FDA Advisory Panel Decision on Avandia Looms

FRIDAY July 9, 2010 -- With a crucial recommendation on the fate of the controversial diabetes drug Avandia due next week, U.S. health officials seem to be gearing up for tough scrutiny over the drug's future.

A U.S. Food and Drug Administration (FDA) advisory committee will be meeting next Tuesday and Wednesday to pore over numerous studies on the drug's safety that have accumulated over the past three years, since doubts about its safety first arose.

At stake is whether Avandia will continue to be marketed in the United States.

The advisory committee's options "range from allowing the continued marketing of Avandia and revising the label to remove the boxed warning, all the way to withdrawal from the U.S. market," explained Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, at a packed news briefing late Thursday. "We're asking them to pick one, vote on it and explain the rationale."

In a similar move, meanwhile, the European Medicines Agency announced Friday morning that it would also review Avandia's safety. The Associated Press reports that the review will be conducted by the agency's Committee for Medicinal Products for Human Use from July 19 to July 22. Depending on the outcome, marketing authorization for the drug in Europe could be revoked or changed.

Avandia (rosiglitazone) is one of two blood-sugar-lowering drugs in the class of medications known as thiazolidinediones (TZDs). The other drug is Actos (pioglitazone), which so far has not raised safety red flags. Both are used by type 2 diabetics.

The first drug in the class, Rezulin (troglitazone), was withdrawn from the market in the late 1990s after reports of liver toxicity, Woodcock noted.

Both Avandia and Actos came with warnings regarding heart failure when they were first approved, though not ischemic (involving restricted blood flow) heart trouble.

Then, in 2005, the FDA asked Avandia's maker, GlaxoSmithKline, to conduct a meta-analysis review of all its clinical trials on the drug.

The analysis, which did show a signal of increased risk of heart attack, was submitted to the FDA the following year.

FDA then did its own analysis while a number of other trials came out, also showing signals of heart troubles.

In November of 2007, FDA added a boxed warning to the drug, saying that there was a potential risk of increased cardiovascular ischemic events with Avandia. Patients also started receiving a medication guide explaining the risks.

The FDA itself has conducted more analyses since that time and multiple other studies have also been done, all of which will be considered by the committee next week.

For instance, results of the much anticipated RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) were announced in June of 2009. It found that Avandia significantly raises the risk of heart failure (and bone fractures) but not cardiovascular disease or death.

And just last week, three studies emerged with conflicting conclusions about the drug's safety. Two of them, published in major medical journals, found that Avandia did raise heart risks, while the third, released at the American Diabetes Association meeting, found no such connection.

For next week's meeting, the FDA is asking the committee to deliberate on four different categories of data: published observational studies; one study the FDA conducted; short-term controlled trials of both Actos and Avandia, including an updated meta-analysis; and the RECORD and other long-term studies.

"The committee will be discussing the strengths and weaknesses of the data on ischemic cardiovascular events and the drug in comparison to the standard of care and to pioglitazone [which so far has not demonstrated safety problems]," Woodcock stated. "We're going to ask them to vote whether they think the risk is increased and why. We will take the input under advisement after meeting and take appropriate steps."

The FDA is not bound to follow the recommendations of its advisory committees but usually does.

"The carefully selected members of the committee were subject to rigorous conflict-of-interest scrutiny and no waivers were granted for any reason," added Jill Warner, FDA's acting associate commissioner for Special Medical Programs.

"Obviously, we're going to have to look at a lot of information and really understand the advice that we're getting and try to make a decision as quickly as we can under the circumstances," said Dr. Joshua Sharfstein, principal deputy commissioner of the FDA. "This is an FDA decision."

More information

There's more on this class of drugs at the U.S. National Library of Medicine.

Posted: July 2010


View comments

Hide
(web1)