Avandia may cause heart attacks

GlaxoSmithKline misinterpreted crucial details of a study finding that Avandia, its blockbuster diabetes drug, is safe, a medical reviewer for the Food and Drug Administration said Friday.

Correctly interpreted, the study actually supports critics’ contentions that Avandia may cause heart attacks, said the reviewer, Dr. Thomas Marciniak, in a posting on the F.D.A.’s Web site.

The company’s misreadings of the study, known as the Record trial, were so profound, he concluded, that they “suggest serious flaws with trial conduct.”

“One does not have to be a mathematician or to perform calculations,” he wrote, to come to the conclusion that a combined look at all the trials of Avandia would demonstrate that it causes heart attacks.

The review is part of a broad reassessment of Avandia’s safety by F.D.A. medical officers to educate a panel of experts who will gather next week in Gaithersburg, Md., to advise the agency whether Avandia should be withdrawn from the market — after millions of prescriptions, billions of dollars in sales and 11 years of wide use.

The panel’s decision will have broad repercussions not only for GlaxoSmithKline — which recorded $1.2 billion in Avandia sales last year and could face significant liability if the drug is withdrawn — but also for the F.D.A. The agency has been riven for years by fierce internal disagreements about Avandia’s uncertain risks. It was the F.D.A.’s delay in issuing stronger warnings about Avandia that led Congress in 2007 to give the agency greater powers over drug makers.

GlaxoSmithKline said in a statement that Avandia was safe.

“Since 2007, we have seen results from six controlled clinical trials looking at the cardiovascular safety of Avandia, and together they show that this medicine does not increase the overall risk of heart attack, stroke, or death,” said Dr. Murray Stewart, the company’s vice president for clinical development.

Avandia helps patients get better control of blood sugar levels, but its known risks are substantial: it can increase the risks of bone fractures and can cause swelling that can leads to heart failure and eye problems. And a number of studies, including some by GlaxoSmithKline, suggest that it could increase the risks of heart attacks, stroke and death.

Within the F.D.A., some officials insist that the evidence is mixed and others say it is strong enough to merit the drug’s withdrawal. An advisory meeting in 2007 concluded that Avandia did increase the risks of heart attack but that it should remain on the market.

In response, Avandia’s sales fell sharply, to $1.2 billion last year from a peak of $3.2 billion in 2006. But while endocrinologists have advised against its use, Avandia remains popular — with nearly two million prescriptions last year.

During that 2007 advisory meeting, the Record trial — specifically designed to assess Avandia’s heart risks — was a significant source of reassurance for Avandia’s supporters. GlaxoSmithKline insisted that the trial had proven that the drug was safe. In a news conference on Thursday, Dr. Janet Woodcock, director of the F.D.A.’s drug center, called the Record trial one of the “most germane because it’s a study of cardiovascular outcomes.”

Avandia’s critics have long asserted that the Record study was both weakly designed and too short to prove anything. And an investigation by the Senate Finance Committee found that GlaxoSmithKline may have improperly influenced the independent experts in charge of the study.

Now, Dr. Marciniak has found that even the study’s underlying data were misinterpreted. Instead of little risk to the heart, the Record study actually hints at substantial risks, Dr. Marciniak concluded.

Along with a host of observational studies concluding that Avandia is riskier than a similar drug — Actos, made by Takeda — the review by Dr. Marciniak could prove crucial, since it seems to kick away one of the final pillars supporting Avandia’s use.

Another issue the expert committee will be asked to resolve is whether a GlaxoSmithKline study being done at the F.D.A.’s request, comparing the safety of Avandia and Actos, is ethical. Some F.D.A. officials argue that the trial must be stopped, because observational studies — which use health records to measure how patients fared while taking a particular drug — have already proved that Avandia is dangerous.

Others within the F.D.A. say that observational studies are not good enough and that a well-controlled “prospective” study, like the one being conducted by GlaxoSmithKline, is the only sure way to answer whether Avandia is truly dangerous.

In a report released Friday, the Institute of Medicine, the nation’s leading medical advisory group, seemed to side with those who have argued that observational studies are adequate. Indeed, the group seemed to describe almost exactly a study of 227,571 Medicare patients conducted by an F.D.A. reviewer and published June 28 in The Journal of the American Medical Association concluding that Avandia increased the risks of stroke, heart failure and death compared to Actos.

The institute concluded that such studies “can sometimes provide higher-quality safety evidence than randomized controlled trials.”

Still, no matter how the experts vote next week, a final decision about Avandia is the responsibility of the F.D.A. commissioner, Dr. Margaret Hamburg, a public health expert who has shown clear signs that she is more concerned about drug risks than her predecessors in the Bush administration. Her decision could reshuffle the balance of power within the agency and is almost certain to influence hundreds of smaller decisions by staff members on scores of other products for years to come.

“F.D.A. is going to make a decision on behalf of the public,” said Dr. Joshua M. Sharfstein, the agency’s principal deputy commissioner, at a news conference on Thursday.

If you have taken this drug we would like to hear from you, please contact us.