The mid-July FDA advisory committee meeting to decide the fate of GlaxoSmithKline’s Avandia (rosiglitazone) is widely viewed as a test case of how the agency’s new leadership will address controversial drugs with serious risks but confusing data. A request that GSK yank its diabetes blockbuster—three years after first being associated with an increased risk of heart failure, stroke, and other cardiovascular complications—will draw a line in the sand about the public-health priorities of Commissioner Margaret Hamburg and her deputy Joshua Sharfstein.
Of course, reading the tea leaves in FDA’s cup is often an exercise in futility. Determined to make as few waves as possible, FDA officials have perfected the art of “split-the-difference” decision-making. But Hamburg and Sharfstein are reputedly a different breed of leader. And given the longstanding guerilla war between FDA’s safety officials and its drug reviewers, the outcome of Avandia’s trial may signal a possible shakeup inside the agency itself.
But portents aside, will justice be done in the case of GSK’s once-heralded, now much-maligned diabetes drug?
Imagine the process as a courtroom drama. At the prosecution’s table sit two familiar doctors: David Graham, the outspoken FDA drug safety expert; and Steve Nissen, the equally outspoken chairman of cardiology at the Cleveland Clinic. Both made their names a decade ago leading the charge against Vioxx, and the Avandia dustup has further burnished their reputations as anti-pharma crusaders. Both advocate Avandia’s withdrawal and have published studies making that case to the FDA advisory panel.
Graham’s study, published June 28 by the Journal of the American Medical Association (JAMA), is based on a retroactive analysis of the 1999–2009 records of 227,571 Medicare patients on Avandia or its same-class competitor, Takeda’s Actos. The report finds that Avandia was associated with a higher risk of stroke, heart failure (but not heart attack), and death, and concludes that more than 47,000 people could have escaped these health emergencies had they been on Actos rather than Avandia. Graham has long maintained that Avandia remains on the market only because FDA reviewers are defending their original decision to approve it.
Nissen’s study, published June 28 by the Archives of Internal Medicine, updated his 2007 meta-analysis, using a database of 56 trials including 35,531 patients. He found that Avandia raised the heart attack risk by 39 percent, compared to placebo; however, the rate of mortality was not elevated. Nissen attributes the differences between his data and Graham’s to the fact that his cohort’s average age was 54, while Graham’s was 74. “It is really impossible to argue that this drug has benefits that exceed its hazard,” Nissen told The New York Times.
Additional evidence includes a February 2010 bipartisan Senate investigation into 250,000 internal GSK documents. The most serious findings charge that GSK knew about the increased cardiovascular risks for two years, and FDA for about half as long, without alerting the public.
At the defense table sit a row of lawyers flanked by PR flaks, with a few slightly rumpled scientists sprinkled in for effect. “Results from six controlled clinical trials have been reported since … FDA last reviewed questions about the cardiovascular safety of Avandia in 2007. Taken together, these trials show that it does not increase the overall risk of heart attack, stroke, or death,” the suits intone as one.
The most recent study, presented on June 28 at the annual meeting of the American Diabetes Association (ADA), was designed to test how best to treat patients with both diabetes and coronary artery disease. In this 2,400-patient observational study, Avandia was not prescribed randomly but by the individual doctor’s discretion: Some patients got medication alone, others medication plus angioplasty or bypass surgery. At 4.5 years of follow-up, the rates of heart attack, stroke, or death were slightly less for those on Avandia (or Actos) than metformin.
As for the Senate’s accusations about concealing known dangers from the public, GSK denies all such charges. It also insists that the two new studies critical of Avandia, as retrospective analyses, are open to interpretation. Citing opposition by doctors—including ADA and American Heart Association officials—to any move to yank Avandia, GSK’s legal eagles rest their defense with a rhetorical plea to let science prevail over uncertainty.
The FDA advisory committee will certainly sweat over the mass of Avandia science, but uncertainty is likely to remain. Following FDA’s 2007 decision to allow GSK to keep selling Avandia despite possible dangers, the agency ordered the company to conduct a large, randomized trial comparing Avandia to Actos to determine which is safer. Yet with enrollment flagging, the drug may well be off patent before results are in.
Now that study looks like a waste of time and money. As the JAMA editorial accompanying Graham’s study says, “Converging lines of evidence suggest that Avandia is less safe than Actos, whereas no data suggest that the converse is true. The real question is, given all the accumulating safety concerns about Avandia, why, exactly, a patient might want to receive the drug or why a physician would choose to prescribe it when there is an available and quite possibly safer alternative?”
In other words, it is a question not merely of safety and efficacy but also of value. Commissioner Hamburg may decide to ask GSK to pull Avandia to make precisely that point.