The L.A. Times reported on the Rezulin recall history, outlining
notable events in the development from the arrival of Rezulin onto
the market until reports of the federal investigation into Rezulins
The federal health agency, The National Institutes of Health, chooses
Rezulin to use in a $150 million diabetes study, run by Richard
Eastman, the governments top diabetes doctor and hired by
Warner-Lambert, the diabetes drug developer, as a consultant to
launch Rezulin. After the study Warner-Lambert issues a press release
saying that Eastman found Rezulin to correct underlying causes
Rezulin manufacturer, Warner-Lambert applies for the FDA approval
of the diabetes drug under the fast-track procedures
fairly recently enacted.
FDA scientists become concerned with the potential Rezulin appears
to have to harm the liver and heart
in animal studies. The first FDA doctor to look at Rezulin was Dr.
John Gueriguian who was opposed to the drugs approval.
Warner-Lambert has Dr. Gueriguian removed from the Rezulin evaluation
after the manufacturer complains about his intemperate language.
His removal also dismisses his Rezulin review from the FDA files.
Rezulin is presented by Warner-Lambert to an FDA advisory committee
in order to get approval and states that their diabetes drug does
not increase cardiac mass or impair cardiac function.
Rezulin received FDA approval through the fast track
approval procedure that cut the time it took to be approved in half
the normal time. There is no liver testing required.
top of page
The FDA states that Warner-Lambert made false and misleading
claims about Rezulin in a press release, recommending the news release
be immediately discontinued, as well as any other piece of information
containing similar claims.
Warner-Lamberts clinical studies indicated that Rezulin users
were 3.6 times more likely to suffer liver injury than patients
taking placebos, but the company runs a full-page, color magazine
ad describing Rezulin as having side effect comparable to placebo.
The CEO of Warner-Lambert tells investors that Rezulin holds the
potential to be a billion dollar blockbuster.
The FDA Diabetes Group Leader, Dr. Alexander Fleming, finds it
hard to believe that patients with cardiac, liver, or renal
disease would not be adversely affected by the drug.
The FDA receives two reports of Rezulin
top of page
The FDA requires the Rezulin label
be changed http://www.fda.gov/bbs/topics/ANSWERS/ANS00831.html
to recommend liver enzyme tests within the first one to two months
and then every three months during the first year of Rezulin therapy
and then periodically after that. Symptoms of Rezulin liver dysfunction
including, nausea, vomiting, abdominal pain, fatigue, loss of appetite,
or dark urine should get liver function tests performed. Any Rezulin
patient who develops a liver injury should immediately discontinue
the use of the drug. Clinical trials showed approximately 2% of
Rezulin patients should be expected to stop taking the drug due
to an elevated level of liver enzymes.
Dr. Robert I. Misbin, an FDA diabetes specialist that supported
the Rezulin approval, sent an internal report to FDA supervisors
stating that 21 patients treated with Rezulin prior to FDA approval
had to discontinue the drug due to Rezulin liver injury, 13 patients
had markers of Rezulin liver injury 10 to 30 times above normal
which can threaten the lives of patients, and an estimated 2% or
12,350 of the 650,000 patients using Rezulin would experience some
degree of liver injury.
England prohibits sales of Rezulin due to concerns about liver
damage to patients in the U.S. The FDA announces a label
to require more frequent Rezulin liver testing. The new label recommends
liver enzyme tests before starting Rezulin, monthly for the first
six months of treatment, every other month for the next six months,
and periodically thereafter.
top of page
A 55 tear old woman in good health dies of Rezulin liver failure
while participating in the National Institutes of Health diabetes
study. The panel of specialists hired by NIH concluded that her
liver failure was probably due to the use of Rezulin diabetes drug.
The NIH study drops Rezulin due to the risk of liver
damage in the remaining participants.
A press release by Warner-Lambert denies Rezulin killed the woman
and instead claimed her death was the result of complications unrelated
to the study or the diabetes medication. The FDA had then received
21 reports of Rezulin liver failures resulting in death and three
Rezulin liver transplant patients.
The consumer group Public Citizen filed a petition for the immediate
ban of Rezulin. At this point the FDA had received 26 reports of
Rezulin liver failure deaths.
top of page
The FDA required another Rezulin label change http://www.fda.gov/medwatch/safety/1998/rezuli.htm
to increase the frequency of liver testing. The recommendation then
stated a Rezulin patient be tested before using Rezulin, monthly
for the following 8 months and every two months for the rest of
the year and periodically after that.
The FDA Commissioner orders a reevaluation of Rezulin after the
series of articles by the Los Angeles Times investigated the fast
track drug Rezulin tied to 33 Rezulin liver failure deaths.
After two months of FDA research the findings are present to an
FDA advisory panel. The report found that an estimated 430 or more
Rezulin patients have suffered a liver failure, Rezulin patients
incur 1,200 times more risk of liver failure, one out of every 1,800
Rezulin patients can expect t suffer a liver failure, and liver
function tests do not provide enough protection due to the rapid
and unpredictable way Rezulin can affect the liver. In addition,
Rezulin patients did not follow the recommended liver function tests
after more than 4 months on the drug.
A Rezulin patient undergoing monthly monitoring in a Warner-Lambert
clinical trial dies of liver failure.
The FDA requires the Rezulin label be changed http://www.fda.gov/bbs/topics/ANSWERS/ANS00960.html
for the fourth time now, increasing the frequency once again for
liver tests. The new label recommended Rezulin patients get monthly
liver monitoring for the first year on the diabetes drug.
top of page
The Los Angeles Times reports 21 Rezulin patients have died of
liver failure since the March 26, 1999 report by Dr. Graham to the
FDA Advisory Panel. Graham begins a new analysis of Rezulin despite
his supervisors having no knowledge of his actions.
Dr. Graham sends an email to 14 FDA officials with the opinion
that Rezulin is unsafe and should be stopped due to the liver failure
problems occurring. Graham stated there was no existing data to
support the idea that monitoring can prevent the Rezulin liver failures
The FDA diabetes specialist who had analyzed the first cases of
liver failure in October to November 1997 sends eight members of
Congress internal FDA emails discussing Rezulin liver toxicity.
Included in the email was the correspondence he had received from
Dr. Janet B. McGill who had conducted early research on Rezulin
for Warner-Lambert saying the company deliberately omitted
reports of liver toxicity and misrepresented serious adverse events
experienced by Rezulin patients in their clinical studies.
The FDA opens an internal-affairs investigation after Warner-Lambert
complains about the leaks.
The FDA withdraws Rezulin from the U.S. market (http://www.fda.gov/bbs/topics/NEWS/NEW00721.html)
after finding the benefits of other diabetes drugs offer the same
benefits Rezulin did without the same risks. Up to this point Warner-Lambert
had grossed $2.1 billion in Rezulin sales. The FDA had reports of
63 Rezulin liver failure deaths.
The L.A. Times reports about the Federal prosecutors examining
the FDAs quick approval method and the delayed withdrawal
of Rezulin. It was reported that both the FDA and Warner-Lamberts
actions were being examined.
top of page