Public Policy Center

The History Of FDA's Opposition To Ephedra

HHS Ephedra Meeting Summary

On August 8-9, 2000, the Department of Health and Human Services (HHS) Office on Women's Health (OWH) sponsored a public meeting to discuss the safety of dietary supplements containing ephedrine alkaloids. This meeting stemmed from the criticisms contained in the July 1999 General Accounting Office (GAO) report titled "Dietary Supplements: Uncertainties in Analyses Underlying FDA's Proposed Rule on Ephedrine Alkaloids," and FDA's withdrawal of the substantive portions of its June 1997 proposed rule regarding dietary supplements containing ephedrine alkaloids.

At the meeting, the Food and Drug Administration (FDA) presented a panel of FDA personnel and outside consultants. FDA and its consultants presented their individual views but expressed the same opinion: that, based on the adverse event reports (AERs) that FDA has received, based on the published literature, and based on the lack of any benefit from the products, dietary supplements containing ephedrine alkaloids are associated with serious adverse health effects. However, independent researchers and leading academic experts consulting with industry showed that the AER database was not useful from a scientific standpoint, that FDA had seriously mischaracterized the published literature, and that FDA and its consultants had ignored data on the benefits of these products.

Several prominent clinical researchers and experts in the area of obesity presented new or published data and called for continued access to ephedra products given the data supporting safety and efficacy. This evidence was backed by numerous reports from consumers and treating physicians of the enormous health benefits directly attributable to these products, as well as data showing exponential increases in sales with an overall decline in reporting of adverse events.

A panel of leading experts in cardiology, epidemiology, neurology, and risk assessment presented consensus findings that directly contradicted and dispelled the findings of the individual FDA presenters. The panel concluded that the FDA's AER database is so flawed as to be worthless from a scientific standpoint and that what information could be derived from the AERs showed no association between the serious events of concern to FDA and the ephedra products when consumed according to national industry standards. The panel also concluded that FDA's analysis of the published literature was in serious error and that FDA's analysis mischaracterized the available data and its relevance to ephedra products. Finally, the panel agreed that the available data supported the usefulness of the products for weight loss and that research in this area should continue.

The overwhelming quantitative and qualitative testimony offered at the HHS meeting showed that ephedra products are safe and useful when consumed according to national industry standards and that FDA's position that ephedra products are a public health concern is not supported by the available data or by FDA's own actions. A summary of this testimony is set forth below.

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OVERVIEW OF THE HHS EPHEDRA MEETING

Presentations on Ephedra's Effectiveness in Weight Loss

Several leading obesity experts testified on the effectiveness of dietary supplements containing ephedrine alkaloids in helping people lose weight. Dr. George Bray, one of the most prominent researchers in the area of obesity, argued forcefully for continued consumer access to these products to help combat one of America's foremost public health problems ‚ obesity. Dr. Bray also discussed the results of completed clinical trials that show that dietary supplements containing ephedrine alkaloids are effective and safe as weight loss products.

Dr. Arne Astrup, one of the leading researchers in the treatment of obesity, discussed data from his own research supporting the safety and efficacy of ephedrine caffeine combinations in weight loss. Drs. Patricia A. Daly and Carol Boozer, who conducted two clinical trials of ephedra/caffeine combination products at hospitals associated with Harvard and Columbia Universities, presented data from an 8-week study showing significant weight loss and reported that a longer-term, more comprehensive follow-up study had been completed and was currently being prepared for publication. These researchers reported that there were no serious adverse events seen in this latest study.

Finally, Dr. Gary Huber of the Texas Nutrition Institute reported on his own research data on ephedra used alone or in combination with caffeine and on his findings that these products are safe and effective for weight loss. Dr. Huber was accompanied by three patients who recounted their personal experiences with the products and the enormous physical and mental health benefits that resulted from their significant loss of excess weight. Many other consumers and several treating physicians also testified at the HHS meeting with similar stories of the significant health benefits derived from the use of dietary supplements containing ephedrine alkaloids.

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The Ephedra Education Council

A seven-member expert panel presented on behalf of the Ephedra Education Council (EEC). Unlike FDA's panel, the EEC panel presented consensus findings relevant to the safety of dietary supplements containing ephedrine alkaloids. The EEC's experts discussed the scientific validity of FDA's AERs, the world literature on the safety of dietary supplements containing ephedrine alkaloids, and the scientific review of the outside consultants retained by FDA to review FDA's AERs. The EEC expert panel's conclusions include the following:

• No Association Between AERs and Appropriate Ephedra Consumption
  
  The EEC expert panel concluded that the "[a]vailable information does not demonstrate an association between the use of dietary supplements containing ephedrine alkaloids and serious adverse events when used according to the American Herbal Products Association (AHPA) trade recommendation for ephedra products."
  
  
• Serious Events Reported in AERs Are Consistent with Background Rates
  
  Dr. Stephen Kimmel, an expert in cardiac epidemiology and Assistant Professor of Medicine and Epidemiology at the University of Pennsylvania School of Medicine, is the chair of the EEC panel. Dr. Kimmel presented a detailed analysis of the AERs in relation to the experience in the general population and thus to the background risks for the serious events at issue: seizure, stroke, and heart attack. Dr.ÝKimmel's review of the published literature showed that the estimated rate of seizures in young adults is 20-60/100,000; of strokes, 3-60/100,000; and heart attacks, 5-41/100,000. In the aggregate, approximately 75,000 people under the age of 45 have strokes each year in the U.S., and between 22,000 and 66,000 people under the age of 40 have heart attacks. Dr. Kimmel then compared the rate of these events reported to FDA, taking care to make assumptions to overestimate risk, and found that, in all cases, reporting rates for persons using ephedra were below or within the expected range for the general population.
  
  Despite numerous requests to do so, FDA has refused to assess whether the reports it has received are consistent with background risk. Dr. Kimmel's analysis also directly refutes FDA's concern that dietary supplements containing ephedrine alkaloids are causing the serious events. His analysis also provides important new evidence that is consistent with the views of other independent reviewers and that is supported by the EEC panel's review of the AERs themselves: the reported events do not support the conclusion that dietary supplements containing ephedrine alkaloids cause serious adverse events.
  
  
• FDA's Literature Review Is Seriously Flawed
  
  Dr. Steven B. Karch, an expert in cardiac pathology and cardiotoxicity and Assistant Medical Examiner of the City and County of San Francisco, presented a point-by-point rebuttal of FDA's literature review to show that FDA's review is fundamentally based on misrepresentations of the scientific literature and on inappropriate studies. The overall impact of FDA's review is designed to give the misleading impression that dietary supplements containing ephedrine alkaloids cause adverse health effects. As an example, Dr. Norbert Page, an expert in toxicology and risk assessment and former senior official in risk assessment at both the Environmental Protection Agency (EPA) and the National Cancer Institute (NCI), found that of the 294 references cited by FDA in its literature review, less than half are relevant to the analysis of dietary supplements containing ephedrine alkaloids.
  
  Dr. Karch's and Dr. Page's concerns were independently supported by a videotaped presentation from Dr. Arne Astrup, a prominent researcher in Denmark, who discussed his own research data to show how it had been "mischaracterized" and "distorted" in FDA's literature review to support FDA's concerns over ephedrine alkaloids.
  
  
• No Evidence of Adverse Nervous System Effects
  
  Dr. John W. Olney, a leading researcher in the effects of food ingredients and other chemicals on the brain and a Professor of Psychiatry and Neuropathology at Washington University School of Medicine, reviewed the 28 AERs associated with the nervous system as well as FDA's and its outside consultants' findings regarding these AERs. Dr. Olney showed that FDA and its outside consultants could not agree on a single AER that they believed was strongly associated with an adverse nervous system event. Illustrating the uselessness of the FDA AER database for scientific purposes, Dr. Olney showed that FDA's outside consultants could agree on only two AERs that they believed were likely related to ephedra consumption and that these two were among the 12 AERs FDA disqualified from its own review because of "insufficient information."
  
  Dr. Olney also reviewed the world literature pertaining to the neurotoxic side effects of ephedrine alkaloids, and he found that "[i]t is reasonable to conclude that ephedrine alkaloids contained in dietary supplements are safe if used in doses recommended by AHPA (not to exceed 25 mg ephedrine per serving, four servings per day), and if used in keeping with all other AHPA-recommended label instructions."
  
  
• No Evidence That Ephedra Was a Factor in Reported Deaths
  
  Dr. Grover M. Hutchins, a leading researcher in pathology and cardiac pathology and a Professor of Pathology at The Johns Hopkins University School of Medicine, reviewed all 22 deaths reported to FDA, which the agency included as possibly associated with the consumption of dietary supplements containing ephedrine alkaloids. Dr. Hutchins reported that there was "[n]o consistency of clinical or pathologic features . . . in the whole group of cases, nor was there evidence to show that ephedrine alkaloids was a contributing or causative factor in the death[s]."
  
  
• FDA's AER Database Is Inadequate
  
  Both Dr. Page and Dr. Theodore M. Farber, an expert in food, plant, and drug toxicology and former senior official in risk assessment at both FDA and EPA, reviewed all of the AERs released by FDA and found that the AERs are comprised of anecdotal accounts of adverse effects reported by a lay public and do not constitute an adequate database from which to perform a scientific causality analysis. In addition, they found that some of the alleged medical conditions cited in the AERs are medically implausible or obviously due to some other risk factor, such as ovarian tumors and deaths due to hyperthermia and/or violent exercise and bodily abuse.
  
  
• No Evidence of Abuse or Dependence Associated with Ephedra Consumption
  
  Dr. Edgar H. Adams, an expert in substance abuse and former senior official at the National Institute on Drug Abuse, found that there is no evidence of significant abuse of or dependence on ephedra products.

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Presentations of Other Experts

Other experts, consumers, non-profit groups, and trade associations presented their views on the safety of these products. The overwhelming evidence from the meeting and the general consensus of the other presenters was that dietary supplements containing ephedrine alkaloids are safe and useful when consumed in amounts consistent with the national industry standard.

There was also general consensus that FDA had not evaluated the safety issues in a scientific manner, as was detailed in a presentation by Dr. Bill Soller from the Consumer Healthcare Products Association. General consensus was also reached that, in large part because of the enormous public health problems that obesity presents and the benefits that ephedra products have shown in this regard, more research should be conducted and funded by the federal government.

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Conclusions

FDA's concern about the safety of dietary supplements containing ephedrine alkaloids is not based on valid science, but rather on the furtherance of its own regulatory agenda. Contrary to the recommendations of the GAO in its 1999 report, FDA has once again based its concerns primarily on AERs that do not contain the information necessary to make a causality analysis and that would not constitute a valid scientific basis for concern even if these reports were more complete. In addition, FDA has created a literature review that intentionally mischaracterizes published studies and includes a large proportion of irrelevant studies in order to support FDA's preordained conclusions over the alleged dangers of ephedra consumption. FDA has also incorrectly assumed that consumption of ephedra produces no benefits so as to avoid considering this important positive factor.

Independent researchers, as well as industry and trade association experts, presented existing as well as new data that demonstrated the lack of any association between dietary supplements containing ephedrine alkaloids and serious adverse events. These data, supported by consumer testimony, also showed that ephedra, when consumed according to current national industry standards, is safe and effective for weight loss and that the potential public health gains from continued access to these products are enormous.

The HHS meeting was overwhelmingly supportive of ephedra; however, given the current and prior arbitrary regulatory attitude of the FDA, this does not mean that the subject has been satisfactorily completed and closed. The EEC now intends to work with other trade associations and with HHS, the National Institutes of Health (NIH), and FDA to assure that the completion of FDA's assessment of the safety of these products is done in a scientific manner.

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