Otsuka Sues FDA Over “Corrected” ABILIFY Approval; Alleges Violation of the Most Fundamental Precept of FDA’s Statutory Drug Approval Authority

By Kurt R. Karst –   

Does FDA has the authority to approve a new indication for an approved drug when that new indication has not been shown to be safe and effective by adequate and well-controlled studies submitted by the sponsor of the application?  And under what circumstances can FDA omit from generic drug labeling protected pediatric information included in the labeling of a Reference Listed Drug approved for multiple indications?

Those are the two core questions posed in a lawsuit Otsuka Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Development & Commercialization, Inc., and Otsuka America Pharmaceutical, Inc. (collectively, “Otsuka”) filed earlier this week against FDA in the U.S. District Court for the District of Maryland concerning the atypical antipsychotic blockbuster drug ABILIFY (aripiprazole).  ABILIFY is approved under several NDAs (NDA 021436, NDA 021713, NDA 021729, and NDA 021866) in various dosage forms (tablets, oral solution, orally disintegrating tablets, and injection) for:

1. the treatment of schizophrenia;
2. the acute treatment of manic and mixed episodes associated with bipolar I disorder;
3. the maintenance treatment of bipolar I disorder;
4. use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder;
5. the treatment of irritability associated with autistic disorder;
6. the acute treatment of agitation associated with schizophrenia or bipolar disorder (manic or mixed); and . . . most recently and most importantly for the issues at hand . . .
7. the treatment of Tourette’s disorder (or is it, as discussed below, the treatment of pediatric patients with Tourette’s Disorder?). 

Each version of ABILIFY is listed in the Orange Book with several patents expiring years from now; however, it was widely expected that FDA might approve ANDAs for generic versions of ABILIFY come April 20, 2015 when the period of pediatric exclusivity associated with U.S. Patent No. 5,006,528 (listed in the Orange Book as a drug product, drug substance, and method-of-use patent) expires.  But that shouldn’t happen says Otsuka in the company’s March 24, 2015 Complaint and Motion for Summary Judgment.  And a decision needs to be made soon to avoid irreparable harm, according to Otsuka’s Motion to Expedite the court proceedings. 

By way of background – and we’ll try to keep things as simple as possible (ha-ha!) – FDA, on January 25, 2006, designated Otsuka’s ABILIFY as an orphan drug for the “[t]reatment of Tourette’s syndrome.”  Meanwhile, Otsuka conducted Phase 3 clinical trials of aripiprazole in pediatric patients with Tourette’s Disorder demonstrating that the drug is safe and effective for use in pediatric patients.  In February 2014, Otsuka submitted Supplemental NDAs to FDA seeking approval for the treatment of pediatric patients with Tourette’s Disorder.  On December 12, 2014, FDA approved the Supplemental NDAs stating, among other things, that “[t]hese ‘Prior Approval’ supplemental new drug applications provide for labeling revisions based upon two adequate and well-controlled trials that demonstrate the efficacy for the new indication in pediatric patients with Tourette’s Disorder.”  Not long after that, FDA’s Orphan Drug Designations and Approvals database was updated to show the “Orphan Approval Status” as “Approved for Orphan Indication,” and the “Approved Labeled Indication” as “Treatment of pediatric patients with Tourette’s.”  FDA’s Orange Book (Cumulative Supplement No. 2, Feb. 2015) was then updated to reflect the addition of a period of orphan drug exclusivity expiring on December 12, 2021.      

So far, so good; just the typical approval and outcome you’d expect.  But then things got interesting. . . really interesting . . . .   

As stated in Otsuka’s court filing:

Counsel for Otsuka thereafter wrote to FDA’s Chief Counsel setting forth the company’s position that FDA’s approval of Abilify of an orphan indication for treatment of pediatric patients with Tourette’s Disorder meant that FDA was precluded from approving an ANDA for a generic version of Abilify for any indication pending the expiration of Otsuka’s statutory seven-year period of orphan drug market exclusivity for the new indication.  Id. ¶ 22, Att. E.  As counsel’s letter explained, none of the narrow exceptions to the general “same labeling rule” that requires generic drugs to contain the same information on their labels as their respective brand-name predicate (or reference listed) drug were applicable and, therefore, the general “same labeling rule” controlled.  Id. Att. E. [(Emphasis added; copies of the various attachments referenced are available here.)]

The position set forth by Otsuka’s counsel concerns FDC Act § 505A(o), which is part of the Best Pharmaceuticals for Children Act.  The provision, titled “Prompt approval of drugs under section 355(j) when pediatric information is added to labeling,” states:

(1) General rule – A drug for which an application has been submitted or approved under section 355(j) of this title shall not be considered ineligible for approval under that section or misbranded under section 352 of this title on the basis that the labeling of the drug omits a pediatric indication or any other aspect of labeling pertaining to pediatric use when the omitted indication or other aspect is protected by patent or by exclusivity under clause (iii) or (iv) of section 355(j)(5)(F) of this title.

(2) Labeling – Notwithstanding clauses (iii) and (iv) of section 355(j)(5)(F) of this title [(concerning 3-year new clinical investigation exclusivity)0, the Secretary may require that the labeling of a drug approved under section 355(j) of this title that omits a pediatric indication or other aspect of labeling as described in paragraph (1) include—

(A) a statement that, because of marketing exclusivity for a manufacturer—

(i) the drug is not labeled for pediatric use; or

(ii) in the case of a drug for which there is an additional pediatric use not referred to in paragraph (1), the drug is not labeled for the pediatric use under paragraph (1); and

(B) a statement of any appropriate pediatric contraindications, warnings, or precautions that the Secretary considers necessary.

This section of the law has come up in the past.  It has been used as a basis to delay approval of competing products until the expiration of exclusivity (see here), but it also facilitated ANDA approvals with pediatric information (e.g., sildenafil).

According to Otsuka, because FDC Act § 505A(o) refers only to protected pediatric labeling information protected by patent or 3-year exclusivity, “[t]he statute undeniably does not allow the omission of pediatric information protected by orphan drug exclusivity, which is granted pursuant to Section 527 of the FDCA (21 U.S.C. § 360cc).”

After receiving the above-referenced correspondence from Otsuka’s counsel, FDA changed course, alleges Otsuka, for an “improper extra-legal reason”: to prevent a result that would bar generic competition.  According to Otsuka:

On February 24, 2015, FDA sent Otsuka a letter, informing Otsuka that “as the first sponsor of [aripiprazole] to obtain marketing approval for this indication, [Otsuka] is entitled to seven years of orphan-drug exclusive approval . . . for treatment of Tourette’s disorder.”  Id. ¶ 23, Att. F.  That same day, FDA sent Otsuka a “corrected” approval letter, in which FDA went further and, without explanation or elaboration, advised that its earlier December 12, 2014, approval letter “contained an error in the ‘indications’ section,” an “error” FDA purported to change unilaterally by changing (broadening) the approved indication from treatment “in pediatric patients with Tourette’s Disorder” to treatment of “patients with Tourette’s Disorder.”  Id. ¶ 23, Att. A. [(Emphasis in original)]

Feeling forced into a corner, and with the threat of generic competition right around the corner, Otsuka sued, alleging violations of the Administrative Procedure Act (“APA”) and the FDC Act by FDA stemming from the Agency’s “corrected” approval.  Specifically, Otsuka alleges first that FDA violated the APA by abusing its discretion and by acting in an arbitrary and capricious manner that is contrary to the law when the Agency reversed its original approval decision:

This claim rests firmly on three closely related contentions.  First, when FDA approved a broader indication that that which Otsuka requested and when this broader indication was not supported by Otsuka’s adequate and well-controlled studies, FDA acted well outside its authority under the FDCA.  Second, FDA’s broadened approval is arbitrary and capricious because it is without factual or evidentiary support.  Otsuka conducted clinical trials with pediatric patients only and FDA does not conduct its own independent clinical trials to determine the safety and efficacy of a requested new indication.  Third, FDA “corrected” and broadened its original approval for a legally impermissible reason. FDA’s “corrected” its decision for reasons altogether unrelated and extraneous to the proper use of Abilify in the treatment of Tourette’s Disorder. Instead of operating within the boundaries of the FDCA’s approval provisions, FDA acted – and improperly so – in an effort to seek to deny Otsuka the rights and benefits to which it is entitled under the Orphan Drug Act.

Otsuka’s first contention is particularly interesting to us.  Indeed, we’ve seen at least one recent instance in which FDA decided on its own to broaden the indication for a drug over the objection of the NDA sponsor.  That happened with the August 13, 2013 approval of NDA 204308 for EPANED (enalapril) for oral solution, 1 mg/mL, for the treatment of hypertension (see here). The sponsor had pursued approval (and obtained orphan drug designation) for the treatment of hypertension in pediatric patients; however, FDA refused to approve the drug for anything less that treatment of hypertension in adults and children. 

Otsuka, in Count Two of the company’s Complaint, assumes (without conceding) the validity of FDA’s “corrected” (and broadened) approval and alleges that FDA is precluded from approving any generic versions of ABILIFY on April 20, 2015 based on FDC Act § 505A(o) and the fact that ABILIFY’s labeling is “loaded with pediatric information.”  “FDA is barred from omitting from the generic’s label the ample and multiple pediatric references in the FDA-approved Abilify label for the broadened population at large indication,” says Otsuka.  “Those references are protected by orphan drug exclusivity, and pediatric information pertaining to orphan drug exclusivity is not a category of information that Congress permitted to be omitted.”

Given the intense interest in the drug and what is likely a long line of ANDA applicants for generic ABILIFY, we’ll probably see some interventions in the case.  A conference call between the parties and the court was held on Wednesday, March 25, 2015 at 3:00 PM.  Afterwards, the court issued a Scheduling Order setting a hearing on April 14, 2015 at 10:00 AM for Otsuka's Motion for Summary Judgment and any cross-motions.