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 May 12, 2005
FDA Whistleblower Warns of Cox-2 Risks
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By Amanda Gardner, HealthDay Reporter

THURSDAY, Feb. 17 (HealthDay News) -- FDA whistleblower Dr. David Graham delivered damning testimony on Vioxx and other cox-2 inhibitors Thursday at government hearings on the drugs.

"There's a one-in-50 chance that a male aged 65 to 74 will have a heart attack this year. Increase that fivefold with high doses [of Vioxx]," Graham testified before a standing-room-only crowd as the second of three days of Food and Drug Administration hearings commenced in Washington, D.C.

"That's what happened with VIGOR [a 2000 manufacturer's trial comparing gastrointestinal effects of Vioxx and another painkiller, naproxen]. If you have millions of people taking high doses, you're going to get numbers that balloon out. Because of the high background rate of the underlying event, there are many more cases."

The fact that randomized controlled trials such as VIGOR tend to include healthy people may have skewed the perception of risk, the FDA scientist added during two hours of testimony.

"People are harmed by rofecoxib [Vioxx]," Graham bluntly told the panel of FDA advisers who are reviewing the safety issues of all the cox-2 inhibitors, the class of painkillers originally designed to reduce the risk of gastrointestinal danger.

Vioxx was pulled off pharmacy shelves by its manufacturer Merck and Co. last fall after trials showed an increased risk of heart and stroke damage. The two other cox-2s still on the market, Celebrex and Bextra, have also shown increased cardiovascular risks in more recent studies.

The committee of 30 scientists and doctors -- who make up two FDA advisory groups on drug safety and arthritis -- will weigh all the testimony from manufacturers, scientists and the public before making their recommendations, which could come as soon as Friday and could range from banishing all cox-2s to providing sterner labeling for any or all of them.

Meanwhile, the European Medicines Agency, Europe's most powerful drug regulators, on Thursday trumped the FDA and mandated stronger warnings for all cox-2 painkillers, the Associated Press reported.

The U.S. meeting is one that Graham is partially responsible for bringing about. The medical officer for the FDA's Center for Drug Evaluation and Research is a longstanding critic of Vioxx who said he was censured for trying to reveal information about the drug. At Thursday's hearing, he thanked acting FDA Commissioner Dr. Lester Crawford who "exercised great leadership" in allowing him to present the information he wanted to present.

In their testimony, both Graham and Dr. Richard Platt, of Harvard Medical School, tried to demystify the different types of studies available on nonsteroidal anti-inflammatory drugs (NSAIDs), the group of medications that includes cox-2s.

While Platt was matter-of-fact in his descriptions of how different studies are designed and how that might affect outcomes, Graham was more forthcoming on which specific studies he deemed good or bad.

Graham said he believed the negative cardiovascular effects of Vioxx were dose-dependent, meaning higher doses had a bigger effect, and that the risk kicked in immediately, within the first 30 days. Both issues have been subjects of debate.

Celebrex had no effect on the heart at doses of 200 milligrams or less, Graham added, but did have an increased risk at higher doses. Naproxen, which is a traditional NSAID, has no protective effect, he contended.

"Unless you're willing to believe that naproxen confers lifelong immunity from heart attacks, none of the positive studies provide credible evidence of a protective effect," he said.

The little information that exists on Bextra indicates no risk at small doses, he added.

Graham seemed to contradict himself when asked whether the committee should issue warnings for specific drugs or should consider a warning for the entire class of cox-2 drugs.

"There doesn't appear to be a need for cox-2 selective NSAIDs," Graham first said.

But later, he added, "We need to weed the garden of bad actors, try to identify drugs that, based on the evidence we have, appear to be less risky. I'd be trying to identify right off the bat the bad actors and let's get rid of them. And things that actually look safe, don't appear to have cardiovascular risk, let's identify them and shift the market towards that end."

"We maybe need to look at it drug by drug," Graham acknowledged.

"We need to look for consistency across studies," he added. "Some light in the storm is better than no light in the storm."

On Wednesday, the panel heard testimony from the drug manufacturers and the FDA officials who reviewed the drug data before giving their approval.

More information

More about the hearings is available at the FDA (www.fdaadvisorycommittee.com ).

SOURCES: Feb. 17, 2005, U.S. Food and Drug Administration (FDA) advisory panel hearings, with Richard Platt, M.D., Harvard Medical School, and David Graham, M.D., medical officer, Center for Drug Evaluation and Research, FDA, Washington, D.C.

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