Key Physician Urges Rezulin Be Withdrawn

WASHINGTON —  The physician most closely involved with the government’s approval and continued support of the controversial diabetes pill Rezulin has urged its withdrawal from the U.S. market.

“I see no reason why any well-informed physician would continue to prescribe [Rezulin],” Medical Officer Robert I. Misbin wrote in a Jan. 24 e-mail to his superiors at the Food and Drug Administration. “Neither do I see any reason why FDA should delay in taking steps to remove [Rezulin] from the market.”

Unless the FDA withdraws the drug, Misbin warned, “additional cases of preventable liver failure” may occur. A copy of the two-page e-mail was obtained by The Times.

Misbin’s correspondence and interviews with people familiar with the matter suggest that pressure is building within the FDA to take Rezulin off the market, despite opposition from the drug’s manufacturer, New Jersey-based Warner-Lambert Co. Misbin, 52, is a veteran diabetes specialist whose job at the FDA is to evaluate the safety and effectiveness of proposed and existing drugs.

Rezulin, which the FDA made one of the fastest-approved prescription drugs over the last decade, has generated $1.8 billion in sales since March 1997. It is used to treat adult onset diabetes, a disease characterized by high blood-sugar levels.

The number of injuries and deaths attributable to Rezulin has continued to mount since the first fatalities were acknowledged in the fall of 1997. New data gathered by the FDA reveal that nearly twice as many Rezulin patients have suffered liver failure than officials cited at a public hearing just 11 months ago.

Dr. Janet Woodcock, director of the agency’s drug review center, said in a prepared statement this week that the FDA has received 85 reports of liver failure that are considered “possibly or probably related” to use of Rezulin. Of those, 58 patients died and 10 required liver transplants, Woodcock said.

Last March, FDA officials acknowledged that 43 liver-failure cases, including 28 deaths, could be attributed to use of Rezulin.

Woodcock said in her statement to The Times that the agency “at this time” believes the benefits of Rezulin still outweigh its risks; she would not elaborate. Misbin said Friday that he would not comment.

At Warner-Lambert, Dr. Robert L. Zerbe, the company’s senior vice president of worldwide clinical research, said Friday that he was unable to discuss the number of liver failure cases attributable to Rezulin. Company officials did not respond to requests for any elaboration. Warner-Lambert repeatedly has sought to assure doctors and patients that the drug is safe and effective if used as recommended.

‘I Would Not Use It, Myself’

A member of the 12-person FDA advisory committee that examined Rezulin 11 months ago said Friday that he was “not surprised” to hear of the doubling of reported liver-failure cases associated with use of the drug.

“I’m really very concerned about the continued use of it,” said Dr. Jules Hirsch, physician-in-chief emeritus, at Rockefeller University in New York. “I would not use it, myself.”

Rezulin’s propensity to cause liver failure and the inability of doctors to predict which diabetic patients might be stricken has helped make the drug among the most controversial in the American marketplace. Rezulin was withdrawn in Britain in December 1997, and officials there have refused to allow its reintroduction.

Officials at the FDA have kept Rezulin on the market, while overseeing four safety-related changes in the drug’s labeling.

Within the agency, Misbin had been an advocate of Rezulin. He supported the original approval in January 1997. When fatalities were first reported, Misbin assumed responsibility for overseeing the drug’s safety risks. Based in part on his medical reviews, the agency twice approved expanded recommended uses of the drug, most recently in June.

While he consistently backed keeping Rezulin on the market, Misbin also warned his supervisors in November 1997 that as many as 2,000 patients then taking Rezulin could suffer serious liver injury unless they were monitored closely.

Long before Misbin’s change of view toward Rezulin, two other FDA physicians who studied the drug closely had raised alarms.

In October 1996, Medical Officer John L. Gueriguian cited Rezulin’s potential to harm the liver in his recommendation not to approve the drug.

Last March, Dr. David J. Graham, a senior agency epidemiologist, publicly warned the FDA advisory committee that every Rezulin patient was at risk of sudden liver failure and that no reliable way existed to protect them. Graham said that the longer patients stay on Rezulin, the greater their risk of liver failure.

Graham presented data indicating that the monitoring of liver functions recommended for Rezulin patients--monthly blood tests for one year--was insufficient to save them from spiraling into sudden liver failure.

The FDA in June followed the advice of the committee and Misbin by approving a new recommended use for Rezulin, in combination with two other diabetes pills. At the same time, the agency suggested that Rezulin no longer be used as a drug of first choice in treating adult-onset diabetes. No fewer than 11 other prescription drugs are available on the U.S. market for the disease.

Debate Continues Over Drug

Now, Rezulin’s status is once again at a crossroads.

In his e-mail, Misbin noted, “there appeared to be broad agreement that continued marketing of [Rezulin] was not justified” during a Jan. 6 staff meeting of specialists at the FDA’s drug-review center.

Misbin wrote that he was “perplexed by what happened” when agency officials next convened on Jan. 13.

At that meeting, a deputy director of the FDA’s drug-review center, Dr. Murray M. Lumpkin, unveiled steps that would slow any movement toward withdrawal, according to people familiar with the session. For instance, Lumpkin scheduled meetings with representatives of Warner-Lambert on Feb. 2 and March 1.

Lumpkin has directed that, before any decision is reached to withdraw Rezulin, FDA physicians must first reassess the safety of Avandia and Actos, two newer, chemically similar pills, officials said. The FDA’s obligation under law is to ensure that no drug is approved or remains on the market unless it is safe and effective for its recommended use.

Lumpkin did not return messages seeking his comment.

As for Avandia and Actos, the FDA staff does not believe that Actos has been associated with liver failure. The agency staff believes that the liver failure of one Avandia patient, who recovered, was “possibly or probably” related to the drug, according to Dr. Woodcock. The FDA approved Avandia in May and Actos in July.

The FDA over the last 2 1/2 years has overseen the withdrawal of seven prescription drugs. In each of those instances, the company involved either acted without prompting or at the encouragement of the FDA.

If a company asked to withdraw a drug is intransigent, the government is empowered under law to remove the compound immediately if it poses an “imminent hazard to the public health.”

In his recent e-mail, Misbin said that FDA officials on Jan. 6 “seriously entertained” declaring Rezulin an imminent hazard.

In 1977, Health, Education and Welfare Secretary Joseph A. Califano Jr. invoked this provision to ban another diabetes drug, called phenformin.

The decision of whether to withdraw Rezulin rests ultimately with FDA Commissioner Jane E. Henney. She referred all questions posed by The Times to her subordinate, Dr. Woodcock.

Rezulin prescriptions have declined over the last year, from 488,000 in January 1999 to 309,000 that were started or refilled last month, according to IMS Health, a health care information company.

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