When purchased, over-the-counter (OTC) drugs will most certainly have undergone a Food and Drug Administration (FDA) review that assures the consumer that the drug is safe and effective as labeled. Many Americans assume that dietary supplements have been subjected to the same government regulations as the OTC medications. A recent study of how consumers perceive health claims and nutrient content claims in food labeling stated that 90% of consumers interpreted a nutrient content claim as a claim about the food's health benefits (Levy et al., 1997). The safety and effectiveness of OTC drugs are assessed through the FDA's OTC drug review, and a detailed monograph has been prepared to describe the labeling and formulation of products containing the biologically active ingredient. Prescription drugs are approved through the rigorous new drug application process.

In stark contrast, dietary supplements are regulated as foods and are subject to different requirements that place the determination of their safety on the FDA. Essentially, the FDA must determine that a dietary supplement ingredient poses a “significant or unreasonable risk of illness of injury” instead of requiring the manufacturer to provide safety data, as is done with new drugs, pesticides, and food additives. The process available to the FDA is spelled out in the Dietary Supplement Health and Education Act of 1994 (DSHEA). Moreover, DSHEA provides a legal definition of a dietary supplement as 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) an 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)”.

Products may be pure single entities of known or unknown chemical constituents, mixtures of which all or some of the components are known, or mixtures of unknown chemical components. Note that ingredients not traditionally recognized as having nutritional characteristics such as botanicals and hormones are included.

Dietary supplements are also 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 such as capsule, powder, softgel, gelcap, tablet, liquid, tinctures, teas, or any other form not represented as conventional food or as sole items of a meal or of the diet.

According to the FDA, there are more than 29,000 different dietary supplements available to consumers today. The momentum for this market has its roots in consumer interest in health and self-care and suggests that Americans are searching for alternatives to conventional foods for nutritional reasons or to improve health and well being. Nevertheless, research supports that the optimal health and nutritional strategies for reducing chronic disease are to rely on the nutrients from a variety of traditional foods (Hunt, 1996; Hunt and Dwyer, 2001). Whether or not this is true of “botanical supplements” is uncertain. Currently, the question is the subject of considerable research, largely conducted at the National Institutes of Health National Center of Complementary and Alternative Medicine and the Office of Dietary Supplements.

Herbals/botanicals (a plant or plant part or an extract or mixture of these used to prevent, alleviate, or cure disease; called also herbal, herbal medicine) have been used since ancient times to supplement diets usually with the intent to prevent or eliminate specific symptoms. Thus, a wealth of historical and anecdotal information has been accumulated over the years, and this information has been used to provide guidance on the effectiveness and safety of the products involved. Given the fact that herbal and botanical products may vary considerably in the content of their “active ingredient” due to growing conditions at any given time or place, it is no surprise that this historical information is not a reliable guide to the safety and effectiveness of a given plant. Moreover, there is the common problem of plant misidentification leading to ingestion of a material that may have considerably different properties than intended.

In the United States, patent medicines became popular in the 1800s and were commonly sold directly to consumers and often had “secret formulations”. Federal regulation of these products was nonexistent, and consumers had no means to distinguish between false and valid claims. During this same period, the pharmaceutical industry was developing, and it typically marketed its products directly to health professionals. As with the patent medicines, there were no regulations in place to assure health professionals or consumers of a given product's effectiveness and safety.

By the early 1900s, the federal government enacted legislation to assure the characterization of effectiveness and safety of food and drugs largely driven by growing fraud within the respective industries (Barkan, 1985). A listing of important federal legislation in the United States over the years is given in Table 1.

In the 1940s, the FDA attempted to use litigation to regulate the botanical and vitamin industry by treating them as unapproved drugs not only if they made claims concerning the treatment or prevention of disease, but also if they made claims of the products' effects on the structure and function of the body. Moreover, the FDA did not use the Food, Drug, and Cosmetic Act's third definition of a drug, namely that which categorizes as drugs all products listed in the USP, National Formulary, or the Homeopathic Pharmacopoeia of the United States. Using this definition, most vitamins and minerals and many botanical preparations would have been legally considered as drugs. In the end, a significant factor that led to the enactment of DSHEA was an attempt to resolve a debate about First Amendment rights and labeling restrictions. At the time, supplement manufacturers sought to avoid FDA enforcement of labeling claims by publishing self-help books and other articles to explain claims and intended uses. The FDA broadened its description of labeling to include books and articles, which was seen by some as denial of First Amendment rights to free speech.

DSHEA established safety standards for dietary supplements that say that a dietary supplement will be considered adulterated if it “presents a significant or unreasonable risk of illness or injury under condition of use recommended or suggested in labeling”. Thus, although the manufacturer is required to make certain that its product is safe, the manufacturer is not required to disclose the basis of its safety assessment unless the FDA alleges in court that the product is adulterated. New dietary ingredients marketed after 1994 are considered adulterated unless the new ingredient has been in the food supply in a form whereby the food has not been chemically altered or there is a history of safe use under conditions specified on the label. The determination of whether an ingredient is new is the responsibility of the manufacturer; if new, the manufacturer must notify the FDA 75 days in advance of entering the product into the marketplace. Interestingly, FDA approval is not required before sale, and a new combination of ingredients marketed prior to 1994 does not need the 75-day notification.

Given that the manufacturer of a dietary supplement generally is not required to reveal the basis for safety before marketing, the FDA must use its resources to discover potential safety issues. Often there are insufficient data available to make a sound scientific decision concerning the safety of the product, and without data representing a reasonable certainty of no harm, the FDA does not have the authority to remove it from the marketplace. It should be noted, however, that legal rules governing complementary and alternative medicine are new and evolving (Cohen, 2003; Cohen et al., 2005). A partial list of resources for information on dietary supplement products and/or ingredients is given in alphabetical order in Table 2.

In recent years, the FDA has taken action against certain supplements when evidence of possible harmful effects is strong. The action taken may be as simple as warning consumers of potential adverse effects, as it did with comfrey (Symphytum officinale) and lipokinetix (lipokinetix is marketed for weight loss and contains the ingredients norephedrine, caffeine, yohimbine, diiodothyronine, and sodium usniate) in 2001, or the FDA may warn physicians and ask that the adverse effects be reported, as it did also in 2001 with lipokinetix and kava (Piper methysticum). At another level, the agency may ask for a voluntary recall by manufacturers and distributors, as occurred with aristolochic acid in 2001. The FDA warned manufacturers and distributors of its intention to remove ephedrine alkaloids in 2003 on the basis of finding unreasonable risk (Food and Drug Administration, U.S. Department of Health and Human Services, 2004). Finally, makers of androstenedione received FDA notice that the ingredients were new dietary ingredients and that the FDA had not received notice 75 days in advance of it being put into the marketplace and the failure to cease distribution could result in enforcement action.

In response to the dilemma posed to the FDA in outlining a process, or framework, for a science-based, cost-effective approach to evaluating the safety of a massive line of dietary supplement products, the FDA asked the Institute of Medicine and the National Research Council of The National Academies to provide such a framework. In response, the Committee on the Framework for Evaluating the Safety of Dietary Supplements was formed under the auspices of the Food and Nutrition Board of the Board on Life Sciences. A report entitled Dietary Supplements: A Framework for Evaluating Safety was the result (The National Academies Press, 2004; http://www.nap.edu).

The Committee's task was 4-fold:

(1) develop a proposed framework for categorizing and prioritizing dietary supplement ingredients sold in the United States based on safety issues, (2) describe a process for developing a system of scientific reviews, (3) utilize the proposed framework to develop at least six scientific review monographs as prototypes, and (4) revise the framework based on comments received.

The final framework characterizes the nature of the scientific evidence encountered and describes a process for organizing this evidence to assess where a dietary supplement ingredient lies on a spectrum of concern. “As the level of concern increases, so does the potential for a significant or unreasonable risk, the standard warranting regulation under the FDC Act, as amended by DSHEA”.

The final report details how the process works and defines how the FDA should apply science-based principles to establish risk. One important part of the process was stressed strongly, namely that “the FDA's attention should focus on signals which indicate that a serious health problem may result due to ingestion of a dietary supplement ingredient”. Four categories of specific information were identified for use in deciding whether any potential for serious harm may arise from ingestion of a dietary supplement. They are 1) human data, 2) animal studies, 3) in vitro experiments, and 4) information on related substances. Several factors were identified to guide the FDA in applying the framework. Two of these factors are expressed as follows: 1) “the appropriate scientific standard to be used to overturn this basic assumption of safety is to demonstrate significant or unreasonable risk, not prove that an ingredient is unsafe”; and 2) “approaches taken by diverse organizations and governmental bodies, both within and outside the United States, which evaluate the safety and at times efficacy of dietary supplement ingredients, vary in their relevance to the protection of the American public from risks associated with consumption of dietary supplement ingredients”.

Although not part of the framework, the following recommendations were made as a part of the report to the FDA:

(1) Prospective systematic monitoring and tracking mechanism for dietary supplement ingredients should be maintained and refined, (2) Adequate resources to protect the consumer under DSHEA must be provided, (3) Adverse Event Reporting: (a) DSHEA should be amended to require that a manufacturer and distributor report to the FDA, in a timely manner, any serious adverse event associated with use of its marketed product of which the manufacturer or distributor is aware; (b) The FDA should continue to work with the Poison Control Centers as a source of adverse event reports, and sufficient resources to support this activity should be provided; (c) The FDA should increase efforts to inform health care professionals and consumers that they should use the MedWatch adverse event reporting program to report adverse events associated with the use of dietary supplement ingredients; and (d) The FDA MedWatch toll-free telephone number should be provided on product labels to facilitate reporting of adverse events. (4) To initiate the 75-day premarketing review period, the distributor and manufacturer should be required to provide the FDA with all available data, both favorable and unfavorable, regarding the safety of the product. (5) When the formulation or processing of a dietary supplement ingredient is changed, it should be considered a new dietary ingredient and subject to regulatory oversight as such. (6) The FDA initiative to establish Good Manufacturing Practices (GMPs) for dietary supplement ingredients is supported and additional efforts to develop standards for content uniformity should be undertaken. Sufficient resources to support these efforts should be provided by Congress. (7) Adoption of the labeling changes recommended in Inspector General Report: Dietary Supplement Labels: Key Elements is urged. (8) Additional Research on the Potential to Cause Harm: (a) the continued development of effective working relationships and partnerships between FDA and the National Institutes of Health is encouraged; (b) The FDA should ensure that its own National Center for Toxicological Research and the overall Department of Health and Human Services National Toxicology Program are optimally utilized when research is needed to further evaluate concerns; (c) All federally supported research on dietary supplements conducted to assess efficacy should be required to include the collection and reporting of all data on the safety of the ingredient under study.

Dietary supplements contain ingredients that are biologically active, just as are conventional pharmaceuticals. Survey data confirm that consumers use dietary supplements for medicinal purposes, even in the face of knowledge that these supplements have not undergone rigorous efficacy or safety testing. It is becoming abundantly clear that the dietary supplements are not a group of innocuous substances that complete a nutritious diet. Alone they may be toxic to some or all individuals and importantly are known to interact with other supplements or OTC and prescription drugs (Hardy, 2001; Jang et al., 2004; Herr, 2005).

A coalition of dietary supplement industry stakeholders commissioned a survey from June 28 through July 1, 2001 to understand the attitudes of Americans toward vitamins, minerals, herbs, and specialty supplements (http://www.supplementinfo.org/latest_news/survey_results.htm). They found that 60% of the 1027 Americans aged 18 and older regularly used a dietary supplement. Almost half take a daily multiple vitamin/mineral product, whereas a third take single vitamins. Approximately a quarter of those surveyed regularly use herbs and specialty supplements. The main reasons given by 72% of the respondents for the use of these products was to “feel better”, to prevent sickness (67%), help to get better when sick (51%), live longer (50%), build strength (17%), or manage weight (12%). More than half of the respondents (53%) thought that supplements offer benefits not matched by conventional drugs or offer the same benefit with fewer side effects.

The same survey found that 91% of respondents thought it was necessary to follow recommended dosages for prescription drugs, whereas only 71% thought the same for dietary supplements. Moreover, many consumers did not report their supplement use to their doctors (49%). Finally, the survey found that consumers do not understand how supplements work and demonstrated misperceptions about their use.

The structure of the dietary supplement industry is characterized as one with a large number of firms selling products and inputs that are undifferentiated and where entry and exit of firms are unrestricted. In general, this would be true for most industries where there is no government regulation, no one firm holds a patent on a product, no one firm owns the entire stock of a critical input, or where a single firm can supply the entire market. Table 3 reports the sales of dietary supplements by category as of 1996 and 2000 (Dietary Supplement Education Alliance, 2004; http://www.supplementinfo.org/industry/marketplace.htm).

Table 3 also shows that by 2000 the industry had grown from $10 million to nearly $17 million in U.S. sales (Dietary Supplement Education Alliance, 2004). Vitamins remain the largest seller, with the leading product being multivitamin preparations; however, meal supplements and specialty supplements gained market share from 1996 to 2000. Certain herbal supplements, such as soy supplements (90%) and green tea extracts (42%), had exceptional growth. Other herbal supplements enjoying popularity with consumers were valerian (Valeriana officinalis), saw palmetto (Serenoa repens), black cohosh (Actaea racemosa), milk thistle (Silybum marianum), grape seed extract (Vitis vinifera), and red clover (Trifolium pratense). Demand for weight-loss and joint-care products also grew over the period.

Along with the growth of the industry, there was the finding of numerous complaints of false and unsubstantiated claims of benefits of several dietary supplements from all categories. For example, there was a deceptive claim that a food bar containing l-arginine was effective against cardiovascular disease; that coral calcium could treat or cure cancer and other diseases such as multiple sclerosis and heart disease; or that colloidal silver could treat or cure 650 different diseases, eliminate all pathogens in the body, and was medically proven to kill every destructive bacterial, viral, or fungal organism in the body, including anthrax, Ebola, and flesh-eating bacteria. Perhaps worst, there were claims that companies sold only dietary supplement products containing ingredients that appear on the FDA's list of ingredients generally recognized as safe (GRAS). Actually, many products contain the herbal ingredient comfrey, which is not on the GRAS list and is known to pose a significant risk to humans, including liver damage, when used internally or externally on open wounds. Consequently, it is obvious that certain members of the dietary supplement industry take great advantage of the opportunity to market products not shown to be efficacious or safe.

Thus, some botanical products can have powerful pharmacological effects that raise safety concerns. Consumers may make incorrect assumptions that these products are inherently safe or safer than synthetic drug products because they are “natural”. The Interstate Trade Commission believes that it may be appropriate in certain circumstances to require warnings about significant safety risks associated with the use of these products and particularly about the safety implications of exceeding recommended doses (Federal Trade Commission for the Consumer, 2003; http://www.ftc.gov/bcp/reports/dietadvertisingcases.htm). One way to manage this problem is to require companies making statements of nutritional support to include, both in their substantiation file and in their FDA notification letter, an interpretive summary, prepared by a qualified expert, of the evidence supporting the claim. Such a summary requirement could assist companies in framing claims that accurately reflect the supporting evidence. It could also be a valuable starting point for both the FDA and FTC in assessing claims for dietary supplements.

Consumers should also be given accurate and understandable information so that they can assess the benefits and safety of a particular supplement. However, if not objectively prepared and carefully qualified, this information could itself be misleading or misunderstood. To reasonably inform consumers about the implications of the scientific evidence, consumer summaries would need to fairly present the state of the evidence available to support the claim. Where the supporting evidence is consistent, clear, and compelling, a summary would be unlikely to deceive. But where the evidence is mixed, conflicting, or preliminary, summaries would need to be carefully crafted and qualified. Consumer research indicates that caveats about the limitations of supporting scientific evidence are often ineffective to prevent a significant number of consumers from taking an absolute message that science has proven the claimed effect. The evidence needed to substantiate a statement of nutritional support will vary depending on a number of factors, including the nature of the statement made; that it is appropriate to consider various types of evidence, including epidemiological studies, human clinical studies, animal studies, and in vitro studies; that all relevant evidence, including contrary evidence, must be considered; and that the weight of the evidence should substantiate the claim. Consumers, for example, may not be able to make accurate assessments about the relative weight of in vitro, animal, and controlled human clinical studies or understand certain basic principles of scientific research that may have a significant impact on the strength of support for a claim—such as whether a study has a control, whether it is double-blinded, or whether it uses the same form and strength of active ingredient as that contained in the supplement. Several recent FTC cases challenged misleading ads that referred to scientific studies as proving the product's efficacy, when in fact for various methodological reasons the studies did not support the specific claims made in the advertising.

In November 2004, the FDA announced three major regulatory initiatives relating to the implementation of DSHEA to “improve the transparency, predictability, and consistency of its scientific evaluations and regulatory actions to protect consumers against unsafe dietary supplements and dietary supplements making unauthorized, false, or misleading claims”. They are 1) to publish a regulatory strategy, 2) to hold an open public meeting, and 3) to provide a draft guidance document for industry. The regulatory strategy will assure that the FDA collaborates with its federal and other partners to improve safety and enforcement decisions about dietary ingredients and supplements. In addition, the FDA will monitor labeling claims, including claims in accompanying literature such as flyers, brochures, and catalogs and in internet labeling. Finally, the guidance the FDA has issued reminds “marketers that claims about the benefits of dietary supplements must be truthful and substantiated by high quality scientific evidence” (FDA News, 2004).

Also in November 2004, the Life Sciences Research Office (LSRO, 2004; http://www.LSRO.org/), a nonprofit organization that provides expert evaluation of issues, opportunities, data, programs, and proposals in the food, health, and bioscience sectors, released a report entitled “Recommendations for Adverse Event Monitoring Programs for Dietary Supplements”. The LSRO report “concluded that an effective post-market surveillance program can enhance the likelihood that true adverse effects, unknown at the time of marketing, are identified”. Furthermore, the LSRO report suggested “if a voluntary surveillance program were to be adopted by dietary supplement companies, it would be inappropriate to use the methods being used for mandatory surveillance programs for prescription medications”. The report suggested instead that surveillance systems for dietary supplements had to be tailored to accommodate the voluntary and consumer-driven nature of supplement adverse event reporting. Such a system would be “practical and auditable; simple and concise; use a standardized questionnaire and resolve issues of risk management and quality assurance”. In addition, in response to concerns regarding the relative lack of dietary supplement regulation, the American Society for Clinical Pharmacology and Therapeutics established the Task Force on Dietary Supplements, under the purview of its Government Affairs Committee, to examine this issue and provide recommendations for changes in DSHEA that would increase the safety of these agents (Morrow et al., 2005).

In conclusion, we urge Congress to give substantial consideration to the recommendations offered to the FDA by the Committee on the Framework for Evaluating the Safety of Dietary Supplements, the FDA, and the LSRO. Moreover, we recommend that the cost of implementing these recommendations be borne by the manufacturers of the dietary supplements. There is a substantial challenge facing the scientific community regarding dietary supplements because they pose an ever-enlarging component of health care provision for which there is little oversight and regulation at a time when resources are severely strained.