Thursday, November 15, 2007

Avandia’s Black Box: FDA Office of New Drugs Wins

Yesterday FDA settled a very public internal disagreement by adding another “black box” warning to GlaxoSmithKline’s diabetes drug rosiglitazone Avandia.

The message to biopharmaceutical companies is that the agency’s Office of New Drugs within the Center for Drug Evaluation & Research is the final arbiter of drug safety decisions—not the drug safety group housed by the Office of Surveillance and Epidemiology.

OND’s opinion clearly carried more weight than the OSE staff headed by Gerald Dal Pan when it came to a final resolution on how to handle the heart attack risks associated with Avandia.

A joint panel meeting of FDA Metabolic & Endocrinologic Drugs and Drug Safety & Risk Management advisory committees on July 30 showcased a fissure between OND and OSE. Two high-ranking officials, OSE’s Dal Pan and Office of Drug Evaluation II Director Robert Meyer, openly disagreed over whether Avandia should stay on the market.

Dal Pan staked his reputation by agreeing with OSE director of science and medicine David Graham that Avandia be withdrawn. “While I may disagree with [Graham] on some minor technical issues and the strength of any one given piece of evidence or other, he and I have both concluded that when we look at the data, the balance of benefits and risks of rosiglitazone is not favorable,” Dal Pan said at the meeting.

Meyer countered OSE’s presentation: “I think it is important the committee understand there is a fundamental disagreement within CDER on the scientific conclusions that should be drawn from the information available.”

Months after the meeting, in October, FDA’s drug safety oversight board voted 8-7 to keep the drug on the market, according to Senator Chuck Grassley (R-Iowa) and his investigational staff. The board is made up of federal officials from FDA and other agencies and deliberations are not public.

Fast forward to FDA’s November 14 announcement on Avandia: “We are keeping Avandia on the market because we have concluded that there is not enough evidence to conclude that the risk for heart attack or cardiac ischemia is higher than for other Type 2 diabetes drugs,” FDA chief medical officer and acting CDER director Janet Woodcock said during a media briefing.

Here is what the new box warning says:

A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared Avandia to placebo, showed Avandia to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 patients), comparing Avandia to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive.

FDA is requiring GSK to conduct a long-term study to evaluate the potential cardiovascular risk of Avandia compared to an active control agent and develop a MedGuide for patients including new information on the potential risks of rosiglitazone.

GSK must be popping champagne right now as this was the best possible outcome for the company considering the situation. Check out the timeline for the randomized trial: the final protocol for the study is due by July 31, 2008; the study is expected to start by November 30, 2008; and the final study report of full results is due by the end of March 2014. The first patents for Avandia expire in 2011, with some running until 2017, according to FDA’s Orange Book.

In other words, the company just bought seven years of continued marketing for Avandia.

FDA says the public will know more about the drug before the end of the study. “There would be interim data probably,” Woodcock added. “It isn’t as if we’re going to be clueless until 2014.”

Nevertheless, there is no doubt that there was a chasm-like split over keeping Avandia on the market or removing it. In the end, the Office of New Drugs’ opinion carried the day.

You can read our in-depth takes on the Avandia debacle and fallout in The RPM Report and IN VIVO here and here.

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