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”

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reports unequivocally suggest an increased risk of rhabdomyolysis, and how long was it from then until the drug was withdrawn?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 Cerivastatin was not withdrawn from the market until August 2001—about 20 months after the analyses of December 1999.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.

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.