It’s Finally Here! FDA’s VASCEPA Exclusivity Determination on Remand: NCE Exclusivity Granted!

By Kurt R. Karst –      

It’s been just over a year – May 28, 2015 – since Judge Randolph D. Moss of the U.S. District Court for the District of Columbia handed down his 40-page Opinion in a lawsuit lodged by Amarin Pharmaceuticals Ireland Limited (“Amarin”) against FDA challenging the Agency’s February 21, 2014 Exclusivity Determination that Amarin’s VASCEPA (icosapent ethyl) Capsules, 1 gram, which FDA approved on July 26, 2012 under NDA 202057, is not eligible for 5-year New Chemical Entity (“NCE”) exclusivity. Our year-long patient waiting came to an end on May 31, 2016 when FDA finally issued a new Exclusivity Determination concluding that VASCEPA is eligible for (i.e., granted) 5-year NCE exclusivity.  The 16-page Exclusivity Determination, announced by Amarin, is the latest – and perhaps the last – chapter in an exclusivity saga that started years ago.  And it comes on the heels of the so-called “NCE-1” date when an ANDA for a generic version of a drug product granted NCE exclusivity and containing a Paragraph IV certification can be submitted to FDA: July 26, 2016.

As readers of this blog know, in May 2015, Judge Moss ruled for Amarin, granting the company’s Motion for Summary Judgment and denying FDA’s Motion for Summary Judgment. In setting aside FDA’s exclusivity decision, Judge Moss wrote:

[FDA’s] ultimate conclusion that Vascepa, a drug “no active ingredient of which . . . has been approved” in a previous NDA, was not entitled to exclusivity, is contrary to the statute’s plain meaning. Rather than explaining this discrepancy, the administrative decision only adds to the problem by emphasizing the divergence between the Agency’s regulatory inquiry and the statutory requirement.  Whether the problems with the FDA’s decision are characterized as failures under Chevron step one, step two, or the APA’s requirement of reasoned decision-making, the Agency’s decision must be set aside.

Judge Moss remanded the matter to FDA for further proceedings consistent with his Opinion.

We won’t repeat all of the facts and circumstances – and the twists and turns – that led up to FDA’s May 31, 2016 Exclusivity Determination. You can refer to our previous posts for that – see here and here.  But in a nutshell, FDA’s rationale for denying NCE exclusivity was 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),” that  FDA approved on November 10, 2004 under NDA 021654.  Specifically, in denying NCE exclusivity for VASCEPA, FDA rejected the “one-to-one” framework and relationship between active ingredient and active moiety traditionally applied when deciphering the active moiety in a drug product.  Instead, for naturally derived mixtures, such as LOVAZA, FDA applied a “one-to-many” approach.  According to FDA, “[i]n 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,  . . . [t]he 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.”  Judge Moss flatly rejected this “one-to-many” approach and FDA’s rationale for it as inconsistent with the statute.  

Going back to the drawing board with Judge Moss’ decision in hand, FDA says that the Agency “reevaluated whether the ‘one-to-many’ or the ‘one-to-one’ framework should be applied to Lovaza to determine whether EPA is an active moiety previously approved in Lovaza,” and thus, whether or not VASCEPA contains an NCE and should be granted 5-year exclusivity.  Upon reevaluation, and given “[m]ultiple factors unique to this matter,” FDA landed on adopting the “one-to-one” framework in this case, and ultimately concludes that EPA was not previously approved. FDA lays out those factors in the May 31, 2016 Exclusivity Determination:

First and foremost, the Agency took into consideration the Court’s Opinion, and, in particular, the Court’s finding that, in light of FDA’s previous decision that the entire mixture is the active ingredient of Lovaza, the application of FDA's exclusivity regulations to Lovaza under the “one-to-many” framework was inconsistent with the statutory language.

Second, the Agency considered its prior active ingredient determination for Lovaza and the reasons underlying it. At the time of approval, FDA determined that the active ingredient of Lovaza was the entire mixture. Also at the time of approval, FDA explicitly rejected the suggestion from Lovaza’s sponsor that Lovaza’s established name should consist of the names “EPAee” and “DHAee,” determining instead that the name “omea-3-acid ethyl esters” would be suitable because it “was designed to correspond to the mixture.”

In addition, in its Lovaza Strength Citizen Petition Response, FDA reaffirmed its conclusion that Lovaza's active ingredient is the entire fish oil mixture.

Third, FDA reviewed previous Agency 5-year NCE exclusivity decisions in the context of naturally derived mixtures and notes again that at least some of those decisions are consistent with the “one-to-one” framework. As the Agency acknowledged in its initial Vascepa exclusivity determination, “the few relevant prior Agency statements and prior actions where FDA considered 5-year NCE exclusivity matters in the context of naturally derived mixtures have not necessarily resulted in consistent outcomes.”  Some of those decisions, however, suggest that the Agency could consider the entire mixture to be both the active ingredient and the active moiety for Lovaza, as it did in the exclusivity determinations for the lung surfactants InfaSurf and Curosurf and for products containing pancrelipase and hyaluronidase.

Fourth, the Agency considered the lack of guidance describing how FDA makes exclusivity determinations for naturally derived mixtures. Prior to the issuance of the Vascepa exclusivity determination, there was no explicitly defined framework for identifying active moieties in the context of naturally derived mixtures for purposes of 5-year NCE exclusivity, nor could one easily be gleaned from the applicable statute, regulations, and precedent.  As discussed above, the statute and regulations do not expressly address 5-year NCE exclusivity in the context of naturally derived mixtures.  In fact, the prior Agency statements and actions regarding this matter were difficult to reconcile. Although guidance is not required before FDA can act, FDA believes the lack of guidance and diversity of practice also counsels in favor of applying the “one-to-one” framework on remand.

Lastly, the Agency considered whether any of the reasons it had provided for declining to adopt the “one-to-one” framework when it previously considered the active moiety for Lovaza bars adopting the “one-to-one” framework for Lovaza now. . . . [J]ust as the Court recognized that FDA is free to determine whether any particular naturally derived mixture is better understood as containing one or multiple active ingredients, so too the Agency believes it has regulatory and scientific discretion to determine whether any particular naturally derived mixture can be described as containing one or multiple active moieties.  Accordingly, as explained in this letter, the Agency has determined, in order to bring the Agency’s decision in harmony with the Court’s Opinion, that the active moiety of Lovaza, a partially characterized mixture, is the entire mixture.

FDA takes great pains to emphasize that the Agency’s May 31, 2016 Exclusivity Determination applies only in the case of LOVAZA/VASCEPA, noting that the ruling is made “under the narrow circumstances of this case” and given the “unique” factors of the matter. Despite FDA’s best efforts, however, creative lawyers will find ways to use Judge Moss’ decision to their benefit when arguing for (or perhaps against) a future FDA exclusivity determination.