FDA, Drug Firm Continue to Debate Worthiness of Rezulin


On the eve of a showdown meeting concerning the diabetes drug Rezulin, the maker of the pill and physicians at the Food and Drug Administration are sharply at odds over the medication’s worthiness.

The New Jersey-based Warner-Lambert Co. maintains that the worst side effect linked to Rezulin--liver failure--is largely a problem of the past. But according to the FDA, new cases of liver failure attributable to use of the drug continue to emerge.

The controversy is now in the hands of Dr. Murray M. Lumpkin, 46, a senior FDA executive who in 1997 oversaw Rezulin’s “fast-track” approval. Last month, he rebuffed suggestions by agency physicians to promptly withdraw the drug. Lumpkin will preside at a private meeting with Warner-Lambert representatives on Wednesday at FDA headquarters in Rockville, Md.

Key Decision in FDA’s Hands


Lumpkin and his superiors--FDA Commissioner Jane E. Henney and Dr. Janet Woodcock, head of the agency’s drug-review center--could announce a decision promptly or not for weeks. They have several options that include imploring the company to voluntarily withdraw Rezulin, declaring that the FDA no longer believes the benefits of Rezulin outweigh its risks or leaving the drug on the market without change.

Lumpkin did not return phone calls seeking his comment.

Lumpkin often has advocated “managing” the risks of drugs through the safety labeling, or recommended use, that appears in packaging and in medical reference publications. Lumpkin has overseen four safety changes to the labeling of Rezulin since the drug went on the market in March 1997. Each label change has recommended stricter steps to monitor patients’ liver functions.

However, staunching the incidence of liver failure and related organ injuries among patients has proved difficult.


As of mid-February, the FDA said that 85 cases of liver failure--including 58 deaths--could “possibly or probably” be linked to patients’ use of Rezulin. This is more than double the number of such cases acknowledged by the FDA in March 1999.

Adverse reactions to Rezulin and other prescription drugs are reported voluntarily by doctors and others. Because of fears of malpractice lawsuits and other factors, the reports can represent as few as 1% of the total events, according to specialists.

The FDA’s senior epidemiologist warned officials in March that every patient taking Rezulin was at risk of liver failure--and there was no reliable way to protect them. Furthermore, Dr. David J. Graham said that the longer a Rezulin patient remains on the drug, the higher the chance of liver failure.

Rezulin is one of at least 11 drugs that can lower blood-sugar levels for patients with adult-onset diabetes. When the FDA granted fast-track review and approval to Rezulin, no evidence from clinical trials was presented showing that the drug prolonged lives.

Warner-Lambert executives, who originally marketed Rezulin as having side effects “comparable to placebo,"--have over the last 2 1/2 years repeatedly assured prescribing physicians that the risk of liver failure was very rare and declining.

A review of the many safety claims made by Warner-Lambert--capped by its most recent assurance to physicians, last week--illuminates how the company has characterized Rezulin’s ongoing risk amid a climbing total of reported deaths:

Dec. 1, 1997: Just over a month after acknowledging the first liver-failure death of a Rezulin patient, the company said in a “Dear health care professional” letter: “You will be reassured to know that the additional reports received since early November [when the label was first changed] do not indicate a greater frequency of liver injury or potential for serious harm than had been previously estimated.”

June 5, 1998: While denying Rezulin caused the liver failure and death of a participant in a nationwide clinical trial, Warner-Lambert said: “Recent changes in Rezulin labeling [in December 1997], which introduced new liver monitoring guidelines, have proven effective. Since then, reported liver events have steadily decreased.”


Dec. 7, 1998. A company news release said that each of 33 Rezulin liver-failure deaths acknowledged as of this point by the FDA “occurred with patients that started therapy prior to the most recent changes in labeling [in July 1998].” The company added: “Since the first label revisions in 1997 that recommended periodic monitoring of liver function, the rate of serious liver-related adverse events has fallen substantially.”

March 26, 1999. On the day of an FDA advisory committee hearing to review Rezulin’s safety, a Warner-Lambert “fiction vs. fact” statement said that “most” Rezulin-related liver deaths “were before the last label change [in July 1998].” The company also said that the risk of liver failure from Rezulin dropped dramatically after the first six months of treatment. “The risk for jaundice and death due to liver failure and transplant substantially declines after six to eight months of therapy,” Warner-Lambert’s Dr. Mark Pierce told the advisory committee.

This claim was rejected at the time by Graham, the FDA’s senior epidemiologist, who noted that relatively few patients used the drug longer than six months. Yet according to FDA data provided to The Times last month, about 27% of the Rezulin-related liver failures now confirmed by the agency occurred with patients who took the drug for seven months or longer.

Feb. 24. In a prepared statement, Warner-Lambert said that, among patients starting Rezulin “after the most recent label revision” on June 16, 1999, the company did not believe any liver-failure deaths or transplants could rightfully be attributed to the drug.

FDA Says Risk of Liver Failure Continues

But the FDA indicated the risk of liver failure persists. On Friday, an FDA spokeswoman, Laura Bradbard, said: “We have received reports of six cases of liver failure with onset from July 1999 forward [possibly or probably related to Rezulin]. Of these six cases, three died, one recovered and [the] outcome is unknown in two of them.”

A spokeswoman for Warner-Lambert declined on Monday to specifically address the six cases, saying the company “will not debate the number of adverse liver events in the media.”

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