FDA asks for stiff Avandia warning

The agency urges GlaxoSmithKline, maker of the diabetes drug, to stress the risk of congestive heart failure

WASHINGTON -- In the face of mounting pressure from lawmakers and medical experts, federal drug regulators are pressing GlaxoSmithKline to put the strongest possible warning on Avandia, the firm's popular diabetes pill, which has racked up $3 billion in sales.

The Food and Drug Administration has asked the British drug maker, which has one of two U.S. headquarters in Research Triangle Park, to highlight Avandia's risk for congestive heart failure with a black box, the highest caution, according to written testimony from FDA Commissioner Andrew C. von Eschenbach released Wednesday during a Congressional hearing.

That request, which GSK has not agreed to, came on May 23, two days after a study linking Avandia to heart attacks and more than a year after FDA safety reviewers recommended the warning.

But the FDA is not requesting that the label carry a warning about a higher risk of heart attacks, mainly because the agency is still reviewing data. As a condition of Avandia's approval in 1999, an FDA medical reviewer recommended a long-term study to assess the drug's heart-attack risks. But the agency never followed up on the recommendation.

"The FDA dropped the ball," said Rep. Henry Waxman, the California Democrat who heads the oversight committee that held Wednesday's hearing,

Waxman called Avandia a case study of the need to reform the nation's drug safety laws, an effort that is under way in the Senate and the House.

But Moncef Slaoui, head of GSK's research and development, countered that Avandia has undergone a more comprehensive and rigorous scientific drug safety analysis than any other diabetes pill on the market, involving more than 52,000 patients in 116 studies.

Slaoui testified that two of the studies demonstrated that Avandia's cardiovascular risks are comparable to those of other, frequently prescribed diabetes pills.

Avandia is an important weapon against diabetes, he added. It is also an important drug for GSK. Avandia generated $3 billion in worldwide sales last year, providing about 7 percent of GSK's total revenue. About 6 million Americans have taken Avandia at some point in their lives.

Lawmakers became aware of concerns about Avandia and three similar drugs -- Actos, Avandaryl and Avandamet -- on May 21, when the New England Journal of Medicine published an article by Dr. Steven Nissen, a leading cardiologist at the Cleveland Clinic in Ohio. Nissen's study linked Avandia to a 43 percent increased risk of heart attack.

Criticism of the FDA and GSK has increased since then as details have emerged about early efforts to get the FDA to require more disclosure about the risks of the drugs.

Pressure reported

Among those who testified were Dr. John Buse, head of the University of North Carolina Diabetes Care Center in Chapel Hill.

Buse told the committee that company executives pressured him to stop questioning the safety of Avandia when it came on the market in 1999.

After he raised concerns about the medicine's heart risks at a medical conference, Buse testified, he received threatening phone calls in which he was characterized as a liar and accused of being for sale. According to UNC records, Buse received $73,288 in grants from SmithKline Beecham and from GlaxoSmithKline between 1998 and 2000 but has not received grant money from the drug maker since then.

Buse also testified that he was told his actions "were scurrilous enough to attempt to hold me liable" for hurting the company's stock.

"It was the possibility of being sued -- $4 billion was mentioned. I took that as pressure," Buse said in a phone interview after testifying.