FDA Rules on the Scope of ABILIFY 3-Year Exclusivity and Approves ARISTADA With NCE Exclusivity

By Kurt R. Karst –

Hatch-Waxman controversies are often like trains barreling down railroad tracks.  They first appear in the distance as small objects, seemingly moving at a slow velocity.  But with each passing moment, the object grows larger and more distinct, and appears to pick up speed.  Finally, the train is upon you and we’re in the middle of litigation.  Take, for example, FDA’s February 2009 decision to invoke the Agency’s Application Integrity Policy (“AIP”) against Ranbaxy’s Paonta Sahib, India manufacturing facility, and the Consent Decree Ranbaxy entered into with FDA in January 2012.  The AIP affected several pending Ranbaxy ANDAs, and the Consent Decree identified some ANDAs for which Ranbaxy risked losing (forfeiting) eligibility for 180-day exclusivity.  At the time of the AIP in 2009, and later in 2012 with the Consent Decree, it seemed inevitable that FDA would be dragged into court over 180-day exclusivity for at least one Ranbaxy ANDA affected by the company’s compliance woes.  In fact, FDA was sued multiple times over several ANDAs (see our previous posts here, here, here, and here).  

Although we’re not yet (to our knowledge) at the point of litigation, FDA’s October 5, 2015 approval of Alkermes plc’s (“Alkermes”) 505(b)(2) NDA 207533 for ARISTADA (aripiprazole lauroxil) Extended-elease Injectable Suspension, a prodrug of N-hydroxymethyl aripiprazole (and which N-hydroxymethyl aripiprazole is a prodrug of aripiprazole), for the treatment of schizophrenia may very well end up in court.  Accompanying the approval of ARISTADA is FDA’s 31-page denial of a July 13, 2015 Citizen Petition (Docket No. FDA-2015-P-2482) submitted on behalf of Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceuticals Co., Ltd. (collectively “Otsuka”) that primarily concerns the scope of 3-year exclusivity. 

Otsuka is the sponsor of several NDAs for aripiprazole drug products marketed under the proprietary name ABILIFY.  The Orange Book lists three unexpired periods of non-patent exclusivity for ABILIFY Tablets, ABILIFY Oral Solution, ABILIFY DISCMELT Orally Disintegrating Tablets, and ABILIFY Injection, which expire on December 12, 2021 (orphan drug exclusivity), December 12, 2017 (concerning treatment of pediatric patients with Tourette’s Disorder), and June 9, 2017 (concerning labeling revisions relative to a study in pediatric patient with irritability associated with autistic disorder).  Another ABILIFY product, ABILIFY MAINTENA, is listed in the Orange Book with two unexpired periods of 3-year exclusivity expiring on February 28, 2016 (new dosage form) and December 5, 2017 (identified in an Orange Book addendum as “addition of the results of a controlled clinical study treating adult patients with schizophrenia experiencing an acute relapse”). 

Otsuka has already shown a willingness to protect the ABILIFY estate in court with a lawsuit – ultimately unsuccessful – filed against FDA earlier this year after the Agency approved ANDAs for generic aripiprazole drug products notwithstanding unexpired periods of exclusivity for ABILIFY (see our previous post here).  For the past several months we’ve watched the volley of comments from Otsuka and Alkermes as they debated the scope of ABILIFY’s 3-year exclusivity vis-à-vis ARISTADA.  Of course, the recent decision from the U.S. District Court for the District of Columbia in Veloxis Pharmaceuticals, Inc. v. FDA, No. 14-cv-2126, 2015 U.S. Dist. LEXIS 77559 (D.D.C. June 12, 2015), concerning the scope of 3-year exclusivity (see our previous post here) has played a central role in the debate.  As in the Veloxis case, the ARISTADA 505(b)(2) NDA does not cite as a listed drug the particular drug product covered by 3-year exclusivity and the scope of which is alleged to extend to  a second-in-time 505(b)(2) NDA (rather, the ARISTADA 505(b)(2) cites a different Otsuka aripiprazole drug product as its listed drug).  Other FDA letter decisions related to the Veloxis decision and an exclusivity decision we posted on this blog concerning FDA’s rationale for granting exclusivity for abuse-deterrent OXYCONTIN (see our previous post here) have also popped up in comments to Otsuka’s Citizen Petition.

Otsuka’s July 2015 Citizen Petiton requests that FDA delay or withhold final approval of NDA 207533 for ARISTADA “at least until Otsuka’s 3-year exclusivity for the conditions of approval of aripiprazole expires on December 5, 2017.”  Otsuka also requests that FDA refuse to approve NDA 207533 in its entirety because it “does not satisfy the substantial evidence of effectiveness requirement prescribed in section 505(b)(1)(A)” of the FDC Act insofar as the ARISTADA NDA “is supported with only one adequate and well-controlled clinical trial . . . of the drug (aripiprazole lauroxil) for which Alkermes seeks approval.”   This second request was the subject of a September 9, 2014 Otsuka Citizen Petition (Docket No. FDA-2014-P-1354) that FDA denied without comment in February 2015. 

Before delving into the issues raised in Otsuka’s Citizen Petition, FDA first provides a rather detailed (and helpful) analysis of ARISTADA and the eligibility of the 505(b)(2) NDA drugh product for New Chemical Entity (“NCE”) exclusivity.  According to FDA:

Aripiprazole lauroxil is an ester ofN-hydroxymethyl aripiprazole, and not an ester of aripiprazole.  N-hydroxymethyl aripiprazole differs from aripiprazole because of the addition of a hydroxymethyl group, connected by a covalent C-N bond.  Because the Agency excludes the ester-bonded portion of the drug substance for the active moiety determination, the active moiety of aripiprazole lauroxil is N-hydroxymethyl aripiprazole.  Under FDA's “structure-based” approach for determining the active moiety, because of the covalent, non-ester C-N bond, FDA includes the hydroxymethyl group in determining the active moiety of aripiprazole lauroxil, even though that bond is eventually hydrolyzed in the body to yield aripiprazole.  Therefore, N-hydroxymethyl aripiprazole is the active moiety of aripiprazole lauroxil.  Furthermore, N-hydroxymethyl aripiprazole has not been approved by FDA in any other application submitted under section 505(b) of the FD&C Act.  Therefore, Aristada contains an NCE entitled to 5-year NCE exclusivity, which will expire in 2020.

With that, FDA moves to the primary question raised in Otsuka’s Citizen Petition: whether the periods of 3-year exclusivity for ABILIFY MAINTENA block the approval of the 505(b)(2) NDA for ARISTADA “(1) even though the NDAs are for different active ingredients (aripiprazole versus aripiprazole lauroxil) and different active moieties (aripiprazole versus N-hydroxymethyl aripiprazole) and (2) even though Aristada includes an NCE and has earned its own period of 5-year NCE exclusivity.”  Otsuka contends that the conditions of approval for which ABILIFY MAINTENA received 3-year exclusivity overlap with the conditions of approval sought for ARISTADA, and asserts that the scope of 3-year exclusivity for ABILIFY MAINTENA is for “long-acting, monthly injectable formulations of aripiprazole for the treatment of schizophrenia with conditions of approval for both maintenance and acutely relapsing patients,” thereby blocking approval of the NCE exclusivity-qualifying ARISTADA NDA.

The answer to the question above is simple, says FDA: the ARISTADA approval cannot be blocked by 3-year exclusivity applicable to ABILIFY because the drug products contain different active moieties.  According to FDA:

In general, if Abilify Maintena and Aristada contained the same active moiety, FDA would begin its analysis, as the Agency did in the Veloxis Letter, with the nature of the innovation in the Abilify Maintena NDA and supplement and would determine which clinical studies were the new clinical investigations essential to approval of the NDA or supplement with exclusivity.  However, because the scope of the 3-year exclusivities for Abilify Maintena, like the scope of any 3-year exclusivity, is tied to the active moiety of Abilify Maintena and because Aristada contains a different active moiety than Abilify Maintena, FDA concludes that approval of the Aristada NDA is not blocked.  To determine whether approval of Aristada is blocked, the Agency need not examine the other details of the new clinical investigations essential to the approval of Abilify Maintena; nor does it need to determine the extent to which Abilify Maintena’s exclusivities would block a different product that contains aripiprazole as an active moiety.   

FDA goes on to explain why the Agency believes its decision on the scope of ABILIFY’s 3-year exclusivity is consistent with the Agency’s interpretation of the statutory phrase “conditions of approval of such drug in the approved subsection (b) application” concerning 3-year exclusivity, as articulated in the Veloxis Letter Decision and elsewhere.  “If FDA were to take the position that 3-year exclusivity described in section 505(c)(3)(E)(iii) or 505(c)(3)(E)(iv) of the FD&C Act could block approval not only of drugs containing the same  active moiety as the product with exclusivity but also of drugs containing a different active moiety, the scope of 3-year exclusivity would be broader than the scope of 5-year NCE exclusivity in section 505(c)(3)(E)(ii),” writes FDA.  “Thus, the 3-year exclusivity for Abilify Maintena could block approval of Aristada, whereas the 5-year NCE exclusivity of an Abilify product could not block approval of Aristada.”  That result would be inconsistent with FDA precedent and the Hatch-waxman Amendments, explains FDA:

Under the result for Aristada urged by Otsuka, the 3-year exclusivity granted to any drug in a 505(b) NDA could potentially block the approval of any other later-in-time 505(b)(2) NDA as long as the two products shared certain conditions of approval.  The two products would not need to share an active moiety or even be in the same chemical class of compounds.  FDA rejects this approach because, among other things, it would extend the scope of 3-year exclusivity in a manner that would upset the balance Congress intended.  Such an outcome could hinder the availability of therapeutic alternatives and discourage or delay the development of innovative new drugs.

FDA also explains why the Agency is hesitant to go down the rabbit hole of evaluating “end metabolites” for exclusivity purposes.  “Assuming that FDA were to limit the inquiry for determining possible blocking exclusivities to products that share active metabolites, this inquiry would also pose difficult and potentially insurmountable challenges from a regulatory and scientific standpoint,” writes FDA. 

Metabolites are formed after a drug product is ingested, and frequently different metabolites are formed at different stages of bioconversion. . . .  In some cases, such as that of aripiprazole lauroxil, one or more of the metabolites (e.g., N-hydroxymethyl aripiprazole) is further converted into a different metabolite (e.g., aripiprazole).  In still other instances, many metabolites are formed after a drug product is ingested.  This raises the complex question of which metabolite would be relevant for exclusivity purposes (e.g., those created after the first stage of bioconversion, those created after subsequent stages of bioconversion, or all metabolites).  Furthermore, in many cases, it may not be possible from a scientific perspective to identify all of the metabolites and their relative activity at the time of drug approval. . . .  FDA has adopted an approach focusing on the drug’s chemical structure that can be applied consistently with scientific rigor across drug products.

Moving on to Otsuka’s argument that FDA cannot approve a 505(b)(2) NDA for an NCE that is supported by a single adequate and well-controlled clinical trial and that relies on the Agency’s findings of safety and effectiveness for a listed drug, FDA says that this argument is without merit.  “[A] 505(b )(2) NDA, like a stand-alone NDA, is approved under [FDC Act § 505(c)] and must meet the ‘full reports’ requirement in section 505(b)(1)(A).  The difference between a 505(b)(2) NDA and a stand-alone NDA is the source of information relied on for approval,” writes FDA.  “Alkermes conducted a single adequate and well-controlled clinical trial and bridged to the findings of safety and effectiveness for Abilify (aripiprazole) Tablets (NDA 021436) to support approval of its 505(b)(2) NDA for Aristada.  FDA has determined that Alkermes has provided substantial evidence that Aristada is effective under the conditions of use prescribed, recommended, or suggested in the drug’s labeling.”  Indeed, as FDA points out in the petition decision, there are several instances where FDA has approved 505(b)(2) NDAs for NCEs that rely on the Agency’s findings of safety and effectiveness for a previously approved drug.

We’ll be closely watching the various court dockets over the next few days to see if the the Hatch-Waxman train once again barrels into court, this time with a challenge to FDA’s ARISTADA approval and Citizen Petition decisions.  As always, we’ll keep you updated.