FDA is not asking GlaxoSmithKline to take any specific action regarding an emerging safety signal for its diabetes therapy Avandia until the agency has completed its own evaluation of cardiovascular safety data.

Agency officials indicated during a May 21 call that current Avandia (rosiglitazone) labeling, which was updated in 2006 to include cardiovascular risk information, sufficiently communicates the existence of a safety signal.

The new safety concerns stem from a meta-analysis of clinical trials of Avandia showing a statistically significant increase in the risk of myocardial infarction and an increase in the risk of death from cardiovascular causes of borderline significance.

The analysis, conducted by former chair of FDA's Cardio-Renal Advisory Committee Steven Nissen and Kathy Wolski (both from the Cleveland Clinic), was released May 21 and will be published in the June 17 issue of the New England Journal of Medicine with an accompanying editorial by advisory committee veterans Bruce Psaty, University of Washington, and Curt Furberg, Wake Forest University.

Nissen and Wolski also penned an article in the Journal of the American Medical Association critical of the cardiovascular profile of Bristol-Myers Squibb's Pargluva (muraglitizar) prior to the termination of development for the type 2 diabetes treatment (¹ Also see "Bristol Joins The Ranks: Firm Bags Pargluva Development" - Pink Sheet, 18 May, 2006.).

FDA is in the process of reanalyzing a meta-analysis of Avandia trials submitted by GSK and cautioned against drawing premature conclusions.

"FDA has not confirmed the clinical significance of the reported increased risk in the context of other studies. Further, FDA does not know whether the other approved treatments in the same class of drugs ... have less, the same or greater such risks," Office of Drug Evaluation II Director Robert Meyer said during the conference call.

"Other published and unpublished data from long-term clinical trials of Avandia, including an interim analysis of data from the RECORD trial, a large, ongoing, randomized, open-label trial, and unpublished reanalyses of data from the DREAM study, a previously conducted placebo-controlled randomized trial, provide contradictory evidence about the risks in patients treated with Avandia," Meyer noted.

The agency is convening an advisory committee to address cardiovascular risks observed with the thiazolidinedione class of type 2 diabetes therapies.

Members of Congress quickly responded to the drug safety news with promises of investigations. Senators Max Baucus, D-Mont., and Charles Grassley, R-Iowa, have issued letters seeking information from GSK, and a June 6 hearing is already scheduled for the House Oversight and Government Reform Committee.

- Brian Marson (b.marson@elsevier.com)

Avandia Safety Under The Microscope

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