The Troglitazone story

Source: Avorn J. Powerful medicines: the benefits, risks, and costs of prescription drugs. New York: Knopf, 2004. Chapter 4. Too sweet to be true.

References to the first reports on ciglitazone.

US Patent 4,572,912 filed by Yoshioka; Takao (Hiromachi, JP); Kitazawa; Eiici (Hiromachi, JP); Kurumada; Tomoyuki (Hiromachi, JP); Yamazaki; Mitsuo (Hiromachi, JP); Hasegawa; Kazou (Hiromachi, JP) as follows:

Thiazolidinedione derivatives, their preparation and compositions containing them.

Assignee: Sankyo Company Limited (Tokyo, Japan)

Jerrold Olefsky, Tammy Antonucci, Dean Lockwood, and Rebecca Norris file U.S. Patent No. 5,478,852 for the use of thiazolidinedione derivatives and related antihyperglycemia agents in the treatment of impaired glucose tolerance in order to prevent or delay the onset of non insulin-dependent diabetes mellitus.

Assignee: Sankyo

The New England Journal of Medicine publishes an article on troglitazone which concludes that “troglitazone decreases insulin resistance and improves glucose tolerance in obese subjects with either impaired or normal glucose tolerance. The ability of troglitazone to reduce insulin resistance could be useful in preventing NIDDM.”

One of the authors is Jerrold Olefsky (see 23 August 1994, 28 April 1995)

Olefsky files another U.S. patent (5,708,012) for the use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of insulin resistant subjects with normal glucose tolerance in order to prevent or delay the onset of non insulin-dependent mellitus.

Assignee: Sankyo.

Warner-Lambert launches a strategy for transforming Rezulin® into a billion-dollar blockbuster. Early slide-show pitches made to Wall Street analysts emphasize the market of America’s 15 million adult-onset diabetics and Rezulin®’s “new mechanism of action”. Warner-Lambert and its affiliates paid speaking or other fees to more than 300 doctors, from endocrinologists to family practitioners. The company flew diabetes specialists to the 1996 Olympic Games in Atlanta and provided accommodation at the Chateau Elan Winery and Resort.

Source: Willman D. The rise and fall of the killer drug Rezulin®. LA Times: June 4, 2000. Reprinted in the LE Magazine September 2000.

Warner-Lambert pleads guilty to concealing deficiencies from the FDA in its manufacture of several drugs. The company agrees to pay a $10-million fine - one of the largest ever imposed on a drug manufacturer. The prosecution resulted from a joint inquiry by the FDA and the Justice Department.

Company officials vow to put the episode in the past and to recommit to developing a new, big-selling drug. "We have placed our pharmaceutical research dollars squarely behind compounds we firmly believe capable of producing a large health care dividend," the company tells shareholders.

Source: Willman D. (1998). Drugmaker hired NIH researcher. LA Times, 7 December.

See also Statement by Sidney M. Wolfe, MD, Concerning Warner-Lambert Criminal Conviction and Poor Manufacturing Practices... Includes Dilantin Recalls (HRG Publication #1380)

Richard C Eastman, Director, Division of Diabetes, Endocrinology and Metabolic Diseases at the National Institutes of Health (NIH) enters into a formal consulting arrangement with Warner-Lambert.

Warner-Lambert's annual report describes Rezulin® as "a breakthrough drug" that "may delay the onset of diabetes".

"The company believes this breakthrough therapy, once approved, could become one of the largest-selling pharmaceuticals it has ever marketed."

Willman D. Drugmaker hired NIH researcher. LA Times, 7 December 1998.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD), part of the National Institutes of Health (NIH), announces a nationwide research study to determine whether lowering blood sugar levels in people with impaired glucose tolerance (IGT) can help prevent or delay the development of type 2 diabetes.

4000 volunteers will be randomly assigned to one of four groups: intensive lifestyle changes to reduce weight by seven per cent; intervention with the drug metformin, currently used to treat type 2 diabetes; intervention with the drug troglitazone, currently being tested for the treatment of type 2 diabetes; and a control group, who will take placebo pills in place of the two drugs and will receive information on diet and exercise.

The $150 million study will be overseen by Dr Richard C Eastman, the NIH's top diabetes researcher. Corporate support is being provided by Parke-Davis (Warner-Lambert), and Sankyo Pharmaceutical Company as well as Bristol-Myers Squibb and Lipha Pharmaceuticals.

NIDDKD. National Institutes of Health asks the question... can type 2 diabetes be prevented? 10 June 1996.

National Diabetes Education Program. Diabetes Prevention Program Fact Sheet.

Diabetes Prevention Program. Powerpoint presentation

In their press release, the Warner-Lambert chairman and CEO, Melvin R Goodes, states that "diabetes imposes tremendous costs on society. With troglitazone, we may now have a tool at hand to help prevent this dread disease. It is a truly breakthrough therapy".

Randall W. Whitcomb, Senior Director, Clinical Research, Diabetes and Metabolic Diseases at Warner-Lambert's Parke-Davis division goes on to say that "Troglitazone is the first and only drug with a mechanism of action that targets insulin resistance, now believed to be the primary cause of IGT and type II diabetes. This opens up the exciting possibility that one day we may be able to delay or even prevent the onset of type II diabetes in patients at risk."

According to Dr. Richard Eastman, director, Division of Diabetes, Endocrinology and Metabolic Diseases, NIDDK and NIH, "The group of investigators conducting the study unanimously chose to use troglitazone after considering all other potential agents because they felt it had a favorable safety profile, few side effects and it corrects the underlying cause of diabetes -- insulin resistance."

What the press release fails to mention is that Dr Eastman was hired by Rezulin® manufacturer Warner-Lambert as a consultant to launch Rezulin®. Eastman accepted over $78,000 from Warner-Lambert in 1997. A lawyer for the US DHHS had already warned him in 1996 that this represented a conflict of interest.

Sources:

Willman D. Drug maker hired NIH researcher. LA Times, 7 December 1998.

Avorn J. Powerful medicines: the benefits, risks, and costs of prescription drugs. New York: Knopf, 2004. Chapter 4. Too sweet to be true.

Approval

Warner-Lambert applies for FDA approval of Rezulin® under the "fast-track" procedure, which has recently been enacted. Within a month, FDA officials agree to a six-month "priority" review.

According to a summary of an FDA staff meeting, Dr. John L. Gueriguian (initially responsible for vetting Rezulin®’s safety and effectiveness) “emphasized that [Rezulin®] offered very little significant therapeutic advantage” over existing diabetes drugs.

Source: Willman D. The rise and fall of the killer drug Rezulin. LA Times: June 4, 2000. Reprinted in the LE Magazine September 2000.

The first advertisement in the pre-launch campaign devised by Lally McFarland and Pantello appears.

It has the headline, "How come the biggest breakthrough in diabetes happened 75 years ago?" with an illustration of a mammoth test tube containing a melancholy pig.

The text tells the history of diabetes and concludes "A significant gap seems to exist between what we know about diabetes and how we treat it.".

Further details of the advertising campaign.

FDA medical officer Gueriguian expresses his concerns about Rezulin® to superiors and colleagues at the FDA.

Gueriguian found worrying incidences of liver injury among patients in two trials conducted by Warner-Lambert. He was also concerned that 23 out of 140 patients (16%) experienced heart problems, compared with 7% of patients in the placebo group.

Willman D. 'Fast track' drug to treat diabetes tied to 33 deaths. LA Times, 6 December 1998.

Misbin, a diabetes specialist assigned to review the small print that would appear on Rezulin® labels, expresses concerns in a memorandum to Gueriguian

"I do not believe that [Warner-Lambert] has made a convincing argument that failure to make [Rezulin®] rapidly available would put a significant number of diabetic patients at risk. I believe the greater danger may be to make [Rezulin®] available to patients who do not really need it before we have been convinced of its safety.... In particular, careful attention should be paid to the [events] you have already identified" including liver toxicity and heart problems."

However, Misbin later backs approval and does not urge that patients undergo liver tests.

 Willman D. 'Fast track' drug to treat diabetes tied to 33 deaths. LA Times, 6 December 1998.

The second advertisement in the prelaunch campaign for Rezulin® appears.

It describes the effects of insulin resistance and ends with the question; "Is it possible to specifically treat or even prevent the insulin resistance associated with type II diabetes?" The launch campaign would provide an answer in April 1997.

Further details of the advertising campaign.

FDA medical officer Gueriguian concludes that Rezulin® is unfit for approval and warns of its potential to harm both the liver and the heart.

Warner-Lambert complain about Gueriguian's "intemperate" language and Murray Lumpkin orders him to be removed from the evaluation of Rezulin®. His medical review is removed from FDA files.

The evaluation of Rezulin® is taken up by Gueriguian's immediate manager, Fleming.

Fleming presents the scientific evaluation of Rezulin® to an FDA Endocrinologic and Metabolic Drugs Advisory Committee. The Committee is not informed of Gueriguian's concerns and votes 8:0 for fast-track approval.

“To summarize then, with regard to the indication of troglitazone for the treatment of type II diabetes in conjunction with insulin, the committee has voted eight to nothing, right, that the study designs and efficacy endpoints and other information presented, taken together, are adequate to assess the efficacy and safety of this drug for the proposed patient population, which we have described several times now. And based on the data presented, the committee has unanimously recommended approval of the drug for the indication. And we look forward to seeing the larger package in the relatively near future.”

Dr. Randall W. Whitcomb tells the Committee that the liver damage incidence was comparable to placebo.

"…We have also looked carefully at liver function tests in these patients based upon the fact that some hepatocellular hypertrophy was seen in some of the animal studies. This is looking at AST and ALT levels, people that were anywhere above normal, two times or three times normal. When you look at the just above upper limits of normal, there are actually more placebo patients than Rezulin® treated patients. Two times are basically identical, 2 percent. And when you look on a percentage basis above three times normal, they are very similar on a percentage basis. But I do want to comment upon these 14 patients that are over here. Seven of these patients were treated through without even knowing that their liver enzymes had gone up, and they went back down again. The other seven did have the drug discontinued with reversibility of the liver function test elevations after the drug was discontinued. We have had one patient who has what looks like was an idiosyncratic reaction to the drug and did develop jaundice, which was reversible with discontinuation of the drug as well. " (pp 146-147)

"So in terms of summarizing the safety profile of ... the drug ... There are transient, reversible increases in liver function tests which are seen in approximately 1 percent of patients. This incidence is comparable to placebo. And there is no evidence of LV mass increase after two years at high doses of Rezulin®, specifically at 1800 milligrams per day." (pp 152-153)

The panel noted that the drug reached concentrations within rat liver 30 times greater than those in the plasma and commented : “at least in rats we have reason to be concerned about what might happen ultimately in liver, a target tissue.".

To read a pdf of the full transcript (354 pages) click here.

At the time, the company knew that at least 12 people had suffered serious cases of Rezulin® liver damage during clinical trials. In reality, though, the placebo studies were not comparable to Rezulin® patients. Just 0.6% of the placebo pills suffered liver problems opposed to 2.2% of the Rezulin® liver damage patients. When asked about this discrepancy after the Rezulin® recall, Whitcomb claimed the numbers were not “all that different.”

Source: Rezulin newsletter

Warner-Lambert’s shares soar to a then all-time high on the New York Stock Exchange.

Source: Willman D. Drugmaker hired NIH researcher. LA Times, 7 December 1998.

Rezulin® receives FDA approval through the fast-track procedure, i.e. in half the normal time. It becomes the most quickly approved diabetes drug in the FDA's 60-year history.

Rezulin® is indicated for use in patients with type II diabetes currently on insulin therapy whose hyperglycaemia is inadequately controlled (HbA1c > 8.5%) despite insulin therapy of over 30 units per day as multiple injections. No liver testing is required.

This initial approval limits its potential usefulness and thus market share.

Source: Avorn J. Powerful medicines: the benefits, risks, and costs of prescription drugs. New York: Knopf, 2004. Chapter 4. Too sweet to be true.

Launch

In a press release announcing the approval of Rezulin®, the Parke-Davis Division of Warner-Lambert claims that:

• Rezulin® is the first antidiabetes drug designed to target insulin resistance…
• Rezulin® is the first drug to work at the cellular level to improve insulin resistance directly-enhancing the effects of circulating insulin…. Until now, other therapies lowered blood glucose by increasing insulin production or decreasing hepatic glucose output.

These claims are later judged by the FDA to be misleading (see 24 February 1997)

The FDA issue a Talk Paper announcing the approval of Rezulin®. See also the Doctor's Guide press release

Mark Askine, Regulatory Review Officer at the Division of Drug Marketing, Advertising and Communications of the FDA notifies Warner-Lambert (Parke-Davis) that the press release of 30 January (see above) contains “false and misleading” statements violating the Federal Food, Drug and Cosmetic Act, namely:

"Rezulin® is the first antidiabetic drug designed to target insulin resistance"

"Rezulin® is the first drug to work at the cellular level to improve insulin resistance, directly enhancing the effects of circulating insulin. ... Until now, other therapies lowered blood glucose by increasing insulin production or decreasing hepatic glucose output."

The FDA recommends that the news release should be discontinued immediately, along with any other material containing similar claims.

Warner-Lambert launches Rezulin® in the U.S.

Until the launch of Rezulin®, sales for oral hypoglycaemic agents totalled $994 million. Glucophage (Bristol-Myers-Squibb) is the market leader with a 30% share.

Source: 1997 at a glance. IMS America Business Watch).

FDA Consumer Magazine carries an article about Rezulin®. The drug should be prescribed with caution in patients with advanced heart failure or liver disease.

Marketing of Troglitazone in the USA begins. A full-page, colour magazine advertisement describes Rezulin® as having side-effects comparable to placebo.

“Facing the creative challenge of introducing new scientific information while gaining and maintaining interest, the introduction of the diabetic drug Rezulin® used concept and ad testing to find the right balance for success.

Emotion didn't work. Scientific exposition didn't work. A straightforward demonstration of the drug's action aimed at the physician's frustration in dealing with the illness was the answer.” William G Castagnoli.

Further details of the advertising campaign.

The FDA approves Rezulin® labelling changes.

Warner-Lambert's clinical studies indicate that Rezulin® users are 3.6 times more likely to suffer liver injury than patients taking a placebo, but the company runs a full-page, colour advertisement in the New England Journal of Medicine describing Rezulin® as a drug with breakthrough effectiveness with "side-effects comparable to placebo".

Source: Rezulin newsletter

Warner-Lambert CEO, Melvin R Goodes tells investors that Rezulin® and a cholesterol pill, Lipitor, are the company's new profit engines.

"We plan to double our profits as we enter the next millennium".. "We believe that both Lipitor and Rezulin® have the potential to be billion-dollar blockbusters".

Source: Willman D. Drugmaker hired NIH researcher. Los Angeles Times.

Four months post-launch, Rezulin® has captured almost 2% of the total prescription market with 433,000 dispensed prescriptions. Sales reach $75.6 million, 12% of the market.

Source: IMS America Business Watch

In the U.K. Summary of Product Characteristics submitted by Glaxo Wellcome is approved by the Medicines Control Agency.

In the U.K., Glaxo Wellcome and Sankyo Pharma are granted National MAs for troglitazone.

The FDA approves broader uses of Rezulin®, in combination with other type 2 diabetes drugs (sulfonylureas), and as a monotherapy in the treatment of type II diabetes. Click here to download the approval package (pdf 4,789 kb). New labelling is produced.

Glaxo-Wellcome begins to market troglitazone in the U.K.

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."

Source: Rezulin newsletter

Rezulin® becomes one of the fastest selling drugs in history. Sales estimated at US$137 million in the 3 months to October 1997.

In the U.K. Glaxo Wellcome launch troglitazone as Romozin®.

Problems

The FDA receives two reports of liver failure in patients using Rezulin®. Two Warner-Lambert executives inform Murray Lumpkin of the first liver failure.

Source: Willman D. The rise and fall of the killer drug Rezulin. LA Times: June 4, 2000. Reprinted in the LE Magazine September 2000. Also available here.

The FDA announce that 35 post-marketing reports of liver injury of various degrees have been received. These reports ranged from mildly elevated blood levels of the liver transaminase enzymes to liver failure leading to one liver transplant and one death. Whether the drug was solely responsible for all of these reports of liver injury is as yet unknown, due to confounding medical factors in some of the reported cases.

For further information see FDA Talk Paper, 3 November 1997.

The Parke-Davis division of Warner-Lambert issues a Dear Healthcare Professional letter, warning that

“rare cases of severe idiosyncratic hepatocellular injury…usually reversible, but very rare cases of hepatic failure, including death, have been reported”.

They recommend that "serum transaminase levels be checked within the first one to two months and then every three months during the first year of troglitazone therapy, and periodically thereafter. Liver function tests also should be obtained for patients at the first symptoms suggestive of hepatic dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine. Rezulin should be discontinued if the patient has jaundice or if laboratory measurements suggest liver injury (e.g., ALT > 3 times the upper limit of normal)."

These changes are detailed in a Talk Paper published by the FDA.

In the U.K., Glaxo Wellcome issues a Dear Doctor letter recommending that troglitazone be discontinued in the presence of unexplained deterioration of hepatic function.

“In all patients, liver function should be checked prior to treatment, and then monitored within the first one to two months, then three-monthly for at least six months, and periodically thereafter.”

The FDA recommends 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 thereafter.

"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. Approximately 2% of Rezulin patients should be expected to stop taking the drug due to an elevated level of liver enzymes."

"Based on clinical trials, approximately two per cent of patients on Rezulin can be expected to have to stop taking the drug because of elevated liver enzymes. Few, if any, of these patients will go on to develop permanent liver damage if the drug is stopped."

The FDA also urges health care providers to report any Rezulin®-related adverse events, especially those suggestive of possible liver injury, to the manufacturer.

FDA Talk Paper, 3 November 1997

Dr. Robert I. Misbin, an FDA diabetes specialist who supported the Rezulin® approval, sends an internal report to FDA supervisors stating that 21 patients treated with Rezulin® prior to FDA approval had to discontinue the drug due to liver injury, 13 patients had markers of liver injury 10 to 30 times above normal, and that an estimated 2% or 12,350 of the 650,000 patients using Rezulin® would experience some degree of liver injury.

Willman D. 'Fast track' drug to treat diabetes tied to 33 deaths. LA Times, 6 December 1998.

The new labelling approved by the FDA includes the following warning:

“Rare cases of severe idiosyncratic hepatocellular injury have been reported during marketed use…. It is recommended that serum transaminase levels be checked within the first one to two months and then every three months during the first year of troglitazone therapy, and periodically thereafter… Rezulin should be discontinued if the patient has jaundice or laboratory measurements suggest liver injury (e.g. ALT > 3 times the upper limit of normal)."

The Chairman of Glaxo-Wellcome faxes the British Medicines Control Agency with data from Warner-Lambert and Sankyo demonstrating a dramatic increase in the number of reports of serious adverse events, specifically affecting the liver. The report sent to Glaxo-Wellcome is likely to have contained details of 135 cases of serious liver toxicity and 6 deaths.

Lumpkin and Woodcock (Director of the FDA's Drug Evaluation Center) are made aware of U.K.'s Committee on the Safety of Medicine's plans to announce the withdrawal of Romozin® in the U.K.

Source: Willman D. The rise and fall of the killer drug Rezulin. LA Times: June 4, 2000. Reprinted in the LE Magazine September 2000.

GlaxoWellcome issue a “Dear Doctor” Letter in the U.K.: announcing the suspension of the availability of troglitazone.

.“…we have received a substantial number of further reports of hepatic dysfunction from the US and Japan (…). In the light of this information, our senior medical group has decided that it is currently impossible to predict accurately the incidence of adverse events.”

Glaxo-Wellcome voluntarily withdraw troglitazone from the UK in the light of mounting reports of liver injury in the U.S.

“Overall, it is considered that, based on present information, the risks of troglitazone therapy outweigh the potential benefits”. A subsequent statement by the government agency commented that “at present, no clear risk factors for the development of hepatic reactions have been identified which might allow the drug to be used safely in some patients”.

For further information see Current Problems in Pharmacovigilance, December 1997.

The UK was the reporting country for European approval, and thus only Japanese and US citizens were exposed to risks relating to these drugs, and only Japanese and Americans were to suffer liver injury and death in consequence.

The withdrawal of troglitazone in the U.K. triggers an 18.5% plunge in Warner-Lambert's stock on the New York Stock Exchange.

Willman D. 'Fast track' drug to treat diabetes tied to 33 deaths. Los Angeles Times, 6 December 1998.

The FDA announces that patients taking the diabetes drug Rezulin® (troglitazone) should be monitored more frequently for signs of liver injury. In addition, warning information about potential liver toxicity will be more prominently featured in the drug's labelling.

Liver enzyme levels should be measured in patients taking Rezulin® at the start of therapy, every month for the first six months of treatment, every other month for the next six months, and periodically thereafter. In addition, liver function tests should be performed on any patient on Rezulin who develops symptoms of liver dysfunction, such as nausea, vomiting, fatigue, loss of appetite, or dark urine and jaundice. The product's current labelling advises that patients with significant elevation of these liver enzymes stop taking the drug.

Further information.

At the same time, the Parke-Davis division of Warner-Lambert issues a further Dear Health Care Professional letter

"Warner-Lambert and the FDA have already completed a thorough review of the worldwide safety experience with Rezulin. On November 3 the FDA asked physicians for reports on additional adverse events. You will be reassured to know that the additional reports received since early November do not indicate a greater frequency of liver injury or potential for serious harm than had been previously estimated. Rezulin has been shown to be very effective in helping patients achieve glycemic control. The FDA continues to find a favorable benefit to risk relationship for Rezulin therapy in appropriately selected and monitored type 2 diabetics."

Mayer B Davidson, president of the American Diabetes Association comments on the withdrawal of troglitazone in the UK because of safety concerns. “I personally don’t think it is cause for alarm…”

Source: Vedantam S. Diabetes drug pulled in Britain, called safe. U.S. doctors say patients should not stop taking Rezulin as benefits outweigh its effects on the liver. The Philadelphia Inquirer, 3 December 1997, p A02.

The labelling changes made by Warner-Lambert are approved by the FDA.

It is recommended that:

"serum transaminase levels be checked at the start of therapy, monthly for the first six months of therapy, every two months for the remainder of the first year of troglitazone therapy, and periodically thereafter. Liver function tests also should be obtained for patients at the first symptoms suggestive of hepatic dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine. Rezulin therapy should not be initiated if the patient exhibits clinical or laboratory evidence of active liver disease (e.g., ALT > 3 times the upper limit of normal) and should be discontinued if the patient has jaundice or laboratory measurements suggest liver injury (e.g., ALT > 3 times the upper limit of normal)."

Sales of Rezulin® in the 10 months since it was launched reach $324.6 million, 22% of the market.

Source: IMS America Business Watch

The New England Journal of Medicine publishes a letter from Paul Watkins of the University of Michigan and Randall Whitcomb of Warner-Lambert Parke-Davis detailing the baseline data on liver function accumulated in the course of pre-marketing trials of troglitazone. Analysis of these baseline data from 2510 patients shows that 48 (1.9%) had levels of the liver enzyme alanine aminotransferase (ALT - a marker of liver cell damage) over 3 times the normal range, that 20 were taken off the drug for this reason; 5 of these (1:500 users) had a 20-fold increase.

Watkins PB, Whitcomb RW. (1998). Hepatic dysfunction associated with troglitazone. New England Journal of Medicine; 338:916-7.

The accompanying editorial warns that:

“Because of the possibility of drug-induced hepatic dysfunction, however, therapy with troglitazone should be limited to patients who can be evaluated frequently until the incidence and severity of hepatic dysfunction with this drug become clearer”

Imura H. (1998). A novel antidiabetic drug, troglitazone - reason for hope and concern. New England Journal of Medicine; 338: 908-909.

Audrey LaRue Jones, a 55-year-old woman in good health participating in the NIDDKD diabetes study, dies following liver failure and a liver transplant in spite of taking the strict precautionary measures recommended by the FDA and Warner-Lambert . The clinical course and ultimate death of the patient were complex but a three member panel of experts conclude that drug-induced liver toxicity was probably the cause of liver failure.

NIKKD discontinues troglitazone arm of "diabetes prevention program" clinical trial. 4 June 1998.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKH) discontinues the troglitazone arm of its Diabetes Prevention Program Clinical Trial due to the risk of liver damage in the remaining 584 troglitazone recipients.

More information.

A press release from Warner-Lambert denies Rezulin® killed Audrey LaRue Jones and instead claims that her death was the result of "complications unrelated to the study or the diabetes medication".

By now the FDA has received 21 reports of Rezulin® liver failures resulting in death and three Rezulin® liver transplant patients.

Willman D. Drugmaker hired NIH researcher. Los Angeles Times, 7 December 1998.

Case reports are published in the medical press as follows:

Gitlin N, Julie NL, Spurt CL, Lim KN, Juarbe HM. Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Annals of Internal Medicine 1998; 129 (1):36-38.

Neuschwander-Tetri BA, Isley WL, Oki JC, Ramrakhiani S, Quiason SG, Phillips NJ et al. Troglitazone-induced hepatic failure leading to liver transplantation. A case report. Annals of Internal Medicine 1998; 129 (1): 38-41.

The FDA requires another Rezulin® label change to increase the frequency of liver testing. The recommendation states that 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. ALT is reduced to 1.5 times the upper limit of normal (formerly 3.0)

More information

Sidney M Wolfe and Larry Sasich, of the Public Citizen’s Health Research Group, petition Michael Friedman of the FDA to ban troglitazone, asking “how many more Americans will have to die or require liver transplants?”

Public Citizen petition

The Parke-Davis division of Warner-Lambert issues a Dear Healthcare Professional Letter describing the modified requirements relating to more stringent liver enzyme monitoring as reflected in the new product labelling approved by the FDA on 22 July 1998.

UK Summary of Product Characteristics updated and submitted in preparation for the possible reintroduction of Romozin onto the UK market.

Warner-Lambert hold a party - the flyer invites employees to "celebrate Rezulin at the billion dollor bash".

Source: Evidence presented at the US FDA Center for Drug Evaluation and Research, Drug Safety and Management Advisory Committee Meeting, 21 July 2002

The Sub-Committee on Pharmacovigilance (COP) informs the Committee on the Safety of Medicines (CSM) that Glaxo Wellcome and Sankyo Pharma have submitted a joint proposal to update the product information for troglitazone to address the issue of hepatotoxicity in order to justify its reintroduction into the U.K. market. Advice will be sought from external experts as well as COP and CSM.

According to CSM Meeting papers (dated 25 February 1999), there have to date been 47 deaths and 4 liver transplants.

18 deaths occurred in the US between December 1997 (when labelling changes were introduced) and 31 October 1998.

Richard Sykes, the Chairman of Glaxo-Wellcome responsible for withdrawing troglitazone from the UK market, publishes an editorial in the British Medical Journal which concludes “As a knowledge-based industry we understand well the value of information, and we want to create a climate of openness where the evidence for prescribing our products is clear”.

Sykes R. (1998). Being a modern pharmaceutical company involves making information available on clinical trial programmes. BMJ 317:1172.

Two more case reports are published in the medical press:

Shibuya A, Watanabe M, Fujita Y, Saigenji K, Kuwao S, Takahashi H et al. An autopsy case of troglitazone-induced fulminant hepatitis. Diabetes Care 1998; 21(12):2140-2143.

Vella A, De Groen PC, Dinneen SF. Fatal hepatotoxicity associated with troglitazone. Annals of Internal Medicine 1998; 129(12):1080.

The first Los Angeles Times report about deaths from Rezulin® appears. A series of articles follows, winning the author, David Willman, the Pulitzer Prize 2001.

Willman, David. Fast track drug to treat diabetes tied to 33 deaths. LA Times, 6 December 1998.

Henry A Waxman, Member of Congress writes to Dr Harold Varmus, Director of the National Institutes of Health regarding conflicts of interest raised by the relationship of the Warner-Lambert with NIH employee Richard C. Eastman.

Waxman, Henry. Letter to Dr Harold Varmus, Director of the National Institutes of Health, 7 December 1998.

Stephen J. Mock, a vice president at Warner-Lambert, states in an interview that he is not aware of a single Rezulin®-related death since July, when the company and the FDA issued a third, stricter set of liver-monitoring recommendations.

"The reported events relating to ...deaths or liver transplants since the label was changed July 28 is zero," Mock said.

In fact, Warner-Lambert had reported 31 deaths to the FDA from 28 July to 17 December.

Source: Willman, D. Death toll challenges Rezulin safety claim. LA Times, 18 March 1999.

Following the article by David Willman in the LA Times on 6 December, Congressman Henry Waxman, writes to Dr Jane Henney, Commissioner at the FDA raising a number of questions re the safety of Rezulin® and the manner of its approval.

Waxman, Henry. Letter to Dr Jane Henney, 18 December 1998.

Rosa Delia Valenzuela, 63 dies. She took Rezulin five weeks before she died of liver failure.

Source: Willman, D. For recent victim, risk wasn’t known. LA Times, 18 March 1999.

Harold Varmus, Director NIH, responds to Henry Waxman’s letter of 7 December.

Varmus, Henry. Letter to Henry Waxman, regarding the relationship of Dr Richard Eastman of the National Institute of Diabetes and Digestive and Kidney Diseases with the pharmaceutical company Warner-Lambert. Bethesda, MD: NIH, 29 December 1998.

Warner-Lambert assures the FDA that liver-related deaths linked to Rezulin® have declined dramatically from the previous year.

"The number of deaths in patients initiating [Rezulin®] therapy in 1998 is approximately 65% lower than the number for patients initiating therapy in 1997".

Source: Willman D. Death toll challenges Rezulin safety claim. LA Times, 18 March 1999.

Public Citizen draws the attention of the FDA to misleading direct-to-consumer advertising. The advertisement appeared in EI Tiempo Latino in Spanish, but with the official labelling with warnings and risks in English.

Wolfe SM. Letter to Minnie Baylor-Henry, Director, Division of Drug Marketing, Advertising and Communications, Food and Drug Administration. Washington, D.C.: Public Citizen, 6 January 1999.

The FDA Commissioner, Dr. Jane E. Henney, orders a reassessment of Rezulin® after a series of articles by the Los Angeles Times.

Source: Willman, D. The rise and fall of the killer drug Rezulin. LA Times, 4 June 2000.

Warner-Lambert also announces that it will halt two major studies intended to find new uses for Rezulin® following negotiation with FDA officials. The future of the two studies will be decided after the FDA Advisory Committee meeting on 26 March 1999.

Source: Willman, D. FDA orders reassessment of diabetes drug's safety. LA Times, 16 January 1999.

Another case report is published:

Herrine SK, Choudhary C. (1999). Severe hepatotoxicity associated with troglitazone. Annals of Internal Medicine; 130(2):163-164.

Parke-Davis division of Warner-Lambert issues a new Rezulin® package insert.

To date, the FDA is aware of 100 Rezulin patients who suffered adverse liver effects with a fatal outcome. 33 of those were “associated” with the use of Rezulin®. In addition the FDA identified 738 other possible causes of serious “adverse reactions”, including disability, life-threatening injuries and admission to hospital.

Source: Willman D. Death toll challenges Rezulin claim. LA Times, 18 March 1999.

Harold Varmus responds to Henry Waxman’s letter of 7 December 1998.

Varmus, Harold. Letter to Henry Waxman, 19 February 1999, responding to Question 5 in Henry Waxman's letter of 7 December 1998.

The Sub committee on Pharmacovigilance of the Committee on Safety of Medicines is informed that the MA holders for troglitazone, GlaxoWellcome and Sankyo Pharma, have submitted joint proposals to address the issue of hepatotoxicity with troglitazone in order to re-introduce troglitazone back on to the UK market.

The Committee agrees that the evidence does not support the proposal that the introduction of monitoring liver function tests would prevent serious and fatal hepatotoxicity with troglitazone. The Committee also agrees that it would not be possible to identify patient groups who are not at risk of developing hepatotoxicity with troglitazone. Further data from clinical trials and post-marketing experience in countries where troglitazone had remained available would be needed to clarify the incidence, risk factors and outcome. Post-marketing surveillance data from the USA would be appropriate. A risk has been clearly identified which appears to outweigh the benefits of treatment.

The Committee suggests that liver function tests should be more closely monitored in clinical trials, particularly where major elevations occurred. It also suggests that the patient population studied in clinical trials should more closely reflect the post-marketing population and, in particular, that trials should be conducted in patients likely to be at risk such as those with cardiac failure.

Read the full report.

The Committee on Safety of Medicines discusses the risks and benefits of troglitazone.

It was noted that troglitazone monotherapy had similar efficacy to metformin and sulphonylureas, and as monotherapy, troglitazone is not associated with hypoglycaemia. There was little evidence on the use of troglitazone in combination with metformin as this has only been evaluated in a few small trials. The use of troglitazone plus sulphonylureas was noted to improve glycaemic control but concerns were raised that this combination of drugs may possibly increase the risk of hepatotoxicity. It was considered that troglitazone plus insulin was a useful combination with proven benefits on glycaemic control.

The Committee agrees that there is strong evidence to support a causal relationship between troglitazone and hepatotoxicity, noting that, up to the end of October 1998, 47 cases of fatal hepatotoxicity in association with troglitazone and 4 liver transplants had been reported.

The Committee agreed that it would not be possible to identify risk factors clearly. The Committee proposed that more information regarding the risks of developing hepatotoxicity was required and it would be possible to undertake a post-marketing study in the US, which would clarify the incidence of hepatic reactions and may identify risk factors for developing hepatotoxicity. The Committee commented that preventability of serious cases of hepatotoxicity had not been demonstrated. Liver function test monitoring in the USA and Japan had resulted in a decrease in the number of reports of serious hepatotoxicity but had been unable to prevent such cases.

Read the meeting report.

Diane Thomson, Associate Commissioner for Legislative Affairs, FDA, responds to Henry Waxman’s letter of 18 December 1998, regarding the safety of Rezulin®.

Thomson DE. Response to letter from Henry Waxman dated 18 December 1998, regarding the safety of Rezulin. Rockville, Md: FDA, 25 February 1999.

Dr. David J. Graham, a senior scientist for the FDA, warns that no reliable way exists to protect Rezulin® patients from liver failure.

Misbin's review of the use of Rezulin® as a combination therapy recommends:

"The use of troglitazone should not be restricted in patients with type 2 diabetes whose hyperglycaemia is resistant to insulin treatment.

Troglitazone should not be considered a first-line drug. Patients already on troglitazone monotherapy may be allowed to continue but new patients should not be treated. If this distinction cannot be made clear in a label, the monotherapy indication should be withdrawn entirely."

United States. Department of Health and Human Services. Center for Drug Evaluation. Application number: 020720, S12, S14. Medical Reviews.

In the LA Times, David Willman reports the analysis of FDA data of 2971 adverse drug reactions between 27 March 1997 (shortly after Rezulin® was introduced) and 9 February 1999:

• Warner-Lambert was aware of most of the deaths. In 129 cases, the events were reported directly to the FDA by the company
• The number of reported deaths did not drop following changes to the liver monitoring recommendations on 28 July 1998
• Nearly 60% of the reported deaths involved liver problems

Dr Edward S Horton (Vice President and Director of Clinical Research at the Joslin Diabetes Center and Professor of Medicine at Harvard Medical School) writes to the FDA expressing strong opposition to the petition filed by Public Citizen on 27 July 1998.

GlaxoWellcome announces that the UK Medicines Control Agency has rejected the company’s application to re-introduce Romozin® for the treatment of type 2 diabetes in the UK, after consulting with the Committee on Safety of Medicines.

Source: GlaxoSmithKline. Troglitazone not approved for re-introduction in the UK. London: GlaxoSmithKline, 22 March 1999.

The Endocrine Society writes to the Endocrinologic and Metabolic Drug Advisory Committee of the FDA supporting the continued availability of Rezulin®.

Horwitz KB & Mallin S. Re: Rezulin (troglitazone). Bethesda, MD: Endocrine Society, 24 March 1999.

The FDA appoints two new members to an advisory panel – both have ties to the drug’s manufacturer – Dr Mayer B Davidson of the UCLA School of Medicine and Dr Saul Genuth of Cleveland. Both have received income during the last two years as leaders of a private diabetes education group (National Diabetes Education Initiative) funded exclusively by Warner-Lambert.

Source: Willman D. Two new FDA panelists have ties to Rezulin maker. LA Times, 25 March 1999.

In the event, Davidson decided not to attend.

Source: Willman D. FDA advised to restrict Rezulin use for diabetes. LA Times, 27 March 1999.

After two months of FDA research the findings are presented to the Endocrinologic and Metabolic Drugs Advisory Committee of the FDA's Center for Drug Evaluation.

David Graham of the FDA's office of Post-Marketing Drug Risk Assessment states 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.
  
• 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.

Sidney Wolfe, Director of Public Citizen, also presents evidence at the Committee and calls for the withdrawal of Rezulin.

The Committee votes 11 to one to recommend keeping Rezulin® on the market, but with limitations:

• Rezulin® should be used only with other diabetes drugs, like insulin, unless no other therapy works for the patient (some 20% of patients take Rezulin® as a stand-alone treatment)
  
• There must be new labelling and a new patient education program designed to emphasize the risks of liver damage and / or death
  
• There must be more frequent monitoring of the liver in patients taking the drug.

Warner-Lambert issues various press releases:

Warner-Lambert pleased by FDA Advisory Committee recommendation on Rezulin.

Rezulin: fiction vs fact

New facts about Rezulin

Risk-benefit assessment of Rezulin

The postmarketing surveillance system

The incidence of liver effects in Rezulin clinical trials and postmarketing surveillance

Their share price falls on the New York Stock Exchange.

A Rezulin® patient, Adrian C. Seay, undergoing monthly monitoring in a Warner-Lambert clinical trial dies of liver failure.

Source: Willman, D. The rise and fall of the killer drug Rezulin. LA Times: June 4, 2000. Reprinted in LE Magazine, September 2000

The Office of Clinical Pharmacology and Biopharmaceutics / Division of Pharmaceutic Evaluation II of the CDER, FDA approves application for the use of Rezulin® as a combination therapy with metformin or metformin and sulfonylureas in patients with type 2 diabetes.

Center for Drug Evaluation and Research. Clinical Pharmacology and Pharmaceutics Reviews. Application number 020720, S12, S14. Rockville, MD: Food and Drug Administration, 29 April 1999.

The FDA approves rosiglitazone to treat type II diabetes.

United States. Department of Health and Human Services. Food and Drug Administration. FDA approves rosiglitazone to treat type II diabetes. Rockville, MD: FDA, 26 May 1999.

Following the FDA meeting on 26 March 1999, FDA and the Parke-Davis division of Warner-Lambert agree to changes to the labeling and recommended uses for Rezulin®.

Rezulin® is no longer indicated as initial single agent therapy but is now indicated for use in combination with a sulfonylurea drug together with metformin for patients who are not adequately controlled with the combination of a sulfonylurea and metformin.

The labeling changes include recommendations for more extensive monitoring of liver function in patients using Rezulin®. A patient information sheet has been added to the labeling and will be available for distribution to patients by pharmacists with each Rezulin prescription. Labelling revised to incorporate information on a new indication - use in combination with metformin and sulfonylurea in patients with type II diabetes.

The Parke-Davis division of Warner-Lambert issues a Dear Healthcare Professional letter highlighting the important modifications to the Rezulin® prescribing information approved by the FDA.

A new prescribing and patient information leaflet is also issued.

The FDA approves pioglitazone to treat type II diabetes.

Cigna Healthcare removes Rezulin® from its preferred list of prescription drugs because of increasing reports of liver toxicity, coupled with the fact that alternatives are available.

Source: Willman D. Deaths climb since FDA got Rezulin warning. LA Times, 15 December 1999.

The LA Times reports that investigators examining the case of Eastman will also be asked to review Jerrold M Olefsky’s ties to Rezulin®. Olefsky, who held prominent leadership positions in the NIH diabetes prevention programme study, is listed on two separate patents (23 August 1994 and 28 April 1995) as either the sole or the first-named inventor or Rezulin®’s potential use for preventing diabetes.

Source: Willman D. 2nd NIH researcher becomes a focus of conflict probe. LA Times, 4 September 2005.

Warner-Lambert issue statement to the effect that it “will continue to make this important therapy available”

Source: Willman D. Deaths climb since FDA got Rezulin warning. LA Times, 15 December 1999.

The Los Angeles Times reports that 21 Rezulin® patients have died of liver failure since the 26 March 1999 report by Dr. Graham to the FDA Advisory Panel. This brings the total reported deaths since the drug was introduced to 215.

Graham begins a new analysis of Rezulin® despite his supervisors having no knowledge of his actions.

In an email to 14 FDA officials, Graham claims that Rezulin® is unsafe and should be withdrawn and that there was no existing data to support the idea that monitoring can prevent liver failure.

By the end of the year sales of Rezulin® have reached $625 million.

Source: Pfizer Annual Report 2001 (p. 27)

Graham shares his latest analysis at an FDA staff meeting – a consensus forms for Rezulin®’s prompt withdrawal.

Source: Willman, D. The rise and fall of the killer drug Rezulin. LA Times: June 4, 2000. Reprinted in LE Magazine, September 2000.

Lumpkin meets with the same FDA specialists and directs them to shift focus and assess the safety of two newer drugs Avandia and Actos. He arrange two meetings between FDA staff members and Warner-Lambert executives on 2 February and 1 March.

Source: Willman, D. The rise and fall of the killer drug Rezulin. LA Times: June 4, 2000. Reprinted in LE Magazine, September 2000.

Medical Officer Robert I. Misbin emails his superiors at the FDA:

"I see no reason why any well-informed physician would continue to prescribe [Rezulin]", "Neither do I see any reason why FDA should delay in taking steps to remove [Rezulin] from the market."

A copy of the email was obtained by The LA Times.

The FDA press office confirms 85 cases of liver failure, including 58 deaths.

Pfizer Inc. agree to buy rival Warner-Lambert Co for $90 billion in stock, creating the largest US pharmaceutical company and the 2nd largest in the world (behind GlaxoSmithKline formed in January 2000 by the merger of Glaxo Wellcome and Smith Kline Beecham). The deal brings together the industry's two fastest growing companies to form a pharmaceutical powerhouse generating annual revenues of $28 billion and with a research and development budget of $4.7 billion in 2000.

Sources:

Pfizer press release, 7 February 2000

Woodcock issues a statement reaffirming the FDA's confidence in Rezulin®.

Source: Willman, D. The rise and fall of the killer drug Rezulin. LA Times: June 4, 2000. Reprinted in LE Magazine, September 2000

Warner-Lambert issue a press release denying that Rezulin® is being withdrawn.

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. Graham stated there were no existing data to support the idea that monitoring can prevent the Rezulin liver failures from occurring.

The FDA diabetes specialist who had analysed the first cases of liver failure from 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 Public Citizen's Health Group files a petition to the FDA calling for the relabelling of troglitazone, rosiglitazone and pioglitazone, and for the withdrawal of Rezulin®. They also issue a press release to this effect.

Misbin is warned by senior officials of the FDA that he must cooperate with the investigation; failure to do so may result in disciplinary actions up to and including dismissal.

Public Citizen writes to the FDA requiring a criminal investigation of Warner-Lambert/Parke Davis.

Kenneth King, Senior Vice President Worldwide Regulatory Affairs, Warner-Lambert/Parke-Davis requests that the FDA schedule a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee to review the most current data regarding the safety and efficacy of Rezulin® in comparison with other anti-diabetes drugs.

John B Buse, Associate Professor of Medicine, University of North Carolina and Director of the Diabetes Care Center writes to Jane Henney, Commissioner of the FDA re Public Citizen's petition to immediately require class labelling for troglitazone, rosiglitazone and pioglitazone.

Kenneth F King, Senior Vice President Worldwide Regulatory Affairs, Warner-Lambert/Parke-Davis responds to allegations made by the Public Citizen’s Health Research Group to the FDA on 14 March 2000.

Withdrawal

The FDA asks Parke-Davis/Warner-Lambert to remove troglitazone from the market, citing the availability of other drugs in the glitazone class with a better safety profile.

Rezulin to be withdrawn from the market. HHS NEWS, March 21, 2000

The Warner-Lambert press release issued the same day states:

“The Company has always believed that it is essential for patients and physicians to receive accurate and objective information regarding the benefits and risks of Rezulin. It was for this reason that Warner-Lambert requested a public meeting of the FDA’s expert advisory committee. However, repeated media reports sensationalizing the risks associated with Rezulin therapy have created an environment in which patients and physicians are simply unable to make well-informed decisions regarding the safety and efficacy of Rezulin”.

More information: FDA press release

Warner-Lambert issues Dear Doctor and Dear Pharmacist letters, announcing the withdrawal of Rezulin®.

Public Citizen writes to Donna Shalala, Secretary of the Department of Health and Human Services asking that the Code of Ethics for Government is enforced. The Code states "any person in Government Service should put loyalty to the highest moral principles and to country above loyalty to persons, party or Government country".

Analysts predict that the withdrawal of Rezulin® should have little long-term effect on Warner-Lambert or its pending merger with Pfizer Inc.. Stock price ended the day at 93 5/8, down 1 3/8.

As Warner-Lambert hopes that the Rezulin controversy will begin to fade, its prospects rest on another drug, Lipitor, which is expected to become the top-selling drug in the world, with annual revenue exceeding $5 billion.

Pfizer spokesman Andy McCormick issued a statement dismissing any significant impact from the loss of Rezulin, which was expected to bring in $400 million in sales this year, down from $773 million in 1999. "The cessation of Rezulin sales by Warner-Lambert is not material to either the closing of the Pfizer-Warner-Lambert merger or the anticipated ongoing operations of the combined companies," he said. The company will have the largest research staff in the world.

Getter L. Pharmaceuticals: The sudden withdrawal of Rezulin won't hobble Warner-Lambert, or its pending merger with Pfizer, analysts say. Los Angeles Times, 23 March 2000.

The FDA announces that it plans to make a public presentation of the data underlying and the rationale for the decision to request the withdrawal of Rezulin®. The presentation will be made to the next meeting of the Endocrine and Metabolic Drugs Advisory Committee.

Source: FDA Press Release, 24 March 2000

Warner-Lambert issues Dear Doctor letter regarding the treatment of individuals who have stopped using Rezulin®.

The FDA Center for Drug Evaluation and Research, Endocrinologic and Metabolic Drugs Advisory Committee holds its 74th meeting:

"a presentation of the data and rationale for regulatory action regarding the withdrawal from the United States market of Rezulin, which is troglitazone, produced by the Parke Davis Pharmaceutical Research Division of Warner-Lambert, for the treatment of type II diabetes mellitus".

Murray Lumpkin's slide presentation recommends that troglitazone should be withdrawn.

Warner-Lambert merge with Pfizer.

CBS News Reporter Sharyl Attkisson recounts claims made by Dr Janet McGill that she was pressured into downplaying liver problems when she was principal researcher on a Warner-Lambert sponsored study of Rezulin®.

Drug maker wants rezulin review. CBS News 20 July 2000.

Warner-Lambert formally requests the FDA to schedule a public meeting of the Advisory Committee on Endocrinologic and Metabolic Drugs to discuss the safety of Rezulin® and other drugs in the same chemical class.

The LA Times reports that the FDA and Warner-Lambert are being examined by the Federal prosecutors.

The final report on liver failure risk with troglitazone (NDA: 20-720) by David J Graham, Associate Director for Science for the FDA Office of Postmarketing Drug Risk Assessment is published.

Graham D, Green L (2000)
Memorandum. Final report: Liver failure risk with troglitazone (Rezulin) NDA: 20-720. USDHHS, FDA, Center for Drug Evaluation and Research, Bethesda. 19 December.

Pfizer agree to pay 30 million to settle a case in Texas filed by a Rezulin user who doctors say is dying of liver failure. A jury had ordered Pfizer to pay $43 million earlier that day and was considering punitive damages when the settlement was announced.

The case is among the first of more that 4,000 suits to go before a jury on allegations that Warner-Lambert officials hid or downplayed the health risks of Rezulin®.

Pfizer unit settles in suit over Rezulin. Los Angeles Times, 28 December 2001

Pfizer settle out of court with plaintiff Shirley Griggs. In a statement released after the settlement, Pfizer spokesman Robery J. Fauteux said trial evidence showed Griggs' liver was damaged by a pre-existing condition, not by Rezulin®.

Lawyers for Griggs, a retired bank teller, had sought at least $1 million for costs associated with a liver transplant. They argued that Griggs suffered irreversible liver damage in the seven months she took Rezulin®.

Shares of Pfizer dropped 27 cents Thursday to close at $40.35 in trading on the New York Stock Exchange.

Pfizer unit settles in suit over Rezulin. Los Angeles Times, 28 December 2001

A Texas jury finds that the Warner-Lambert Company was not responsible in the death of Doris Brown. The trial took place at the 348th Judicial District Court in Tarrant County, in Fort Worth. Pfizer is pleased with the decision in this case; the company is continuing to defend vigorously Rezulin® suits.

Texas verdict finds Warner-Lambert not liable in Rezulin trial. New York: Pfizer, 19 February 2003

The California Court of Appeal affirms a lower court's January 2002 decision denying certification of a proposed class action on behalf of California residents who had been treated with Rezulin®, a prescription medication to treat diabetes that was marketed by the Warner-Lambert Company from 1997 to 2000. The proposed class action alleged consumer claims based on the Warner-Lambert Company's advertising and marketing for Rezulin®.

The Court of Appeal decision follows a September 2002 federal court ruling that denied certification of a nationwide class of people who had been treated with Rezulin® and who had asserted medical monitoring and consumer claims.

California court of appeal affirms denial of class certification to Rezulin plaintiffs. New York: Pfizer, 31 March 2003.

Pfizer Inc announces that it will seek to set aside a New York County jury verdict which today found that the Warner-Lambert Company, which supplied the prescription diabetes drug Rezulin® before Pfizer acquired Warner-Lambert in June 2000, was liable for injury to the plaintiff. The jury awarded Concepcion Morgardo $2 million in compensatory damages and determined that there were no punitive damages.

In reaching their verdict, the jury found that the plaintiff was injured by unspecified misrepresentations by Warner-Lambert, but, at the same time, found that Warner-Lambert's warnings about the risks of Rezulin® given to the plaintiffs doctor were adequate. Under New York law, when a jury renders an inconsistent verdict, the defendant is entitled to a new trial. Pfizer plans to seek to set aside this inconsistent verdict and to ask for a new trial.

Pfizer will seek to set aside a New York Rezulin verdict. New York: Pfizer, 3 April 2003

The West Virginia Supreme Court of Appeals reverses a lower court's November 2001 order denying class certification of a proposed class-action involving Rezulin®.

The ruling also orders the lawsuit returned to trial court for further proceedings as a class action.

Pfizer pointed out that the court did not decide the case on its merits, but ruled only on whether it would proceed as a class-action. The court did not determine that Warner-Lambert had done anything wrong, nor that the plaintiffs are entitled to any relief, the company said. That will be determined in a trial. Pfizer said it will defend the case vigorously.

Pfizer also notes that the decision, which is binding only in West Virginia, is inconsistent with previous decisions that have denied class-action status in Rezulin® cases both on the federal level and in California.

The West Virginia complaint asserted claims for reimbursement under the state's Consumer and Credit Act and a medical monitoring program to diagnose alleged possible "latent effect" injuries that might develop after a patient stopped taking Rezulin®.

Pfizer noted that there is no valid scientific basis for concluding that Rezulin® had any adverse "latent effects"; that could result in patient injuries.

West Virginia Supreme Court of Appeals reverses order denying class certification to Rezulin plaintiffs. New York: Pfizer, 4 July 2003.

A California jury finds that Warner-Lambert Company was not liable for the deaths of Manuel Cervantes and Lupe Contreras and the illness of Leonard Clinkenbeard. The trial, which began on 12 April, took place in California Superior Court, Los Angeles County. The jury, in a 12-0 decision, determined that the facts in the case did not support the plaintiffs claims that Rezulin® caused or contributed to the deaths or liver disease of the three long-time diabetes sufferers.

California verdict finds Warner-Lambert not liable in Rezulin trial. New York: Pfizer, 27 May 2004.

Pfizer announces the details of an agreement with plaintiffs to resolve a state class action lawsuit in Madison County, Illinois involving Warner-Lambert's diabetes drug, Rezulin®. Upon final approval of the agreement, which has been preliminarily approved by the court and is subject to class notification, a hearing and court authorization, Pfizer will establish a $60 million settlement fund.

Pfizer reaches agreement to settle Rezulin lawsuit in Illinois. New York: Pfizer, 2 July 2004.