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FDA to review restrictions on GSK's diabetes drug Avandia

Advisory committee to discuss re-analysis of diabetes drug’s safety data

FDA headquarters White Oak

US regulators are to review the safety restrictions imposed on GlaxoSmithKline's (GSK) diabetes drug in Avandia almost three years ago.

Avandia (rosiglitazone) was withdrawn in Europe and had its use limited in the US in late 2010 after it was linked to an increase in the risk of cardiovascular events, but now the FDA could reconsider its stance following a meeting this week of a 28-member advisory committee of doctors.

The hearing was prompted by an independent re-analysis of the GSK-backed RECORD trial into Avandia's cardiovascular safety, which, when originally published in 2009, suggested that the heart risk posed by the drug was less than that demonstrated by a meta-analysis of data from other studies.

The design of the RECORD trial was subject to heavy criticism, however, and the FDA ordered it to be reviewed, stating that “important questions arose about potential bias in the identification of cardiovascular events” and additional clarity was needed.

This review, which was undertaken by Duke Clinical Research Institute (CDRI), has now been completed and appears to back the original assertion that Avandia is not as big a risk for heart failure as to warrant the restrictions imposed by the FDA.

GSK will await the results of the discussion with a keen interest, considering that at its peak, Avandia was the world's biggest-selling diabetes drug, recording annual revenues of $3.4bn.

The drug's legacy has taken a dramatic toll on GSK's fortunes, however, with the pharma company paying out billions to settle charges that it withheld safety data and made unsupported safety claims about Avandia among other inappropriate promotion activities.

Despite the DCRI review's apparent support for Avandia's safety, the RECORD trial still has its critics, including FDA medical team leader Dr Thomas Marciniak.

In a memo to the agency concerning the DRCI's review, he said the “the readjudication cannot address many of the trial design flaws documented previously”, with specific criticisms including the open-label nature of the design.

Dr Marciniak also cast doubt on the independence of the DCRI's review, claiming GSK was financially responsible for the costs of the readjudication, and some DCRI personnel had received financial compensation from GSK in the past.

This mainly focused on principle investigator Dr Kenneth Mahaffey, although the FDA refuted these accusations, saying that Dr Mahaffey had listed 24 companies he had provided consulting or other services to, and that his GSK activities involved his participation in continuing medical education rather than direct compensation.

The briefing notes for the advisory committee meeting this week include a memo response to Dr Marciniak from Dr Norman Stockbridge, director of the Division for Cardiovascular and Renal Products; Dr Ellis Unger, director of the Office of Drug Evaluation; and Dr Robert Temple deputy director for clinical science at the Center for Drug Evaluation and Research.

In it the three doctors not only criticise Dr Marciniak's allegations about the independence of the review, but also his “unprofessional language” and “disparaging remarks about FDA staff and review units”.

“As noted, we welcome and thrive on honest debate, but it is unprofessional to insult someone because he or she disagrees with you,” states the memo.

“We stand by the reviews of [investigators] Dr Preston Dunnmon and Dr Karen Mahoney, and agree that the re-adjudication of RECORD is acceptable... after re-adjudication, we do not find a cardiovascular 'signal' of concern in RECORD. The mortality data are, in fact, reassuring.”

5th June 2013

From: Regulatory



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