FDA Panel: Keep Rosiglitazone On the Market, But With More Warnings, Restrictions

An FDA advisory committee has recommended that rosiglitazone (Avandia, GlaxoSmithKline) stay on the U.S. market as a treatment option for patients with type 2 diabetes, but with restrictions on use and revised labeling that includes additional warnings about cardiovascular safety.

Twelve of the 33 panel members voted to withdraw rosiglitazone from the market. Ten recommended continued marketing with additional warnings about myocardial infarction and congestive heart failure, and restrictions such as patient and provider education; just three recommended no changes to the current label.

“I absolutely could not vote for withdrawal,” Arthur J. Moss, MD, PhD, professor of medicine and cardiology at the University of Rochester, N.Y., said of his vote. “I wanted to send a message to the FDA because a proper trial should have been done going all the way back to 1993 — and that trial still needs to be done.”

Lamont G. Weide, MD, PhD, said his concern was taking away a drug that provides benefit to some patients.

“I would hate to take away a drug without definitive evidence from the few patients who need it,” said Weide, chief of diabetes and endocrinology at University of Missouri-Kansas City.

Alternative therapies to rosiglitazone are available, Abraham Thomas, MD, MPH, division head of endocrinology, diabetes, bone and mineral disorders at Henry Ford Hospital, said, adding that if rosiglitazone is banned “we can still take care of diabetes.” He said that black box warnings are not enough to convey the drug’s CV risks because the average physician “tends not to read them.”

TIDE trial to continue?

The joint Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee remained split on other votes, including whether the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial should be continued if rosiglitazone stays on the market. Twenty members recommended continuation, 10 recommended against, two abstained and one did not vote.

The randomized prospective, controlled, postmarketing clinical trial was required by the FDA following the decision at the 2007 FDA meeting on the safety of rosiglitazone and subsequent black box warnings for TZDs. TIDE will determine whether TZDs reduce CV and serious health outcomes and whether rosiglitazone and pioglitazone (Actos, Takeda) have similar or different CV effects, study investigator Hertzel C. Gerstein, MD, MSc, said during a presentation to the panel.

Study critics said the design is unethical and is designed to establish proof of harm.

The panel agreed that evidence on rosiglitazone compared to pioglitazone remains inconclusive.

“A definitive study needs to be done and this is the first time that the FDA can demand such,” Moss said.

CV, mortality risks

The committee also voted:

  • 21-3 that available data suggest rosiglitazone increases the risk for cardiac ischemic events relative to pioglitazone; nine said data are insufficient.
  • 18-6 that available data suggest rosiglitazone increases the risk for cardiac ischemic events relative to non-TZD antidiabetes drugs; nine said data are insufficient.
  • 21-2 that available data do not suggest that rosiglitazone increases the risk for mortality relative to non-TZD antidiabetes drugs; 11 said data are insufficient.
  • 7-12 that available data suggest that rosiglitazone increases the risk for mortality relative to pioglitazone; 14 said data are insufficient.

While the FDA is not required to follow the recommendations of the advisory committee, it usually does.

“The agency takes the advice of our committee’s very serious,” Janet Woodcock, MD, director of the FDA Center for Drug Evaluation and Research, said at the close of the two-day meeting. “We will evaluate these proceedings and the regulatory options that are available to us and will come to a decision as soon as possible.”

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