Increased Scrutiny of Pharmaceutical Company Clinical Trials: The Defense Perspective

In recent large-scale pharmaceutical litigation, plaintiffs' counsel have concentrated significant resources seeking the details of how individual patients in pre- and post-marketing company clinical trials were assessed, characterized, and reported to the Food and Drug Administration ('FDA'). The reason is clear: They are seeking to develop (in the author's opinion unfairly) a story that the pharmaceutical company hid risks and overstated benefits. The efficacy and safety data generated by industry-sponsored studies, and the manner in which the data are analyzed and reported, have therefore become the focus of large-scale pharmaceutical litigation.

Recent events in the Vioxx' litigation show that plaintiffs' counsel are now expanding this approach to industry-sponsored studies submitted to medical journals, with apparent success. The editors of the New England Journal of Medicine ('NEJM') claim that they recently obtained information revealing inaccuracies in the data reported in the VIGOR (Vioxx Gastrointestinal Outcomes Research) study that calls into question some of the study's conclusions. (Curfman GD, Drazen JM, Morissey S. Expression of concern: Bombardier et al., Comparison of upper gastrointestinal toxicity of rofexicib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520-8. N Engl J Med 2005; 353: 2813-14.) Although the VIGOR study was designed to compare gastrointestinal events in patients with rheumatoid arthritis treated with either rofecoxib (Vioxx) or naproxen (Naprosyn'), data on cardiovascular events were also monitored. According to the editors, three myocardial infarctions (heart attacks) in Vioxx patients were incorrectly omitted from the data submitted to the NEJM. The editors concluded that the omission of the three additional heart attacks ' which raised the total number of heart attacks in Vioxx patients from 17 to 20, as opposed to 4 in Naprosyn patients ' rendered certain calculations and conclusions in the VIGOR article 'incorrect' and 'misleading.'

According to Merck & Co., the manufacturer of Vioxx, the VIGOR article fairly and accurately represents the results of the study. (Tesoriero HW, Tomsho R, Winslow R. Vioxx plaintiffs seek mistrial after allegation on Merck study. The Wall Street Journal. Dec. 10-11, 2005 A1, A9.) Merck contends that the three heart attacks at issue were appropriately excluded from the data presented in the article because the heart attacks occurred after the pre-specified data cutoff point for counting adverse events in the study. As cutoff dates are used in every clinical trial to define the period during which benefits and risks of a treatment are measured, Merck was simply abiding by the pre-specified study protocol. Furthermore, by February 2001, within 3 months after the publication of the article, Merck had provided to the FDA all of the data from the VIGOR study, including the three additional heart attacks.

However, the NEJM editorial contended that the heart attacks ' even if they occurred after the effective study protocol cutoff date ' were of such import to the findings that they necessarily should have been included in the article. The editorial referenced internal company documents obtained by subpoena in the Vioxx litigation in support of the editors' contention that the study authors were in fact aware of the three additional heart attacks well in advance of the article's publication. Moreover, the editors claimed that they determined from a computer diskette that other data on cardiovascular adverse events relevant to the article were deleted from the manuscript 2 days before it was initially submitted to the journal. The NEJM editors asserted that their new findings called into question the integrity of the data on adverse cardiovascular events reported in the article.

What makes this litigation mini-battle particularly noteworthy is that the NEJM editorial was directly prompted by the deposition of its executive editor, Gregory D. Curfman, M.D., taken as part of the Vioxx litigation. Shortly after Dr. Curfman's deposition, the NEJM rushed the editorial to its Web site 3 weeks in advance of publication of the journal. While it is not clear that this was the NEJM's intent, the editorial was published while a federal court jury was deliberating a Vioxx case in Texas. In that case, plaintiffs' counsel moved for a mistrial based on the claims made in the NEJM editorial. The motion was not granted, but ultimately the court declared a mistrial because of a deadlock within the jury. The plaintiff in a Vioxx case defended successfully by Merck in New Jersey has also cited the NEJM editorial in support of a motion for a new trial. (Smith, A. Vioxx retrials for Merck? Plaintiffs: report from medical journal may be grounds for retrial in Houston and New Jersey. CNNMoney.
com. Dec. 9, 2005.)

The NEJM editorial came at a time when industry-sponsored studies published in top medical journals are receiving increased scrutiny. For example, the Journal of the American Medical Association ('JAMA') recently updated its policies for reporting conflicts of interest and disclosing financial support, as well as the requirements for reporting of industry-sponsored studies. (DeAngelis CD, Fontana-rosa PB, Flanagin A. Reporting conflicts of interest, financial aspects of research and role of sponsors in funded studies. JAMA. 2005; 294:110-11.) For industry-sponsored studies, JAMA now requires that an investigator who is not employed by any commercial funding source provide a statement that he or she had full access to all of the study data and accept responsibility for the integrity of the data and the accuracy of the data analysis. Industry-sponsored studies in which the data analysis has been conducted only by statisticians employed by the company sponsoring the research will no longer be accepted for publication. An additional independent biostatistician at an academic institution or government research institute must review the entire raw data set, study protocol, and pre-specified plan for data analysis, and provide written confirmation of his or her raw data analysis and verification of the analytical plan. Also, while not a requirement for publication, JAMA prefers studies where data collection and data management are conducted indepen-dently of the study sponsor under the auspices of an independent data and safety monitoring committee.

The NEJM editorial and JAMA reporting requirements provide important lessons and guidance with regard to litigation preparation and defense:

• Pharmaceutical companies need to be aware that their dealings with journals will be the subject of litigation scrutiny. This may mean that all protocols and pre-specified plans for data analysis for a data set used in an article must be repeatedly spelled out in order to reduce the risk that plaintiffs will successfully draw a medical journal onto their side in a litigation proceeding.
• Once a company is enmeshed in litigation, the NEJM editorial is further proof of the need to undertake an early, critical look at clinical trial data ' even down to the individual patient level ' because it is clear that well-funded, sophisticated plaintiffs' lawyers will do so in their efforts to attack company conduct.
• If plaintiffs seek to turn journal editors and authors into litigation witnesses, be prepared to use the depositions of the journal witnesses effectively. These depositions are not merely events to be survived but vital opportunities to communicate how the company approached a particular clinical trial or patient.

In assessing how the company will fight a major litigation in the public realm, be proactive in defending the propriety of the company's handling of the company's clinical trial data.

Jeffrey Horowitz is a senior associate with Kaye Scholer LLP and a member of the firm's product liability department. Horowitz, a trial lawyer, has represented a wide range of clients in major product liability and other complex litigation, though he also counsels clients on litigation avoidance. He has been a key member of national trial counsel teams representing manufacturers of pharmaceuticals, including Pfizer (Rezulin) and Novartis (PPA).

In recent large-scale pharmaceutical litigation, plaintiffs' counsel have concentrated significant resources seeking the details of how individual patients in pre- and post-marketing company clinical trials were assessed, characterized, and reported to the Food and Drug Administration ('FDA'). The reason is clear: They are seeking to develop (in the author's opinion unfairly) a story that the pharmaceutical company hid risks and overstated benefits. The efficacy and safety data generated by industry-sponsored studies, and the manner in which the data are analyzed and reported, have therefore become the focus of large-scale pharmaceutical litigation.

Recent events in the Vioxx' litigation show that plaintiffs' counsel are now expanding this approach to industry-sponsored studies submitted to medical journals, with apparent success. The editors of the New England Journal of Medicine ('NEJM') claim that they recently obtained information revealing inaccuracies in the data reported in the VIGOR (Vioxx Gastrointestinal Outcomes Research) study that calls into question some of the study's conclusions. (Curfman GD, Drazen JM, Morissey S. Expression of concern: Bombardier et al., Comparison of upper gastrointestinal toxicity of rofexicib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520-8. N Engl J Med 2005; 353: 2813-14.) Although the VIGOR study was designed to compare gastrointestinal events in patients with rheumatoid arthritis treated with either rofecoxib (Vioxx) or naproxen (Naprosyn'), data on cardiovascular events were also monitored. According to the editors, three myocardial infarctions (heart attacks) in Vioxx patients were incorrectly omitted from the data submitted to the NEJM. The editors concluded that the omission of the three additional heart attacks ' which raised the total number of heart attacks in Vioxx patients from 17 to 20, as opposed to 4 in Naprosyn patients ' rendered certain calculations and conclusions in the VIGOR article 'incorrect' and 'misleading.'

According to Merck & Co., the manufacturer of Vioxx, the VIGOR article fairly and accurately represents the results of the study. (Tesoriero HW, Tomsho R, Winslow R. Vioxx plaintiffs seek mistrial after allegation on Merck study. The Wall Street Journal. Dec. 10-11, 2005 A1, A9.) Merck contends that the three heart attacks at issue were appropriately excluded from the data presented in the article because the heart attacks occurred after the pre-specified data cutoff point for counting adverse events in the study. As cutoff dates are used in every clinical trial to define the period during which benefits and risks of a treatment are measured, Merck was simply abiding by the pre-specified study protocol. Furthermore, by February 2001, within 3 months after the publication of the article, Merck had provided to the FDA all of the data from the VIGOR study, including the three additional heart attacks.

However, the NEJM editorial contended that the heart attacks ' even if they occurred after the effective study protocol cutoff date ' were of such import to the findings that they necessarily should have been included in the article. The editorial referenced internal company documents obtained by subpoena in the Vioxx litigation in support of the editors' contention that the study authors were in fact aware of the three additional heart attacks well in advance of the article's publication. Moreover, the editors claimed that they determined from a computer diskette that other data on cardiovascular adverse events relevant to the article were deleted from the manuscript 2 days before it was initially submitted to the journal. The NEJM editors asserted that their new findings called into question the integrity of the data on adverse cardiovascular events reported in the article.

What makes this litigation mini-battle particularly noteworthy is that the NEJM editorial was directly prompted by the deposition of its executive editor, Gregory D. Curfman, M.D., taken as part of the Vioxx litigation. Shortly after Dr. Curfman's deposition, the NEJM rushed the editorial to its Web site 3 weeks in advance of publication of the journal. While it is not clear that this was the NEJM's intent, the editorial was published while a federal court jury was deliberating a Vioxx case in Texas. In that case, plaintiffs' counsel moved for a mistrial based on the claims made in the NEJM editorial. The motion was not granted, but ultimately the court declared a mistrial because of a deadlock within the jury. The plaintiff in a Vioxx case defended successfully by Merck in New Jersey has also cited the NEJM editorial in support of a motion for a new trial. (Smith, A. Vioxx retrials for Merck? Plaintiffs: report from medical journal may be grounds for retrial in Houston and New Jersey. CNNMoney.
com. Dec. 9, 2005.)

The NEJM editorial came at a time when industry-sponsored studies published in top medical journals are receiving increased scrutiny. For example, the Journal of the American Medical Association ('JAMA') recently updated its policies for reporting conflicts of interest and disclosing financial support, as well as the requirements for reporting of industry-sponsored studies. (DeAngelis CD, Fontana-rosa PB, Flanagin A. Reporting conflicts of interest, financial aspects of research and role of sponsors in funded studies. JAMA. 2005; 294:110-11.) For industry-sponsored studies, JAMA now requires that an investigator who is not employed by any commercial funding source provide a statement that he or she had full access to all of the study data and accept responsibility for the integrity of the data and the accuracy of the data analysis. Industry-sponsored studies in which the data analysis has been conducted only by statisticians employed by the company sponsoring the research will no longer be accepted for publication. An additional independent biostatistician at an academic institution or government research institute must review the entire raw data set, study protocol, and pre-specified plan for data analysis, and provide written confirmation of his or her raw data analysis and verification of the analytical plan. Also, while not a requirement for publication, JAMA prefers studies where data collection and data management are conducted indepen-dently of the study sponsor under the auspices of an independent data and safety monitoring committee.

The NEJM editorial and JAMA reporting requirements provide important lessons and guidance with regard to litigation preparation and defense:

• Pharmaceutical companies need to be aware that their dealings with journals will be the subject of litigation scrutiny. This may mean that all protocols and pre-specified plans for data analysis for a data set used in an article must be repeatedly spelled out in order to reduce the risk that plaintiffs will successfully draw a medical journal onto their side in a litigation proceeding.
• Once a company is enmeshed in litigation, the NEJM editorial is further proof of the need to undertake an early, critical look at clinical trial data ' even down to the individual patient level ' because it is clear that well-funded, sophisticated plaintiffs' lawyers will do so in their efforts to attack company conduct.
• If plaintiffs seek to turn journal editors and authors into litigation witnesses, be prepared to use the depositions of the journal witnesses effectively. These depositions are not merely events to be survived but vital opportunities to communicate how the company approached a particular clinical trial or patient.

In assessing how the company will fight a major litigation in the public realm, be proactive in defending the propriety of the company's handling of the company's clinical trial data.

Jeffrey Horowitz is a senior associate with Kaye Scholer LLP and a member of the firm's product liability department. Horowitz, a trial lawyer, has represented a wide range of clients in major product liability and other complex litigation, though he also counsels clients on litigation avoidance. He has been a key member of national trial counsel teams representing manufacturers of pharmaceuticals, including Pfizer (Rezulin) and Novartis (PPA).