CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`207202Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`IND 115927
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`MEETING MINUTES
`
`
`Otsuka Pharmaceutical Development &
`Commercialization, Inc.
`Attention: Jeffrey Yuan, Ph.D.
`Director, Global Regulatory Affairs
`508 Carnegie Center
`Princeton, New Jersey 08540
`
`
`Dear Dr. Yuan:
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`of the Federal Food, Drug, and Cosmetic Act for aripiprazole tablet with an ingestible event
`marker (IEM) from Proteus® (the Proteus Ingestible Sensor).
`
`We also refer to the meeting between representatives of your firm and the FDA on May 5, 2015.
`The purpose of the meeting was to gain alignment with us on the proposed NDA structure and
`content, on the handling of packaging and environmental assessment, on the acceptability of the
`human factors validation data for review, on the proposed labeling, and on the handling of the
`Otsuka Medical Software in the NDA.
`
` A
`
` copy of the official minutes of the meeting is enclosed for your information. Please notify us
`of any significant differences in understanding regarding the meeting outcomes.
`
`If you have any questions, please email Simran Parihar, PharmD, Regulatory Health Project
`Manager, at simran.parihar@fda.hhs.gov.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Mitchell Mathis, M.D.
`CAPT, USPHS
`Director
`Division of Psychiatry Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Enclosure:
`Meeting Minutes
`Sponsor’s Slide Presentation
`
`Reference ID: 3775040
`
`
`
`

`

`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`
`
`
`MEMORANDUM OF MEETING MINUTES
`
`
`Type B
`Pre-NDA
`
`Meeting Type:
`Meeting Category:
`
`Meeting Date and Time: Tuesday, May 5, 2015 9:00 -10:30 AM (ET)
`Meeting Location:
`
`White Oak Building 22, Conference Room: 1315
`Application Number:
`IND 115927
`Product Name:
`
`aripiprazole tablet + ingestible event marker (IEM)
`Indication:
`
`
`Schizophrenia
`Sponsor/Applicant Name: Otsuka Pharmaceutical Development & Commercialization, Inc.
`
`
`FDA ATTENDEES
`Mitchell Mathis, M.D.
`Tiffany Farchione, M.D.
`Jing Zhang, M.D.
`
`Aisar Atrakchi, Ph.D.
`David Claffey, Ph.D.
`
`Director, Division of Psychiatry Products (DPP)
`Deputy Director, DPP
`Clinical Team Leader
`Pharmacology/Toxicology Supervisor
`CMC Team Leader, Office of Pharmaceutical Quality
`(OPQ)
`Director (acting), Office of Policy for Pharmaceutical
`Quality (OPQ)
`Deputy Director (Acting), Science and Policy
`Associate Director, Division of Medication Error
`Prevention and Analysis (DMEPA)
`Safety Evaluator, DMEPA
`Team Leader, DMEPA
`FDA/ISMP Safe Medication Management Fellow, DMEPA
`Regulatory Pharmaceutical Fellow, Medication Safety, DMEPA
`Deputy Director, Office of Combination Products (OCP),
`Office of Commissioner (OC)
`Clinical Associate Director, OCP/OC
`Branch Chief (Acting), Cardiac Diagnostic Devices
`Branch, CDRH
`Deputy Director, Cardiac Diagnostic Devices Branch,
`CDRH
`Lead Reviewer, 513(g)
`Regulatory Health Project Manager, DPP
`
`
`
`
`
`
`Ashley Boam, MSBE
`
`Richard Lostritto, Ph.D.
`Irene Z. Chan, Pharm.D., BCPS
`
`Loretta Holmes, BSN, Pharm.D.
`Danielle Harris, Pharm.D., BCPS
`Ariane Conrad. Pharm.D.
`
`Katelyn Brown, Pharm.D.
`
`Patricia Love, M.D.
`
`Bindi Nikhar, MD
`Shawn Forrest, MS
`
`Mitchell Shein, MS
`
`
`Luke Ralston
`Simran Parihar, Pharm.D.
`
`
`
`
`
`
`
`
`
`Reference ID: 3775040
`
`

`

`Director of Product Management Digital Health
`Director of Labeling, Global Regulatory Affairs
`Senior Director of Global Regulatory Affairs
`Manager, Medical Regulatory Affairs
`Senior Director, Pharmaceutical Technology
`Senior Director, Global Clinical Development
`Director of Global Regulatory Affairs
`Senior Vice President of Global Regulatory Affairs
`Language Services Specialist
`
`
`
`
`Cofounder and Chief Medical Officer
`Head, Regulatory Affairs
`
`BACKGROUND
`
`IND 115927
`Page 2
`
`SPONSOR ATTENDEES
`
`Otsuka Pharmaceutical Co., Ltd
`Janet Ahn
`
`
`
`Michael Fahmy, M.S.
`
`Elora Gupta, Ph.D.
`
`
`Kenji Tomikawa
`
`
`David Unger, Ph.D.
`
`
`Tim Peters-Strickland, M.D.
`Jeffery Yuan, Ph.D.
`
`
`Henrietta Ukwu, M.D.
`
`Yukako Tsuzaki, M.A.
`
`
`Proteus Digital Health
`George Savage, M.D.
`Jafar Shenasa
`
`
`1.0
`
`The sponsor, Otsuka Pharmaceutical Co., Ltd (Otsuka), is developing a combination drug-device
`that consists of an aripiprazole tablet plus an embedded ingestible event marker (IEM) from
`Proteus (the Proteus Ingestible Sensor), which is also referred to as aripiprazole + IEM, under
`the Investigational New Drug (IND) 115927. IND 115927 was allowed to proceed on Oct 24,
`2013. The purpose of the aripiprazole + IEM tablet is to be used in conjunction with a system to
`.
`
`
`The sponsor’s agenda for this meeting is to gain concurrence with FDA that adequate evidence is
`available to file a NDA for TRADEMARK. The proposed claim is “TRADEMARK
`
` The sponsor requests concurrence with the FDA that the
`preliminary results from the Human Factors Validation study provide sufficient support for the
`claim that the NDA may be filed and approved. The Human Factors Validation study included
`36 patients from three different diagnostic groups (schizophrenia, major depressive disorder,
`bipolar 1 disorder) who were divided between two conditions of use (assisted and unassisted).
`
`No new treatment indication is proposed for the aripiprazole + IEM combination beyond those
`currently approved for Abilify (aripiprazole) in the adult oral tablet formulation:
`
` •
`
` Schizophrenia; acute and maintenance treatment
`• Acute treatment of manic and mixed episodes associated with bipolar I disorder, and as
`monotherapy or adjunctive for maintenance treatment
`• Adjunctive treatment of major depressive disorder
`
`The Sponsor states that TRADEMARK is not intended to address the treatment of the disease
`(i.e., schizophrenia, bipolar I disorder, or MDD), because that has been demonstrated by
`approval of the aripiprazole oral tablet (NDA 21-436).
`
`
`
`
`Reference ID: 3775040
`
`(b) (4)
`
`(b) (4)
`
`

`

`IND 115927
`Page 3
`
`The sponsor plans not to submit an integrated summary of efficacy or safety in the proposed
`NDA, since the efficacy and safety of the components have already been demonstrated and the
`indications for TRADEMARK are the same as those for the Abilify oral tablet in adults. At the
`Feb 4, 2015 Type C meeting, the sponsor indicated that clinical safety data from trials that used
`the TRADEMARK product would be provided.
`
`
`
`2. DISCUSSION
`
`
`2.1. General
`
`
`Question 1: As discussed at the 04 Feb 2015 Type C meeting, the TRADEMARK
`product consists of the following 4 components: aripiprazole + IEM tablet; Proteus Patch
`+ MDDS; Patient Component of the Otsuka Medical Software; and Healthcare Provider
`and Caregiver Web Portals of the Otsuka Medical Software. Based on previous meetings
`with the Agency on the TRADEMARK development program and requirements for
`registration (see minutes from meetings on 29 Sep 2012, 13 Aug 2013, 10 Feb 2014, and
`04 Feb 2015) and International Conference on Harmonisation M4 “Organisation of the
`Common Technical Document for the Registration of Pharmaceuticals for Human Use,”
`the NDA will consist of chemistry, manufacturing, and control, human factors validation
`data, safety data from trials using TRADEMARK, and proposed labeling. Appropriate
`cross-references to the already approved and cleared components of TRADEMARK will
`be made in the NDA.
`
`The proposed content and structure of the NDA will include a summary of clinical safety
`and a clinical overview. As previously indicated, the sponsor will cross-reference the
`Abilify NDAs and Proteus 510(k)s for the efficacy and safety of the drug and device
`components, as appropriate, and will not provide an integrated summary of efficacy in
`this NDA.
`
`Does the Agency agree with the proposed structure and table of contents for the NDA?
`
`FDA Response to Question 1:
`From clinical point of view, the proposed structure and table of contents for the NDA
`appears acceptable.
`
`We agree with your proposal to cross-reference the drug substance information to NDA
`21436, but request that you, at minimum, include the current drug substance
`specification in Section 3.2.S.
`
`Discussion at meeting: There was no further discussion.
`
`
`Question 2: The TRADEMARK NDA will be reviewed as a non-new molecular entity
`(NME) original NDA, as confirmed by the FDA at the pre-IND Meeting, 14 Aug 2013.
`
`
`
`Reference ID: 3775040
`
`

`

`IND 115927
`
`Page 4
`
`The targeted review performance goal will be 10 months from receipt (Prescription Drug
`User Fee Act [PDUFA] Reauthorization Performance Goals and Procedures, 2013-2017).
`
`The program has been granted Fast Track status based on the potential for the integrated
`system
`mm)
`
`The sponsor maintains that TRADEMARK fills this serious unmet medical need. (hm)
`
`Will the Agency consider an expedited review (Priority Review) of the NDA based on
`these considerations? It is understood that the official review designation will be granted
`after NDA submission.
`
`FDA Resgonse to Question 2:
`There are approved treatmentsfor all the indicationsfor which this product would be
`approved. Therefore, this product does not address an unmet medical need and does not
`qualifi)for expedited review.
`
`Discussion at meeting: There was nofurther discussion.
`
`Question 3: TRADEMARK consists of both already approved and cleared components
`(aripiprazole, Proteus IBM, and Proteus Patch) for which safety and efficacy have already
`been demonstrated. No clinical phase 3 trials are needed for the proposed NDA and the
`sponsor is not seeking a new indication.
`
`Furthermore, the application will not raise significant public heath questions concerning
`the role of TRADEMARK in diagnosis, cure, mitigation, treatment, or prevention of
`disease.
`
`Therefore, based on the FDA‘s criteria for the need for an advisory committee, the
`sponsor believes an advisory committee is not needed for TRADEMARK.
`
`Does the Agency agree?
`
`FDA Resgonse to Question 3:
`No, we do not agree. During the submission review, we will determine the needfor an
`advisory committee.
`
`Discussion at meeting: FDA clarified that we have not yet identified any issues that
`would warrant an advisory committee; however, we intend to keep this option open.
`Whether or not an AC will be necessary is always a matter of review once we receive the
`NDA submission.
`
`Reference ID: 3775040
`
`

`

`IND 115927
`Page 5
`
`
`
`
`Question 4: After review of the regulations and the safety data for TRADEMARK, the
`sponsor does not believe that there is any risk that requires a Risk Evaluation and
`Mitigation Strategy (REMS).
`
`Does the Agency agree on the proposed risk management activities?
`
`FDA Response to Question 4:
`Given that the system is purported to be physiologically inert and the drug substance is
`already approved, the Division tends to agree; however, this is ultimately a matter of
`review.
`
`Discussion at meeting: There was no further discussion.
`
`
`Question 5: For Module 3, Section 3.2.R.2 Method Validation Package, 4 representative
`sample kits will be assembled per 21 CFR 314.50(e). The sponsor will provide in the
`sample kit sufficient quantity for the FDA to perform testing of the aripiprazole + IEM
`tablets.
`
`The Proteus Patch, which is part of the commercial kit, will not be provided in the sample
`kit as it has been cleared in 510(k) K113070 (DEN120011), K131009, K131524, and
`K133263.
`
`Does the Agency agree?
`
`FDA Response to Question 5:
`This approach appears appropriate to meet requirements under 21 CFR 314.50(e)(i);
`However, per 21 CFR 314.50(e)(ii), we also request three samples of the finished market
`package, including the patch, that you intend to commercially distribute.
`
`Discussion at meeting: FDA clarified that the three samples of the finished market
`package, including the patch, should be included at the time the NDA is submitted.
`
`
`Question 6: The environmental analysis in Module 1, Section 1.12.14 will be conducted
`for the aripiprazole drug substance only. The device components of the product have
`already been cleared and are exempted as per 21 CFR 25.34 and will be used as per their
`intended uses.
`
`Does the Agency agree?
`
`FDA Response to Question 6:
`Yes.
`
`
`
`
`Reference ID: 3775040
`
`

`

`Discussion at meeting: There was no further discussion.
`
`
`Question 7: On 27 Jan 2015, the sponsor received the Agency’s review of the human
`factors validation protocols. Appropriate revisions have been made to the validation
`protocols and will be addressed in the validation and summary reports. An initial
`summary from the validation studies is provided below and indicates that TRADEMARK
`can be safely and correctly used by the intended patient population. An initial summary
`from the validation studies is provided in the appendices of this briefing book.
`
`Does the summary of the validation trial results support the filing and review of the
`NDA?
`
`FDA Response to Question 7:
`DMEPA response: To support the filing and review of the NDA, we request that you
`submit study reports for all HF validation studies. These reports must include:
`
`
`•
`
`the information outlined under Appendix A of FDA’s Draft Guidance for
`Industry: Applying Human Factors and Usability Engineering to Optimize
`Medical Device Design;
`• raw data collected from each participant, including observed and subjective data;
`• a copy of the study protocol implemented;
`• a copy of the IFU tested;
`• samples of the finished market package, including the patch, that you intend to
`commercially distribute (see response to question 5 above); and
`• agreed upon information as stated in Appendix 3 of your briefing document
`
`IND 115927
`Page 6
`
`
`
`Additionally, if further changes were made to the user-interface (e.g., product design,
`IFU, other labeling) after completion of the HF validation studies, all changes should be
`described along with your rationale for implementing these changes and any additional
`validation data to support the additional changes. In the event that further changes were
`made to the IFU after completion of the HF validation studies, please submit a side-by-
`side comparison of the two versions (tested version versus intend-to-market version) that
`clearly points out where changes were made.
`
`
`The acceptability of the study results to support safe and effective use of the combination
`product as well as any claims will be a review issue. Please note that the evaluation of
`any proposed claims will be based on the totality of data submitted to your NDA.
`
`Discussion at meeting: There was no further discussion.
`
`
`Question 8: As a follow up to the 4 Feb 2015 Type C meeting, the sponsor has provided
`details and supporting rationale on the format of the proposed label along with draft
`labeling.
`
`
`
`
`Reference ID: 3775040
`
`

`

`IND 115927
`
`Page 7
`
`Does the Agency agree with the proposed format and labeling?
`
`estion 8:
`use to
`FDA R
`
`
`CDRH comment:
`
`We recommend cross-referencing a cleared device
`
`with an indication that aligns more closely with theproposed indication.
`
`Discussion at meeting: There was no further discussion.
`
`uestion 9:
`
`Does the Agency agree with this proposal?
`
`FDA Rmnse to fiestion 9:
`At this time, we are not able to determine the
`
`discretion.
`
`In addition, the briefing document indicates that the NDA will cross-reference K113070
`(DEN120011), K131009, K131524, and KI33263 to support the devicefitnctionality.
`Please confirm whether the most recently cleared version ofthe device (K133263) is the
`intended version to be considered in the NDA. In addition in the NDA, please identyj/ and
`state the relevance ofany version to the device intendedfor the NDA copackage
`
`Discussion at meeting:
`
` is part ofthe combination product. As such
`
`the risks relate to
`
`e entire co mauon and the sofiware is part of the overall review.
`
`0 Regarding the cross-referenced 510(k) submissions, Otsuka stated that it will cross
`reference the most recently applicable cleared version of the Proteus device. Also,
`during the discussion other versions were mentioned. FDA requested that the NDA
`
`Reference ID: 3775040
`
`

`

`IND 115927
`
`Page 8
`
`very clearly indicate (and tabulate) what aspects of the 51000 or 510(k)s are cross-
`referenced and for what purpose.
`
`FDA noted that the intended use of the new software is unclear (e.g., what decisions
`are being made based on seeing the data from the app?). The risk analysis is
`associated with the display information and the source of the information. mm)
`
`(D) (4)
`
`The HCP can only
`access data that the patient has explicitly given him/her permission to access, and the
`patient can revoke that permission at any time via the app. The Otsuka software is
`specifically designed for use by mental health patients (i.e., those with schizophrenia,
`bipolar disorder, etc.).
`
`Additional Comments Regarding NDA and MAF Content:
`
`FDA clarified that the MAF should contain data that is confidential trade secret to the
`
`NDA holder.
`
`(m4)
`
`. At that point, FDA would review the MAF.
`
`Regarding the Otuska NDA data: the Otsuka data and any common Proteus data
`known to Otsuka should be in the NDA. Also, the NDA should contain the
`
`qualification data for the sensor in aripiprazole.
`
`The comparability protocol for submission to the NDA should provide Otsuka’s
`proposal for certain anticipated changes that could be made postapproval and the type
`of reporting (NDA supplement or annual report) proposed for each. Also, for changes
`made to the Proteus system (e.g., those made in rapid response to the mobile phone
`operating system updates), the submission should include a proposal for those
`changes as well.
`
`FDA asked the sponsor to propose a location for the Otsuka Medical Software
`documentation and Comparability Protocol in the proposed NDA. In a post—meeting
`email correspondence, the sponsor proposed the following:
`
`o Otsuka proposes to incorporate the documentation for the Otsuka Medical
`Software into module 1.11.1, Quality Information Amendment of the eCTD
`structure, alongside the Human Factors Validation and Summary Reports. This
`
`Reference ID: 3775040
`
`

`

`IND 115927
`
`Page 9
`
`documentation of the sofiware would be in a format similar to what would be
`
`provided to CDRH as a MAP (Device Master File).
`
`0 Alongside the software documentation, Otsuka also proposes to include the
`Comparability Protocol in module 1.11.1. As discussed on Tuesday, this protocol
`will focus primarily on the handling ofpost approval updates to the Otsuka
`Medical Sofiware; therefore, it is proposed to be included in the same section as
`the sofiware documentation.
`
`In a further follow up to this communication, FDA advised the sponsor to link the
`video file(s) into the backbone, and also provide a PDF file of the video for archival
`purposes. Acceptable video file formats are .wmv and .mpg, which can be viewed
`with Windows Media Player, standard on reviewer workstations. Also, video files
`should not be sent separately to individual reviewers, nor left out of the eCTD
`backbone. Any files submitted for review should always be linked into the backbone.
`We also noted that the sponsor should include the word "video" in the leaf title of the
`Video file, so reviewers can quickly identify the file.
`
`Labeling — The labeling should specify the compatible mobile devices and include a
`warning to alert patients not to change their phone operating system (or change
`phones) without checking with the manufacturer to confirm compatibility. The
`submission should include data to show lockout from other patches in vicinity (9 1)
`
`Patient labeling is in the form of the help menu and videos on the phone. No printed
`patient labeling is planned.
`
`Additional Discussion at meeting: Video Demonstration
`
`Following the demonstration provided by Otsuka, the Agency sought clarification
`regarding app and patch functionality. Otsuka provided the following clarification points:
`(I!) (4)
`O
`
`o The patch battery lasts one week and any data generated afier the battery dies are
`not transmitted.
`
`o The patch “status icon” serves to indicate to the user the quality of the patch
`connectivity. The icon will display as “red” in the event that the connectivity is
`poor due to (l) insufficient Bluetooth connectivity, (2) inadequate contact of
`patch with skin, (3) patch needing replacement or (4) unsuccessfill pairing with
`app. This and other icons were tested in human factors studies for participant
`knowledge/comprehension.
`o The app does not have to be “on” at all times to ensure data collection. Data will
`transmit when the app is “synced.”
`M“)
`
`o The HCP/caregiver is unable to access the patient’s information until access is
`granted by the patient. The patient can deny access at any time. They can also
`reconnect.
`
`Reference ID: 3775040
`
`

`

`IND 115927
`
`Page 10
`
`0 Only one phone can be paired to the patch. If the cell phone in use is lost or
`damaged, the previously generated data will still be available in the cloud, but
`new data will not be captured.
`
`cum)
`
`0 The patch is designed to be water resistant.
`o The patch should be removed prior to an MRI.
`
`mu)
`
`0
`
`In the real-world setting, Otsuka anticipates that HCPs/Caregivers will be trained
`on use of the patch and app and will, in turn, train patients and assist patients
`with onboarding. The Agency recommended that the onboarding process be
`included in Section 17 of the labeling.
`
`(m4)
`
`(0) (4)
`
`3.0
`
`DISCUSSION OF THE CONTENT OF A COMPLETE APPLICATION
`
`As stated in our March 6, 2015, communication granting this meeting, if, at the time of
`submission, the application that is the subject of this meeting is for a new molecular entity or an
`original biologic, the application will be subject to “the Program” under PDUFA V. Therefore, at
`this meeting be prepared to discuss and reach agreement with FDA on the content of a complete
`application, including preliminary discussions on the need for risk evaluation and mitigation
`strategies REMS) or other risk management actions. You and FDA may also reach agreement
`on submission of a limited number of minor application components to be submitted not later
`than 30 days after the submission of the original application. These submissions must be of a
`type that would not be expected to materially impact the ability of the review team to begin its
`review. All major components of the application are expected to be included in the original
`application and are not subject to agreement for late submission.
`
`Discussions and agreements will be summarized at the conclusion of the meeting and reflected in
`FDA’s meeting minutes. If you decide to cancel this meeting and do not have agreement with
`FDA on the content of a complete application or late submission of any minor application
`components, your application is expected to be complete at the time of original submission.
`
`In addition, we remind you that the application is expected to include a comprehensive and
`readily located list of all clinical sites and manufacturing facilities.
`
`Reference ID: 3775040
`
`

`

`PREA REQUIREMENTS
`
`IND 115927
`Page 11
`
`Finally, in accordance with the PDUFA V agreement, FDA has contracted with an independent
`contractor, Eastern Research Group, Inc. (ERG), to conduct an assessment of the Program. ERG
`will be in attendance at this meeting as silent observers to evaluate the meeting and will not
`participate in the discussion. Please note that ERG has signed a non-disclosure agreement.
`
`Information on PDUFA V and the Program is available at
`http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm272170.htm.
`
`4.0
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Please be advised that under the Food and Drug Administration Safety and Innovation Act
`(FDASIA), you must submit an Initial Pediatric Study Plan (iPSP) within 60 days of an End of
`Phase (EOP2) meeting. In the absence of an End-of-Phase 2 meeting, refer to the draft guidance
`below. The PSP must contain an outline of the pediatric study or studies that you plan to conduct
`(including, to the extent practicable study objectives and design, age groups, relevant endpoints,
`and statistical approach); any request for a deferral, partial waiver, or waiver, if applicable, along
`with any supporting documentation, and any previously negotiated pediatric plans with other
`regulatory authorities. The PSP should be submitted in PDF and Word format. Failure to include
`an agreed iPSP with a marketing application could result in a refuse to file action.
`
`For additional guidance on the timing, content, and submission of the PSP, including a PSP
`Template, please refer to the draft guidance for industry, Pediatric Study Plans: Content of and
`Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM360507.pdf. In addition, you may contact the Division of Pediatric and Maternal Health at
`301-796-2200 or email pdit@fda.hhs.gov. For further guidance on pediatric product
`development, please refer to:
`http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.ht
`m.
`
`
`
`Reference ID: 3775040
`
`

`

`PRESCRIBING INFORMATION
`
`IND 115927
`Page 12
`
`
`5.0
`
`In your application, you must submit proposed prescribing information (PI) that conforms to the
`content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57 including the
`Pregnancy and Lactation Labeling Rule (PLLR) (for applications submitted on or after June 30,
`2015). As you develop your proposed PI, we encourage you to review the labeling review
`resources on the PLR Requirements for Prescribing Information and PLLR Requirements for
`Prescribing Information websites including:
`
`
`• The Final Rule (Physician Labeling Rule) on the content and format of the PI for human
`drug and biological products
`• The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of
`information related to pregnancy, lactation, and females and males of reproductive
`potential in the PI for human drug and biological products
`• Regulations and related guidance documents
`• A sample tool illustrating the format for Highlights and Contents, and
`• The Selected Requirements for Prescribing Information (SRPI) − a checklist of 42
`important format items from labeling regulations and guidances.
`• FDA’s established pharmacologic class (EPC) text phrases for inclusion in the
`Highlights Indications and Usage heading
`
`6.0 MANUFACTURING FACILITIES
`
`To facilitate our inspectional process, we request that you clearly identify in a single
`location, either on the Form FDA 356h, or an attachment to the form, all manufacturing
`facilities associated with your application. Include the full corporate name of the facility and
`address where the manufacturing function is performed, with the FEI number, and specific
`manufacturing responsibilities for each facility.
`
`Also provide the name and title of an onsite contact person, including their phone number,
`fax number, and email address. Provide a brief description of the manufacturing operation
`conducted at each facility, including the type of testing and DMF number (if applicable).
`Each facility should be ready for GMP inspection at the time of submission.
`
`Consider using a table similar to the one below as an attachment to Form FDA 356h. Indicate
`under Establishment Information on page 1 of Form FDA 356h that the information is
`provided in the attachment titled, “Product name, NDA/BLA 012345, Establishment
`Information for Form 356h.”
`
`
`
`Reference ID: 3775040
`
`

`

`IND 115927
`
`Page 13
`
`Federal
`
`Site Address
`
`'
`
`or Type of Testing
`[Establishment
`
`Establishm
`ent
`
`Indicator
`
`(FBI) or
`Registratio
`
`
`
`Plior to submission of your proposed PI, use the SRPI checklist to ensure confonnance with
`the format items in regulations and guidances.
`
`7.0
`
`ATTACHMENTS AND HANDOUTS
`
`Sponsor’s Slide Presentation and Demo video
`
`5 Page(s) has been Withheld in Full as b4 (CCIITS) immediately following this page
`
`Reference ID: 3775040
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MITCHELL V Mathis
`06/04/2015
`
`Reference ID: 3775040
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`IND 115927
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`MEETING MINUTES
`
`
`Otsuka Pharmaceutical Company, Ltd.
`Attention: Jeffrey Yuan, Ph.D.
`Director of Global Regulatory Affairs
`508 Carnegie Center
`Princeton, NJ 08540
`
`
`Dear Dr. Yuan:
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`of the Federal Food, Drug, and Cosmetic Act for aripiprazole tablet with an ingestible event
`marker (IEM) from Proteus® (the Proteus Ingestible Sensor).
`
`We also refer to the meeting between representatives of your firm and the FDA on February 4,
`2015. The purpose of the meeting was to gain alignment with the Agency on the description of
`the MIND1 system and its components, on the proposed labeling and instructions for use, and on
`the handling of post approval changes to the system.
`
` A
`
` copy of the official minutes of the meeting is enclosed for your information. Please notify us
`of any significant differences in understanding regarding the meeting outcomes.
`
`If you have any questions, please email Simran Parihar, PharmD, Regulatory Health Project
`Manager, at simran.parihar@fda.hhs.gov.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Mitchell Mathis, M.D.
`CAPT, USPHS
`Director
`Division of Psychiatry Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`
`
`Enclosure:
`Meeting Minutes
`
`Reference ID: 3712272
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`PIND 115927
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`MEETING MINUTES
`
`Proteus Digital Health, Inc.
`Attention: Dr. George Savage, MD
`Co-founder & Chief Medical Officer
`2600 Bridge Parkway, Suite 101
`Redwood City, CA 94065
`
`
`Dear Dr. Savage:
`
`Please refer to your Pre-Investigational New Drug Application (PIND) file for Abilify
`(aripiprazole) tablets with embedded Proteus Ingestible Event Marker.
`
`We also refer to the meeting between representatives of your firm and the FDA on August 14,
`2013. The purpose of the meeting was to discuss the 1) content of the upcoming IND
`submission; 2) unmet medical need being addressed by this program; 3) stability proposal for
`aripiprazole tablets with embedded Proteus Ingestible Event Marker; 4) procedural questions on
`the proposed NDA; and 5) potential labeling for the device/drug combination.
`
` A
`
` copy of the official minutes of the meeting is enclosed for your information. Please notify us
`of any significant differences in understanding regarding the meeting outcomes.
`
`We would also like to call your attention to a guidance released by the FDA on August 14, 2013,
`pertaining to the development of wireless devices. This guidance may be found at:
`http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocum
`ents/ucm077272.pdf.
`
`If you have any questions, please email, Simran Parihar, PharmD, at
`simran.parihar@fda.hhs.gov.
`
`
`Sincerely,
`{See appended electronic signature page}
`
`Mitchell Mathis, M.D.
`CAPT, USPHS
`Director (Acting)
`Division of Psychiatry Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Enclosure:
` Meeting Minutes
` Sponsor’s Slides
`
`Reference ID: 3359371
`
`
`
`

`

`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`
`
`MEMORANDUM OF MEETING MINUTES
`
`
`Type B
`Pre-IND
`
`Meeting