preamble When in 1997 Hong Kong became the Special Administrative Region (SAR) of the People’s Republic of China, the basic law guaranteed the independence of social, economic, political and judiciary system for Hong Kong until the year 2047. This enables Hong Kong to work directly with the international community to control trade in strategic commodities, such as food and drugs. Hong Kong has its own food and agricultural import regulations, which are different from those in mainland China (12). With a population of about seven million and a significant tourism industry, Hong Kong is a substantial market for all kinds of food products (13). Health foods are commonly sold in the domestic market and include vitamin and mineral supplements, shark liver oil and cartilage, deep-sea fish oil, Chinese medicinal fungi, herbal pills, royal jelly extracts, pollen tablets and ale extracts (14). Examples of functional foods are probiotics represented mainly by Yakult drinks and nutritive drinks (tonics) which have long been considered to provide mental and physical benefits, ranging from immune system properties, improving digestive health and enhancing physical beauty. Bird nest and essence of chicken are two of the most popular products. Dietary supplements in Hong Kong are much more varied with products such as evening primrose oil, glucosamine and co-enzyme Q10 becoming increasingly available in the market (15). Due to growing consciousness about health food through social dynamics and media, the Hong Kong market is demanding more health foods (16). Life style underlined by the high-density population and resulting space-constrained living quarters, as well as a growing number of women in the workforce, has increased the acceptance of Hong Kongese for variety of convenient but healthy food habits. ‘Value for money’ is one of most important consideration of Hong Kong consumers. Products with attractive, eye-catching packaging are gaining acceptance of the consumers. The most popular on the market are beautifying and slimming products for women and from western health foods, fish oil and omega fatty acids. Many of the dietary supplements and slimming products sold in Hong Kong fall within the general food category. At least two-thirds of healthcare products sold in Hong Kong contain traditional Chinese medicine (TCM). TCM is a system of healing that has been practised by Chinese for centuries. The Chinese practitioners believe that the body yin and yang imbalance may be corrected by eating the right mix of hot and cold foods. Although TCM is different than functional foods, the underlining principles of the disease prevention rather than treatment are the same. Therefore, the acceptance of TCM by Hong Kongese is the major factor giving rise to the popularity of functional foods (17). In Hong Kong, similar to the other countries, there is no universally accepted definition of health foods or functional foods. Alternative terms such as dietary supplements, nutraceuticals, designed foods, functional foods and natural health products are used on different occasions to refer to similar products. The growing interest in health/functional

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foods was reflected by organizing the first International Functional Food Conference (IFFC) in Hong Kong in August 2004. Over 140 companies, universities and government representatives attended the conference, which offered an excellent forum to share ideas about global regulations and standards for functional foods.

Health Foods Regulations Hong Kong does not have specific regulations established for health and wellness healthcare products. Depending on food composition, health foods (functional foods) may be regulated under the following Ordinances (18): ● ● ● ●

Pharmacy and Poisons Ordinance (PPO; Cap. 138) Chinese Medicine Ordinance (CMO; Cap. 549) Public Health and Municipal Service Ordinance (PHMSO; Cap.132) Undesirable Medical Advertisements Ordinance (UMAO; Cap. 231).

The law in Hong Kong does not provide a legal definition of health/functional foods products. In the absence of a legal definition, regulation of health food products is based on their ingredient content. Health foods are subject to the same acts and regulations as conventional foods. Retailers are required to provide truthful labeling as regulated by PHMSO (Cap. 132, Sec. 61 – False Labeling and an Advertisement of Food or Drugs). Healthcare food products that cannot be classified as Chinese medicine or western natural health products are regulated as general foods and they are subjected to the regulation of the PHMSO (Cap. 132). The manufacturers and sellers should ensure that their products are fit for human consumption. Health foods should not include medicinal ingredients, or they may be regarded as pharmaceutical products. If they contain medicines or claim to have medicinal effect, they are required to be registered under the Health Department and are regulated by the PPO (Cap. 138). Any product carrying a claim for the diagnosis, treatment, prevention alleviation or mitigation of disease or any symptoms of disease is classified as a pharmaceutical product and medicine and is regulated according to the above ordinance (Cap. 138, Sec. 2). On the contrary, some Chinese medicines may be regarded as health foods and they are subject to the CMO regulations (Cap. 549). This Ordinance controls also health products containing Chinese medicines as active ingredients. Although substantiated health claims are allowed, the UMAO (Cap. 231) prohibits advertisements claiming that a product has curative or preventive effects on any of the diseases listed in the schedule (Table 24.2) to the Ordinance (19). Pharmaceutical products and medicine are defined in PPO (Cap. 138). Chinese medicine is defined in CMO (Cap. 549) while food is defined in PHMCO (Cap. 132). Foods fortified with vitamins and minerals and some other bioactives may also be considered as functional foods and can be found in the Hong Kong market. The calcium-enriched foods are dominating the calcium supplement market, ranging from dairy products through to biscuits (15). According to Euromonitor, there were very few probiotic supplements in Hong Kong and their sales remained negligible in 2003. Nevertheless, Euromonitor expects

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Hong Kong 373

Table 24.2 Diseases in respect of which advertisements are prohibited or restricted under the Undesirable Medical Advertisements Ordinance of Hong Kong (UMAO, Cap. 231). 1. 2. 3. 4.

5. 6.

7. 8. 9. 10. 11. 12. 13. 14.

Any benign or malignant tumor Any viral, bacterial, fungal or other infectious disease, including tuberculosis, hepatitis and leprosy Any parasitic disease Any venereal disease, including syphilis, gonorrhea, soft chancre, lymphogranuloma venerum, genital herpes, genital warts, urethritis, vaginitis, urethral or vaginal discharge, acquired immunodeficiency syndrome (AIDS) and any other sexually transmitted disease Any respiratory disease, including asthma, bronchitis and pneumonia Any disease of the heart or cardiovascular system, including rheumatic heart disease, arteriosclerosis, coronary artery disease, arrhythmias, hypertension, cerebrovascular disease, congenital heart disease, thrombosis, peripheral artery disease, edema, retinal vascular change and peripheral venous disease Any gastrointestinal disease, including gallstone, cirrhosis, gastrointestinal bleeding, diarrhea, hernia, fistula-in-ano and hemorrhoids Any disease of the nervous system, including epilepsy, mental disorder, mental retardation and paralysis Any disease of the genitourinary system, including kidney stone, nephritis, cystitis, any prostatic disease and phimosis Any disease of the blood or lymphatic system, including anemia, neck glands, bleeding disorders, leukemia and other lymphoproliferative diseases Any disease of the musculoskeletal system, including rheumatism, arthritis and sciatica Any endocrine disease, including diabetes, thyrotoxicosis, goiter and any other organic or functional condition related to under or over activity of any part of the system Any organic condition affecting sight, hearing or balance Any disease of the skin, hair or scalp

the future of vitamins and dietary supplements to be dynamic, experiencing growth of 66% in China and 14% in the more mature Hong Kong market between 2003 and 2008. Unfortunately, there is no specific regulation on the nutrient fortification in food in Hong Kong. However, reference can be taken from the Codex Alimentarius, which issued a general Principles for the Addition of Essential Nutrients to Foods in 1987 and subsequently amended the principles in 1989 and 1991 (19).

Food Labeling Regulations Labeling regulations applicable to conventional foods apply as well to health foods. The Food and Drugs Regulations require food manufacturers and packers to label their products in a prescribed, uniform and legible manner. All pre-packaged food must be labeled according to regulations described in the Composition and Labeling (Cap. 132). The following information, in appropriate language (Chinese, English or both), must be included on the label except for ‘exempted items’ as provided in the regulations: ● ● ●

Name of the food, list of ingredients Indication of ‘best before’ or ‘use by’ date Statement of special conditions for storage or instruction for use

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● ●

Name and address of manufacturer or packer Count, weight or volume.

The Food Labeling Regulations were amended in 2004. The amendment stated that the food label should declare in the list of ingredients the presence of ingredients which are known to cause allergy in some individuals. The full list of such substances is included in the amendment. Some examples of such substances are cereals containing gluten, eggs and egg products, peanuts and their products, some food additives and others. Hong Kong does not have any specific regulations with regards to labeling of novel food products that may encompass such categories like genetically modified foods, functional foods or other biotech foods. There is no distinction between general foods labeling and biotech foods labeling requirements. The Working group established under the Center for Food Safety prepared a draft guideline related to labeling of biotech foods and suggested that: ● ●

●

●

The labeling of biotech food will comply with the existing food legislation The threshold level applied in the guideline for labeling purpose is 5%, in respect to individual food ingredients Additional declaration on the food label is recommended when significant modifications of the food, e.g. composition, nutrition value, level of anti-nutritional factors, natural toxicant, presence of allergen, intended use, introduction of an animal gene etc, have taken place Negative labeling is not recommended.

This voluntary guidance applies to pre-packaged food, is voluntary and has no legal effect. However, if products are found to have misleading labeling, such as negative labeling (e.g. GMO free, free from GM ingredients), a retailer may be subject to prosecution under Cap. 132, Section 61 – False Labeling and Advertisement of Food or Drugs of Public Health and Municipal Services (12).

Nutrition Labeling, Nutrition Claims and Health Claims Currently, there are no specific regulations on nutrition labeling for pre-packaged food products in Hong Kong. Hong Kong allows food products to have nutrient claims in any format. The Government has proposed to implement a nutrition labeling system, which will run on a voluntary basis for a period of 5–10 years, before becoming mandatory. All pre-packaged food, including functional foods, will eventually be subject to nutrition labeling. The target date for introduction of the legislative amendments was early 2007. With the provision of grace period, 2011 will be the earliest that nutrition labeling will take full effect. The proposed nutrition requires the listing of energy plus nine nutrients, including protein, carbohydrate, total fat, saturated fat, sodium, cholesterol, sugars, dietary fiber and calcium. It also requires nutrient amount to be expressed in absolute amount in kcal/metric unit per 100 g (or 100 ml) of food (12,20).

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South Korea 375

In Hong Kong, there are no regulations on health claims, except for the prohibition of disease prevention and cure claims and there are regulations on health claims in advertisements as well (20). The advertising regulations (21) state that: ●

●

●

Claims relating to the nutritional and dietary effects of products or services should be handled with care Claims of effects or treatment for conditions of health for which qualified medical attention or advice should reasonably be sought are not acceptable Claims made in food advertisements must be based on scientific evidence or be substantiated.

Unfortunately, many health foods can be found in the Hong Kong market claiming unsubstantiated beneficial effect on health. According to a large survey conducted by the Consumer Council in Hong Kong, seven categories of products, including health and functional foods, have been implicated in questionable, fake and ambiguous claims (22). Health claims such as ‘anti-cancer’ and ‘anti-aging’ benefits for shark liver oil, or ‘detoxifying the body’ claims for dietary supplements are claims that are incapable of substantiation (18). The need for regulations for health claims had been acknowledged during February 2, 2001 meeting of Advisory Council on Food and Environmental Hygiene. According to those discussions, the Health and Welfare Bureau would study the feasibility of developing a framework to monitor and regulate health claims, so as to protect the consumers from misleading information and exaggerated claims (23). The Director of Health will be empowered to prohibit products from making irresponsible health claims. Initially, the Administration has proposed to confine the restriction to food products, and to expand the restriction to cover other products in light of experience in due course. The Administration has proposed that food products claiming health benefits would fall under two categories (18): ●

●

Those claiming to be able to prevent or cure a specific disease or clinical condition should be first registered with the Director of Health for premarket approval, with claims properly substantiated by research or trials Those claiming to have general beneficial effects on health will be exempted from registration, with the Director of Health retaining the power to determine whether the claim made is a general or specific one.

South Korea Preamble Only recently, South Korea introduced the regulatory venue for the ‘functional health foods’. This term encompasses all natural health products and nutritional supplements. As a result of these changes, Korea, with its 48 million population, is currently among the largest Asian markets for functional health foods. Total market size for supplements was estimated at US$2 billion in 2004. Major leading products in

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the Korean market include aloe, squalene, chitosan, glucosamine, chlorella, multivitamins and minerals. There is a growing interest in herbal ingredients and plant extracts among local consumers. In addition to domestic products, dietary supplements and natural health products from the USA and Japan account for the largest source of the Korean import. This segment is so significant that the Korean government imposed the regulations on both domestic and imported products. Started on January 1, 2004, all products labeled or advertised as nutritional supplements in the form of capsules, tablets, powder, granule and liquid fall under the Health Functional Food Act. According to the law, Korean importers for nutritional supplements are required to complete import notification to the Korea Food and Drug Administration (KFDA), which categorizes products into one of 32 groups of active ingredients allowable for nutritional supplements (24). A transition in nutritional practices and products has occurred in Korea over the last 10–15 years (25). This transition reflected major changes in consumer eating and nutritional patterns. Consumption of food of animal origin increased relative to the consumption of foods of plant origin. Subsequently, intake calories from animal fat were higher over the last decade as compared with the traditional Korean food pattern in the past. These current changes led to an increase in overweight and obesity and subsequently in the risk of chronic diseases such as diabetes and coronary heart disease (26). Parallel with these adverse changes in nutrition, the Korean Food and Drug Agency (KFDA) brought forth positive amendments of food regulations. In 2004, the Korean Health Functional Food Act (HFFA) was introduced to encourage the industry to produce and market health foods that are easy and convenient to use by the fast pace average Korean consumer.

Korean Food and Drug Administration The first step in the creation of Korean Food and Drug Administration (KFDA) was establishing the Korean Food & Drug Safety Headquarters and six Regional Offices (KFDS) in April 1996. Subsequently, KFDS was raised to the administration status of KFDA. Korean FDA is the principal government agency with the role of promoting public health by ensuring the safety and efficacy of foods, pharmaceuticals, medical devices and cosmetics, as well as supporting the development of the food and pharmaceutical industries. The KFDA mission statement in relation to health functional foods is stated as: ‘Overseeing manufacture, importation and distribution of food and health functional foods and their safety’. KFDA is responsible for setting and implementing standards and specifications for food in general, functional foods, food additives, food packaging and equipment (27). The KFDA headquarters in Seoul consists of four divisions and two of the six departments are dedicated to food related issues only. KFDA headquarters also oversee six regional KFDA offices. KFDA publishes its food related regulations, including Food Code, Labeling Standards for Food, Functional Food Code and functional foods regulations. The Food Code, which could be compared to a compendium pharmacopeia, promulgates standards and specifications for manufacturing, processing, usage, cooking,

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storage of food and equipment, containers and packaging for food products. The code describes individual standards and specifications for 151 food categories delineated into 20 groups. The food code was last updated June 22, 2005 (27). The Functional Food Code (FFC) was established on January 31, 2004 and revised on May 26, 2005. The Code contains general standards and specifications governing functional food, individual standards and specifications for 37 functional food categories (26). Functional foods must be in the form of tablet, pill, capsule, granule, powder, or liquid. A food product that meets the criteria for one of the 37 defined categories is permitted to carry a health efficacy claim. Anyone wishing to export a functional food that is not one of the 37 categories specified in the Code can apply to KFDA for: ● ●

Recognition of raw materials that have specific health effects (efficacy) Recognition of the new category.

Details about recognition procedures, required documents or any related issues are provided on the KFDA website www.kfda.go.kr in the Korean language (27). There are two divisions within KFDA related to food, Food Headquarters and Nutrition and Functional Foods Headquarters. Food Headquarters consists of the four following teams: ● ● ● ●

Food safety policy team Food management Food import Food safety assurance.

The focus of those teams is issues related to general policy for food safety management such as: ●

●

● ●

Supervising the overall food hygiene matters including surveillance for illegal and adulterated food Supervising food importation and exportation and conducting imported food inspections Handling all issues relating to genetically modified foods Codex Alimentarius activities.

The Nutrition and Functional Food Headquarters consists of the following teams: ● ● ● ● ●

Health functional foods team Novel food team Health functional food standard team Nutrition evaluation team Food additives team.

There are six regional governmental KFDA agencies located in Seoul, Busan (3 branches), Gyeongin (3 branches), Daegu, Gwangju and Daejeon (28). Each

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agency serves as a field operation base conducting food and drug surveillance and imported food inspections at its local laboratory. In addition, there are nine national quarantine stations located in Gunsan, Mokpo, Yeosu, Masan, Tongyeong, Ulsan, Pohang, Donghae and Jeju. There are four categories of products that require import notifications: ● ● ● ●

Food (meat, dairy, egg and fish products) Food additives Apparatus, container-packages Health functional foods.

Food Laws Korea is one of the few Asian countries that recently introduced the functional food regulations. Until 1998, the Korean Ministry of Health and Welfare (MHW) retained all food regulations authorities. With the establishment of the Korea Food and Drug Administration (KFDA) in 1998, the MHW relinquished most of its authorities to KFDA. It did, however, retain authority to legislate changes to the Food Sanitation Act (FSA) and the Functional Food Act and their implementing Presidential Decree and Ministerial Ordinance. The FSA defines functional foods as health foods and nutritional supplements (27). It is worthy to note that functional foods are sold in tablets, pills, potions and other medicinal formats that resemble the US dietary supplement defined under the Dietary Supplement Health and Education Act (DSHEA) of 2004. It includes herbal products as well as essential nutrients.

Food Sanitation Act and Presidential Decree The Food Sanitation Act (FSA) is legislated by the National assembly and is the legal basis for the food safety related work conducted by MHW and KFDA. The Act aims for the improvement of national health by ameliorating the quality of nutrition and preventing sanitary hazards during the preparation of food. Presidential Decree establishes provisions to implement the FSA. It provides more defined guidance on interpretation and implementation of the Act. Ministerial ordinance to the FSA prescribes more detailed guidance on the implementation of the FSA and Presidential Decree. This ordinance provides relevant instructions for conducting business in Korea, including penalties for the lack of compliance. Standards and regulations for food-related business in Korea are provided in the form of the Food Code, Functional Food Code, Guidelines, Notices and others. All of these directives are administered by KFDA.

Functional Food Act and Presidential Decree The Functional Food Act (FFA) is legislated by the Korean National Assembly and it represents a legal basis for MHW and its executive branch, KFDA, to oversee the functional foods. The Act mandates the improvement of national health and consumer protection by ensuring the safety and quality of functional foods and encouraging sound distribution and sales of such products.

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Presidential Decree, issued December 18, 2003, established provisions to implement matters regulated by the FFA. The Ministerial Ordinance, issued on January 31, 2004, prescribed more detailed guidance on how the FFA and its Presidential Decree are to be implemented. This ordinance addresses inspection of imported functional food, penalties for violations and applications for import inspection among others. The Functional Food Code, Guidelines for Labeling of Functional Food, Guidelines for Advertisement of Functional Food and relevant Notices provide specific standards and regulations. The administration, amending and promulgation of standards and regulations are the responsibility of KFDA (27).

Health Functional Food Act Health functional food is defined as ‘a processed food used with intention to enhance and maintain human health by (consuming) physiologically functional ingredients and/or components in forms of tablets, capsule, powder etc’. There is one critical element in this definition that makes it so different from the definition used in the Western regulatory jurisdictions such as Canada, the USA and EU. Korean functional foods are doseable and can be used in the medicinal formats. As has been mentioned above, it resembles more the form of dietary supplements that are regulated in the USA under DSHEA, rather than functional foods as defined in Canada and the EU. There are 37 types of health functional foods/nutraceutical ingredients listed in the Act including vitamins, minerals, essential amino acids, proteins, dietary fiber, essential fatty acids and other nutrient supplements such as ginseng products, aloe, squalene and chlorella (24). Table 24.3 shows examples of generic ingredients that are listed in the Act (26). The HFF Act refers to two types of functional foods, generic and product-specific health functional foods. If the functional ingredient is on the official HFF Code list, food containing this ingredient is classified as generic and the active ingredient does not require extensive characterization and specific proof of its efficacy in functional food products. Many new physiologically active ingredients used in the formulation of functional foods are not listed in the HFF Code and require approval by KFDA. If the standards or specifications are not included in the HFF Code, the manufacturer or importer may prepare their own standards or specifications and submit them for approval to KFDA [Article 14(2)], (29). For such ingredients, scientific evidence needs to be provided by the Sponsor (food manufacturer) to the KFDA, proving that the new physiologically functional ingredient is safe and effective; a process that must occur before marketing of foods including such an ingredient. According to HFF Act [Article 14(1)], the Commissioner of the Korean Food and Drug Administration (KFDA) has the responsibility to prepare and distribute the Health Functional Food (HFF) Code containing standards, specifications and labeling requirements applicable for manufacturing, usage and maintenance of health functional foods (29).

Business Permit Anyone who intends to start a manufacturing business for functional foods should first file an application and obtain permission from KFDA. The same applies to

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Table 24.3 List of categories of generic health/functional products containing physiologically active ingredients Major categories of health/functional products Nutritional supplement Ginseng Red ginseng Eel oil EPA/DHA-containing product Royal jelly Yeast Pollen Squalene-containing product Yeast-containing product Probiotics-containing product Chlorella Spirulina Gamma-linolenic acid-containing product Embryo bud oil Embryo bud Lecithin Octacosanol-containing product Alcoxy-glycerol-containing product

Grape seed oil Fermented vegetable extract Mucopolysaccharide Chlorophyll-containing product Mushroom Aloe Japanese apricot extract Soft-shelled turtle Beta-carotene Chitosan-containing product Chito-oligosccharide -containing product Glucosamine-containing product Propolis extract Green tea extract Soy protein-containing product Phytosterol-containing product Fructo-oligosccharide-containing product Red yeast rice

EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid. Modified from (26).

anybody who intends to start an importing business for the functional food industry. The process requires submitting a business application to the Regional branch of KFDA office. Selling and/or distributing the functional food without manufacturing also require filing a business application and obtaining approval from the local authority, such as the City Office, District Office, or County Office (in Korean Si/Gun/Gu).

Quality and Manufacturing Process In order to improve controls over the quality and manufacturing process for health/ functional foods, the KFDA Commissioner issued a special Notice emphasizing the role of quality controls and good manufacturing practices (GMPs) in manufacturing sites involved in production of health/functional foods. According to this notice, effective February 2006, each functional food manufacturing site must assign a quality manager responsible to assure sanitary conditions of the manufacturing facility and provide necessary guidance and supervision to the manufacturing personnel. In addition, following GMPs in the functional food manufacturing sites will be mandatory for venture companies and toll manufacturing facilities. There is no current confirmation available describing the status of implementation of such programs.

Labeling Requirements Since June 1998, KFDA has been the legal authority for food labeling standards. The Food Safety Division, KFDA, is responsible for establishing labeling standards and

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KFDA regional offices, and/or provincial government health officials, enforce the labeling standards. Labeling standards for functional foods were established in January 31, 2004. According to HFF Act, Article 14(1), the Commissioner of KFDA has the responsibility to prepare and disseminate labeling requirements that are applicable to health/functional foods. The food labels should have printed, legible inscriptions including product name, product type, importer’s name and address, manufacture date (month and year). Shelf-life, contents (weight, volume or number of pieces), ingredient names and content, nutrients, other items designated by the detailed labeling standards for food (e.g. radiation-processed product, drained weight for canned products (29)). It should also be noted, that effective September 2006, the names of all ingredients have to be included on food labels. In addition, food items considered as allergens (eggs, milk, peanuts, crab, tomatoes etc) must be indicated on the label in the Korean language. All imported food products are required to be labeled with the necessary information in the Korean language. Stickers may be used instead of manufacturer printed information in the Korean language. The sticker should not cover the original labeling and cannot be easily removable. For functional foods, however, stickers on packages are not permitted (29). Manufacture printed Korean language labels instead must be used for such products. Nutritional labeling is optional for most food products, with some exceptions. However, foods with functional ingredients must have nutritional labels. This includes: ● ● ● ●

Health functional foods Special nutritional foods Health supplementary foods Foods with nutrient content claims (e.g. if product is labeled as ‘calcium enriched yogurt’, the content of calcium must appear on the label).

Korea currently does not allow health efficacy claims on food product labels except for products that meet the criteria for functional foods. Similarly to the labeling regulations in the USA and Canada, use of such emphatic terms as ‘non’ or ‘low’ are prohibited for food that is naturally low in a particular nutrient (e.g. low fat apples, low cholesterol vegetable oil). These terms can be used when a specific nutrient had been reduced through a manufacturing process. When the emphatic term ‘non’ or ‘low’ is to be used for saturated fat, the amount of cholesterol contained in the product should be stated. Labeling standards for functional foods were established in January 2004. In accordance with those standards, a manufacturer’s printed Korean language label must be on the product. It should have the following information, in addition to those required for general food products (29): ● ● ● ●

Indication that this is a functional food A statement regarding the efficacy claim Directions of use and warnings A statement that the product is not a pharmaceutical product that prevents, cures or mitigates disease

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●

Other required information as per the detailed labeling guidelines for functional food.

Regulations Pertaining to Health Functional Foods The following regulations that pertain to health functional foods were established in accordance with Health Functional Food Act: ●

●

●

●

Regulations on recognition of standards and specifications for health functional foods (30) Regulations on recognition of raw materials or ingredients of health functional foods (31) Regulations on imported health functional food notification and inspection procedures (32) Labeling standards for health functional foods (33).

Recognition of Standards, Specifications and Ingredients for Health Functional Foods The HFF Act describes a procedure for the review of health functional foods for which standards and specifications are not yet established (Article 14, paragraph 4, (44)) and/or ingredients that are new and require reviewing by KHDA (Article 15 Paragraph 3, (31)). To apply for the recognition of health functional foods standards, specifications and ingredients, an application accompanied by supporting documents must be submitted to KFDA Commissioner. If the criteria for health functional food standards and specifications are met, the Commissioner will issue a health functional food recognition certificate to the applicant. The following criteria must be met: ● ●

● ● ●

Compliance with the HFFA Compliance with the regulations on the standards and specifications as well as with regulations pertaining to raw materials and active ingredients used in functional foods Benefits for human health Scientifically proven safety and functionality of foods Intended functionality of the product as linked to bioactive ingredients.

It is important to note that the KFDA recognition approval apply for both domestic as well as imported food products. For food products that are specifically developed for importation, KFDA will inspect products under the provisions provided in the ‘Inspection Guidelines for Imported Food’. An application for the recognition of new ingredients must contain all safety data, animal and human clinical studies that have been conducted under the scientifically sound methodologies and good laboratory practices.

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KFDA provides the English translation of this guideline on its website (see http:// www.kfda.go.kr/eng/download/eng2000-20.doc).

Importation of Functional Foods to Korea Imported health functional foods must comply with the same requirements of the HFF Act, label and labeling and other applicable laws as foods that are produced in Korea. The regulations of the importation are promulgated in Article 8 of the HFFA and Article 10 of the Enforcement Regulations Act. The KFDA requires prior notice of imported functional foods and inspection by the designated laboratory either at the Regional KFDA or National Quarantine Station (NQS) (32). A notification must be submitted to Regional KFDA 5 or more days before the scheduled date of arrival of food shipments. The inspection is needed to verify whether functional foods are in compliance with the established labeling and advertising standards (Articles 17 and 18 of the Act). If health functional food is determined to be non-compliant, the importer may apply for the conversion of a non-compliant imported functional food for the other purpose than human consumption, in accordance with Article 7 paragraph 1 of the regulations Notice #2004–8.

Labeling Standards and Information for Health Functional Foods Labeling standards are applied to both domestic and imported health functional foods (HFFA, Article 17, (33)). It is important to provide consumers with accurate information, to enable them to make appropriate food choice in relation to reducing the risk and dietary management of chronic disease. The following information has to be provided on a label: ● ● ● ● ● ● ●

●

●

●

Indication that this is a Health Functional Food Product name Name and address of Manufacturer Shelf-life and storage instructions Net weight and ingredient list Description of use and warnings Nutritional facts, including specific amounts of nutrients with percentages of the reference values or recommended nutrient amounts Functional facts, including specific amounts of functional ingredients or marker ingredients of functional materials The statement that the products is not a pharmaceutical product intended to prevent or treat a disease Other information as required by the labeling standards for health functional foods.

The regulation provides detailed instructions related to methods of labeling, including nutrition and functional information and nutrient reference values.

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Malaysia Preamble The diet-related chronic diseases have been on the rise in Malaysia as well as other countries of South-East Asia including Brunei, Indonesia, Philippines, Singapore and Thailand. This is especially pronounced among the urban communities. Coronary heart disease was identified as a major cause of death in this region (34). To combat chronic diseases, the nutritional trends have changed dramatically during the last two decades. There has been greater focus given on the preventive role of nutrition. Being aware of these facts, consumers are now paying greater attention to the nutritive value of their diet. The food industries have also increased efforts to improve nutritional quality of foods, including increasing concentration of desirable and decreasing undesirable nutrients. New scientific developments in food science offer a range of possibilities to increase the health-promoting properties of specific food products. Examples of such foods are functional foods and nutraceuticals. This category of foods includes foods that are enriched with vitamins and minerals, as well as other food components, such as plant sterol and dietary fiber. According to the International Life Sciences Institute (ILSI), Southeast Asian nutritional scientists generally agree that functional foods should follow certain criteria (35): ●

●

●

●

Be in the form of conventional foods and possess sensory characteristics such as appearance, color, texture, consistency and flavor of food products Contain nutrients and other constituents that confer a physiological benefit above the basic nutritional properties. These components should not be used at the levels for medicinal or therapeutic purposes Possess scientifically proven functional benefits that are delivered upon consumption of regular amounts of these foods Contain ‘functional’ components (bioactives) that may be naturally present or may be added to the food and have been proven to be safe over long-term usage for the intended target population.

Functional Foods Although there is no specific regulation or standards for functional foods and the definition of functional foods is still inconclusive, the Malaysian government is actively proposing an international guidance to provide a better regulatory control of this category of foods. Working groups have been established to view recent developments. The functional claims criteria have been developed under the general principles of nutrition labeling and claims provision promulgated in the Food Regulations in 1985 and subsequently gazetted in 2003. These regulations cover requirements for food declaration, nutrient content claims and nutrition function claims. While there are currently 27 permitted nutrient function claims, health claims are prohibited.

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Malaysia 385

However, the market has a wide range of functional foods and products are manufactured locally or abroad in conventional food forms or beverages (36). Although functional foods may be regulated under the food supplement category, functional foods that are in the food format have to be in line with the current law and regulations regarding food safety and labeling. Nutrition labeling of foods is one of the strategies assisting consumers in adopting healthy dietary practices. Labeling provides a means for conveying information of nutrient content of the food product, thereby helping consumers to make better food choices when planning their daily meals. It is equally important to food industry, food manufacturers and retailers to become more aware of the nutritional properties of their products and be encouraged to emphasize these properties to consumers (34). Nutrition labeling is important for traditional foods, but it is even more important for novel foods such as functional foods, where consumers may not be as familiar with those foods or their components. Therefore, frequent questions raised by customers are often centered on safety of functional foods. The safety issue is also raised by dietitians (37). Their concern is that the existing Malaysian law, which regulates registration of functional foods, does not provide sufficient control of quality and safety of those products, especially in situations where nutrient composition of the functional food product is unknown and effectiveness is not frequently substantiated by scientific evidence and clinical studies. It should be noted, that functional foods are distributed under the food supplement category and are not covered by the Food and Drug Act (37). Therefore, the less restrictive regulatory environment creates a potential for supplements to be prone to quality control problems. Some dietitians promote the Malaysia Food Pyramid strategy (model) which incorporates a variety of foods comprising all nutrients required for health. This approach proposes a good diet to ensure health rather than single food items or food ingredients to prevent diseases. In order to control the quality and safety of functional foods, the Malaysian government, under the jurisdiction of Ministry of Health, has assigned three bodies to participate in the implementation of laws concerning functional foods (38). These include the Department of Food Quality Control Ministry of Health, the Malaysian National Codex Committee and the National Pharmaceutical Bureau. It has been proposed that functional foods in the conventional format containing original bioactive components may be registered with the Department of Food Quality Control Ministry of Health. Functional foods in the form of tablets should be registered under the National Pharmaceutical Bureau, as outlined in the Drugs and Cosmetic Act, 1984. The Department of Food Quality Control is responsible for reviewing of the product label to determine its composition. Acts and regulations used in this confirmation are the Foods Act 1983 and Food Regulations 1985 (37).

Food Laws and Regulations The Food Act of 1983 (Act 281 of the Laws of Malaysia) and its regulations, such as Food Regulations of 1985, is the primary legislative document for foods in Malaysia. Those regulations deal with food hygiene, labeling, imports, exports, advertising and analytical assessment (39).

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Specific Requirements for Nutrition Labeling Under the Food Act (1983) and the Food Regulations (1985), the information that must be listed on the label of food products includes the name of the product and the manufacturer, packer or importer, the weight or volume of the product as well as the designated food brand, content or list of ingredients provided in accordance to proportion or weight. The content of food additives and storage instructions for the food product must also be provided on the label. Since more than half of the Malaysian population is Muslim, labeling requirements for products containing pork and/or alcohol, are very strict. Expiry dates, under the Food Regulations 1985, are only compulsory for certain types of products such as bread, canned foods and others. Nutrition labeling means a description intended to inform the consumer of the nutrient content of a food. Although in some countries, such as the USA and Canada, nutrition labeling is mandatory for the pre-packaged foods, the situation in Malaysia with its current food laws is similar to most Asian countries where nutrition labeling is optional for the majority of food products, with the exception of ‘special purpose foods’. This category includes ‘functional foods’ that are enriched or fortified with specific vitamins or minerals. Many manufacturers, however, voluntarily place nutrition labeling on their food products, although without having a common format for nutrition labeling, some errors or inconsistencies occur in labeling. In August 2000, the Malaysia Ministry of Health announced the intention to amend the current regulations to have mandatory nutrition labeling for a wide variety of foods (40, 41). The proposal was to have mandatory nutrition labeling for a number of core nutrients, namely energy and macronutrients, such as carbohydrates, protein and fat, for a variety of pre-packed foods including functional foods, soft drinks with botanicals, soybean drinks and others. Beside the four nutrients that must be present on the label, other nutrients, such as minerals and vitamins are permitted, providing that they are listed in the nutrient reference values (NRV) (Table 24.4). For foods with a nutrition claim, it is mandatory to include a nutrition label and the amount of any other nutrient for which a nutrition claim is made in respect of the food (43). Examples of such nutrients are dietary fiber, omega-3 fatty acids and cholesterol. The proposed format for nutrition labeling follows the Codex Alimentarius guidelines (44). In this respect, the amounts of nutrients are expressed as a percentage of the NRV instead of percentage of recommended daily intake/allowance (RDI/ RDA) (Table 24.5). In general, the amendments proposed by the Ministry of Health follow closely the guidelines of the Codex Alimentarius, also recommended by FAO/WHO with few exceptions. These exceptions are necessary to meet the local needs in Malaysia. The Malaysian government enacted regulations on nutrition labeling and claims in 2005 (43), thus making it possible also to use them for functional foods. The three groups of nutrition claims for functional foods are: ● ● ●

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Nutrient content claims Nutrition comparative claims Nutrient function claims.

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Malaysia 387

Table 24.4 Nutrient reference values (NRV) and the Malaysian recommended daily allowance (RDA) values for vitamins and minerals Name of nutrient

Units

NRV

RDA

Vitamin A Vitamin D Vitamin C Thiamin Riboflavin Niacin Vitamin B6 Folic acid Vitamin B12 Calcium Magnesium Iron Zinc Iodine

μg μg mg mg mg mg mg μg μg mg mg mg mg μg

800 53 60 1.4 1.6 18 2 200 1 800 300 14 15 150

750 N/A 30 1.0 1.5 16.7 N/A 200 N/A 450 N/A 9 N/A N/A

Note: as it can be seen from this table, the NRV values are not very different from those of RDAs (42).

Table 24.5 Conditions for nutrient contents for use of nutrition claims (Malaysia) Component

Claim

Conditions (not less than)

Protein*

Source High Source

10% of NRV per 100 g (solids) 5% of NRV per 100 ml (liquids) or per 100 kcal (at least 2 times the values for ‘source of ’ ) 15% of NRV per 100 g (solids) 7.5% of NRV per 100 ml (liquids) or 5% of NRV per 100 kcal (at least 2 times the values for ‘source of ’)

Vitamins and minerals

High

*Nutrient Reference Value for Protein is 50 g (45).

Nutrient Content Claims A nutrient content claim describes directly, or indirectly, the level of a nutrient in a food or a group of foods. There are basically two types of nutrient content claims; the first being a negative claim that allows a food to carry ‘low’, ‘free’ or ‘non-addition’ statements in respect to the certain health-adverse food constituents, such as cholesterol, sodium, saturated fat or trans fat. Example of such a claim is the ‘cholesterol free’ statement listed on foods that contain not more than 5 mg cholesterol per 100 g for solids or per 100 ml for liquid foods (41). The second type of claims are considered positive claims that allow label statements such as ‘good/excellent source’, ‘high’, ‘enriched’, ‘fortified’ in food constituents that are beneficial to health (41). An example of an expression used in this claim is ‘a source of ’ vitamin C. To make this claim, food must contain at least 15 percent of the NRV value. To claim ‘high in’ vitamin C, food must contain at least 30 percent of the NRV value.

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Nutrient Comparative Claims Nutrient comparative claims involve similar foods, another brand of the food product, or different version of the food source. The claims may be expressed on a label in the relation to the nutrient content present in the food product which carries the claim and the food that it is being compared to. The latter food has to be clearly identified. For example, if a new food formulation has lower or reduced sodium content compared with a previous formulation, the label on the new formulation may claim to have ‘reduced sodium’ (41).

Nutrient Function Claims Nutrient function claim is defined as a nutritional claim that describes the physiological role of the nutrient in the growth, development and normal function(s) of the body. There are specific prohibitions, however, regarding the use of these claims, which can be summarized below (45): ●

●

●

A nutrient function claim shall not imply or include any statement relating to curing, mitigating or treatment of disease No label which describes any food shall include any claims relating to the function of a nutrient in the body unless the food for which the nutrient function claim is made shall contain at least the amount of nutrient in the level to be considered as a source of that nutrient per reference amount, as specified in Table 24.5 No label on a package containing any food shall bear a nutrient function claim except those permitted in the regulation or with prior written approval of the regulatory authorities.

Except as otherwise provided in these Regulations, only the following nutrient function claims are permitted (45): ● ● ● ● ● ● ● ● ● ● ●

Calcium aids in the development of strong bones and teeth Protein helps build and repair body tissues Iron is a factor in red blood cell formation Vitamin D helps the body utilize calcium and phosphorus Vitamin B1/thiamine is needed for the release of energy from carbohydrates Vitamin B2/riboflavin is needed for the release of energy from proteins Niacin is needed for the release of energy from proteins, fats and carbohydrates Folic acid is essential for growth and division of cells Vitamin B12/cyanocobalamin is needed for red blood cell production Vitamin C enhances absorption of iron from non-meat sources Magnesium promotes calcium absorption and retention.

These claims show the relations between nutrients and maintaining the function of the body necessary to good health and normal growth and are very similar to the Canadian biological role claim nutrients.

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Malaysia 389

In contrast to the Canadian regulations, Malaysian nutrient function claims are allowed for foods with bioactives such as probiotics and prebiotics as well as with ingredients with hypocholesterolemic properties. This type of claim can only be made provided the food meets the criteria for ‘source of ’ and other conditions listed in Table 24.6 (46). The bioactives such as dietary fiber and plant sterols are constituents of truly functional foods in Europe and USA. Examples of the model function claims for foods containing discussed bioactives are listed below: ●

●

Inulin helps increase intestinal bifidobacteria and helps maintain good intestinal environment Oligofructose (fructo-oligosaccharide) helps increase intestinal bifidobacteria and helps maintain a good intestinal environment

Table 24.6 Conditions for the Malaysian nutrient function claims for prebiotics, probiotics and hypocholesterolemic ingredients (46) Component

Source

Other conditions

Inulin and oligofructose (fructo-oligosaccharide, FOS)

Inulin:2 g per serving Oligo fructose (fructo-oligosaccharide, FOS)1.25 g per serving

Addition and claim for inulin and oligofructose (fructooligosaccharide, FOS) are not permitted in infant formula

Oat soluble fiber (β-glucan)

2 g per 100 g (solids)

Also contains total dietary fiber not less than amount required to claim as ‘source’: 3 g per 100 g (solids) 1.5 g per 100 ml (liquids)

Plant sterol/stan

1.3 g per 100 g (solids) 160 mg per 100 ml (liquid)

Soy protein

5 g per serving

Bifidobacterium lactis

2 ⫻ 107 cfu/g (powdered)

1. Addition and claim for plant sterol/plant stanol only permitted in milk, milk product, soy bean milk and soy bean drink (Reg. 82,83,357 and 358 respectively) 2. Types of plant sterol or plant stanol permitted: ‘plant sterol/plant stanol, phytosterols/phytostanol, sitosterol, campesterol, stigmasterol or other related plant stanol’ 3. Maximum amount in daily serving for product added with plant sterol/plant stanol is not more than 3 g plant sterol/ plant stanol per day 4. Declaration of the total amount of plant sterol/plant stanol contained in the products shall be expressed in metric units per 100 g or per 100 ml or per package if the package contains only a single portion and per serving as quantified on the label 5. Only the teams ‘plant sterols’ or ‘plant stanol’ shall be used in declaring the presence of such components 6. There shall be written on the label of food making such claim a statement a) ‘Not recommended for pregnant and lactating women and children under the age of 5 years’ b) ‘Persons on cholesterol-lowering medication shall seek medical advice before consuming this product’ c) ‘That the product is consumed as part of a balanced and varied diet and shall include regular consumption of fruits and vegetables to help maintain the carotenoid level’; or d) ‘With added plant sterols’ or ‘With added plant stanols’ in not less than 10 point lettering To include the statement: ‘Amount recommended to give the lowering effect on the blood cholesterol is 25 g per day’

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● ● ● ● ● ●

Inulin is bifidogenic Oligofructose (fructo-oligosaccharide) is bifidogenic Bifidobacterium lactis helps improve a beneficial intestinal microflora Oat soluble fiber (β-glucan) helps lower or reduce cholesterol Plant sterol or plant stanol helps lower or reduce cholesterol Soy protein help to reduce cholesterol.

The other wordings with similar meaning are permitted to use for the functional claims.

Nutrient Function Claims versus Health Claims The health claim is constructed to link diet with certain chronic disease conditions. The statement describing the health claim must be specific to the proposed health benefit of the food, or the presence of a specific constituent (e.g. bioactive) that upon ingestion affects the risk reduction and/or prevention of a particular disease condition. For example, the statement: ‘Food A is a high source of iron. Iron may help reduce the risk of anemia’ is a health claim, because food A, being a high source of iron can be used in the health claim to link the presence of iron (bioactive) with a disease condition, which is manifest by anemia. The nutrient function claim for iron would state: ‘Iron is a factor in red blood cells formation’; thus this example refers specifically to the function of iron. Malaysian regulations do not include elaborate provisions for health and nutritional claims. There are, however, several requirements that are related to health and nutrition claims. For instance, Regulation 18(3) of the Food Act prohibits the description of any food which includes the word ‘compounded’, ‘medicated’, ‘tonic’ or ‘health’ or other descriptions which refer primarily to drugs. According to regulation 26(7) of the Act, food labels cannot claim the food to be ‘enriched’, ‘fortified’, ‘vitaminized’, ‘supplemented’ or ‘strengthened’, or that the food is a source of one or more vitamins or minerals unless a reference quantity of the food contains no less than the amount of the nutrient in question as specified in Table 24.3 (42). However, the labels on a food product enriched with essential amino acids, or essential fatty acids, may contain a claim that the food is enriched or supplemented with these nutrients. In practice, claims on ‘low fat’, low or no cholesterol, ‘high in fiber’, ‘contains fatty acids’ (such as omega-3 fatty acids) and various vitamins or mineral enrichment are being made.

Forbidden Claims There are some provisions in the current regulations that prohibit the making of certain claims on the label. The proposed amendments include some additional prohibitions: ●

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Claims stating that any given food will provide an adequate source of all essential nutrients

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Malaysia 391

●

● ●

●

Claims implying that a balanced diet, or ordinary intake of foods cannot supply adequate amounts of all nutrients Claims that cannot be substantiated by scientific evidence Claims as to the suitability of a food for use in the prevention, alleviation treatment or cure of a disease, disorder or particular physical condition unless they are permitted in this regulation Claims which could give rise to doubt the safety of a similar food or which could arouse or exploit fear in the consumer

Health and Medicinal Food Products The National Pharmaceutical Control Bureau (NPCB) regulates all health and medicinal food products. Under the Dangerous Drugs Act 1952, Control of Drugs and Cosmetics Regulation 1984, NPCB determines if the health or medicinal food products should be registered. For imported food products, an import license may be required that can be issued by the Compliance Unit. In order to register with the NPCB, the exporter or appointed distributor must apply in writing to NPCB stating the name of the food products, its ingredients and the content. In addition, claims/ usage along with an attached copy of the label/product literature must be made available.

Food and Drug Interface: Regulatory Process In Malaysia, all drugs and cosmetic products have to be registered under the Control of Drugs and Cosmetics Regulations 1984 by the National Pharmaceutical Control Bureau (NPCB) and Drug Control Authority (DCA); a situation in contrast to foods which fall under Food Quality Control Division. However, if a food product contains less than 80% of food-based ingredients and more than 20% of the active ingredients, such a product shall be regulated by NPCB (47). However, some highly potent ingredients, which are below 20% of the total food content, need to be assessed by the committee and may be regulated by NPCB if necessary. Malaysian dietary supplements are products formulated to supplement diet in the form of pills, capsules, liquids or powders and not represented as conventional foods. This practice is contrary to some Asian countries, such as China, where bioactives in the medicinal format are defined as functional foods. In Malaysia, dietary supplements may include ingredients such as vitamins, minerals, amino acids, natural substances of plant/animal origin, enzymes and substances with nutritional/physiological functions. The criteria for manufacturing and registration of dietary supplements are unique. Manufacturing processes must comply with good manufacturing practices requirements and should conform to established standards of quality; registration process is through NPCB (single stage on-line registration process). These products can be registered for a maximum period of 5 years. In order to extend the registration, the manufacturer must provide updated information regarding the safety and efficacy of the product. Products will not be registered if there are public health concerns based on safety considerations (47).

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Indonesia Preamble Although there is no clear regulatory system and definition of functional foods in Indonesia, for the most part, traditional foods contain natural bioactive components. These foods, which may provide health benefits to consumers, have been available in Indonesia for a long time and have the potential to be developed as functional and supplemental foods. Currently, there has been a great deal of attention given to the functionality of foods that are endemic to this country. A good example is the research that has been carried out in Indonesia and Malaysia on crude palm oil. A new study showed that a diet rich in crude palm oil, a trans-free product often procured in Malaysia and Indonesia, may reduce blood triacylglycerol levels (48).

Functional Foods Functional foods in Indonesia can be marketed using the same regulatory system that is applied for conventional foods, as long as this category of foods will contain foodapproved ingredients. Functional foods may be classified as dietary foods and/or may be in line with the food fortification program that was launched in 1996 to improve the nutritional status of the community (49). The most popular constituents of functional foods, promoted by food industries for young children, are the very long essential polyunsaturated fatty acids, such as omega-3 (eicosapentaenoic acid and docosahexaenoic acid) and omega-6 fatty acids as well as calcium. Furthermore, functional foods enriched with iron, calcium and traditional herbal components such as ginseng, ginger and yohimbi are also popular among men and women (50). It is worthwhile to notice that some of the functional foods approved in the USA have been granted approval for sale in Indonesia. For example, phytosterol-containing foods for heart health, such as Nesvita milk, was approved as a functional food in Indonesia by The National Agency of Drug & Food Control (Badan Pengawas Obat dan Makanan Republic Indonesia). Functional foods may qualify for some health claims that are allowed in Indonesia. Foods with health claims must have nutrition labeling on the package.

Nutritional Labeling Specific requirements for nutritional labeling are outlined in a compilation of food regulations prepared by Department of Health Indonesia (51,52). Nutritional labeling is mandatory only for certain types of foods, such as baby foods, dietary foods, milk products and other foods, as specified by the Director-General. The regulations apply also to foods that make health claims that contain specific nutrients, including energy, protein and carbohydrate content, levels of vitamins and minerals, as well as fortified and enriched foods with specific nutrients as required by the national legislations. The regulations apply also to the voluntary labeling of all types of foods. The Indonesian Regulations (52) provide detailed conditions for nutrient content and comparative claims for energy, protein, fat and fatty acids content and enrichment with vitamins and minerals. For instance, no claim for ‘source’ of energy is permitted

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unless there is at least 300 kcal per reference amount of food. For claims ‘source of protein’, at least 20% by weight of the calories should be derived from protein and there is at least 10 g of protein in the suggested amount of food consumed per day.

Health Claims Ten health claims are permitted under the Indonesian regulations, which are similar to the US claims under the NLEA regulations. All health claims are disease risk reduction claims. An example provided for calcium and osteoporosis explains acceptable format of such claims: ‘An active life style and a healthy diet with sufficient calcium intake helps teenagers and women to maintain healthy bones and reduce the risk of osteoporosis in later life’. The permitted health claims are listed below: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Calcium and osteoporosis Dietary fat and cancer Dietary saturated fat and cholesterol and coronary heart disease (CHD) Fiber-containing grain products, fruits and vegetables and cancer Fruits, vegetables and grain products that contain fiber, particularly soluble fiber and risk of CHD Sodium and hypertension Fruits and vegetables and cancer of the digestive system Folate and neural tube defect Sugar alcohols do not increase dental caries Soy protein and risk of CHD.

It is worthwhile to note that the regulations prohibit making certain claims for instance: ‘good health and longevity can only be maintained by vitamin supplements’, or ‘normal healthy individuals can look younger and live longer with vitamin supplements’.

Philippines Preamble Similar to other countries in South-East Asia, the Philippines does not have specific regulations for functional foods. However, this country is endowed with numerous natural products that are potential ingredients for functional foods. At least 10 000 plants have been documented and 2000 species are being subjected to research. Without being labeled as a functional food, some of these foods are recognized to have medicinal functions or health benefits beyond the basic nutritional value (53).

Functional Foods The Philippines adapted the Codex Alimentarius definition of functional foods as being a: food that satisfactorily demonstrates that it beneficially affects one or more target functions in the body beyond adequate nutritional effects, in a way which

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is relevant to either an improved state of health and well-being, or reduction of risk to disease. The term ‘functional foods’ may include foods that are fortified with minerals and vitamins and which are regulated under the Philippine Food Fortification Act of 2000. The government has implemented this act to make the fortification of certain staple foods mandatory in order to help combat the problem of malnutrition in the country. However, functional foods can also be promoted under this act to be an effective solution to the above problem. Dietary supplements in medicinal format may also be considered as ‘functional foods’. In February 2004, the Bureau of Foods and Drugs of the Department of Health introduced a draft Administrative Order on the ‘Rules and Regulations Governing Nutrition and Health Claims of Pre-packaged Food Products Distributed in the Philippines’ (54).

Nutritional Labeling and Health Claims According to the Philippine Regulations, nutritional labeling applies to fortified foods (55). Nutrition information may be presented in a tabulated form on the food package, along with another column that gives the amount of nutrient remaining after cooking, in relation to average or usual serving sizes (expressed in terms of slices, pieces or specified weight or volume of the food product). The regulation also stipulates the minimum amounts of nutrients that must be present at any one point of the inspection. The methodology used in sampling and analysis of food content must follow the Official Methods of Analysis of the Association of Official Analytical Chemists (AOAC) International. Nutrition regulation will permit such claims as ‘high’, ‘rich’, ‘good source’, or ‘low’, however, the criteria for making these claims are different than those provided in the Codex guidelines. Currently, only two health claims are permitted in the Philippines: the first of the claims is associated with calcium to reduce the risk of osteoporosis; and, the second associates consuming foods low in fat to reduced risk of cancer. The Philippine regulations also prohibit claims that suggest that a specific food is effective in the prevention, cure or treatment of any disease or its symptoms.

Singapore Preamble In a developed market, such as Singapore, consumers are paying more attention to the potential health significance of foods (e.g. functional foods that contain bioactives are believed to promote general well-being or even reduce the risk of chronic diseases). The increased proportion of the aged consumers with the disposable income in this country also contributes to the popularity of functional foods. Older consumers are often more concerned with nutrition and weight maintenance than the younger population.

Functional Foods Although Singapore does not have specific regulations regarding functional foods, the government does feature relevant standards that are applied internationally and

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Singapore 395

have been adopted and/or modified to suit Singapore’s conditions. Such controls are in place for public health, security or safety reasons. Under circumstances where any foodstuff or ingredient falls outside the scope of the Food Regulations, permission is first required from the Food Control Department of Singapore (FCDS). In addition, all new food ingredients that are introduced into the country need to be submitted to the Food Advisory Committee for approval before they can be accepted for use by food processors in Singapore. For foods that contain novel bioactive components that are not listed as permitted food additives under the Food Regulations Act, all applications related to these products must be submitted to the FCDS for approval. Approval may be granted on a case-by-case basis. Recently, the regulatory authorities have considered the approval of phytosterols-containing functional foods such as fat spreads and milk-type products sold for special dietary purposes. Interestingly, the products must be labeled according to the EU novel foods regulations, with the exception that the use of a health claim is not allowed and the content information needs to contain: ●

●

●

●

●

●

A statement that the product is intended exclusively for people who want to lower their blood cholesterol level A statement that patients on cholesterol lowering medication should only consume the product under medical supervision A statement that the product may not be nutritionally appropriate for pregnant and breast-feeding women and children under the age of 5 years Advice must be given that the product should be used as part of a balanced and varied diet, including regular consumption of fruit and vegetables to help maintain carotenoid levels A statement that the consumption of more than 3 g/day of added phytosterols should be avoided A definition of a portion of the food (in g or ml) with a statement of the phytosterols amount that each portion contains.

Figure 24.3 shows the example of approved functional food product. It is worthwhile to notice that even though health claims are not allowed in Singapore, the statement referring to ‘product is intended exclusively for people who want to lower their blood cholesterol level’ communicates very well the intended health function of this food.

Nutritional Labeling and Nutrition and Health Claims In Singapore, mandatory nutrition labeling is only required for foods that are enriched or fortified with permitted vitamins, minerals or essential fatty acids and amino acids (Regulation 11, (56)). In 1997, a voluntary program to introduce nutrition labeling was introduced and the Ministry of Health in Singapore published a Nutritional Labeling Handbook which explains the format of a typical nutrition information panel. A nutrition information panel should include the serving size of each food as well as the listing or a core group of eight nutrients per serving and as per 100 g or 100 ml (57).

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NESTLE® Omega Plus® ActiCol™ is formulated exclusively for people who want to lower their blood cholesterol level. Two glasses a day provide the recommended 1.2g of plant sterols that you need. Consumption of more than 3g/day of added plant sterols should be avoided. Include NESTLE® OMEGA PLUS® with added plant sterols as part of a balanced diet that contains plenty of fruits and vegetables to help maintain carotenoid levels. For persons on cholesterol-lowering medication, seek medical advice. Not recommended for pregnant and lactating women and children under the age of 5 years. Figure 24.3 Nestle functional milk enriched with calcium, omega 3 and 6 fatty acids and plant sterols. Although there is no formal health claim, the product is designated ‘for people who want to lower their blood cholesterol level’. The label also must contain a disclaimer approved by the Singapore government.

In current Regulations, several nutrient content claims are permitted. Examples of such claims include the words ‘source’ of energy, ‘protein’. The Singapore government has progressed further with nutritional claim regulations as evidenced by actions proposed in 1993 that nutritional claims need to be defined to represent a food with nutritive property, whether general or specific and whether expressed affirmatively or negatively. This includes reference to energy, salt, sodium/potassium, amino acids, carbohydrates, dietary fiber, cholesterol, fats, protein and starch or sugars or any other nutrients. Further guidance clarifies the conditions for making claims such as ‘free’, ‘source’, ‘low’, ‘light’, ‘high’, ‘reduced’ etc. In addition, the government introduced the ‘Healthier Choice’ label program in 1997. It is a voluntarily program, jointly implemented by the National Heart Association and Ministry of Health (58). Singapore regulations allow some health claims with a tentative list of 30 acceptable claims (nutrient function and enhanced function claims) prepared by the government and companies which can apply those claims on case-by-case basis. For general food products, permitted claims include those related to probiotics and prebiotics, vitamins and minerals, lactose, protein and dietary fiber. For infant foods, claims on vitamins, minerals, nucleoproteins and essential fatty acids can be considered. The Singapore regulations prohibit making various misleading claims suggesting therapeutic or prophylactic actions of a food in improving human health, or curing any disease or conditions affecting human body.

Thailand Functional Foods Although functional foods is not a new concept in Thailand, the country has little in the way of specific regulations for this category of foods. In the Thai market, one can find a variety of imported and domestically produced functional foods and dietary supplements. Most of these foods, however, lack scientific evidence to substantiate the

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health benefits proposed. Furthermore, there is confusion among consumers and regulators concerning what the regulatory aspect of these food products should entail. Based on the Thai Food and Drug Administration definition, functional foods are grouped under the notification for foods for special dietary uses and defined as foods which are similar in appearance to conventional foods, are consumed as part of a normal diet and exhibit physiological benefits including possibly reducing the risk of chronic diseases. However, sometimes these products cannot be classified as either foods or drugs. Since Thailand does not have a specific regulation for functional foods, most of these foods are now being confused with drugs. A clear-cut identification is necessary in the premarketing process in order to classify whether a product is under the Drug Act or the Food Act. To classify a functional food as a drug or a food depends mainly on the type and concentration of active ingredients in the product and the claims made. If a product is classified as a food, three aspects need to be considered together, namely safety, quality and efficacy (59).

Nutritional Labeling and Nutrition and Health Claims In Thailand, nutritional labeling is mandatory only for the following categories of foods: ● ●

● ●

Foods with nutrition claim, comparative or nutrient function claim Foods with claims of specific benefits or functions to the body or specific ingredients Foods for specific target groups, for instance school children and the elderly Other foods prescribed by the Food and Drug Administration Office.

Nutritional labeling may be applied to other foods not mentioned above, under a condition that the stipulated format and regulations are observed. The regulations provide examples of the full format and brief format, which is similar to that of the US Food and Drug Administration (FDA) (34). Three types of nutrition claims are identified in the Thai Regulations: ● ● ●

Nutrient content claims Comparative claims Nutrient function claims.

The claims are similar to those in the Codex (Alimentarius) guidelines. Examples of nutrient content claim are ‘source of calcium’, ‘high in fiber’ and ‘low in fat’. Regulations prohibit making a claim of ‘free’ or ‘low’ if the food is naturally free or low in that nutrient. Examples of nutrient function claims are: ● ●

Calcium is an important component of bones and teeth Folate is an important component of red cell formation.

In order to make these aforementioned claims, the nutrient must be present in food in certain quantities. Health claims are not permitted under current food regulations, however, the health authorities are examining the draft Codex document on health claims and developing claims that can be used in support of functional foods (60).

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Note Forbes Medi-Tech Inc. does not endorse a brand or firm names mentioned in this chapter.

Acknowledgment To my wife Ula for her finest gift of immense help and encouragement.

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Intellectual Property, Branding, Trademark and Regulatory Approvals in Nutraceuticals and Functional Foods 25

Intellectual Property, Branding, Trademark and Regulatory Approvals in Nutraceuticals and Functional Foods 26 Challenges of Intellectual Property and Branding on Regulatory Approvals

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Intellectual Property, Branding, Trademark and Regulatory Approvals in Nutraceuticals and Functional Foods

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Leighton K. Chong, Lawrence J. Udell and Bernard W. Downs Udell Associates, Castro Valley, CA, USA

Abstract The passage of the Dietary Supplement Health and Education Act (DSHEA) in 1994 created an extraordinary environment for research, intellectual property development and market opportunities unprecedented in the natural products industry up to that time. Research intensified and focused on harnessing the benefits of nature to improve human health, delivering a significant return on investment (ROI) to researchers and marketers. Exciting new ingredients and the benefits they promised catapulted growth and drove market expansion. The natural products industry experienced dramatic growth over the following 4–5 years followed by a painful lull. Some categories even experienced shrinkage for about 2–3 years thereafter. While there had been a significant increase in research, marketing and market growth, in most cases, market makers had rushed to market ahead of the protection and support afforded by obtaining patents and related intellectual property. This proved to be a very costly and painful error. Pursuant to the extraordinary success caused by market making ingredients, a flood of cheap counterfeit knock-off ingredients poured into the market from an ever-increasing number of merchants, diluting market equity and cratering growth. The ability of the pioneering market Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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406 Intellectual Property, Branding, Trademark and Regulatory Approvals

makers to continue heavily promoting their original higher priced/valued products was eventually terminated. To create and sustain long-term growth, a strategic change was necessary. The next phase of market growth is dependent on valid scientific research for new product technologies, patents, stronger more effective branding and trademark strategies in product marketing and international regulatory compliance.

Introduction Intellectual property (IP) can be a relatively mundane topic. However, the information presented in this chapter opens up a variety of creative issues that not only demonstrate how to acquire and position IP (and IP relationships), but how to utilize that IP properly. This information will be practical, innovative and useful in bridging the gap between the creation and development of IP and successfully marketing it using powerful and protective branding strategies that better insulate the long-term return on investment. Having been involved in the big wide world of intellectual property creation, management and marketing for more than 70 years, the authors offer a unique perspective based on a wealth of successful experiences. How do you transfer to paper diversified experiences in working with inventors and entrepreneurs in a multitude of industries? Let us first explore and understand the values of intellectual property (IP) and its relationship to the industry of nutraceuticals. The knowledge of this very special business started many years ago with the inception of ‘alternative’ and complementary medicine, even before it was discussed openly and generally accepted. It is important to understand that IP in this industry does not only encompass what is normally recognized as patents and trade marks. The business of harnessing and commercializing the power of nature relies on the ability to transform nature’s creations into proprietary compounds marketed in the forms of liquids, powders, capsules, tablets and topicals. The resulting IP is comprised of formulas, methods and procedures for combining those derivatives in a unique manner into products that have the novel ability and characteristics positively to affect the user. Novel product technologies are derived from every imaginable plant, insect, reptile, mammal, etc. Plants are the source of a plethora of phytonutrients; various proteins with therapeutic and analytical benefits are being isolated from insects (1); reptiles are a source for a number of novel substances (i.e. antivenom and immune complexes, etc.); and mammals contribute a host of therapeutic agents from proteins to undenatured collagen (2); glandular extracts and everything in between. The scientists who are creating these potentially remarkable products are a special group imbued with a lust for finding the secrets that will reduce needless pain and suffering and increase the opportunities to improve health, possibly thrusting themselves into fame and fortune in the process. However, their motivation for discovery is not totally aligned with recognition, but truly enhanced by reaching out to touch the future and the lives of potentially millions of people they will never know. All of the results and motivation are enhanced by the knowledge that their creations will (hopefully) be protected by the existing intellectual property laws that exist in the majority of countries throughout the world along with powerful branding and marketing strategies.

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This is the primary focus of this chapter. After spending untold millions of dollars in research and development (R&D), the benefits to the researchers and their companies are weighed in the potential value of their inventions and their subsequent transformation into commercial products.

Nutraceuticals, Patent Rights & Bioprospecting As defined in Wikipedia, ‘nutraceutical’ is a word phrase combination of ‘nutrition’ and ‘pharmaceutical’ and refers to foods thought to have a beneficial effect on human health. It can also refer to individual chemicals which are present in common foods (and therefore may be delivered in a non-drug form). Many such nutraceuticals are phytonutrients, which are plant compounds possessing both health protecting and promoting properties. Nutraceuticals are often used in nutrient premixes or nutrient systems in the food and pharmaceutical industries. Nutraceuticals are also sometimes called ‘functional foods’, but are probably more accurately identified as components of functional foods. For example, red wine (containing resveratrol) is an antioxidant (3) and an anticholesterimic (4), broccoli (containing sulforaphane) is a cancer preventive (5), and soy and clover (containing isoflavonoids) are nutraceuticals used to improve arterial health in women (6), inhibit undesirable blood vessel formation in tumerous tissues (7) and possess anti-tumor effects (8,9). Except for newly discovered foods, which must be an extremely rare occurrence given the course of human history and foods, all nutraceuticals by definition involve food or food nutrients that are already known to be used by the world’s populations and cultures. Any ‘discovery’ in nutraceuticals then would consist of identifying, isolating, and making a composition containing the active ingredient or nutrient in an already known food substance found to have a previously unknown beneficial effect on human health or formulated with other ingredients in an effective but previously unknown manner and/or for a previously unknown benefit or purpose. Commercial entities commonly seek to obtain intellectual property rights in discoveries and utilize strong branding strategies in order to reap the benefits of their investment of time and resources in research and to incentivize discoverers. Under the intellectual property regimes existing in the world today, the primary form of intellectual property protection for discoveries is to obtain a patent, i.e. to obtain a government patent grant for the exclusive right to a discovery. The patent has a limited term, typically 20 years from the first application. But, in seeking to obtain a patent for identifying, isolating and making a composition of an active ingredient, from an already known food substance, the inventor is only entitled to patent claim coverage of only that contribution found by the inventor to be both ‘new’ and ‘non-obvious’ over all prior public knowledge about the already known food substance. Thus, attempts by food and pharmaceutical companies to secure patents on nutraceuticals will invariably raise tensions between a company’s claim for exclusive patent rights in making a new and non-obvious discovery and the common heritage of the public to continue to access what was already known about foods. The more well known an existing food substance and its benefits are, the less likely is a

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company’s claim to exclusive rights to a nutraceutical made from the food’s active ingredient to be broadly defined, granted and/or upheld. Conversely, if a food substance and its benefits are not considered to be widely known, or perhaps are hitherto undocumented, the more likely it will be that a company can obtain broad patent rights in them. Knowledge about a food substance and its benefits are often undocumented when it is known only to a primitive or indigenous people and transmitted only through folklore or sacred practices. The practice of companies conducting research in remote areas for naturally occurring biological substances that may be found to have benefits undocumented or unknown to the world at large is called ‘bioprospecting’. The ethics, fairness and potential harm from current practices in biotechnology research are being increasingly questioned as Third World governments, indigenous peoples and ethnic populations worldwide have developed a growing awareness and interest in controlling the use of and sharing the benefits of bioprospecting research. An increasingly complex national and international policy framework arising out of the 1992 World Convention on Biodiversity (CBD) seeks to have companies conduct bioprospecting research under formal agreements entered into with the sovereign governments, indigenous peoples and local communities who control or occupy the lands on which such research is to be conducted (10). Article 15 of the Convention addresses the terms and conditions for access to genetic resources and traditional knowledge, informed consent and benefit-sharing. It recognizes the sovereignty of states over their natural resources and provides that access to these resources shall be subject to the prior informed consent of the contracting party (signatory country) providing such resources. It also provides that access shall be based on mutually agreed terms in order to ensure the sharing of benefits arising from the commercial or other utilization of these genetic resources with the contracting party providing such resources. In 1999, work was begun to operationalize the mandates of the CBD and resulted in issuance in April 2002 by the CBD Secretariat of the ‘Bonn Guidelines on Access to Genetic Resources and Benefit Sharing’, which were adopted unanimously by CBD treaty members (11). The Bonn Guidelines were adopted to assist contracting parties, governments, providers, users and other stakeholders in developing overall access and benefit-sharing strategies and in identifying the steps involved in the process of obtaining access to genetic resources and benefit-sharing. More specifically, the Guidelines are intended to help them when establishing legislative, administrative or policy measures on access and benefit-sharing and/or when negotiating contractual arrangements for access and benefit-sharing. While a signatory to the CBD, the USA has in fact not yet ratified the treaty. The US State Department has formed a coordinating agency as the US National Focal Point under the CBD Clearing-House Mechanism (12). For the time being, the US National Focal Point has deferred responsibility to the various national agencies having jurisdiction of regions or lands under federal control in which bioprospecting may be permitted, such as national park lands, federal conservation trust lands, Indian reservations, etc. If the US ratifies the CBD Treaty, the US National Focal Point and designated national authorities would have a duty to assist participating

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parties in bioprospecting negotiations. Furthermore, these authorities would need to advise and assist state agencies (as regional authorities) in the development of policies regulating bioprospecting in compliance with the CBD framework in an effort to ensure the equitable sharing of benefits with all involved parties from the commercialization of these resources. The Bonn Guidelines place great emphasis on the obligation for research users to seek the prior informed consent of bioaccess providers. They also identify the basic requirements for mutually agreeable terms and define the main roles and responsibilities of, and stress the importance of, the substantive involvement of all stakeholders. They also cover other elements such as incentives, accountability, means for verification and dispute settlement. Finally, they enumerate suggested elements for inclusion in material transfer agreements and provide a suggested checklist for monetary and non-monetary benefit sharing. The focal point of the ongoing arbitration of rights in bioprospecting has centered on intellectual property rights (IPR) and, specifically, patent rights in discoveries derived from bioprospecting. The Conference of Parties (COP) organized for ongoing negotiations of Contracting Parties under CBD requested the World Intellectual Property Organization (WIPO), an international agency dealing with world intellectual property issues under the auspices of the United Nations, to conduct studies on the interface of IPR protocols with bioprospecting mandates. WIPO formed the Intergovernmental Committee (IGC) on Genetic Resources, Traditional Knowledge and Folklore in 2000 to conduct, among other subjects, studies of the interface of bioprospecting mandates and IPR rights (13). At least 17 countries are active participants on the WIPO/IGC Committee and many non-governmental organizations and activist groups have observer status to the Committee’s deliberations. Patents are government-sanctioned grants of exclusive rights to inventors (and their companies) to exploit commercially their new discoveries, mainly through deriving profits from the sale of products based on those discoveries. When discoveries are based on genetic resources or traditional knowledge obtained from bioprospecting, issues arise as to whether the researchers had proper permission to access biological materials in the field, including obtaining the informed consent of the providing party affected, whether they derived their inventions from already known or traditionally known substances or healing practices, whether their use of the biological materials and information was proper and whether there was an equitable sharing of benefits with the local authorities who permitted access for such research. The WIPO/IGC studies have raised the issue whether the patent systems of participating countries should be changed to implement CBD mandates by requiring disclosure of bioprospecting agreements in patent applications (14). A majority of IGC members favor imposing an affirmative duty on research companies to state that their research was conducted pursuant to and in legal compliance with a valid bioprospecting agreement, subject to sanctions including patent invalidity if the requirement is not met. More conservative IGC members (such as Japan and the USA) have expressed concern that such a substantive bioprospecting disclosure requirement could have unintended adverse consequences on patent systems and the objectives of rewarding innovation and investment in research.

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A WIPO draft statement on a bioprospecting disclosure requirement was recently transmitted to the CBD Conference of the Parties in May 2006 (14). The biotechnology industry in the USA has generally recognized the implications of the developing international framework on bioprospecting under the Convention on Biodiversity, and the significant milestone reached by unanimous approval of the Bonn Guidelines for member countries, users and providers. Although the Bonn Guidelines are not yet legally binding, biotechnology companies have had to weigh the possible losses that might be incurred through research foregone and benefits relinquished and the considerable costs of compliance, against the risks of incurring local protests, possible legal sanctions, loss of public goodwill and invalidation of patents. Many are concluding that compliance with international mandates on bioprospecting is inevitable, or at least would be good business practice to achieve some degree of compliance with mandates that are likely to become widely adopted. As an example, the Biotechnology Industry Organization (BIO), representing more than 1100 biotechnology companies, academic institutions, state biotechnology centers and related organizations in 50 US states and 31 other nations, recently adopted its recommended Guidelines on bioprospecting to its members (15). The BIO Guidelines identify ‘best practices’ that should be followed by companies engaging in bioprospecting. BIO advises its members that the Guidelines provide only a ‘road map’ but that they ‘have extensive discretion to shape their conduct to meet whatever requirements countries impose with respect to bioprospecting activities’. A member company is not required to follow the Guidelines and those Guidelines are not enforceable against a member company. However, it is conceivable that companies that do not engage in conduct consistent with the Guidelines might be subject to criticism for not following ‘best practices’. The biotechnology industry thus acknowledges that the proper conduct of bioprospecting activities requires the use of formal bioprospecting agreements with the relevant national and local authorities. US Patent Laws require that an applicant disclose, in any patent application, information known to the applicant that is material to the patentability of the patent claims submitted. The relevant Patent Office Rules, 37 Code of Federal Regulations, state in pertinent part, as follows: § 1.56 Duty to disclose information material to patentability (a) … Each individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section. The duty to disclose information exists with respect to each pending claim until the claim is cancelled or withdrawn from consideration, or the application becomes abandoned. The duty to disclose all information known to be material to patentability is deemed to be satisfied if all information known to be material to patentability of any claim issued in a patent was cited by the Office or submitted to the Office in the manner prescribed by §§ 1.97(b)–(d) and 1.98. However, no patent will be granted on an application in connection with which fraud on the Office was

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practiced or attempted or the duty of disclosure was violated through bad faith or intentional misconduct. The Office encourages applicants to carefully examine: (b) The closest information over which individuals associated with the filing or prosecution of a patent application believe any pending claim patentably defines, to make sure that any material information contained therein is disclosed to the Office. The applicant’s duty of disclosure under existing US Patent Office rules would require the disclosure of relevant information as to prior uses, traditional knowledge and/or source materials where relevant to a particular patent application. Likewise, the written description and enablement requirements of the US Patent Laws, Section 112, would require US applicants to identify relevant source materials on which claims to invention are made. However, it is important to keep in mind that biotech discoveries are often made following many steps or levels of extraction, modification, refinement or synthesis away from a naturally occurring material or traditional remedy or practice product, such that the importance of the initial material investigated may no longer be relevant to the patentability of the invention. Nevertheless, a patent applicant may deem it safer to disclose source materials initially investigated in the patent application or during patent prosecution rather than take the risk of having to litigate the issue later.

Branding – and A Hypothetical Case Scenario Now That We Have Patent Protection, We Can Successfully Market Our Natural Creations … Right? (Not Quite … There’s More) Great disappointment and potentially huge legal defense expenses await the inventors of patent-protected nutraceutical products and/or technologies if they attempt to take their creations to market in a big way solely on the strength of the patents, without establishing powerful branding and trademark strategies. The key factor here is ‘in a big way’. Just ask the original IP-based suppliers of products like Cat’s claw, Ginkgo, St John’s wort, Garcinia cambogia, Hoodia, Citrus aurantium, grape seed extracts, chromium nicotinate, noni, mangosteen and countless others. The evidence-based technology and patent protection are only half the story when it comes to propelling and insulating the market success of a patented nutraceutical product. To complete the equation required for long-term market success, strong branding strategies are a must. The principle seems to be that the greater the market impact and success an invention/creation has, the greater the lure for copy-cat knock-off suppliers to bring competing products to market. ‘But I have a patent and am protected’, you might say. The patent provides a basis to defend the invention, not to prevent it from being infringed, although, the hope is that patent protection should discourage infringement. But to savvy knock-off artists, a commercially successful patented product can offer an enormous opportunity for copy-cat windfall profits.

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How so? The following is an (oversimplified) example. Suppose you discovered a botanical species (call it ‘Onlyess importantium’) that was a powerful antioxidant and had a profound effect on turning off unopposed chronic inflammation. For the purpose of this illustration, Onlyess importantium has already been sold as a botanical detoxifier since before 1994 (no New Dietary Ingredient approvals by the Food and Drug Administration (FDA) are required). So the species has been commercially available, but for other applications. Further investigation finds that one previously inconspicuous component in Onlyess importantium made the most significant contribution to achieving the greatest therapeutic effect on inflammation; call it an ‘inflammanoid’. So, you developed a solvent-free extraction method to achieve a 50% concentration of the inflammanoid (and inflammanoid glycosides), which naturally occurs at about 6% of the total composition. When tested, this product had an oxygen radical absorbance capacity (ORAC) value off the charts and turned off the inflammation process like a switch, promoting profound and rapid unopposed healing (which required conservatively a $250 000 investment in a clinical study). It is sensational. You go through the process of applying for and receiving patents on the extraction method, the novel composition of the 50% inflammanoid and for its application as an antioxidant and downregulator of (chronic) inflammation (requiring a significant investment as well). Keep in mind that you are still incurring business and research expenses during the period of research, presentations and publication (hopefully) of the study, prior to its intended market launch. Now, you have to tell the world about your invention. So, you create a new raw material product and call it ‘AntioxInflam’. In one go-to-market strategy, you contract with an infomercial company to promote AntioxInflam, a proprietary source of inflammanoid. The infomercial cost about $200 000 to produce and about $1.5 million per month to run. Plus, you have to invest in manufacturing a few thousand bottles to start and arrange for fulfillment, unless the infomercial company takes care of this. All of this costs money. The infomercial is a success and the phones at the call center are ringing off the hook. Your inventory requirements at the fulfillment center skyrocket. Assuming that you are in strict compliance with FDA and Federal Trade Commission (FTC) guidelines and are making only supportable structure function claims, you are selling 100 000 bottles a month at $34.95 each. You are making a boatload of money and helping an enormous number of people. Life is good! However, you have now jumped high onto everybody’s radar; especially opportunistic competitors. Keep in mind that once you make AntioxInflam and Onlyess importantium household names, competitors can enter the market, but don’t need to make any claims at all. They also don’t need to duplicate your extraction methods. They don’t need to infringe on your patents to sell products. They only need to manufacture a reasonable concentrate, extracted the old (non-infringing) way and supply a very cheap generic/ commodity version of Onlyess importantium (Oi) to as many branded finished product marketers as possible. Recall that these copy-cat merchants have none of the costs associated with research & development nor creating and building the market. So, eliminate the R&D and market building costs (that you incurred), factor in the significantly cheaper raw material costs, and even with a product costing a fraction of

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your original product, these copy-cat merchants can make a significantly higher profit percentage than you on a much lower suggested manufacturers retail price (SMRP). Again, they only need to supply other finished product companies with their version of the raw material for which no claims need to be made. You already popularized the Onlyess importantium and have an exponentially higher breakeven point than them. They don’t have to do anything except supply the market. And, depending on the magnitude of your success, the market will be flooded with counterfeit versions all appearing to be enough like the original (yours) that consumers will buy those much cheaper products in hopes of receiving similar benefits. Knock-off artists are experts at creating the illusion of quality without actually fulfilling that value promise. This results in ever increasing numbers of consumers switching from your product to counterfeit versions, cratering your sales and potential for ROI. The knock-off counterfeiter just loves your infomercial. And, they will enter the market in increasing numbers as long as the opportunity to sell Onlyess importantium exists. But, the Market Pie can only be sliced in so many pieces before the return on investment potential is destroyed for everyone, including the knock-off artists. They will even put each other out of business in vicious price wars. By the way, purchasing agents of major companies are often paid a bonus based on the amount of money saved in lowering product costs; and most purchasing agents (and executives and investors in profit sensitive public companies) are not scientists with an understanding of analytical chemistry or the differences between different sources of the same raw materials. So, if it looks the same and costs less, chances are the lower priced product will replace higher priced versions; and lost consumer confidence is the irrevocable casualty. It has been proposed that this phenomenon played a major role in the nutraceutical market crash of the mid to late 1990s. Now for the dilemma; how long and to what magnitude do you continue to invest in your market building promotions once competing low-cost counterfeit market predators have a plethora of alternative products blitzing consumers? In this scenario, the answer is not very long. And, now the activities and costs of defending your patents become an excruciating requirement against diminishing sales and profits. In addition, your ability to monitor the influx and potential of patent infringers diminishes against the increasing magnitude of counterfeit product marketers and time. For all the companies that don’t make any claims, there will be some that do. But, as the crowd of competitors gets larger, the ability to identify these violators gets more difficult. And, to aggravate further the situation, your ‘benefit sharing’ partners of the source technologies are becoming increasingly cynical over the sudden change in fortunes and don’t understand what has happened; because the product category (all Onlyess importantium products) appears to be gaining in popularity and experiencing explosive growth. Potential suspicion, friction, blame and retribution by them could inflame things further. So, can this process be averted? Absolutely yes … but how?

Protecting Your Patents with Branding … The Right Way Not to overstate the obvious, but the traditional role of branding is to establish a value promise that is linked to a unique ‘branded’ trade name (and supposedly a uniquely

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superior product or service). This certainly sounds simple enough. However, most people view branding in a very one-dimensional way, limited to a consumer product or service label (i.e. Band-Aid®). In the nutraceutical, cosmeceutical, functional food and beverage categories, branding can incorporate the value promise/reputation of the company (brand), the finished product (brand), the ingredient (brand) and/or any branded valuations/validations (i.e. Good Housekeeping, ANSI, USP, GRAS, Kosher, Organic, GMP, etc.). This strategy validates the value promise with ‘layers of branding’ representing layers of validation. In this aspect, the most important factor is differentiating the unique identity and therefore the superiority of the product. In regard to where competition is directed (at you), this means beginning with your raw material. So, even the species of Onlyess importantium must now somehow be differentiated from all the other sources. Since you have developed a different product, even though you have trade named the finished raw material (AntioxInflam), you still need to identify that this unique raw material has different properties than its generic counterparts or else … When research is published (in scientific journals, industry and lay publications), editors and publishers are very reluctant to publish branded trade names for fear of appearing to endorse products and losing the credibility of being unbiased. For this reason, they (at least the respected publications) almost unanimously publish only the generic name of an ingredient. Therefore, consider that when your ‘independent’ research is published, if the benefits of AntioxInflam are attributed only to the Onlyess importantium species, then your potential competitors will be given the most powerful market weapon to use against you … scientific support for Generic Onlyess importantium. And, to any industry or lay publications that reviles using branded trade names, attributing the research benefits to just Onlyess importantium, bolsters the opportunities for market exploitation by all of your knock-off competitors. Therefore, you must give your raw material a unique identity in addition to the generic name. One tactic is to assign a research code to the material (Ex. XYZ123). Now AntioxInflam is officially a unique XYZ123 form of Onlyess importantium. By the way, this code must appear in the research publications, at least in the ‘Materials and Methods’ section. If publishers and editors refuse to identify the brand name, they will still be very reluctant to delete the research code in association with the generic name, which only you have. This tactic is also valuable for creating other branding options when and/or if needed. As an example, if one very large company wants to have an exclusive for a period of time in a specific channel, you have the means to create a separate brand name exclusive to that customer, as long as you link the brand to the XYZ123 research code. This enables that different brand to base the product claims on original validated research. And you have successfully created your own competition, which is a far superior option to having a vicious counterfeit competitor. The more you establish your other patent-protected brands of Onlyess importantium in the market, the more of a disincentive you can create for knock-off products, as the market can appear to be filling up with competitive products, reducing the knock-off profit potential and ROI. Now your science, IP, significant investments and the product’s ultimate value promise are all better insulated from market piracy.

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References 415

There are other effective strategies that improve the potential for long-term success in the nutraceutical industry. However, discussions regarding those methods are more the subject of an advanced marketing course on branding and outside the scope of this chapter. Suffice it to say, this information provides a basic knowledge and guide on how to create a successful strategic agenda for developing, validating and marketing nutraceutical intellectual property from source to consumer.

Conclusion Prior to DSHEA in 1994, the nutritional products industry was characterized more by flash-in-the-pan product popularity that usually lasted at most for about 2 years. These popular products sparked a fad-like following that usually dissipated with the next new product fad. During those years preceding 1994, there was not a very significant incentive to do the kind of research that would reveal a nutritional product’s powerful health correcting and/or promoting properties. The regulations prohibited making just about any kind of important and/or informative claims. So the market opportunities were relatively small and the arsenal of intellectual property was comparatively sparse. Since the passage of DSHEA, the opportunities to do exciting research, develop new product technologies and obtain important IP are almost endless. We believe that this growing industry will find, through extensive R&D, some remarkable and beneficial new materials that will continue to benefit humankind in ways that will amaze the medical and scientific communities. Furthermore, we expect that in the future, nutraceutical technologies and intellectual property will be increasingly administered with and/or in place of conventional pharmaceutical medicine. The next phase of market growth is dependent on valid scientific research for new product technologies, patents, stronger more effective branding and trademark strategies in product marketing and international regulatory compliance.

References 1. Beall EL, Lewis PW, Bell M, Rocha M, Jones DL, Botchan MR. (2007). Discovery of tMAC: a Drosophila testis-specific meiotic arrest complex paralogous to Myb-Muv B. Genes Dev 15, 904–919. 2. Bagchi D, Misner B, Bagchi M, Kothari SC, Downs BW, Preuss HG. (2002). Effects of orally administered undenatured type II collagen against arthritic inflammatory diseases: a mechanistic exploration. Int J Clin Pharmacol Res 22, 101–110. 3. Quincozes-Santos A, Andreazza AC, Nardin P, Funchal C, Goncalves CA, Gottfried C. (2007). Resveratrol attenuates oxidative-induced DNA damage in C6 glioma cells. Neurotoxicology 28, 886–891. 4. Pal S, Naissides M, Mamo J. (2004). Polyphenolics and fat absorption. Int J Obes Relat Metab Disord 28, 324–326. 5. Dinkova-Kostova AT, Fahey JW, Wade KL et al. (2007). Induction of the phase 2 response in mouse and human skin by sulforaphane-containing broccoli sprout extracts. Cancer Epidemiol Biomarkers Prev 16, 847–851.

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6. Clarkson TB. (2002). Soy, soy phytoestrogens and cardiovascular disease. J Nutr 132, 566S–569S. 7. Fotsis T, Pepper M, Adlercreutz H et al. (1993). Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci USA 90, 2690–2694. 8. Barnes S, Sfakianos J, Coward L, Kirk M. (1996). Soy isoflavonoids and cancer prevention. Underlying biochemical and pharmacological issues. Adv Exp Med Biol 401, 87–100. 9. Wietrzyk J. (2007). The influence of isoflavonoids on the antitumor activity of vitamin D3. Postepy Hig Med Dosw (Online) 61, 253–260. 10. Convention on Biodiversity, available online at http://www.biodiv.org/convention/ default.shtml 11. Bonn Guidelines on Access to Genetic Resources and Benefit Sharing, Secretariat of Convention on Biological Diversity, April 2002, available at http://www.biodiv. org/doc/publications/cbd-bonn-gdls-en.pdf 12. CBD, National Focal Points, see listing at http://www.biodiv.org/convention/default. shtml 13. WIPO, IGC Committee, Genetic Resources and Intellectual Property: An Overview, http://www.wipo.int/tk/en/genetic/background/index.html 14. WIPO Technical Study on Disclosure Requirements Concerning Genetic Resources et al., documents available at http://www.wipo.int/tk/en/genetic/proposals/index.html#resources 15. Guidelines for BIO Members Engaging in Bioprospecting, July 2005, available at http://www.bio.org/ip/international/200507guide.asp

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Meggan F. Duffy, Michael R. Graham, Alisa Simmons and Jeffrey S. Sharp Marshall, Gerstein & Borun LLPChicago, IL, USA

Abstract This chapter provides basic information and guidance about various forms and challenges of intellectual property relative to nutraceuticals and functional food products. The forms of intellectual property discussed include patents, trade secrets and trademarks. The patent section addresses the basic principles of a US patent grant, the intent of the US patent system, the requirements of patentability and the enforcement of patent rights and provides examples of the same for nutraceutical and functional food products. A brief discussion of patents outside of the USA is also provided. The trademark section addresses the essential role trademarks can play in the marketing of nutraceuticals and functional foods and the development of brands for nutraceutical and functional food products. General principles of trademark selection, registration and protection for nutraceuticals and functional foods are discussed. Also addressed are the advantages of trademarks for nutraceutical companies and developers and the effective use and commercialization of trademarks for the same.

Introduction Intellectual property exists in various forms, including patents, trademarks, copyrights and trade secrets, with each form protecting a different aspect of companies’ valuable property. A patent is a monopoly granted by a national government for a fixed period of Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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418 Challenges of Intellectual Property and Branding on Regulatory Approvals

time to exclude others from making or using a new and useful invention. A trademark is a word, symbol or slogan that identifies the source of goods or services. A copyright right protects the original expression of an idea, such as a book, painting, sculpture, or recording, but not the idea itself. A trade secret is valuable information kept secret by a company concerning the operation of its business. This chapter provides basic, useful information and guidance about patents, trade secrets and trademarks.

Patents What are Patents? A US utility patent is ‘a grant to the patentee, his heirs or assigns, of the right to exclude others from making, using, offering for sale, or selling throughout the United States, or importing the invention into the United States’ (1). To obtain this right to exclude, the invention must be useful, novel (new) and not obvious. If an inventor meets these three patentability requirements, the United States Patent and Trademark Office (USPTO) grants this right to exclude to the inventor for a period of 20 years from the date the application for patent was filed in the USA, provided maintenance fees are paid throughout the term (2). Each patent includes at least one claim that defines the scope of the invention. The claims have been likened to real property in that they define the ‘metes and bounds’ of the invention. Each word in a patent claim is significant, as it may substantially alter or affect the way the patent claim is construed. To understand the meaning of the claims, one looks to the claims in view of the specification (3). The specification typically includes a background of the disclosure, a detailed description of the disclosure, a summary of the disclosure and a drawing or drawings associated with the disclosure, if the subject matter of the invention lends itself to drawings. The modern right to exclude of the US patent system originates from the United States Constitution (4). Specifically, Article 1, § 8, cl. 8 of the United States Code (U.S.C.) gives Congress the power to ‘promote the Progress of Science and useful Arts, by securing for limited times to Authors and Inventors the exclusive right to their respective writings and discoveries’ (5). This clause ‘reflects a balance between the need to encourage innovation and the avoidance of monopolies which stifle competition without any concomitant advance in the “Progress of Science and useful arts”’ (6). ‘Soon after the adoption of the Constitution, the First Congress enacted the Patent Act of 1790, which allowed the grant of a limited monopoly of 14 years to any applicant that “hath … invented or discovered any useful art, manufacture, … or device or any improvement therein not before known or used” ’ (6). Today’s patent statute is similar to the Patent Act of 1790 in that protection is offered ‘to any new and useful process, machine, manufacture or composition of matter, or any new and useful improvement thereof ’ (7).

Intent of the Patent System The right to exclude is granted to inventors in exchange for full disclosure of the invention to the public. ‘From their inception, the federal patent laws have embodied a careful balance between the need to promote innovation and the recognition that

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innovation and refinement through imitation are both necessary to invention itself and the very lifeblood of a competitive economy’ (6). ‘The federal patent system thus embodies a carefully created bargain for encouraging creation and disclosure of new, useful, and nonobvious advances in technology and design in return for the exclusive right to practice the invention for a period of years’ (8). ‘The ultimate goal of the patent system is to bring new designs and technologies into the public domain through disclosure’ (8).

What Can Be Patented? Ideas alone are not patentable, nor are scientific principles or laws of nature, such as Einstein’s theory of relativity. To be eligible for patent protection, the invention must be one of: 1. 2. 3. 4.

a process a machine a manufacture a composition of matter (9).

Processes include methods of making, methods of using, methods of treatment and business methods (10). For example, nutraceutical ingredients can be patented as well as combinations of ingredients. Foods and beverages containing the nutraceutical ingredients can also be patented. Therapeutic methods of treating or preventing illnesses can also be the subject of patents. Methods of purifying or producing nutraceutical ingredients can also be patented.

Requirements of Patentability Even though the subject matter of the invention may be patent eligible subject matter, i.e. a process, machine, manufacture or composition of matter, the subject matter must also meet the three requirements of patentability to be patentable. Specifically, each claim presented in a US utility patent application must be useful, novel (new) and not obvious. Utility

In addition to setting forth the categories of patent eligible subject matter, section 101 of 35 U.S.C. also provides the utility requirement. Section 101 provides that ‘whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefore, subject to the conditions and requirements of this title’ (11). In other words, each claim must have some use. The requirement for utility before the USPTO is different from the requirement that safety and efficacy be established before the Food and Drug Administration. In the case of nutraceutical products, it is merely required that the product or treatment be asserted to have a ‘specific and substantial utility’ and that such an ‘assertion would be considered credible to a person of ordinary skill in the art’ (12).

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Thus, where the mode of operation alleged ‘can be readily understood and conforms to the known laws of physics and chemistry, operativeness is not questioned’ (13). Novelty

Each claim must also be novel or new, as defined in section 102 of title 35 of the United States Code. Section 102 provides that a person ‘shall be entitled to a patent unless’ and then lists six sections, (a)–(g), each of which delineates particulars that, if met, destroy the novelty of an invention. Sections (a), (e) and (g) tie novelty to the date of the invention and not the date of filing (14). These sections embody the first to invent (as opposed to first to file) system of the US patent system. In other words, the US patent system gives priority of invention to the inventor who was the first to invent and not the first to file a patent application covering the invention, and is one of the few countries to do so. Sections (b) and (d) of 35 U.S.C. § 102, however, set forth the statutory bar sections of the novelty provision and are not tied to the invention date, but to the filing date (14). For example, section 102(b) provides: ‘a person shall be entitled to a patent unless … (b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of the application for patent in the United States’ (15). In other words, if an inventor publicly uses or offers for sale a product covered by the claim or claims of the patent application more than one year before the date of filing, the claim is barred from patentability under 102(b). Put another way, under 102(b) an inventor enjoys a grace period of one year from the time of public disclosure or use or sale or offer to sell a product or process relative to the claim in a patent application. Sections 102(b) and 102(d) are sometimes referred to as the ‘loss of right’ sections of section 102, as activities of the inventor and unrelated third parties that occur one year before the filing date of the application can result in a forfeiture of one’s patent rights. A lack of novelty rejection will be sustained in the situation in which a claimed nutraceutical ingredient was previously known. Nevertheless, there are frequently cases in which a ‘new use’ for an old ingredient is discovered. In such cases, it may be possible to obtain patent protection for ‘a method of administering [old ingredient X] for treatment of [new disorder Y]’. Similarly, the combination of an old ingredient X with other ingredients to produce a composition having improved properties over the old ingredients alone might be novel where such a combination was not previously known. The treatment of subjects with an old ingredient via a new mode of administration might also provide novelty. Non-obviousness

Section 103 of the Patent Act sets forth the non-obvious requirement for patentability and provides that a ‘patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was

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made to a person having ordinary skill in the art to which said subject matter pertains’ (16). The framework for applying the statutory language of section 103 includes: 1. determining the scope and content of the prior art 2. ascertaining the differences between the prior art and the claims at issue; and 3. resolving a level of ordinary skill in the art (17). Secondary considerations are also used to ‘give light to the circumstances surrounding the origin of the subject matter sought to be patented’ (18). Such secondary considerations include the commercial success of the product or method covered by the claim, long felt but unsolved needs relative to the need the claim addresses, the failure of others of skill in the art to solve the problem the claim addresses, skepticism by others of skill in the art that the invention would work, and unexpected results (18). Unexpected results might include an unexpected synergy in therapeutic effect resulting from a combination of old ingredients or other unexpected improvements resulting from other modifications of previously known products or processes. In the context of methods of isolation or production, unexpected results might lie in the discovery of unexpected improvements in yields or purities. Disclosure Requirements

Even if a claim is patentable, i.e. useful, novel and not obvious, a patent is granted only if a full disclosure of the invention is provided to the public. The disclosure requirements are set forth in 35 U.S.C. § 112, paragraphs one and two. For example, the applicant must provide: 1. a written description of the invention 2. information that enables a person of ordinary skill in the art to make and use the invention without undue experimentation; and 3. the best mode of practicing the invention known to her (19). Each of the disclosure requirements must be satisfied at the time the application is filed. For example, the best mode of carrying out the invention may very well change from the time the application was filed to the time the patent issues, but the inventor applicant has no duty to update the application if such best mode changes during the pendency of the patent application or even the patent term. The disclosure requirements ultimately try to prevent an inventor from ‘having his cake and eating it too’, in that the inventor applicant is arguably prevented from hiding the ball or masking a critical part of the invention in the disclosure. If an inventor does so and still obtains the right to exclude, the owner of the patent then runs the risk of having each of the claims invalidated for failure to comply with the disclosure requirements.

Enforcement of Patents Types of Infringement

If a third party ‘makes, uses, offers to sell, or sells any patented invention, within the United States, or imports into the United States any patented invention during the

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term of the patent’, without permission from the patentee, the third party is directly infringing the patent (20). A patentee may enforce her right to exclude others from making, using, selling, offering to sell and importing into the USA by filing a patent infringement suit in federal district court (21). The United States International Trade Commission (ITC), an independent administrative agency that has jurisdiction over disputes under 19 U.S.C. section 1337, may also prevent importation of infringing products. Specifically, the ITC may initiate an investigation relative to whether unfair methods of competition and unfair acts in the importation of articles into the USA, including patent infringement, occurred (22). The Patent Act further provides protection against importation of a product produced by a patented method outside of the USA. Specifically, 35 U.S.C. § 271(g) provides ‘[w]hoever without authority imports into the United States or offers to sell, sells, or uses within the United States a product which is made by a process patented in the United States shall be liable as an infringer, if the importation, offer to sell, sale, or use of the product occurs during the terms of such process patent’. Section 271(g) further provides a ‘product which is made by a patented process will, for purposes of this title, not be considered to be so made after – 1) it is materially changed by subsequent processes; or 2) it becomes a trivial and nonessential component of another product’ (23). In the chemical context, ‘a “material change” in a compound is most naturally viewed as a significant change in the compound’s structure and properties’ (24). Before the enactment of this statute, ‘a patentee holding a process patent could sue for infringement if others used the process in this country’, but had ‘no cause of action if such persons used the patented process abroad to manufacture products, and then imported, used, or sold the products in this country’ (25). In that case, ‘a process patent owner’s only recourse was to seek an exclusion order of such products from the International Trade Commission (ITC) under section 337a of the Tariff Act of 1930, 19 U.S.C. § 1337(a) (1982)’ (25). Direct and Indirect Infringement A defendant may directly or indirectly infringe a patent claim. For example, a defendant who himself is committing infringing acts is a direct infringer (20). A defendant whose acts induce acts of direct infringement by some third party is also an infringer, but is an indirect infringer (26). A defendant who ‘offers to sell or sells within the United States or imports into the United States a component of a patented machine, manufacture, combination or composition, or a material or apparatus for use in practicing a patented process, consisting a material part of the invention, knowing the same to be especially made or especially adapted for use in an infringement of said patent, and not a staple article or commodity of commerce suitable for substantial noninfringing use’ is commonly known as a contributory infringer, also an indirect infringer (3). ‘Only proof of a defendant’s knowledge, not intent, that his activity causes infringement’ is necessary to establish contributory infringement under 35 U.S.C. § 271(c) (27). On the other hand, proof of actual intent to cause the acts which constitute infringement is a necessary prerequisite to finding active inducement of infringement under 35 U.S.C. § 271(b) (28).

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In the biotech, pharmaceutical and nutraceutical industries, for example, it may often be the case that the patented claims are directed to a method of administering an old substance to treat a new condition. In that case, the patentee can’t go against the manufacturer of the product directly, i.e. for direct infringement under 35 U.S.C. 271(a), but can go against inducers who promote their product for treatment of a particular condition. Literal Infringement and Infringement under the Doctrine of Equivalents A patent claim may be infringed literally or under the doctrine of equivalents. Literal infringement occurs when an accused product or method, for example, includes each and every element and limitation of a claim at issue, i.e. is the exact same as the claim. If a product or process does not literally meet the claim, a court may still find infringement under the doctrine of equivalents provided the accused product or process contains elements identical or equivalent to each claimed element of the patented invention (29). The proper time for evaluating infringement is at the time of infringement and not the time the patent issued (29). The basic inquiry involves assessing whether a substitute element of the accused process or product matches the function, way and result of the claimed element or whether the substitute element is substantially different from the claimed invention (30). If the substitute element of the accused process or product matches the function, way and result of the claim, a finding of infringement under the doctrine of equivalents is warranted. The first step in any infringement inquiry is to interpret or determine the meaning of the claims at issue. To do so, one first considers the claims, the specification and the prosecution history (31). Extrinsic evidence, which is all evidence external to the patent and prosecution history, including expert and inventor testimony, dictionaries and learned treatises, may also be considered (32). Remedies for Infringement

If a court finds that the patent claim is infringed (and not invalid), it must then determine an appropriate remedy. The patentee may be entitled to one or more of preliminary injunctive relief, permanent injunctive relief, and monetary relief. Injunctive Relief: Preliminary Injunction The Patent Act provides ‘the several courts having jurisdiction of cases under this title may grant injunctions in accordance with the principles of equity to prevent the violation of any right secured by patent, on such terms as the court deems reasonable’ (33). A court must consider four factors when deciding whether a patentee or patent owner is entitled to a preliminary injunction: 1. whether the movant has sufficiently established a reasonable likelihood of success on the merits 2. whether the movant would suffer irreparable harm if the injunction were not granted 3. whether the balance of hardships tips in the movant’s favor; and 4. what impact, if any, will the injunction have on the public interest (34).

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Injunctive Relief: Permanent Injunction A court may grant a permanent injunction after a finding of infringement, which essentially forbids the infringer from engaging in the infringing activities until the patent term expires. While courts typically grant a permanent injunction after finding infringement, a permanent injunction is not automatic, but rather is within the discretion of the court (35). Monetary Damages The Patent Act further provides ‘upon finding for the claimant the court shall award the claimant damages adequate to compensate for the infringement but in no event less than a reasonable royalty for the use made of the invention by the infringer, together with interest and costs as fixed by the court’ (36). While intent is not a requirement to a finding of infringement, if a court finds a defendant has intentionally or willfully infringed the patent, the court may increase the damages up to three times the amount found or assessed (37). In exceptional cases, the court may also award ‘reasonable attorney fees to the prevailing party’ (38). Thus, at a minimum a patentee is entitled to a reasonable royalty and may further be entitled to lost profits or damages on the profits on sales he would have made absent the infringement, i.e. the sales made by the infringer. To do so, the patentee must prove: 1. a demand for the patented product 2. the absence of acceptable non-infringing substitutes 3. the manufacturing and marketing capability to meet the demand for the patented product; and 4. the amount of profit the patentee would have made but for the infringement (39).

Patents Outside of the USA Patents are governed by the national laws of each country and, as such, there exist no ‘international patents’. In addition, patents are limited in their effect to the territory of the nation which has granted the patent. Thus, a US patent cannot be enforced outside the territory of the USA, although composition of matter claims could be enforced against goods manufactured outside the USA but imported into the USA. The laws of other countries operate in similar fashion. Each country has its own laws governing examination of applications, patentability and enforcement of issued patents. Those laws generally parallel the principles adopted by the USA with respect to novelty and non-obviousness (sometimes referred to as ‘inventive step’) of the claimed subject matter. The laws also have disclosure requirements similar to those of the USA, although many countries do have an explicit ‘best mode’ requirement. The patent laws of some non-USA countries differ from those of the USA in ways that specifically affect the pharmaceutical and nutraceutical industries. Some countries, such as India and Thailand, have historically not allowed patents on pharmaceuticals or processes for therapeutic treatment of humans or animals. While World

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Trade Organization (WTO) member countries including India and Thailand, are required to comply with TRIPS (trade related aspects of intellectual property rights) and grant intellectual property protection to pharmaceuticals, the grant and enforcement of such rights continues to evolve as of the time of this writing. Many other countries that have historically permitted claims covering therapeutic compositions do not permit claims to medical methods of treatment. Nevertheless, claims are permitted to methods of using known compounds for the production of medicaments for treatment of specific diseases. Such claims, which are sometimes known as ‘Swiss-type claims’ can be enforced against those who manufacture and supply such medicaments for such intended uses but could not be enforced against physicians or the patients who actually use the therapeutic compounds. The most significant difference between USA and non-USA countries relates to ‘absolute novelty’ of the invention claimed. While US law provides for a one-year grace period between a publication, public use, sale or other disclosure and the filing of a patent application, most non-USA countries have no such grace period. Thus, any public disclosure of a claimed invention prior to placing a patent application on file will act to destroy novelty of the disclosed invention. Thus, in cases where nonUSA patent protection might be desired, it is imperative that a USA or other application be on file prior to such disclosure! In this regard, it is helpful that the USA and most other industrialized countries around the world are parties to various treaties in which an application filed in one country will serve to preserve a ‘priority date’ which can be claimed in other national filings. In addition, treaties such as the Patent Cooperation Treaty (PCT) provide efficiencies and cost savings for inventors who wish to file in multiple countries worldwide. The European Patent Convention created the European Patent Office (EPO) in which the patentability examination function for a large number of (mostly western) European countries is consolidated into one process.

Trade Secrets A trade secret is any information that can be used in the operation of a business or other enterprise, that is sufficiently valuable and secret, and that affords some actual or potential economic advantage over others (40). While patents often provide the best option for inventors, in some cases, obtaining trade secret protection for a particular patentable process, for example, is a better form of intellectual property protection. For example, US utility patents have a limited term of 20 years from the date of filing, while trade secrets can be maintained indefinitely, provided the trade secret is kept a secret. Consider Coca-Cola, who, instead of obtaining patent protection for its well-liked and commercially valuable cola formula, decided decades ago to maintain its valuable cola recipe a secret. This was an excellent decision, as the cola formula is still an extremely valuable and secret part of Coca-Cola’s business today. Further, because part of the deal of obtaining patent protection is providing a full disclosure of the method of making and using the

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invention and the best mode of carrying out the invention, in some cases an innovator may choose to maintain her invention as a trade secret is she feels she might have difficulty monitoring and enforcing against infringement. This is particularly true for valuable processes which are more difficult to detect. However, if a product is being released that is made by a patentable process, for example, consideration should be given to how easily one may be able to reverse-engineer the process, as reverseengineering a process is a defense to a claim of trade secret infringement.

Trademarks Trademarks can play an essential role in the marketing of nutraceuticals and functional foods and the development of brands for nutraceutical and functional food products. Regardless of whether a product is entitled to patent protection, trademarks help distinguish one company’s products and technologies from other companies’ products. Companies can build and protect market share of particular products by selecting a strong, unique trademark and building consumer recognition of and demand for products sold under that trademark. Companies can also use trademarks to build brands and brand awareness through use and marketing with various products or as part of house marks or trade name trademarks. Trademarks can therefore be powerful tools for building consumer product and brand awareness and loyalty. They also help ensure fair and free competition by entitling their owners to prevent the use of trademarks by competitors which are likely to cause confusion with the first used trademarks and those for which registration has been sought. Once established, trademark rights continue and can be extended for the life of the products for which they are used. Furthermore, trade names can be used and protected as trademarks, as either brands or house marks, for either goods (trademarks) or services (service marks). However, to be entitled to the maximum trademark rights and protection, trademarks, service marks and trade names (collectively as ‘trademarks’) should be distinctive, distinguishable from any existing trademarks, registered and actively protected. The section discusses the general principles of trademark selection, registration and protection, how nutraceutical companies or developers can take advantage of trademarks and how companies can most effectively use and commercialize their trademarks. While this chapter discusses some issues about the use and registration of trademarks internationally, the emphasis is on the application of US law.

What Are Trademarks? Trademarks can consist of words, symbols, slogans or a combination of these that identify to consumers the source of a good or service and that serve to distinguish the particular good or service from those of others. US trademark law defines a trademark as ‘any word, name, symbol, or device, or any combination thereof ’ which is used ‘to identify and distinguish’ one’s ‘goods … from those manufactured or sold by others and to indicate the source of the goods’ (41). The purpose of a trademark is to prevent consumers from being confused about the source of goods or services.

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When one thinks of a traditional trademark, one may first think of brand names that may consist of words, such as Coke or Microsoft, or designs such as the Nike Swoosh or the Cadillac crest. However, three-dimensional objects, colors, sounds, scents and even product packaging may also serve as trademarks. In the context of nutraceuticals and functional foods branding, trademarks can be used to identify one or more of a nutraceutical, a functional food product, a line of nutraceuticals and functional foods or an ingredient used in a nutraceutical or functional food product. Trademarks function to assure purchasers of the quality of the nutraceutical that they are buying and, over time, will create business goodwill in the minds of those purchasers. A good trademark will allow a company to distinguish its nutraceutical and functional food products from those of others, while simultaneously creating an easy way for consumers to recognize and purchase the company’s products. In addition, owners of trademarks for their nutraceutical compounds can license the use of the trademark as either a product trademark or to identify an ingredient of the product.

Trademark Protection for Nutraceuticals and Functional Foods Building strong trademarks entitled to protection involves three steps. The first is selecting a strong mark. The next is registering the mark. And the third step is protecting the mark through proper use and enforcement. Selecting and Clearing a Trademark

To obtain the best results from its trademarks, a company should select strong trademarks. The more distinctive a trademark is in relation to the goods it identifies, the stronger that trademark will be. A strong trademark increases the potential that the mark has to gain consumer recognition and heightens the level of legal protection that will be afforded to that mark. Marketing departments often want to choose trademarks that describe features or attributes of products rather than choosing trademarks that distinguish products from those of competitors in order to have immediate consumer recognition of the product application. However, such trademarks are relatively weak. The money saved by not having to educate the public about what goods the marks are used for is more than offset by the loss of distinctiveness of the mark. Categories of Trademarks Trademarks fall into one of four types: 1. 2. 3. 4.

fanciful arbitrary suggestive descriptive.

The strongest, most distinctive types of trademarks are those that are fanciful, made-up, or coined terms, such as Google or Kodak. The next strongest tier of trademarks includes those that are arbitrary. Arbitrary marks are understandable

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terms used for unlikely and unrelated goods or services, such as Apple for computers. Suggestive trademarks follow arbitrary marks in the spectrum of trademark distinctiveness and suggest some quality or characteristic about the nature of the goods that they identify, such as Slim-fast for food supplements or One a day for vitamin tablets. Suggestive marks suggest some qualities of the product or service, but do not only or primarily describe the product. Descriptive marks are the least distinctive type of trademarks and they describe a quality, feature, attribute or application of a product, such as Healthy for vitamins or Seven grains for bread made with grains. Descriptive marks include laudatory or geographically descriptive marks. Descriptive terms are not inherently distinctive trademarks but must be distinguished from generic terms, which are the common descriptive names for products or types of categories of goods, such as ‘supplements’ or ‘vitamins’. Generic terms are never protectable as trademarks. Descriptive terms, however, can, over the course of time and through promotion and exclusivity, become recognized as trademarks and registered and protected. Tips for Selecting Trademarks Choosing or developing a new trademark is both a science and an art. Generally, strong marks are short, contain three syllables or less and are easy to spell, pronounce and remember. Avoid choosing a mark that describes the goods or lauds the quality of the product, as competitors in the marketplace will likely want to use and may use those same terms to describe their products. Product naming companies, advertising agencies and market research studies can all be helpful in choosing a mark. Trademark Searching Before selecting a mark, it is essential that you confirm that the mark is available for use and registration and is not confusingly similar to any existing or registered trademark for similar goods or services. In the USA, trademark rights arise either from use of a trademark or the filing of an application to register a mark and the US Patent and Trademark Office (USPTO) will not register a trademark that it considers to be confusingly similar to another mark already registered or in the process of registration. Clearance searches help ensure that a new mark is not confusingly similar to a previously used or registered mark. Clearance searches also enable a company to determine whether a trademark it is using without registration may face problems due to existing registrations, if the company tries to register it. Conducting clearance searches at the outset of the trademark selection process helps avoid the cost of having to change marks, the loss of established goodwill and the threat of possible litigation. Trademark clearance searches range from simple ‘knock-out’ searches of the free USPTO online database or proprietary computer trademark searches to more comprehensive full searches of USPTO records and unregistered common law uses. Computer searches of the USPTO database and state trademark offices are good quick ways to determine whether a confusingly similar mark is pending or has been registered with the USPTO. Computer searches are limited, however, to finding only identical or similar registered or applied for marks and are limited by the software used for searching and search strategies.

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Because US trademark rights arise from use in the USA and not only registration, companies should have full searches performed for new marks that have not yet been used in commerce and for major brand marks and company name marks. Full searches include broader searching of trademark registrations and pending applications and in-depth searching of common law materials, publications, filings, and the Internet to identify common law uses and unregistered marks, trade names, references and Internet domain names. For marks that a company plans to use internationally, it is essential to conduct searches of foreign trademark registries, through both online searches and searches by foreign search services. Because of the differences between and nuances of language and trademark laws and practice, foreign agents should be retained to conduct and review searches wherever feasible. Although potentially expensive – worldwide full searches can cost $60 000 to $100 000 for a single mark – such searches are essential for major trademarks being used worldwide. As with domestic US searches, commercial search services provide more limited and less expensive searches for identical marks. As soon as a company selects and clears a trademark, the company should register it with the USPTO and in any other countries in which the mark will be used. Trademark Registration

Benefits of Registration US registration confers on the registered trademark a presumption of validity and ownership by the registrant and provides for national constructive notice of a company’s rights in its trademark (42). Constructive notice arising from US registration is valuable because of its effect in litigation to help enforce the registered mark against any entity that adopts a trademark confusingly similar to the registered mark after a registration for that mark has issued. Because of the constructive notice conferred by the registration, the entity that adopted the mark after registrant’s registration issued cannot claim innocence or lack of notice or knowledge of the registrant’s mark as a defense. Registration also establishes a priority date based on the date of first use or, in the case of applications based on an intent to use the mark, a date based on the filing date of the application. Also, once a mark has been registered for 5 years, the registration becomes eligible for incontestable status, which limits the grounds upon which third parties may challenge it (43). US trademark registrations have effect in the 50 states and all US territories. Registration of a trademark in the USA is also important because it establishes federal jurisdiction over the trademark in the event that the mark is later infringed (41). Federal jurisdiction means that the registrant has access to the US federal court system should it need to initiate legal action to enforce its trademark rights. The federal court system provides a much more extensive body of federal case law of previously decided trademark cases on which a registrant may rely in litigation compared to the individual state courts and state case law. Another benefit of a US trademark registration is the ability of owners of US trademark registrations to record their US trademark registrations with US Customs

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and Border Patrol in an effort to prevent the importation of infringing goods from foreign countries, the mechanics of which is discussed later in this chapter. The Registration Process In the USA, an applicant may apply to register a mark based upon actual use of a mark in interstate commerce or based upon a bona fide intent to use a trademark in interstate commerce (44). Filing based upon an intent to use is useful for parties developing products because this filing procedure allows applicants that have not yet used the mark but plan to in the near future to apply to register their marks without waiting for actual use. Applicants who choose the latter filing basis will be required to show to the USPTO actual use of the mark in interstate commerce later in the application process to perfect a registration. Filing based upon actual use means that the applicant is currently using the mark to be registered on the goods or on packaging for the goods or in the marketing and sale of services in interstate commerce. Applicants filing applications based on actual use will be required to provide the USPTO with specimens of labels, packaging materials, photographs of the product, etc., showing this use during the examination of the application. The USPTO adheres to an international classification system that divides the myriad types of goods and services for which registration can be sought into 45 different classifications. International class 5 is the class in which nutritional and dietary supplements and vitamins belong. For each class of goods covered by an application, the USPTO charges a filing fee. For applications filed electronically with the USPTO, the current per class filing fee is $325. For paper applications, the current per class filing fee is $375. Presently, the majority of applicants file electronically. The registration process in the USA generally takes 1–2 years from the date of filing for applications filed based upon actual use of a mark in commerce. It is important for companies to retain records about its first use and continuing use of a trademark. Trademark registration records should include copies of materials showing use of the trademark and invoices showing the date of first shipment over state lines of the goods bearing the mark. If the labels or packaging for the goods change over time, you should maintain examples of each to show the different ways in which your company used its mark. These materials would be vital to proving your company’s claim of first use in commerce and continuing use should a third party ever challenge your company’s mark or registration. After the USPTO receives an application, the USPTO assigns an examiner to examine the application to determine whether the application is in order and whether the mark is registerable (45). A USPTO examiner would issue an office action during the examination process if the examiner determined that the applicant must supply more information or amend the application, and the USPTO would provide an applicant with 6 months to respond to any such office action (46). Once the examiner determines that the application is acceptable, the examiner approves the application for publication by the USPTO (47). The USPTO then publishes the application in the Official Gazette, the official publication of the USPTO, and provides third parties with 30 days from the date of publication of the application to oppose the registration of the mark (48). If no third party

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opposes, then the USPTO would issue a certificate of registration for applications filed based upon actual use of the mark or a notice of allowance for applications filed based upon an intent to use the mark (496). Intent to use applicants would then have 6 months from the date of the notice of allowance to file proof with the USPTO of use of the mark in interstate commerce (50). Intent to use applicants may extend the time period for filing proof of use of the mark in commerce in 6-month increments (51). The USPTO permits up to five 6-month extensions of time, which applicants can obtain by filing requests for an extension of time with the USPTO before the expiry of each allotted 6-month time period (51). After an intent to use applicant files an acceptable proof of use of the mark in interstate commerce, the USPTO would issue a certificate of registration (52). Once granted, a trademark registration is valid for 10 years from the date of registration (53). In order to maintain the registration, however, the registrant must, between the fifth and sixth years after registration, file a declaration with the USPTO confirming that the mark is still in use (53). If the registrant does not file this declaration, then the USPTO will cancel the registration (53). The registrant can also renew the registration for additional 10-year terms, as long as the registrant or its licensees continue to use the mark for the goods or services identified in the registration (54). Foreign Trademark Registration Unlike in the USA, where trademark rights arise from use, in most foreign countries trademark protection arises from registration of that trademark. Foreign countries are therefore known as ‘first to file’ countries in relation to obtaining trademark protection. Nutraceutical and functional food companies that plan to use a mark on products outside the USA should give early consideration to registering the mark in foreign countries. Most foreign countries have national trademark offices and systems and procedures for registering trademarks similar to those existing and used in the USA. By virtue of international treaties, a company may be able to claim the filing date of its corresponding USA application in subsequent foreign applications, depending upon when the company filed those foreign applications. Moreover, by utilizing the Madrid Protocol, an international application procedure developed by treaty, a company may apply for foreign registration of its marks through the USPTO. The procedure is economical because the protocol limits the application fees and an applicant will need foreign agents only if the national trademark offices raise objection to registration. Consult with your local trademark counsel when selecting and applying to register trademarks both domestic and foreign.

Trademark Use Guidelines Trademark owners must use their marks consistently and correctly in order to establish and maintain rights and goodwill and to prevent the marks from becoming weak or losing rights. For example, using a trademark as the name of the type of product can result in the trademark becoming the generic, common descriptive term for the product. While marketing efforts should encourage consumers to recognize a company’s

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trademarks as indicating high quality products, you do not want the products to be identified as being named by your mark. Examples of terms that used to be trademarks in the USA but are now generic terms are escalator, thermos and aspirin. While third party product resellers may use a product trademark without a license in connection with the resale of the branded product, trademark owners must monitor how third party resellers use their trademarks to prevent improper use. Following are guidelines for proper trademark use. Follow these to avoid losing rights in valuable trademarks and to build brand awareness. Always Use Trademarks as Proper Adjectives

Grammatically, a trademark is always a proper adjective, never a noun or verb. Because a trademark is a proper adjective, always use a generic term that identifies what the product is immediately after the trademark in written materials, such as One a day vitamins. Emphasize Trademarks

Give trademarks additional emphasis in written materials. Use the word ‘brand’ after the mark but before the generic term, such as One a day brand vitamins. Print the trademark in all capital letters or in distinctive typeface. At the very least, use trademarks with ‘Initial caps’ and quotation marks or with initial caps. Other alternatives for distinguishing trademarks include using italic and boldface font. Do Not Pluralize Trademarks

Trademarks are adjectives, not nouns, and should never be pluralized. Instead, pluralize the generic term following the trademark, such as Burger King restaurants or Kodak cameras. Similarly, never make trademarks possessive, unless the trademark is itself possessive like the trademarks Hershey’s for cocoa and McDonald’s for restaurants. Instead, make the generic term following the trademark possessive, for example, the Burger King restaurant’s location or the Kodak camera’s lens. Use Proper Trademark Notices

Along with using trademarks as proper adjectives, use appropriate trademark notices with the mark. The® registration symbol indicates that, and may only be used when, a trademark has been registered with a governmental agency or agencies. The ™ symbol indicates that the trademark is an unregistered or common law trademark. The ® and ™ symbols should follow the trademark and usually appear in superscripted font. It is not necessary to use these symbols with each and every use of the trademark, but you should use the appropriate one with the most prominent use of the mark on labels and packaging for the goods and in text with the initial use of the trademarks in order to put third parties on notice of the trademark status of the mark. If a company uses the same packaging worldwide, then the company should include an ownership notice for the trademark, such as ‘[X] is a trademark or registered trademark of [Y]’.

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Use Trademarks Consistently

Use trademarks in the same form on materials. Do not alter the form, format or presentation of the mark unless necessary. In this regard, it is useful to create company brand use guidelines. Guidelines should clearly set forth the mark and the particular color(s), font, script, placement, etc. that may be used for the trademark. The company should also monitor its use of trademarks and confirm that the marks are being used consistently and that the guidelines are followed. Consistency in use will build consumer recognition. Inevitably, over time, a mark may evolve, such as the type of font or colors used, but the overall mark and consumer impression should not be changed without good reason.

Licensing Opportunities Licensing enables trademark owners to reach different geographic areas with its branded products and to extend the types of products for which the trademark is used. Often a trademark owner may be presented with the opportunity to partner with others in the marketplace to offer products. Examples of these opportunities include packaging particular products together and indicating that a product contains a particular ingredient. Trademark owners should always use licenses to accomplish these business opportunities to ensure that the licensee uses trademarks consistently and provides products which meet the licensor’s standards and to build trademark rights which inure to the benefit of the trademark owner. As long as the trademark owner controls and oversees the quality and nature of the goods bearing the mark, the trademark owner may license others to use its mark. The purpose of monitoring the quality of the goods produced by a licensee is to ensure that the goods bearing the trademark are of a consistent quality and controlled source. If the trademark owner fails to ensure the quality of the goods, the trademark owner could lose rights in the trademark. A license which does not include some type of a quality control requirement or over which no control is actually exercised is known as a ‘naked license’ and results in the loss of trademark rights. A license should therefore include provisions clearly setting forth and ensuring compliance with the standards established by the licensor, along with ways for the trademark owner to monitor and test the licensee’s goods to confirm the quality and integrity of the goods. Trademark licenses should also include provisions clearly setting forth the ownership of the trademark by the licensor and the manner in which the licensee may use the mark. Trademark licenses also should include standards addressing issues such as the governing law of the parties, jurisdiction for disputes, waiver, use and protection of confidential information, assignment of the license, duration of the license, amendment of the license, warranties and disclaimers, indemnity and insurance coverage, among others.

Trademark Protection Monitoring third party trademark use and registration and preventing or, if necessary, stopping third party use of marks and designations which create confusion with a

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434 Challenges of Intellectual Property, Branding on Regulatory Approvals

company’s trademarks are essential steps in protecting one’s trademark. Failure to police and enforce trademark rights may lead to a loss of trademark rights. Subscribing to trademark watch services is one way to monitor third party activity and a number of vendors offer trademark watch services which may be tailored to a company’s needs. Watch services report when similar applications are filed, published or registered in a national register, regionally or worldwide. Another tool for monitoring third party activity is to encourage employees and distributors to keep an eye on what competitors offer. Paying close attention to consumer feedback also provides a company with an opportunity to monitor third party activity. For example, a consumer may pose a question to the customer service department about a competitor’s product that turns out to have a brand name identical or similar to your company’s trademark. Knowing what third parties are doing affords the company with the opportunity to act quickly to protect its trademark. When a company learns of a third party application to register a mark that is confusingly similar to the company’s mark for the same or related goods, the company should consider contacting the third party to request that it abandon its application and not use the trademark. If the third party maintains its application, and the registration of the mark would damage the company or its trademark, the company can file an opposition to the third party application during the appropriate stage of the application process before the mark can officially register (55). An opposition is an inter parties proceeding that takes place before the Trademark Trial and Appeal Board of the USPTO. Basically, the opposition is a form of litigation against registration that takes place on paper. The opposer may base its opposition on any basis that a trademark examiner could have used as the basis for the opposition, such as descriptiveness or confusing similarity with an existing mark. The result of an opposition will be either that the application is not allowed or that the mark is allowed to proceed to registration. An opposition provides no opportunity to seek and receive financial awards. When a third party adopts and uses or threatens to adopt and use a mark that is confusingly similar to the company’s mark for the same or related goods, a company should consider suing that third party in court for trademark infringement or unfair competition (depending on whether the company’s trademark is registered or common law) in order to enforce the company’s trademark rights and to prevent infringement of the company’s trademark. The usual test for infringement is whether the junior mark would create a likelihood of confusion with the existing mark (56). This test applies factors to determine whether consumers seeing both marks will likely be confused about whether the goods or services of a third party originate with, are sponsored by, or associated in some way with the goods or services of the registrant (56). The main factors that federal courts use to measure likelihood of confusion include: similarity of the marks in terms of sound, appearance and meaning; similarity of the goods; whether the goods move in the same channels of trade; the sophistication of the purchasers (impulsive versus careful purchase); strength of the prior mark; and whether actual confusion between the marks has occurred (57). Infringement litigation affords a trademark owner the opportunity to receive equitable remedies, such as, injunctions and destruction of infringing articles, as well as

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monetary remedies (58). To bring an infringement suit in federal court, a trademark owner must prove ownership of a valid trademark and that use of an unlicensed mark by a third party is likely to cause confusion with the trademark owner’s mark. In defense, a third party may argue that the trademark owner lacks the claimed trademark rights, that no likelihood of confusion exists, that the third party has priority of use over the trademark owner, and that the third party makes a fair use of the trademark owner’s mark (59). The remedies available to a trademark owner in an infringement suit include injunctions, orders to destroy infringing products and damages or profits, as well as attorney fees and heightened damages awards in the event that the infringement is found to have been willful (60). As mentioned earlier in this chapter, the owner of a US trademark registration may record its US registration with the US Customs and Border Patrol (CBP) (61). Recording the registration with CBP permits the CBP to enforce trademark rights at US borders by intercepting and seizing infringing goods at ports of entry into the USA (62). Once recorded with the CBP, the CBP adds the trademark to its electronic database of recorded intellectual property rights. This electronic database also includes information concerning any goods and trademarks that may have been the subject of an International Trade Commission exclusion order. The CBP uses this electronic database to enforce trademark rights. If the CBP encounters illegally imported goods bearing recorded trademarks, CBP officials will seize such goods (62). Sometimes, the CBP officials contact the trademark owner to determine whether the goods seized as infringing goods bearing recorded trademarks are counterfeit, though federal regulations do not require that the CBP notify trademark owners (63). In addition to recording a trademark registration with the CBP, a vigilant trademark owner should also provide the CBP officers of particular ports of entry with any information that it may have concerning the shipment of counterfeit imports to enable the CBP to act to protect US consumers, as well as the trademark owner’s mark. Foreign countries offer similar procedures and protections through their respective customs departments and bureaus.

Future Marks – Brand Extension, Product Extension Companies can also use trademarks to create brand names, which are the extension of the use of particular trademarks over a range of goods or services. Companies can also create families of trademarks based on the brand, with each mark in the family sharing common elements, such as a particular style of lettering, color or color scheme. Consumers are then able to recognize these common elements as collectively indicating the source of a product. Along with brand names and families of trademarks, companies can adapt or develop a house mark, to be used on all its products, which is often the company trademark or logo. House marks such as General Mills’ Big G or the Kellogg K appear on packaging for the goods in addition to the more prominent product brand name. Sometimes companies choose ways to indicate source beyond brand names, such as using the shape of the product or the product packaging to designate source. Some unconventional source indicators include fragrance or scent and sound.

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These sensory elements can act as trademarks so long as they do not describe the goods for which they are or will be used. Continuously promoting a mark on goods over which the trademark owner consistently monitors the quality can afford the trademark owner the opportunity to create consumer brand recognition across product lines. Marks recognized by consumers for consistently high quality products build valuable good will, which a mark owner can then use to extend its brand and product lines either directly or through licensing arrangements. Essentially, trademark rights once well established, unlike other forms of intellectual property, endure for so long as the mark owner or its authorized licensees use the trademark.

References 1. See 35 U.S.C. §154(a) (2007) (‘if the invention is a process’ the patent is a grant ‘of the right to exclude others from using, offering for sale or selling throughout the United States, or importing into the United States, products made by that process, referring to the specification for the particulars thereof ’); see also 35 U.S.C. §100(c) (‘(t)he word “patentee” includes not only the patentee to whom the patent was issued but also the successors in title to the patentee’). 2. See 35 U.S.C. §154(a)(2) (2007) (‘Subject to the payment of fees under this title, such grant shall be for a term beginning on the date on which the patent issues and ending 20 years from the date on which the application for the patent was filed in the United States.’). 3. Markman v. Westview Instruments, 52 F.3d 967 (Fed. Cir. 1995). 4. Adelman et al. Cases and Materials on Paten Law, ch. 1, sec. 1.2, p. 4 (West 2003). 5. US Constitution, Art. 1, s. 8, cl. 8. 6. See Adelman et al. ‘Cases and Materials on Patent Law’, ch. 1, sec. 1.2., p. 4 (West 2003). 7. See 35 U.S.C. §101 (2007). 8. See Adelman et al. ‘Cases and Materials on Patent Law’, ch. 1., sec. 1.2, p. 7 (West 2003). 9. See 35 U.S.C. § 101 (‘(w)hoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefore’). 10. See also 35 U.S.C. 100 (b) (‘(t)he term process means process, art, or method, and includes a new use of a known process, machine, manufacture, composition of matter, or material’). 11. 35 U.S.C. 101 (2007) (emphasis added). 12. MPEP 2107 13. Nelson v. Bowler, 626 F. 2d 853, 856 (CCPA 1980) 14. Adelman et al. Cases and Materials on Patent Law, ch. 4, p. 160–161 (West 2003) 15. See 35 U.S.C. 102(b) (2007). 16. See 35 U.S.C. 103(a) (2007). 17. See Graham v. Deere, 383 U.S. 1, 17–18 (1966) (‘Under 103, the scope and content of the prior art are to be determined; differences between the prior art and the

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References 437

18. 19.

20. 21. 22.

23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.

claims at issue are to be ascertained; and the level of ordinary skill in the pertinent art resolved. Against this background, the obviousness or nonobviousness of the subject matter is determined.’). Graham, 383 U.S. at 18. See 35 U.S.C. 112 (2007) (‘(t)he specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention’). See 35 U.S.C. § 271(a) (2007). See 35 U.S.C. 281 (2007) (‘A patentee shall have remedy by civil action for infringement of his patent.’). See Adelman et al. ‘Cases and Materials on Patent Law’, ch. 18, sec. 18.3, p. 1022–1023 (West 2003) (explaining that 19 U.S.C. 1337 ‘prohibits unfair methods of competition and unfair acts, including patent infringement, in the importation of articles into the United States’). U.S.C. §271(g). See Eli Lilly v. American Cyanamid Co., 82 F.3d 1568 (Fed. Cir. 1996). Eli Lilly v. American Cyanamid Co., 82 F.3d 1568 (Fed. Cir. 1996). See Hewlett-Packard v. Bausch & Lomb, 909 F.2d 1464 (Fed. Cir. 1990). See 35 U.S.C. § 271 (c). See 35 U.S.C. § 271(b) (‘whoever actively induces infringement of a patent shall be liable as an infringer’). Warner-Jenkinson Co. v. Hilton Davis, 520 U.S. 17 (1997). See WarnerJenkinson Co. v. Hilton Davis, 520 U.S. 17 (1997). See Markman v. Westview, 52 F.3d 967 (Fed. Cir. 1995). Markman v. Westview, 52 F.3d 967 (Fed. Cir. 1995). See 35 U.S.C. § 283 (2007). See Adelman et al. ‘Cases and Materials on Patent Law’, ch 17, sec. 17.1, p. 933 (West 2003). See Adelman et al. ‘Cases and Materials on Patent Law’, ch 17, sec. 17.1, p. 940 (West 2003). 35 U.S.C. §284 (2007). See 35 U.S.C. § 284 (2007). See 35 U.S.C. § 285 (2007). See Panduit v. Stahlin, 575 F.2d 1152 (6th Cir. 1978). See Uniform Trade Secrets Act, 14 U.L.A. 438 (1990). 15 U.S.C. §1127 (2007). 15 U.S.C. §§1057(b) and 1072 (2007). 15 U.S.C. §1065 (2007). 15 U.S.C. §1051(a)-(b) (2007). 15 U.S.C. §1062 (2007); 37 C.F.R §2.61(a) (2007); TMEP 704. 15 U.S.C. §1062 (2007); 37 C.F.R §§2.61 and 2.62 (2007). 15 U.S.C. §1062 (2007); 37 C.F.R. §2.80 (2007).

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48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67.

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15 U.S.C. §§1062 and 1063(a) (2007); 37 C.F.R. §2.80 (2007). 15 U.S.C. §1063(b) (2007); 37 C.F.R. §2.81 (2007). 15 U.S.C. §1051(d)(1) and (d)(2) (2007). 15 U.S.C. §1051 (d)(2) (2007); 37 C.F.R. §2.89 (2007). 15 U.S.C. §1062 (2007). 15 U.S.C. §1058 (2007). 15 U.S.C. §1059 (2007). 15 U.S.C. §1063 (2007). 15 U.S.C. §§1114(1)(a) and 1125(a)(1)(A) (2007). In re E.I. DuPont de Nemours & Co., 476 F. 2d 1357 (C.C.P.A. 1973). 15 U.S.C. §§1114, 1116, and 1117 (2007). 15 U.S.C. §1115 (2007). 15 U.S.C. §§1116, 1117, and 1118 (2007). 15 U.S.C. §1124 (2007). 15 U.S.C. §1124 (2007); 19 C.F.R. §133.22 (2007). 19 C.F.R. §133.25 (2007). 15 U.S.C. §1114(1)(a) (2007). 15 U.S.C. §1121 (2007). Hewlett-Packard v. Bausch & Lomb, 909 F.2d 1464 (Fed. Cir. 1990). See Adelman et al. ‘Cases and Materials on Patent Law’, ch. 1, sec. 1.2, p.4 (West 2003).

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Index

Addition of Vitamins, Minerals and certain other Substances to Food Regulation, The 203, 207 Addition of Vitamins and Minerals to Foods 2005: Health Canada’s Proposed Policy and Implementation Plans 166–167 Administration Regulation for Health Food 298 adulterated food 96 adverse reaction 162, 163 Advisory Committee on Novel Foods and Processes (ACNFP) 235 Africa 341–347 Agreement on Technical Barriers to Trade (TBT) 149 American Association of Cereal Chemists (AACC) 16, 77 American Chamber of Commerce of Japan (ACCJ) 252 appropriate level of protection (ALOP) 155 aquaceutical 85 As Low As Analytical Methods Can Detect (ALAAMCD) 184 As Low As Reasonably Achievable (ALARA) 184 Asia 365–397 Association of Official Analytical Chemists (AOAC) 16, 67, 72, 74, 76, 394 Association of South East Asian Nations (ASEAN) 26 astaxanthin 235 Australia 239–248 The Australia New Zealand Therapeutics Products Authority (ANZTPA) 239, 240, 241, 247, 248 Nutraceutical and Functional Food Regulations ISBN: 978-0-12-373901-8

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Australian Adverse Drug Reactions Advisory Committee (ADRAC) 242 Australian Register of Therapeutic Goods (ARTG) 241, 244 Australian Regulatory Guidelines for Complementary Medicines (ARGCM) 242 Australian Self-Medication Industry 242 bar/chip coding 110–112 Basic Food Safety Law 272 Biologically Active Food Supplements (BAFS) 305–315 Biotechnology Industry Organization (BIO) 412 botanical nutraceuticals 200–217 Brazil 349–363 Canada 159–171 Canadian Health Food Association 169 Center for Drug Evaluation and Research (CDER) 100 Centers for Disease and Control (CDC) 138 China 291–302 China Food Additive Association (CFAA) 293 Chinese Medicine Ordinance (CMO) 372 Cholestin® 95 chondroitin sulfate 79 clinical trial application (CTA) 164 Clinical Trials for Natural Health Products Guidance Document 164 Closer Economics Relations (CER) 247 Code of Federal Regulations (CFR) 135, 136 Codex Alimentarius 23, 26, 151, 184, 270, 327, 365, 373, 377, 386, 393, 397 Copyright © 2008, Elsevier Inc. All rights reserved

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440 Index

Codex Alimentarius Commission (CAC) 24, 77, 143, 150, 151, 154, 283 Commision for Nutrition and Foods for Special Dietary Uses (CNFSDU) 24 Commonwealth Department of Health and Aging 240 Communication of the European Commission on the Precautionary Principle (2000) 180 Complementary Healthcare Council of Australia 242 Complementary Medicines Evaluation Committee (CMEC) 242 Complementary Medicines Transition (COMET) 246 Compliance and Narcotics Division 258 Cortislim 53 cosmeceutical 85 Cosmetic Regulations 166 Council for Responsible Nutrition 60 daily value (DV) 134, 136 Department of Food Quality Control 385 Department of Health-Taiwan (DOH) 367, 368 Department of Health-Indonesia 392 Dietary Supplements Regulations (1985) 245 Director General of Health Services 324 docosahexaenoic acid (DHA) 235, 266 Drug Identification Number (DIN) 160, 161, 162 echinacea 79 echium oil 236 EHP Code of Practice 147 England’s Adulteration of Food Acts of 1860 and 1972 60 Environmental Health Practioners (EHP) 147 Environmental Protection Agency (EPA) 111 ephedra 69, 72, 77, 78 EU Concerted Action 13 EU Dietary Supplement initiative 59 EU Food law 173, 174, 177, 224–225 EU Member States 173, 177, 178, 185, 189, 190, 194, 211, 224, 225, 227, 232, 234, 235, 237 EU Standing Committee on the Food Chain and Animal Health 204 European Commission 173, 176, 177, 184, 190, 192, 194, 206, 209, 210, 213, 224, 226, 228, 229, 234


European Commission 2000 White Paper on Food Safety 173, 188 European Commission v. Austria 184 European Commission v. Germany 184 European Court of Justice 176, 184, 202, 224 European Economic Community (EEC) 225 European Food and Veterinary Office 184 European Food Labeling directive 206 European Food Safety Authority (EFSA) 173–184, 186, 194, 200, 207–216, 221, 225, 226, 227, 228, 230, 235 European Parliament 173, 174, 176, 178, 185, 190, 194, 224, 228 European Patent Office (EPO) 427 European Responsible Nutrition Alliance (ERNA) 178 European Union (EU) 173–194, 200–205, 221–238 Fair Trade Commission of the Minister’s Cabinet Office 256 FDA-Consumer Health Information for Better Nutrition Initiative 128, 138, 139 FDA-Food and Drug Modernization Act (FDMA) 87, 88, 117, 118, 126, 138, 139 FDA-General Requirements for Health Claims 121 FDA-Health and Diet Survey (2002) 160 Federal Food, Drug and Cosmetic Act (FFDCA) 40, 85, 86, 87, 93, 94, 95, 116, 117, 122, 128, 129, 130 Federal Trade Commission (FTC) 47–54, 69, 116, 131, 414 fiber 15, 16, 117, 124, 125, 126, 136, 212 Food Act-Malaysia (1983) 385 Food Additive Hygiene Standard 296, 301 Food Administration Act (FAA) 370 Food and Agriculture Organization (FAO) 11, 23, 26, 151, 270, 327, 386 food and drug act (FDC Act) 42, 43 Food and Drug Administration (FDA) 21, 22, 39, 40, 41, 42, 43, 44, 45, 48, 51, 54, 59–62, 68, 72, 77, 83, 84, 86–89, 91–104, 111, 115–118, 120–131, 134, 136–140, 160, 299, 397, 414 Food and Drug Regulations 160, 161, 165, 166, 168 Food and Drugs Act 160, 161, 169

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Index 441

Food and Environment Protection Act (1985) 226 food-borne bioterrorism 112 Food Control Department of Singapore (FCDS) 395 Food Hygiene Act 282 Food Hygiene Law (1995) 291–292, 293 Food Hygiene Law of the People’s Republic of China 292 Food Label Package Survey 141 Food Labeling Regulations (1996) 230 food recall 333–334 Food Safety Act (1990) 226 Food Safety and Standards Act (2006) 323–324, 325, 328–338 Food Safety and Standards Authority (FSSA) 328, 332, 338 Food Safety Commission (FSC) 256, 272, 273 food safety objective (FSO) 155 Food Sanitation Act (FSA) 378 Food Sanitation Law 254, 257, 260–261, 262, 263, 264, 265 Food Standards Act (1999) 226 Food Supplement Definition 203 Food Supplement Directive 207, 237 foods for particular nutritional uses (PARNUTS) 192–194, 202, 208, 209, 226 Foods for Specific Health Use (FOSHU) 11, 12, 13, 14, 25, 87, 89, 204, 205, 249–254, 263, 265, 266, 265–271, 275, 277, 278, 366 Foods with Nutrient Function Claims (FNFC) 252 foodstuffs 175, 177, 193, 202, 235 Fortified Foods Regulation 217 Frankenstein Foods 187 Functional Food Act (FFA) 378, 379 Functional Food Code (FFC) 377 Functional Food Science In Europe (FUFOSE) 13, 205, 215 General Food Law Regulation (EC) No 178/2002 174–194, 202 Generally Recognized As Safe (GRAS) 85, 86, 87, 88, 97, 103, 235, 416 genetically modified (GM) 342 genetically modified organisms (GMO) 145, 187, 188, 209 ginko 79


Global Agreement on Tariffs and Trade (GATT) 146, 148, 149, 151 global positioning (GPS) 109, 110, 112 Good Agricultural Practice (GAP) 210, 275 Good Clinical Practice (GCP) 266 Good Hygiene Practice (GHP) 143, 151, 154 Good Laboratory Practice (GLP) 266 Good Manufacturing Practices (GMP) 59–69, 73, 143, 151, 154, 162, 163, 164, 246, 249, 251, 274, 278, 368, 380, 416 Government of India (GOI) 324 Green Paper on Food Law (1997) 174 Guides Concerning the Use of Endorsements and Testimonials in Advertising 52, 53 Hazard Analysis and Critical Control Point (HAACP) 63, 109, 110, 111, 112, 145, 147, 148, 151, 152–155 Health Canada 166–169 Health Food Control Act (HFCA) 367, 368, 369, 370 Health Foods and Dietary Supplements Association (HADSA) 327, 328, 338 Health Functional Food Act 379, 381, 382, 383 Health/Functional Food Act (HFFA) 281, 282, 283 Health Promotion Law 260, 261 high performance liquid chromatography (HPLC) 77, 79 Homeopathic Medicine Drug Identification Number (DIN-HM) 162 homeopathic medicines (HM) 161 Hong Kong 371–375 Hygiene Administration Regulation for New Resource Foods 296 identity preservation (IP) system 145 Imported Health Food Approval Certificate 300–301 India 323–338 Indian Health Foods and Dietary Supplements Association (INHADSA) 327 Indonesia 392–393 intellectual property (IP) 408 Intelligent Product Delivery System (IPDS) 112 Intergovernmental Committee (IGC) 411 Interim Administrative Measures for Health Food Registration 298

6/18/2008 6:19:48 PM

442 Index

International Alliance of Dietary Food Supplement Associations (IADSA) 11, 25 International Functional Food Conference (IFFC) 372 International Life Sciences Institute (ILSI) 13, 178, 205, 206, 215, 231, 384 International Office of Epizootics (OIE) 150 International Plant Protection Convention (IPPC) 150 International Standardization Organization (ISO) 77 International Trade Commission (ITC) 424 investigational new drug (IND) 41, 43 Japan Agricultural Standards Law 254, 261 Japan Health Food & Nutrition Food Association 26 Japanese Agricultural Standards 261 Japanese Health and Nutrition Food Association (JHNFA) 274 Japanese Institute for Health Food Standards 274 Japanese Ministry of Education 251, 252 Japanese Ministry of Education, Culture, Sports, Science and Technology 251 Japanese Ministry of Health and Welfare (MHW) 12, 25, 87, 205, 249 Japanese Ministry of Health, Labor and Welfare (MHLW) 249, 252–260, 262, 263, 270, 271, 274–279 jelly bean rule 123 Korea 281–290 Korean Food and Drug Administration (KFDA) 281, 285, 287, 288, 289 Korean Food and Drug Administration (KFDA) 376–383 Korean Health and Welfare Committee 282 Korean Ministry of Health and Welfare 378 liquid chromatography/mass spectroscopy (LC/MS) 77 Malaysia 383–391 Malaysian Ministry of Health 385, 386 Malaysian National Codex Committee 385 Medical Devices Regulations 166 Medicines Act (1981) and Regulations (1984) 240, 245


Medicines and Health Products Regulatory Agency (MHPRA) 230 metabolomics 100 Mevacor® 95 microbiological risk assessment (MRA) 152, 154 Ministry of Agriculture, Forestry and Fisheries (MAFF) 261 Ministry of Economy, Trade and Industry (METI) 262 Ministry of Food Processing Industries 325, 328, 338 Ministry of Health (MOH) 292–302 Ministry of Health and Family Welfare 324, 326, 328, 329, 335 Misuse of Drugs Act (1975) and Regulations (1977) 240, 245 nanotechology marker assays 109 The National Academy of Science (NAS) 138 National Advertising Division of the Better Business Bureaus (NAD) 48, 49 National Agency of Drug and Food Control 392 National Health Surveillance Agency (ANVISA) 349, 350, 351, 352, 358, 360 National Institutes of Health (NIH) 67, 72, 138, 279 National Pharmaceutical Control Bureau (NPCB) 385, 391 Natural Health Product (NHP) 159–171, 346 Natural Health Products Directorate (NHPD) 159–171 Natural Product Number 162 new dietary ingredient (NDI) 39, 40, 41, 42, 43, 44, 45 New Dietary Ingredient Notification (NDIN) 96, 97, 103 New Resource Food Registration Certificate 302 New Zealand 239–248 New Zealand Food Safety Authority (NZFSA) 245 New Zealand- Medicines and Medical Devices Safety Authority (Medsafe) 239–246 NFx 4, 5, 6, 7, 8 NHP-GMP 163 NHP-Regulations 159, 164, 165, 167, 169

6/18/2008 6:19:48 PM

Index 443

NHPD-Adverse Reaction Reporting Guidance Document 163 Noni juice 235 The North Karelia Project 14 Novel Food Regulation – China 296–298 Novel Foods procedure 186–187 Novel Foods Regulation 189–190, 192, 202, 209, 210, 221, 222, 224, 231–237 Nutraceutical-Industrial Complex 5 nutragenomics 100 Nutrilab v. Schweiker 130 Nutrition and Health Claims Regulation 200, 203, 205, 206, 217 nutrition facts 134 Nutrition Improvement Law 260 Nutritional Labeling and Education Act (NLEA) 87, 88, 117, 118, 121, 123, 125, 126, 134, 137, 222, 332, 393 Office of Dietary Supplements (ODS) 67 Olestra® 86 One-a-Day WeightSmart 53 Pacific rim 365–397 Patent Cooperation Treaty (PCT) 427 Pearson v. Shalala 126, 127 People’s Central Government Ministry of Public Health 292 Pharmaceutical Affairs Law 253, 254, 255, 257, 261, 265 Pharmaceutical and Medical Safety Bureau 258 Pharmacy and Poisons Ordinance (PPO) 372 Phillipine Food Fortification Act (2000) 394 Phillipines 393–394 phytosterol esters 236–237 polynuclear aromatic hydrocarbons (PAH) 184 population safety index (PSI) 178 Prevention of Food Adulteration Act of India (1954) 325, 326, 327, 334 Process for the Assessment of scientific support for claims (PASSCLAIM) 13, 200, 215–217, 231 Product License Application (PLA) 161, 162, 164, 166, 169 Public Health and Municipal Service Ordinance (PHMSO) 372 Pyridorin® 95


Qualified Health Claims (QHC) 91, 92, 98, 126, 138, 139 Quality Assurance Report (QAR) 163 quality assurance system (ISO 9000) 155 quality control 65 radioallergosorbent test (RAST) 237 radiopharmaceuticals 161 randomized control trial (RCT) 5, 6 Recommended Daily Allowance (RDA) 94, 283, 284, 350, 386 reference amount customarily consumed (RACC) 118, 119, 120, 123, 136 Regulation for Food Sanitation Control for Trial Implementation 292 Regulations on the Administration of Food Hygiene 292 research and development 409 risk assessment 154 Rospotrebnadzor Orders 308 Russia 305–315 Russian Federation Laws 308 Sanitary and epidemiological well-being of the population’ 308 sanitary or phytosanitary measure 150 Sanitary regulations and norms (SanRaN) 308, 311, 313 saskatoon berries 235 saw palmetto 79, 123 Scientific Committee on Food (SCF) 178, 179 semicarbazide (SEM) 181, 182 Significant Scientific Agreement (SSA) 88, 89, 91, 98, 117, 121, 124, 125, 126, 127, 128, 138, 139 Singapore 394–395 site license application (SLA) 163, 170 South Korea 375–383 Special Administrative Region (SAR) 371 State Drug Administration 298 State Food and Drug Administration (SFDA) 298–302 State Policy in Healthy Nutrition of the Population of the Russian Federation 306 structure/function claims 115, 128, 130, 131, 136–137, 141 supplement facts 134

6/18/2008 6:19:49 PM

444 Index

Taiwan 366–370 Technical and Scientific Committee on Functional Food and Novel Ingredients (CTCAF) 349, 351, 352, 359, 360, 362 Thai Food and Drug Administration 397 Thailand 396–397 Therapeutic Drugs Directorate 162 Therapeutic Goods Act (1989) 240, 241, 242 Therapeutic Goods Administration (TGA) 239, 240, 241, 242, 243 Therapeutics Goods Regulation (1990) 242 Tobacco Act 161 Tokyo Metropolitan Health Bureau and Life Culture Bureau 279 Trade Descriptions Act (1968) 226 traditional Chinese medicine 371 Traditional Herbal Medicinal Products directive 201, 204, 222 Trans Tasman Mutual Recognition Arrangement (TTMRA) 247 Treaty of Waitangi 248 trehalose 236 Trimspa 53 UK Food Standards Agency 147, 227, 230, 235, 236 UK Joint Health Claims Initiative (JHCI) 230–231 Undesirable Medical Advertisements Ordinance (UMAO) 372 United Kingdom Ministry of Agriculture, Fisheries and Food 205 United States Code (USC) 420, 421, 422, 423, 424 United States Congress 420 United States Constitution 420 United States Department of Agriculture (USDA) 60, 111, 116


United States Patent and Trademark Office (USPTO) 420, 421, 430, 431, 432, 433, 436 United States Pharmacopoeia Standard 164 Upper Tolerable Safe Intake Levels (UL) 178 Uruguay Round of Multilateral Trade Negotiations 149 US Code of Federal Regulations 74, 76, 117, 118, 332 US Congress 84, 117 US Court of Appeals 126 US Customs and Border Patrol (CBP) 437 US Dietary Supplement Health and Education Act (DSHEA) 12, 21, 22, 25, 39, 40, 45, 60, 69, 87, 92, 93, 95, 96, 97, 103, 115, 117, 128, 129, 130, 138, 201, 222, 323, 332, 346, 378, 379, 407, 417 US patent 413, 414, 419–438, 426 US Patent Act 422, 424, 425 US Pharmacopeia (USP) 77, 419 US Trademark 428–438 weight loss products 53 Whitaker v. Thompson 123, 128 World Bank 147 World Cancer Research Fund (WCRF) 216 World Convention on Biodiversity (CBD) 410, 411, 412 World Health Organization (WHO) 11, 23, 26, 151, 159, 216, 223, 270, 327, 386 World Intellectual Property Organization (WIPO) 411, 412 World Trade Organization (WTO) 143, 144–149, 150, 151, 370, 427 WTO-Sanitary and Phytosanitary Practice (SPS) 143, 148, 149–151 Xenadrine 53

6/18/2008 6:19:49 PM

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Food Science and Technology

Functional Food Product Development (Hui: Food Science and Technology)

Food Plant Sanitation (Food Science and Technology)

Food Process Design (Food Science and Technology)

Food Plant Sanitation Food Science and Technology

Waste Management for the Food Industries (Food Science and Technology) (Food Science and Technology)

Food Emulsions (Food Science and Technology)

Food Plant Design (Food Science and Technology)

Food Chemistry (Food Science and Technology)

Asian Functional Foods (Nutraceutical Science and Technology)

Dairy-Derived Ingredients: Food and Nutraceutical Uses (Woodhead Publishing in Food Science, Technology and Nutrition)

Frozen Food Science and Technology

The Nutrition Transition: Diet and Disease in the Developing World (Food Science and Technology International) (Food Science and Technology)

Food Culture in the Mediterranean (Food Culture around the World)

Functional Foods and Biotechnology (Food Science and Technology)

Phytochemical Functional Foods (Woodhead Publishing in Food Science and Technology)

Food Polysaccharides and Their Applications (Food Science and Technology)

Food Intolerance and the Food Industry (Woodhead Publishing in Food Science and Technology)

Phytosterols as Functional Food Components and Nutraceuticals (Nutraceutical Science and Technology, 1)

Food Intolerance and the Food Industry (Woodhead Publishing in Food Science and Technology)

Chromatography in Food Science and Technology

Marine Nutraceuticals and Functional Foods (Nutraceutical Science and Technology)

Global Issues in Food Science and Technology

Carbohydrates in Food, Second Edition (Food Science and Technology)

Food Preservation Techniques (Woodhead Publishing in Food Science and Technology)

Aflatoxin and Food Safety (Food Science and Technology)

Food Preservation Techniques (Woodhead Publishing in Food Science and Technology)

Innovations in Food Packaging (Food Science and Technology International)

Polysaccharide Association Structures in Food (Food Science and Technology)

Extraction Optimization in Food Engineering (Food Science and Technology)

Nutraceutical and Functional Food Regulations in the United States and Around the World (Food Science and Technology)

Food Science and Technology

Functional Food Product Development (Hui: Food Science and Technology)

Food Plant Sanitation (Food Science and Technology)

Food Process Design (Food Science and Technology)

Food Plant Sanitation Food Science and Technology

Waste Management for the Food Industries (Food Science and Technology) (Food Science and Technology)

Food Emulsions (Food Science and Technology)

Food Plant Design (Food Science and Technology)

Food Chemistry (Food Science and Technology)

Asian Functional Foods (Nutraceutical Science and Technology)

Dairy-Derived Ingredients: Food and Nutraceutical Uses (Woodhead Publishing in Food Science, Technology and Nutrition)

Frozen Food Science and Technology

The Nutrition Transition: Diet and Disease in the Developing World (Food Science and Technology International) (Food Science and Technology)

Food Culture in the Mediterranean (Food Culture around the World)

Functional Foods and Biotechnology (Food Science and Technology)

Phytochemical Functional Foods (Woodhead Publishing in Food Science and Technology)

Food Polysaccharides and Their Applications (Food Science and Technology)

Food Intolerance and the Food Industry (Woodhead Publishing in Food Science and Technology)

Phytosterols as Functional Food Components and Nutraceuticals (Nutraceutical Science and Technology, 1)

Food Intolerance and the Food Industry (Woodhead Publishing in Food Science and Technology)

Chromatography in Food Science and Technology

Marine Nutraceuticals and Functional Foods (Nutraceutical Science and Technology)

Global Issues in Food Science and Technology

Carbohydrates in Food, Second Edition (Food Science and Technology)

Food Preservation Techniques (Woodhead Publishing in Food Science and Technology)

Aflatoxin and Food Safety (Food Science and Technology)

Food Preservation Techniques (Woodhead Publishing in Food Science and Technology)

Innovations in Food Packaging (Food Science and Technology International)

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