The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee broke with the recent track record of the agency in recommending against an application for a lipid-lowering agent based on a surrogate endpoint, asking instead for results of an ongoing cardiovascular outcomes trial before recommending approval.

There was no disputing the triglyceride-lowering effects of Amarin Pharmaceuticals Inc.’s Vascepa, which is already marketed as monotherapy for severe hypertriglyceridemia. Supplemental approval expanding the indication for the drug to mixed dyslipidemia should have been a slam dunk based on the agency’s history, but discussion of whether lipid changes as surrogate endpoint were good enough turned unexpectedly serious.

The proposed new indication is for use of Vascepa (icosapent ethyl) in combination with a statin drug for reduction of triglycerides, non-high density lipoprotein cholesterol, apolipoprotein B, low-density lipoprotein (LDL) cholesterol, total cholesterol and very low density lipoprotein (VLDL) cholesterol in adults with mixed dyslipidemia and coronary heart disease or a risk equivalent.

The question before the committee was whether the efficacy results from the ANCHOR trial would translate to meaningful reduction in cardiovascular risk among the target population. After FDA and sponsor presentations and an open hearing period, the committee turned to discussion of that question. Among its first concerns were interpretations of the statistical analysis and the potential risk of bleeding events with the product.

In response to suggestions that the agency had “glossed over” some safety issues in the application, FDA Deputy Director Eric Colman clarified, “We didn’t see any obvious, glaring safety issues that hadn’t been touched upon before. . . . I don’t think we glossed over it.”

When it came to the main point of discussion, and the potential efficacy of Vascepa at reducing cardiovascular risk, there were many questions raised.

Committee member Ellen W. Seely, a professor of medicine with Harvard Medical School, said, “I’m still kind of stuck. . . . I just don’t know if it’s going to lower CVD risk. We could approve it for lowering triglyceride, if that’s the way the question is raised.”

The committee generally agreed that there was no way to predict the results of the ongoing cardiovascular outcomes trial, REDUCE-IT, until that trial is complete in 2016. As well, the agency has no mechanism for provisional approval until those results are available.

Another concern of the committee was the negative placebo effect. In the ANCHOR trial, patients received 12 weeks of treatment with Vascepa 4 g per day or mineral oil placebo. The results showed reductions in fasting triglycerides and many other lipid values. However, the placebo group showed consistent and in some cases large increases in those values across the board, exaggerating the difference between the two groups. The placebo effect created the potential for overstating the efficacy of the product.

The committee voted 9 to 2 against recommending approval of Vascepa in the new indication.

William Hiatt, a professor of medicine at the University of Colorado School of Medicine, voted no, explaining, “The evidence today is not convincing that lowering triglycerides is clinically beneficial.”

Consumer representative Diana Hallare voted no, as well, citing the need for cardiovascular outcomes data and greater diversity in the study population.

Acting chairman Robert Smith was one of the two members that supported approval. “My vote was based on considering the balance of efficacy and safety,” he said.

The vote sent ripples through the industry, as it was expected to go in favor of Amarin’s application. Jefferies analyst Tom Tarrant predicted seven yes votes, including Ellen Seely, who he said had “the most positive voting record of any panelist in this division.”

Seely, however, voted no due to the uncertainty of the ultimate cardiovascular benefit.

Joseph Schwartz, of Leerink Swann, had greater concerns about voting outcome. “This morning we hosted a Pulse Call with a MEDACorp lipidology KOL who after reviewing the FDA briefing documents expects a close vote in the 10/16 Panel on Vascepa label expansion. The specialist believes that the framing of the ANCHOR Advisory Committee question raises a high bar since AMRN is at the center of a broader question at the Agency: Is the demonstration of efficacy on biomarkers such as triglycerides (TG) or LDL cholesterol on their own sufficient for FDA approval?”

Schwartz noted that the framing of the panel discussion could signal a major shift in how the FDA views efficacy requirements for chronic therapies. “Such a shift in FDA standards could stem from the fact that multiple other TG lowering agents including Fibrates and Niacin were able to confer a benefit on traditional cardiovascular biomarkers but subsequently failed to validate this benefit in post-approval outcomes studies,” Schwartz wrote.