REZULIN: Fast-Track Approval and a Slow Withdrawal

 Diabetes drug stayed on the market a year after being listed among the most

Wednesday, December 20, 2000 |  Print this story

By DAVID WILLMAN, Times Staff Writer

     Soon after Warner-Lambert Co. submitted the diabetes drug Rezulin for
FDA review in the summer of 1996, the medical officer assigned to examine it
began finding problems. Dr. John L. Gueriguian cited Rezulin's potential to
harm the liver and the heart. He questioned its viability in lowering blood
sugar for patients with adult-onset diabetes.

Rezulin: Diabetes Drug in Question
     Gueriguian was stripped of the assignment in November 1996 after
Warner-Lambert complained that he used intemperate language while discussing
the drug. His medical review--recommending against approving Rezulin--was
purged from agency files and withheld from an FDA advisory committee.
     Officials completed the review of Rezulin within six months and
approved it in January 1997. Warner-Lambert's chief executive told investors
he foresaw a "billion-dollar blockbuster."
     By fall 1997, dozens of patients on Rezulin had been hospitalized and a
handful of cases of sudden liver failure had been reported to the FDA.
     Those first cases prompted the removal of Rezulin from the market in
Britain on Dec. 1, 1997--sparking an 18% drop in Warner-Lambert's stock on
the New York Stock Exchange. But senior FDA officials stood behind Rezulin
by embracing a series of incremental labeling changes.
     Two changes came in late 1997 and a third came in July 1998. Each
change recommended the monitoring of patients' liver functions as a means of
safeguarding against organ failure.
     In March 1999, a senior FDA epidemiologist, Dr. David J. Graham, warned
that Rezulin was among the most dangerous drugs on the American market. He
said that patient monitoring would not protect them from liver failure.
Indeed, three patients who were monitored monthly in controlled studies,
including one by the National Institutes of Health, suffered liver failure
and died.
     "The death of the patient . . . in [the] NIH study in May 1998 provided
strong evidence that Rezulin could not be used safely," Dr. Robert I.
Misbin, an FDA medical officer, wrote in a July 3, 2000, letter to the House
Energy and Commerce Committee.

     Rezulin had not been proved to save lives or to reduce the serious
complications of adult-onset diabetes. A fourth label change was implemented
in June 1999. But deaths and hospitalizations continued.
     The FDA announced on March 21 that Rezulin would be pulled from the
market. By that time, the agency had tied 63 liver failure deaths to the
drug. Reports filed with the agency through June 30 cited Rezulin as a
suspect in a total of 391 deaths.
     Officials have never estimated how many Rezulin patients died of
heart-related complications. As a condition of approval, the FDA had
requested that Warner-Lambert perform a study of the drug's effect in
heart-failure patients; the study was never completed.
     Before and after the withdrawal, FDA officials overstated Rezulin's
scientifically proved benefits. For instance, agency ombudsman James
Morrison wrote in June that Rezulin "has been shown to reduce or delay
long-term, serious effects of diabetes, including death." Asked the basis
for this claim, FDA spokesman Laurence Bachorik said the comments "were not
intended as definitive scientific observations."
     Six specialists who were involved in Rezulin's approval recently
questioned why the drug was given a fast-track review. A "Lessons Learned"
report posted in November on the agency's Web site said: "A final major
concern of the subjects interviewed . . . was the lack of adequate time to
review the application."
     Woodcock said agency specialists had hoped Rezulin would offer
"significant improvement" over the nine or more existing treatments for
adult-onset diabetes. As for the decisions that kept Rezulin on the market,
Woodcock said she wanted first to see if two newer drugs approved in 1999
were less toxic to the liver. Gueriguian said Rezulin is an example of how
senior FDA officials relied on a company's hopes at the expense of public
     "It really doesn't matter if it was incompetence or dishonesty," he
said. "The result is the same: People died unnecessarily."
     Rezulin generated sales totaling $2.1 billion for Warner-Lambert in its
three years on the U.S. market.