Amarin Sues FDA After the Agency Denies 5-Year NCE Exclusivity for VASCEPA

By Kurt R. Karst –  

It’s “Exclusivity Week”!  First there was FDA’s Draft Guidance that, if finalized, would reinterpret the 5-year New Chemical Entity (“NCE”) exclusivity provisions of the FDC Act to award NCE exclusivity to a newly approved Fixed-Dose Combination (“FDC”) drug containing an NCE and a previously approved drug.  That announcement was immediately followed by an FDA response to three Citizen Petitions denying NCE exclusivity to previously approved FDCs (see our previous post here).  Then there was FDA’s decision on the scope of 3-year new clinical investigation exclusivity applicable to PLAN B One-Step (levonorgestrel) Tablets (see our previous post here).  

The latest “Exclusivity Week” entrant is Amarin Pharmaceuticals Ireland Limited (“Amarin”).  On February 27, 2014, Amarin, which is represented in court by Covington & Burling LLP (Hyman, Phelps & McNamara, P.C. represented Amarin before FDA), 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 (icosapent ethyl) Capsules, 1 gram, which FDA approved under NDA No. 202057 on July 26, 2012, is not eligible for NCE exclusivity.  Instead, FDA awarded 3-year exclusivity, as Amarin announced last Friday. 

In a nutshell, FDA’s rationale for denying NCE exclusivity is that eicosapentaenoic acid (“EPA”), “the single active moiety in Vascepa, was also an active moiety contained in another, previously approved drug, Lovaza (omega-3-acid ethyl esters) Capsules (Lovaza).”  FDA approved LOVAZA on November 10, 2004 under NDA No. 021654.  But, of course, in reality, the issue is much more . . . shall we say . . . complex than the nutshell description, because FDA needed to address NCE exclusivity in the context of naturally derived complex mixtures.  In doing so, FDA articulated a rather interesting postition, and one that FDA hinted at in a recent response (in footnote 18) to a Citizen Petition (Docket No. FDA-2013-P-0148) concerning LOVAZA.  (There, FDA stated: “A naturally derived mixture that constitutes the active ingredient of a drug product may contain more than one active moiety.”).  According to FDA’s VASCEPA Exclusivity Determination:

You urge FDA to adopt an approach in which the entire mixture is considered to constitute both the single active ingredient and the single active moiety of the drug, rather than focusing on the individual component molecules in making either determination.  This “one-to-one” relationship between active ingredient and active moiety generally exists in drugs with “simple” active ingredients that consist of a single molecule and thus can be applied’without difficulty in that context.  In addition, for some naturally derived mixtures which are so poorly characterized that it is difficult to determine with any certainty as to which molecules in the mixture are consistently present or potentially are responsible for the physiological or pharmacological activity of the drug, or where there is no precise way of identifying the molecules or ions that are consistently present and active in the mixture, identifying the entire mixture as the active moiety of the drug may be appropriate.  In such cases, each new version of such a naturally derived mixture would be eligible for 5-year NCE exclusivity; that exclusivity, however, typically would not block submission or approval of an application for any subsequent drug product that contains a similar active ingredient (exhibiting a similar lack of characterization), because FDA cannot determine whether the subsequent drug product contains the same active moiety as in the previously approved drug.

While this approach is born of necessity for some poorly characterized mixtures, nothing in the statute or regulations requires that this approach be maintained for all naturally derived mixtures.  In cases where at least part of the mixture is well characterized and some components of the mixture that are consistently present and active are identifiable or have been identified, an approach in which the mixture is identified as both the active ingredient and the active moiety appears inconsistent with the definition of active moiety as a “molecule or ion. . . responsible for the physiological or pharmacological action of the drug substance.”  The approach that is the most consistent with the relevant definitions, facts, and policies present in this case is one in which the entire mixture is the single active ingredient, but that active ingredient may contain more than one component active moiety.  This approach recognizes that there can be a “one-to-many” relationship between the active ingredient and its component active moieties.

FDA then proceeds to lay out three criteria for when the Agency will consider certain component molecules of a naturally derived complex mixture to be previously approved active moieties for the purpose of determining a subsequent drug’s eligibility for NCE exclusivity. 

(1) Characterization: The previously approved mixture has been characterized such that one or more specific molecules in the mixture have been identified;

(2) Consistent Presence: The evidence demonstrates that one or more specific molecules identified in criterion 1 are consistently present in the mixture; and

(3) Activity: The evidence demonstrates that the molecule or molecules identified in criteria 1 and 2 are responsible at least in part for the physiological or pharmacological action of the mixture, based on a finding that they make a meaningful contribution to the activity of the mixture.

“If these criteria are met,” says FDA, “the molecule or molecules would be identified as the active moiety or moieties of a naturally derived mixture. ”  And if “such a molecule is an active moiety in a subsequently approved drug, it will be considered a previousy approved active moiety” and NCE exclusivity will be denied.  Applying these criteria to VASCEPA, FDA determined that the EPA active moiety in VASCEPA is also an active moiety in LOVAZA, and the Agency denied NCE exclusivity.

Amarin alleges in its Complaint that FDA’s exclusivity decision is contrary to law:

The controlling statutes grant 5-year exclusivity to any new drug, no “active ingredient (including any ester or salt of the active ingredient)” of which has been previously approved by FDA. It is undisputed that the “active ingredient” of Lovaza is an undifferentiated fish oil mixture. That mixture is not the same as Vascepa’s active ingredient (icosapent ethyl). Nor is the mixture an ester or salt of icosapent ethyl, or vice versa. In refusing to recognize Vascepa’s 5-year statutory exclusivity, FDA has improperly substituted the words “active moiety” for the statute’s words (“active ingredient”). FDA has also concluded (in violation of the statute and regulations) that a drug with a complex mixture as its single active ingredient may have multiple active moieties, none of which is a salt or ester of the active ingredient.

Citing to several precedent approvals where FDA granted NCE exclusivity, such as with CONDYLOX (podofilox) (NDA No. 019795), QUTENZA (capsaicin) (NDA No. 022395), various lung surfactant drug products, including SURVANTA (beractant) (NDA No. 020032), INFASURF (calfactant) (NDA No. 020521) and CUROSURF (poractant alfa) (NDA No. 020744), and other approvals where FDA applied a presumption in favor of NCE exclusivity (see our previous posts here and here), Amarin alleges that FDA’s denial of NCE exclusivity for VASCEPA is arbitrary and capricious:

FDA has repeatedly recognized 5-year exclusivity for pioneer drugs in materially indistinguishable circumstances involving drug products with multiple constituents. In denying Amarin’s request for similar treatment, FDA disowned these relevant Agency precedents and failed to offer a reasonable explanation for its reverse in policy or for applying its new approach retroactively to Vascepa.

Moreover, Amarin alleges that FDA’s application of its newly announced policy to VASCEPA is without observance of procedure required by law.  “FDA must continue to apply its past policy that the active moiety of a complex mixture is the mixture itself until FDA revises that interpretation of the applicable regulations through notice-and-comment rulemaking.”

Amarin is seeking declaratory and injunctive relief and a vacatur of FDA’s denial of NCE exclusivity.  Specifically, Amaring wants a declaratory judgment that VASCEPA is protected by the FDC Act’s NCE exclusivity provisions; a declaratory judgment that FDA may not accept for filing any ANDA or 505(b)(2) NDA citing VASCEPA as a listed drug until after the expiration of NCE exclusivity; and both a preliminary and permanent injunction prohibiting FDA from accepting any ANDA or 505(b)(2) NDA for a generic version of VASCEPA until permitted under the FDC Act’s NCE exclusivity provisions.  In addition, Amarin asks the court to set aside any ANDA or 505(b)(2) NDA FDA may have already accepted for generic VASCEPA until permitted under the statute’s NCE exclusivity provisions.