Health Professionals

An Examination of the 276 Adverse Event Reports That FDA Released in April 2000

Issue: Whether the 276 adverse event reports (AERs) that the Food and Drug Administration (FDA) released in April 2000 comprise an adequate database from which a meaningful scientific or medical analysis may be made to assess the safety of dietary supplements containing ephedrine alkaloids.

Findings: The 276 AERs do not comprise an adequate database from which to conduct a scientific or medical analysis of the safety of these products. The AERs consist mostly of anecdotal accounts of adverse effects reported by a lay public, and they lack vital information necessary to perform a legitimate causality analysis. The few reports that are well-documented do not support an association between the dietary supplements containing ephedrine alkaloids consumed according to industry standards and serious adverse events.

Methodology: Dr. Norbert P. Page and Dr. Theodore M. Farber, both members of the Ephedra Education Council (EEC) Expert Panel, reviewed all 276 AERs that FDA released to the public in April 2000. Drs. Page and Farber assessed each AER to determine whether it had adequate information from which a causality analysis could be made. Drs. Page and Farber also conducted an assessment of each AER of the likelihood of a casual association with the event reported.

Analysis ‚ The AERs Cannot Be Used to Form Scientific Conclusions:

Approximately 73% of the AERs Do Not Contain Sufficient Information to Be Useful

Drs. Page and Farber found that the AER database contained numerous inaccuracies, inconsistencies, and omissions, and in some cases, the adverse effects were not even documented. For example:

• In at least 17 AERs, the product alleged to have caused the reported adverse effect is not identified.
• In several AERs where the product is identified, information regarding its constituents is missing.
• More than 34 AERs list products for which there is no indication that any ephedrine alkaloids were even present in the product.
• There are no medical records for 159 AERs.
• With respect to the 117 AERs that do contain at least some medical records, many are difficult to read and/or contain too little information such that they are of little utility.
• Sixty-four AERs (approximately 23%) have no dosage information (that is, dosage amount, frequency, or duration).
• Ninety-seven AERs (approximately 35%) are missing data on the dose amount of product ingested.
• One hundred three AERs (approximately 37%) are missing dosage frequency data.
• Ninety-six AERs (approximately 35%) lack data on dosage duration.

By combining the total number of AERs lacking medical records with the number of AERs containing medical records but lacking information on dose amount, dose frequency, or dose duration, Drs. Page and Farber found that 202 AERs (approximately 73%) are missing information for at least one data parameter considered essential to any legitimate causality analysis.

FDA Itself Acknowledged the Inadequacy of the AERs

In performing a causality analysis of 142 of the 276 AERs, FDA determined that 72 of them were so flawed that they had to reject them from their analysis. FDA found another 38 to have serious deficiencies and could therefore only classify them as "supportive" cases. Of the 22 cases that FDA classified as "attributable," FDA's three outside AER reviewers disagreed with FDA's classification in 10 of these cases.

The AERs Include Events That Could Not Be Caused by Ephedra

Furthermore, Drs. Page and Farber found that many of the AERs alleged medical conditions for which there is no scientific or medical foundation that ephedrine alkaloids caused the medical conditions based on the known biological activity and mechanism of action of ephedrine alkaloids. Among the alleged medical conditions that are considered medically implausible or obviously due to some other risk factor are:

• Deaths due to hyperthermia and/or violent exercise and bodily abuse
• Death due to congenital heart defect
• Ovarian tumor
• Thyroid tumor
• Mastitis
• Pancreatitis and hypertriglyceridemia

Despite the inadequacy of the AERs, Drs. Farber and Page prepared a detailed chart for the entire set of 276 AERs that includes the relevant information from each report as well as their conclusion as to the likelihood of a casual connection. This chart was then provided to each of the EEC Expert Panel members for further review and analysis.

There Is No Association between Ephedra When Appropriately Consumed and Serious Adverse Events

After detailed review by the entire panel, the panel reached a consensus conclusion that there is no 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.

Conclusion: FDA's AER database is not useful as a basis for determining whether dietary supplements containing ephedrine alkaloids cause adverse health effects.

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