Health Professionals

An Examination of the Process FDA Has Used to Conduct Its Scientific/Regulatory Decision Regarding the Safety of Ephedrine Alkaloids

Issue: Whether the Food and Drug Administration (FDA) has used the appropriate process to conduct a scientific/regulatory decision regarding the safety of ephedra.

Findings: FDA has not used the appropriate process to make a sound scientific/regulatory decision regarding the safety of ephedra. Rather, "FDA has used a fragmented and inconsistent approach to its review of ephedra that undermines the accepted scientific/regulatory approach to ingredient safety." Statement of William Soller, Ph.D., Consumer Healthcare Products Association (CHPA), at the August 8-9, 2000 HHS Public Meeting on the Safety of Dietary Supplements Containing Ephedrine Alkaloids.

According to Dr. Soller, "[s]cientific/regulatory decisions on ingredient safety are made case-by-case, in a weight-of-all-the-evidence, data-driven and dialogue-driven process that includes all the relevant data and information." Moreover, public health decisions affecting ingredient availability or labeling "must be based on data that are scientifically documented, clinically significant and important to the safe and effective use of the product by the consumer." Although FDA has a long-standing policy in using this process, FDA has not used it in its assessment of the safety of dietary supplements containing ephedrine alkaloids.

FDA Is Not Evaluating the Safety of Ephedrine on a Case-By-Case Basis

FDA has included safety information on other sympathomimetics in its docket, which breaks away from the case-by-case standard of review of ingredient safety. For example, 56 references in FDA's review of published literature are cerebro- and cardiovascular-related references; however, only 34% of these references are related to ephedrine and the rest relate to other sympathomimetic agents. Ephedrine is different from other sympathomimetic agents, including phenylpropanolamine (PPA). Dr. Soller's findings are consistent with that of Dr. Page and Dr. Karch, EEC Expert Panel members.

By including this other information in the docket, it appears that FDA believes that an evaluation of the safety profile of other marketed sympathomimetics is important to evaluate the safety of ephedra. However, this is incorrect because, as Dr. Soller noted, "the intended use of an ingredient is fundamental in its safety evaluation," and "different marketed sympathomimetics have different intended uses, based on their very well known and unique pharmacologic structure-activity relationships."

FDA Is Not Considering the Weight of All the Evidence

FDA has selectively included information in its docket, thus it is impossible for FDA to consider the weight of all of the evidence. For example, FDA recently entered in the docket a study addressing PPA and hemorrhagic stroke. However, CHPA has submitted to FDA in years past and even very recently voluminous information, including both published and unpublished clinical studies, that support PPA's safety. Nevertheless, FDA did not include this information in the docket.

FDA Is Not Using Data That Is Scientifically Documented

FDA instructed three of its consultants to review a selection of AERs to determine whether ephedrine is safe. However, this is inappropriate. As Dr. Soller noted, AERs are individual reports that lack important details and give "more likely explanations of the reported event." Therefore, AERs are considered to be "hypothesis-generating" and not "hypothesis-testing" data sets. Moreover, most AERs do not have sufficient information to make a causality analysis. Their utility, consequently, is very limited.

Conclusion: FDA has not used the appropriate process to evaluate the safety of dietary supplements containing ephedrine alkaloids.

FDA's review of the safety of ephedra falls short of meeting the standard of the scientific/regulatory approach that, as noted by Dr. Soller, "evaluates each ingredient on its own merits; focuses on scientific documentation first; and relies on the weight of all the evidence." FDA should carefully consider all of the evidence available on the safety of ephedra and, therefore, should wait until current studies on the substance are completed before making a regulatory decision. Finally, FDA should eliminate from consideration that information that is irrelevant to an evaluation of the safety of ephedra.

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