Rezulin Recall

Notable Quotes

“The Times, citing Warner-Lambert emails and memos, said the company knew as early as 1993 of at least one case of a patient who showed liver damage after taking Rezulin.”

MSNBC, March 11, 2001

“I am writing to enlist your aid in convincing my superiors at FDA that Rezulin should be removed from the market because of its unacceptably high risk of causing liver failure.”

Dr. Robert Misbin, FDA medical officer and Rezulin reviewer
(CNN, 3-22-00)

“Easily more people have died between the time of our petition and when this belated…(FDA)…action was taken.”

Sidney Wolfe, Public Citizen director of the time it took the FDA to withdraw Rezulin and the July 1998 petition. (CNN, 3-22-00)

“The Echo Study was not properly conducted, according to the standard protocol. I was not made aware of the fact that the patients from this site, in particular, for whatever reason, whether it was due to technique or whatever, that they had increased left ventricular mass.”

Dr. Paresh Dandona, endocrinologist who served as Warner-Lambert’s principal investigator for the Buffalo Echo Study (studying Rezulin’s relation to heart damage).
(LA Times, 3-26-00)

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Rezulin Causes Possible Heart Damage

Since Rezulin was approved on the fast track a complete clinical trial to determine possible heart damage caused by Rezulin was not completed. Instead, the Echo Study was put together to determine whether the use of Rezulin for 48 weeks would result in a change in the left ventricle. The endocrinologist who served as Warner-Lambert’s principal investigator for the Echo study in Buffalo, Dr. Paresh Dandona, said “The Echo Study was not properly conducted, according to the standard protocol. I was not made aware of the fact that the patients from this site, in particular, for whatever reason, whether it was due to technique or whatever, that they had increased left ventricular mass,” (LA Times, 3-26-00).

After the FDA approval of Rezulin on January 29, 1997, officials had negotiated a nonbonding pledge from Warner-Lambert to start a new study to assess Rezulin’s effect on patients who had preexisting heart disease evidence. Few patients were enrolled, and this study was never completed. Rezulin patients did die of heart failure, but doctors claimed many of these patients had preexisting heart problems. Guston Turner, a pharmacist from the FDA’s scientific investigations division had found inconsistencies in research measuring Rezulin’s effect on the heart. Turner felt that the FDA “should have delayed approval of Rezulin until all the questions were addressed.”

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Rezulin Recall Timeline

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 Rezulin’s approval.

6-11-96

The federal health agency, The National Institutes of Health, chooses Rezulin to use in a $150 million diabetes study, run by Richard Eastman, the government’s 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 of diabetes.

7-31-96

Rezulin manufacturer, Warner-Lambert applies for the FDA approval of the diabetes drug under the “fast-track” procedures fairly recently enacted.

10-9-96

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 drug’s approval.

11-4-96

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.

12-11-96

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.

1-97

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.

2-24-97

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.

5-1-97

Warner-Lambert’s 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.

5-5-97

The CEO of Warner-Lambert tells investors that Rezulin holds the potential to be a billion dollar blockbuster.

9-30-97

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.”

10-10-97

The FDA receives two reports of Rezulin liver failure.

11-3-97

The FDA requires the Rezulin label be changed 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.

11-12-97

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.

12-1-97

England prohibits sales of Rezulin due to concerns about liver damage to patients in the U.S. The FDA announces a label change 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.

5-17-98

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.

6-4-98

The NIH study drops Rezulin due to the risk of liver damage in the remaining participants.

6-5-98

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.

7-27-98

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.

7-28-98

The FDA required another Rezulin label change 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.

1-99

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.

3-26-99

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 to 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.

3-29-99

A Rezulin patient undergoing monthly monitoring in a Warner-Lambert clinical trial dies of liver failure.

6-16-99

The FDA requires the Rezulin label be changed 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.

12-15-99

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.

3-3-00

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 from occurring.

3-00

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.

3-21-00

The FDA withdraws Rezulin from the U.S. market 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.

8-16-00

The L.A. Times reports about the Federal prosecutors examining the FDA’s quick approval method and the delayed withdrawal of Rezulin. It was reported that both the FDA and Warner-Lambert’s actions were being examined.

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