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Authors’ Reply to Bayer’s Response to "Potential for Conflict of Interest in the Evaluation of Suspected Adverse Drug Reactions: Use of Cerivastatin and Risk of Rhabdomyolysis"
Bruce M. Psaty, MD, PhD;
Curt D. Furberg, MD, PhD;
Wayne A. Ray, PhD;
Noel S. Weiss, MD, DrPH
JAMA. 2004;292:2658-2659. Published online November 22, 2004 (doi:10.1001/jama.292.21.2658)
INTRODUCTION
The published literature on drug safety in general and the HMG-CoA reductase inhibitors (statins) in general is a matter of public record. These publications have helped to shape our views, and all of us have actively contributed to the public discussion.1-3 In our work with plaintiffs’ attorneys, we reviewed confidential company documents, and we were bound by protective order to keep this information confidential unless that information became public through another means, as indeed some of it did in the Haltom trial. For our review, we used only publicly available documents. Bayer alone can decide whether additional documents can or should be made available for public scrutiny.
In terms of cerivastatin and the risk of rhabdomyolysis, the key questions are when did the spontaneous adverse event reports unequivocally suggest an increased risk of rhabdomyolysis, and how long was it from then until the drug was withdrawn? As early as December 1999, analyses of the adverse event data suggested that cerivastatin monotherapy was associated with a 10-fold higher risk of rhabdomyolysis than other statins.4 Previously, sometime before July 1999, Bayer had completed a clinical trial of 1.6-mg cerivastatin, a dose that was never approved for use by the Food and Drug Administration (FDA). In this trial, the incidence of creatine kinase (CK) elevations to greater than 10 times the upper limit of normal was about 12%, and some of the patients experienced clinical symptoms.5 The FDA medical review of the clinical trials of 0.8-mg cerivastatin, submitted to the FDA as part of the supplement in September 1999, identified thin older women as a subgroup with an increased incidence of CK levels greater than 10 times the upper limit of normal.6 These clinical trial results provided an important context for interpreting the reports of adverse events related to rhabdomyolysis. Cerivastatin was not withdrawn from the market until August 2001—about 20 months after the analyses of December 1999.
Recently, FDA scientists published an analysis of data on rhabdomyolysis that confirmed earlier reports.7-8 Using the FDA Adverse Event Reporting System database, they identified cases of rhabdomyolysis that occurred in the United States. Two other sources were used to identify the numbers of US prescriptions for statins. The reporting rates for cerivastatin, with or without gemfibrozil, were much higher than for any other statin (Table). For monotherapy, for instance, the reporting rate ratio (RRR) was 59-fold higher for cerivastatin than for atorvastatin (95% CI, 43-84). For combination therapy with gemfibrozil, the RRR was 2532 times higher for cerivastatin than for atorvastatin (95% CI, 1149-6959). Compared to most published epidemiologic associations, these rate ratios and their lower 95% CIs are large.
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Table. Reporting Rates per 100000 Prescriptions for US Cases of Rhabdomyolysis Associated with Statins Through July 31, 2001*
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Piorkowski’s concern that Bayer could not use spontaneous report data from the products of other companies underscores our recommendation for revisions to the current approach to postmarketing surveillance precisely because that comparison provides such strong epidemiologic evidence about the risks of rhabdomyolysis associated with the use of cerivastatin. Had an independent evaluation been performed, it could have led to recommendations based on the results of a cross-statin comparison.
While Piorkowski, as an attorney representing Bayer, properly defends some of the company’s specific actions, the purpose of our article was to raise an important public health issue. For us, the cerivastatin-rhabdomyolysis case report served as an illustration. We were primarily concerned to demonstrate how the current postmarketing surveillance system and the current FDA regulations may not, under certain circumstances, be adequate to protect the health of the public.
AUTHOR INFORMATION
Corresponding Author: Bruce M. Psaty, MD, PhD, Cardiovascular Health Research Unit, Suite 1360, 1730 Minor Ave, Seattle, WA 98101 (psaty{at}u.washington.edu).
Financial Disclosures and Disclaimer: In 2002 to 2003, each of the authors was retained by plaintiffs’ attorneys as experts in cases related to cerivastatin and rhabdomyolysis or myopathy. In that capacity, they were compensated for reviewing this issue and providing expert opinions for use in litigation. Plaintiffs’ attorneys reviewed and commented on written expert reports resulting from this work. These expert reports were disclosed to the defendants in the cases, including Bayer Corporation, and the authors have been questioned in deposition regarding the reports.
This article is based solely on published literature and public record documents; none of the confidential information reviewed in the authors’ capacity as experts during the litigation has been used in this article. Like this article, the litigation expert reports also included information from the published literature about drug safety and HMG Co-A reductase inhibitors. Much of the review for the plaintiffs’ attorneys was conducted with confidential company documents under court protective orders. The present article was developed after some, but not all, of these documents became publicly available during the trial of the Haltom case in Nueces County, Texas. Information that is not publicly available has been excluded from this article.
The initial review of these now public documents was supported in the authors’ capacity as plaintiff experts. The costs of obtaining trial exhibits from the Nueces County Clerk were paid by the authors, and the time and effort expended on this project by the authors have been in their capacity as professors at their universities. Although as described above plaintiffs’ attorneys commented on the expert reports, this manuscript reflects the views of the authors, and multiple drafts were written and revised without the participation of the attorneys representing plaintiffs in the cases related to cerivastatin. The authors were not compensated by plaintiffs’ attorneys for the time spent in preparation of this article.
As of September 2004, Bayer AG had agreed to settle 2861 cerivastatin lawsuits out of court.
There continues to be litigation related to cerivastatin and rhabdomyolysis or myopathy. The majority of cases that the authors were involved with have been settled by the manufacturer. Specifically, Dr Psaty is not involved in any ongoing cases. On January 14, 2003, Dr Weiss received a letter that confirmed his agreement to serve as an expert for plaintiffs in the Baycol Products Liability Litigation, MDL No. 1431, in the US District Court in Minnesota, and that retention is still active. Several of the cases for which Dr Furberg has served as an expert remain to be settled, and some may go to trial. Dr Ray is still involved in one case. In 2001, Dr Psaty served as a consulting expert in epidemiology on behalf of Bayer Corporation to review reports on another medication that had become the subject of lawsuits.
Funding/Support: None.
REFERENCES
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1. Moore TJ, Psaty BM, Furberg CD. Time to act on drug safety. JAMA. 1998;279:1571-1573.
FREE FULL TEXT
2. Psaty BM, Weiss NS, Furberg CD, et al. Surrogate end points, health outcomes, and the drug approval process for the treatment of risk factors for cardiovascular disease. JAMA. 1999;282:786-790.
FREE FULL TEXT
3. Ray WA. Population-based studies of adverse drug effects. N Engl J Med. 2003;349:1592-1594.
FREE FULL TEXT
4. Plaintiff Exhibit 1744, Hollis N. Haltom and Eleanor R. Haltom vs Bayer Corporation, Trial Court Cause No. 02-60165-2, Nueces County, Texas.
5. Plaintiff's exhibit 254, Hollis N. Haltom and Eleanor R. Haltom vs Bayer Corporation et al, Trial Court Cause No. 02-60165-2, Nueces County, Texas.
6. Food and Drug Administration Medical Review. Center for Drug Evaluation and Research Application Number 20-740/S008/S013 [cerivastatin]. Available at: http://www.fda.gov/cder/foi/nda/2000/20-740S008_Baycol.htm. Accessed November 4, 2004. Last updated May 2003.
7. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539-540.
FREE FULL TEXT
8. Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf. 2004;13:417-426.
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