FDA Responds to Senate Concerns Over Rosiglitazone; Will "Reassess" Tide Trial

Shelley Wood

April 19, 2010

April 19, 2010 (Silver Spring, Maryland) — The FDA plans to hold a joint advisory panel meeting in July to assess the totality of evidence for diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) and on the basis of that meeting, to decide whether to halt the ongoing Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, comparing rosiglitazone and pioglitazone, according to a letter from the offices of FDA commissioner Dr Margaret Hamburg [1].

Hamburg's letter, sent March 30, 2010 to Sen Charles Grassley (R-IA), is in response to a report issued in February by the Senate Committee on Finance, reported by heartwire at that time, that concluded there are "serious health risks associated with Avandia." Grassley's report, coauthored by Sen Max Baucus (D-MT), also criticized the FDA for how the agency handles drug approvals and drug safety.

Reporting on the letter, a Wall Street Journal story quotes Hamburg's principal deputy, Joshua Sharfstein, hinting that if TIDE is halted, the agency would also reevaluate whether the drug should stay on the market, since the trial "cannot be delinked from the agency's view of Avandia" [2].

In her letter, Hamburg says that she has reviewed the "recent history" of rosiglitazone's safety and met with GlaxoSmithKline as well as Dr Steven Nissen (Cleveland Clinic, OH), who has led the charge questioning the drug's cardiovascular safety profile over the past several years. Most recently in a commentary in the Journal of the American Medicine Association [3], Nissen provided a detailed account of his dealings with GlaxoSmithKline and in particular, a meeting between him and company executives that he secretly recorded, as previously reported by heartwire . She writes that the FDA is also conducting a "comprehensive review" of data from the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, and that review, as well as data from other clinical trials and observational studies, will be presented to a joint meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory committees. Depending on the upshot of the joint panel discussion and the FDA's own review, the agency "will reassess the rationale for the TIDE trial, review the trial's enrollment, and respond accordingly," the letter reads.

Hamburg's letter points out that the FDA regulates conduct of institutional review boards (IRBs), which are responsible for the safety of people participating in trials like TIDE. As such, the FDA's Center for Drug Evaluation and Research has asked GlaxoSmithKline to check with the IRBs overseeing the TIDE study sites to make sure they are aware of the data and concerns over rosiglitazone's cardiovascular safety and that they took such concerns into account when deciding to approve the study and when reviewing and modifying the patient informed-consent paperwork.

Hamburg says she is also taking steps to address criticisms about the FDA drug-review processes, which were also cited in Grassley and Baucus's original report. She has asked "senior counselors" at the agency to lead an internal review of the drug safety decision-making process at the FDA and has called on the Institute of Medicine to conduct a study addressing "the scientific and ethical issues involved in drug safety research."

Her letter concludes reaffirming her appreciation of the senate committee's work on drug safety and her own commitment to the FDA's responsibility to protect the safety of the drug supply. "I will share with you the recommendations of our internal review on drug safety decision-making, the guidance we receive from the Institute of Medicine on comparative safety studies, and the agency's assessment and decisions on Avandia."

GlaxoSmithKline responded much more swiftly to the finance committee's report, issuing a 30-page "white-paper" response in late February, insisting the company has been "proactive in investigating the safety data" of rosiglitazone and has kept all regulatory agencies, including the FDA, aware of its investigations.

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