http://www.latimes.com/news/nation/reports/fda/lat_rezulin001220.htm
Wednesday, December 20, 2000
REZULIN:
Fast-Track Approval and a Slow Withdrawal
Diabetes drug stayed on the market a year after being listed among
the most risky.
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.
SPECIAL REPORT
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 health.
"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.
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