After years of debate over the safety of GlaxoSmithKline’s diabetes drug Avandia, U.S. and European regulatory agencies have finally made a decision about the future of the drug. European authorities have recommended suspending marketing of the drug, while FDA is severely restricting access to the drug, but seems to be leaving the door open to further actions. GSK, meanwhile, issued a press release saying it would stop promoting Avandia worldwide.
Today’s announcements mark yet another chapter in the Avandia saga, which began in May 2007, when Cleveland Clinic cardiologist Steve Nissen published an analysis of the combined data from 42 previous clinical trials of GSK’s diabetes drug. The results weren’t pretty: Nissen’s article in the New England Journal of Medicine claimed that patients taking Avandia were 43% more likely to have a heart attack than those who were not on the pill. The next three years brought a series of safety alerts, conflicting data analyses, advisory panels, and questions over whether GSK tried to cover up the cardiovascular safety risk associated with the drug.
In July, a panel of FDA advisors had mixed views on Avandia: 12 of the 33 panelists voted to remove the drug from the market, while 10 said it could stay on the market with strong restrictions on prescribing the drug.
FDA today sided with those 10 panelists and imposed strict limitations on who can take Avandia. The agency will also adjust the drug’s label to reflect the safety risk. Under a risk evaluation and mitigation strategy, or REMS, Avandia can only be prescribed to new patients if they have been unable to control their blood sugar with other diabetes drugs. People already taking Avandia can continue taking the drug, but will have to register in the REMS program and sign a document saying they are aware of the cardiovascular concerns associated with the drug. FDA did not provide a clear timeline on how long it would take to implement the REMS.
“We believe this action will severely limit the number of people on this drug,” Janet Woodcock said this morning in a conference call with reporters. FDA believes the REMS requirement will cause diabetics to “think twice” before they continue on the drug or start taking it, she said. FDA said about 600,000 people are currently taking Avandia, a number that the agency believes will drop precipitously under these new requirements.
Patients will surely be confused by the mixed messages being sent by the agencies: after all, if it’s not safe in Europe, why would it be safe here? FDA defended its action by pointing out that European regulatory authorities lack the ability to monitor approved medications like the U.S. agency can with a REMS. It also argued that the cardiovascular signal has yet to be conclusively proven—and it seems that no one inside or outside the agency can agree on how much weight to put on differing analyses from clinical trials.
FDA seems to be pinning its hopes for scientific clarity on a reassessment of a large, randomized, clinical trial called RECORD, or Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes. Data from the trial showed that Avandia, also known as rosiglitazone, was no riskier than metformin and sulfonylurea, two standard diabetes drugs. But the trial design has been criticized. FDA, worried that not every cardiovascular event was caught in the original analysis of the data, is now requiring GSK to commission an independent review of patients’ records to identify any events that might have gone unreported.
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