by Mark Blumenthal

On February 28, 2003, the U.S. Department of Health and Human Services (HHS) and the U.S. Food and Drug Administration (FDA) released the long-awaited report from the RAND Corporation on the safety and efficacy of dietary supplements (DS) containing the herb ephedra (Ephedra sinica Stapf., Ephedraceae). The FDA also proposed new regulations with strong warnings for the labeling of ephedra supplements.^1,2

FDA requested "rapid public comment" on its proposed rules, including comments as to what "additional legislative authorities, if any, would be necessary or appropriate to enable FDA to address this issue most effectively."² FDA provided a 30-day public comment period, which ended April 7; usually FDA regulations are given 90 days or more for comment. FDAs action followed several weeks of media furor and numerous newspaper editorials calling for a ban after Baltimore Orioles pitcher Steve Bechler died of heat stroke at a Florida training camp while using an ephedra-containing weight loss supplement.

Also, FDA stated that it would immediately initiate a series of actions against companies marketing ephedra products that make unsubstantiated claims about sports performance enhancement. The agency sent warning letters to 26 companies who were selling ephedra products with such claims claims FDA does not consider appropriate, and are not supported by the conclusions of the RAND report (see below).

FDA stated that it would continue to work closely with the U.S. Federal Trade Commission (FTC) to ensure that ephedra products do not make false and misleading claims. "If an ad says a product is safe, the advertisers must have competent and reliable evidence to prove the claim," said FTC Chairman Timothy J. Muris.¹

HHS Secretary Tommy Thompson and FDA Commissioner Mark McClellan, M.D., Ph.D., issued strong warnings to the American public on the potential risks associated with using ephedra in strenuous sports-related activities, in diet programs that stress the cardiovascular system, when used for extended periods of time, or when used with caffeine and other stimulants. "FDA will do all we can to protect Americans from potentially dangerous dietary supplements," McClellan said. "We are particularly concerned about the risks of using products containing ephedra during heavy workouts, with caffeine and other stimulants, in a diet program that stresses the cardiovascular system, or by people under the age of 18. We are also concerned about potential stresses to the body caused by the long-term use of ephedra. The standard for regulating the safety of dietary supplements is largely untested, but we are committed to finding the right public health solution.

"The steps being announced today demonstrate FDAs commitment to taking the most effective actions possible under current law, given the state of the scientific evidence. It may be possible to use ephedra safely, in small doses, for some purposes. But in the face of continued serious adverse events following the use of ephedra, there is a problem. It is a problem we are determined to fix."¹

FDAs Proposed Ephedra Warnings

The main component in the FDAs proposed new rules is the following 75-word "black box" warning for the principal display panel of labels on all ephedra-containing DS products (i.e., inserted in a black lined box on the front panel): "WARNING: Contains ephedrine alkaloids. Heart attack, stroke, seizure, and death have been reported after consumption of ephedrine alkaloids. Not for pregnant or breast-feeding women or persons under 18. Risk of injury can increase with dose or if used during strenuous exercise or with other products containing stimulants (including caffeine). Do not use with certain medications or if you have certain health conditions. Stop use and contact a doctor if side effects occur. See more information []."²

FDA proposed that additional warnings would appear on the outer product label or in product labeling that is an integral part of the outer part of the outer product packaging such that this information may be read at point of purchase (e.g., outer information panel, panel extension, etc.). These additional warnings include the following:

The RAND Report

A significant development that was generally overlooked or underreported by the media is the FDAs release of the results of the long-awaited RAND Report. The report, "Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects",³ was produced by the Southern California Evidence-Based Practice Center RAND under contract to the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services. This work was sponsored by the Office of Dietary Supplements (ODS) and the National Center for Complementary and Alternative Medicine at the National Institutes of Health (NIH). The report is online at <http://www.accessdata.fda.gov/scripts/oc/ohrms/advdisplay.cfm>.

The impetus behind the RAND report is based in 2001 Congressional appropriations, which stated, "The Office [ODS] is encouraged, in consultation with NCCAM, AHRQ, and FDA to review the current scientific evidence on the safety and efficacy of dietary supplements now on the market, which could then form a basis for further research, education of practitioners and consumers, and whether further regulatory requirements are necessary."⁴ Congress further noted, "The number of Americans taking dietary supplements containing ephedra has risen dramatically. The conferees encourage [ODS] to enhance clinical research on the safety and efficacy of these products."⁵

According to a May 29, 2003, email to the author from Paul Coates, Ph.D., ODS director, "Our goal was to get a fair reckoning of the current science as a basis for future research in the area. There is no doubt, however, that this approach could be used by regulatory agencies to fairly and independently determine whether a safety concern exists for a particular ingredient."

If the evidence-based review from RAND had concluded that ephedra was a public health danger, it would have satisfied the legal requirements to justify FDA in removing ephedra from the market, as most industry insiders have speculated FDA has wanted to do for many years. Without objective data from clinical trials or some other definitive proof of causality, and with data supporting short-term weight loss, under the terms of the Dietary Supplement Health and Education Act of 1994 (DSHEA) or other existing standards for safety, FDA would find itself hard-pressed to justify removal of ephedra from the market.⁶

FDA also invited public comment as to "what additional legislative authorities, if any, would be necessary or appropriate to enable FDA to address [the regulation of ephedra] most effectively."² On March 26, Sen. Richard J. Durbin, D-IL, introduced Senate Bill 722, "A bill to amend the Federal Food, Drug, and Cosmetic Act [FDCA] to require that manufacturers of dietary supplements submit to the Food and Drug Administration reports on adverse experiences with dietary supplements, and for other purposes" (also known by its short title, "Dietary Supplement Safety Act of 2003"), which would require pre-market safety approval for all supplements intended for use for stimulant purposes.⁷

However, the RAND Report, while acknowledging safety concerns about ephedra supplements, does not go so far as to conclude a causal connection between ephedra and serious adverse effects (e.g., heart attack, stroke, seizure, death). In its literature review, RAND could only term these serious adverse effects as "sentinel events" (i.e., they could be seen as potential signals to toxicity).

A sentinel event is an "early warning to suggest that certain populations may be susceptible to specific adverse effects," according to Richard Kingston, Pharm.D., of Prosar International Poison Center in Minneapolis, a leading expert in product safety and post-market surveillance. "Hopefully, this will allow closer scrutiny of these types of events to search for any cause-effect relationships," he added.⁸

The FDA press release summarizes, "The RAND study has concluded that ephedra is associated with higher risks of mild to moderate side effects such as heart palpitations, psychiatric and upper gastrointestinal effects, and symptoms of autonomic hyperactivity such as tremor and insomnia, especially when it is taken with other stimulants. Moreover, its review of some 16,000 adverse event reports revealed two deaths, four heart attacks, nine strokes, one seizure, and five psychiatric cases involving ephedra in which the records appeared thorough and no other contributing factors were identified. RAND called such cases sentinel events, because they may indicate a safety problem but do not prove that ephedra caused the adverse event. The study recognized that such case studies are a weak form of scientific evidence. Other unmeasured factors may have contributed, and such serious adverse events are likely to happen (albeit at very low rates) among the millions of users of ephedra anyway. The study also identified other such events potentially associated with ephedra, in which other factors may have contributed to the adverse events or in which records were inadequate."¹

The RAND Report evaluated 52 controlled clinical trials on ephedra and ephedrine for evidence of efficacy for weight loss or athletic performance (46 for weight loss), including ephedrine-caffeine combinations. The authors also reviewed adverse event reports from a variety of sources including the FDA Medwatch, published literature, and the files of a large manufacturer. They documented parameters: dose of ephedra reported, timing of the dose of ephedra (last dose within 24 hours for acute events), product taken, the adverse event, other medical information, and any subsequent investigation of the adverse event. They also "sought evidence that an adequate investigation had assessed and excluded other potential causes." Cases that met these criteria (well-documented event, plausible time frame, and elimination of other causes) were labeled "sentinel events."³

RAND makes the following conclusions: "Ephedrine, ephedrine plus caffeine, and ephedra-containing dietary supplements with or without herbs containing caffeine all promote modest amounts of weight loss over the short term. There are no data regarding long-term effects on weight loss. Single-dose ephedrine plus caffeine has a modest effect on athletic performance. The available trials do not provide any evidence about ephedrine or ephedra-containing dietary supplements, as they are used by the general population, to enhance athletic performance. Use of ephedra or ephedrine plus caffeine is associated with an increased risk of gastrointestinal, psychiatric, and autonomic symptoms. The adverse event reports contain a sufficient number of cases of death, myocardial infarction, cerebrovascular accident, seizure, or serious psychiatric illness in young athletes to warrant a hypothesis-testing study, such as a case-control study, to support or refute the hypothesis that consumption of ephedra or ephedrine may be causally related to these serious adverse events."³

Adequate Authority to Protect

The public controversy about the safety of ephedra has long been a concern among many people in the herb and DS industry, who see the ephedra issue as an Achilles heel for the industry, possibly "bringing down the heat" on all other herbs and supplements. The logic holds that the mounting concerns about ephedra may endanger the regulatory status of many relatively benign herbs and other supplements. Others, particularly representatives of ephedra manufacturers, argue that FDA caused the bad publicity on ephedra by mishandling the science from the start, and that industry should not permit any ingredient to be removed from the market based on bad press and bad science, as that would serve as a precedent with which industry could not live, which eventually would be counter to public interest. This position is rooted in part in the FDAs proposed ephedra regulations issued in June 1997; the agency proposed small doses of ephedra alkaloids (8 mg per serving; 24 mg per day limit) and other proposals⁹ that were later deemed by the U.S. General Accounting Office as being scientifically unfounded.¹⁰

As noted above, in its proposed regulations FDA requested comments as to what additional legislative authority, if any, might be appropriate to enable it to deal with ephedra most effectively. This request is consistent with the views of some in the medical community, who have commented that dietary supplements are not sufficiently regulated.

An editorial in the Journal of the American Medical Association (JAMA), accompanying the publication of a meta-analysis of ephedra clinical trials by the authors of the RAND report,¹¹ calls for "major changes" in the regulation of DS.¹² It states that dietary supplements are readily available to the American public often with unsubstantiated claims of benefit and rarely with any mention of potential hazards. [The new American Botanical Council (ABC) Safety Labeling Program attempts to remedy some of this situation. Ed.]

Curiously, the editors may have mischaracterized one of the conclusions of the RAND report that did find evidence in controlled clinical trials of a modest level of weight loss (about 2 pounds per month) associated with ephedra DS. Referring to the meta-analysis of ephedra trials,¹¹ they write, "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 ... 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 [i.e., DSHEA] do so little to protect them from the hazards posed by these potentially dangerous compounds 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."

They conclude, "The reports by Shekelle et al, along with other studies documenting the increased risk of adverse reactions associated with ephedra, 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."¹²

In comments to FDA, ABC noted that previous FDA officials stated that FDA does have the authority and power to protect the public against unsafe dietary supplements.¹³ ABC cited testimony to the U.S. Congress by former FDA commissioner Jane Henney, M.D.: "FDA has tools at its disposal to take enforcement actions against dietary supplements found to have safety, labeling or other violations of the [FDCAI], as amended by DSHEA I also believe that DSHEA provides FDA with the necessary legal authority to protect the public health."¹⁴

ABC also cited Stephen H. McNamara, a leading food and drug law attorney and former Associate Chief Counsel for Food at FDA, who wrotethat FDA does possess adequate authority to protect the public.¹⁵ He specifically cites relevant sections of DSHEA and ADCA and concludes, "It appears that FDA has substantial and sufficient regulatory authority to protect the American public from any dangerous or otherwise unsafe herbs or other ingredients in dietary supplement products despite statements to the contrary from FDA officials."

FDAs proposed regulations and public comments can be found on Docket No. 95N-0304, OC 200362: "Dietary Supplements Containing Ephedrine Alkaloids; Reopening of the Comment Period." It is available online at <http://www.fda.gov/OHRMS/DOCKETS/98fr/95n-0304-npr0003.pdf>.

On March 1, 2003, ABC made available on its website, <www.herbalgram.org>, the ephedra monograph from its new book, The ABC Clinical Guide to Herbs, which discusses safety issues, recent regulatory history, and includes a table summarizing seven clinical trials.¹³

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