Live from FDA: Nissen speaks on Avandia

GAITHERSBURG, MD -- Today is the day--the long awaited joint meeting of the FDA's Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees to discuss the cardiovascular risks of GlaxoSmithKline's (NYSE: GSK) Avandia. And, as expected, the room was packed for the start of the two-day meeting.

FDA Commissioner Margaret Hamburg kicked things off with a quick pep talk, urging the panel to "follow the science, wherever it leads, and the rest will fall into place." She was followed by the FDA and sponsor presentations, during which GSK tried to made the case that Avandia helps meet an unmet need in patients with diabetes. Furthermore, when used appropriately, Avandia has a positive risk-benefit profile and should remain a treatment option, company representatives emphasized.

Avandia critic Dr. Steve Nissen (photo) of the Cleveland Clinic also appeared before the panel in a feisty mood. He pointed to the Avandia approval package from 1999, saying the increase in LDL cholesterol in these patients should have raised more concerns. The one thing medical professionals don't want to do, he said, is increase LDL cholesterol in this patient population. But in the haste to replace Rezulin, which was raising hepatotoxicity concerns, the FDA approved Avandia, letting the "genie got out of the bottle"--and we've been trying to get it back in ever since.

Nissen also slammed the RECORD trial, which was funded by GSK and supposedly showed the drug was safe, as being "unacceptable in quality," titling one slide: "Record - How not to Perform a Safety Study." The trial is flawed, he emphasized, because there was "extraordinary unblinding," with GSK and Quintiles getting unrestricted availability to the treatment codes. RECORD, which he calls full of flaws and inherent biases, should not be used to influence the panel's decision that affects so many lives. Furthermore, with an alternative in the same class--Actos (pioglitazone)--with favorable effects on cardiovascular outcomes, "continued marketing of rosiglitazone cannot be medically or ethically justified," Nissen concluded.

Regarding his New England Journal of Medicine article critical of Avandia, Nissen said he knew it would be controversial, but the public had a right to know about the safety concerns regarding Avandia, and he doesn't regret what he did.

Thomas Marciniak, a reviewer for the FDA center that approves new drugs, then took the stage. He was very frank, saying just as all Gaul is divided into three parts, the FDA is divided into three factions regarding Avandia--those in favor, those against, and himself, who just recently entered the debate. He said a circus atmosphere has caused a bit of a distraction, and then got right into his analysis. The open-label nature of RECORD was problematic, he noted, adding that the trial was inadequately designed to provide any reassurance about the cardiovascular safety of the drug. In fact, he bluntly stated he would have rejected the study design. However, he does believe that some information can be salvaged from RECORD, if one looks at the raw data rather than the GSK reports.

The panel meeting comes with the news that in the fall of 1999, SmithKline Beecham began a secret study to find out if Avandia was safer than Takeda's Actos. GSK was delivered a major blow when the study results showed Avandia no better than Actos, but the study also provided clear signs it carried greater cardio risks.

- check out the NYT's coverage