FDA Panel Weighs Evidence on Cardiovascular Safety of Rosiglitazone

An FDA panel was presented with conflicting evidence about the cardiovascular safety of rosiglitazone at a Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee.

The 33-member panel is expected to vote today to recommend whether the drug should remain on the U.S. market as a treatment option for patients with type 2 diabetes.

At the start of the meeting, FDA commissioner Margaret Hamburg urged the panel to “follow the science wherever it may lead, and the rest will fall into place.”

The safety of rosiglitazone (Avandia, GlaxoSmithKline) has been questioned since 2007, when a meta-analysis by Steven E. Nissen, MD, of the department of medicine at Cleveland Clinic, showed that the drug increased the risk for myocardial infarction by 43%. The findings were published in The New England Journal of Medicine.

This is not the first time that rosiglitazone has been the topic of discussion at an FDA advisory committee meeting. In July 2007, the joint committee voted 20-3 that available data suggest that rosiglitazone increases cardiac ischemic risk in type 2 diabetes and voted 22-1 that the overall risk-benefit profile of rosiglitazone supports its continued marketing in the United States.

At the current meeting, GlaxoSmithKline and FDA reviewers presented new data and analyses made available after the 2007 FDA meeting. Much of the discussion focused on the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemic in Diabetes (RECORD) study, which analyzed more than 4,400 patients with type 2 diabetes assigned to rosiglitazone vs. metformin/sulfonylurea for about 5.5 years. Results showed no increased risk for MI and a similar rate of CV hospitalizations and death in both treatment groups.

“Overall, when used appropriately, rosiglitazone has a positive benefit-risk profile and should remain a treatment option for patient with type 2 diabetes,” Murray Stewart, vice president for clinical development at GlaxoSmithKline, said. GlaxoSmithKline said six randomized controlled trials, including RECORD, demonstrate no increased risk for MI, stroke or death with rosiglitazone.

Some FDA reviewers had a different perspective. Thomas Marciniak, MD, of the FDA division of CV products, criticized the study design, conduct and results of RECORD. He said the study was inadequately designed to determine safety and biases suggest that the true MI risk may be higher than reported.

Further presentations revealed split opinions among FDA reviewers. Ellis Unger, MD, deputy director of the FDA office of drug evaluation, shared concerns about the quality of the RECORD data but said Marciniak’s analysis should be viewed as “exploratory.”

Additional presentations are expected on the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial, a randomized, prospective, controlled, postmarketing clinical trial that the FDA required following the decision at the 2007 FDA meeting and subsequent black box warnings for TZDs.

David Graham, MD, of the FDA Center for Drug Evaluation and Research, criticized the primary analysis and ethics of the trial, saying that “the emphasis of TIDE is really shifted from its true CV purpose.” Graham published results of a study published in the Journal of the American Medical Association in June showing that rosiglitazone was associated with increased risks for stroke, heart failure and all-cause mortality in Medicare patients aged 65 years and older.

Nissen, speaking at the meeting, said TIDE will not be completed for some time.

“I’ve calculated, based upon current enrollment, that it will take at least another 8 years to complete and we will not have a final answer until 2020. Are we willing to wait that long with a drug with this hazard?” he said.

More panel discussion and a vote are scheduled for today. While the FDA is not required to follow the recommendations of the advisory committee, it usually does.

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