November 23, 2004

Report: Bayer Held Back on Drug Dangers

Another pharmaceutical company may have concealed safety information about a dangerous drug - this time Bayer and its once-popular cholesterol medication Baycol - according to a report in a prominent medical journal.

Baycol was pulled from the market in 2001, but an analysis released Monday by the Journal of the American Medical Assn. argued there were strong indications of its dangers three months after its introduction in 1998.

The report adds to concerns that the Food and Drug Administration's drug monitoring system is too lax. The FDA is being criticized for its handling of Vioxx, the arthritis drug that remained on the market after concerns were raised that it increased the risk of heart attacks and strokes. Its manufacturer, Merck & Co., pulled Vioxx off the market in September.

Baycol belongs to a class of cholesterol-lowering drugs known as statins, which have been shown to reduce the risk of heart attacks, but have also been linked to a toxic muscle degeneration known as rhabdomyolysis, which can cause kidney problems and death. Baycol had by far the highest rate of rhabdomyolysis of any statin, said Dr. Bruce Psaty, a professor of medicine and epidemiology at the University of Washington and the report's coauthor.

In a response to be published in the Dec. 1 issue of JAMA but released early with the other reports, a lawyer for Bayer, Joseph Piorkowski, questioned the objectivity of the authors, who had served as expert witnesses in lawsuits against the company. Piorkowski argued that muscle degeneration was a known risk of all statins, that FDA surveillance had worked effectively, and that the company's conduct "was responsible, appropriate and consistently motivated by concern about the safety and welfare of patients."

The dangers of Baycol, known generically as cerivastatin, cast suspicion over all statins. But a separate study in the same issue of JAMA analyzed data from 250,000 patients who took statins between 1998 and 2001 and showed that three of the most common - Lipitor, Pravachol and Zocor - proved to be relatively safe.

The risk of the rhabdomyolysis rose slightly when combined with medications known as fibrates, which lower triglyceride fats and are often prescribed in conjunction with statins. Baycol, taken alone, posed 10 times the risk of other statins, the study said. When taken with fibrates, the danger was enormous: 10% of patients got the muscle disorder.

The study was led by Dr. David J. Graham, the FDA scientist who told a Senate panel last week that his agency was failing to monitor the safety of drugs it had approved. During clinical trials to win FDA approval for Baycol, there were no signs of serious side effects. When the drug was released in February 1998, it carried a standard warning that statins had been linked to muscle degeneration. But in the first three months of sales, seven cases of rhabdomyolysis were collected through the FDA's adverse-event reporting system. Six of the patients had also been taking a fibrate, according to Psaty.

Psaty, whose analysis was partially based on internal Bayer documents made public during a lawsuit, said the six cases should have been a serious warning. "There were opportunities to advance science and protect patients that were missed," he said.

In December 1999, Bayer changed the label to warn against an interaction with the fibrate gemfibrozil. By the time Bayer removed the drug in 2001, the number of rhabdomyolysis cases was estimated to have reached the tens of thousands. By this fall, the company had settled 2,861 lawsuits over Baycol.

A JAMA editorial questioned the FDA's system of monitoring drug safety. The editors said the FDA relied too much on the drug companies to collect information about dangerous side effects of their products. They supported calls for an independent body to monitor drugs on the market. (by Alan Zarembo, Los Angeles Times

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.
Bruce M. Psaty, MD, PhD; Curt D. Furberg, MD, PhD; Wayne A. Ray, PhD; Noel S. Weiss, MD, DrPH