Why Has FDA Withdrawn Portions Of Its Proposed Rule?Why Has FDA Withdrawn Portions Of Its Proposed Rule?A number of companies that marketed ephedra products were legitimately concerned about the safety issues that FDA raised in its June 1997 proposal to prohibit most uses of ephedra products. These companies had sold thousands and in some cases millions of servings of ephedra products, but had either received no reports, or only isolated reports, of problems with their products. Several of these companies decided to hire qualified independent experts to review the scientific basis for FDA’s proposed rule. Although there were several separate efforts to review FDA’s basis for the proposed rule, the conclusions of these efforts were essentially the same; FDA did not have a valid scientific basis for the proposed rule.
Over 20,000 comments to the proposed rule, the vast majority opposing the rule, were filed with FDA. One set of comments, filed by the Small Business Administration (SBA), deserves special mention. SBA was highly critical of FDA’s proposed rule as a result of FDA’s serious underestimation of the number of small businesses that would be impacted. However, the SBA also raised serious questions about the lack of any apparent scientific basis for the proposed rule, and about FDA’s cost/benefit analysis. The SBA comments were instrumental in activating congressional involvement with FDA’s Ephedra proposal. After review of the relevant information, including the SBA comments, the House Committee on Science, by letter dated May 12, 1998, requested the GAO to conduct an audit of FDA’s scientific basis for the proposed serving limits (less than 8 mg ephedrine alkaloids per serving, less than 24 mg per day) and duration limit (no more than 7 days). The Committee on Science also requested that GAO examine the quality of the cost/benefit analysis FDA had included to justify the need for a regulation. The GAO made its completed audit public in early August, 1999. The GAO concluded that FDA did not have a sufficient scientific basis for the serving and duration limits that the agency proposed, and also concluded that the cost/benefit analysis was deficient in several important ways. With respect to FDA’s reliance on just 13 adverse event reports (AERs) to establish a serving limit, the GAO stated While FDA used these 13 AERs to set a dosing level, the agency did not perform a causal analysis to determine whether the reported events were, in fact, caused by the ingestion of dietary supplements containing ephedrine alkaloids. Our review of these 13 AERs found numerous problems that raise questions about the causal relationship between ingestion of the implicated product and the adverse events observed. For example, • three AERS included physician reports that stated the cause of the event was not related to a dietary supplement; • one consumer-related sample was obtained and tested 2 years after the initial event, and possible reformulations of the product might have resulted in different levels of ephedrine than the product implicated in the reported adverse event; • three individuals reporting adverse events had experienced similar problems prior to or well after using the dietary supplement; • one individual who experienced the event was eating only one meal a day; and one AER contained no medical records.
Some of the 13 AERs had more than one of these problems. As a result, there are uncertainties in FDA’s conclusions in setting a specific dosing limit since this limit was based on a small number of adverse events—events which may or may not have been a result of ingestion of dietary supplements containing ephedrine alkaloids. GAO Report, pages 13-14. With respect to FDA’s proposed duration limit, the GAO concluded that FDA did not present scientific evidence specifically pointing to an increase in adverse events beginning at 7 days and under normal use conditions. Rather, the scientific information FDA used to support a 7-day limit outlined problems associated with extended use (months and years) of ephedrine alkaloids. The agency also cited support for its 7-day limit from studies involving other sympathomimetic agents, such as cocaine and methamphetamines, but these studies also involved long-term use of the drug. GAO report, page 14. As a result of these and other problems, the GAO found that “there are uncertainties in the agency’s analysis of the relationship between duration of use of dietary supplements containing ephedrine alkaloids and the occurrence of adverse events.” GAO report, page 14. GAO also found numerous serious problems with FDA’s cost/benefit analysis, including the following:
FDA made errors that tended to inflate the benefits of the proposal. The GAO found that not even FDA could repeat the analysis. The GAO’s findings, when combined with the criticisms of the Small Business Administration (SBA) that FDA has seriously underestimated the costs of the proposed limits on small businesses, made it impossible to rely on FDA’s claim that there was any public health benefit to the proposed rule, or that any such benefit would be greater than the costs of the regulation. The simple answer to the question of why FDA has had to withdraw its proposed ban on Ephedra is that the GAO exposed FDA’s lack of science in a way that it was impossible for FDA to ignore. The message that FDA could not go forward without real science to support any future proposal was included in GAO recommendations to the Department of Health and Human Services and to FDA: Given the uncertainties in the information upon which FDA based its proposed rule, we recommend that the Secretary of Health and Human Services direct the Commissioner of FDA to obtain additional information to support conclusions regarding the specific requirements in the proposed rule for dietary supplements containing ephedrine alkaloids before proceeding to final rulemaking. Specifically, FDA needs to provide stronger evidence on the relationship between the intake of dietary supplements containing ephedrine alkaloids and the occurrence of adverse reactions that support the proposed dosing levels and duration of use limits. GAO report, pages 24-25. Despite taking over four years to compile a scientific basis to support its proposed limits for Ephedra, FDA has failed to do so. Now that the FDA has withdrawn the original proposal, FDA should adopt industry standards for these products, and work with industry to further examine whether the clinical data and other information warrant any changes to these standards. Related:Suggested Reading: |
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