CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`207202Orig1s000
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`SUMMARY REVIEW
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`Cross Discipline Team Leader Review
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`Cross—Discipline Team Leader Review
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`Date
`October 20, 2017
`From
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`m Cross-Disci n line Team Leader Review
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`Otsuka Pharmaceutical Coman Ltd.
`
`Date of Submission
`April 21, 2017
`PDUFA Goal Date
`October 21, 2017
`
`disorder in adult 0 atients.
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`Proprietary Name /
`Established
`S ‘
`
`names
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`Abilify MyCite (aripiprazole tablets with sensor)
`
`Dosa_e forms / Stren_ h
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`Tablets with Sensor/ 2, 5, 10, 15, 20 and 30 my
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`Proposed Indication(s)
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`The system is intended to track ingestion of aripiprazole
`tablets as indicated for schizophrenia, acute treatment of
`manic and mixed episodes associated with bipolar I
`disorder, and adjunctive treatment of major depressive
`
`1. Introduction and Background
`
`Aripiprazole is an atypical antipsychotic originally approved on November 15, 2002
`(tradename Abilify; NDA 021436). It is indicated in adults for the treatment of schizophrenia,
`acute treatment of manic and mixed episodes associated with bipolar I disorder, and adjunctive
`treatment of major depressive disorder. With this Class 2 resubmission, the Applicant (Otsuka)
`is seeking approval of Abilify MyCite (aripiprazole tablets with sensor), a system intended (04’;
`for the above indications in adult patients.
`The Applicant is not pursuing approval for aripiprazole’s pediatric indications (i.e., irritability
`associated with autistic disorder or for the treatment of Tourette’s disorder).
`
`The proposed product is a drug-device combination in which the Applicant’s product,
`aripiprazole (Abilify tablets), is combined with a 510(k)-cleared device manufactured by
`Proteus Digital Health (hereafter, “Proteus”). The Proteus device, cleared in February, 2014,
`includes an ingestible sensor or ingestible event marker GEM) and a wearable patch to detect
`when the IBM has been ingested. The product under review includes the IBM embedded
`within aripiprazole tablets, the wearable patch, a medical device data system (MDDS) that
`runs on the patient’s smartphone, a smartphone application (app), and a web portal for use by
`the prescriber if permission is granted by the patient. When used together, the Applicant claims
`that this system (known as “MlNDl” during development) will allow patients in the currently-
`indicated populations listed above
`M“); if the patient chooses,
`he or she can also allow others (e.g., physician, caregivers, etc.) to review the information
`recorded.
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`Page 1 of 8
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`Reference ID: 41 80408
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`Cross Discipline Team Leader Review
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`This resubmission is a response to the complete response (CR) action taken on April 26, 2016.
`A CR action was taken mainly due to the risk to the patient
`«1114)
`
`Another related problem noted in the
`initial review was the relatively high number of ingested tablets the system failed to detect and
`the high variability in latency times for data transmission within the system. The CR letter also
`stated that the Human Factors (HF) study did not provide sufficient data to conclude that the
`app’3 user interface supported safe and effective use of this product. The Agency requested
`improvements to the user interface to mitigate the risk for medication errors and to ensure that
`the product could be used safely by intended users for intended uses and environments. In the
`CR letter, the Agency also agreed that the removal of the
`M“) of the app was an
`acceptable risk—mitigating step to address these concerns.
`
`In response to the CR action, the Applicant:
`(m4). Because the
`0 Updated the app and removed the
`was removed, the Agency agreed in the June 28, 2016, Type A Meeting Preliminary
`Comments that the additional clinical trial requested in the CR letter was no longer
`necessary.
`
`('3) (4)
`
`0 Resubmitted all software documentation after incorporating the changes to address the
`human factors deficiencies.
`
`0 Updated the proposed comparability protocol for postmarketing system updates and
`routine revisions, following completion of the human factors studies.
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`0 Provided the full commercial drug product manufacturing batch records for each dose
`strength.
`
`0 Conducted another HF validation study to test the app.
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`2. CMCIDevice
`
`The Office of Pharmaceutical Quality (OPQ) and Center for Devices and Radiological Health
`(CDRH) reviews were conducted by the following team of reviewers:
`
`DISCIPLINE
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`PINIARY/SECONDARY
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`REVIEWER
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`Mariappan Chelliah/Wendy
`Drug Substance & Drug Product
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`Wilson
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`Process and Microbiology
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`Hang Guo/Akm Khaimzzaman
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`Steven Henz/PeterQiu
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`
`
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`CDRH Software Reviewer
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`Natalie Yarkony
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`RBPM
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`Application Technical Lead
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`Teshara Bouie
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`David Claffey
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`Cross Discipline Team Leader Review
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`All members of the OPQ and CDRH review team and their consultants recommend approval
`for this resubmission.
`
`In summary, the proposed drug-device combination product is composed of the following
`main components (see Figure 1):
`1. Aripiprazole immediate-release tablets imbedded with an IEM sensor in the same
`strengths as the approved Abilify tablets (2, 5, 10, 15, 20 and 30 mg). The composition
`of the proposed tablets is qualitatively and quantitatively identical to Abilify tablets,
`except for the addition of the IEM sensor and the use of different amounts of colorants
`to distinguish them from Abilify tablets.
`2. MyCite Patch: This is a wearable sensor which adheres to the torso; it picks up the
`signal from the IEM
` and transmits it to the patient’s
`smartphone (via Bluetooth).
`3. Smartphone software (app): Receives data from the patch and displays data about the
`ingestion event for the patient. The app can also transmit the data to the Otsuka Cloud-
`based server. This allows the designated healthcare professional (HCP) or caregiver to
`review the data if the patient grants the necessary permissions.
`
`Figure 1: Product Overview
`
`The OPQ Office of Policy for Pharmaceutical Quality (OPPQ), in consultation with US
`Pharmacopeia (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.
`
`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.
`The April, 2016, CR letter included deficiencies related to an Otsuka manufacturing site
`(FEI:3003808559). The Applicant has resolved these issues.
`
`Luke Ralston from CDRH reviewed the hardware for the original application and for this
`resubmission. In his latest review, he concludes that “the data support use of the
`TRADEMARK system for tracking and trending now that the
` has been
`removed from the mobile app”.
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`(b) (4)
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`Cross Discipline Team Leader Review
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`It should be noted that the app software
`
`M“)
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`processes this information for display on the phone. The Otsuka
`component also transmits the data to the Otsuka Cloud-based server for sharing with
`designated parties. Nathalie Yarkony and Linda Ricci from CDRH evaluated the app in this
`review cycle.
`
`Note that the proposed use of the patient’s mobile device to perform data analytics changes its
`classification in the 510(k)-cleared Proteus device as an accessory (under the Mobile Medical
`Application paradigm) to the primary monitor — a Class 11 medical device not subject to
`enforcement discretion.
`
`3. Nonclinical Pharmacology/Toxicology
`
`No new nonclinical data were provided with this resubmission.
`
`4. Clinical Pharmacologleiopharmaceutics
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`No new clinical pharmacology information was provided with this resubmission.
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`5. Clinical Microbiology
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`No clinical microbiology information was submitted with this application.
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`6. Clinical/Statistical- Efficacy
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`No new clinical efficacy data were submitted with this application.
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`7. Safety
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`The Applicant successfully demonstrated bioequivalence between the approved oral
`aripiprazole tablets and the proposed product during the original NDA submission. The
`Applicant relies on the Agency’s previous efficacy and safety findings for aripiprazole oral
`tablets for the proposed product for the intended indications. No new clinical data were
`submitted in this review cycle.
`
`Daniel Lee, MD, was the clinical reviewer for this resubmission; he recommends approval. As
`previously discussed, a major concern during the initial review cycle was the potential for
`patients to take additional tablets,
`M“) if the system failed to register
`an ingestion. Dr. Lee agrees with other review team members that the removal of this function
`sufficiently mitigates this risk. In reviewing the entire safety data provided by the Applicant
`during the first review cycle, Dr. Lee notes frequent but mild and self-limited rashes at patch
`application site in trials extending up to 12 weeks. However, he believes the risks for skin
`imitation can be mitigated with labeling.
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`Finally, Dr. Lee is concerned that 21 (12.1%) of 174 subjects exposed to the proposed product
`in three trials experienced infections. These infections varied widely from gastroenteritis,
`sinusitis, fungal, urinary tract, upper respiratory tract, and tooth or gum infections. He
`compared his observation to the infection rates seen in previous aripiprazole trials and post-
`marketing data and found the MyCite rates to be “9-18 times the predicted percentage of total
`adverse events.” Dr. Lee recommends that postmarketing studies further evaluate this risk. In
`my opinion, the low number and high variability of infection-related adverse events (AEs) in
`these trials do not allow us to draw any substantive conclusions regarding an increased risk of
`infection. Furthermore, one must be careful in comparing MyCite trials with other oral
`aripiprazole trials, due the significant differences in trial design and subject characteristics.
`Finally, a direct comparison against postmarketing data is also difficult to interpret due to
`multiple confounding factors. I remain unconvinced that an increased risk exists for infection-
`related AEs in patients using MyCite..
`
`8. Advisory Committee Meeting
`No Advisory Committee meeting was held. This resubmission was discussed internally at a
`Medical Policy Council (MPC) on October 20, 2017. In summary, it was decided that the
`application could be approved with appropriate disclaimers in product labeling (to be
`discussed in detail in the following sections).
`9. Pediatrics
`The Applicant has an agreed Pediatric Study Plan (June 11, 2014). No changes to the agreed
`pediatric plan were proposed with this resubmission.
`
`10.
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`Other Relevant Regulatory Issues
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`Comparability Protocol
`Still outstanding is the issue of post-approval software design control. A comparability
`protocol (CP) is being negotiated between the Agency and the Applicant. The CP will
`delineate
`. The CP has
`undergone several iterations in this review cycle and a final CP has not yet been agreed upon.
`
`Web Portal Regulation
`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, because it
`is described as part of the product in the product’s labeling. Software regulation is an evolving
`topic, especially since the recent passage of the 21st Century Cures Act. Ashley Boam,
`Director of OPQ OPPQ, determined that the web portal software does not need to be regulated
`in its present form, as the user is the healthcare provider and the information being provided
`merely summarizes the patient-level information and provides no treatment recommendations.
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`Cross Discipline Team Leader Review
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`Human Factors Studies
`In the previous review cycle, the Division of Medication Error Prevention and Analysis
`(DMEPA) found the results of the HF patient interface validation study unacceptable, as just
`one out of 36 participants successfully used the product.
`
`As requested in the CR letter, this resubmission includes the results from a new simulated-use
`HF validation study. The study included 35 patients who represented three distinct user groups
`based on diagnosis [schizophrenia (n=12), bipolar I disorder (n=12), and major depressive
`disorder (n=11)]. The participants were randomly assigned to an assisted onboarding or an
`unassisted onboarding group. Each participant completed two sessions, separated by a period
`of approximately 24 hours. Onboarding tasks were conducted on Day 1 and the remaining
`tasks conducted on Day 2. The user groups and use scenarios (assisted and unassisted) were
`considered representative of real-world use by DMEPA.
`
`The results showed there were tasks failures where participants indicated they would take or
`would consider taking an additional tablet. DMEPA evaluated the task failures, the
`Applicant’s root cause analyses of these, and the existing mitigation strategies and they
`concluded that the risks of extra dose and dose omission have been sufficiently minimized.
`Based on discussions with the review team, DMEPA understands that infrequent ingestion of
`an extra dose or dose omission is unlikely to result in clinically significant harm to the patient.
`While it is possible that additional changes to the app user interface could further reduce the
`residual risk, they found that the residual risk is mitigated to an acceptable level and changes
`to the app user interface are not necessary prior to approval.
`
`Office of Prescription Drug Promotion
`The Office of Prescription Drug Promotion (OPDP) reviewers, Aline Moukhtara and Shawna
`Hutchins found the Medication Guide (MG) acceptable after their feedback was incorporated.
`Because the Agency did not consider the web-based portal for HCPs and caregivers to be
`approved labeling, OPDP recommended that the portal be removed from the label. However,
`the rest of the review team considered the portal to be a purposeful component of the MyCite
`system and disagreed with this recommendation.
`
`Numerous questions also arose in relation to the app. OPDP had concerns regarding what was
`to be considered promotional vs. approved labeling, whether promotional labeling could
`coexist with approved labeling electronically, and how to differentiate between these within
`the app. In this product, the Instructions for Use (IFU) are electronic and in the app
`(considered approved labeling). In addition to tracking medication ingestion, the app has
`features to track mood, activity, and rest; these are considered promotional labeling and are
`subject to regulation. OPDP recommended that these additional features be completely
`removed from the app. These recommendations were discussed internally at the MPC meeting
`held on October 20, 2017. During this meeting, it was decided that these features (i.e., mood,
`rest, and activity tracking) could remain functional within the app provided than an adequate
`disclaimer (i.e., that these features have not been evaluated by the FDA) is clearly displayed in
`the app and the label. The exact language for this disclaimer should appear in the Limitations
`of Use (see Section 11) in the product’s label, the app’s login screen, physician web portal
`login screen, and web portal summary screen.
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`11.
`
`LabeHng
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`The proprietary name Abilify MyCite was conditionally accepted by DMEPA. OPQ, in
`consultation with USP, determined that the nonproprietary name would be “(aripiprazole
`tablets with sensor)” or “(aripiprazole) tablets with sensor”. The Applicant proposed a label
`claim that this product is
`(m4) Given that there are no
`controlled trials to support this claim and the known limitations of the proposed product, the
`review team thought the term
`(hm) would have promotional implications and that a
`more appropriate claim would be that it is “intended to track drug ingestion.”
`
`The following Limitations of Use (LOU) were added to the label:
`0 The
`(m4) of ABILIFY MYCITE to improve patient compliance or modify
`aripiprazole dosage has not been established.
`0 The use of ABILIFY MYCITE to track drug ingestion in “real-time” or during an
`emergency is not recommended because detection may be delayed or not occur.
`
`Additionally, language related to the fimctions not evaluated by the FDA will be included in
`the app and web portal. The final language is being negotiated at the time of this writing but
`will be similar to the following statement:
`0
`
`(mm
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`The Applicant has agreed to these changes.
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`12.
`
`Recommendations/Risk Benefit Assessment
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`The Applicant demonstrated substantial evidence of Abilify Mycite usability in one simulated
`use trial. When used in conjunction with the Medical Information Device #1 (MINDl) system,
`97% of Abilify + IEM ingestions are detected by the wearable sensor and detection is
`accurately communicated to both the MyCite app and the clinician/caregiver web portal.
`However, 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.
`(m4)
`
`Individual results will depend on the patient’s ability to use the product correctly. This greatly
`depends on the IFU, both printed and electronic. DMEPA’s evaluation of the task failures in
`the HF study and the Applicant’s root cause analyses, and the existing mitigation strategies
`concluded that the risks of extra dose and dose omission have been sufficiently minimized.
`The risk of extra doses was greatly mitigated by the removal of the
`(lam) in this
`review cycle. Addition of LOU statements to the labeling further mitigates the risk and ensures
`that the patient does not take immediate action based on the recorded ingestion data in the app.
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`It also states that, as noted above, the product has not been demonstrated to increase
`compliance.
`
`If the MyCite system fails, patients will not incur additional risk; they will continue to receive
`the exact treatment benefits of aripiprazole tablets without tracking. If the system works as
`intended and the patient choses to share the data with the HCP, the drug ingestion data could
`potentially help guide the prescribing physician on treatment interventions. No new safety
`signals were identified in the development program and the overall benefit-risk ratio for the
`proposed product remains similar to that of aripiprazole oral tablets.
`
`Although the novelty of the proposed product and its components led to unique questions
`during the review process, the review team has reached a consensus to approve Abilify MyCite
`with the LOU highlighted in Section 11. Decisions regarding the contents and regulation of the
`app and the web portal are highlighted in Section 10. The labeling and MG have been
`negotiated with the Applicant to satisfaction. I agree with the review team’s decision to
`approve this product.
`
`Recommendation for Postmarketing Risk Evaluation and Management Strategies:
`None.
`
`Recommendation for other Postmarketing Requirements and Commitments:
`The final postmarketing requirements are being finalized as of the time of this writing. The
`final language and dates will be included on the Approval Letter.
`1. Conduct a human factors usability study using the to be marketed product in
`pediatric patients with bipolar I disorder and irritability with autistic disorder ages
`10 to 12 years and 6 to 12 years, respectively.
`2. Conduct a human factors usability study using the to be marketed product in
`pediatric patients ages 13 to 17 years with schizophrenia, bipolar I disorder, and
`irritability with autistic disorder.
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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/
`----------------------------------------------------
`
`JAVIER A MUNIZ
`11/13/2017
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`MITCHELL V Mathis
`11/13/2017
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`Reference ID: 4180408
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`