Scarcely two weeks after the Senate overwhelmingly passed legislation touted as a major fix of FDA’s failing effort to assure drug safety, The New England Journal of Medicine published an analysis linking the diabetes drug Avandia to a 40% increase in the risk of heart attack. This finding is especially troubling because people with diabetes are already at high risk of cardiovascular problems. A million diabetics are estimated to be current Avandia users in the U.S.

The review of safety data from dozens of trials was conducted by Cleveland Clinic cardiologist Steven Nissen, MD, and biostatistician Kathy Wolski, MPH. In 2005, another Nissen-led study concluded that an about-to-be-approved diabetes drug, Pargluva, had a high risk of cardiovascular problems, a finding that convinced the FDA not to grant approval. Avandia and Pargluva are both members of a class of diabetes drugs known as PPAR. Another drug in the class, Rezulin, was withdrawn in 2000 because of its liver toxicity; while a fourth, Actos, remains a best-seller.

Subsequent revelations have raised even more questions about the FDA’s ability to assure drug safety. According to The New York Times, John B. Buse, MD, Chief of Endocrinology at the University of North Carolina and President-elect of the American Diabetes Association, wrote to the FDA seven years ago warning of Avandia-associated heart problems. And almost a year ago, Glaxo, maker of Avandia, informed the FDA that its own internal analysis suggested cardiac risks associated with the drug.

But the FDA has said that the evidence of safety problems is inconclusive and that there is no cause for regulatory action. Not so with the FDA’s European counterpart. The European Medicines Agency, which apparently has a lower threshold for action, put out strong warnings about cardiovascular risk back in September 2006. And the director of the FDA division responsible for post-market safety recently told members of Congress that his staff’s recommendation of a black box warning for the drug’s label was overruled by senior management.

So, will the recently passed Senate bill fix the FDA’s poor record in assuring drug safety? In an editorial commenting on the Avandia review, drug safety experts Bruce M. Psaty, MD, and Curt D. Furberg, MD, concluded, “While the Senate bill has many strengths…none of its provisions would necessarily have identified the cardiovascular risks of rofecoxib [Vioxx] or rosiglitazone [Avandia] in a timely fashion.” I agree and suggest that any hope for meaningful changes at FDA now rests with several proposed bills being discussed in the House of Representatives. And, I believe, the Avandia experience identifies the most critical reforms that must be part of any legislation if it’s to make a difference.

First, there must be complete transparency of all trial data and FDA access to insurance industry (including Medicare) databases so the agency can determine how drugs are being used and what outcomes they are generating. The public’s health can only benefit from having good minds like those of Nissen and Wolski analyzing data and reaching their own conclusions. Second, unlike FDA’s handling of Avandia, the public should always be immediately alerted to any signals of toxicity.

Most important, Congress must mandate creation of an independent FDA drug safety office, one that is all about public protection. A dedicated safety office would likely have been watching more vigilantly for signs of problems with PPAR diabetes drugs given their poor safety record.

Arthur A. Levin, MPH, Center for Medical Consumers ©
June 2007