Due to the "ambiguous vote" July 14 by FDA advisers and the mounting body of data surrounding the diabetes drug rosiglitazone (Avandia, GlaxoSmithKline), the FDA has only two choices: Either enact stronger warnings for the drug or remove it from the market all together, according to Clifford J. Rosen, MD, of the Maine Medical Center Research Institute in Scarborough, Maine, and an FDA advisory committee member.

Rosen's commentary published online July 21 in the New England Journal of Medicine questions what has changed since the 2007 FDA committee meeting where 24 members of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted to keep rosiglitazone on the shelves even after agreeing that its use showed its potential to increase the risk of MI.

Rosen said three lines of evidence have recently surfaced fueling the two-day (July 13-14), 20-hour joint FDA hearing regarding the safety of rosiglitazone. In addition to the RECORD trial, a 52-trial meta-analysis—with 10 added trials/studies since 2007—showed that rosiglitazone had the potential to raise the risk of MI by 30 to 80 percent.

Additionally, other studies showed that rosiglitazone may leave patients worse off than those treated with pioglitazone (Actos, Takeda), raising CV events or death by almost 25 percent—those on pioglitazone showed no heightened risk, as well as protection against MI. It is this evidence, according to Rosen, that is telling the industry that “federal action is now required.”

At the recent hearing with 33 committee members, 12 voted for rosiglitazone to be pulled off the market, 10 (including Rosen) voted for stricter control of drug administration, seven voted for additional warnings, three voted for no change and 1 abstained. The votes “clearly indicated” that the FDA must provide a stricter course of action for Avandia besides the current black box label, Rosen said.

While Rosen said that “black box warnings sound impressive,” a million rosiglitazone prescriptions are still written each year despite the publicized warnings.

“Although there is evidence that black box warnings [added in 2007] and notifications from the FDA have an impact, results from the Medicare database and the totality of evidence from committee hearings would argue against limiting new FDA action to the addition of further warnings,” said Rosen.

During the committee meetings, members often raised concerns and skepticism with the RECORD trial design and data integrity, which was conducted to provide further analysis of rosiglitazone's risks and benefits after the FDA in 2007 recommended that more studies be performed. “Postmarketing studies require more careful designs and safeguards to protect data integrity and objectivity," Rosen said.

Lastly, Rosen said that FDA hearings should advise members to discuss the risk-benefit balance of particular drugs, but during the meetings, "there was virtually no discussion of any unique benefits of rosiglitazone,” only about its risk.

”The vote may reflect a desire to balance patient protection with the availability of the broadest range of therapies for a complex, chronic disease, but the clear risk demonstrated by the aggregate data calls for serious measures," Rosen concluded.

“Thus, in my view, the FDA must consider only two choices: Either stronger warnings plus the use of informed consent and a registry for compassionate use of rosiglitazone or removal of the drug from the market."