Comments on HHS OIG Study of Adverse Event Reporting for Dietary Supplements
April 24, 2000
We are very concerned about the dangerous inadequacy of FDA's adverse reaction reporting system for dietary supplements — wherein, for 1994 through 1999, the number of such reports filed with the American Association of Poison Control Centers (AAPCC) was 35,400, more than ten times higher than the approximately 3,000 reported to the FDA. This must be viewed, however, as just a symptom of the larger issue: the crippling effect that the Dietary Supplement Health and Education Act of 1994 (DSHEA) has had. However, it will not be possible to significantly remedy most of the health hazards which have arisen or will continue to arise as a result of that law without its repeal or, at the least, significant health-strengthening amendments. Despite this, the FDA has, in deference to the industry and its congressional supporters, refused to acknowledge the fact that their authority under the law has been so damaged. During a March 25,1999 testimony before the House Government Reform Committee, Chairman Dan Burton asked FDA Commissioner Dr. Jane Henney, “Do you think that the FDA has enough authority right now to deal with dietary supplements?” Her answer was “ I believe, as outlined in the act, appropriate authority is either given to the agency within the context of the Dietary Supplement Act or in the law that it is embodied in the basic FDA Act as well. … We believe that we have the appropriate authorities that we need.”
In recent testimony before the same committee, March 20, 2001, FDA Center for Food Safety and Applied Nutrition (CFSAN) director Joe Levitt reaffirmed Dr. Henney's official FDA policy against asking for more legislative authority and tried to make the case that as long as more financial resources were made available, CFSAN could do its job implementing DSHEA and would “provide consumers with a high level of confidence in the safety, composition and labeling of dietary supplements.”
We agree with all of the limited Inspector General recommendations for additional legal authority and funding to improve FDA performance but the recommendations do not go far enough. Without the additional legal authority to require evidence of safety and effectiveness for dietary supplements as a condition of continued marketing, the FDA is still in the position of waiting until enough deaths or injuries have been caused by a specific dietary supplement and detected by the agency before pushing for a recall. In that context, the FDA relies on DSHEA authority to declare ingredients adulterated if they present “a significant or unreasonable risk of illness or injury.” This after-the-fact form of regulation is painfully reminiscent of the situation for prescription drugs before 1938. In that earlier era FDA authority to take action against a drug could only occur after the agency bore the burden of showing, based on marketing experience, that the drug's risks were unacceptable rather than the post-1938 requirement of placing the burden for establishing safety on the manufacturer.
The eagerness or guts to use even this limited present authority is questionable since the FDA has not yet acted to ban ephedra-containing products even though they clearly present “a significant or unreasonable risk of illness or injury.” The following chart shows the close chemical structures of PPA, ephedrine and amphetamine:
It can be seen that the only structural difference between PPA, now banned because of its cardiovascular toxicity, and ephedrine is the existence of a CH3 or methyl group on ephedrine instead of the H in the same position in PPA. The well-documented concerns about the cardiac (arrhythmias) toxicity and brain toxicity of ephedrine (also associated with a large number of strokes due to bleeding in the brain), the known brain toxicity of amphetamine and the use of amphetamine as an appetite suppressant confirm that there are pharmacological as well as chemical similarities between all of these compounds.
In addition to the excellent ephedra chronology included in the Inspector General's report there are two reviews of 140 adverse reaction cases reported by FDA consultants to the FDA involving the use of ephedra alkaloids that confirmed the cardiac toxicity of ephedra. The first study found that 47% of cases involved the cardiovascular system (17 cases of hypertension, 13 with palpitations or fast heartbeat, 10 strokes). There were also 7 reports of seizures. The second study found that of the 104 reports in which causation by ephedra was very likely, there were 10 cases of sudden death, nine cardiac arrhythmias, another 23 possible arrhythmic events, three heart attacks, ten cases of chest pain and 15 severe strokes.
Short-term and Long-term Remedies
Right now, legislation should be introduced — combined with the right signals during the FDA appropriation process and a strong version of the Good Manufacturing Practice (GMP) regulations — to rapidly lessen the damage being done by this dietary supplement industry wish list having the force of, a federal law, DSHEA. These improvements include a mandatory adverse event reporting requirement for all dietary supplement manufacturers, mandatory warning labels for risks, requirements for company and product registration, and identification of the raw ingredients and the source (by country) for each of the ingredients in each product. This latter requirement is necessary to ensure that BSE-contaminated recycled cow organs do not appear on the shelves in this country as dietary supplements. In addition, mandated funds are necessary to implement and enforce the Good Manufacturing Practices regulation that will hopefully be finalized soon. In addition, the FDA should be appropriated the funds to purchase the entire dietary supplement database of the AAPCC. At present, only the ephedra alkaloid cases have been contracted for by the FDA.
In the long run, DSHEA will either be significantly modified or repealed so that pre-marketing safety and efficacy testing become the preferable alternative to post-marketing human experimentation.
 U. S. Food and Drug Administration Center for Food Safety and Applied Nutrition. Dietary Supplements Strategy (10 Year Plan), January 2000. http://vm.cfsan.fda.gov/~dms/ds-strat.html.
 Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. New Engl J Med 2000;343:1833-8.
 Letter from Ray Woosley, M.D., Ph.D, Georgetown University School of Medicine, August 18, 1999 to the FDA.