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FDA Scientist Sees Problems With Entire Class Of Painkillers

Whistle-blower tells panel that high doses of Cox-2 inhibitors endanger heart

Feb 18, 2005 | Baltimore Sun

Food and Drug Administration whistle-blower David J. Graham told a panel of scientists yesterday that he believed high doses of the Cox-2 inhibitor drug Celebrex pose a risk of increased heart attack or stroke but the risk drops at lower doses.

Graham, testifying on his findings on the safety of several painkillers widely used by arthritis patients, also raised the possibility of cardiovascular risk in taking Mobic, or meloxicam. The top-selling drug is from a more traditional class of anti-inflammatory medications.

The remarks by the FDA medical officer came on the second day of hearings by a joint panel of two advisory committees examining an entire class of painkilling drugs, Cox-2 inhibitors. The session at a hotel conference room here drew patients who urged the panel to continue to make the drugs available so they and their doctors can weigh the benefits and risks.

The advisory panel, composed of arthritis and drug safety experts, is expected to make a recommendation to the FDA today on whether to restrict or ban Cox-2 inhibitors such as Celebrex and Bextra. The two drugs, both made by Pfizer, remain on the market in the United States. Vioxx, which Merck voluntarily withdrew last fall, showed an increased risk of cardiovascular problems at all dosages.

Making clear that he was speaking for himself and not the FDA, Graham said he believed all drugs that work by suppressing the Cox-2 enzyme associated with inflammation are risky to the heart.

"I believe there is a Cox-2 effect, and that it is dose-dependent," said Graham, who made headlines in November by telling a congressional panel that the FDA was not able to protect the public against dangerous drugs such as Vioxx.

Pfizer, the maker of Celebrex, has defended it as "an effective and safe therapy."

Meanwhile yesterday, the European Union's public health officials concluded after four days of meetings in London that the entire class of Cox-2 drugs caused an increased risk of cardiovascular problems. They immediately imposed restrictions.

The European Medicines Agency said doctors should not prescribe Celebrex, Bextra or Merck's Arcoxia, which hasn't been approved in the United States, for patients with a history of heart disease or stroke.

They told doctors not to prescribe Arcoxia for patients with high blood pressure and instructed doctors to keep the dose as low as possible and prescribe the drug for the shortest treatment time possible.

In the hearing here yesterday, Graham also said he had concluded there was no need for the Cox-2 drugs, including Celebrex and Bextra, because they didn't seem to be easier on the stomach than older anti-inflammatory drugs. The newer drugs were originally billed as being gentler, but the FDA found only Vioxx to have such a gastrointestinal benefit.

Since Vioxx has been off the market and doctors have become wary of other Cox-2 drugs such as Celebrex, Mobic emerged in the last month as the No. 1 non-steroidal anti-inflamatory drug in the country for new prescriptions. It has been used worldwide by 11 million people since 1996 and in the United States since 2000.

Graham's findings about the drug were from a new study he co-authored with Stanford University adjunct professor of medicine Gurkirpal Singh. The study of California Medicaid beneficiaries has not yet been peer-reviewed or published. Graham had originally been asked by his FDA superiors to refrain from presenting it because of its preliminary status.

John Yonsky, a spokesman for Boehringer Ingelheim, the maker of Mobic, said the company had not heard before of any assertion of increased risk of heart problems with its drug.

"We have observed no trends in post-market studies that would indicate that increased risk." Yonsky said it was impossible to respond to Graham's charges because they were based on preliminary, unpublished data he had not seen.

Graham said the preliminary data from his study also showed an increased risk of cardiovascular problems in the drug indomethacin, marketed by Merck as Indocin, calling it "a bad actor." The drug is often used to treat acute gout.

Noting that the data Graham presented were from an unpublished study, Merck spokeswoman Casey Stavropoulos said the company has not had a chance to review his findings and could not comment further.

Asked by some of the panel members for guidance on deciding how to deal with the more traditional painkillers, given the fact that some of them suggest risks, Graham said his own advice would be to look at all the drugs individually.

"Weed the garden of the bad actors," he said. "Try to identify drugs that, based on the evidence we have, appear to be less risky, and then, in a rational way, shift the market toward them."

Doctors on the advisory panel said that in weighing the risk of the drugs against the benefits the key question they must consider in deciding what to recommend to the FDA they had to consider how much their patients rely on the drugs.

Dennis W. Boulware, rheumatologist at the University of Alabama, asked Graham whether he thought there were cases where the clinical benefit of the drugs made the risk acceptable: "For patients I see, not giving them any of these drugs will confer a great deal of risk on them and physical impairment."

During a session reserved for public comment, patients who rely on the Cox-2 drugs and doctors pleaded with the panel to keep them easily available.

"I am a standing benefit, in front of you," said Amy Leong, a health care consultant and arthritis sufferer. "It's my choice to work with my physician to determine what's at higher risk for me and what is not."

Judith Fogel of Ithaca, N.Y., said that after suffering for years with arthritis she started on Celebrex three years ago and now on most days feels "better than I did 30 years ago."

"I feel like Celebrex was created for me," she said.

An army doctor even told the panel that soldiers depend on Cox-2 painkillers because of the concern about excess bleeding associated with more traditional drugs such as aspirin. Dr. Christopher Grubb said drugs such as Celebrex are "essential to the global war on terrorism."