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Rosiglitazone: a case of regulatory hubris

BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f7428 (Published 11 December 2013)
Cite this as: BMJ 2013;347:f7428

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  1. Steven E Nissen
  1. 1chairman of cardiovascular medicine, Cleveland Clinic, Cleveland, Ohio
  1. nissens{at}ccf.org

The FDA’s defensiveness over its decisions means further drug safety disasters may occur

The recent announcement by the US Food and Drug Administration (FDA) lifting restrictions on the prescription of rosiglitazone is the latest twist in a tortured saga dating back more than a decade.1 Rosiglitazone was approved in 1999 to treat type 2 diabetes, on the basis of results of small and limited duration studies designed primarily to show that this drug lowered blood glucose concentrations.2 At this time the regulatory requirements for approval of antidiabetes drugs emphasized reduction in glycemic indices as the principal basis for approval, not improvement in health outcomes.

Although the pre-approval studies were small, they showed two disturbing findings: that rosiglitazone raised concentrations of low density lipoprotein cholesterol by a mean of 18.6%; and that there was an excess number of ischemic cardiovascular events, approaching significance (hazard ratio 1.8 (95% confidence interval 0.9 to 3.6)). The US regulators approved the drug, but European authorities insisted on a post-approval clinical outcome trial, known as the RECORD (rosiglitazone evaluated for cardiovascular outcomes and regulation of glycemia in diabetes) trial.

After approval, the drug, marketed as Avandia, rapidly became a huge money maker for GlaxoSmithKline, eventually becoming the largest selling antidiabetes drug in the world. But something was clearly wrong. In 2005, at the insistence of the World Health Organization, GSK performed a meta-analysis of all …

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