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Mixed messages from FDA staff over Avandia safety
  12 July 2010
Staffers at the US Food and Drug Administration are divided as to what action, if any, should be taken on GlaxoSmithKline?s Avandia ahead of an eagerly-anticipated advisory committee meeting concerning the diabetes drug this week.
The FDA has released documents ahead of a joint meeting of the Endocrinologic and Metabolic Drugs and the Drug Safety and Risk Management advisory committee on July 13-14 to evaluate Avandia (rosiglitazone). The review will focus primarily on the cardiovascular safety of the drug and panelists will look at results from the RECORD study, and different meta-analyses, some comparing Avandia to Takeda?s Actos (pioglitazone).
Janet Woodcock, director of the Center for Drug Evaluation and Research at the agency, admits that "there is not complete unanimity within the FDA about interpretation of the data" and this is clear looking at the slides published on the regulator?s website, especially regarding RECORD. Thomas Marciniak, medical team leader for the Division of Cardiovascular and Renal Products at the CDER, said the 4,427-patient trial was "inadequately designed and conducted to provide any reassurance about the CV safety of rosiglitazone". He argues that RECORD "confirms and extends the recognised concerns" regarding increased heart failure deaths with Avandia and suggests it increases the risk for myocardial infarction.
However, Ellis Unger, deputy director at the Office of Drug Evaluation-I at the CDER?s Office of New Drugs, says the results of RECORD do not substantiate the findings from the 2007 meta-analysis published in the New England Journal of Medicine on MI and cardiovascular death. He did acknowledge that the results are not as definitive as they might have been, because of not "casting a wide net" to ascertain endpoint events, "possible ascertainment bias by investigators" and "questions regarding mortality follow-up".
GSK has backed its data from RECORD, saying they are "robust and reliable". Since 2007, "we have seen results from six controlled clinical trials looking at the cardiovascular safety of Avandia and together they show that this medicine does not increase the overall risk of heart attack, stroke or death," noted Murray Stewart, the firm?s vice president for clinical development.
The FDA panellists will vote on several possible courses of action and while most analysts believe that Avandia will not be withdrawn, the review may end up putting even more restrictions on its use.
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