Physician Who Opposes Rezulin Is Threatened by FDA With Dismissal

Food and Drug Administration officials are threatening to fire an agency medical officer who has pushed in recent weeks for withdrawal of the diabetes pill Rezulin, government documents show.

The FDA’s threatened dismissal of Dr. Robert I. Misbin--detailed this week in e-mail correspondence obtained by The Times--comes as the agency is facing mounting questions about its handling of Rezulin.

Misbin examined in depth the risks and benefits of Rezulin before the FDA approved the drug in 1997 and before the agency twice subsequently endorsed widening its recommended use. He had supported each of the FDA’s previous actions.

However, since early January, Misbin and at least four other FDA physicians--most of them more senior--have told colleagues that Rezulin should be withdrawn because of its propensity to cause liver failure and death.

As of last week, the FDA had linked 89 voluntarily reported liver failures, including 61 deaths, to the use of Rezulin. Through January of this year, Rezulin had generated sales topping $1.8 billion.

The FDA physicians’ repudiation of the drug was captured, in part, in e-mail correspondence that Misbin provided recently to members of Congress. Now, Misbin’s distribution of that correspondence appears to have placed him in jeopardy with his superiors and with FDA internal affairs investigators.

In an e-mail dated March 13, the acting chief of the FDA’s endocrine drugs division, Dr. John K. Jenkins, warned Misbin: “You are required to cooperate with the investigation and failure to cooperate may result in disciplinary actions up to an[d] including dismissal from federal service.”

Jenkins told Misbin that the investigation was “related to possible inappropriate release of information to individuals outside the FDA” and was “separate from the ongoing internal discussions regarding what, if any, regulatory actions are warranted at this time with regard to Rezulin.”

The threat of disciplinary action was underscored in a subsequent e-mail to Misbin from investigator David S. Bodge.

The e-mails show that Misbin, 52, was informed that he could not bring a witness with him while being interrogated by an FDA internal affairs investigator. Misbin’s request that all questions be put to him in writing was also rejected, according to the correspondence.

Citing policy, an FDA spokeswoman, Laura Bradbard, said Thursday that the agency could not comment. Misbin said that he too would not discuss the matter.

Jenkins distributed a copy of the March 13 e-mail to his boss, Dr. Murray M. Lumpkin, director of the FDA’s Center for Drug Evaluation and Research. Lumpkin serves as the FDA’s point man for ensuring that the agency reviews and approves new drugs more quickly than in the past.

Previously undisclosed government records and interviews show that Lumpkin has provided crucial support for Rezulin over the last 3 1/2 years:

In October 1996, Lumpkin stripped another FDA medical officer, Dr. John L. Gueriguian, of further involvement in reviewing Rezulin after Gueriguian, citing potential liver and heart toxicity, recommended that the agency reject the drug. Lumpkin acted at the request of Rezulin’s manufacturer, Warner-Lambert Co., whose executives complained that Gueriguian had used intemperate language in a meeting to discuss Rezulin.

“Mac [Lumpkin] basically was hoping that the Gueriguian thing would go away and we could just kind of lose the review,” one physician, who was involved with the FDA’s “fast-track” approval of Rezulin, said this week. “The company didn’t feel that [it] should have to respond to anything that Gueriguian was saying.”

Lumpkin agreed with Warner-Lambert, according to the physician involved, who spoke on condition of anonymity. “He just said that the Gueriguian review doesn’t exist because it was in draft form and hadn’t been finalized. . . . Obviously, in hindsight, it should have been handled differently.”

This physician and others have said that, before approving Rezulin, the FDA shared Gueriguian’s review with Warner-Lambert and later purged the document from agency files.

A year later, in fall 1997, Lumpkin oversaw the FDA’s decision to keep Rezulin on the U.S. market, despite the drug’s withdrawal in Britain. On Nov. 26, 1997, Lumpkin spoke by phone with an official at the Medicines Control Agency in London.

According to an e-mail that Lumpkin distributed that day to his boss, drug center director Janet Woodcock, Misbin and six other FDA officials, the British agency thought it was “reasonable” to withdraw Rezulin, based on deaths and liver injuries in the United States and Japan. The impetus for the withdrawal had come from Glaxo-Wellcome, the company with rights to market Rezulin in Europe.

Glaxo officials had concluded, Lumpkin wrote, that “they no longer believed the risks outweighed the benefits” for at least two reasons: There was no way to predict which Rezulin patients would be harmed, and the pace of liver injuries and deaths was by that point “unacceptably high.”

The next day a Warner-Lambert executive, Irwin G. Martin, wrote to the FDA, proposing “a meeting to review the status of the Rezulin safety reports and to finalize” a change in Rezulin’s safety labeling. Martin said that the company “would encourage Dr. Lumpkin’s participation” at the meeting, along with two other senior officials.

On Dec. 1, 1997, the FDA announced a safety-labeling change, the second in less than a month for Rezulin. The newer label recommended that patients should submit to more frequent liver-function tests.

Lumpkin also oversaw the third and fourth changes in Rezulin’s labeling, in July 1998 and June 1999. Each labeling change called for more frequent liver-function testing. Each was followed by an increase in the total number of Rezulin patients suffering liver failure and death. Lumpkin has declined to be interviewed and did not return calls Thursday.

Misbin, the FDA medical officer who now finds himself at risk of being fired, noted a contrast in the agency’s response to the dangers of Rezulin and in the public disclosure of his and others’ alarm.

“The ‘inappropriate release of information to individuals outside the FDA’ could undermine [public] trust and should be the subject of a timely and vigorous investigation,” Misbin wrote in a March 14 e-mail response to Jenkins, his boss. “But had FDA been equally vigorous in dealing with the Rezulin problem, we would not be at the impasse that we currently face.”

The FDA is also reviewing a letter issued Tuesday by Dr. Sidney M. Wolfe of the Ralph Nader-founded group, Public Citizen, asking FDA Commissioner Jane E. Henney to seek “criminal prosecution” of Warner-Lambert for the manner in which the company depicted certain severe cases of liver toxicity during original clinical testing of Rezulin.

In interviews with The Times in the fall of 1998, a Warner-Lambert executive, Dr. Randall W. Whitcomb, and a senior FDA official, Dr. James M. Bilstad, said that the liver cases now called into question by Wolfe were reported to the agency before the drug was approved on Jan. 29, 1997.

Wolfe on Thursday did not dispute that the cases may have been reported in a timely manner to the FDA but speculated that Warner-Lambert buried them “within three feet of other data.” A spokeswoman for the company called Wolfe’s letter “baseless.”

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