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Why The FDA Probably Won't Approve An Expanded Indication For Amarin's Vascepa

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On Wednesday an FDA advisory  panel will consider an expanded indication for Amarin Pharmaceuticals' Vascepa, an EPA fish oil product currently indicated only for people with severe hypertriglyceridemia (>500 mg/dl). The new indication would greatly expand the patient population eligible to receive Vascepa, from the relatively few people with severe hypertriglyceridemia to the many millions with elevated triglycerides (>200 mg/dl) and existing CV disease or at high risk for CV disease. The NDA for this indication is based on the ANCHOR trial, which showed that Vascepa lowered triglycerides in the target patient population.

The FDA review (available here) raises 2 troubling issues. The first is fairly simple and relates to the performance of the placebo in ANCHOR.  In its briefing documents the FDA raises the disturbing and unusual possibility that the mineral oil placebo used in the trial may not have been biologically inert. LDL levels in the placebo group went up 9% in the placebo group and this will make it difficult to assess the true effect of Vascepa. It's unlikely that this issue by itself will entirely derail the NDA, but it may well serve to undermine confidence in the trial and put the panel in a critical frame of mind.

More significant, to my mind, is the lack of any evidence for any important improvement in clinical outcomes that can be tied to Vascepa. Now some people believe that ANCHOR provides enough data to justify the expanded indication, as it technically met its primary endpoint and reduced triglycerides. The argument here is that improvements in lipid parameters have traditionally been accepted by the FDA, and that there is no current approved and effective treatment to treat high risk people with moderately elevated triglycerides.

The counter-argument against approval is made clearly and strongly in the FDA briefing documents. Although the FDA agreed to the ANCHOR protocol, it also specifically noted that the interpretation of the trial would clearly depend on the results of several large ongoing outcomes trials testing the hypothesis that non-statin therapies (nitrates, fibrates) would reduce residual risk. Since that time the results of these trials have been published and they have uniformly failed to demonstrate any clinical benefit. Although the FDA notes that these trials have been controversial and are subject to different interpretations, the burden of evidence now remains on those wishing to prove that reducing residual risk with non-statin therapies is beneficial.

An apparent contradiction to  this perspective is the fact that the FDA has actually approved a number of lipid and diabetes drugs in recent years based on surrogate outcomes. An example is the approval of 2 new drugs from Aegerion and ISIS to treat people with extremely high cholesterol levels due to homozygous familial hypercholesterolemia. Although these drugs raised all kinds of red flags over both safety and efficacy, the FDA advisory panel members and the FDA itself ultimately decided in favor of the new drugs.

The decisive argument in these cases was that physicians needed as many options as possible in treating patients. This principle trumped concerns about the lack of outcomes. But there's an important reason why this argument may not work in the case of Vascepa.

No matter what the FDA decides now, Vascepa will be available as a treatment option to physicians. Since it is already approved, physicians will still be able to prescribe it for off-label usage. The main effect of a negative decision would be to prevent Amarin from marketing and promoting the drug for this off label usage.

The fact that Vascepa is already on the market provides cover to the panel members. They will be less likely to make a recommendation based on the emotional appeal of expanding physician options and more likely to take a strong stance in favor of outcomes trials. The most likely scenario is that they will withhold approval of an expanded indication until the results of  REDUCE-IT, Amarin's outcome trial with Vascepa, become available in 2016.

Correction: In an earlier version of this article I mistakenly stated that Vascepa was a DHA fish oil. It is of course an EPA fish oil.