The Need for Regulation of Dietary Supplements—Lessons From Ephedra

Dietary supplements encompass a wide spectrum of products, including vitamins and minerals, such as folate and calcium; herbal therapies and botanical agents, such as ephedra and ginkgo biloba; and enzymes or extracts from organs or glands, such as some "hormone" preparations.¹ Dietary supplements are readily available in pharmacies, grocery stores, and health food stores, as well as by mail and via the Internet. These products are widely promoted, often with unsubstantiated claims of benefit and rarely with any mention of potential hazards. In the United States, dietary supplements are used by millions of people every day and account for billions of dollars in sales annually.

Dietary supplements are regulated by the US Food and Drug Administration (FDA), although under different regulations than those governing prescription medications and over-the-counter drugs.¹ The Dietary Supplement Health and Education Act (DSHEA) of 1994 established that substances classified as dietary supplements are not "drugs" and substantially changed the role of the FDA in regulating these products.² The DSHEA amended the existing federal Food, Drug, and Cosmetic Act with provisions that created a new regulatory framework governing the safety and labeling of dietary supplements.¹

Under the provisions of DSHEA, manufacturers of dietary supplements are not required to provide evidence of efficacy or safety prior to marketing the product. Moreover, except for a supplement that contains a "new dietary ingredient," dietary supplements are not required to have FDA approval or to be registered with the FDA before they are produced and marketed. Manufacturers are responsible for establishing their own manufacturing practice guidelines, because there are no FDA regulations to ensure the identity, purity, quality, composition, or strength of dietary supplements.¹ Once a dietary supplement is marketed, the FDA must demonstrate that the product is unsafe before it can take regulatory action against the dietary supplement, essentially amounting to a "postmarketing" regulatory framework.^{1 ,3} As for advertising of dietary supplements, the Federal Trade Commission (FTC) is primarily responsible for ensuring that claims in print and broadcast ads, infomercials, catalogs, and direct marketing materials ". . . must be truthful, not misleading, and substantiated."⁴

Despite the widespread use as well as the pervasive and persuasive marketing of these agents, it is increasingly clear that for at least some dietary supplements, lack of sufficient oversight and inadequate regulation may pose a risk to the health and safety of the public. In this issue of THE JOURNAL, Shekelle and colleagues⁵ provide an evidence-based summary of the efficacy and safety of ephedra and ephedrine, which are among the most controversial dietary supplements. Based on their review of 52 controlled trials, the authors concluded that supplements containing these agents promote modest short-term weight loss (approximately 0.9 kg/mo more than placebo). However, the evidence was insufficient to support ephedra use for long-term weight loss or for enhancing athletic performance. Analysis of safety data from 50 trials revealed that ephedra and ephedrine are associated with 2- to 3-fold increases in the odds of psychiatric symptoms, autonomic symptoms, upper gastrointestinal symptoms, and heart palpitations. An additional evaluation of adverse event reports revealed 5 deaths, 5 myocardial infarctions, 11 cerebrovascular accidents, 4 seizures, and 8 psychiatric cases as "sentinel events" associated with prior consumption of ephedra or ephedrine.

The results of this analysis cast doubt on any claims that use of dietary supplements containing ephedra or ephedrine can help achieve long-term weight loss or weight maintenance or can enhance athletic performance. The findings also strongly suggest increased risk of serious adverse effects associated with these products. Moreover, reviewing the accumulated reports of toxicity linked to these compounds, it is hard not to be impressed by the number of serious cardiovascular complications in young adults. The public, aware of recent reports of deaths in young athletes reportedly taking ephedra or ephedrine, is right to be alarmed that the regulation Congress has in place does so little to protect them from the hazards posed by these potentially dangerous compounds.

The article by Shekelle et al⁵ is based on a comprehensive 300-plus page Evidence Report/Technology Assessment on ephedra and ephedrine commissioned by the National Institutes of Health and the Agency for Healthcare Research and Quality (AHRQ) and conducted by the RAND Corporation.⁶ Department of Health and Human Services Secretary Tommy Thompson and FDA Commissioner Mark McClellan, MD, PhD, released the results of the RAND report at a news conference on February 28, 2003,⁷ and also expressed concerns about the safety of ephedra and announced several regulatory actions.

According to a recent White Paper on ephedra,³ the FDA has sent warning letters to manufacturers of ephedra instructing them to remove unproven claims for their products or substantiate those claims, especially those related to athletic performance. The FDA also has proposed "black box" warning labels on all products containing ephedra, indicating that serious adverse events and deaths have been reported after ephedra use.³ In addition, the FDA announced that it was seeking public comment to determine whether in light of current scientific evidence, dietary supplements containing ephedra represent "a significant or unreasonable risk of illness or injury"⁷ and whether "evidence of significant safety concerns, short of a definitive demonstration of a risk profile, is sufficient for new restrictions on products regulated under DSHEA."³

These actions are important and necessary steps in response to the new information on safety and effectiveness of ephedra provided by Shekelle and colleagues.^{5 - 6} However, the current system for regulation of dietary supplements is inadequate for ensuring the protection of the health and safety of the public who choose to use ephedra or other dietary supplements. Major changes in the system used to regulate these products are required.

Labeling for dietary supplements is not permitted to include "disease claims" (eg, prevents Alzheimer disease), but these products nearly always include at least one "structure/function" claim (eg, improves mild memory loss associated with aging). Yet the only way such claims can be valid is if the dietary supplement actually promotes or has inherent biological activity. For example, ephedra alkaloids have biological actions, as evidenced by sympathomimetic pharmacological properties and adverse cardiovascular events.⁸ Another dietary supplement, saw palmetto, has been shown to suppress tissue levels of dihydrotestosterone in men with symptomatic benign prostatic hyperplasia and to alter the DNA chromatin structure and organization in prostate epithelial cells.⁹ Likewise, yohimbine, which is promoted as a remedy for male sexual dysfunction, selectively blocks the presynaptic α₂ receptor and readily enters the central nervous system, where it acts to increase heart rate and blood pressure, enhance motor activity, and produce tremors.^{10 - 11}

If dietary supplements have or promote such biological activity, they should be considered to be active drugs. On the other hand, if dietary supplements are claimed to be safe because they lack or have minimal biological activity, then their ability to cause physiologic changes to support "structure /function" claims should be challenged, and their sale and distribution as products to improve health should be curtailed. Manufacturers of dietary supplements are trying to have it both ways. They claim their products are powerfully beneficial, on the one hand, but harmless on the other. To claim both makes no sense, and to claim either without trials demonstrating efficacy and safety is deceptive. The public should wonder why dietary supplements have effectively been given a free ride.

New legislation is needed for defining and regulating dietary supplements. Dietary supplements that have biological activity should be evaluated and regulated with at least the same degree of oversight as is used for over-the-counter medications, and for some, with regulation similar to prescription drugs. Currently, this is not the case, as dietary supplements are subject to less regulation than virtually any other products available for public consumption (Table 1).¹²

The first step is to address the scope of categories of products included under the definition of dietary supplements, which is too broad. The number of products marketed as dietary supplements has increased considerably in the nearly 10 years since DSHEA was passed into law. Each class of products within dietary supplements should be re-examined, and the types of products within each class should be reviewed and classified according to possible biological action, purported benefit, and potential risks.

Second, dietary supplements should be subject to more rigorous regulation by the FDA. Lewis and Strom¹³ have proposed that manufacturers of any product with a health claim should be held to the same standards as the pharmaceutical industry and have suggested several features for a system to regulate nutritional supplements. Health claims for dietary supplements should meet the same rigorous criteria as claims by drugs used to prevent or treat disease.¹³ Data from acceptable studies must be approved by the FDA before the product can be marketed. Data on efficacy and toxicity should be submitted and carefully evaluated, and recommendations for dosages of supplements must be appropriate and evidence based. Manufacturing practices and quality control processes must be sufficient to ensure product content integrity and purity. Standards to document the content of products should be established and enforced.¹³

Third, formal systems for mandatory postmarketing surveillance and mandatory adverse event reporting should be established to replace the current system of haphazard, voluntary reporting of anecdotal reports. According to a report from the Office of Inspector General,¹² the potential of the current FDA dietary supplement adverse event reporting system to serve as a consumer safeguard is "inherently limited." The Office of Inspector General report noted that the FDA reportedly receives reports of less than 1% of all adverse events associated with dietary supplements; that data on these events are characterized by limited medical information, limited product information, limited manufacturer information, limited information on the affected consumer, and limited ability to analyze trends of adverse event reports; and that "FDA rarely takes safety actions related to the adverse event reporting system."¹²

Fourth, the Federal Trade Commission in cooperation with the FDA should ensure that advertising for dietary supplements is accurate and not misleading. As with advertisements for therapeutic drugs, advertisements for dietary supplements must not make claims without substantiation by scientific evidence and must include appropriate information about adverse effects.

The reports by Shekelle et al,^{5 - 6} along with other studies documenting the increased risk of adverse reactions associated with ephedra,¹⁴ are sufficient evidence to restrict the use of this agent. However, the most important lessons from the new information on ephedra are demonstration of the inadequate nature of the current system of regulation of dietary supplements and recognition that much more rigorous oversight of these biologically active agents is necessary to protect the health and safety of the public.