DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21-436
`
`Otsuka Pharmaceutical Co., Ltd.
`Attention: Gary Ingenito, M.D., Ph.D.
`President and Chief Operating Officer
`2440 Research Boulevard
`Rockville, MD 20850
`
`Dear Dr. Ingenito:
`
`Please refer to your new drug application (NDA) dated and received October 31, 2001, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Abilify (aripiprazole) 2, 5, 10,
`15, 20 and 30 mg Tablets
`
`We acknowledge receipt of your submissions of September 18, October 8, and October 16, 2002.
`
`Your submission of September 18, 2002 constituted a complete response to our action letter of August
`29, 2002.
`
`This new drug application provides for the use of Abilify (aripiprazole) tablets for the treatment of
`schizophrenia.
`
`We have completed our review of this application, as amended. It is approved, effective on the date of
`this letter, for use as recommended in the agreed-upon labeling text.
`
`We note your agreement to the attached labeling as well as the Phase 4 commitments and their
`corresponding time frame completion dates in an e-mail communication dated November 7, 2002.
`
`The final printed labeling (FPL) must be identical to the attached labeling (text for the package insert).
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. For administrative purposes, designate this
`submission “FPL for approved NDA 21-436.” Approval of this submission by FDA is not required
`before the labeling is used.
`
`We remind you of your agreed-upon commitments of September 28, and November 7, 2002, to
`conduct the following postmarketing studies:
`
`
`
`Page 1 of 5
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`OTSUKA EXHIBIT 2007
`ALKERMES v. OTSUKA
`IPR2017-00287
`
`

`

`NDA 21-436
`Page 2
`
`1.
`
`A food effect study on the highest strength (30 mg).
`
`Protocol Submission: Within 2 months of the date of this letter
`Study Start: Within 4 months of the date of this letter
`Final Report Submission: Within 15 months of the date of this letter
`
`We acknowledge that this timeline assumes that there is no need for Agency feedback on the
`protocol (standard food effect design will be employed) and that the 30 mg strength is tolerated
`by healthy volunteers. If this strength is not tolerated by healthy volunteers resulting in the
`need to conduct this study in schizophrenics, the timeline will be impacted and need to be re-
`negotiated with the Agency.
`
`2.
`
`Studies to determine whether or not doses lower than 10 mg are effective.
`
`Within 6 months of the date of this letter
`Protocol Submission:
`Within 12 months of the date of this letter
`Study Start:
`Final Report Submission: Within 42 months of the date of this letter
`
`This timeline incorporates 2 months for Agency review of the design of the protocol. If this
`study demonstrates that lower doses are effective in the treatment of schizophrenia, the results
`should be submitted to the NDA in the form of an efficacy supplement.
`
`3.
`
`Studies to further characterize (e.g., reversibility, functional correlates) and, if possible, to
`determine the mechanism(s) underlying the retinal degeneration observed in the 26-week and
`2-year carcinogenicity studies in Sprague-Dawley rat.
`
`Within 5 months of the date of this letter
`Protocol Submission:
`Within 8 months of the date of this letter
`Study Start:
`Final Report Submission: Within 42 months of the date of this letter
`
`Since the retinal lesion observed in (b)--------------r Sprague-Dawley (SD) albino rats
`administered high doses of aripiprazole has morphologic features characteristic of light-induced
`retinopathy, it is critical that the potential for aripiprazole-related ocular changes be
`investigated in a pigmented rat strain that is less susceptible to light-induced retinal
`degeneration to rule out a direct effect of drug. Therefore, a one-month oral tolerability and
`toxicokinetic study in female (b)------------------ rats will be initiated in November, 2002 to
`determine the suitability of this pigmented rat strain for studying the pathogenesis of the retinal
`degeneration in SD rats. If the clinical tolerability and systemic exposure to aripiprazole in (b
`rats are comparable to that observed in Sprague-Dawley rats at doses resulting in re)--al
`changes, then a draft protocol for the definitive study evaluating the functional consequences,
`reversibility, and pathogenesis of retinal degeneration will be submitted within 5 months of the
`approval letter. If clinical tolerability or systemic exposure to aripiprazole is lower in (b rats
`than in SD rats at comparable doses, then an additional TK/tolerability study in alternate strains
`of pigmented rats will be conducted prior to initiation of the definitive study. We acknowledge
`that this additional pilot study will add approximately 3 to 4 months to the timeline for protocol
`submission, study start, and final report dates each.
`
`
`
`Page 2 of 5
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`

`

`NDA 21-436
`Page 3
`
`4.
`
`Studies investigating the abuse liability of aripiprazole.
`
`N/A
`Protocol Submission:
`July 22, 2002
`Study Start:
`Final Report Submission: Within 5 months of the date of this letter
`
`We acknowledge that you are currently conducting an abuse liability study in monkeys in
`Japan. The timeline above incorporates roughly 2 months needed to translate the protocol into
`English.
`
`5.
`
`Submit the results of Study 138047 to address the longer-term efficacy of aripiprazole in the
`treatment of adults with schizophrenia.
`
`We acknowledge that this study has already been completed and that the safety data were
`reported as part of the 120 Day Safety Update. However, a formal submission of the results of
`this study will be submitted within 30 days of the date of the approval letter. This submission
`should be submitted to the NDA as an efficacy supplement.
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under 21
`CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to this NDA. The status summary should include expected
`summary completion and final report submission dates, any changes in plans since the last annual
`report, and, for clinical studies, number of patients entered into each study. All submissions, including
`supplements, relating to these postmarketing study commitments must be prominently labeled
`“Postmarketing Study Protocol”, “Postmarketing Study Final Report”, or “Postmarketing Study
`Correspondence.”
`
`The text in italics below addresses the application of FDA's Pediatric Rule at [21 CFR 314.55/21 CFR
`601.27] to this NDA. The Pediatric Rule has been challenged in court. On October 17, 2002, the court
`ruled that FDA did not have the authority to issue the Pediatric Rule and has barred FDA from
`enforcing it. The government has not yet decided whether to seek a stay of the court's order. In
`addition, the government has not yet decided whether to appeal the decision; an appeal must be filed
`within 60 days. Therefore, this letter contains a description of the pediatric studies that would be
`required under the Pediatric Rule, if the Pediatric Rule remained in effect and/or were upheld
`on appeal. Please be aware that whether or not these pediatric studies will be required will depend
`upon the resolution of the litigation. FDA will notify you as soon as possible as to whether this
`application will be subject to the requirements of the Pediatric Rule as described below. In any event,
`we hope you will decide to conduct these pediatric studies to provide important information on the safe
`and effective use of this drug in the relevant pediatric populations.
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens must contain an assessment of the safety and effectiveness of
`the product in pediatric patients unless this requirement is waived or deferred (21 CFR 314.55).
`
`Based on information submitted, we are deferring submission of pediatric studies until January 1,
`2007.
`
`
`
`Page 3 of 5
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`

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`NDA 21-436
`Page 4
`
`The pediatric exclusivity provisions of FDAMA as reauthorized by the Best Pharmaceuticals for
`Children Act are not affected by the court's ruling. Pediatric studies conducted under the terms of
`section 505A of the Federal Food, Drug, and Cosmetic Act may result in additional marketing
`exclusivity for certain products (pediatric exclusivity). You should refer to the Guidance for Industry
`on Qualifying for Pediatric Exclusivity (available on our web site at www.fda.gov/cder/pediatric) for
`details. If you wish to qualify for pediatric exclusivity you should submit a "Proposed Pediatric Study
`Request". FDA generally does not consider studies submitted to an NDA before issuance of a Written
`Request as responsive to the Written Request. Applicants should obtain a Written Request before
`submitting pediatric studies to an NDA.
`
`Please note that we have approved an expiration date of 24 months for all strengths of this drug
`product.
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to
`this division and two copies of both the promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`
`Validation of the regulatory methods has not been completed. At the present time, it is the policy of
`the Center not to withhold approval because the methods are being validated. Nevertheless, we expect
`your continued cooperation to resolve any problems that may be identified.
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`If you have any questions, call Steven D. Hardeman, R.Ph., Senior Regulatory Project Manager at
`(301) 594-5525.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert Temple, M.D.
`Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Enclosure
`
`
`
`Page 4 of 5
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`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Robert Temple
`11/15/02 03:41:12 PM
`
`
`
`Page 5 of 5
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