All For One and One For All? NOPE! Court Rejects FDA’s “One-to-Many” Complex Mixture NCE Exclusivity Decision on VASCEPA; Remands to FDA For Further Proceedings

May 29, 2015

By Kurt R. Karst

[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.

That’s the bottom line in a 40-page decision handed down by Judge Randolph D. Moss of the U.S. District Court for the District of Columbia on May 28, 2015 in a lawsuit lodged by Amarin Pharmaceuticals Ireland Limited (“Amarin”) against FDA on February 27, 2014 challenging the Agency’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 5-year New Chemical Entity (“NCE”) exclusivity.

In ruling for Amarin, Judge Moss granted Amarin’s Motion for Summary Judgment and denied FDA’s Cross-Motion for Summary Judgment.  (Amarin’s Reply/Opposition Brief and a Supplemental Submission from FDA are available here and here.)  (As an aside, Amarin is also challenging FDA in court over the company’s First Amendment right to distribute information about unapproved uses of VASCEPA – see here.)

As we previously reported, FDA’s rationale for denying NCE exclusivity for VASCEPA – and instead granting a period of 3-year new clinical investigation 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).”  More specifically, FDA ruled that:

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’s Exclusivity Determination then laid 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.

This 3-part test did not sit well with Judge Moss, however, who says in his Opinion under a Chevron Step One analysis that FDA’s test “suffers from at least three difficulties”:

First, the contention that “active ingredient” means “active moiety” is at odds with the canon against surplusage. . . .  If “active ingredient” means “active moiety,” and “active moiety” is defined as a molecule excluding (among other things) those portions that render the molecule a salt or an ester, 21 C.F.R. § 314.108(a), there are no circumstances in which the parenthetical clause would have any coherent meaning. . . .  The statutory provision includes two references to the term “active ingredient.”  Defining either to mean “active moiety” would render the statute incoherent; reading both to mean “active moiety”—as required to maintain any semblance of consistency in statutory interpretation—results in a mind-numbing muddle.

The second problem with the Agency’s interpretation is that it requires the Agency to interpret the phrase “active ingredient” differently for purposes of the ANDA and exclusivity provisions of the Act. . . .  Absent good reason, it is safe to assume that Congress intended “active ingredient” to have the same meaning when it used that term in different, but closely related, places in the same statute. . . .  [FDA] argues before this Court that the exclusivity and ANDA provisions serve different purposes, because the exclusivity provision is designed to promote novelty while the ANDA provisions require the FDA to ascertain whether generic drugs are safe and effective.  But . . . while the two provisions do, of course, play different roles, they are part of a unified statutory scheme intended to strike a balance between fostering innovation and promoting access to affordable medications.

The third (and related) difficulty with the Agency’s approach is that its focus on a drug component that was never the subject of the FDA’s approval is also inconsistent with the statutory text, which considers whether the new drug contains an “active ingredient” “which has been approved in [a prior] application.”  21 U.S.C. §§ 355(c)(3)(E)(ii), 355(j)(5)(F)(ii) (emphasis added).  Under the FDA’s approach, the relevant “active moieties” are not even identified until the Agency acts on an application for exclusivity. . . .  The FDA’s approach fails to make temporal or substantive sense of the statutory reference to an “active ingredient” “which has been approved,” and thus, once again, is at odds with the statute.  [(Emphasis in original)]

Although Judge Moss could have ended his analysis at Chevron Step One, he continued on to Step Two, writing that FDA’s interpretation also fails there:

Focusing on the analysis actually contained in the FDA’s administrative decision, as opposed to the arguments made by counsel, it is apparent that the decision is both procedurally and substantively flawed.  Most notably, the administrative decision does not offer—or even attempt—any reasoned explanation for how its application of the regulatory focus on “active moiety” can be reconciled with the statutory focus on “active ingredient.” To the contrary, the decision affirmatively embraces the notion that “active ingredient” and “active moiety” have different meanings. . . .  The decision thus concedes that Vascepa’s “active ingredient”—EPA—is not an “active ingredient” in Lovaza . . . but because it concluded that EPA is an “active moiety” in both Vascepa and in Lovaza’s single-active-ingredient mixture, it denies exclusivity. 

The decision’s sole acknowledgment of the apparent divergence between the statutory and regulatory inquiries is both minimal and confounding.  In the course of its 24-page, single spaced administrative decision, the FDA refers to the statutory text only twice—in a background recitation of the governing legal framework, and in a parenthetical in a footnote.  [(Emphasis in original)]

With respect to that footnote – footnote 31, which quotes from FDA’s 1994 Final Rule promulgating, among other things, regulations governing 5-year NCE exclusivity – Judge Moss says that it conflicts with other portions of FDA’s February 21, 2014 Exclusivity Determination: “[A]lthough the footnote appears to treat the phrases ‘active ingredient’ and ‘active moiety’ as synonymous for purposes of the five-year exclusivity determination, the remainder of the [Exclusivity Determination] is emphatic in concluding that the terms have distinct meanings, at least in the context of naturally derived mixtures.”

Moreover, writes Judge Moss:

[A]lthough an administrative decision can rely on an agency’s prior consideration of an issue, the FDA has never addressed why the phrase “active ingredient” should be given different meanings in different provisions of the Act, let alone explained how the regulatory focus on “active moiety” can apply where the “active ingredient” and “active moiety” refer to different substances.  The Agency makes no attempt to explain how its approach furthers Congress’s purposes or is otherwise a reasonable policy choice, especially in light of the clear interest in providing notice to potential innovators of the exclusivity to which they might eventually be entitled.  And the FDA’s regulations do not provide any further gloss on this point.  The decision to identify a mixture’s “active moiety” based on information available at the time the FDA evaluates a subsequent drug’s request for exclusivity, rather than at the time drug was “approved,” is similarly unexplained, and . . . runs counter to the exclusivity provision’s purpose of incentivizing innovation.

The decision from Judge Moss ends a winning streak for FDA on legal challenges involving Hatch-Waxman matters, which we posted on earlier today.

Amarin commented in a press release that the company “believes based on the court's ruling that Vascepa is entitled to five-year marketing exclusivity starting from FDA's approval of Vascepa in July 2012, thus extending NCE exclusivity through July 25, 2017.”  The ruling also confirms, said Amarin, “that acceptance by FDA of [ANDAs] for generic versions of Vascepa is not permitted until July 2016.  The related statutory 30-month stay triggered by patent litigation following generic application resubmissions in July 2016 would then expire in January 2020.”  According to FDA's Paragraph IV Certifications List, the first ANDA submitted to FDA containing a Paragraph IV certification was received as of January 15, 2013.  FDA has 60 days to file an appeal to the U.S. Court of Appeals for the District of Columbia Circuit.