Recently a federal district court spotlighted FDA’s apparently inconsistent definitions of what constitutes an “active ingredient (AI)” in rejecting the Agency’s rationale for denying Amarin Pharmaceuticals Inc.’s fish oil capsule Vascepa (icosapent ethyl) (NDA 202057 approved July 26, 2012), request for 5 years of market exclusivity as a New Chemical Entity (NCE). On Feb. 21, 2014, however, the agency concluded that the drug is not entitled to five-year exclusivity because Vascepa’s AI—a single molecule—is one component of a mixture that makes up the “AI” of another FDA-approved drug. Under the Hatch-Waxman Act, a drug manufacturer is entitled to five-year exclusivity if its newly-approved drug does not contain an “active ingredient” that was previously approved in another drug application. On February 27, 2014, Amarin filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s February 21, 2014 Exclusivity Determination that Amarin’s VASCEPA is not eligible for NCE exclusivity. FDA’s rationale for denying NCE exclusivity is that EPA, “the single active moiety (AM) in Vascepa, was also an AM contained in another, previously approved drug, Lovaza (omega-3-acid ethyl esters; NDA 021654; approved November 10, 2004) Capsules.”
Vascepa labeling (revised 2013) lists a single molecule, icosapent ethyl, as the drug’s AI. Icosapent ethyl is the ethyl ester of eicosapentaenoic acid (EPA), an omega-3 fatty acid. Because the Agency does not consider the ester component of a molecule in determining its AM status, 3 EPA (the de-esterified portion of the icosapent ethyl molecule) is considered the sole AM in Vascepa. Lovaza, a mixture of seven omega-3 fatty acids, primarily EPA and docosaexaenoic acid (DHA), is a prescription “fish oil” approved for the treatment of severe hypertriglyceridemia (> 500 mg/dl).
In a May 28 opinion, a federal judge vacated FDAs earlier decision that Amarin’s new drug Vascepa was not entitled to a five-year period of market exclusivity. It is the first known successful challenge to FDA’s denial of five-year-exclusivity to a drug maker since the Hatch-Waxman Act was passed in 1984 (Covington & Burling LLP, 28 May 2015).
Judge Moss ruled (VASCEPA – FDA Amarin) that “FDA’s ‘active moiety’ approach cannot be reconciled with the statutory text.”
District of Columbia District Judge Randolph Moss said FDA advocates two conflicting definitions of “AI”, sometimes asserting that it is the same as “AM” and at other times making a distinction between the two (referenced in the 01 June 2015 “The Pink Sheet”). He noted in determining exclusivity, the Hatch-Waxman Act considers whether the new drug contains an AI which has been approved in a prior application.
In this instance, AI versus AM centered on the FDA needing to address NCE exclusivity in the context of naturally derived complex mixtures.
The Agency notes in its 2014 Exclusivity Determination for Amarin’s VASCEPA that neither the statute nor the regulations expressly address 5-year NCE exclusivity in the context of naturally derived mixtures.
If we consider the relevant definitions, understanding the relationship or distinction between AI and AM is confusing at best.
Trying to provide clarity, the FDA in the Vascepa Exclusivity Determination ruling clarified it comes down to a “one-to-one” – or “one-to many” relationship.
A one-to-one relationship between AI and AM generally exists in drugs with ‘simple” AI that consist of a single molecule and thus can be applied without difficulty in that context. A “one-to many” relationship between the AI and its component AMs is when the entire mixture is the single AI, but that AI may contain more than one component AM.
So in terms of the Vascepa ruling, FDA concluded that as a product that contains icosapent ethyl as its AI and EPA as its AM, Vascepa’s eligibility for 5-year NCE exclusivity depends on whether EPA is an AM previously approved in Lovaza. Because Lovaza is a well-characterized mixture with respect to its omega-3 acid components, the Agency believes that the “one-to-many” framework described above should apply. The Agency’s recognition of the entire fish oil mixture as Lovaza’s AI is consistent with the Agency’s approach to naturally derived mixtures that are not fully characterized.
Amarin alleged in its Complaint that FDA’s exclusivity decision is contrary to law.
In his May 28 opinion, Judge Moss stated the decision by FDA denying Vascepa NCE exclusivity “is both procedurally and substantively flawed.” He further stated, “The administrative decision does not offer – or even attempt – any reasoned explanation of how its application of the regulatory focus on ‘AM’ can be reconciled with the statutory focus on ‘AI’.
Clearly from these examples – the relationship or distinction of what constitutes an AI versus an AM – is still unclear and possibly in flux should other firms in similar circumstances challenge FDA in court.
Stacey Ayres, Ph.D.
Subject Matter Expert
Bill Stoltman, J.D.
Senior Director of Quality Assurance and Compliance