CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208082Orig1s000
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`OTHER ACTION LETTERS
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`

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`Food and Drug Administration
`Silver Spring MD 20993
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`COMPLETE RESPONSE
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 208082
`
`Teva Pharmaceuticals, Inc.
`Attention: Christine Schulteis, PhD
`Global Regulatory Affairs
`3333 North Torrey Pines Court
`Suite 400
`La Jolla, CA 92037
`
`Dear Dr. Schulteis:
`
`Please refer to your New Drug Application (NDA) dated May 29, 2015, received May 29, 2015,
`and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and
`Cosmetic Act for Austedo (deutetrabenazine) Oral Tablets 6 mg, 9 mg, and 12 mg.
`
`We have completed our review of this application, as amended, and have determined that we
`cannot approve this application in its present form. We have described our reasons for this action
`below and, where possible, our recommendations to address these issues.
`
`CLINICAL PHARMACOLOGY
`
`Your clinical pharmacology studies were not adequate to determine whether all major human
`metabolites of deutetrabenazine have been identified. This information is needed to assess
`whether the bridge to the listed drug on which you are relying (Xenazine) is scientifically
`justified to address the toxicity of all major metabolites of deutetrabenazine.
`
`Please note that the method you proposed in your April 8, 2016, amendment to this NDA to
`assess potential major metabolites is acceptable, on face, and pending demonstration of suitable
`stability.
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`NONCLINICAL
`
`The toxicokinetic analyses of metabolites in the pivotal nonclinical studies of deutetrabenazine
`are limited to quantitation of the primary metabolites of deutetrabenazine (i.e., alpha and beta-
`DHTBZ). If the results of the pending clinical pharmacology analyses identify additional major
`circulating human metabolites, you will need to demonstrate that each has been adequately
`assessed in the appropriate nonclinical studies or that plasma exposure to each does not exceed
`that in humans with Xenazine.
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`Reference ID: 3936052
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`NDA 208082
`Page 2
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`PRODUCT QUALITY
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`. We
`1. The drug substance specification does not include a test for
`acknowledge your commitment dated February 22, 2016, to add a test and acceptance
`criterion of not more than
` as part of
`the drug substance specification and to amend the NDA with this test, acceptance
`criterion, and method validation report on or before March 22, 2016. However, the test
`method was not submitted until April 14, 2016, and validation data were not provided
`until May 9, 2016. These amendments to the NDA will be reviewed in the next cycle.
`
`2.
`
`In your post-approval stability protocol, you indicate that at least one production batch of
`the product in the commercial packaging will be placed on long term stability annually.
`Because the registration stability batches were not manufactured at full commercial scale,
`we request that you update your post-approval stability commitment to include placing
`the first three commercial batches of each strength of the drug product on long-term
`stability through the proposed shelf life, and on accelerated stability for 6 months as per
`ICH Q1A(R2). The data should be tabulated and submitted in the annual report with a
`commitment to withdrawing or discussing any out of specification results in the
`distributed drug product to the Agency.
`
`3. Per 21 CFR 25.15(d), revise your claim for categorical exclusion to include a statement
`that, to the applicant's knowledge, no extraordinary circumstances exist.
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`PRESCRIBING INFORMATION
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`We reserve comment on the proposed labeling until the application is otherwise adequate. We
`encourage you to review the labeling review resources on the PLR Requirements for Prescribing
`Information website, including regulations and related guidance documents and the Selected
`Requirements for Prescribing Information (SRPI) − a checklist of important format items from
`labeling regulations and guidances.
`
`If you revise labeling, use the SRPI checklist to ensure that the prescribing information conforms
`with format items in regulations and guidances. Your response must include updated content of
`labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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`PROPRIETARY NAME
`
`Please refer to correspondence dated, July 2, 2015, which addresses the proposed proprietary
`name, Austedo. This name was found acceptable pending approval of the application in the
`current review cycle. Please resubmit the proposed proprietary name when you respond to the
`application deficiencies.
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`Reference ID: 3936052
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`(b) (4)
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`(b) (4)
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`NDA 208082
`Page 3
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`SAFETY UPDATE
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`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and
`clinical studies/trials of the drug under consideration regardless of indication, dosage form, or
`dose level.
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`1. Describe in detail any significant changes or findings in the safety profile.
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`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
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` Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as the original NDA submission.
` Present tabulations of the new safety data combined with the original NDA data.
`Include tables that compare frequencies of adverse events in the original NDA with
`
`the retabulated frequencies described in the bullet above.
` For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
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`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating
`the drop-outs from the newly completed trials. Describe any new trends or patterns
`identified.
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`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical trial or who did not complete a trial because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
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`5. Describe any information that suggests a substantial change in the incidence of common,
`but less serious, adverse events between the new data and the original NDA data.
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`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
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`7. Provide a summary of worldwide experience on the safety of this drug. Include an
`updated estimate of use for drug marketed in other countries.
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`8. Provide English translations of current approved foreign labeling not previously
`submitted.
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`Reference ID: 3936052
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`NDA 208082
`Page 4
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`ADDITIONAL COMMENTS
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`We have the following comments/recommendations that are not approvability issues:
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`1. When submitting the safety update, include narratives for patients who dropped out of
`Study C-16 for any reason and provide ADaM datasets in the same format as submitted with
`the 120-Day Safety Update.
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`2. Review all Psychiatry system-organ-class (SOC) adverse events in Study C-15 and Study
`C-16 for accuracy of the Preferred Term coding of the verbatim report of the adverse event.
`Provide a separate analysis for each study of all Psychiatry SOC events that led to an adverse
`event, a dose reduction or a dose interruption regardless of whether the event was considered
`related to drug or not.
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`3. The data provided in the application suggest a possible rebound effect following
`withdrawal of deutetrabenazine. You need to conduct a systematic evaluation of clinical
`dependence. We recommend that you evaluate clinical dependence in patients as they
`complete Study ARC-HD (SD-809-C-16). We suggest you evaluate patients for signs and
`symptoms of clinical dependence for two weeks after discontinuing deutetrabenazine. In
`patients who chose to discontinue treatment with deutetrabenazine early, you should extend
`the follow up period after discontinuing deutetrabenazine to 3 weeks.
`
`You should administer the following scales to evaluate patients for signs of rebound:
` Hospital Anxiety and Depression Scale (HADS)
` Columbia Suicide Severity Rating Scale (C-SSRS)
` Epworth Sleepiness Scale (ESS)
` Montreal Cognitive Assessment (MoCA)
` Total Maximal Chorea Score (TMC)
` Unified Huntington Disease Rating Scale, including behavioral and cognitive scores
` Unified Parkinson’s Disease Rating Scale Speech/Dysarthria
` Barnes Akathisia Rating Scale (BARS)
` Berg Balance Test Score (BBT)
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`We recommend you submit for FDA review your planned analyses for abuse potential and
`rebound.
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`CONTAINER LABELS
`
`Our post-marketing experience indicates that similarity of the product code numbers of the NDC
`(middle 3 digits) has led to selecting and dispensing of the wrong strength and wrong drug. The
`middle digits are traditionally used by healthcare providers to check the correct product, strength,
`and formulation. Therefore, assignment of sequential numbers for the middle digits is not an
`effective differentiating feature (e.g., 170, 171, and 172). If these numbers cannot be revised,
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`Reference ID: 3936052
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`NDA 208082
`Page 5
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`increase the prominence of the middle digits by increasing their font size in comparison to the
`remaining digits or putting them in bold type. As an example:
`XXXX-XXXX-XX. See Draft Guidance for Industry: Safety Considerations for Container
`Labels and Carton Labeling Design to Minimize Medication Errors. Food and Drug
`Administration. 2013.
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`OTHER
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`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`request an extension of time in which to resubmit the application. A resubmission must fully
`address all the deficiencies listed. A partial response to this letter will not be processed as a
`resubmission and will not start a new review cycle.
`
`You may request a meeting or teleconference with us to discuss what steps you need to take
`before the application may be approved. If you wish to have such a meeting, submit your
`meeting request as described in the FDA Guidance for Industry, “Formal Meetings Between
`FDA and Sponsors or Applicants,” May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
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`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
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`PDUFA V APPLICANT INTERVIEW
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`FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim
`and final assessment of the Program for Enhanced Review Transparency and Communication for
`NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment
`Letter states that these assessments will include interviews with applicants following FDA action
`on applications reviewed in the Program. For this purpose, first-cycle actions include approvals,
`complete responses, and withdrawals after filing. The purpose of the interview is to better
`understand applicant experiences with the Program and its ability to improve transparency and
`communication during FDA review.
`
`ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about
`the interview process. Your responses during the interview will be confidential with respect to
`the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any
`identifying information to anyone outside their project team. They will report only anonymized
`results and findings in the interim and final assessments. Members of the FDA review team will
`be interviewed by ERG separately. While your participation in the interview is voluntary, your
`feedback will be helpful to these assessments.
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`Reference ID: 3936052
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`

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`NDA 208082
`Page 6
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`If you have any questions, call Stacy Metz, PharmD, Senior Regulatory Project Manager, at
`(301) 796-2139.
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`Sincerely,
`
`{See appended electronic signature page}
`
`Ellis F. Unger, MD
`Director
`Office of Drug Evaluation I
`Office of New Drugs
`Center for Drug Evaluation and Research
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`Reference ID: 3936052
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`

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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/
`----------------------------------------------------
`
`ELLIS F UNGER
`05/27/2016
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`Reference ID: 3936052
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`