1
Introduction and Background

A significant number of new dietary supplement products have appeared in the marketplace since the U.S. Congress passed the Dietary Supplement and Health Education Act (DSHEA) of 1994 (P.L. 103–417). At the time DSHEA was enacted, an estimated 600 U.S. dietary supplement manufacturers produced about 4,000 products (Commission on Dietary Supplement Labels, 1997). The Food and Drug Administration (FDA) estimates that more than 29,000 different dietary supplements are now available to consumers and an average of 1,000 new products are developed annually (Sarubin, 2000).

Consumer interest in health and self-care has been identified as providing the impetus for the expanded market of a wide range of products that includes dietary supplements (Prevention Magazine, 2001). Since 1994, sales of dietary supplements have increased to an estimated $15.7 billion per year (Blendon et al., 2001; Nutrition Business Journal, 2000). Of this total, it is estimated that Americans spend about $700 million per year on herbal supplements (Stein, 2000).

Vitamin and mineral supplement use by the U.S. population has been a growing trend since the 1970s (Bender et al., 1992; Subar and Block, 1990), suggesting that Americans are becoming more receptive to alternatives to conventional food sources for nutritional health benefits (ADA, 2000). This is despite research-based dietary recommendations supporting the position that the best nutrition strategy for optimal health and reducing the risk of chronic disease is to obtain adequate nutrients from a wide variety of foods (Hunt, 1996; Hunt and Dwyer, 2001).

Within its definition of supplements, DSHEA included ingredients that have not traditionally been recognized as nutrients or as having nutritional functions, such as botanicals and hormones (Nesheim, 1999). As with conventional foods, many dietary supplements are considered to be “safe”—that is, there exists a reasonable certainty of no harm when used as recommended. However, questions have been raised about the safety of some dietary supplements. When these questions are raised, FDA must rapidly review and further evaluate the safety of the ingredients. This has created a sizeable regulatory challenge for FDA because of the increased availability and use of supplements, as well as the broad spectrum of ingredients that qualify as dietary supplements under the DHSEA legislation.



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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements 1 Introduction and Background A significant number of new dietary supplement products have appeared in the marketplace since the U.S. Congress passed the Dietary Supplement and Health Education Act (DSHEA) of 1994 (P.L. 103–417). At the time DSHEA was enacted, an estimated 600 U.S. dietary supplement manufacturers produced about 4,000 products (Commission on Dietary Supplement Labels, 1997). The Food and Drug Administration (FDA) estimates that more than 29,000 different dietary supplements are now available to consumers and an average of 1,000 new products are developed annually (Sarubin, 2000). Consumer interest in health and self-care has been identified as providing the impetus for the expanded market of a wide range of products that includes dietary supplements (Prevention Magazine, 2001). Since 1994, sales of dietary supplements have increased to an estimated $15.7 billion per year (Blendon et al., 2001; Nutrition Business Journal, 2000). Of this total, it is estimated that Americans spend about $700 million per year on herbal supplements (Stein, 2000). Vitamin and mineral supplement use by the U.S. population has been a growing trend since the 1970s (Bender et al., 1992; Subar and Block, 1990), suggesting that Americans are becoming more receptive to alternatives to conventional food sources for nutritional health benefits (ADA, 2000). This is despite research-based dietary recommendations supporting the position that the best nutrition strategy for optimal health and reducing the risk of chronic disease is to obtain adequate nutrients from a wide variety of foods (Hunt, 1996; Hunt and Dwyer, 2001). Within its definition of supplements, DSHEA included ingredients that have not traditionally been recognized as nutrients or as having nutritional functions, such as botanicals and hormones (Nesheim, 1999). As with conventional foods, many dietary supplements are considered to be “safe”—that is, there exists a reasonable certainty of no harm when used as recommended. However, questions have been raised about the safety of some dietary supplements. When these questions are raised, FDA must rapidly review and further evaluate the safety of the ingredients. This has created a sizeable regulatory challenge for FDA because of the increased availability and use of supplements, as well as the broad spectrum of ingredients that qualify as dietary supplements under the DHSEA legislation.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements COMMITTEE CHARGE To expeditiously and efficiently monitor the continually evolving and growing patterns of dietary supplement use, as well as their potential interactions with other consumed substances, FDA needs a cost-effective and scientifically sound approach to consider the safety of dietary supplement ingredients. For these reasons, FDA turned to the Institute of Medicine (IOM) of The National Academies to propose a framework for evaluating the safety of dietary supplement ingredients marketed in the United States. Specifically, FDA requested that an IOM committee (1) develop a proposed framework for categorizing and prioritizing dietary supplement ingredients based on safety issues, (2) describe a process for developing a system of scientific reviews with specifications for evaluating the safety of dietary supplement ingredients, and (3) develop at least six scientific reviews as prototypes for the system. The proposed framework is to include a methodology to review data with regard to the safety of dietary supplement ingredients, taking into consideration methods other expert bodies have used to categorize and review supplement safety and efficacy issues. FDA, in its request to IOM, asked that a framework for setting priorities and evaluating the safety of dietary supplement ingredients be proposed and released for comment, followed by the development of six prototype monograph reviews using the procedures outlined in the proposed framework. After development of the prototype monograph reviews, and based on comments received, the framework is to be revised based on the experience and concerns identified following its release. The committee held four meetings while preparing the proposed framework. Three of these meetings included open sessions so the committee could hear from the sponsor and a number of individuals and organizations regarding aspects of evaluating the safety of dietary supplements. In addition, representatives of a number of agencies and organizations that currently evaluate chemical substances for various attributes were invited to discuss their methodologies and frameworks for approaching reviews of such substances. (See Appendix F for a list of those presenting at the open sessions of the committee.) GENERAL BACKGROUND INFORMATION ABOUT DIETARY SUPPLEMENTS Many of the substances currently marketed as dietary supplements fall into the following categories: vitamins, minerals, herbs or other botanicals, amino acids, animal-derived products, hormones and hormone analogs, enzymes, and concentrates, metabolites, constituents, or extracts of these.2 Within each of these categories, products may be pure single entities of known or unknown chemical components, mixtures in which all or some components are known, or mixtures of unknown chemical components. National surveys such as the Third National Health and Nutrition Examination Survey and the 1987 and 1992 National Health Interview Surveys indicate that 40 to 46 percent of Americans reported taking at least one vitamin or mineral supplement at some time within the month surveyed (Balluz et al., 2000; Slesinski et al., 1995). Several investigations have explored nutrient supplement (thought to be primarily vitamin and mineral formulations) use prevalence and trends in the United States (Balluz et al., 2000; Bender et al., 1992; Kim et al., 1993; Koplan et al., 1986; Slesinski et al., 1995; Subar and Block, 1990), as well as motivations for taking 2   While these are not dietary supplement categories specified by DSHEA, they illustrate the diversity of products currently marketed as dietary supplements. The 1994 DSHEA description of what constitutes dietary supplements can be found in Box 1-1.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements vitamin and mineral supplements (Neuhouser et al., 1999) and characteristics of users versus nonusers (Dwyer et al., 2001; Ford, 2001; Hartz et al., 1988; Lyle et al., 1998; Nayga and Reed, 1999; Pelletier and Kendall, 1997; Subar and Block, 1990). However, knowledge about the use prevalence and trends of dietary supplements (which include nonvitamin, nonmineral supplements) is limited (Radimer et al., 2000). Data from national surveys collected before the enactment of DSHEA in 1994 may not reflect current supplement consumption patterns (Costello and Grumpstrup-Scott, 2000), and there are limitations to interpreting user characteristics from sales data (Radimer et al., 2000). Existing studies of reported dietary supplement use suggest an association between increased use of dietary supplements by older individuals and those who report having more healthful lifestyles (Radimer et al., 2000). The most frequent reason given for dietary supplement use in one national survey was desire for self-care (Prevention Magazine, 2001). Some consumers report using supplements because of a belief that these products will ensure good health. Generally, labeling for a dietary supplement may not claim to “diagnose, mitigate, treat, cure, or prevent a specific disease or class of diseases” (DSHEA, P.L. 103–417, § 6, 1994; FDCA, 21 U.S.C. § 343(r)(6)(C), 2001). Despite the legal classification, consumers have reported using supplements for very specific purposes such as treating and preventing illnesses, colds, and flu; increasing “mental sharpness”; and alleviating depression (Prevention Magazine, 2001). Studies conducted among teenagers suggest that dietary supplements are used to enhance athletic performance, build muscle, or lose weight (FDA, 1994; Jonnalagadda et al., 2001; McGuine et al., 2001; Metzl et al., 2001; Smith and Dahm, 2000; Wallace, 2001). There is also a reported link of more frequent dietary supplement use among Americans with one or more health problems (Bender et al., 1992), with specific diseases such as breast cancer (Newman et al., 1998), with higher alcohol consumption, and with obesity (Radimer et al., 2000). Evidence suggests that supplement use may not be associated with better food intake in all populations, and may differ by ethnicity and across income strata (Pelletier and Kendall, 1997; Pelletier et al., in press). Results from a recent national survey of 2,000 adults indicated that 85 percent of respondents had used one or more dietary supplements in the previous 12 months (Prevention Magazine, 2001). If this sample of U.S. consumers was representative of the total population, it would translate into more than 44 million consumers using botanical remedies and an estimated 24 million using specialty supplements (e.g., bee pollen, dehydroepiandrosterone [DHEA], chondroitin sulfate, kava kava, shark cartilage, and S-adenosylmethionine [SAMe]) (Prevention Magazine, 2001; Radimer et al., 2000; Ramos, 2000). Consumer Expectations About Dietary Supplement Safety The American public may assume that dietary supplements are subject to existing government regulations similar to those required for over-the-counter (OTC) medications sold without a prescription. In actuality, dietary supplements are subject to different regulatory requirements in comparison with OTC medications. With the passage of DSHEA, the burden of proof concerning the safety of dietary supplements was placed on FDA by requiring FDA to determine that a substance was unsafe rather than requiring a manufacturer to provide data supporting its safety (Blendon et al., 2001). New dietary supplement ingredients (those not marketed prior to passage of DSHEA), however, must provide advanced notification to FDA prior to marketing.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements Only a few national surveys exploring the views and perceptions of Americans regarding dietary supplements have been conducted. One compilation was based on four national opinion surveys conducted from 1996 to 1999 by the Roper Center for Public Opinion; however, supplement users were not differentiated from nonusers, thereby limiting the usefulness of the findings (Blendon et al., 2001). Another survey that explored general patterns of medication use in the ambulatory adult population from 1998 to 1999 also examined use of vitamins and minerals, as well as herbals and dietary supplements. The Sloan Survey, conducted among 2,590 U.S. consumers, found that 16 percent of prescription drug users also took an herbal or other dietary supplement (Kaufman et al., 2002). A third telephone survey, conducted by the Princeton Survey Research Associates for Prevention Magazine, used a nationally representative sample of 2,000 U.S. adults. The results suggested a high degree of consumer confidence in supplements based on the finding that nearly two-thirds of respondents believed that herbal supplements were either safe or completely safe (Prevention Magazine, 2001). Another analysis used two separate data sources that compared the views of dietary supplement users to nonusers. The first survey, designed collaboratively between researchers at National Public Radio, the Kaiser Family Foundation, and the John F.Kennedy School of Government, used telephone interviews conducted by the Princeton Survey Research Associates with 1,200 randomly selected adults in 1999. A second survey was conducted with 1,013 randomly selected adults (Blendon et al., 2001). Results from the analysis of the two surveys revealed that regular dietary supplement users reported not discussing dietary supplements use with their physicians because they believed that the physicians knew little or nothing about these products and may be biased against them. In addition, many users felt so adamant about the potential health benefits of some of the products used that they would continue to take them even if the products were shown to be ineffective in scientifically conducted clinical studies. Despite these beliefs, the analysis also revealed that there was broad public support for increased government regulation of these products. The majority of those surveyed supported the following positions: FDA should be required to review the safety of new dietary supplements prior to their sale. FDA should be granted increased authority to remove from the market products that are shown to be unsafe. Government regulation should have the capacity to ensure that advertising claims about the health benefits of dietary supplements are truthful (Blendon et al., 2001). History of the Federal Regulation of Dietary Supplements A framework for the evaluation of safety of dietary supplement ingredients must be carried out within the regulatory environment under which the ingredients are to be evaluated. Many herbals and other botanicals have been used much longer than many other types of dietary supplements currently in use, with ancient cultures employing them medicinally. People have long used plants and other substances to supplement their diets in an attempt to prevent or ameliorate specific symptoms. Patent medicines became popular in the 1800s as advertising increased and the lack of available trained medical personnel and the inability of conventional medicines to adequately treat many diseases drove consumers to look elsewhere for help. Such products were often secret formulations and directly marketed to consumers (CDER, 2002).

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements The growing pharmaceutical industry marketed its medicines directly to health professionals. In both cases, there were few regulations to control unsubstantiated claims to assist the consumer or health professional in distinguishing between valid and false assertions made by purveyors of the different products. While some efforts were made by states, federal regulation of these substances and products in the 1800s was essentially nonexistent (Millikan, 1999). Food and Drugs Act of 1906 The Food and Drugs Act of 1906, and its companion bill, the Meat Inspection Act of 1906, were the earliest comprehensive efforts by the U.S. government to bring greater emphasis both to the safety of marketed products and to the accurate characterization of the benefits derived from their use. The 1906 acts resulted from a convergence of public, industry, and scientific support that was partially motivated by concern about the safety of food and patent medicines and widespread fraud in the growing food and drug industry. The triggering event was the exposure of unsafe conditions in the meat packing industry (Sinclair, 1906). The passing of the 1906 acts has also been attributed to industry’s desire to restore competitiveness to their products in weak foreign and domestic markets (Barkan, 1985). The 1906 acts established the broad authority of the federal government to protect the public from adulterated or misbranded food and drugs, and thus imposed new regulations on the food and drug industries. Specifically, the laws introduced accountability by requiring that regulated products be labeled accurately and that they be safe. However, under the Food and Drugs Act, FDA bore the burden of establishing that a food or drug was unsafe before it could take action against the product. Federal Food, Drug, and Cosmetic Act of 1938 A movement for increased regulation of ingested substances came about in the 1930s, eventually culminating in the U.S. Congress passing the 1938 Federal Food, Drug, and Cosmetic Act (FDCA, P.L. 75–717, 52 Stat. 1040 [1938], as amended 21 U.S.C. § 301 et seq., 2001). The FDCA replaced the 1906 law that had become obsolete due to the technological changes in the production and marketing of food and drugs (FDA, 1981). This new Act created a complex system of federal regulations for foods, drugs, cosmetics, and medical devices. Some of the more important changes implemented by the FDCA were further introduction of food standards3 and changing the focus of FDA from that of a policing agency that had been concerned primarily with confiscating adulterated drugs to that of a regulatory agency involved with the oversight of evaluating new drugs (Wax, 1995). The FDCA transferred the responsibility of proving the safety of new drugs to the drug manufacturer and required manufacturers to submit new drug applications (NDAs) establishing safety to FDA before marketing.4 While FDA no longer had the responsibility of establishing that an unapproved new drug was unsafe before taking action against it, FDA continued to be 3   Food standards were required to promote honesty and fair dealing in the interest of consumers (FDA, 1981). The standards consisted of definitions of what constituted a food (e.g., mayonnaise must contain a certain percentage of egg and oil). 4   In 1962, the FDCA was amended to require NDAs to establish the efficacy, as well as the safety, of new drugs.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements responsible for establishing that a conventional food product was unsafe, as it does to this day5 (Commission on Dietary Supplement Labels, 1997). The FDCA contained provisions that applied to foods, drugs, and cosmetics. The application of these provisions to products containing a vitamin, mineral, or botanical ingredient (whether it was considered a drug or a food, for example) depended on the product’s intended use, as determined usually by the labeling and advertising claims for the product. The 1938 Act contains a number of definitions that guide FDA actions according to the regulations derived from it. One definition of a drug is an article “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals…”; a second definition is “articles (other than food) intended to affect the structure or any function of the body of man or other animals…”; and a third definition states that a product is a drug if it is “recognized in the official U.S. Pharmacopeia (USP), official Homeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them.” (FDCA, P.L. 75–717, 52 Stat. 1040 [1938], as amended 21 U.S.C. § 321(g), 2001). The 1938 Act contains no specific provisions for vitamin, mineral, or botanical products, except in Section 403(j), which indicates that a food is misbranded if it is claimed to be “for special dietary uses” but its label does not bear FDA-prescribed statements about its “vitamin, mineral, and other dietary properties” sufficient to inform the consumer about its value for such uses (FDCA, P.L. 75–717 § 403(j), as amended 21 U.S.C. § 343(j), 2001). Congress intended that this Section [403(j)] would allow FDA to regulate claims for vitamins, minerals, and botanical foods more closely than for conventional foods (Pendergast, 1997). However, in enacting Section 403(j), it has been asserted that FDA was most concerned with the problems of nutritional deficiency and inadequacy of the diet, and thus did not address either acceptable claims for vitamins, minerals, and botanical products or when these products should be regulated as drugs as opposed to foods (Pendergast, 1997). Early Attempts to Regulate the Industry Eventually FDA did focus attention on claims for vitamins, minerals, and especially botanical products. FDA began to use extensive litigation directed at claims to regulate the botanical industry in the 1940s. Botanical products were treated as unapproved drugs not only if they made claims concerning the treatment or prevention of disease, but also if they made claims concerning the products’ effects on the structure and function of the body—a type of claim foods were allowed to make without being considered drugs. FDA also took action against manufacturers making therapeutic claims for vitamins and minerals (FDA, 1941). At that time, FDA did not rigorously apply the FDCA’s definition of drugs (those listed in the USP, National Formulary, or the Homeopathic Pharmacopoeia of the United States), a definition that would have included most vitamins and minerals and many botanical preparations. In 1944, when FDA charged that certain vitamin B capsules were misbranded as food and drugs, the courts dismissed the food counts, holding that the capsules were drugs by definition because vitamin B was listed in the USP (Pendergast, 1997). FDA did not fully exploit this reasoning in future cases, however, and appeared to abandon this legal theory after several 5   However, food colors, binders, and other food additives must be approved for safety or determined to be generally recognized as safe (GRAS) prior to use (only the dietary supplement ingredient in a marketed supplement is exempted from food additive regulations), thus technical ingredients are subject to FDA requirements for preapproval.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements court cases in the 1960s, declaring that a USP listing was insufficient to confer drug status on a product (FDA, 1966). FDA’s focus on regulation of labeling claims it deemed unapproved and indicative of drug status was closely followed by increased use of publications such as self-help books and magazine articles that explained claims and intended uses. This approach was a “possible way [for supplement manufacturers] to avoid the FDA [enforcement]” (Pendergast, 1997). Debate about what constituted “labeling” ensued as FDA attempted to broaden labeling to include books and other materials. Characterization that this approach restricted the First Amendment right to free speech resulted in a number of court battles between the 1940s and 1960s.6 The resulting debate about First Amendment rights and labeling restrictions has been considered by some to be a significant factor that eventually led to DSHEA as an attempt to resolve the situation (McNamara, 1995). (The importance of DSHEA is described in greater detail later in the text.) Food Additives Amendment of 1958 Another major approach instituted by FDA that has been identified as a factor leading to the passage of DSHEA was its application of the Food Additives Amendment (FAA) of 1958 (P.L. 85–929, 1958) to botanical products (Kirschman, 1988). The result of FAA was to shift the burden of proof of safety away from FDA for a substance added to food. Manufacturers were required to obtain premarket approval from FDA unless the substance at issue could be considered as “generally recognized as safe” (GRAS) or had been sanctioned by FDA or the U.S. Department of Agriculture prior to 1958. A food additive is defined as “any substance the intended use of which results, or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food…that are not GRAS for intended use” (FDCA, P.L. 75–717, as amended 21 USC § 321(s), 2001). FDA instituted action against many popular dietary supplement ingredients based on contentions of unapproved food additive status. FDA contended that even single ingredient supplements in capsule form contained unapproved food additives. For example, FDA argued unsuccessfully that black currant seed oil in a capsule was a food additive (United States v. Two Plastic Drums…Black Current Oil, 984 F.2d 814 [7th Cir. 1993]). Although the courts struck down FDA’s effort with black currant seed oil, FDA’s application of the food additive provisions to botanical products and other dietary supplement ingredients has also been considered a major precipitating factor in the eventual passage of DSHEA (Kirschman, 1998). 1976 Proxmire Amendments By the 1960s regulation of botanical, vitamin, and mineral supplements was not consistent and was based on a combination of enforcement and judicial decisions. Court actions required long periods of time and considerable resources; thus FDA attempted to have broader impact on dietary supplement use by implementing tighter regulations on vitamin and mineral supplements. In 1973 FDA issued regulations prohibiting certain representations on vitamin and mineral supplement labels, establishing standards of identity for vitamin and mineral supplements, and establishing that preparations containing more than 150 percent of the U.S. Recommended Dietary Allowance (U.S. RDA) per serving were drugs. Both industry and consumers protested 6   See United States v. Detroit Vital Foods, 218 F. Supp. 208 [E.D. Mich. 1963]; United States v. Articles of Drug…Honey, 344 F.2d 288 [6th Cir. 1965]; United States v. Kordel, 164 F2d 913 [7th Cir. 1947], aff’d, 335 U.S. 345 [1948]; United States v. “Sterling Vinegar and Honey”…Balanced Foods, 338F.2d 157 [2d Cir. 1964].

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements these actions, eventually leading Congress to enact the 1976 Vitamins and Minerals Amendments, also known as the “Proxmire Amendments,” that prevented FDA from establishing standards limiting the potency of vitamins and minerals in food supplements or from regulating them as drugs based solely on potency (Pendergast, 1997). FDA revised its vitamin-mineral regulations in response to this legislation and, after a subsequent court challenge, ultimately revoked the regulations in 1979 (FDA, 1979). The Nutrition Labeling and Education Act and Health Claims With the suppression of FPDA’s attempts at more restrictive rulemaking, the realm of products sold as dietary supplements continued to expand and included botanicals and amino acids, as well as vitamin and mineral products. This expansion during the late 1970s and the 1980s was accompanied by reports of serious illnesses attributed to a few of the dietary supplements available at that time. In 1978, for example, an infant with colic was reportedly given a fatal dose of a potassium chloride supplement based on erroneous advice in a parenting book, despite medical knowledge that use of such doses of the supplement would induce cardiac arrest (Wetli and Davis, 1978). In 1989 there were widespread reports that certain tryptophan supplements were associated with eosinophilia-myalgia syndrome. After considerable in-house research by FDA, evidence surfaced that the problem might have been associated with the manufacturing process and FDA took actions that led to the removal of tryptophan from the market. By this time mounting scientific evidence had led several food companies to start promoting their conventional foods based on the potential of some of the ingredients or substances found in the food to reduce the risk of specific diseases. Some have purported that when dietary supplements made similar claims, FDA treated them more harshly, considering them to be unapproved drugs (Pendergast, 1997). This purportedly unequal approach toward regulating supplements versus foods supposedly became more evident when in 1987 FDA described criteria for what it would consider as an acceptable health claim (FDA, 1987). These proposed rules indicated that it might be more difficult for dietary supplement claims to meet FDA’s criteria, which could be interpreted as acknowledging that foods and dietary supplements were not the same (Pendergast, 1997). The Nutrition Labeling and Education Act (NLEA), which was passed in 1990 (P.L. 01–635), explicitly authorized “health claims,”7 but did not silence the controversies surrounding the different treatment of supplements and foods (Pendergast, 1997). Among other things, the NLEA provided that health claims describing the relationship of a nutrient to a disease or health-related condition were allowed for both traditional foods and dietary supplements if the claims complied with FDA regulations. FDA was charged with proposing the criteria needed for foods or supplements to make health claims. Some contend that concerns that FDA would treat supplements too harshly also contributed to the passage of DSHEA (Pendergast, 1997). The Dietary Supplement and Health Education Act In order to provide additional guidance, in 1993 FDA issued an advanced notice of proposed rulemaking regarding dietary supplements, which was accompanied by the suggestion that some 7   A health claim is a claim that “characterizes the relationship” between a substance in a food and damage, disease, or dysfunction of the human body. In effect, this allows a claim that otherwise would be regarded as an illegal drug claim when made for a food.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements products marketed as dietary supplements might be more appropriately considered under other regulatory categories. Amino acids, for example, might be considered unapproved food additives, and some botanicals might be more appropriately considered as drugs (FDA, 1993). Vitamins and minerals were also considered a potential target of regulation, as FDA suggested that their strength should be limited to levels that approximated the U.S. RDAs (FDA, 1993). Industry and consumers reacted quickly and strongly to these potential regulatory restrictions. Extensive public debate ensued over the importance of dietary supplements in health, consumers’ freedom to access information about supplements, and the controversy over FDA’s regulatory approach. As a result, Congress passed legislation limiting FDA regulation of dietary supplements. This legislation, the Dietary Supplement Health and Education Act (DSHEA), was signed into law in 1994. The Regulatory Implications of DSHEA. DSHEA is the most important dietary supplement legislation enacted to date. In its findings, Congress recognized the wide use of dietary supplements and stated in the legislation that currently available dietary supplements are generally safe. Passage of DSHEA was based on the concept that “legislative action that protects the right of access of consumers to safe dietary supplements is necessary to promote wellness” (DSHEA, P.L. 103–417, § 2, 1994; OIG, 2001). DSHEA established the first comprehensive definition of dietary supplements (Hoffman, 2001) (see Box 1-1). More importantly, DSHEA established a new regulatory framework for dietary supplements that limits FDA’s authority over these products, as compared to its authority over food additives and drugs (see Table 1–1 for comparison). BOX 1–1 Legal Definition of a Dietary Supplement as Defined by the Dietary Supplement Health and Education Act of 1994 The term dietary supplement: means a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin; a mineral; an 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 a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E). Dietary supplements are further defined as products that are labeled as dietary supplements and are not represented for use as a conventional food or as a sole item of a meal or the diet. Supplements can be marketed for ingestion in a variety of dosage forms including capsule, powder, softgel, gelcap, tablet, liquid, or, indeed, any other form so long as they are not represented as conventional foods or as sole items of a meal or of the diet (FDCA, as amended, § 402).

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements TABLE 1–1 Current Status of Foods, Drugs, and Dietary Supplements under Food and Drug Administration (FDA) Regulation Status Dietary Supplements Foodsa Food Additives New Drugsb Premarket approval required Noc Nod Yes Yes Risk-benefit analysis conducted by FDA prior to marketing No No No Yes Postmarket reporting or surveillance by industry required No No Rarely Yes Burden of proof for demonstrating safety or lack thereof FDA FDA Manufacturer Manufacturer a Foods (including conventional foods and dietary supplements), unlike drugs, are considered to be safe (reasonable certainty of no harm), and thus risk-benefit analysis is not applicable. b This description applies to “new” drugs. Many over-the-counter drugs are regulated under FDA’s Over-The-Counter Drug Review procedures, which do not provide for postmarketing surveillance. c A 75-day premarket notification, but not premarket approval, is required for dietary supplements containing ingredients not marketed before 1994. d In 2001 FDA proposed a rule requiring marketers of food developed through biotechnology to notify the agency at least 120 days before commercial distribution and to provide information to demonstrate that the product is as safe as its conventional counterpart (FDA, 2001). DSHEA specifically exempts dietary ingredients in dietary supplement products from being regulated under the category of food additives. Because FDA does not have the authority to consider the dietary ingredients as food additives, there is no procedure for a manufacturer to obtain premarket approval or establish GRAS status. Thus, DSHEA eliminates one of the key approaches FDA had taken to restrict the availability of some dietary supplements, especially multi-ingredient products. DSHEA also establishes safety standards for dietary supplements. It states that a dietary supplement will be considered adulterated (i.e., illegal) if it “presents a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling” (DSHEA, P.L. 103–417, § 4, 1994, as codified in FDCA 21 U.S.C. § 342, 2001). Most importantly, it is clear from the law that FDA bears the burden of proof if it decides to assert that a supplement is adulterated. In summary, while a manufacturer is charged with ensuring the safety of its products, the manufacturer is not required to reveal the basis of its safety determination unless the Secretary of the Department of Health and Human Services declares that the product poses an imminent hazard or FDA brings an action in court alleging the product is adulterated (Box 1-2). DSHEA and New Dietary Ingredients Marketed After 1994. DSHEA provided additional requirements for supplements containing “new dietary ingredients” that were not marketed in the United States before October 15, 1994. Such products are deemed adulterated under DSHEA unless the new ingredient has been present in the conventional food supply in a form in which the food has not been chemically altered, or there is a “history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling…will reasonably be expected to be safe” (DSHEA, P.L. 103–417, § 8,

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements BOX 1–2 Safety Standards for Dietary Supplements As Established by DSHEA Section 4. Safety of Dietary Supplements and Burden of Proof on FDA. DSHEA amends § 402 (21 U.S.C. 342) by adding the following: (f) (1) If it is a dietary supplement or contains a dietary ingredient that— presents a significant or unreasonable risk of illness or injury under— conditions of use recommended or suggested in labeling, or if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use; 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; the Secretary declares to pose an imminent hazard to public health or safety, except that the authority to make such declaration shall not be delegated and the Secretary shall promptly after such a declaration initiate a proceeding in accordance with sections 554 and 556 of title 5, United States Code to affirm or withdraw the declaration; or is or contains a dietary ingredient that renders it adulterated under paragraph [402](a)(1) under the conditions of use recommended or suggested in the labeling of such dietary supplement. In any proceeding under this paragraph, the United States shall bear the burden of proof on each element to show that a dietary supplement is adulterated. The court shall decide any issue under this paragraph on a de novo basis. (2) Before the Secretary may report to a United States attorney a violation of the paragraph (1)A for a civil proceeding, the person against whom such proceeding would be initiated shall be given appropriate notice and the opportunity to present views, orally and in writing, at least 10 days before such notice, with regard to such proceeding. SOURCE: FDCA, P.L. 75–717 § 402, as amended 21 U.S.C. § 342(f), 2001. 1994). In addition, the law requires that to avoid adulteration in the latter instance, the manufacturer or distributor must provide FDA with the information that is the “…basis on which [it] has concluded that the dietary supplement containing [the new] ingredient will reasonably be expected to be safe” (DSHEA, P.L. 103–417, § 8, 1994) at least 75 days prior to marketing the ingredient. If FDA does not reply to the notification within 75 days, the company is free to market the ingredient. FDA may examine the submission and conclude that it does not provide sufficient evidence to demonstrate that the ingredient is safe. If a manufacturer or distributor that receives such a response nonetheless chooses to market the product, FDA will consider the product adulterated and the government may take legal action against it. In any such proceeding, the government bears the burden of proof.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements The manufacturer or distributor is responsible initially for determining whether or not an ingredient is new and thus whether to submit information to FDA before marketing a product containing that ingredient (FDCA, P.L. 75–717 (1938), as amended 21 U.S.C. § 413 [350b]a, 2001). If FDA disagrees with a company’s decision to market a product without submitting a 75-day notification, the government bears the burden of proof to show that the substance is a new dietary ingredient requiring such a submission and that the product is therefore adulterated. It is important to note that the 75-day notification period is required for new dietary ingredients, but not new products. A product that is a new combination of ingredients marketed prior to October 1994 does not require submission of a 75-day notification (FDCA, P.L. 75–717 (1938), as amended 21 U.S.C. § 413 [350b]a, 2001). Although less relevant to this report, DSHEA also provided for a government commission to consider the marketing and labeling of dietary supplements. The findings of this commission are described in the Report of the Commission on Dietary Supplement Labels (Commission on Dietary Supplement Labels, 1997), which addressed health claims, nutritional support statements, substantiation files for claims and safety, and publications used in conjunction with sales. Food and Drug Administration Actions Dietary supplement manufacturers are generally not required to share their basis for safety determinations with FDA before marketing. Therefore, FDA determines safety from publicly available information it collects and from data that it generates in its own laboratories. FDA may not be able to gather enough data to be confident about the safety of a particular product, but unless it can be proven in court that a substance does not meet the standard of safety—representing a reasonable certainty of no harm—FDA cannot remove it from the marketplace. FDA has responded to concerns by warning consumers, health providers, or industry of the specific concerns. On occasion, FDA actions have led to voluntary product recall by manufacturers (East Earth Herb, 2000; FDA, 2000; Vital Nutrients, 2001). Examples of warnings about specific dietary supplement ingredients issued in response to a variety of potential health problems identified by FDA as possible concerns are listed in Appendix D. Good Manufacturing Practices As is apparent from the example of contaminated plantain noted in Appendix D, FDA must consider more than the “inherent” safety of specific dietary supplement ingredients to adequately evaluate the potential for public health concerns. Because supplement products vary in their quality and composition, the inherent safety of the ingredients on the label is not the only important variable that is likely to impact the safety of specific products. Dietary supplement products tainted by improper raw materials, heavy metals, pesticides, and microorganisms, for example, can be unsafe due to these contaminants. DSHEA provides that FDA may define current Good Manufacturing Practices (GMPs) for dietary supplement production. GMPs are to address the aspects of product manufacturing that impact safety of the final product. They would not, however, take into consideration whether the dietary supplement ingredients themselves are safe—that is the goal of the framework proposed in this report. FDA has not yet published proposed or final GMPs for the dietary supplement industry, although such rules are in development. In this report, the committee is charged to consider aspects of the inherent safety of dietary supplement ingredients in developing a proposed

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