Washington Editor

GAITHERSBURG, Md. - David Graham, a much-publicized doctor at the FDA, questioned all use of COX-2 selective non-steroidal anti-inflammatory drugs Thursday during the second of a three-day meeting on such products.

"There doesn't appear to be a need for COX-2 selective NSAIDs," he said, adding that some traditional NSAIDs also might be harmful. Graham, who gained prominent attention as a whistleblower following his November congressional testimony in which he charged that the FDA was faulty in handling drug safety, added that the use of high-dose COX-2 drugs was riskier than smoking, diabetes and hypertension.

Of course, such safety issues stem from the pain relievers' association with cardiovascular risk despite their therapeutic benefit to patients with arthritis and other inflammatory conditions. The FDA convened the meeting, a joint gathering of its arthritis advisory committee and drug safety and risk management advisory committee, to focus on overall benefit-to-risk considerations relative to cardiovascular concerns with COX-2 selective NSAIDs in light of their gastrointestinal protection qualities.

Because of the positive properties they do afford, the FDA approved three such drugs in the last six years: Celebrex (celecoxib), Vioxx (rofecoxib) and Bextra (valdecoxib). And during Thursday's public discussion period, a number of speakers articulated their need for the COX-2 drugs because of their benefits and in spite of their risks.

But cardiovascular risk caused Merck & Co. Inc. to remove Vioxx from the market in September. Its decision came nearly in parallel with findings from Graham, who concluded from a variety of retrospective examinations of COX-2 drugs that Vioxx confers a definite increase in cardiovascular risk when used at doses higher than 25 mg, and probably increases risks when dosed at 25 mg or less.

"The risk of myocardial infarction with rofecoxib begins when rofecoxib use begins," he said. Graham added that epidemiological studies better indicate side effect profiles because they are statistically powered to examine such issues more so than clinical studies used to support a product's approval.

The other approved COX-2 drugs, both sold by Pfizer Inc., of New York, didn't escape his dose-response watch. He concluded that Celebrex probably increases risk when used at doses higher than 200 mg, but there is no apparent effect at doses of 200 mg or less. Bextra doses less than or equal to 20 mg do not appear to cause an effect, but Graham noted that little information on the drug exists.

It was approved in 2001, while Celebrex received approval in 1998 and Vioxx was cleared in 1999. During the proceedings, two non-approved COX-2 inhibitors also were discussed. Merck, of Whitehouse Station, N.J., presented data on etoricoxib, which is sold as Arcoxia outside the U.S. Novartis AG, of Basel, Switzerland, detailed its findings on lumiracoxib, which it markets as Prexige outside the U.S.

While the FDA did not call its meeting to approve additional products, the agency invited data on the nonapproved products to better identify class effects for COX-2 inhibitors. All of them, approved and nonapproved, generate cardiovascular side effects, but their industry sponsors note that such risks are mediated through proper dosing.

FDA Focus On Safety Questioned

Graham, whose presentation was not meant to speak for the FDA as a whole, clearly indicated his primary concern.

"When I'm looking at drug safety, I'm trying to find what risk I can exclude," he said, adding that when assessing a drug's benefits, the agency also should examine the upper bounds of its risk profile. "That's my view, not the FDA's."

Graham said the underlying fault at the FDA is its mission to approve drugs based on efficacy while examining safety in a secondary role, and he wasn't the only critic of the agency's record relative to safety. During the public discussion period, additional accusations of carelessness were charged.

Sidney Wolfe, director of the health research group of a consumer watchdog organization, Public Citizen, recently filed a petition with the FDA to remove Celebrex and Bextra from the market. He renewed his call to ban both drugs during a two-minute speech as part.

"I recommend today that Pfizer be criminally prosecuted by the U.S. Attorney's Office," Wolfe added, noting that he expects a Senate investigation also will be launched to further determine whether the drug company buried negative cardiovascular risk findings from a Celebrex study.

In a discussion with BioWorld Today, Wolfe said the safety issues surrounding the entire class of drugs have ballooned because of "negligence on the part of the companies making these drugs and the part of the FDA." At a meeting of the arthritis advisory committee four years ago, he asked for a black box label warning on Vioxx and Celebrex.

"If there had been a black box warning put on four years ago," Wolfe said, "the number of people using Vioxx and Celebrex would have been a small fraction of what there have been, and therefore many of the heart attacks and deaths would have been prevented because people wouldn't use these drugs."

Wolfe and other critics pointed to the apparent COX-2 safety failing as indicative of a wider problem at the FDA, namely that the agency is too tight with drug manufacturers. That closeness, according to Wolfe, has been cemented firmly since the passage of the Prescription Drug User Fee Act, through which the industry funds operations at the FDA to speed the drug review process.

"That's just unworkable," he added, "and when you go through most of the last 15 years with almost no congressional oversight until these couple of hearings last fall, you again allow the FDA to do the industry's bidding instead of helping to protect the public."

Other speakers during the open public hearing echoed his sentiments. One charged that the FDA fails to scrutinize long-term safety data, and cautioned against findings from industry-sponsored post-approval studies. Lawyers also made claims of drug safety failings on the part of pharmaceutical firms.

Drug Benefits Also Deserve Consideration

Among those who spoke on behalf of COX-2 inhibitors were physicians who cautioned against limitations on drugs that provide an obvious benefit to arthritis patients, regardless of their risks. "A known risk can be dealt with," said a patient who ominously added that she has 40 Vioxx pills remaining. Other COX-2 advocates pointed to the drugs' benefits for cancer patients, in whom COX-2 inhibitors are being tested, while a military representative made note of the drugs' popularity with soldiers.

All of those positive and negative considerations will be further dealt with by the FDA committees in today's closing session of the meeting. They will spend most of the day weighing whether the three approved COX-2 inhibitors merit further licensure in light of their benefit-to-risk profile.

Steven Galson, acting director of the FDA's Center for Drug Evaluation and Research, said during the first day that the agency would quickly act on any committee recommendations.

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