Washington Editor

GAITHERSBURG, Md. - Celebrex isn't as risky as Vioxx, according to Pfizer Inc.

That was the takeaway message delivered by the New York-based drug company during Wednesday's opening sessions of a three-day FDA meeting focused on cardiovascular perils associated with COX-2-selective non-steroidal anti-inflammatory drugs (NSAIDs), a commonly used class of pain drugs to which both Celebrex (celecoxib) and Vioxx (rofecoxib) belong.

The agency convened a joint meeting of its arthritis advisory committee and drug safety and risk management advisory committee to discuss overall benefit-to-risk considerations in an effort to gain a better handle on cardiovascular concerns relative to gastrointestinal safety for such products.

"The risk of celecoxib is similar to that of non-selective NSAIDs," said Kenneth Verburg, Pfizer's vice president of inflammation and immunology for clinical research and development, adding that Celebrex's increased cardiovascular risks are less than increases caused by Vioxx. "In our view, celecoxib is an effective and safe therapeutic for arthritis patients."

He based his conclusion on a variety of retrospective studies showing that Celebrex's cardiovascular safety is comparable to non-selective NSAIDs for up to a year, but conceded that beyond that point, there are no data. Nevertheless, Verburg said Pfizer's COX-2 inhibitor is distinguishable from Vioxx.

The latter's manufacturer, Merck & Co. Inc., differed on that point. The company initially viewed Vioxx's cardiovascular side effects as specific to its molecule, but later revised that original theory and now believes that cardiovascular risk is a class effect, and that such risk is time-dependent.

The whole issue began to bubble up after Vioxx was yanked from the market in September by Whitehouse Station, N.J.-based Merck. The product had been sold since its 1999 approval for acute pain, dysmenorrhea and osteoarthritis after being developed to mediate the gastrointestinal side effects associated with traditional NSAIDs. But its link to adverse cardiovascular events proved troubling in light of findings from post-approval studies, particularly from one trial called APPROVe.

Following Vioxx's removal from the market, similar cardiovascular side effects garnered attention for Celebrex, which was approved in 1998, and another COX-2 inhibitor, Bextra (valdecoxib). Pfizer also sells the latter drug, which received FDA approval in 2001.

A chief inside critic at the FDA, David Graham, last year wrote an intra-agency memorandum supporting the idea of Celebrex's better risk profile relative to Vioxx. "Our data suggest that risk of serious coronary heart disease is increased in patients treated with rofecoxib compared with celecoxib use," he noted. "High-dose rofecoxib conferred a 3.7-fold increase in risk and standard dose a 1.5-fold risk increase compared to celecoxib, the most frequently prescribed COX-2-selective agent."

Despite the negative impression of its drug, Merck stressed at the FDA meeting that it also could have continued selling Vioxx with labeling changes. But Ned Braunstein, senior director of Merck Research Laboratories, said that "Merck believes that the voluntary withdrawal served" the public's safety interests. Nevertheless, immediately after the company made its decision, public criticism of Merck and the FDA seemed to reach a fever pitch.

As a result, the agency in recent months has found itself defending its approval of Vioxx and overall handling of safety oversight issues. But as its latest meeting began, the FDA stressed that the event was not called to approve products, though two investigational COX-2 inhibitors are scheduled for discussion. Instead, the gathering has been designed for the advisory committees to examine issues of managing further use of COX-2 inhibitors.

Steven Galson, acting director of the FDA's Center for Drug Evaluation and Research (CDER), noted that "a faulty assumption is made" when the use of an approved drug results in side effects appearing in a subset of patients. In the case of COX-2 inhibitors, which were developed for pain, studies were not designed to predict cardiovascular side effects. "So in many ways," he said, "we're comparing apples to oranges."

Indeed, the agency perhaps didn't fully grasp the cardiovascular risk, despite signals pointing in that direction that four years ago led the arthritis advisory committee to push for labeling changes. Though the FDA received those early indicators on the danger, Lourdes Villballa, a medical officer for CDER, acknowledged that, "Until APPROVe, we really didn't have any information to take any different action than what we had done."

The University of Pennsylvania's Garret Fitzgerald, who spoke at the meeting to focus on the mechanisms underlying cardiovascular events associated with COX-2 inhibitors, said that such problems could have been better predicted if the variability inherent in individual drug use had been taken into account. But the FDA passes its judgments on population-based variability, not individual dose response.

The University of Texas' Byron Cryer said cardiovascular problems could have been avoided if COX-2 inhibitors were not as widely used by patients not at high risk of gastrointestinal side effects from NSAIDs. Physicians should look to alternative approaches, he said, adding that "it's clear that there are other strategies available to reduce NSAIDs' [gastrointestinal] side effects," such as non-selective NSAIDS and co-therapy such as aspirin.

More debate on future uses of COX-2 inhibitors continues today in proceedings that also include a public comment period scheduled for two hours, during which 54 speakers have signed up to get in a few words.

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