FDA Advisers Vote to Keep Rosiglitazone (Avandia) But Cite Risks

FDA Advisers Vote to Keep Rosiglitazone (Avandia) But Cite Risks

MedPage Today Action Points

GAITHERSBURG, Md., July 30—

FDA advisers agreed today that although rosiglitazone (Avandia) increases ischemic heart risks for type 2 diabetes patients, it should stay on the market.

Members of two FDA advisory panels, meeting jointly, voted 22 to one in favor of continued marketing. Arthur Levin, M.P.H., of the Center for Medical Consumers in New York cast the lone dissenting vote, citing public health issues.

Meanwhile, GlaxoSmithKline, said it applauded the FDA advisers' recommendation as "a positive for patients," according to press release.

Although advisors voted overwhelmingly to recommend that the FDA keep the drug on the market, they also made it clear that they want to see a much narrower market for rosiglitazone.

Almost every one of advisers who said they wanted the drug to stay on the market offered the same advice about future labeling of the drug—additional warnings.

Clifford Rosen, M.D., the Bangor, Me., endocrinologist who chaired the meeting, said the drug should not be used by patients requiring insulin, those with a history of coronary heart disease, those with congestive heart failure, and those who are long-time users of nitrates.

The advisers didn't sort out specifics of the new warnings although nearly all used terms like black box or boxed warning. But Robert Meyer, M.D., director of new drug evaluation at the FDA's Center for Drug Evaluation and Research, said at a press conference that it wasn't clear to him that black box warnings had been recommended.

In any case, Dr. Meyer pointed out, while the FDA might follow the advice given by advisory committees the exact actions—and the timing of those regulatory actions—are up to the agency.

He also noted that the FDA has already asked GlaxoSmithKline and Takeda, which makes pioglitazone (Actos), another thiazolidinedione, to add a boxed warning about the risk of congestive heart failure to the labels of their respective drugs.

In an unusual move for agency officials, who normally are reluctant to make on-the-record comments about drugs under review, both Gerald Dal Pan, M.D., M.P.H., director of the FDA's Office of Surveillance and Epidemiology, and David Graham, M.D., M.P.H. associate director of that office, said during the meeting they thought rosiglitazone should be taken off the market.

Dr. Graham said the "point estimates of the relative risk of cardiovascular deaths and non-fatal MIs range from 1.20 to 1.40 to 1.70 for rosiglitazone.

"Using those estimates, Dr. Graham calculated that there are "1,600 to 2,500 excess MIs and ischemic heart disease deaths for every month that rosiglitazone stays on the market."

The panel also agreed that the strongest evidence of ischemic heart disease risk with rosiglitazone came from three meta-analyses of randomized clinical trials—one by GSK, another by FDA staffers, and an analysis done by Steven Nissen, M.D., of the Cleveland Clinic.

Dr. Nissen's analysis, which was published online May 21 by the New England Journal of Medicine, was widely regarded as the spark that turned mild concern about the cardiovascular safety of the drug into a cause célèbre. The analysis, which included data from 42 trials, found a 43% increase in risk of myocardial infarction with rosiglitazone.

Dr. Nissen was asked to serve as a consultant to the advisory panel, but he functioned under a strict set of ground rules that prevented him from sitting at the table with other consultants. He was also allowed to speak only in answer to questions about his meta-analysis and was instructed to refrain from commenting on any of the data presented at the meeting.

Before the meeting Dr. Nissen hinted broadly that he thought the drug should be pulled from the market, but in an interview immediately after the meeting he said he was pleased with the advisers’ actions. Noting that the advisers agreed with his finding of excess risk with rosiglitazone, he said the recommended warnings will be helpful "physicians follow those warnings."