Dietary Supplements:

Uncertainties in Analyses Underlying FDA's Proposed Rule on Ephedrine Alkaloids

HEHS/GGD-99-90: Published: Jul 2, 1999. Publicly Released: Aug 4, 1999.

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Pursuant to a congressional request, GAO reviewed the analyses underlying the Food and Drug Administration's (FDA) proposed rule on the food supplements, ephedrine alkaloids, focusing on: (1) the scientific basis for FDA's proposed rule; and (2) FDA's adherence to the regulatory analysis requirements for federal rulemaking.

GAO noted that: (1) FDA based its proposed rule on numerous reports of adverse events associated with products thought to contain ephedrine alkaloids; it also used evidence from scientific literature indicating that ingestion of ephedrine alkaloids adversely affects some individuals; (2) the number and type of adverse event reports (AER) warranted FDA's consideration of steps to address safety issues; (3) however, GAO has concerns about the strength of some of the information FDA used to support two aspects of the proposed rule: the dosing level and duration of use limits; (4) while there was scientific evidence showing adverse events at levels above 20 milligrams (mg) per serving, FDA's dosing level proposal of 8 mg per serving was based on information associated with only 13 AERs--the quality of which is questionable; (5) for the duration of use limits, FDA relied on scientific studies that showed problems associated with extended use, well beyond the 7-day limit proposed; (6) moreover, FDA did not establish a causal link between the ingestion of ephedrine alkaloids and the occurrence of adverse events for either its proposed dosing level or duration of use; (7) FDA also based its estimate of the benefits of the proposed rule on the annual number of adverse events reported to FDA; (8) however, because FDA did not document which AERs it identified as containing serious events, GAO could not determine the accuracy of FDA's estimated benefits; (9) in addition, FDA has no internal guidance on the use of AERs for rulemaking related to foods and dietary supplements, and the AERs were used differently in this proposed rule than in prior rulemaking; (10) the agency generally complied with the statutory and executive order requirements for rulemaking, but the cost-benefit analysis that accompanied the rule does not reflect the full range of uncertainty associated with the proposed rule; (11) FDA's cost-benefit analysis and other analyses included the primary elements required under Executive Order 12866 and related best practices guidance and the Regulatory Flexibility Act; (12) the Unfunded Mandates Reform Act's requirements did not appear to apply to the rule; (13) although FDA disclosed the basic methodology, data, and assumptions used in its cost-benefit analysis, the agency did not always disclose why certain key assumptions were made or the degree of uncertainty involved in those assumptions; and (14) it also did not disclose that alternative assumptions would have had a dramatic effect on the agency's estimate of the benefits of the proposed actions.

Recommendations for Executive Action

  1. Status: Closed - Implemented

    Comments: FDA is continuing to monitor and evaluate reports associated with the use of ephedrine alkaloid-containing dietary supplements and is reviewing new scientific literature. Within a few months, FDA plans to reassess the requirements of its proposed rule on ephedrine alkaloids and the need for alternative regulations. Consistent with one of GAO's recommendations, in 2003 FDA withdrew the provisions of the ephedrine alkaloids proposal relating to the dietary dosing regime and duration limits and reopened the proposed rule for further comment. After obtaining and reviewing further evidence concerning ephedrine alkaloids' safety and effectiveness, FDA issued a final rule prohibiting the sale of dietary supplements containing ephedrine alkaloids in February 2004.

    Recommendation: Given the uncertainties in the information upon which FDA based its proposed rule, the Secretary of Health and Human Services should 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.

    Agency Affected: Department of Health and Human Services

  2. Status: Closed - Not Implemented

    Comments: Before publishing a final rule, FDA will take appropriate steps to correct the deficiencies in its cost-benefit analysis, and more fully explain the rationale for its assumptions, any related uncertainties, and the implications of plausible alternative assumptions.

    Recommendation: The Secretary of Health and Human Services should direct the Commissioner of FDA to improve the transparency of FDA's cost-benefit analysis in its final rulemaking. Specifically, FDA should more fully explain the bases of its cost-benefit assumptions, the degree of uncertainty associated with those assumptions, and the implications of plausible alternative assumptions to the proposed action and other regulatory alternatives.

    Agency Affected: Department of Health and Human Services

 

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