FDA Documents Reveal Lengthy Delays on Rosiglitazone (Avandia) MI Risks

GAITHERSBURG, Md., July 27 -- Documents prepared by the FDA for Monday's review of the cardiovascular safety of rosiglitazone (Avandia) support published reports of a significant rise in the risk of myocardial infarction for the diabetes drug.

Moreover, the FDA said that treatment with pioglitazone (Actos), a rival thiazolidinedione, "has not been shown to result in an increased risk of myocardial ischemia." Both drugs have, however, been associated with increased risk of heart failure.

At the joint meeting of two advisory committees, the question of rosiglitazone's continued marketing will be addressed.

Among the hundreds of pages of data and analyses prepared by the FDA and by GlaxoSmithKline, the maker of rosiglitazone, in preparation for the meeting is one startling piece of information. Almost a year ago-Aug. 4, 2006-the company asked the FDA to add a warning about myocardial ischemic events to the rosiglitazone label.

At the time, the company said that on the basis of its own "integrated trials analysis" the occurrence rate of myocardial ischemic events was 1.99% among rosiglitazone-treated patients versus 1.51%, which represented a hazard ratio of 1.31 (95% confidence interval 1.01-1.70).

Despite this finding-and its request for a label change-GSK said in its briefing documents that that "there is no consistent or systematic evidence that rosiglitazone increases the risk of MI or cardiovascular death in comparison to other anti-diabetic agents. Therefore, the benefit risk profile of rosiglitazone continues to be favorable."

When the FDA did it's own analysis of the GSK data, it said there was a 40% higher risk of MI among rosiglitazone patients (95% CI, 1.1-1.8, P=0.012) and the risk for either MI or congestive heart failure was also 40% higher for rosiglitazone groups versus comparators (P=0.003).

In a Feb. 6, 2007, memo to Mary Parks, M.D., director of the FDA's division of metabolism and endocrinology products, Kate Gelperin, M.D., M.P.H., a medical epidemiologist at the FDA's division of drug risk evaluation, said GSK's suggested wording was not strong enough.

Dr. Gelperin wrote that the evidence supported a black box warning for rosiglitazone. "Prevention of macrovascular complications of diabetes is a desired benefit of antidiabetic therapy, and the demonstration of a failure to achieve this goal denotes a serious limitation of anticipated therapeutic benefit," she wrote.

Dr. Gelperin's memo was sent more than three months before the online release by the New England Journal of Medicine of a meta-analysis of 42 clinical trials that found a 43% increase in the relative risk of myocardial infarction among type 2 diabetics treated with rosiglitazone.

Meta-Analysis Links Rosiglitazone (Avandia) to Risk of Myocardial Infarction

And GSK's request for a label change went to the FDA 10 months before publication of the NEJM meta-analysis by Steven Nissen, M.D., and Kathy Wolski, M.P.H., both of the Cleveland Clinic.

Nonetheless, it has been the Nissen meta-analysis that has generally been considered the flash point in the rosiglitazone debate.

For example, within hours of its release on May 21, the FDA announced that it was sending a safety advisory to physicians, beefing up the safety warning on the rosiglitazone label, and that it would schedule an advisory panel review of the drug.

FDA Orders New Safety Labels for Rosiglitazone (Avandia) and Pioglitazone (Actos)

That same day, Rep. Henry Waxman (D-Calif.) announced a congressional hearing to investigate the FDA's handling of the drug.

Within a week, the editors of The Lancet published an unsigned editorial urging calm and hinting that Dr. Nissen's conclusions were overblown.

Journal Advises Calm in Rosiglitazone (Avandia) Uproar

The editorial was followed by a letter from Ronald L. Krall, M.D., chief medical officer of GSK, who vigorously defended the drug, noted that three ongoing prospective trials RECORD, BARI 2D, and ACCORD, would provide ample evidence of its safety and efficacy.

Drug-Maker Defends Rosiglitazone in Letter to The Lancet

But just six days later the NEJM released online the results of an unplanned interim analysis of the RECORD trial which offered mixed results and little help for GSK. The analysis found no significant increase in MI or cardiac death, but suggested an increased risk of heart failure. Moreover, the publication opened the trial to a torrent of criticism about its design, which FDA researchers also criticized in the briefing documents.

RECORD Fails to Confirm or Refute Cardiovascular Risk for Rosiglitazone (Avandia)

At Monday's meeting---actually a joint meeting of the endocrinology and metabolic drugs advisory committee and the drug safety and risk management advisory committee-23 FDA advisers will be asked to vote on these questions:

• What are the strengths/limitations of the GSK meta-analysis of 42 controlled clinical trials?
• Do these completed or ongoing trials-DREAM, ADOPT, RECORD, and BARI-2D-adequately address cardiovascular ischemic risk?
• Do the available data support a conclusion that rosiglitazone increases ischemic risk in type 2 diabetes?
• If yes, is that risk greater than the risk with other therapies?

And the really big question-the .2 billion question on the basis of last year's worldwide sales of rosiglitazone-is this: Does the overall risk-benefit profile of rosiglitazone support its continued marketing in the U.S.?

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