FDA Prevails in Otsuka Challenge to Scope of ABILIFY 3-Year Exclusivity, Leaving Intact ARISTADA 505(b)(2) NDA Approval

By Kurt R. Karst –      

Late last week, Judge Ketanji Brown Jackson of the U.S. District Court for the District of Columbia issued a 57-page Memorandum Opinion handing FDA a victory on the scope of 3-year new clinical investigation exclusivity. The decision came in a case initiated last October when Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceuticals Co., Ltd. (collectively “Otsuka”) filed a Complaint challenging FDA’s October 5, 2015 denial of a Citizen Petition (Docket No. FDA-2015-P-2482) submitted by Otsuka and FDA’s approval of Alkermes plc’s (“Alkermes”) 505(b)(2) NDA 207533 for ARISTADA (aripiprazole lauroxil) Extended-release Injectable Suspension notwithstanding unexpired 3-year exclusivity applicable to Otsuka’s ABILIFY MAINTENA (aripiprazole) for Extended-release Injectable Suspension, for Intramuscular Injection (NDA 202971).  ARISTADA is a prodrug of N-hydroxymethyl aripiprazole (and which N-hydroxymethyl aripiprazole is a prodrug of aripiprazole) that FDA approved for the treatment of schizophrenia – the same use for which ABILIFY is approved – and for which a period of 5-year New Chemical Entity Exclusivity was awarded.  In ruling for FDA (and intervenor Alkermes), Judge Jackson granted Motions for Summary Judgment filed by FDA and Alkermes (here and here), and denied Otsuka’s Motion for Summary Judgment (here).

As we previously reported (see our previous posts here and here), Otsuka alleged in its Complaint that FDA violated the FDC Act’s 3-year exclusivity provisions (FDC Act § 505(c)(3)(E)(iii) and (iv), and referred to as “romanette iii” and “romanette iv” in the court’s ruling), the Agency’s regulation governing 3-year exclusivity (21 C.F.R. §§ 314.108(b)(4) and (5)), and the Administrative Procedure Act (“APA”) in approving ARISTADA. All three allegations boil down to a single issue, as the court noted:

What is at issue in the instant case is the scope of the exclusivities that were conferred to Abilify Maintena and its supplement by statute. . . .  In essence, Otsuka maintains that the FDA was plainly prohibited from approving Alkermes’s drug Aristada during the relevant time period, and thus the agency’s authorization of the marketing of Aristada was arbitrary, capricious, and in violation of the law, because the three-year periods of marketing exclusivity that Abilify Maintena and its supplement received under romanettes iii and iv (and their accompanying regulations) were broad enough to block the approval of subsequent drug applications that have the same “conditions of approval.” But the FDA has taken the position that the exclusivity provisions in the FDCA and the agency’s regulations only prohibit approval of a subsequent new drug application that pertains to a drug that has the same active moiety as the drug that received exclusivity, regardless of any overlap with respect to the conditions of approval, and so, the FDA argues, because Aristada and Abilify Maintena have different active moieties, the agency was permitted to approve the Aristada NDA within Abilify Maintena’s exclusivity periods.  [(emphasis in original)]

Applying the familiar deference principles articulated by the U.S. Supreme Court in Chevron, U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837 (1984), and Auer v. Robbins, 519 U.S. 452 (1997), Judge Jackson came down on the side of FDA  and Alkermes for each allegation:

First, the Court concludes that the FDCA’s terms do not unambiguously preclude the FDA from viewing the exclusivity bar as pertaining only to drugs that contain the same active moiety as the drug with exclusivity, and, in fact, the Court finds that the FDA’s interpretation of the FDCA’s exclusivity provisions is entirely reasonable. Furthermore, to the extent that the FDA reads its own implementing regulations in the same way as it has interpreted the pertinent statutory provisions, this Court concludes that the agency’s reading is not plainly erroneous and is entitled to deference. In this same vein, the Court also finds that the agency’s resolution of the regulation’s ambiguity through its active-moiety interpretation is not a “de facto” rulemaking, as Otsuka argues. Consequently, the summary judgment motions that the FDA and Alkermes have submitted must be granted; Otsuka’s motion for summary judgment must be denied; and Otsuka’s claims against the FDA will be dismissed.

Analyzing each allegation separately, Judge Jackson took great pains to parse out the so-called “eligibility” and “bar” clauses of the 3-year exclusivity provisions at FDC Act §§ 505(c)(3)(E)(iii) and (iv). Finding that the provisions are susceptible to “multiple plausible interpretations,” and thus ambiguous with respect to whether or not 3-year exclusivity blocks the approval of a 505(b)(2) NDA for a drug product containing a different active moiety for the same condition of approval as the drug product protected by 3-year exclusivity, Judge Jackson eventually moved on to Chevron Step Two. There, Judge Jackson ruled that the text of FDC Act § 505(c)(3)(E)(iii) (and later FDC Act § 505(c)(3)(E)(iv)) permits  FDA’s “active moiety” interpretation, and that FDA has provided a cogent explanation that is supported by the goals of the FDC Act. 

[I]t makes eminent sense for the FDA to conclude that the scope of the three-year-exclusivity benefit should relate to the particular drug substance that was studied in order to give rise to exclusivity in the first place; indeed, to find otherwise would upset the “careful balance” that Congress struck in the Hatch-Waxman Amendments insofar as it would seemingly permit a drug manufacturer who made investments related to one particular drug substance to prevent the marketing of other drug products and substances that might be safe and effective as treatments for the same or similar conditions.  Nothing in the statutory scheme suggests that Congress intended that result, and in fact, it appears that Congress strongly desired to affect the drug market in precisely the opposite manner.  Thus, an agency interpretation that views romanette iii’s exclusivity as only extending to second-in-time applications for the marketing of drugs that are, in essence, the same as the drug that was previously studied (i.e., those that have the same active moiety) is entirely consistent with the way the statutory scheme was intended to operate and accords fully with the purposes animating Hatch-Waxman.  [(emphasis in original; internal citation omitted)]

Similarly, Judge Jackson found that FDA’s interpretation of the Agency’s 3-year exclusivity regulations at 21 C.F.R. §§ 314.108(b)(4) and (5), which largely mirror the text of FDC Act §§ 505(c)(3)(E)(iii) and (iv), are not plainly erroneous or inconsistent with the text of those regulations.

[T]he regulations clearly permit the agency to employ the same reasoning that it applies when it interprets the statute, which means that “the conditions of approval of the original application” language is permissibly viewed as, in effect, incorporating the nature of the drug in the original application itself. . . . All that the Court has said before with respect to its analysis of romanettes iii and iv applies and leads inexorably to the conclusion that the FDA has not committed plain error or acted inconsistently with its regulations, and indeed, the fact that these regulations involve “a complex and highly technical regulatory program, in which the identification and classification of relevant criteria necessarily require significant expertise and entail the exercise of judgment grounded in policy concerns” makes deference to the FDA’s interpretation “all the more warranted[.]”  These ambiguous regulations do not preclude the conclusion that an active-moiety overlap is needed in order for a second-in-time application to be “for” the “conditions of approval” of an earlier NDA regarding a drug, or “for” a “change approved” in a supplement regarding a drug with exclusivity.  [(internal citation omitted)]

Having ruled for FDA on Otsuka’s first two allegations, it was relatively easy for Judge Jackson to dispense with the third allegation. (In fact, Judge Jackson wrote that the “final claim can be resolved in mercifully short order.”)  “[T]his Court’s prior rejection of Otsuka’s argument that the three-year exclusivity regulations have an unambiguous meaning that foreclosed the FDA’s “active moiety” interpretation and consequent approval of Aristada, also compels the rejection of Otsuka’s contention that the FDA transgressed the APA by improperly ‘amending’ an unambiguous regulation,” wrote Judge Jackson. 

As we’ve noted before, disputes concerning the metes and bounds of 3-year exclusivity have been plentiful over the past few years. And we may very well see more in the months and years ahead as the countours of the statutory 3-year exclusivity provisions are further elucidated through approvals, exclusivity determinations (particularly in the context of abuse-deterrent drug products), and in guidance that FDA is expected to issue, tentatively titled “Three-Year Exclusivity Determinations for Drug Products.”  And while there may be plenty to argue about in the shades of gray, Judge Jackson’s opinion seems to be one clear bookend on the scope of 3-year exclusivity: in order for 3-year exclusivity to have an effect against a competitor’s product, both drug products must share the same conditions of approval and share an active moiety.