Advisory Panel Tells FDA Not To Ban Avandia

By THOMAS H. MAUGH II Los Angeles Times

Published: Jul 31, 2007

The widely used diabetes drug Avandia should remain on the market because its benefits outweigh the risks, but it should carry a strong warning about an increased risk of heart disease, a federal advisory panel said Monday.

The committee concluded that the evidence is suggestive of an increased heart disease risk associated with its use, but that the evidence is not sufficiently strong to remove the drug from the market.

The Food and Drug Administration generally follows the recommendations of its advisory panels but is not obligated to do so.

The panel said that certain groups should not take the drug because their risks are even higher. That includes people taking nitrates such as nitroglycerin to ease pain from angina and those taking insulin for Type 2 diabetes.

"Physicians will have to think twice before they prescribe the drug for these people," said the panel's chairman, Clifford Rosen of the Maine Center for Osteoporosis.

Avandia and another drug in the same family, Actos, carry a warning against use by patients with congestive heart failure, and the FDA recently asked both manufacturers to upgrade that to a so-called black box-warning, giving it greater prominence.

The panel did not agree on how strong the new warnings should be.

Robert Meyer, director of the FDA's Office of Evaluation II, said there was "a fairly unanimous recommendation that came to us" and that the agency would evaluate it carefully in considering labeling changes.

An estimated 21 million Americans suffer from Type 2 diabetes, which most often manifests itself later in life and is associated with obesity. About 1 million of them take Avandia, which had annual sales of $3.4 billion in 2006.

The uproar about Avandia, whose generic name is rosiglitazone, was triggered by a report in May in the New England Journal of Medicine linking Avandia to a 43 percent increase in myocardial ischemia. Ischemia is an inadequate flow of blood to the heart caused by a partial obstruction of an artery and often is a precursor to a heart attack.

Two other analyses, one conducted by the FDA and one by Avandia manufacturer GlaxoSmithKline, yielded similar results, indicating the drug increases the risk of myocardial ischemia by 30 percent to 40 percent.

The so-called meta-analyses were conducted by combining results from several studies to form a database with a large number of patients. Because of that design, panelists said, the results did not conclusively prove cause and effect but merely suggest a possibility that needs to be explored by more directed research.

The panel concluded, however, that the data from other existing clinical trials were insufficient to rebut the meta-analyses and called on GlaxoSmithKline to conduct more research on the heart issues.

David Graham, an FDA reviewer, and Gerald Dal Pan, director of FDA's Office of Surveillance and Epidemiology, had asked the panel to call for withdrawal of Avandia.

Graham noted that 70 percent of diabetics die of heart disease and argued that "any drug that increases the risk of heart disease makes no sense." He also charged that Avandia produces no unique benefits compared with other oral diabetes drugs, so there is no reason to keep it on the market.

Other speakers, including patient advocates, said the drug does have some properties that are different from other drugs. "It is vital to have as many tools in the toolkit as possible," said Raul Fernandes, vice president of the patient advocacy group Mended Hearts.