FDA lifts some safety restrictions on GlaxoSmithKline's Avandia

The FDA announced Monday that it is overturning certain restrictions imposed on the use of GlaxoSmithKline's Avandia (rosiglitazone), citing trial data showing no elevated risk of heart attack or death in patients treated with the diabetes drug, versus standard treatments. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, commented that the decision reflects "the most current scientific knowledge about the risks and benefits of this drug."

The US regulator said its actions include requiring modifications to labelling about cardiovascular safety and changes to the Risk Evaluation and Mitigation Strategy (REMS) programme, as well as releasing the company from a requirement to conduct a post-marketing study. As part of the restrictions, which were imposed in 2010, the agency required that new Avandia prescriptions be limited to patients who could not control their diabetes with other drugs and who had been briefed about the cardiovascular risks. "Once the changes are final, [Avandia's] indication for use will no longer be limited to certain patients," the FDA said.

Specifically, the agency indicated that patients, physicians and pharmacists will no longer need to enroll in the REMS to receive, prescribe or dispense the therapy. The FDA noted that manufacturers of the drug, which will likely have an indication similar to currently available type II diabetes therapies, will be required to ensure that potential prescribers are properly trained on the therapy's cardiovascular risks. The regulator will also no longer require GlaxoSmithKline to conduct a study comparing Avandia to Takeda's Actos (pioglitazone) and to standard diabetes drugs, asserting that the trial was "no longer feasible or necessary."

The FDA's decision was based on results of an analysis of the RECORD study conducted in 2009. The agency noted that the trial, in which patients received Avandia as an add-on to metformin and sulphonylurea, or a combination of metformin plus sulphonylurea alone, failed to identify an increased risk of heart attack or death associated with the drug. The findings contradicted results from a 2007 meta-analysis that concluded the therapy increased heart attack risk by 43 percent and the risk of cardiovascular death by 64 percent, compared with placebo or other treatment regimens. "Given these new results, our level of concern is considerably reduced," remarked Woodcock.

The ruling follows a vote by an FDA advisory panel in June in which the majority of panellists recommended modifying or removing the restrictions. In documents released ahead of the vote, FDA staff had mentioned that the re-analysis of the RECORD study did not find an increased risk of cardiovascular events associated with Avandia, although some had questioned whether the analysis could mitigate flaws in the design of the study.

Commenting on the news, Cleveland Clinic cardiologist Steven Nissen, who authored the 2007 meta-analysis, predicted doctors would not resume prescribing the therapy. "I do not think this decision is in the public interest," said Nissen, adding "this step is from re-analysis of a clinical trial that was not designed properly in the first place and would not meet modern regulatory standards."

Meanwhile, GlaxoSmithKline stated that it "appreciates the agency's robust review of the science with regard to Avandia," and reiterated its view that the drug "is a safe and effective treatment for type 2 diabetes when used appropriately." In June, the company said Avandia, which lost US patent protection in 2011, was being taken by about 3000 patients in the country, down from 120 000 before the restrictions were implemented. Morningstar analyst Damien Conover remarked that "without patent protection, you probably won't see any marketing spending, or anyone out there promoting Avandia."

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