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FDA advisors unanimously voted in favor of an expanded indication for icosapent ethyl (Vascepa) capsules for cardiovascular disease (CVD) risk reduction beyond its current indication as add-on therapy to reduce triglycerides in severe hypertriglyceridemia.

Members of the agency's Endocrinologic and Metabolic Drugs Advisory Committee voted 16-0 that there was sufficient evidence of efficacy and safety, based on last year's positive REDUCE-IT trial, to support manufacturer Amarin's proposed indication for icosapent ethyl -- a pharmaceutical grade fish oil sold by prescription -- in adult patients with high triglycerides who are already on statins.

The FDA often follows the guidance of its advisors regarding approvals for new or expanded drug indications, but is not obligated to do so. Its final decision is expected by the end of December.

The drug was initially approved in 2012 to reduce triglycerides in patients with levels of 500 mg/dL or higher. Drugmaker Amarin has since been trying to win approval for claims that icosapent ethyl improves clinical outcomes.

Despite committee members' backing of an expanded indication, panel members voiced several caveats concerning the exact indication and labeling for it.

First, not all patients shared the same benefits in REDUCE-IT: people age 45 and older with established CVD fared especially well on icosapent ethyl compared to placebo, whereas subgroup analysis showed no significant benefit with this drug for people age 50 and older with type 2 diabetes mellitus and at least one additional risk factor for CVD.

Thus, the secondary prevention data were "overwhelmingly convincing" but the primary prevention data "wholly unconvincing," said panelist James de Lemos, MD, of UT Southwestern Medical Center in Dallas. After having voted for expanded indication, de Lemos said he would limit this indication to CVD risk reduction in patients with established atherosclerotic CVD.

"It may well be a great primary prevention drug. They just haven't established it yet," de Lemos said. "This is a game and we are being played ... If we allow a primary prevention indication now, it'll never be studied [in that population]."

Kenneth D. Burman, MD, of MedStar Washington Hospital Center, said on the other hand that he would back both primary and secondary prevention indications, reasoning that icosapent ethyl appears to be a helpful new addition to clinicians' armamentarium.

"From a biological perspective I dare say that everybody in the [REDUCE-IT] trial probably had the disease. If you did intravascular imaging or looked at endothelial function, I dare say you would see abnormalities in the population of primary prevention. The difference is they haven't had events yet," offered Marvin A. Konstam, MD, of Tufts Medical Center in Boston.

Another issue with Amarin's proposed broader indication was the component of cardiovascular death risk reduction when there were not enough trial data to support this, cautioned Cecilia Low Wang, MD, of the University of Colorado School of Medicine in Aurora.

Moreover, noting that the REDUCE-IT trial had enrolled patients with triglyceride levels at least 150 mg/dL, some committee members also said they would not advise going as low as the proposed 135-mg/dL threshold for giving icosapent ethyl to higher-risk people.

Questions about the trial's mineral oil placebo did not appear to factor much into the committee's votes.

The placebo arm had shown unexpected increases in LDL cholesterol and inflammatory biomarkers from baseline. Some believe mineral oil may have interacted to reduce the absorption of statins, giving the icosapent ethyl group an unfair edge in clinical outcomes.

During the committee meeting, FDA investigators said that as long as the mineral oil did not increase the risk associated with placebo by 20%, REDUCE-IT had demonstrated superiority of icosapent ethyl over inert placebo. They saw the observed LDL increase as having a small effect on outcomes.

The two safety signals that came out of REDUCE-IT -- atrial fibrillation and bleeding -- were not enough to negate icosapent ethyl's cardiovascular benefits, several discussants said.

"I think they can be effectively handled through labeling. We do this all the time," said Elizabeth Chrischilles, PhD, MS, of the University of Iowa in Iowa City. "We do have good opportunities in the post-marketing surveillance to monitor both."

Post-marketing should focus on people on anticoagulation since there were so few REDUCE-IT participants in this subgroup, suggested Thomas Ortel, MD, PhD, of Duke University Medical Center in Durham, North Carolina.

Of note, the mechanism by which icosapent ethyl could confer cardiovascular benefit remains unknown.

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