Biased research; aggressive sales, and harmful drugs

Biased research; aggressive sales, and harmful drugs

Commendation from the U.S. Food and Drug Administration to market a novel drug is a critical waypoint along the path to profits for pharmaceutical producers. Alas, recent case studies have illustrated that FDA approval does not necessarily provide assurances of effectiveness and safety. In this month's Georgetown University Health Policy seminar, we hashed out two examples, anemia drugs and the diabetes drug rosiglitazone (Avandia), which were prominently featured in recent articles by Peter Whoriskey in The Washington Post.

The original impetus for the evolution of the anemia drugs Epogen, Procrit, and Aranesp, which mimic the  actions of the hormone erythropoietin, was to spare dialysis patients with severe anemia the inconvenience and hazards associated with occasional blood transfusions. Still, noted Whoriskey, pharmaceutical companies moved aggressively to market these drugs to a far larger patient population who were much less likely to benefit from them:

The difficulty would arise as the drug makers won FDA approval for vastly expanded uses, forcing it in larger dosages, for milder anemia and for patients with a broader array of maladies. Real rapidly, the market included nearly all dialysis patients, not only the roughly 16 percent who needed blood transfusions. The size of average doses would more than triple. And o'er the following five years, the FDA would approve it to treat anemia in patients with malignant neoplastic disease and AIDS, as easily as those getting hip and knee surgical procedure.

Doctors were motivated to give more doses of these drugs due to generous financial incentives (estimated at between $100,000 and $300,000 per year for a typical oncologist) and the seductive thinking that if some drug was good, more was better. Even the publication of a 1998 study in the New England Journal of Medicine showing no survival advantage to boosting hematocrit levels to normal ranges in cardiac patients did little to discourage overprescribing. Not until 14 years later did an independent researcher obtain access to the complete study report from the FDA and conclude that the NEJM authors had used statistical slight-of-hand to obscure an increased danger of heart attacks and dying in the normal-hematocrit group. In the meantime, lobbyists working for the drug manufacturers successfully blocked efforts by Medicare administrators to finish compensating for the higher (harmful) doses.

Likewise, the evidence that rosiglitazone (Avandia) increased the danger of heart attacks was slow to come to light, due in part to the drugmaker's research emphasis on the surrogate outcome of glycemic control. Although a 2007 meta-analysis first sounded the alarm about rosiglitazone's cardiovascular risks, the manufacturer successfully stalled regulatory action in the U.S. for three more years, during which thousands of new patients were prescribed the drug.

Could the FDA and other U.S. government authorities act more to protect patients from the effects of biased research and aggressive sales tactics for newly marketed drugs? What concrete steps could health policymakers take to encourage research to identify unexpected harms earlier in the drug approval procedure?