FDA Post-Mortem Finds Drug Approval Problems

Key aspects of the Food and Drug Administration’s regulation of prescription drugs should be reevaluated in the wake of the safety withdrawal of the diabetes pill Rezulin, according to a newly issued agency report.

The new report is the first FDA acknowledgment of possible missteps in the agency’s handling of Rezulin, including officials’ decision to examine the safety and effectiveness of the drug within a “fast-track” review of just six months.

Rezulin was withdrawn on March 21 after the FDA attributed 63 liver-failure deaths to use of the drug. Experts believe the actual total of fatalities could be 10 times higher because adverse reactions to prescription drugs, including deaths, are reported only voluntarily by doctors and others.

The report marks the FDA’s first attempt to publicly distribute such a post-mortem of its controversial handling of an ill-fated drug. An FDA spokeswoman, Laura Bradbard, said that officials had no immediate comment on any steps that may be taken in response to the eight-page document, posted this week on the agency’s Web site.

Two “lessons learned,” according to the report: The FDA should focus more attention on the safety of drugs after they are approved and have entered the marketplace. And the agency should reexamine “the adequacy of current [Endocrinologic and Metabolic Drugs] Advisory Committee membership to address issues of risk management.” The recommendations of advisory committees, although not binding on the FDA, are usually adopted by the agency.

The report challenges the expertise in drug safety of members of an FDA advisory committee who backed approval of Rezulin and who later opposed withdrawal of the pill. The document is based on comments gathered by a senior agency official, Dr. Mark Goldberger, from 14 unidentified FDA specialists who were involved with the regulatory decisions.

“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 concludes, adding:

“One interviewee felt that the composition of the advisory committee and the selection of public speakers were intentionally biased in favor of” Rezulin.

The FDA advisory committee unanimously endorsed the approval of Rezulin in December 1996. After the agency opened a formal reassessment of Rezulin, the panel voted 11 to 1 in March 1999 to recommend that the drug be left on the U.S. market.

The advisory committee vote in March 1999 was taken the same week that the office of FDA Commissioner Jane E. Henney appointed two physicians to the panel who were paid consultants to a group established and financed by the manufacturer of Rezulin, the Warner-Lambert Co. After The Times disclosed the eleventh-hour appointments, one of the two physicians declined to participate.

The director of the FDA’s drug-review center, Dr. Janet Woodcock, has cited the advisory committee’s recommendations while defending her decisions to keep Rezulin on the market for nearly 2 1/2 years after it was withdrawn from Britain because of lethal liver toxicity. Woodcock’s longtime deputy director, Dr. Murray M. “Mac” Lumpkin, a staunch defender of Rezulin who opposed the drug’s withdrawal, resigned his senior agency post last month.

The advisory committee chairman, Dr. Henry G. Bone III of Detroit, took exception to the report when reached Wednesday. He said the advisory committee was composed of “extremely well-qualified specialists” who rendered the best advice they could, based on the data that was presented by the FDA staff and Warner-Lambert.

“The issues presented to the committee were thoroughly and thoughtfully considered,” Bone said.

Of the 14 FDA specialists interviewed by Goldberger for the new report, six were described as involved with the fast-track review of Rezulin, which culminated with its approval on Jan. 29, 1997.

“A final major concern of the subjects interviewed who were involved . . . was the lack of adequate time to review the application,” the report states.

Goldberger did not interview the first FDA medical officer who reviewed Rezulin, Dr. John L. Gueriguian. Records show that Gueriguian opposed granting a fast-track review to Rezulin in August 1996. In October of that year, he recommended rejection of the drug in his written medical review. He cited Rezulin’s potential to harm the liver and heart and he questioned the drug’s effectiveness in lowering blood sugar among adult-onset diabetics.

The newly issued FDA report does not acknowledge that the advisory committee was never provided with Gueriguian’s medical review. FDA officials did give Gueriguian’s review to Warner-Lambert executives in advance of the December 1996 advisory committee meeting, records and interviews show.

Another advisory committee member, Dr. Jules Hirsch of Rockefeller University in New York, said in an interview Wednesday that, in retrospect, he thinks the FDA made a “terrible” move by providing Gueriguian’s review to Warner-Lambert, but not to the advisory committee.

“Why should they be provided with anything that the advisory committee isn’t provided with?” Hirsch asked.

Gueriguian, reached at his consulting firm’s office in Paris, said that 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 the December 1997 withdrawal from Britain.

“This is a hypocritical, self-serving piece of literature,” said Gueriguian, who retired from the FDA in fall 1998.

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Times researcher Janet Lundblad in Los Angeles contributed to this story.

The investigative series by staff writer David Willman on the FDA’s fast-track approval of Rezulin is available on The Times’ Web site. Go to: https://www.latimes.com/rezulin