CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`207202Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`Recommendation: Approval
`
`NDA 207202
`
`Review #2
`(with approved Compurnblllty Protocol)
`
`
`
`
`
`
`
`
`
`D . Name/Dosaei‘orm Abili M cite -'i-razoletablctswith sensor
`
`. s
`2m,5m_10m_15m_,20m and30m
`
`_
`
`-__
`
`
`
`.—
`
`
`
`Current Review C cle
`
`
`
`
`
`
`
`
`
`
`
`
`
`SUBMISSION s REVIEWED
`
`Previous Review C cle
`DOCUMENT DATE
`26 JUN 2015
`
`'
`
`DISCIPL
`, s AFFECTED
`
`
`All
`
`'
`
`Process/Dru ; Product/CDRH
`Process/Dru Product/CDRH
`
`
`
`
`
`
`
`
`
`mg— 3AU62015 @—
`N-0013
`'
`2 NOV 2015
`Process/Dru- Product
`mom
`lsNovzols
`N—0017
`27 JAN 2016
`N-0019
`24 FEB 2016
`N-0023
`8 MAR 2016
`
`Quality Review Team
`
`DISCIPLINE
`
`Drug Substance & Drug Product
`
`'
`
`PIMAARY/SECONDARY
`REVIEWER
`
`Mariappan Chelliah/Wendy
`Wilson
`
`Process and Microbiolo
`
`Han_ Guo/Akm Khaimzzaman
`
`
`
`
`
`
`
`'
`
`
`
`
`
`
`
`Reference ID: 41 85545
`
`
`
`
`
`M—
`
`EEE__—
`
`MM-
`
`IE_
`N-0037
`—
`N-0038
`N-0040
`
`10 OCT 2017
`13 OCT 2017
`16 OCT 2017
`18 OCT 2017
`
`Carton and Container Labelin
`
`Co m- arabilit Protocol
`
`PI and labelin-
`
`Com -bi1i Protocol
`
`
`—IEE_— Comanbili Protocol
`
`

`

` QUALITY ASSESSMENT
`
`Table of Contents
`
`Table of Contents......................................;................................................... 2
`
`Quality Review Data Sheet........................................................................... 3
`
`Executive Summary ...................................................................................... 4
`
`OPQ Facilities Review
`
`CDRH 0C Review
`
`CDRH Device Review
`
`CDDRH Software Review
`
`Comparability Protocol
`
`12
`
`19
`
`35
`
`54
`
`62
`
`2
`
`OPQ-XOPQ—NDA 207202
`
`Reference ID: 41 85545
`
`

`

`QUALITY ASSESSMENT
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`TYPE
`
`
`
`
`'
`
`_ ITEM
`HOLDER REFERENCED STATUS
`
`DATE
`REVIEW
`COMPLETED
`
`COMMENTS
`
`
`Adequate --
`
`.
`
`to support
`
`
`NDA
`‘
`
`
`207202
`
`
`
`
`
`B. Other Documents: 1ND, RLD, or sister applications
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`2. CONSULTS: '
`
`DISCIPLINE
`
`STATUS
`
`RECOMMENDATION
`
`
`
`DATE
`
`1 SEP
`
`2017
`
`6 OCT
`2017
`
`13 SEP
`2017
`
`REVIEWER
`
`
`Luke Ralston
`
`Katelyn R.
`Bittleman
`
`Nathalie
`Yarkon
`
`
`
`
`
`
`
`
`CDRH ODE m Approval (see attachment)
`
`
`
`
`CDRH 0C
`
`CDRH Software
`
`.
`
`Complete
`
`Approval (see attachment)
`
`Approval (see attachment)
`.
`
`3
`
`OPQ-XOPQ-NDA 207202
`
`Reference ID: 41 85545
`
`

`

`QUALITY ASSESSMENT
`
`I.
`
`Recommendations
`
`Executive Summary
`
`A. Recommendation and Conclusion on Approvability
`
`Recommendations: Recommend that this application be approved from an OPQ
`perspective. Each of the consulted CDRH reviewers also made approval
`recommendations (attached reviews).
`
`The version of the proposed Comparability Protocol submitted on 8 NOV 2017 was
`
`found acceptable by a review team which included members from OPQ (0NDP, OLDP.
`
`OPF, OPPQ, OPRO), CDRH and DMEPA. Input was also provided from Patrick
`
`Raulerson, CDER ORP.
`
`Rationale behind OPQ approval recommendation:
`
`In the previous review cycle the applicant adequately demonstrated their
`
`capability to manufacture the proposed combination product with defined and
`
`consistent quality as demonstrated by the results of in vitro manufacturing
`
`controls and bench performance testing. A CR action was recommended from an
`“‘4’(hm)
`
`OPQ perspective
`
`applicant removed
`
`of the product
`
`(hm)
`
`.
`.
`In their response to the CR action the
`
`W" from the app. This changes risk profile
`
`mm
`
`to a more passive retrospective diary-type product. '
`
`The product’s known limitations remain. Although under the idealized conditions
`
`of the 316-13-206B study the app detected 90% of tablets within 30 minutes, it
`took over two hours to detect two tablets and it failed to detect 50% of one
`
`subject’s tablets. If the approved label claim is to ‘track drug ingestion’, there is
`
`some evidence that the product can do so with ca. 90% overall reliability within
`
`30 minutes. Individual results will depend on the patient’s ability to use the
`product correctly as demonstrated by Human Factors testing and the availability
`'of smattphones Bluetooth connection. The risk to the patient 'will be reduced by
`
`the recommended addition to the label of these limitations (Limitations of Use).
`
`4
`
`OPQ—XOPQ-NDA 207202
`
`Reference ID: 41 85545
`
`

`

`QUALITY ASSESSMENT
`
`This will ensure that the patient does not take immediate actionbased on the
`
`ingestion data in the app.
`
`It is in this context that OPQ is making an approval recommendation. Note that
`
`the ‘Additional OPQ comments’ and the manufacturing site deficiencies at Otsuka
`
`in the previous CR letter were adequately addressed in the resubmission. A
`
`Comparability Protocol (CP) was negotiated with the applicant in this review
`cycle.
`
`one
`
`The CP underwent significant negotiation with the applicant. The
`version submitted in the 8 NOV 2017 submission was found to be acceptable.
`
`The regulation of the web-based portal and the impact of the mood and
`
`physiological data will be discussed in the CDTL memo.
`
`II.
`
`Executive Summary of Quality Assessments
`
`The Product: The proposed combination product, Abilify Mycite, is a system that is
`intended to
`“M" to aripiprazole and is indicated for the .
`treatment of adults with:
`
`- Schizophrenia;
`- Acute treatment of manic and mixed episodes associated with bipolar l disorder;
`- Adjunctive treatment of major depressive disorder (MDD).
`'
`The Agency requested that the applicant revise the label claim
`”‘4’
`to “track drug ingestion".
`
`After the tablet is ingested it disintegrates in the stomach, exposing an elecu-onic sensor
`(ingestible event marker, or IBM) to the gastric fluid. The aqueous gastric environment
`activates the IBM which sends a signal to the patient’s smartphone via a patch (wearable
`sensor) which is worn on the patient’s torso. The smartphone can share the data with the
`patients’ HCPs or caregivers via the Cloud.
`
`
`"=
`
`Primary Monitor
`or Cloud server
`
`(“23" ‘ 5—"
`it“
`
`The System: The Abilify MYCITE system is a combination product with the following
`three main components:
`
`5
`
`OPQ-XOPQ-NDA 207202
`
`Reference ID: 41 85545
`
`

`

`
`
`l. ABILIFY MYCITE: Aripiprazole immediate-release tablets imbedded with an
`ingestible event marker (IBM) sensor.
`'
`
`2. MYCITE Patch: This is a wearable sensor which adheres to the torso, which
`picks up the signal fiom the IBM— and transmits it to
`the iPhone (via Bluetooth)
`
`3. Software within an iPhone, aka the app, which picks up the signal item the patch
`and which displays data about the ingestion event for patient. The app can also
`transmit the data to the Otsulta Cloud-based Server. This allows health care
`,
`professions and others (at patients‘ request) to view the data via a web portal. The
`system also collects other mood and physicological data about the patient which
`canbe viewed on the app and web portal.
`
`The kit is assembled atthe— Thispackaging site was
`
`found to be acceptable.
`
`ABILIFY MYCITE (aripiprazole) tablets with sensor: The tablet component ofthe
`combination products consists of aripiprazole tablets (2, 5, 10, 1'5, 20 and 30 mg
`strengths) embedded with an IBM sensor. The composition of the proposed tablets is
`qualitatively and quantitatively identical to Abilify tablets, except for the addition of the
`IBM sensor. In addition, the amount of colorant is- to distinguish it from Abilify
`tablets.
`The tablets are manufactured by Otsuka in Tokushima, Japan. The site underwent a
`preapproval inspection and was found to be acceptable.—
`
`
`
`The tablets then undergo release and stability testing. Stability data support the proposed
`36 month expiry period. The drug product specification is identical to that ofAbility
`tablets - with the exception ofthe addition of a test for the functionality of the IBM —
`called the DFAT test.
`
`6
`
`OPQ-XOPQ-NDA 207202
`
`Reference ID: 4185545
`
`

`

`
`
`
`
`The IBM is manufactured by Proteus Digital Health in Hayward,
`CA. A preapproval inspection of this site was carried out and it was found to be
`adequate.
`
`Although the details of the IBM were provided in the NDA, more supporting information
`was provided by Proteus in DMF 29332 (submitted to CDER). This DMF was evaluated
`CDRH, led by Luke Ralston and found to be adequate to support this application.
`
`— 2 configurations:
`
`1.- - this was theoriginnl model produced by Proteus prior to 2013 and used
`by Otsuka through most ofproduct development.
`
`2.- — this is the proposed mmmencial version ofthe IC
`
`Proteus developed the
`
`much of the developmental work and most of the registration stability batches were
`manufacwred with tablets with the older
`IBM: The two versions are physically
`identical, just
`
`in 2013 This change resulted in challenges during the review process as
`differs.
` These difi‘erences added uncertainty to bridging the placebo formulation
`
`used in the 206B clinical studies to the commercial formulation.
`
`‘ T
`
`his was found to be acceptable.
`
`MYCITE Patch (wearable sensor): All information for the patch Was cmss referenced
`to cleared 510k applications. Two versions of the patch are described in the application.
`
`8
`
`OPQ-XOPQ-NDA 207202
`
`Reference ID: 4185545
`
`

`

`' QUALITY ASSESSMENT ‘_
`
`“M"
`The RP4 version was used through most of development and worked with the
`version of the IBM. The DWS version is the proposed commercial version and was
`designed to work with the commercial W" version of the IBM. The patch is
`manufactured for Proteus at Avery Dennison Corp, Mentor, OH. The site underwent a
`preapproval inspection and was found to be acceptable. Note that the labeling describes
`this component as ‘MYCITE Patch”. Use of the term ‘wearable sensor’ was considered,
`as ‘patch’ could be confused with the commonly used term for a transdermal system drug
`product. It was decided to use the applicant’s term ‘MYCITE Patch’, mainly because the
`patients would more intuitively understand the term and there would be less likelihood of
`it being confused with the IBM ‘sensor’. This approach was agreed to by DMEPA, OGD
`policy, OPQ policy, CDRH and DPP.
`
`Software/Firmware: The sofiware on the app
`
`(”N0
`
`processes this information for display on
`the phone. This also transmits the data to the Otsuka Cloud based server for sharing with
`designated parties via a. web portal. Nathalie Yarkony and Linda Ricci fi'om CDRH
`evaluated the app in this review cycle and found it adequate (13 SEP 2017 review
`attached).
`
`Web Portal: The web portal is the website used by the caregiver or HCP to access the
`patient’s ingestion data. Questions arose over whether the software was subject to
`Agency regulation —~ as it is described as part of the product in product labeling. Sofiware
`regulation is an evolving topic, especially since the recent passage of the 21St Century
`Cures Act. This issue together with the patient mood and physiologic data and any
`disclaimers will be addressed in the CDTL memo.
`
`In Vivo Studies: In the initial review cycle a human factors study tested whether subjects
`could use the kit, including the patch and the app. This study was evaluated by DMEPA
`at that time, and found that only one out of 36 subjects successfully used the product. In
`this review cycle human factors testing results were found acceptable after the applicant
`modified the instructions. Two in vivo studies were completed to measure the accuracy of
`IBM detection and determine the data latency throughout the system. These were the
`Osmitter 316—13-206A and Osmitter 316—13—206B studies. Osmitter 206A used the
`
`older M“) IBM, The results found poor detectability (ca 75%) and long lag times.
`(m4)
`Osmitter 206B study is more relevant to this application as it used the commercial
`[EM but in a placebo tablet. The results were generally better — out of 1 l6 ingestions 4
`were not detected and 7 took greater than 30 minutes to be detected. 90% ofthe
`ingestions were detected within 30 minutes and 95% within two hours.
`
`CDRH Hardware Review: In the first review cycle Luke Ralston evaluated the device
`performance sections of the application and found that “the bench testing and in vitro
`data has adequately quantified the performance of the device within the tablet in idealized
`conditions.” However he found that the Osmitter in vivo studies “demonstrate that the
`
`W" — has significant data latency that is
`Otsuka software —
`not consistent with the IBM cleared under 510(k). Even under idealized study conditions
`
`9
`
`OPQ-XOPQ-NDA 207202
`
`Reference ID: 41 85545
`
`

`

`QUALITY ASSESSMENT
`
`0”“)
`a substantial fraction ofpatients will not receive positive detection confirmation
`This performance is not adequate to ensure
`safety and efi‘ectiveness for the intended use.” However in the resubmission, he
`concluded that “the data support use of the TRADEMARK system for tracking and
`trending now that the
`“M": has been removed from the mobile app”. As stated
`above the removal of the
`0"" changed the overall risk-benefit profile of
`this product.
`
`CDRH 0C and OPQ Facilities reviews: Katelyn R. Bittleman reviewed the application
`in this review cycle from a CDRH Office of Compliance perspective. They found the
`application acceptable from their perspective (6 OCT 2017 review attached). A post
`approval inspection was recommended for the M“) packaging facility. OPQ facilities
`made and approval recommendation in this review cycle (18 SEP 2017 review attached).
`
`Comparability Protocol (CP): The CP has undergone several iterations in this review
`cycle and the most recent version (from 8 NOV 2017 submission) is attached to this
`review. The CP was agreed upon by members of DMEPA, CDRH, OPQ OLDP, OPQ
`OPRO, OPQ OPF and OPQ ONDP.
`
`Nonproprietary Name: OPQ OPPQ in consultation with USP determined that the
`nonproprietary name will be “aripiprazole tablets with sensor”. The term ‘with sensor’
`will be added to ‘an upcoming USP General Chapter to describe products of this type. The
`applicant agreed to this change (N-0036), choosing to place the parentheses around the
`entire nonproprietary name, i.e. (aripiprazole tablets with sensor).
`
`Biopharmaceutics Considerations:
`1. BCS Classification:
`
`0 Drug Substance: 2 (low solubility, high permeability). The
`absolute BA of Abilify® is ~87%.
`- Drug Product: rapid to very rapid dissolution at pH 1.2 and 4.5,
`but not pH 6.8 .
`
`The Applicant’s biowaiver request is granted per 21 CFR 320.22(d)(4). The following is
`the agreed upon dissolution method and acceptance criterion:
`
`
`
`
`
`
`Spindle}
`Medium/
`Rotation1.
`Volume/'l‘em erature
`
`
`
`
`ifratus
`
`
`
`
`
`
`-cceptanceCriterion
`
`
`
`2, Paddle
`
`'
`900 mL pH 1.2 USP Buffer
`(degassed), at 37,:h 0.5 °C
`
`(b)
`=(4)% at 30 min
`
`OVERALL ASSESSMENT AND SIGNATURES: EXECUTIVE
`SUMMARY
`
`10
`
`OPQ-XOPQ-NDA 207202
`
`Reference ID: 41 85545
`
`

`

`
`
`
`
`11
`
`OPQ-XOPQ-NDA 207202
`
`Reference ID: 4185545
`
`

`

`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
`Office of Device Evaluation
`
`
`
`Date:
`To:
`
`September 1, 2017
`David Claffey, Ph.D.
`Brendan Muoio '
`
`Reviewer:
`
`Luke Ralston, Biomedical Engineer
`
`Branch:
`Division:
`
`CDDB
`DCD
`
`File:
`
`NDA 207202 (SN0030) —- Resubmission to Complete Response Letter
`
`Otsuka Pharmaceutical
`Applicant
`New Drug Application (NDA) — Combination Product
`Type:
`DMF 029332
`Linked file:
`Referenced file: K150494
`
`Recommendation: Approve
`
`Di 1 ital Si ~ nature Concurrence Table
`
`
`
`RewewcrSign-Off —
`
`
`_—
`
`I.
`
`Overview and Background
`
`Scope of Review
`I have been asked to review the design and performance information submitted for the IBM
`and patch hardware components of the TRADEMARK system. The system is also variously
`referred to as ABILIFY MYCITE and MINDI throughout the submission. The documents
`reviewed for this consult (SN0030) were:
`1.2.2
`Reviewer Guide
`2.5.1
`Clinical Overview/Product Development Rationale
`2.7.4
`Summary of Clinical Safety
`5.3.5.4
`Comparability Protocol, Software MAP, and Human Factors report
`
`This resubmission ofNew Drug Application (NDA) 207202 (aripiprazole + ingestible event
`marker [IEMD fi'om Otsuka Pharmaceutical is in response to the deficiencies outlined in the
`FDA Complete Response Letter (CRL) dated April 26, 2016. A subsequent Type A Meeting
`also provided additional comments to the sponsor on June 28, 2016. The NDA resubmission
`includes the following information to address the CRL:
`
`NDA 207202 (SN0030) — Resubmission to Complete Response Letter
`
`Page I of 19
`
`Reference ID: 41 85545
`
`

`

`0 As agreed upon with FDA in the June 28, 2016 Type A Meeting, the additional
`clinical trial requested in the CRL is not necessary given that the
`has been removed from the System.
`0 The data previously provided in Section 9.1.3 (Communication Timing) of the Type
`A Meeting Package are included in Module 2.5.1.2 of SN0030.
`o All software documentation has been resubmitted after incorporating the changes to
`address the human factors deficiencies. These documents are located in Module
`
`(ll) (4)
`
`5.3.5.4 [Notez software consulting review is provided in a separate memo by Nathalie
`Yarkony]
`0 The proposed comparability protocol for postmarket system updates and routine
`revisions has been updated following completion of the human factors studies and is
`located in Module 5.3.5.4.
`
`The IEM (Ingestible Event Marker) and patch components are'510(k)-cleared devices
`manufactured by Proteus Digital Health. Proteus Health has also submitted a Drug Master
`File (DMF 029332) for their IEM,
`tum)
`.. Several deficiencies were found in the DMF during review of the
`original NDA and no updates to the DMF were submitted concurrent with SN0030.
`
`Resubmission Material for NDA 207202
`
`The sponsor reassessed all studies conducted for validation of the IBM, patch, patient app, or
`HCP web portal as shown in the table below.
`
`Trill
`cm!
`08!
`
`A”! h It“
`TRADEMARK C
`
`
`3's.”W W Placebo mus
`emu Medw W
`* '5'“
`' m" M“
`ms..._ncrand “m
`Coupe-mt CNN:
`“‘0m
`
`“6'13“204’
`
`“with!!!
`Winder
`
`Opulakl.
`sidearm
`
`
`
`
`316.”205’ -
`
`Michell-fl
`
` “--
`mom—mm
`
`
`
`316-1!215:
`
`6-14-20
`M14
`
`07 h! 2015
`
`x
`Mm)
`
`a min
`
`NOTE: Only trial 316-13-215 is new information submitted with SN0030. It did not collect
`any data on IBM function, event detection rate, or patch performance.
`
`In response to the issues enumerated in FDA’s 4/26/2017 CRL, the sponsor recognizes that
`variable communication times along the data chain to the phone are to be expected.
`Contributors to communication timing include the patient and Patch being out of the
`
`NDA 207202 (SN0030) — Resubmission to Complete Response Letter
`
`Page 2 of 19
`
`Reference ID: 41 85545
`
`

`

`Bluetooth (BT) range of the compatible mobile device, or the mobile device being in an
`environment with poor data connectivity to the cloud. Other contributors can include the
`mobile device operating system prioritizing other tasks such as a phone call over cloud or BT
`data transfer. Date loss is prevented because the Patch is designed to store all data for the
`device’s 7-day lifespan.
`
`The sponsor has resubmitted the data from Trial 316-13-206b which demonstrates that the
`95th percentile for communication time for all time points and ingestionsrangcd from 28.6 to
`68.4 minutes (see table below). Most of the ingestions (110 of 116; 94.8%) were recorded in
`less than 120 minutes. The sponsor believes that the risk of longer communication times
`causing dosing errors and potential overdose situations will be appropriately mitigated by
`removing the
`m”.
`
`Table 2.5.1.2-2
`
`Frequencies of Subjects “'Ilo Received 'I‘imeline Ingestion
`Tiles on the Smartphone within Different Tuneframes (I'I'I
`Sample)
`
`umPoint
`
`. utes
`
`: our
`
`
`
`——‘_—
`——-Z--_
`——-__—
`
`r_-z-—
`
`—_—_
`34
`29
`90Minutes
`————
`How ——-Z--H-
`‘
`l
`
`aNumberofsubjectsinl'ITSampleingestinglEMathnsO 2 4_ M6
`bNumberofsubjectswithtilesreceivedbydiemrtphouewiflliufliechecidugfimeperiodforeach
`
`REVIEWER COMMENT: I agree that the data support use of the TRADEMARK system for
`tracking and trending now that the
`ma) has been removed from the mobile app.
`See Section VIII of this memo for the updated review of IBM functionality and validation.
`
`II.
`
`Device Description:
`
`This New Drug Application (NDA) requests approval for the TRADEMARK system and the
`proposed label claim:
`(m4)
`
`of adults with:
`
`to aripiprazole and is indicated for the treatment
`
`- Schizophrenia;
`0 Acute treatment of manic and mixed episodes associated with bipolar I disorder;
`0 Adjunctive treatment of major depressive disorder (MDD).
`
`NDA 207202 (SN0030) — Resubmission to Complete pronse Letter
`
`Page 3 of 19
`
`Reference ID: 41 85545
`
`

`

`TRADEMARK is composed of distinct components: (1) the Drugddevice Combination
`(aripiprazole + IEM, which is the investigational product); (2) the Proteus Patch; (3) the
`Patient Component (app) of the Otsuka Medical Soflware, (4) the Cloud-based Server; and
`(5) the Web Portals of the Otsuka Medical Software. The components of TRADEMARK are
`illustrated in the Figure below.
`
`
`
`TRADEMARK System
`
`NOTE: Although the sponsor attempts to describe the Proteus MDDS and the Patient
`Component (app) as separate components of the system, they bOth run on the patient’s
`mobile device so have been reviewed as one component.
`
`
`
`
`
`Table 2.3.1-1
`
`Currently Supported Mobile Devices and Operating Systems
`
`Mobile Devices
`iPhone (OMSS App)
`
`6. 68 60$ 93: or later)
`
`Pane-a app
`Version 2.0.0
`
`
`
`
`
`The Patient Component (app) of the Otsuka Medical Software, which resides on a paired
`mobile computing device (currently iPhone 6 or later), receives data from the Proteus
`software also installed on the mobile device. The mobile device transmits data via cellular or
`Wi-Fi connectivity to the Otsuka Cloud-based Server. The Patient Component(app) of the
`Otsuka Medical Software has both automatic and optional features; the automatic features
`include:
`
`0 Registration of aripiprazole + HEM ingestion (i.e., after the ingestion of an'piprazole
`+IEM, the IBM is activated in the stomach, communicates with the Patch, which then
`registers the IEM’s ingestion date and time on the Patient app);
`
`.
`
`om)
`
`have been removed from this submission;
`0 Daily, weekly, and monthly views ofmedication adherence behavior are
`automatically available for review by the patient in the Patient Component (app) of
`the OtsukalMedical Sofiware;
`mu) data are automatically transmitted to the
`In addition, these
`Otsuka Cloud-based Server for processing and display on the HCP Web Portal of the
`OtSuka Medical Sofiware.
`
`o
`
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`Optional features ofthe Patient Component (app) ofthe Otsuka Medical Software include the
`options for the patient:
`0 Toshare—datawithhis/hercaregiver;
`0 To legister moodandrestquality,which canbereviewedand, if elected, sharedwith
`the patient’s HCPand/or caregiver;
`0 To share Patch-registered activity and rest data with the patient’s HCP and/or
`caregiver.
`
`The Proteus system has been cleared using the product code OZW under the following
`510(k) submissions:
`K113070/DEN120011
`
`K131009
`
`K131524
`
`K133263
`
`K150494
`
`Aripiprazole + [EM tablets (2, 5, 10, 15, 20 and 30 mg strengths) are developed as drug-
`device combination
`
`
`uct.
`
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`
`
`flaiswastheoriginalmodelpmduoedbyProteuspriortozms'andused?
`Otsukainsomephases ofpmductdevelopment. Itis alsorefen'edtoas
`msome ofthe development documents.
`—thisis the current model
`ed'in the TRADEMARKsystem. It'1s also
`referred toas- in some 0 the development documents.
`
`1.
`
`2 configumfions:
`
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`

`III.
`
`Shelf LifeIStabilifl
`Some shelf-life/stability data was submitted in Section 2.3.8.7 of the DMF; however, it only
`included the- design and did not contain any drug component.
`
`
`
`IV- mum:
`No biocompatibility information is provided in the NDA. I defer to the CDER lead office for
`the‘need for a Pharmacology and Toxicology review.
`
`V- W
`A software cousin: was provided by Nathalie Yarkony (CDRH/ODE/DCD/CDDB).
`
`
`
`
`
`REVIEWER COMMENT: I defer to the review by Nathalie Yarkony for determination of
`adequate software development and validation. I defer to CDER Product Jurisdiction team
` for determination of the final comparability protocol.
`
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`

`VI.
`
`EMC & Electri Mechanical and Th
`
`Saf
`
`During the classification of ingestible sensors in 2012, CDRH identified 8 risks to health
`shown in the table below:
`
`
`
`
`
`
`
`
`
`Electrical Safety
`
`Electrical/Mechanical failure
`
`
`
`Failure to mark event
`
`‘
`
`Failure to excrete
`
`
`
`
`
`
`
`
`
`Animal and Clinical testing
`.
`
`Human Factors testing
`Usability
`
`'
`Batten)? design,
`Low—power transmission (heating and tissue stimulation)
`
`Battery and IC design
`
`Animal and Clinical testing .
`
`
`
`NOTE: I defer to the CMC review for the adequacy oftime manufacturing controls and
`implementation for the final finished combination product.
`
`
`
`
`
`Electrical Failure
`
`
`
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`

`
`
`REVIEWER COMMENT: EMC & Electrical, Mechanical, and Thermal safety are adequate.
`
`VII We
`Reviewed by CDRH Office ofCompliance and not includedto this memo.
`
`VIII. Moe Verifieem:1 mg Validation
`
`Bench Testing
`Thebmchteefing for-thispmduet focusedonIEM acfivafionafieringestionandlEM
`functionality. Since activation is dependent upon exposure to the patient’s stomach acid, the
`sponsor performed dieselution studies to demonstrate proper activation The sponsor also
`condmtedseparatemfingtodanonstrateIEM fimctionalityafierthenewmmfiacturingand
`storage conditions required by the drug substance.
`
`
`
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`
`
`l) Dissolution performance
`.To confirm that insertion ofthe IBM had no impact on physicochemical and biological
`properties ofthe proposed combination product, two comparative dissolution studies were
`conducted. It is noted that lEM activation depends more on tablet disintegration than
`dissolution so this CDRH review focused only on data relevant to disintegration.
`
`The first comparative dissolution study in three dilferent dissolutiOn media, pH 1.2, 4.5 and
`6.8, were conducted to demonstrate that the proposed Aripiprazole + IEM, would behave
`equivalently to commercially available Abilify tablets. The second comparative dissolution
`smdywasconductedtodemonsmtecompmbilityofthefinalAfipipmzoleHEM’
`formulation which will use- colorant in order to distinguish it from current Abilify tablets.
`
`The sponsor concludesthat “the presence of an IBM has no adverse impact on the dissolution
`performance (drug release) from the proposed combination tablet and thus the same
`
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`dissolution method with the same limit for commercial Abilify tablets (
`minutes) is proposed for this combination product.”
`
`A in 30
`
`These studies
`criteria of
`
`'d not provide any information about tablet disintegration and the acceptance
`
`/o within 30 minutes raised concerns about
`
`NOTE: The results summarized below only include the- design with no data
`submitted for the- design.
`
`
`
`
`
`
`“mu
`
`
`"mm—m
`
`
`
`
`
`————-EZEE-
`
`Distribution of Tablet Disintegration Times (minuteszseconds)
`
`
`
`Mean- and Minimum IEM Lifetime Measurements (seconds)
`
`IEM + mm vs. LEM + An'pjmle
`Section 3.2.P.2.2.1.3 uses DFAT to compare currently cleared IEM + placebo tablet to the
`proposed IEM + Aripiprazole at all dosages of the API. The results show a slightly longer
`' IEM lifetime in the IBM + Aripiprazole compared to placebo. The smallest difl‘erence was in
`the 2mg Aripiprazoie formulation which showed an approximate 50% greater lifetime ofthe
`Aripiprazole batches. The mean IEM lifetime was progressively longer for each of the 5mg,
`10mg, 15mg, 20mg, and 30mg formulations.
`
`Thesponsmexplainedmmmedifl'mencemfifefimeisbecmiselfiMacfivafiondepmdson
`
`
`
`NDA 207202 (SN0030) — Resubmission to Complete Response Letter
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`

`(b) (4)
`
`CDRH COMMENT: The bench testing and in-vitro data has adequately quantified the
`performance of the device within the tablet in idealized conditions. The sponsor has
`
`conducted clinical testing to demonstrate in-vivo performance.
`
`Animal Testing
`No animal testing was included in this NDA.
`
`A number of animal studies were submitted in DMF 029332. These were for studies that had
`
`been performed for prior product development and partly in support of 510(k) submissions
`for the stand-alone IBM reviewed by CDRH. Dr. Annabelle Crusan provided a consulting
`review for the DMF and identified 5 deficiencies which were sent to Proteus. In a 2/8/16
`
`teleconference, Proteus acknowledged the deficiencies in the animal testing but does not plan
`to submit the requested information. Ultimately, the animal data was not used to support any
`section of this NDA but did not require resolution since Otsuka submitted clinical testing as
`discussed in the next section of this memo.
`
`Clinical Testing
`Given the difference in performance between the IBM + placebo and [EM + Aripiprazole in
`bench testing, Otsuka conducted 2 clinical studies under their OSMITTER protocol.
`OSMITTER 206A — validate in-vivo performance of IBM (
`0”“? version) + placebo and
`IBM ( W" version) + Aripiprazole combination
`OSMITTER 206B — validate in—vivo performance of [EM W" version) + placebo
`
`The purpose of these studies was twofold:
`1. Validate [EM detection
`
`2. Validate data transmission capabilities of all system components
`
`OSMITTER 206A
`
`This trial was conducted to determine the accuracy of IBM detection by completing a series
`of patch applications and IBM ingestions in the clinic. The study subjects were not
`responsible for any aspect of patch placement, pairing to the mobile device, data
`interpretation, or troubleshooting; Following placement of the patch by clinic stafi', subjects
`ingested one IEM tablet approximately every 2 hours, for a total of4 ingestions. The subjects
`ingested one 10—mg aripiprazole—embedded IEM (aripiprazole + IEM) tablet without food I
`(Hour 0), one placebo-embedded IBM (placebo + IBM) tablet without food (approximately
`Hour 2), one placebo + [EM tablet with a high—fat meal (apprOximately Heur 4), and one
`_ placebo + IBM tablet without food (approximately Hour 6).
`
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`Results are shown in the table below:
`
`Hour 2b
`
`Hour 4c
`
`30
`
`30
`
`22 (73.3)
`
`1.9 (63.3)
`
`23 (76.7)
`
` Proportion of Subjects with Ingestible Event Marker Detection
`
`IEM Detected (’/o)
` Timepoint
`
`90% CI (%, %
`Subject lngestions
`30
`Hour 0“
`
`
`
`
`
`
`Hour 6"
`30
`28 (93.3)
`(80.5, 98.8)
`
`
`
`(69.4, 82.9)
`92 (76.7)
`120
`Total
`a * aripiprazole * IEM without food; b = placebo - IEM without food; c = placebo - IEM 30 minutes after high—fut meal
`
`(57.0, 86.0)
`
`(46.7, 77.9)
`
`(60.6, 88.5)
`
`This study has a number of limitations and discrepancies:
`0 Only I = 0 evaluated aripiprazole + IBM
`0 Only the
`mm) version was used in this study
`0 At t = O, 2, 4 deteetion is far below 97% historical average
`
`I The study did not use final commercial-release versions of the patch or software
`
`In an attempt to reconcile the poor performance of detection the sponsor conducted a post-
`hoc analysis of data transmission times. As shown in the table below, there was significant
`latency noted when sending data from the Proteus patch to the Proteus sofiware application.
`
`(b) (4)
`
`'
`
`All units are in minutes;
`Otsuka app software
`
`OSMITTER 206B
`
`(”(4)— proprietary Proteus software that receives data from the patch and inputs to
`
`As a result of the limitations and poor performance in the 206A study, Otsuka conducted the
`206B study.
`
`The primary objective was to measure the accuracy of IBM detection using the placebo +
`IBM, and to evaluate the latency period between site-reported ingestion time and detection of
`the ingestion event by the Patch. Secondary objectives were to measure the latency period
`between the Patch detection of the ingestion event and transmission of the event in the
`Otsuka Cloud-based Server.
`
`NDA 207202 (SNOO30) — Resubmission to Complete Response Letter
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`

`The trial was conducted with the DWS Proteus Patch (Patch) and Otsuka application (app)
`software version 1.5.2.
`
`Proportion of Subjects with lngestible Event Marker Detection
`
`Timepoint
`
`Subject lngestions
`
`um Detected 0/.)
`
`95% C] m, %)
`
`.
`
`29
`
`29
`
`29
`
`29
`
`28 (96.6)
`
`26 (89.6)
`
`28 (96.6)
`
`29 (100)
`
`_
`
`(82.2, 99.9)
`
`(—, —)*
`
`(82.2, 99.9)
`
`(88.1, 100.0)
`
`Hour 2
`
`Hour 4
`
`Total
`
`1 11 (95.6)
`
`
`Overall detection accuracy improved in study 2063. Data latency also improved but still
`showed an