Opinion ID: 781623
Heading Depth: 2
Heading Rank: 2

Heading: Allegations in Plaintiffs' complaint

Text: 5 According to Plaintiffs' complaint, the allegations of which must be accepted as true for the purposes of a motion to dismiss, see Conley v. Gibson, 355 U.S. 41, 45-46, 78 S.Ct. 99, 2 L.Ed.2d 80 (1957), Rezulin first gained prominence in June 1996, when the National Institutes of Health (NIH) announced a $150 million clinical study to test the drug's effectiveness. The NIH's decision to include Rezulin in the study was heavily influenced by Dr. Jerrold Olefsky, who held prominent positions in the NIH, and by Dr. Richard Eastman, the NIH's senior diabetes researcher who had overall responsibility for the study. Both doctors had financial interests in promoting the drug: Dr. Olefsky is listed as inventor or co-inventor on three patents regarding Rezulin's use for preventing diabetes and was co-chair of a Warner-Lambert-created group that promoted the drug; Dr. Eastman was a board member of two organizations financed by Warner-Lambert and the drug's developer. And, as it turned out, Dr. Eastman received more than $78,000 in undisclosed compensation from Warner-Lambert while he was overseeing the study. When these payments were brought to light in December 1998 — prompting a conflict-of-interest investigation by the Inspector General's office — Dr. Eastman was forced to resign from the NIH. 6 Warner-Lambert submitted a New Drug Application (NDA) for Rezulin to the FDA on July 1, 1996, and the FDA agreed to give the drug a fast track (six month) review. The FDA initially assigned Dr. John L. Gueriguian as the chief medical officer to oversee the review. After concluding that the drug posed serious health and safety concerns, Dr. Gueriguian recommended against approval in a detailed written evaluation dated October 9, 1996. Specifically, Dr. Gueriguian found very worrisome liver toxicity, 1 and concluded that Rezulin offered very little therapeutic advantage over existing diabetes medications. He noted that Warner-Lambert's clinical trial data showed that Rezulin users developed liver problems at four times the rate of control patients who received a placebo, and also expressed concern about potential cardiovascular damage from the drug. 2 Dr. Gueriguian met with Warner-Lambert representatives in September 1996 and suggested the drug's prospects were not good. Warner-Lambert then met with Dr. Gueriguian's superiors at the FDA who, in November 1996, removed Dr. Gueriguian from the Rezulin review. 7 Dr. Gueriguian was replaced by Dr. G. Alexander Fleming, whose medical review noted that Warner-Lambert's clinical trials had identified significant safety issues and suggested unpredictable damage associated with Rezulin. Nevertheless, Dr. Fleming's presentation to the FDA's Endocrinologic and Metabolic Drugs Advisory Committee made no mention of either Dr. Gueriguian's reservations about the drug, or of the problematic results of Warner-Lambert's clinical trials. Three advisory committee members later told the press that, if they had been informed of the adverse liver results, they would have required liver-function monitoring as a condition of approval. The advisory committee voted unanimously (8-0) to recommend approval of Rezulin and, on January 29, 1997, the FDA approved the drug, but only for use in combination with insulin or with metformin or sulfonylurea drugs. In August 1997, this approval was broadened to allow the use of Rezulin as a stand-alone therapy. 8 Warner-Lambert marketed Rezulin aggressively, and priced it at nearly three times the cost of appropriate treatments by other drugs. It touted Rezulin as the first anti-diabetes drug designed to target insulin resistence. That statement prompted the FDA to accuse Warner-Lambert of making false and misleading claims, and to recommend that the company immediately discontinue circulating new releases containing the claim. More significant to this litigation, Warner-Lambert published two full-page color advertisements — one in the May 1, 1997 issue of The New England Journal of Medicine, and one in the June 19, 1997 Washington Post — describing Rezulin as a drug with breakthrough effectiveness, and Side Effects Comparable to Placebo. The company allegedly made this statement while knowing that its own clinical trial data showed Rezulin users were three to six times more likely to suffer liver injury than patients taking the placebo. 9 By July 1997, seven people receiving Rezulin had died from the same side effects that Warner-Lambert had observed in its pre-market Rezulin tests. By the fall of 1997, the FDA began to receive reports of Rezulin patients suffering serious liver injuries, including death following liver failure. The FDA appointed a Dr. Misbin to evaluate the adverse event reports. He estimated that more than 12,000 Rezulin users would experience some liver injury, and that 2,000 of those patients might die unless their liver functions were closely monitored. 10 Warner-Lambert sent a letter to doctors in October 1997, reporting that thirty-five Rezulin users had experienced idiosyncratic hepatocellular injury ranging from mild effects to one liver transplant and one death. The letter said these reports were RARE, but nevertheless recommended that liver function be tested within the first month or two of Rezulin use, every three months for the first year thereafter, and then periodically. 11 On December 1, 1997, Warner-Lambert sent a second letter to healthcare professionals, announcing a label change on the drug which recommended more frequent liver-function monitoring for patients using Rezulin. The letter suggested that the FDA remained an advocate of Rezulin and a partner with Warner-Lambert in assuring safety to the drug's users. 12 On that same day, December 1, the sale of Rezulin's active ingredient was banned in the United Kingdom, based on a conclusion by the company marketing the drug that there was no way to predict which Rezulin patients would be harmed, and the pace of liver injuries and deaths was by that point `unacceptably high.' Warner-Lambert reacted by issuing a press release on December 7 stating it was disappointed with the mischaracterization of its actions and intentions regarding the development and marketing of Rezulin, and that it was particularly disturbed by media reports that focused on the drug's risks while ignoring its significant benefits. Moreover, Warner-Lambert reaffirmed that the FDA supported the drug, and noted that the injured patients may not have been monitored as recommended in the labeling. 13 Throughout this period, the NIH study of Rezulin continued. In May 1998, Audrey Jones, a healthy, non-diabetic participant in the study who had taken Rezulin, died, following a liver transplant made necessary by the irreversible liver failure she had developed. Mrs. Jones had undergone the monitoring tests that Warner-Lambert recommended. Warner-Lambert issued a press release stating that Mrs. Jones had died apparently due to complications unrelated to her Rezulin use. This report, however, was contradicted by NIH physicians, who concluded that the patient's death had probably been caused by Rezulin. The following month, citing concerns about the safety of the remaining 580 participants in the study, Rezulin was withdrawn from the NIH study. 14 In July 1998, Warner-Lambert sent a third letter to health care professionals announcing another label change for Rezulin. The letter noted that a few new cases of hepatocellular events since 1997 had occurred in patients who may not have been monitored as recommended in the labeling. The statement allegedly was made despite the company's knowledge that Mrs. Jones had been tested and carefully monitored, in accordance with Warner Lambert's recommendation, by the NIH. Under the new label change, liver testing was required for all Rezulin patients monthly for the first eight months, every two months for the remainder of the first year, and periodically after that. Despite the new label calling for additional monitoring, the reports of patients suffering liver failure continued to rise. In November 1998, two patients who had been monitored as recommended by the safety labels then in effect developed liver failure within two weeks of the tests, and died. 15 The complaint alleges that Warner-Lambert did not stop misdescribing the drug as safe. In a March 1999 article in the Los Angeles Times, a Warner-Lambert vice president asserted that he was unaware of any deaths related to Rezulin after the July 1998 label change. But, in fact, Warner-Lambert had itself reported to the FDA the deaths of thirty-one Rezulin users between July 28 and December 17, 1998. 16 On March 26, 1999, the FDA convened a second advisory committee meeting to evaluate Rezulin. At that meeting, a senior FDA epidemiologist verified that Rezulin had been implicated by the FDA in forty-three reported cases of liver failure, and that the drug could be expected to cause liver failure in one out of every 1,800 patients. The committee recommended that the FDA withdraw its approval of Rezulin as a stand-alone therapy. On that same day, Warner-Lambert sent out a series of press releases claiming, inter alia, that the new labeling had substantially reduced the reported rate of liver events. 17 In June 1999, the FDA announced that it was allowing Rezulin to remain on the market, but was requiring another label change. Under the new label, Rezulin could no longer be used as a stand-alone therapy, and the required liver-function monitoring was again increased. Patients using the drug were required to undergo liver-function testing before beginning treatment, monthly for the first 12 months, and quarterly during the second year. 18 Despite these changes, mortality statistics of Rezulin users continued to climb, and Warner-Lambert allegedly continued to lie about them. In February 2000, the company released a statement claiming that it believed there were no liver-failure deaths attributable to Rezulin after the June 1999 label change. The day after this statement was made, the FDA discredited it, saying the agency had been informed of six cases of liver failure with onset after July 1999, of which at least three resulted in death. 19 In March 2000, doctors at the FDA and elsewhere became even more concerned about Rezulin, with one doctor writing to others that at each juncture in the management of Rezulin's liver failure risk, hindsight shows that [the monitoring] had little or no effect and that Warner-Lambert's assertions that the liver failure problem was solved were proved false. Another doctor, who had formerly been a principal researcher in Warner-Lambert 1994 Echo study, wrote to Senator Edward Kennedy that she believe[d] that the company... deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by patients in their clinical studies. Moreover, an article in the March 10, 2000 Los Angeles Times reported that the FDA had linked Rezulin to eighty-nine liver failures, including sixty-one deaths. 20 On March 21, 2000, Warner-Lambert withdrew Rezulin from the U.S. market. The withdrawal was at the request of the FDA, which had concluded that continued use of Rezulin now poses an unacceptable risk to patients. Since then, the FDA has acknowledged reports of liver damage occurring after patients were taken off the drug, which indicates that the risk of harm does not disappear with the withdrawal of the drug.