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Vernakalant should not be approved as an injection for rapid conversion of recent-onset atrial fibrillation (Afib), despite its convenience, FDA advisors said.

The Cardiovascular and Renal Drugs Advisory Committee voted 11 to 2 Tuesday against approval for the multiple ion channel blocker proposed for patients in the first 7 days of Afib onset (or within 3 days of Afib onset after cardiac surgery).

In discussing the New Drug Application (NDA) re-submission by the sponsor Correvio, committee members largely agreed that the safety profile of vernakalant is still not well characterized despite additional safety data collected since its original 2006 NDA, which floundered over concerns related to hypotension, arrhythmias, and conduction disturbance.

ACT V, a study conducted in response to the FDA's concerns about vernakalant's safety, ended up with one otherwise healthy participant with Afib and no known structural heart disease developing cardiogenic shock and dying shortly after getting an infusion of the drug.

This prompted the FDA to put vernakalant on clinical hold in 2010. The agency has not budged over years of attempts by sponsors to lift the ban.

"In order to take a risk, there has to be a clear benefit ... Here there is a risk of a very infrequent but fatal, catastrophic event. What's the advantage? It's convenience," said panelist C. Michael Gibson, MD, MS, of Harvard Medical School, who voted no today on vernakalant's approval.

Getting out of the hospital quicker is not necessarily an advantage to the health of the patient undergoing cardioversion, whereas the unpredictable risks of the drug are concerning, Gibson said. "So in my mind the benefits did not outweigh the risks."

Also voting no was Milton Packer, MD, of Baylor University Medical Center in Dallas, who said he couldn't think of a patient population for whom vernakalant's risk-to-benefit ratio would be favorable.

Much of the safety discussion focused on the SPECTRUM post-marketing registry out of Europe, where vernakalant has been approved under the brand name Brinavess since 2010. The observational report showed no deaths and 70.2% conversion of Afib to sinus rhythm in the first 90 minutes after the drug was administered to 1,778 patients.

But the FDA "is not reassured" by the SPECTRUM cardiovascular safety data, said agency medical officer Preston Dunnmon today before the panel vote.

Selection bias is a possibility given that enrollment was based on physician discretion, and it was not clear that all people who were eligible for vernakalant treatment were actually screened for treatment, Dunnmon said.

Gibson flat-out said he found it hard to believe that mortality was as low in SPECTRUM as reported, voicing concern that the investigators did not adequately capture some events.

On the other hand, the SPECTRUM data were somewhat reassuring to John Alexander, MD, MHSc, of Duke University School of Medicine in Durham, N.C., who voted yes to giving vernakalant the green light.

"Patient selection is key, and more work needs to be done to identify the patients with the favorable risk-benefit profile. It's clear there's a really low-risk population and a really high-risk population. It's the middle gray zone that's the problem," according to Alexander.

The other person to vote yes was Matthew Needleman, MD, of Walter Reed National Military Medical Center in Bethesda, Maryland.

"An option like this would be good for a select group of patients. I understand the concern of the committee releasing this to the wild, but for select patients this has a role," he argued.

The FDA characterizes vernakalant as a negative inotrope that prolongs the QRS and is not atrial-specific. Given its mechanism of action, it can be expected to cause serious events such as hypotension, bradycardia, ventricular arrhythmias, and death.

Indirect comparisons with electrical cardioversion and other drugs -- dofetilide (Tikosyn) and ibutilide (Corvert), for example -- suggest that vernakalant is less safe than existing treatments for new-onset Afib, according to an FDA staff presentation.

If this drug were approved, it should be restricted to people with the most experience -- namely electrophysiologists and some cardiologists, said James Floyd, MD, of University of Washington in Seattle. He suggested a Risk Evaluation and Mitigation Strategy (REMS) action requiring registration and training of physicians before they use vernakalant on patients.

For its part, Correvio proposed having a pre-infusion checklist accompany each vial of vernakalant to help healthcare providers identify patients who might experience serious adverse events due to the drug. This risk mitigation tool had been consulted in about two-thirds of cases in SPECTRUM.

Yet the checklist is not enough to predict who might be harmed from vernakalant, according to Dunnmon. Furthermore, harm cannot be prevented through risk mitigation: there was a case of serious hypotension without bradycardia in ACT V in which the person was unresponsive to vasopressors for 40 minutes. "When harm occurs, in some cases, it cannot be treated," he said.

Ultimately, today's vote flipped the general sentiment from the 2007 meeting in which advisory committee members for vernakalant given its demonstrated efficacy as a pharmacologic conversion agent: 52% patients converted from Afib to sinus rhythm in the ACT I and ACT III trials.

The FDA had decided a year later that there were enough serious adverse events (eight among 375 people) that the drug needed to show better before getting approved.

The agency is not required to follow the recommendations of its advisory committees on approval, although it often does.

It was apparent that safety remains a concern to this day.

"I don't want this vote to imply that we should shut down pharmacologic cardioversion or that this drug be abandoned," said Paul Ridker, MD MPH, of Harvard Medical School and Brigham and Women's Hospital.

He suggested that the FDA lift its clinical hold on vernakalant to allow further study on the drug. "I do believe pharmacologic cardioversion has a role. There's a future in this, we just have to get there."

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