FDA's Cardiovascular and Renal Drugs Advisory Committee recommended the approval of Sanofi-Aventis' Multaq , but with a narrower indication than the sponsor had proposed.

In a vote of 10-3, committee members agreed that Multaq (dronedarone) should be approved to treat patients with non-permanent atrial fibrillation. The panelists also agreed that Multaq could be used in patients with atrial flutter as well.

Sanofi, however, was hoping to snatch up a mortality claim that Multaq has been shown to decrease the combined risk of cardiovascular hospitalization or death, and while a few members who voted to approve Multaq said they would be in favor of expanding the indication to include a statement about a decrease in cardiovascular hospitalization, they were unanimous in denying a statement about mortality.

"I would like to make sure the claim is narrow in scope," said advisory committee chair Robert Harrington. "I would not support including the mortality claim at all in the label."

The recommendation not to approve a mortality claim follows the conclusion reached by FDA reviewers (Also see "FDA Not Forgetting Sanofi’s Previous Failed Trial In New Multaq Review" - Pink Sheet, 16 March, 2009.).

Committee members wrestled with competing data from the failed trial ANDROMEDA and from the subsequent pivotal ATHENA trial, in a refined patient population - ultimately deciding their discrepancies and the poor data collection (some of which could not be avoided) make it impossible to include a statement about mortality.

The first roadblock for Sanofi was the trials' remarkably different patient populations: ATHENA was in patients with atrial fibrillation/atrial flutter, while ANDROMEDA was in patients hospitalized for decompensated heart failure. Importantly, the committee unanimously agreed that the adverse effects in ANDROMEDA were related to clinical instability of its patient population, and the specific causes of death in the study are consistent with that theory.

The second stumbling block was the variability that comes along with data collection by investigators. Different physicians admit patients into the hospital for different reasons, and investigators were given only a box to "tick" to record why a patient was admitted. Committee members criticized the data collection method, saying it provided an incomplete picture.

The committee also took issue with ATHENA's secondary endpoints: all-cause mortality and cardiovascular hospitalization alone or cardiovascular death. The endpoints were originally arranged to be analyzed sequentially. All-cause mortality trended non-significantly lower in the Multaq treatment arm. Since the main secondary endpoint failed, the sponsor was not supposed to evaluate the next secondary endpoints. However, Sanofi did review the other secondary endpoint data anyway, and that was the backbone for their proposed mortality claim.

Despite the committee's majority vote, they did recommend that the drug be contraindicated for patients with heart failure Class III or above with a boxed warning, parallel to Sanofi's proposed risk management strategy that included a MedGuide and different communication plans to target patients and physicians.

The committee also stressed the importance of conducting further dosing studies to identify additional effective doses. Sanofi proposed a 400 mg BID regimen which was formed from the DAPHNE study, which also looked at 600 mg and 800 mg BID (the higher doses proved intolerable). Harrington also advised that additional post-marketing trials be done in ethnic minorities.

-Lauren Smith (lauren.smith@elsevier.com)

Committee Recommends Sanofi’s Multaq For Approval

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