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Institute of Medicine (US) and National Research Council (US) Committee on the Framework for Evaluating the Safety of Dietary Supplements. Dietary Supplements: A Framework for Evaluating Safety. Washington (DC): National Academies Press (US); 2005.

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Dietary Supplements: A Framework for Evaluating Safety.

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1Introduction 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 marketed about 4,000 products (CDSL, 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 introduced 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). In 2002, sales of dietary supplements increased to an estimated $18.7 billion per year, with herbs/botanical supplements accounting for an estimated $4.3 billion in sales (NBJ's Annual, 2003). 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).

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, and enzymes, as well as concentrates, metabolites, constituents, or extracts of these.1 Within each of these categories, products may be pure single entities of known or unknown chemical constituents, mixtures in which all or some components are known, or mixtures of unknown chemical components.

Within its definition of dietary supplements (Box 1-1), DSHEA included ingredients that have not traditionally been recognized as nutrients or as having nutritional functions, such as botanicals and hormones (Nesheim, 1999). It clarified that these substances could be considered supplement ingredients, not drug ingredients, when labeled appropriately. As with conventional foods, dietary supplements are to be presumed safe—that is, it is assumed that they do not present a significant2 or unreasonable risk of injury or illness when consumed as recommended.

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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 (more...)

However, questions have been raised about the safety of some dietary supplements. When these questions are raised, FDA needs a methodology to rapidly review and further evaluate the safety of ingredients about which it has concerns. 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 DSHEA legislation.

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 and the National Research Council 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 a committee develop a proposed framework for categorizing and prioritizing dietary supplement ingredients based on safety issues, describe a process for developing a system of scientific reviews with specifications for evaluating the safety of dietary supplement ingredients, and develop at least six scientific reviews as prototypes for the system. The proposed framework was 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, 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 on the initial framework released for comment, the framework was to be revised (see Appendix B for the detailed scope of work and the comments received).

The committee held a total of seven meetings while preparing the initial framework, reviewing comments on it, and revising the framework. Six 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 supplement ingredients. In addition, representatives of a number of agencies and organizations that currently evaluate chemical substances for safety or efficacy were invited to discuss their methodologies and frameworks for conducting their reviews. (See Appendix L for a list of those who contributed comments or made presentations to the committee at the open sessions.)

GENERAL BACKGROUND INFORMATION ABOUT DIETARY SUPPLEMENTS

National surveys, such as the Third National Health and Nutrition Examination Survey (1988–1994) 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). However, 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). Several studies have also explored the prevalence of nutrient supplement (thought to be primarily vitamin and mineral formulations) use 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 users' motivation for taking 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).

Results from a more 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, chondroitin sulfate, kava kava, shark cartilage, and Sadenosylmethionine) (Prevention Magazine, 2001; Radimer et al., 2000; Ramos, 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]). Nonetheless, consumers have reported using supplements for purposes such as to treat and prevent illnesses, colds, and flu and to alleviate depression (Prevention Magazine, 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 (Radimer et al., 2000), 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 (Kraak et al., 2002; Pelletier and Kendall, 1997).

Consumer Expectations About Dietary Supplement Safety

Surveys have suggested that many Americans may assume dietary supplements are subject to existing government regulations similar to those required for over-the-counter (OTC) drugs sold without a prescription (Blendon et al., 2001). When consumers purchase OTC drugs, such drugs have typically undergone an FDA review that has deemed them to be safe and effective as labeled. Most OTC drugs have been through FDA's OTC Drug Review, in which the agency assesses the safety and effectiveness of the active ingredients of OTC drugs and then issues detailed monographs restricting the labeling and formulation of products containing these ingredients. Other OTC drugs have been specifically approved by FDA under its rigorous new drug application (NDA) process and then have been reviewed by the agency again before being changed from prescription to OTC status.

Only a few national surveys exploring the views and perceptions of Americans regarding the safety of 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). The Sloan Survey explored general patterns of medication use in the ambulatory adult population from 1998 to 1999 and examined use of vitamins, minerals, botanicals, and other dietary supplements, in addition to drugs. Conducted among 2,590 U.S. consumers, it reported that 16 percent of prescription drug users also took one or more “herbal or other natural supplements” (Kaufman et al., 2002). A more recent 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 was based on two separate data sources that compared the views of dietary supplement users with those who were nonusers (Blendon et al., 2001). In the first survey reviewed, which was designed collaboratively by researchers at National Public Radio, the Kaiser Family Foundation, and the John F. Kennedy School of Government and conducted by the Princeton Survey Research Associates in 1999, 1,200 randomly selected adults participated in telephone interviews. A second survey was conducted with 1,013 randomly selected adults. Results from the analysis of these two surveys revealed that regular users of dietary supplements reported not discussing use of dietary supplements with their physicians because they believed that the physicians knew little or nothing about these products and might be biased against them (Blendon et al., 2001). In addition, many users felt so strongly 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 (Blendon et al., 2001).

Because dietary supplements are regulated as foods, they are subject to different regulatory requirements in comparison with OTC medications or other drugs. 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 dietary supplement ingredient presents a “significant or unreasonable risk of illness or injury” (see Box 1-2), rather than requiring a manufacturer3 to provide data supporting its safety, as is done with food additives4 (21 C.F.R. § 170) and new drugs (21 C.F.R. § 314). Manufacturers of dietary supplements that contain new dietary ingredients (those ingredients not in use prior to the passage of DSHEA) must notify FDA at least 75 days before introducing the dietary supplement into interstate commerce and provide FDA with information that is the basis upon which the manufacturer has concluded that the dietary supplement will reasonably be expected to be safe (DSHEA, P.L. 103-417, § 8 [1994]). This submission is not a premarket approval process, as further described below.

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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:

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; thus the regulatory history of dietary supplements is received here. Many herbals and other botanicals have been used much longer than other types of dietary supplements, as ancient cultures employed 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 trained medical personnel and the inability of conventional medicines to adequately treat many diseases drove consumers to look elsewhere for help. Patent medicines were often secret formulations and were directly marketed to consumers (CDER, 2002).

In the early years of development, the growing pharmaceutical industry marketed its medicines directly to health professionals. There were few regulations for these or patent medicines 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 Federal Food and Drugs Act (also known as the Pure Food and Drug Act) of 1906 (21 U.S.C. 1 et seq.), and its companion bill, the Federal Meat Inspection Act of 1906 (21 U.S.C. 601 et seq.), 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 concerns about the safety of food and patent medicines, as well as about widespread fraud in the growing food and drug industry (Barkan, 1985; FDA, 2002). The triggering event was the exposure of unsafe conditions in the meat packing industry (Sinclair, 1906). The passage 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 foods and drugs, and thus imposed new regulations on these industries (Barkan, 1985; FDA, 2002). Specifically, the laws introduced accountability by requiring that regulated products be labeled accurately and that they be safe. With the passage of the Food and Drugs Act in 1906, FDA5 was placed in a “policing” role (rules of conduct specified; agency has authority to punish violators). Also, FDA bore the burden of establishing that a food or drug was adulterated or misbranded 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 Congress passing the Federal Food, Drug, and Cosmetic Act in 1938 (FDCA, P.L. 75-717, 52 Stat. 1040 [1938]). 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 standards6 and a refocus of FDA from that of a policing agency that had been concerned primarily with challenging adulterated drugs to that of a regulatory agency involved with oversight for evaluating new drugs (but not foods) (Wax, 1995).

The FDCA transferred the responsibility of proving the safety of new drugs to the drug manufacturer and required manufacturers to submit NDAs to FDA that establish safety before marketing.7 While FDA no longer had the burden of establishing that an unapproved new drug was unsafe before taking action against it, FDA continued to bear the burden of establishing that a conventional food product was adulterated, as the agency does to this day8 (CDSL, 1997).

The FDCA contained provisions that applied to foods, drugs, and cosmetics. The applicability of these provisions to products containing a vitamin, mineral, or botanical ingredient (e.g., whether the product was considered a drug or a food) depended on the product's intended use, as determined usually by the labeling and advertising claims for the product.

The 1938 act, as originally enacted, contains a number of definitions that continue to 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 original 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) [1938], as amended 21 U.S.C. § 343(j) [2001]).

Congress intended in 1938 that 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 that made therapeutic claims for vitamins and minerals (FDA, 1941).

FDA did not, however, rigorously apply the FDCA's third definition of drugs, the definition that categorizes as drugs all products listed in the USP, the offical Homeopathic Pharmacopoeia of the United States, or the National Formulary. This definition 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 as 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 premise after several court cases in the 1960s (Pendergast 1997), 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 FDA [enforcement]” (Pendergast, 1997). Debate about what constituted “labeling” ensued as FDA attempted to broaden labeling to include books and other materials. Some characterized this approach as restricting the First Amendment right to free speech, resulting in a number of court cases between the 1940s and 1960s.9 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).

Food Additives Amendment of 1958

FDA's attempt at applying the Food Additives Amendment of 1958 (P.L. 85-929, 72 Stat. 1784 [1958]) to botanical products has also been described as a factor leading to the passage of DSHEA (Pendergast, 1997). A food additive is defined by statute 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 … if such substance is not generally recognized … to be safe under the conditions of its intended use” (FDCA, 21 U.S.C. § 321(s) [2001]). Unless the substance at issue could be considered as “generally recognized as safe” (GRAS) by the manufacturer for its intended use or had been sanctioned or approved by FDA or the U.S. Department of Agriculture prior to 1958, manufacturers were required to obtain premarket approval from FDA for the substance. In general, the result of the Food Additives Amendment was to shift the burden of proof of safety for new substances added to food away from FDA and to the manufacturers (FDA, 2002).

While the Food Additives Amendment provides a petition process by which FDA can approve a food additive that has not been determined to be GRAS, manufacturers also have the option of determining for themselves that a substance is GRAS. The GRAS determination of a substance by a manufacturer must be based on “generally available and accepted scientific data, information, methods, or principles, which ordinarily are published …” and there must be a “consensus among qualified experts about the safety of the substance for its intended use” (FDA, 1997). If these conditions are met, manufacturers can “self-affirm” the GRAS status of a substance. Alternatively, they may either petition FDA to affirm their determination (21 C.F.R. § 170.35) or voluntarily notify FDA that the manufacturer has determined the substance to be GRAS, pursuant to the interim policy delineated in the proposed rule regarding the notification procedure (FDA, 1997).

In notifying FDA that it has determined a substance to be GRAS for its intended use, the manufacturer voluntarily provides FDA with a summary of the basis upon which it has made the determination. FDA can respond with a letter of no objection to its determination of GRAS or can identify a problem with the notice. The manufacturer can also determine the food substance to be GRAS and market a product containing it without prior notification of FDA. If it does so, and then FDA determines that it is not GRAS, FDA can take action by declaring the product adulterated, seizing the product, and removing it from commerce.

Shortly after the Food Additives Amendment was passed, FDA clarified the regulatory status of many food substances that were in use prior to 1958, listing them as GRAS when used for the purposes indicated and in accordance with good manufacturing practice (GMP). Moreover, over the years, FDA has affirmed GRAS status for other substances upon petition from manufacturers and others. Substances not so listed or affirmed, or those that are to be used for purposes other than those indicated on the GRAS listing, are required to either be evaluated via the food additive petition process or to be subjected to the GRAS self-determination mechanisms described above.

Some have pointed to parallels between the processes for regulating GRAS substances and food additives and the system of regulating older (before October 15, 1994) versus newer dietary ingredients as delineated by DSHEA. The presumption that for both substances added to foods prior to 1958 and dietary ingredients in use prior to October 15, 1994 are to be considered safe based on prior common use is similar. However, there is a major difference in the evaluation of new ingredients to be used in food versus new dietary ingredients to be used in dietary supplements (Table 1-1). The underlying principle of law is different. The starting assumption is one of safety for dietary supplements because FDA bears the burden of determining that a “significant and unreasonable risk of harm” exists in order to prevent a new dietary ingredient from being marketed in a dietary supplement (DSHEA, P.L. 75-717; see Box 1-2). By contrast, the starting assumption is one of a lack of safety for new food ingredients because, before FDA approves a food additive or affirms or determines that it is GRAS, the manufacturer must demonstrate to FDA a reasonable certainty of no harm for the substance when added to food (21 C.F.R. § 170.3 (i); FDA, 1997). The difference in the underlying assumption has a major impact in determining what is allowed to be sold in interstate commerce, as is illustrated with the botanical stevia (see Box 1-3).

TABLE 1-1. Current Status of Foods, Food Additives, Drugs, and Dietary Supplements Under the FDA Regulations.

TABLE 1-1

Current Status of Foods, Food Additives, Drugs, and Dietary Supplements Under the FDA Regulations.

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BOX 1-3

Regulation of Stevia Under the Dietary Supplement and Health Education Act (DSHEA) Versus as a Food Additive. The status of the botanical stevia illustrates how the different starting assumptions for dietary supplements and for food additives, based on (more...)

Prior to the passage of DSHEA, FDA instituted action in the early 1990s against many popular dietary supplement ingredients, applying food additive regulations and contending that they were unapproved food additives. FDA interpreted the definition of “food additive” as applying to single ingredient supplements in capsule form. For example, FDA argued, unsuccessfully, that black currant seed oil in a capsule was a food additive (United States v Two Plastic Drums … Black Currant Oil, 984 F2d 814 [7th Cir 1993]). The courts eventually struck down FDA's efforts to broadly interpret the food additive definition (United States v Two Plastic Drums … Black Currant Oil, 984 F2d 814, 819 [7th Cir 1993]; United States v An Article of Food, 792 F Supp. 139 [D Mass 1992]).

1976 “Proxmire Amendments”

Prior to the overturn by the court in 1993 of FDA's attempts to apply the food additive provisions to dietary supplements, the regulation of botanical, vitamin, and mineral supplements had been inconsistent and was based on a combination of enforcement and judicial decisions. Court actions required long periods of time and considerable resources; thus in the 1970s FDA attempted to have a broader impact on dietary supplement use by implementing tighter regulations of vitamin and mineral supplements, consistent with the U.S. Supreme Court's endorsement in 1973 of FDA action to control entire product classes with regulations rather than relying only on litigation (FDA, 2002).

In 1973 FDA issued regulations that prohibited certain representations on vitamin and mineral supplement labels, established standards of identity for vitamin and mineral supplements, and established that preparations containing more than 150 percent of the U.S. Recommended Daily Allowance (U.S. RDA) per serving were drugs (FDA, 1973). Both industry and consumers protested the attempts by FDA to set maximum levels (Hutt and Merrill, 1991; Khatcheressian, 1999; Pendergast, 1997), eventually leading Congress to enact the Health Research and Health Services Amendments in 1976. Also known as the “Proxmire Amendments,” these amendments prohibited FDA from “… establishing standards limiting potency of vitamins and minerals in food supplements or regulating them as drugs based solely on potency” (FDA, 2002). FDA revised its vitamin–mineral regulations in response to this legislation and, after a subsequent successful court challenge (National Foods Associations v Matthews, 557 F2d 325 [2d Cir 1977]), ultimately revoked its 1973 regulations about maximum potency and drug status in 1979 (FDA, 1979).

The Nutrition Labeling and Education Act of 1990 and Health Claims

With the suppression of FDA'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 some 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 some L-tryptophan supplements were associated with eosinophilia-myalgia syndrome.10

Both the L-tryptophan incidents and FDA's concerns about unsubstantiated claims appearing on the label led to new attempts by FDA to regulate the industry in the 1980s. By this time, mounting scientific evidence had led several food companies to start promoting their conventional foods based on the potential of some of their ingredients or substances to reduce the risk of specific diseases. While not endorsed by FDA, some have purported that when similar claims were made in reference to dietary supplements, FDA responded more harshly, contending that by virtue of claims made regarding the supplement they were unapproved drugs (Pendergast, 1997). This unequal approach toward regulating supplements versus foods became more evident when in 1987 FDA proposed 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 Congress passed in 1990 (P.L. 101-535), explicitly authorized “health claims,”11 but did not silence the controversies surrounding the different treatment of supplements and foods (Pendergast, 1997). 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 (NLEA, P.L. 101-535, § 3(b) 104 Stat 2353, 2361 [1990]). Concerns that FDA would treat supplements too harshly may have contributed to the subsequent passage of DSHEA (Pendergast, 1997). Food industry advocacy efforts first resulted in a 1-year moratorium on NLEA provisions being applied to supplements (Prescription Drug User Fee Act, P.L. 102-571, 106 Stat. 4491 [1990]); such advocacy efforts continued until DSHEA was passed (Khatcheressian, 1999).

The Dietary Supplement and Health Education Act of 1994

In 1993, following the passage of the NLEA, FDA issued an advance notice of proposed rulemaking regarding dietary supplements, which was accompanied by the suggestion that some products marketed as dietary supplements might be more appropriately considered under other regulatory categories (FDA, 1993). 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. RDA (FDA, 1993).

The dietary supplement industry and consumers reacted strongly to these potential regulatory restrictions (Khatcheressian, 1999). 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. Subsequently, Congress passed DSHEA, signed into law October 15, 1994, which limited and proscribed the regulation of dietary supplements by FDA (DSHEA, P.L. 103-417, § 2 [1994]).

DSHEA can be characterized as 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 (see Box 1-1), resulting in botanicals and amino acids being considered as foods based on intended use, as were vitamins and minerals, which were already classified as food based on intended use. Importantly, DSHEA established a new regulatory framework for dietary supplements that limited FDA's authority over these products to that of conventional foods, as compared with its authority over food additives or new drugs (see Table 1-1 for comparison and Box 1-3 for discussion of an example).

DSHEA specifically exempted dietary ingredients in dietary supplement products from being regulated under the category of food additives (DSHEA, P.L. 103-417 [1994]). Because FDA does not have the authority to consider dietary supplement ingredients as food additives unless they are added to a conventional food and marketed as a food, there is no requirement for a manufacturer to obtain premarket approval (Khatcheressian, 1999) or establish GRAS status (McNamara, 1995; Pendergast, 1997). Thus DSHEA eliminated one of the key approaches FDA had taken to restrict the availability of some dietary supplements (e.g., black currant oil and especially multi-ingredient products).

DSHEA and Dietary Supplement Safety. DSHEA also established 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, FDA now bears the burden of proof if it decides to assert that a supplement is adulterated (Khatcheressian, 1999; McNamara, 1995). 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 (see 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. Products containing them 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 unless 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 [1994]). In addition, the law required that to avoid adulteration in the latter instance, the manufacturer 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” at least 75 days prior to marketing the ingredient (DSHEA, P.L. 103-417, § 8 [1994]). FDA may examine the submission and indicate to the manufacturer that the submission does not provide sufficient evidence to demonstrate that the ingredient is safe. However, FDA approval is not required before sale (Young and Bass, 1995). If a manufacturer receives such an FDA response and nonetheless chooses to market the product, FDA may decide to take legal action against the product. However, as with the case of pre-1994 ingredients, in any such proceeding the government bears the burden of proof (21 U.S.C. § 342 (f)(1); Young and Bass, 1995).

The manufacturer is responsible initially for determining whether or not an ingredient is new (i.e.,“… present in the food supply as an article used for food in a form in which the food has not been chemically altered …” [DSHEA, P.L. 103-417, § 8, 108 Stat. 4331-4332 {1994}]; Young and Bass, 1995). If the ingredient is “new,” the manufacturer must notify FDA 75 days in advance of introducing it or a dietary supplement containing it into commerce (DSHEA, P.L. 103–417, § 8, 108 Stat. 4331 (1994)]. If FDA disagrees with a manufacturer's determination of new when a manufacturer sells an ingredient without giving the 75-day notification to the agency, 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 containing it is therefore adulterated.

It is important to note that the 75-day notification period applies to 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.

DSHEA and Marketing and Labeling

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 (CDSL, 1997), which addressed health claims, nutritional support statements, substantiation files for claims and safety, and publications used in conjunction with sales.

FDA Actions Following DSHEA

Since a dietary supplement manufacturer is generally not required to share its basis for safety determinations with FDA before marketing, FDA determines possible safety issues from publicly available information it collects and from data that it generates in its own laboratories. In some cases, FDA may not be able to gather enough data to be confident about the safety of a particular product; without demonstrating that a substance does not meet the standard of safety—representing a reasonable certainty of no harm—FDA has no authority to remove it from the marketplace. FDA has acted when aware of possible harmful effects with various levels of response: it may warn consumers as it did in 2001 with comfrey and lipokinetix; it may warn health care practitioners that a supplement may be a serious health risk and ask them to review and report cases of adverse effects as it did with lipokinetix and with kava in 2001; or it may request a voluntary recall by manufacturers and distributors as it did with aristolochic acid in 2001. In the case of ephedrine alkaloids in 2003, for the first time FDA issued a warning letter to the manufacturer or distributor of a dietary supplement ingredient indicating that it intended to take action to remove a product; this was incorporated into a final rule in 2004 (21 C.F.R. § 119). Recently, manufacturers of androstenedione were notified by FDA that their products were considered adulterated as the agency had determined that their ingredients were new dietary ingredients about which FDA had not been notified 75 days in advance of sale, and that failure to cease distribution of the product could result in enforcement action (CFSAN, 2004).

Consumer and health care advisory letters from FDA cautioning use have occasionally led to voluntary product recalls by manufacturers (East Earth Herb, 2000; FDA, 2000; Vital Nutrients, 2001). In addition, warnings about specific dietary supplement ingredients issued in response to a variety of potential health problems identified by FDA as possible concerns have been posted on FDA MedWatch website (FDA, 2004).

Good Manufacturing Practices

As dietary supplements, like foods, can be contaminated with foreign toxic substances, FDA must consider more than the “inherent” safety of specific dietary supplement ingredients to adequately evaluate the potential for public health concerns. Supplement products vary in their quality and composition, which impacts the safety of specific products. Dietary supplement products tainted by improper raw materials, heavy metals, pesticides, or microorganisms, for example, can be unsafe due to these contaminants. DSHEA provides that FDA may define current GMPs for dietary supplement production. Proposed GMPs for the dietary supplement industry were published in early 2003 (FDA, 2003). While GMPs are designed to enhance safety, they are focused on purity and consistency rather than whether a dietary supplement ingredient itself is safe. As requested by FDA, this report focuses on evaluating the inherent safety of a dietary supplement ingredient in the absence of such contamination.

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Footnotes

1

While these are not dietary supplement categories specified by DSHEA, they illustrate the diversity of products currently marketed as dietary supplements.

2

The origin of the use of the standard “significant or unreasonable risk” relative to dietary supplements is the DSHEA legislation; thus “significant” is used qualitatively and does not imply a statistical determination.

3

The term “manufacturer” is used for simplicity, but the statutes refer to both manufacturers and distributors, which may not be the same for a dietary supplement ingredient or product.

4

Food ingredients not declared or listed as generally recognized as safe (GRAS).

5

For clarity, FDA and its predecessors are referred to in this text simply as “FDA.” The actual name Food and Drug Administration was established in 1930. Predecessors were the Bureau of Chemistry, which began in 1862, and the Food, Drug, and Insecticide Administration, which was created in 1927 when regulatory functions of the Bureau of Chemistry were separated from nonregulatory research (FDA, 2002).

6

Food standards were required to promote honesty and fair dealing in the interest of consumers (FDA, 1981). The standards consist of definitions of what constitutes a food (e.g., mayonnaise must contain a certain percentage of egg and oil, etc.).

7

In 1962, the FDCA was amended to require NDAs to establish the efficacy, as well as the safety, of new drugs.

8

However, food colors and food additives must be approved by FDA via the food additive petition process; other substances added to food that are not approved via this process must be declared or affirmed to be GRAS based on intended use before they may be sold in a food product. Dietary ingredients marketed in dietary supplements are exempt from this requirement.

9

See United States v Detroit Vital Foods, 218 F Supp 208 (ED Mich 1963); United States v Articles of Drug … Honey, 344 F2d 288 (6th Cir 1965); United States v Kordel, 164 F2d 913 (7th Cir 1947), aff'd, 335 U.S. 345 (1948); and United States v “Sterling Vinegar and Honey” … Balanced Foods, 338 F2d 157 (2d Cir 1964).

10

Evidence suggesting that the problem might have been associated with the manufacturing process eventually surfaced, but the issue has not been definitely resolved (FDA, 2001a).

11

A health claim is defined as a claim that “characterizes the relationship” between a substance in a food and damage, disease, or dysfunction of the human body (NLEA, P.L. 101-535). In effect, the NLEA allowed claims that previously would have been regarded as illegal drug claims if made for a food.

Copyright 2005 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK216048

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