Scientists debate painkiller safety

FDA panels hold hearings on whether Cox-2 drugs all pose cardiac risks

February 17, 2005|By Susan Baer | Susan Baer,SUN NATIONAL STAFF

GAITHERSBURG -- A scientist with Merck & Co. -- which originally took Vioxx off the market believing that similar drugs were not linked with cardiovascular problems -- said yesterday that the company's scientists now believe the entire class of drugs poses such risks.

At the first of three days of Food and Drug Administration hearings to examine the safety of such painkillers, Merck senior director Ned S. Blaustein said the drug company now believes that all drugs that work as Vioxx does increase the risk of heart attacks and strokes.

The class of drugs, called Cox-2 inhibitors, includes Celebrex and Bextra, both made by Pfizer.

In a presentation yesterday before two FDA advisory committees at a packed hotel conference room, Blaustein said the data "strongly suggest" the entire class of drugs carries the risks.

Assessing dangers

The FDA panels are to recommend to the agency whether all Cox-2 inhibitors are as dangerous to the heart as Vioxx, which Merck pulled from the market in September. Cox-2 inhibitors work by blocking an enzyme that is important in the process of inflammation.

Yesterday, another key presenter, Dr. Garret A. Fitzgerald of the University of Pennsylvania School of Medicine, said he had concluded that all Cox-2 drugs pose similar risks to the heart.

"Given the book of evidence," including five studies with three distinct drugs, it seemed that "most rational people would accept" that all of the Cox-2 drugs were problematic, he said.

On the other side of the debate, Dr. Kenneth M. Verberg, Pfizer's vice president for inflammation and immunology, defended the company's billion-dollar drug Celebrex as "an effective and safe therapy for arthritis patients."

But he said more long-range testing is needed because there is little data on use of the medication for more than one year.

Dr. Alastair J.J. Wood, the chairman of the meeting and professor of pharmacology at Vanderbilt University Medical Center, said at the outset of the hearing that the committees' mission was not "to delegate blame or revisit the past." Still, a number of scientists took shots at both the FDA and Merck for being too slow to respond to the cardiovascular problems with Vioxx that began to show up in studies over the past five years.

"What would it have taken, what kind of data would it have taken ... for the FDA to either put a black-box warning [the strongest warning label] or remove Vioxx from the market?" Dr. Steven L. Shafer of Stanford University asked an FDA official, pointing to a 2000 study that showed increased heart problems in Vioxx users.

FDA medical officer Lourdes Vallalba said the agency had not been "sleeping behind the wheel," but rather was "confused" by conflicting data on the various painkilling drugs.

When Vallalba said the information on Vioxx had to be "put into context," Wood snapped at the FDA official: "That's what my teenage kids say as well."

Doctors also attacked Merck and the FDA for waiting 14 months to put a warning label on Vioxx after studies picked up potential cardiovascular problems -- and for making the label too vague for doctors.

And they sharply criticized both the agency and drug company for failing to follow up with study participants who dropped out because of adverse reactions from the drugs.

"That was a mistake," said Dr. Steven Nissen, medical director of the Cleveland Clinic. "Lessons learned."

Yesterday's meeting was attended by busloads of doctors, drug company scientists, lawyers, government employees and public health officials from as far away as Australia and Japan, eager to see what, if any, action the agency might take to address the growing concern over the Cox-2 drugs.

Recommendations could include limiting these drugs to people with a low risk of heart problems, reducing the dose or duration of use, putting "black box" or other warnings on the label or even taking the drugs off the market. But panel members said they did not expect to recommend a ban.

Benefit vs. risk

The drugs, which have been on the market for six years, were initially praised as being easier on the stomach and less likely to cause ulcers or other, sometimes fatal, gastrointestinal problems than earlier pain medication such as ibuprofen.

FitzGerald said that, just as low-dose aspirin affords heart protection at a small but absolute risk of gastrointestinal problems, so do the Cox-2 inhibitors "afford gastro protection at a small but absolute risk of cardiovascular events."

But instead of banning the entire class of drugs, he suggested managing the risk by restricting their use to those with low risk of heart problems who might benefit from the increased stomach protections.

He noted, however, that only two drugs have a proven gastrointestinal benefit: Vioxx, now off the market, and Prexige, not approved in the United States.

FitzGerald said that, considering the health risks now known, new Cox-2 drugs should clear higher hurdles to win approval, and those already on the market ought to meet the same standard to retain approval.

Although a Pfizer scientist said that Celebrex provided improved gastrointestinal safety compared with the older class of anti-inflammatory drugs, the drug has not been proven to demonstrate such a feature.

Only Vioxx was authorized by the FDA to make that claim.

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