NEW YORK, Mar 12 (Reuters Health) - Drug giant Warner-Lambert downplayed the potentially fatal risks associated with the diabetes drug Rezulin during the approval process and received help from federal drug regulators in pushing the drug toward marketing approval, according to an article published in Sunday's edition of the Los Angeles Times.

The Times obtained company and government documents, as well as e-mail communications, which showed that Warner-Lambert officials had collaborated closely with certain senior officials within the US Food and Drug Administration during the approval process and later, when the company was being pressured to take the drug off the market.

Rezulin (troglitazone) was initially approved by the FDA in January 1997 for treatment of type 2 diabetes. The drug was pulled from the market in March 2000 due to the number of reports of liver failure associated with its use. At an FDA advisory committee meeting last year, regulators reported that there were 90 cases of liver failure among patients taking the drug since its launch.

Pfizer said on Monday that of the roughly 1.9 million patients who were prescribed Rezulin, fewer than 100 reported acute liver failure that lead to death or transplant.

According to the LA Times, Warner-Lambert executives knew that some patients in clinical studies had sustained life-threatening liver damage, but they assured an FDA panel that the risk was trivial. The paper reported that Warner-Lambert's Dr. Randall W. Whitcomb told an FDA advisory committee on December 11, 1996 that occurrences of liver damage among Rezulin patients was "comparable to placebo" in the clinical studies.

In fact, the paper reports, the incidence of liver damage among users of Rezulin was more than three times higher than patients given a placebo. Among patients taking Rezulin, 2.2% experienced liver injury compared with 0.6% of patients who received an inactive placebo.

Whitcomb now serves as a consultant to Pfizer, which purchased Warner-Lambert last year.

In addition, the paper details efforts by Murray M. Lumpkin, the former second in command of the FDA's Center for Drug Evaluation and Research who tendered his resignation in October 2000, to help curtail criticism of the drug by other FDA officials. The Times cites an e-mail from Warner-Lambert's executive vice president for regulatory affairs, Irwin G. Martin, that suggested Lumpkin canceled a scheduled speech by FDA medical officer Dr. Robert I. Misbin about liver toxicity associated with Rezulin use in 1998.

In addition, FDA officials had pulled Dr. John L. Gueriguian, the medical officer assigned to review Rezulin in the early 1990s, off the review after Warner-Lambert complained that he used profanity to describe Rezulin. Gueriguian had expressed concern as early as 1994 about potential toxicities related to Rezulin. He was removed from the review of Rezulin roughly a month before the drug was presented to the advisory committee.

In addition, according to the paper, Lumpkin told Warner-Lambert officials that Gueriguian's review would not be made available under the Freedom of Information Act, thus keeping its content out of the view of the media and public. Members of the advisory committee were allegedly unaware of the existence of Gueriguian's review when they met to vote on a recommendation for approval.

The paper also details the cooperation of Dr. Henry G. Bone III, chairman of the FDA advisory committee that reviewed Rezulin, in keeping the drug on the US market, even after the committee reviewed reports of the serious adverse events associated with the drug.

Neither Lumpkin nor Bone returned calls to the LA Times seeking comment. Lumpkin has been considered a candidate for the FDA Commissioner slot that has yet to be filled in the Bush administration.

As of mid-October, Pfizer faced 383 lawsuits in state and federal courts related to Rezulin. In addition, the US attorney's office in Greenbelt, Maryland, has questioned FDA officials about the approval process for the drug.

From the time of its approval to market withdrawal, Rezulin brought in revenues of $2.1 billion for Warner-Lambert.

In a statement issued on Monday afternoon, Pfizer said that it "strongly disagrees" with the LA Times' characterization of Warner-Lambert's behavior. "While it does not comment in detail on matters related to current litigation, Pfizer affirmed today that Warner-Lambert appropriately disclosed the risk of adverse liver events before Rezulin...was commercially marketed," the statement reads.

The company also said that Warner-Lambert had disclosed post-marketing adverse events to the FDA in a timely manner, revised Rezulin's label to reflect the new information and sent a letter to physicians advising them of the reports of adverse liver events.

The statement also cited comments made by FDA's Misbin at a public hearing in April 1999, which said that Warner-Lambert's Parke-Davis division had provided complete cooperation shortly after receiving the first report of liver failure. According to Pfizer, Misbin said at that hearing, "speculation that there was foot dragging here is totally without foundation."

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