FDA Panel Recommends Restricting Avandia

July 14, 2010 — -- The blockbuster diabetes drug Avandia is likely to be sold in a strikingly different way, even if the U.S. Food and Drug Administration chooses to keep it on the market, as a majority of expert panelists have recommended.

The FDA advisory panel voted 20-12 today to recommend keeping the controversial treatment on the market but 17 voted in favor of stricter warning labels or restrictions on its sale. Only three voted not to change the existing warning.

One member abstained from voting. No member voted to take the current warning label off the box.

The culminating vote came after a majority of panel members thought analyses of previous studies persuaded them the drug was linked to significant heart risk in diabetes patients and that its market competitor, Actos, showed to be a stronger alternative.

Based on the panel's recommendations, it is likely the drug will face more restrictions on labeling and marketing.

"Today, the risk clearly outweighs the benefits in Rosi [Avandia]," panel member Dr. Curt Furberg said. "The benefit is modest at best."

The 33-member panel voted on nine questions, one of which addressed whether the drug should be pulled from the market in light of ongoing analyses suggesting that Avandia could worsen certain risk factors for heart disease.

The panel found that the data presented was sufficient to raise significant safety concerns for heart risk in patients with Type 2 diabetes compared to other diabetes treatments, including market competitor Actos. The panel also voted 20 to 12 that researchers continue the TIDE trial, a study that is comparing Avandia to Actos.

"I think the totality of evidence is much stronger -- it's still not absolute -- but it's stronger [than 2007]," panel member Dr. Clifford Rosen said.

Some panel members said they found no clarity in either the safety or risk of Avandia in the past two days than when Avandia's safety was initially called into question in 2007.

"This drug is not for everybody but that may be that it's not for anybody," panel member Rebecca Killion said today during discussions prior to voting.

Some members said studies on Avandia made it difficult to tell whether the data was accurate enough to predict that the drug may be linked to stroke, heart attack and even death in some patients. The studies reviewed by the panel included an evaluation of many studies, known as a meta-analysis, along with observational studies; two study designs that some members thought were insufficient to show serious risk with the drug.

"I think if you have a lot of short-term trials, you don't have a lot of deaths," Geller said. "Overall, I think the evidence is missing."

Longer-Term Studies Suggested

Indeed, the majority voted that the data presented on Avandia was insufficient to raise safety concerns for death in diabetic patients compared to other treatments. And a majority of members were unable to conclude whether patients who took Avandia have a higher risk of death compared to those who took Actos.

"There's absence of evidence but I want to emphasize that doesn't mean there's evidence of absence," said panel member Dr. Thomas Flemming, who voted that the data makes it unclear whether Avandia contributes to a higher risk of death.

As with others, Flemming recommended longer-term studies to more accurately understand the risks and benefits of the drug.

Regardless of the unknown risk of death, stroke or heart attack, many members thought the increased risk of congestive heart failure and fractures in women, along with Actos as a class alternative, was enough to suggest that the risk outweighed the benefits of Avandia.

"Remember, we're not getting rid of the class, we're just thinking about that one drug," Rosen said.

In a written response to the FDA Advisory Committee's recommendations, Avandia's maker GlaxoSmithKline said the studies available showed that Avandia is safe and effective, "when used in the appropriate patient and in accordance with labeling."

"Following today's recommendations, we will, of course, continue to work with the FDA in the best interest of diabetes patients who face this chronic and serious disease," said Dr. Ellen Strahlman, drugmaker GlaxoSmithKline's Chief Medical Officer, in the written response.

FDA Decision Catching Up to the Norm, Some Experts Say

Avandia's safety was first publicly called into question in 2007 when an analysis by Dr. Steve Nissen, chair of cardiovascular medicine at the Cleveland Clinic, found that those on the drug had a 43 percent higher risk of heart attacks and a 64 percent higher risk of dying from heart disease.

More recently, Food and Drug Administration associate director of drug safety Dr. David Graham called for Avandia to be removed from the market in a February report. He said the drug could be linked to about 500 more heart attacks and 300 more cases of heart failure each month than would occur if its competitor, Actos, were used exclusively.

Panel member Dr. John Teerlink said that compared to 2007, it's clear that Actos is a stronger drug than Avandia. But, Teerlink said, perhaps it's not necessary to pull the drug from the market but let the drug die on its own.

"Maybe the marketplace will drive the bad drug out when the good drug comes in," he said.

Some experts did not wait for an official FDA vote before deciding to stop prescribing Avandia to many of their patients

"For my patients on Avandia, many of them have already asked to be switched to Actos," said Dr. Andrew Carroll, a family physician based in Chandler, Ariz.

"Based on prior studies I had read, I stopped prescribing Avandia about two years ago, and have been sticking with Actos," he added, saying that until the FDA makes a recommendation or further studies prove the drug is safe, he will be steering clear of Avandia.

Dr. Neil Brooks , a primary care physician in Vernon, Conn., said he hasn't prescribed Avandia for many years after many of his patients experiencing weight gain, and even heart failure.

But while the drug may be dangerous to some patients, he said, they should understand that there are alternative diabetes treatments that may fare better for their health.

"Simply giving the public the message that this stuff you have been taking for 10 years is possibly causing you harm will further erode the public's trust in both the pharmaceutical and medical systems," Brooks said. "It would be far better to say that after prolonged evaluation it has been found that alternative therapies have improved outcomes and the less-effective treatments will be withdrawn."

Dr. Eric Larson, executive director of Group Health Research Institute, said he does not prescribe Avandia and even cancelled a research study on the drug after earlier reports of the drug's toxicity.

"The Senate documents and FDA hearings only confirm our earlier assessments of the safety of this drug," he said. "It's gratifying to have our decisions confirmed but terribly disappointing that this hasn't been resolved earlier or even by now, apparently."

The FDA will consider the panel's recommendation as it ultimately decides whether to keep or pull the drug from the market.