GSK's Avandia survives FDA panel vote but damage may have been done

The majority of a 33-member FDA advisory panel has voted against the complete market withdrawal of GlaxoSmithKline's Avandia. However, considering the safety concerns surrounding the drug, and with 12 of the panelists voting for withdrawal, Avandia's sales are likely to decline further even if it remains on the market.

The future of GlaxoSmithKline's type 2 diabetes drug Avandia (rosiglitazone) is still unclear after the two-day FDA advisory panel hearing on the safety of the drug.

In the crucial vote on the withdrawal of Avandia, the majority of the expert panel showed strong concern about Avandia's risks by voting for withdrawal (12 votes) or increased restrictions on availability (10 votes). Seven panel members voted for stronger warnings and only three members voted for the drug labeling to remain unchanged. The FDA must now decide on Avandia's future.

The issue facing the panel was the possibility, first raised publicly in 2007, that Avandia may increase the risk of heart attacks and other ischemic events relative to other antidiabetic drugs. In comparison, Takeda's Actos (pioglitazone), a competitor drug in the same class as Avandia, has demonstrated no such risks.

While several meta-analyses and patient outcome studies have shown increased risk of ischemic events in Avandia patients, GlaxoSmithKline argues that clinical trials do not show evidence of cardiovascular risk. Recently, however, the company-sponsored RECORD trial, designed to study Avandia safety, has come under attack for poor methodology and breaches of protocol.

The FDA advisory panel heard a range of evidence and opinion before voting on questions about Avandia's safety and continued use. Majorities on the advisory panel voted that there was sufficient evidence to raise concerns about ischemic cardiovascular risks with Avandia relative to Actos and to other antidiabetic drugs, but decided that evidence was insufficient to find increased risk of overall mortality in each of these comparisons.

The inconclusive nature of the testimony presented was reflected by the fact that, despite having expressed concerns about Avandia's safety, a panel majority voted for the continuation of the TIDE trial comparing Avandia and Actos. Panel members require more evidence for Avandia's safety despite a market presence of 11 years. However, enrolment has been lower than expected in the TIDE trial and it seems likely that the latest FDA panel vote will not improve matters. Indeed, in June, the Indian government halted Avandia trials there because of safety concerns.

The fate of Avandia rests in part on the FDA's action on the advisory panel's mixed recommendations. In the absence of stronger evidence for risk, there may be an incentive to keep Avandia on the market to allow for wider clinician choice, a view expressed in panel discussions. Nevertheless, even if the FDA does not follow the panel's advice to withdraw or restrict prescribing of Avandia, physician and patient concerns about safety and litigation (and the availability of alternative therapies for most patients) are likely to lead to continuing decline in Avandia sales.

Avandia's decline opens the door for further growth by the antidiabetics that have already filled the gap created after the initial Avandia safety scare in 2007, namely class leader Actos and Merck's blockbuster DPP-4 drug Januvia (sitagliptin). With Avandia hit by safety fears and Actos approaching patent expiry in 2011, there is also the possibility for newer drug classes to seize market share, maintaining the attractiveness of type 2 diabetes as a commercial and clinical target.

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