July 30, 2007

Diabetes Drug Backed, but With Warnings

By GARDINER HARRIS
Published: July 31, 2007

GAITHERSBURG, Md., July 30 — A federal drug advisory committee voted overwhelmingly on Monday to recommend that the diabetes drug Avandia remain on the market, even after finding that it raised the risks of heart attacks.

Panel members said that studies concerning Avandia were too murky to merit drastic regulatory action and that other diabetes medicines might have similar risks.

The votes — 20 to 3 on the heart attack risk and 22 to 1 on the marketing — were cast after an extraordinary meeting in which officials from the Food and Drug Administration, which brought the committee together, openly disagreed with one another on the course to take.

Dr. David Graham, a drug safety officer at the federal agency, called for withdrawing the drug and estimated that its toxic effects on the heart had caused up to 205,000 heart attacks and strokes, some fatal, from 1999 to 2006. For every month that Avandia is sold, Dr. Graham said, 1,600 to 2,200 patients will suffer more of those problems.

Dr. Robert Meyer, director of the F.D.A. office that approved the initial Avandia application, immediately disagreed.

“I think it’s important that the committee understand there’s a fundamental disagreement” within the agency, Dr. Meyer said.

Other diabetes drugs also have risks, he added, and doctors and patients need a variety of options.

After the votes, Rebecca Killion of Bowie, Md., a patient representative on the advisory panel, said, “My feeling here is that we’re being asked to take a very draconian action based on studies that are very inadequate for us to make that kind of decision.”

The panel did say the agency should require strict warnings on Avandia labels.

“When this particular drug is used,” said Dr. Gerald Van Belle, a committee member from the University of Washington, “there must be some care taken in who gets it.”

The division in the agency reflects a fierce debate among diabetes experts since The New England Journal of Medicine published a study in May suggesting that Avandia, made by GlaxoSmithKline, increased the risks of heart attacks.

In a cascade of reports since then, agency officials have said that GlaxoSmithKline told the agency about this risk nearly two years ago but that because of internal disagreements, it never warned patients.

In Europe, regulators required that the drug label reflect some concerns about the risks.

The lack of action here helped persuade some lawmakers to support a measure giving the agency more money and power to police drug safety. That bill has passed both houses of Congress and is expected to go to President Bush in days.

About a million patients in the United States took Avandia last year. A nearly identical number took Actos, a similar pill made by Takeda, which some studies suggest may be safer. Avandia global sales last year were $3.4 billion, but they have plunged since May.

The controversy largely revolves around highly complex statistical analyses of dozens of studies on Avandia and the heart attack risks.

Separate from this argument, the evidence is overwhelming that Avandia and Actos worsen heart failure, a chronic condition in which the heart can no longer pump enough blood through the body.

GlaxoSmithKline argued strongly to the panel that its drug was safe. A vice president, Dr. Murray Stewart, said the company had in recent months examined data on 1.35 million diabetes patients from large managed care companies. The analyses, Dr. Stewart said, showed that patients on Avandia suffered no greater risk of heart problems than patients on other drugs.

The committee disagreed, with most members calling for strict warning labels.

“I also think there needs to be a stiffening of the warnings,” said Dr. Peter J. Savage, a panel member from the National Institutes of Health, echoing others’ comments.

Dr. Steven Nissen, a Cleveland Clinic cardiologist who wrote the May study, said in an interview after the hearing that he would have voted to remove Avandia from the market. But Dr. Nissen said he was cheered that the panel had “affirmed the finding that there was an increased cardiovascular risk from the drug.”

The disagreements within the agency affected almost every aspect of the hearing. In their presentations, Dr. Graham and his boss, Dr. Gerald Dal Pan, referred to studies suggesting that Actos had fewer heart risks than Avandia. The agency has not thoroughly reviewed the Actos studies, and the underlying data were not given to panel members.

Dr. Graham said, “We were promised that that would be done for this meeting,” but added that officials said the agency did not have enough resources to finish the analysis done for the meeting.

“So then I’m faced with a dilemma,” he said. “Do I keep silent about that and not breathe a word of it or do I present it?”

The debate on Avandia has led to a remarkable number of independent examinations of its safety, and researchers shared their findings with the committee.

Executives of Tricare, a managed care company that serves active and retired military personnel, and WellPoint, a huge health insurer, said they had found no evidence in their records that patients given Avandia had suffered more heart attacks.

Dr. Sidney Wolfe of Public Citizen, the drug safety advocate, said agency records showed Avandia had many more associated problems than just heart risks, including increased risks of fractures and liver failure.

“If Avandia were up for approval today,” Dr. Wolfe said, “based on what we know now, it would be rejected.”

Source: www.nytimes.com