FDA Acknowledges ‘Possible Missteps’ in Handling Rezulin

In an internal report released yesterday, the FDA acknowledged that it has learned from its mistakes following the withdrawal of the diabetes drug Rezulin and should reevaluate its regulation of prescription drugs, the
Los Angeles Times reports. In its first public acknowledgement of "possible missteps" in its handling of Rezulin, the FDA said it has learned two "lessons" from the incident. Firstly, the agency should focus more attention to the safety of drugs after they are approved and put on the market; secondly, the agency needs to reexamine the "adequacy of current Advisory Committee membership to address issues of risk management." Approved by the FDA in January 1997 after a "fast track" review lasting only six months, Rezulin, produced by Warner-Lambert, was withdrawn from the market last March after it was linked to 63 liver-failure deaths. The report interviewed 14 FDA specialists, six of whom were "involved" with the fast-track review of Rezulin. FDA spokesperson Laura Bradbard said that agency officials "had no immediate comment" on what measures may be taken in response to the document. The report is scheduled to be posted this week on the FDA's Web site at http://www.fda.gov.

The new report "challenges the expertise in drug safety" of the members of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee, who unanimously backed approval of Rezulin and who in March 1999 voted 11-1 to keep it on the market. "A number of concerns were raised about the clinical bias of advisory committee members (who voted on Rezulin) and the need for more expertise in risk management either through the addition of epidemiologic experts ... or by the formation of a 'safety' advisory committee," the report states. The report also pointed to possible conflicts of interest in the approval process, revealing that one interviewee believed that the composition of the advisory committee and the choice of public speakers "were intentionally biased in favor of" Rezulin (Willman, Los Angeles Times, 11/16).

FDA appointed two diabetes researchers who had "been on [Warner-Lambert's] payroll" to the advisory committee on the eve of its meeting to review evidence linking Rezulin to liver failure, even though one of the member's ties to the drug maker "were known by the agency." Committee Chair Dr. Henry Bone "took exception" the report, stating that he believed the committee was composed of "'extremely well-qualified specialists who rendered the best advice they could,' based on data that was presented by the FDA staff and Warner-Lambert." He added that the committee evaluated the issues "thoroughly and thoughtfully."

The report also brings into question the short approval period for Rezulin and the amount of data presented to the advisory committee on the drug. Six of the officials interviewed in the report said they were "concern[ed]" with "the lack of adequate time to review [Rezulin's] approval." Dr. John Gueriguian, the first FDA medical officer to review Rezulin, objected to the fast-track approval of Rezulin, and later "recommended rejection of the drug" in his written medical review because of its "potential to harm the liver and
heart." The FDA gave Gueriguian's report on the drug to Warner-Lambert executives before the advisory committee's meeting to review the drug.

Advisory committee member Dr. Jules Hirsch of Rockefeller University in New York said that the FDA made a "terrible" move by providing the documents to Warner-Lambert in advance. The report "does not acknowledge that the advisory committee was never provided with Gueriguian's medical review." Gueriguian, however, said the new FDA report "should have more sharply fixed accountability on those officials who agreed to grant the fast-track review, who approved Rezulin and who kept it on the market following the first liver failures" that prompted Great Britain to withdraw the drug in December 1997. "This is a hypocritical, self-serving piece of literature," he concluded (Los Angeles Times, 11/16).