FDA Panel Mulls Whether All COX-2 Drugs Have Same Risk

The makers of the arthritis drug Vioxx, which was taken off the market last year, said yesterday that they believe all medications in its class carry the same increased risks for heart attack and stroke as their drug.

At the opening of an unusual three-day meeting of a Food and Drug Administration expert advisory panel, Merck & Co. officials said all COX-2 inhibitors, such Vioxx and Pfizer Inc.'s Celebrex and Bextra, appear to increase cardiovascular problems in some patients.

The company's statement speaks to the central question at the meeting -- whether there is a dangerous "class effect" for all COX-2 drugs, and, if so, what the agency should do. Sales of the drugs, hailed in the late 1990s as a breakthrough in treating arthritis pain and aggressively advertised to patients, could be restricted or stopped as a result of the meeting.

Before an overflow crowd in Gaithersburg, Pfizer officials disputed Merck's contention -- saying that there is reason to believe its COX-2 drugs may be different than Vioxx and that any possible increased cardiovascular risk would be very small.

That position, however, was roundly criticized by many members of the expert panel, and Chairman Alastair J. Wood said key aspects of the Pfizer presentation "don't pass the laugh test." Several panel members accused the company of ignoring a recent study, published in the New England Journal of Medicine, that showed significant heart and stroke problems in patients taking Celebrex. Celebrex and Bextra are still being sold.

The day began with a statement by Steven Galson, acting director of the FDA's Center for Drug Evaluation and Research, that the agency would act on the panel recommendations, expected tomorrow, within several weeks. The FDA usually is guided by its advisory panels.

Galson emphasized that the panel should weigh not only the possible safety risk of COX-2 drugs, but also the benefits that the drugs provide to arthritis patients who have gastrointestinal problems caused by other painkillers.

Lourdes Villalba, the FDA medical officer who supervised Merck's application for approval to market Vioxx, defended her agency's much-criticized handling of the once-popular drug and its safety risks. Outlining years of frustrating work trying to assess the potential dangers of COX-2 drugs, she said her goal "is to show that we were not sleeping behind the wheel; we were actually engaged in reviewing a lot of data."

Some of the day's strongest testimony came from Garret A. FitzGerald of the University of Pennsylvania. He told the committee that just as low-dose aspirin is known to protect the heart while raising the risk of stomach and intestinal problems, COX-2 inhibitors "afford gastrointestinal protection and a small but absolute risk of cardiovascular events."

FitzGerald, who has been aggressive in arguing that all COX-2 inhibitors can cause heart problems and stroke, also said that different patients respond very differently to the drugs, and that their use has to be tailored to the person. That point was later emphasized by a National Cancer Institute researcher who said COX-2 drugs show promise for treating colorectal cancer.

One theme that developed was that the harmful effects of COX-2 drugs seem to appear after months of use, while the clinical tests conducted to gain approval for the drugs were much shorter. There was also considerable discussion of the relative risks posed by older arthritis painkillers, such as ibuprofen, naproxen and aspirin. Merck officials, as well as panel members, said it is possible that those drugs cause problems such as those linked to COX-2 drugs.

Nonetheless, Wood, of Vanderbilt University Medical Center, seemed to speak for many on the panel when he said he was concerned that COX-2 drugs were initially approved because they provided a safety benefit, reducing gastrointestinal problems for longtime users, not because they were better painkillers. "I find it worrisome when a drug that is approved to produce a safety benefit results in increased mortality," he said.

David J. Graham, an FDA safety officer and whistle-blower, is scheduled to testify this morning about cardiovascular risks detected in epidemiological studies of COX-2 and traditional painkillers. Graham, who has accused agency leaders of trying to silence him and other critics of FDA safety policies in the past, has said his full testimony is again being restricted.