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Rezulin� was the first drug of the thiazolidinedione class of compounds, which are also known as insulin resistance reducers, to be approved by the Food and Drug Administration. Clinical studies demonstrated that Rezulin (chemically named troglitazone) was an effective treatment for Type II diabetics whose blood glucose could not be controlled even when insulin was combined with other pre-glitazone antidiabetic drugs. Before Rezulin was introduced, medical science had no effective therapy to offer these patients. With Rezulin, many patients were able, for the first time, to control their blood sugar, which is essential to preventing the serious complications of diabetes. This made Rezulin an important breakthrough medication to treat Type II diabetes. Nevertheless, Warner-Lambert, the manufacturer of Rezulin, has been embroiled in litigation and has ceased to manufacture and distribute this drug. This article will give a brief overview of the litigation from the defense perspective. As of Feb. 27, 2001, 324 cases were pending against Warner-Lambert in 27 states. State complaints identify 544 plaintiffs, including the named plaintiffs in 21 proposed class actions. In federal court, 323 cases have been, or are being, transferred into the MDL proceeding in the Southern District of New York before Judge Lewis Kaplan. The federal complaints identify 1,010 plaintiffs, which include the named plaintiffs in 52 proposed class actions. There are also 167 unfiled claims in 24 states. Because new cases are filed daily, keeping track of the exact number of cases filed is a difficult task. Plaintiffs’ lawyers are advertising heavily in print, radio and on television. In a number of states, including Mississippi, Texas, Louisiana, Illinois and California, plaintiffs’ lawyers have said they are evaluating hundreds of new cases and will file them over the next six months. So far, no mass filings have materialized. REZULIN FACTS Type II diabetes, which is sometimes called adult-onset diabetes or non-insulin-dependent diabetes mellitus (NIDDM), is a treatable but incurable, chronic condition that afflicts approximately 16 million Americans. Even with all of the miracles of modern medicine, Type II diabetes is a devastating illness. Insulin resistance is a principal underlying cause of Type II diabetes. None of the currently available diabetes medications, alone or in combination, is a completely adequate long-term treatment for this disease. All of the currently available medications for Type II diabetes are associated with serious and often life-threatening adverse events. Rezulin was an important new drug that directly treated the underlying cause of Type II diabetes by improving the body’s utilization of insulin. Rezulin provided many therapeutic benefits over other treatments then available. In conjunction with other therapies, Rezulin helped patients obtain optimal glucose reduction. Warner-Lambert’s Parke-Davis division distributed Rezulin during the three-year period between March 1997 and March 2000, during which time approximately 1.9 million patients started therapy. No cases of liver failure occurred in clinical trials involving 2,500 patients. A small number of clinical trial patients, approximately 2 percent, experienced elevated liver enzyme values, but all those enzyme values reversed and resolved without any permanent injury. In post-marketing use, fewer than 100 individuals reported acute liver failure leading to death or transplant. WARNER LAMBERT’S PRODUCT WARNINGS CONCERNING REZULIN Warner-Lambert’s initial product labeling, based on clinical studies of 2,500 patients, warned of the risk of liver function test abnormalities. The first reports of post-marketing liver failure associated with Rezulin use were received by Warner-Lambert’s Parke-Davis division in late September 1997, after more than 500,000 patients had been treated with the drug. Based on that new information, Warner-Lambert, with the FDA’s approval, revised Rezulin’s label in October 1997 to include the following specific warning and to recommend that physicians monitor patients’ liver enzyme levels during the initial stage of therapy: WARNINGS. Hepatic. RARE CASES OF SEVERE IDIOSYNCRATIC HEPATOCELLULAR INJURY HAVE BEEN REPORTED DURING MARKETED USE. (SEE ADVERSE REACTIONS, POSTINTRODUCTION REPORTS.) THE HEPATIC INJURY IS USUALLY REVERSIBLE, BUT VERY RARE CASES OF HEPATIC FAILURE, INCLUDING DEATH, HAVE BEEN REPORTED. INJURY HAS OCCURRED AFTER BOTH SHORT- AND LONG-TERM TROGLITAZONE TREATMENT. (October 1997 package insert) (emphasis in original). In December 1997, this warning was put at the top of the Rezulin labeling in a black box. After Warner-Lambert and the FDA agreed on the text and placement of the warning, the FDA approved and mandated both. WARNER-LAMBERT PROMPTLY REPORTED ADVERSE EVENTS When Warner-Lambert first received post-marketing reports of liver failure in late September 1997, it promptly reported these events to the FDA and the medical community. As Dr. Robert Misbin, an FDA official, publicly stated, within two weeks of the first report “we actually had joint statements by the FDA and Parke-Davis in an attempt to correct this problem. This could not have been done without the complete cooperation of Parke-Davis. And so any speculation that there was foot dragging here is totally without foundation.” April 23, 1999, Advisory Committee Hearing Transcript, pp. 92-93. Moreover, Warner-Lambert did not only change the labeling to reflect its post-marketing knowledge. It also sent 500,000 “Dear Doctor” letters to the medical community specifically to alert physicians to the risk of liver failure and to highlight the importance of liver enzyme monitoring. In late October and early November 1997, Warner-Lambert sent the first “Dear Healthcare Professional” letter, titled “Important Drug Warning.” A second letter was sent Dec. 1, 1997. That letter stated that “heightened awareness following the earlier labeling change has, as expected, generated some additional reports of hepatic dysfunction.” The letter recommended that liver enzymes and bilirubin levels of Rezulin-treated patients be measured at the start of therapy and monthly for the first six months of therapy. On Dec. 15, 1997, Warner-Lambert sent yet another “Dear Healthcare Professional” letter. This letter reiterated that “[i]t is important to note that rare cases of severe hepatocellular injury have been reported during marketed use. The hepatic injury is usually reversible, but very rare cases of hepatic failure, leading to death or liver transplant, have been reported.” This letter also enclosed an FDA talk paper, which highlighted the risk of serious liver injury, including death, but concluded, “Although FDA will carefully monitor and evaluate reports of liver problems associated with Rezulin, at present the agency continues to find the benefits outweigh the risks for treating appropriately selected and monitored type-2 diabetes patients with Rezulin.” Thus, in addition to including the FDA-backed explicit warnings of the risk of liver failure, Warner-Lambert also reached out to the medical community both to increase awareness of the rare, but real, risk of liver failure, and to encourage physicians to monitor patients in order to reduce the risk of liver injury. Any claims that Warner-Lambert concealed information from the FDA or the medical community are refuted by this factual record. STATUS OF CASES FILED TO DATE As of this writing, Warner-Lambert has successfully obtained coordination of all Rezulin cases in California, West Virginia and New Jersey state courts, as well as all cases filed in New York County. In addition, all cases pending in the 3rd and 5th Judicial Administrative Regions in Texas have been consolidated. There are indications that each of those courts will be amenable to coordinating discovery with the MDL. California has 38 cases with one statewide proposed class action for disgorgement under consumer statutes. New Jersey has 100 cases, including numerous proposed class actions. In West Virginia, six cases have a total of eight plaintiffs, including three proposed class actions; in Texas, there are 25 cases. The state of Mississippi itself brought a suit to recover the amounts paid to reimburse patients for the cost of Rezulin, and in a similar situation, Blue Cross filed a suit seeking the same relief, both in Mississippi and Louisiana. GENERAL STRATEGY Warner-Lambert is evaluating all state court actions for possible removal, particularly in those cases where the doctor or pharmacy has been fraudulently joined solely to defeat federal jurisdiction. Warner-Lambert is opposing remand motions and seeking orders to stay discovery in such cases pending a determination of the remand. On March 1, Judge Lewis Kaplan of the Southern District of New York denied remand in 14 actions originally brought in Alabama, Louisiana, Mississippi, Texas and West Virginia, in which pharmacies, territory representatives and/or physicians were named. In denying the remands, Judge Kaplan held that those nondiverse defendants had been fraudulently joined to defeat removal. Once removed, Warner-Lambert had deferred all deposition and document discovery in anticipation of the multidistrict litigation (MDL) establishing a discovery program. On Dec. 5, Judge Kaplan issued Case Management Order No. 4, which adopted a fact sheet to be completed by plaintiffs in all MDL cases. Warner-Lambert is now in the process of collecting medical records pursuant to authorizations provided by the plaintiffs with the completed fact sheets and will shortly begin taking depositions of the plaintiffs. On March 21, the MDL plaintiffs’ executive committee began their initial round of depositions of Warner-Lambert’s corporate representatives. In states with numerous non-removable cases, where it appears likely that defendants will be required to produce documents and deponents, Warner-Lambert is seeking statewide coordination to prevent duplicative discovery. Where state courts are forcing document and deposition discovery, defendants are working to limit the scope of that discovery to those documents that have already been made available to the plaintiffs — namely the IND/NDA (investigational new drug/new drug application), the custodial and departmental files and the territory representative files and a limited number of other regulatory documents. Warner-Lambert has already made the IND/NDA and related materials available for inspection. As additional company documents are processed and coded, they will be added to the depository. As of March 11, Warner-Lambert company witnesses had been deposed in cases pending in Missouri, Texas and West Virginia and in the MDL, and only two of those depositions had been completed. THE PLAINTIFFS’ ALLEGATIONS AGAINST WARNER-LAMBERT Plaintiffs claim that Warner-Lambert manufactured a drug that it knew was dangerous, and that did, in fact, prove to be unsafe. Further, plaintiffs claim that Warner-Lambert continued to advance its assertion that Rezulin was safe, and contend that Warner-Lambert attempted to mislead the public through inaccurate and false information, and through material omissions. Plaintiffs accuse Warner-Lambert of attempting to enlist the support of the medical community in order to ensure high market demand for Rezulin. Plaintiffs allege that Warner-Lambert relinquished its affirmative obligation to present factual information to the general public. Finally, it is plaintiffs’ contention that the adverse reactions, including liver failures and deaths, should have resulted in a more tempered marketing strategy. Instead, plaintiffs accuse Warner-Lambert of “driving consumer demand” for Rezulin. WARNER-LAMBERT’S RESPONSE Warner-Lambert has responded to each of these allegations. According to the company, the promotional materials distributed by Parke-Davis, the Warner-Lambert division responsible for distribution of Rezulin, were balanced, fair and accurate, reflecting Parke-Davis’ knowledge of the risks. In developing and disseminating its promotional materials, Parke-Davis adhered to its strict review protocol and fully complied with the FDA’s guidelines and suggestions. Parke-Davis timely and fully disseminated information concerning label changes and monitoring requirements. It established relationships with thought leaders in the diabetes community to ensure that the market received timely and accurate knowledge concerning Rezulin’s safety and efficacy. Moreover, Parke-Davis exhibited corporate responsibility in conjunction with its marketing of Rezulin. It chose to adopt a responsible message in response to unbalanced and irresponsible adverse publicity. Perhaps the single most telling fact regarding the correctness of the FDA’s decision to endorse the drug based on its risk/benefit analysis occurred in March 1999. At that time the FDA convened an advisory committee to reassess Rezulin in light of the postmarketing liver experience and the allegations being leveled at it by both the Los Angeles Times and Public Citizen. After hearing all the facts, including accusatory testimony, the committee voted unanimously to keep Rezulin on the market. FDA PRIORITY REVIEW Numerous articles have criticized Warner-Lambert and the FDA for the alleged “fast-track” approval of Rezulin. Plaintiffs in many cases have relied on this allegation in claiming that Rezulin was approved for marketing without appropriate testing. This allegation, according to Warner-Lambert, is wholly untrue. The company notes that the FDA gave Rezulin a “priority review,” not “fast track” review. Priority review is granted for drugs that “would be a significant improvement compared to marketed products … in the treatment, diagnosis or prevention of a disease.” (FDA, Center for Drug Evaluation and Research, Manual of Policies and Procedures 6020.3, Priority Review Policy (April 22, 1996). The FDA determined that Rezulin met this standard because it was a novel therapy that fulfilled an unmet need — demonstrated efficacy in treating patients poorly controlled on insulin who had no other effective strategy. Priority review has no effect on the quality or thoroughness of the FDA’s review. It does not shorten the time required to conduct clinical trials, assemble the required data or prepare the new drug application (NDA) that is submitted to the FDA. Priority review does not allow for fewer clinical trials or lower the quality or extent of the FDA’s review of an NDA. Priority review means that the FDA allocated additional resources to review the Rezulin NDA and put the Rezulin NDA ahead of applications for other, less important new drugs. WHY REZULIN WAS ULTIMATELY REMOVED FROM THE MARKET In mid-1999, the FDA approved two new diabetes drugs, Avandia (rosiglitazone) and Actos (pioglitazone). These newer drugs have a mechanism of action similar to Rezulin’s and are in the same class of glitazone drugs. They have also been associated with adverse liver events, although at a lower rate than Rezulin. The current product labels for Avandia and Actos recommend that patients have a liver function test before initiating therapy and periodically thereafter to check for elevated enzymes. By March 2000, Rezulin had been the subject of a considerable amount of media attention and adverse publicity, much of it allegedly incorrect. Furthermore, with the introduction of two new glitazone drugs having the initial appearance of a safer adverse event profile, the FDA felt that the scales had tipped and that the benefit of Rezulin no longer outweighed its risks. In addition, Rezulin faced increasing competition from Actos and Avandia. As a result of the adverse publicity and the competition from the newer drugs, Warner-Lambert concluded that distribution of Rezulin should cease. The company voluntarily discontinued marketing Rezulin on March 21, 2000. Warner-Lambert claims that Rezulin was an important new breakthrough drug that helped thousands of people afflicted with a serious and debilitating chronic disease. Therefore, the company continues to defend Rezulin lawsuits vigorously. Jay P. Mayesh is a partner and Mollie D. Roth and Laurie J. Sternberg are associates with Kaye Scholerin New York. They are representing Warner-Lambert in the Rezulin litigation. Telephone: (212) 836-8000.

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