FDA?s proposal was based primarily on the more than 800 adverse event reports that the agency had received between 1993 and June 1997. FDA stated that it had purposefully not considered the long record of safety for the more potent over-the-counter ephedrine drug products for asthma because, according to FDA, asthmatics are less sensitive to ephedrine.
However, FDA cited no scientific evidence for this assertion, and subsequent review of the medical literature has revealed no basis for rejecting this wealth of safety data. FDA also asserted that clinical studies on ephedrine for use in the treatment of obesity were also not relevant to the safety of Ephedra because obese individuals may be less sensitive to ephedrine, but again FDA cited no studies to support this theory.
In the end, careful examination of FDA?s very lengthy proposed rule showed that the proposed limits were based almost entirely on the adverse event reports, reports that FDA had historically found to be unreliable and therefore not useful for determining product risk. Therefore, the scientific validity of FDA?s proposal rose or fell depending on the quality of the adverse event reports and their relationship to Ephedra consumption.
Surprisingly, congressional inquiry into FDA?s proposed rule revealed that FDA never examined the adverse event reports on which it relied to determine if there was any relationship between the event and the consumption of Ephedra. Indeed, a number of the reports related to products that did not even contain Ephedra, but were nonetheless counted by FDA as Ephedra-related events.
As a direct result of FDA?s failure to perform even the most simple quality review of its reports, FDA?s record for the proposed rule included absurd reports such as the following:
a report of a woman whose blood alcohol was twice the legal limit and who died of a fractured skull after driving her truck into a tree at 90 mph;
a report of a man who shot himself;
a report of a suicide from a gunshot wound;
a report of a man who died of environmental hyperthermia;
a report stating "Shot and killed store clerk";
a report of a woman who "got pregnant though using Norplant"; and
reports of excessive hairiness, a 75-year old woman menstruating, a possible diagnosis of multiple sclerosis, a case of impotence and a case of constant erection.
Careful analysis of the record that FDA had compiled showed that at least 85 percent of the reports on which FDA had relied were so lacking in information essential to a scientific assessment of their relationship to the consumption of Ephedra that they were informationally worthless. Further, FDA had relied on just 13 of the reports as a basis for the proposed dose limits, even though the agency never reviewed these few reports to determine if they were causally related to the consumption of Ephedra. These immediate problems with FDA?s proposed rule led to more thorough review of the rule by Congress, a critical review by the General Accounting Office (GAO), and to the eventual and unprecedented withdrawal of the key portions of the 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.
The vast majority of the adverse event reports, approximately 85 percent, were informationally worthless because they lacked essential information such as how much Ephedra was consumed and for how long, the identity of the product at issue, and medical records including prior medical history.
The proposed serving limits were based on just 13 out of more than 900 reports, and FDA admitted in the proposed rule that it did not attempt to determine whether any of the 13 reports were causally related to the consumption of Ephedra. Independent expert review revealed that the 13 reports could not be scientifically attributed to Ephedra.
There was no scientific basis for either FDA?s duration limit (no more than seven days of use), which led FDA to prohibit use for weight loss and other uses that would encourage longer-term use, or for the agency?s prohibition on combining Ephedra with caffeine.
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 failed to consider whether state regulations being developed or already in place were sufficient to address FDA?s concerns, and therefore did not establish that there was (or is) any need for the regulation. GAO report, pages 43-44.
FDA did not establish a base-line level of risk for the adverse events at issue, and as a consequence FDA never considered whether the proposed rule would provide any benefit compared to taking no action. GAO report, pages 45-46.
FDA?s estimates of yearly averages of serious events, in addition to being based on an undocumented set of AERs, were also based on the unsupported and unscientific assumption that 80 percent of the AERs were in fact caused by ephedra products. GAO report, pages 48-50. In fact, the GAO found that FDA had never reviewed the AERs used as a basis for the proposed rule and the cost-benefit analysis to determine if any of the AERs were actually a result of the products at issue. GAO report, pages 11, 14, and 49-50.
The GAO found that, when FDA established its assumed percentages of events caused by ephedra products, FDA chose a high estimate within a large range of possible estimates, again without explanation. The GAO concluded that FDA?s use of inflated numbers "drove up the estimated number of actual adverse events and, as a direct consequence, the estimated benefits of the proposed rule." GAO report, page 49.
Finally, the GAO found that FDA also failed to conduct a "sensitivity analysis" or to consider the implications of "alternative assumptions," GAO report, page 51-55. As the GAO noted, "[c]hanges in any of [FDA?s assumptions] could have dramatically changed FDA?s estimates of the proposed rule?s benefits. GAO report, page 19.
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.
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