In a surprising turn of events, an expert panel convened by the Food and Drug Administration voted yesterday to keep the diabetes drug Avandia on the market, leaving many to wonder why a drug that seems to raise the risk of heart problems should continue to be a treatment option. For the past three years, the evidence against Avandia has been building. A 2007 study found a 43 percent increase in heart attacks and a 64 percent spike in heart disease deaths in diabetics taking Avandia (meaning the absolute risk of a heart attack or cardiovascular death would rise from roughly 2 percent a year to 3 percent) compared to those who took other drugs. A later study by an FDA researcher reached similar conclusions. The manufacturer's own safety study revealed no increased heart risk, but the FDA found that the study had wrongly excluded a number of patients who had heart complications or who died during the study. If they had been included, Avandia would have been deemed heart damaging. Manufacturer GlaxoSmithKline also appears to have deliberately hid safety data, according to internal company documents released by the Senate, leading the panel of experts to question the company's trustworthiness.
Yet even with all the growing evidence—and the negative press and growing calls for Avandia to be yanked from the market—the FDA panel of outside experts voted against a ban. Only 12 of the 33 members voted to withdraw Avandia, while an additional 10 voted to allow the drug to be prescribed only with severe limitations such as requiring physicians and patients to be educated about its risks. The panel, like the FDA itself, was largely divided over what to make of Avandia's potential health risks. (FDA commissioner Margaret Hamburg will ultimately decide Avandia's fate.) The problem? Most of the panel members weren't satisfied with the quality of the studies conducted since the drug was approved 11 years ago, and some said they couldn't conclude from the evidence that Avandia was any riskier than Actos, its major rival in the same drug family. During the hearing, one member Lewis Nelson, an associate professor of emergency medicine at New York University School of Medicine, wondered "why there isn't better data at this point"—a notion seconded by the others.
Panel member Arthur Moss, a professor of cardiology at the University of Rochester School of Medicine and Dentistry, voted in the minority to keep Avandia on the market and not to restrict its sales. He spoke with U.S. News about the reasons for his vote. (Neither he nor the other panel members accepts money from GSK or other diabetes drug manufacturers.) Here are edited excerpts of the interview:
Why didn't you vote to ban Avandia given all the concerns that have been raised about its possible heart risks?
I felt the quality of the studies has been very compromised. Some data indicated that Avandia increased heart attack risk but the increased risk was small—about 20 to 25 percent—and I'm still not sure it's truly valid. The drugs that have been taken off the market in the past have had increases in risk on the order of 200 or 300 percent.
Who's responsible for the lack of good data?
My own personal feeling is that the FDA should have demanded more from the diabetes drug industry. When Avandia was first approved, FDA reviewers knew that it increased "bad" LDL cholesterol and saw a possible link to heart attacks and heart failure, but the agency didn't initially order GSK to do a specific safety study to look at these risks. The safety study called Record that GSK finally conducted years later wasn't well designed or conducted; I don't think it gives us much quality information. By the same token, Actos has been associated with an increased risk of bladder cancer, but we still don't have enough data to determine if that link is real. The FDA has a legal responsibility to demand that manufacturers conduct appropriate clinical trials. I don't think they followed through on this for either Avandia or Actos. So what we have is a body of evidence that's uncertain.
What sort of study would you like to see conducted?
I'd like to see Actos and Avandia compared against each other and against older diabetes drugs like metformin and glyburide. I'd like to know whether one drug is actually superior to another or works better in certain individuals like those who have had diabetes for years as opposed to newly diagnosed diabetics.
Isn't the ongoing Tide study, which is meant to compare the safety of Actos and Avandia, already doing that?
No, not in my opinion. It's designed to test the heart hazards of Avandia and Actos compared to a group taking placebos. So while it may tell you whether Avandia is riskier for the heart than Actos, it won't tell you whether one drug in general provides more benefits than the other or how they compare to other diabetes drugs. I voted for the Tide trial to continue, but several of us on the panel felt that it lacks scientific scrutiny, and we'd like to see a better study conducted.
Given all this uncertainty, how should patients respond? Should they switch to Actos just to be on the safe side given that an FDA analysis found that Actos appears safer for the heart?
I think patients need to discuss this with their doctor. I voted to keep Avandia on the market because it may have some usefulness, and it's always nice to have more potential therapies. Some patients may still benefit from Avandia if they don't respond to other diabetes drugs or have side effects like an upset stomach from Actos. But I also think that patients should discuss the possible risks with their doctors and make a decision that they're comfortable with.
