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

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`
`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 207202
`Priority or Standard Standard
`
`
`Submit Date(s) 04/21/2017
`Received Date(s) 04/21/2017
`PDUFA Goal Date 10/21/2017
`Division/Office DPP/ODE1
`
`
`Reviewer Name(s) Daniel J. Lee, MD
`Review Completion Date 10/26/2017
`
`
`Established Name aripiprazole
`(Proposed) Trade Name Abilify Mycite
`Applicant Otsuka Pharmaceutical Development and Commercialization,
`Inc
`
`
`Formulation(s) Oral tablet, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
`Dosing Regimen once daily
`Proposed Indication(s)
`
`Intended Population(s)
`
`
`
`
`
`Recommendation on
`Regulatory Action
`Recommended
`Indication(s) (if applicable)
`
`
`Approve
`
`schizophrenia, acute treatment of manic and mixed episodes
`associated with bipolar I disorder, bipolar I maintenance, and
`adjunctive treatment of major depression
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`1
`
`Reference ID: 4173048
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`
`Table of Contents
`
`Glossary ........................................................................................................................................... 7
`
`1
`
`Executive Summary ................................................................................................................. 9
`
` Product Introduction ........................................................................................................ 9
`
` Conclusions on the Substantial Evidence of Effectiveness .............................................. 9
`
` Benefit-Risk Assessment ................................................................................................ 10
`
`2
`
`Therapeutic Context .............................................................................................................. 15
`
` Analysis of Condition ...................................................................................................... 15
`
` Analysis of Current Treatment Options ......................................................................... 15
`
`3
`
`Regulatory Background ......................................................................................................... 15
`
` U.S. Regulatory Actions and Marketing History ............................................................. 15
`
`
`
`
`
`Summary of Pre-Submission/Submission Regulatory Activity ....................................... 16
`
`Foreign Regulatory Actions and Marketing History ....................................................... 16
`
`4
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety................................................................................................................. 17
`
` Office of Scientific Investigations (OSI) .......................................................................... 17
`
` Product Quality .............................................................................................................. 17
`
` Clinical Microbiology ...................................................................................................... 17
`
` Nonclinical Pharmacology/Toxicology ........................................................................... 17
`
` Clinical Pharmacology .................................................................................................... 17
`
` Mechanism of Action .............................................................................................. 17
`
` Pharmacodynamics ................................................................................................. 17
`
` Pharmacokinetics .................................................................................................... 17
`
` Devices and Companion Diagnostic Issues .................................................................... 18
`
` Consumer Study Reviews ............................................................................................... 18
`
`5
`
`Sources of Clinical Data and Review Strategy ....................................................................... 18
`
` Review Strategy .............................................................................................................. 20
`
`6
`
`Review of Relevant Individual Trials Used to Support Efficacy ............................................. 20
`
` MIND1 System 2016 Human Factors Patient Interface Validation [DC-001576] .......... 20
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`2
`
`Reference ID: 4173048
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`
` Study Design............................................................................................................ 20
`
` Study Results ........................................................................................................... 21
`
`Table 3: Demographic Information Tracked by Applicant ........................................................ 23
`
` Trials Reviewed During the First Review Cycle .............................................................. 26
`
` Confounding in Repeat-Dose Trials ........................................................................ 26
`
`7
`
`Integrated Review of Effectiveness ....................................................................................... 26
`
` Assessment of Efficacy Across Trials .............................................................................. 26
`
` Additional Efficacy Considerations ................................................................................. 26
`
` Considerations on Benefit in the Post-Market Setting ........................................... 26
`
` Other Relevant Benefits .......................................................................................... 26
`
`
`
`Integrated Assessment of Effectiveness ........................................................................ 26
`
`8
`
`Review of Safety .................................................................................................................... 26
`
`
`
`Safety Review Approach ................................................................................................ 27
`
`The submitted trial contained no safety data. ......................................................................... 27
`
` Adequacy of Applicant’s Clinical Safety Assessments .................................................... 27
`
` Issues Regarding Data Integrity and Submission Quality ....................................... 27
`
` Categorization of Adverse Events ........................................................................... 27
`
` Routine Clinical Tests .............................................................................................. 27
`
`The submitted trial contained no safety data. ......................................................................... 27
`
`
`
`
`
`Safety Results ................................................................................................................. 27
`
` Infection Risk ........................................................................................................... 27
`
`Safety in the Post-Market Setting .................................................................................. 28
`
` Safety Concerns Identified Through Post-Market Experience ............................... 28
`
` Expectations on Safety in the Post-Market Setting ................................................ 29
`
` Additional Safety Issues from Other Disciplines ............................................................ 29
`
`
`
`Integrated Assessment of Safety ................................................................................... 29
`
`9 Advisory Committee Meeting and Other External Consultations ......................................... 29
`
`10 Labeling Recommendations .................................................................................................. 29
`
`
`
`Prescribing Information .............................................................................................. 29
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`3
`
`Reference ID: 4173048
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`
`
`
`
`
`Patient Labeling .......................................................................................................... 30
`
`Non-Prescription Labeling .......................................................................................... 30
`
`11 Risk Evaluation and Mitigation Strategies (REMS) ................................................................ 30
`
`12 Appendices ............................................................................................................................ 31
`
`References .................................................................................................................. 31
`
`Financial Disclosure .................................................................................................... 31
`
`
`
`
`
`
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`4
`
`Reference ID: 4173048
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`
`Table of Tables
`Table 1: Summary of FDA-Approved Long-Acting Antipsychotics................................................15
`Table 2: Table of Clinical Studies..................................................................................................19
`Table 3: Demographic Information Tracked by Applicant............................................................23
`Table 4: Listing of All Participant Failures in DC-001576..............................................................24
`Table 5: Rates of Infection Noted in Repeat-Dose Abilify Mycite Trials.......................................28
`
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`5
`
`Reference ID: 4173048
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`
`Table of Figures
`
`
`None
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`6
`
`Reference ID: 4173048
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`
`Glossary
`
`
`AC
`
`AE
`
`BLA
`
`BPCA
`
`BRF
`
`CBER
`
`CDER
`
`CDRH
`
`CDTL
`
`CFR
`
`CMC
`COSTART
`CRF
`
`CRO
`
`CRT
`
`CSR
`
`CSS
`
`DMC
`
`ECG
`
`eCTD
`
`ETASU
`FDA
`
`FDAAA
`FDASIA
`GCP
`
`GRMP
`ICH
`
`IND
`
`ISE
`
`ISS
`
`ITT
`
`MedDRA
`mITT
`
`NCI-CTCAE
`NDA
`
`NME
`
`OCS
`
`
`advisory committee
`adverse event
`biologics license application
`Best Pharmaceuticals for Children Act
`Benefit Risk Framework
`Center for Biologics Evaluation and Research
`Center for Drug Evaluation and Research
`Center for Devices and Radiological Health
`Cross-Discipline Team Leader
`Code of Federal Regulations
`chemistry, manufacturing, and controls
`Coding Symbols for Thesaurus of Adverse Reaction Terms
`case report form
`contract research organization
`clinical review template
`clinical study report
`Controlled Substance Staff
`data monitoring committee
`electrocardiogram
`electronic common technical document
`elements to assure safe use
`Food and Drug Administration
`Food and Drug Administration Amendments Act of 2007
`Food and Drug Administration Safety and Innovation Act
`good clinical practice
`good review management practice
`International Conference on Harmonization
`Investigational New Drug
`integrated summary of effectiveness
`integrated summary of safety
`intent to treat
`Medical Dictionary for Regulatory Activities
`modified intent to treat
`National Cancer Institute-Common Terminology Criteria for Adverse Event
`new drug application
`new molecular entity
`Office of Computational Science
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`7
`
`Reference ID: 4173048
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`
`OPQ
`
`OSE
`
`OSI
`PBRER
`PD
`
`PI
`
`PK
`
`PMC
`
`PMR
`
`PP
`
`PPI
`
`PREA
`
`PRO
`
`PSUR
`
`REMS
`SAE
`
`SAP
`
`SEALD
`SGE
`
`SOC
`
`TEAE
`
`
`
`Office of Pharmaceutical Quality
`Office of Surveillance and Epidemiology
`Office of Scientific Investigation
`Periodic Benefit-Risk Evaluation Report
`pharmacodynamics
`prescribing information
`pharmacokinetics
`postmarketing commitment
`postmarketing requirement
`per protocol
`patient package insert
`Pediatric Research Equity Act
`patient reported outcome
`Periodic Safety Update report
`risk evaluation and mitigation strategy
`serious adverse event
`statistical analysis plan
`Study Endpoints and Labeling Development
`special government employee
`standard of care
`treatment emergent adverse event
`
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`8
`
`Reference ID: 4173048
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`1 Executive Summary
`
`
`
`Product Introduction
`
`Aripiprazole is an atypical antipsychotic that received U.S. approval on November 15, 2002
`(ABILIFY; NDA 021436). Aripiprazole is indicated for the treatment of schizophrenia, acute
`treatment of manic and mixed episodes associated with bipolar I disorder, bipolar I disorder
`maintenance, adjunctive treatment of major depression, irritability associated with autistic
`disorder, and for the treatment of Tourette’s disorder. Approved aripiprazole oral dosages
`range from 2mg to 30mg per day. Currently approved aripiprazole formulations include oral
`tablets, orally disintegrating tablets, oral solution, short-acting intermuscular injection, and a
`long-acting intramuscular injection.
`
`The Applicant developed Abilify Mycite by embedding a sensor into aripiprazole tablets. The
`sensor powers on when exposed to stomach acid and transmits a signal to a wearable sensor
`(i.e., patch) placed over the upper left abdomen. The wearable sensor then transmits the data
`to a mobile application intended for patients and a web-portal intended for clinicians and
`caregivers. The Applicant developed Abilify Mycite
`
`
`
`
`
`Conclusions on the Substantial Evidence of Effectiveness
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`9
`
`Reference ID: 4173048
`
`(b) (4)
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`The Applicant successfully demonstrated bioequivalence between approved oral aripiprazole tablets (the reference product) and
`oral aripiprazole tablets with embedded IEM in the original submission dated Jun 26, 2015. This application relies on FDA’s previous
`efficacy and safety findings for the reference drug, aripiprazole oral tablets (NDA 021436).
`
`The Applicant demonstrated substantial evidence of Abilify Mycite usability in one simulated use trial involving the intended
`population. When used in conjunction with the Medical Information Device #1 (MIND1) system, 90% of aripiprazole + IEM ingestions
`are detected within 30 minutes and 97% of aripiprazole + IEM ingestions are detected within two hours by the wearable sensor.
`Detection is accurately communicated to both the Mycite mobile application and the clinician/caregiver web-portal.
`
`. Rates of adherence to the MIND1
`system noted during the first review cycle were no different than rates of adherence noted in real-world adherence trials for daily
`oral antipsychotics.1 The simulated use trial performed for the re-submission provides no additional data regarding adherence or
`data regarding data transmission times. Considering these limitations, the most accurate statement regarding Abilify Mycite’s
`capabilities is that “Abilify Mycite successfully tracks ingestion of aripiprazole with embedded sensor.”
`
`
`
`Benefit-Risk Assessment
`
`Benefit-Risk Summary and Assessment
`Schizophrenia, Bipolar disorder, and Major Depressive Disorder (MDD) are serious and common mental disorders in the United States.
`Depressive disorders account for 40.5% of the disability caused by mental illness worldwide. In 2014, an estimated 15.7 million adults [6.7%
`of the adult population] in the United States had at least one major depressive episode in the past year. The estimated prevalence for
`schizophrenia and bipolar disorder in the U.S. population is roughly 1% and 3%, respectively.
`
`Poor patient adherence to pharmacological treatment is common in this patient population.1 All three disorders commonly require long-
`term or lifelong adherence to daily treatment to avoid relapse. Epidemiologic and clinical trials observe that relapse through non-adherence
`decreases rates of response to treatment, particularly response to previously effective drugs. While once widely accepted that parenterally
`administered depot antipsychotics improved treatment adherence, recent trials cast doubt upon this assertion. Newer trials suggest
`parentally administered depot antipsychotics merely delay non-adherence.2-4 However, depot antipsychotics maintain the advantage of
`predictable timeframes in which clinicians and caregivers know repeat dosing is required and intervene accordingly. Adherence to depot
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`10
`
`Reference ID: 4173048
`
`(b) (4)
`
`

`

`Clinical Review
`
`Daniel J. Lee, MD.
`NDA 207202
`
`aripiprazole + MIND1 system (Abilify Mycite)
`
`antipsychotics is also relatively easy to monitor, as clinicians know when they last administered the injection. Currently, seven FDA-
`
`approved, long-acting antipsychotic products exist. These include long-acting forms of haloperidol, fluphenazine, risperidone, paliperidone,
`
`aripiprazole, aripiprazole lauroxil, and olanzapine. Required frequency of long-acting parenteral antipsychotic administration ranges from
`
`weekly to quarterly.
`
`Abilify Mycite adds to the current treatment armamentarium for schizophrenia and mood disorders by allowing clinicians and caregivers
`
`another way to track aripiprazole ingestion, provided the right type of patient receives the product. Aripiprazole + MIND1 is not uniquely
`
`efficacious compared with other approved treatments and potential benefits decrease if prescribed to non-compliant, cognitively
`
`challenged, or oppositional patients.
`
`Mitigation of risks associated with delay in data transmission and wearable sensor-related adverse events are achieved through labeling.
`
`Mitigation of unanticipated risks associated with unstudied functions of the mobile application are achieved through the placement of a
`
`disclaimer statement in labeling and the mobile application. For regulatory purposes, the mobile application and web—portal are considered
`
`drug labeling. The required disclaimer will remind users and prescribing clinicians that drug ingestion is the only function of the mobile
`
`application that has been reviewed by the FDA. I recommend approval of the proposed product after obtaining agreement from the
`
`Applicant regarding the incorporation of a disclaimer statement into Limitations of Use (LOU). LOUs are required to appear in traditional
`
`labeling, the log—in screen for the mobile application, the log-in screen for the web—portal, and the summary screen of the web-portal.
`
`
`
`m Evidence and Uncertainties
`
`Conclusions and Reasons
`
`0 Schizophrenia, Bipolar disorder, and Major Depressive Disorder are
`
`0 Epidemiologic and clinical trials observe
`
`serious and common mental disorders in the United States.
`
`that relapse through non—adherence
`
`o Depressive disorders account for 40.5% of the disability caused by
`
`decreases rates of response to treatment,
`
`mental illness worldwide. In 2014, an estimated 15.7 million adults
`
`particularly response to previously
`
`in the United States had at least one major depressive episode in
`
`effective drugs.
`
`the past year.
`
`0 The need for polypharmacological
`
`o Sustained remission from symptoms for each of these disorders often
`
`treatment is likely reduced When patients
`
`requires polypharmacological treatment.
`
`are adherent to prescribed antipsychotics.
`
`CDER Clinical Review Template 2015 Edition
`
`11
`
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 41 73048
`
`

`

`Clinical Review
`
`Daniel J. Lee, MD.
`MBA 207202
`
`aripiprazole + MIND1 system (Abilify Mycite)
`
`m Evidence and Uncertainties
`
`Conclusions and Reasons
`
`0 Poor patient adherence to pharmacological treatment is common in
`this patient population.1
`
`Expanding interventions that potentially
`improve adherence to prescribed
`
`o All three disorders commonly require long-term or lifelong adherence
`
`antipsychotics is critically important to the
`
`to daily treatment to avoid relapse.
`
`public health.
`
`0 FDA-approved long-acting formulations of antipsychotic drugs include
`
`While once widely accepted that
`
`haloperidol, fluphenazine, risperidone, paliperidone, aripiprazole,
`
`parenterally administered depot
`
`aripiprazole lauroxil, and olanzapine.
`
`antipsychotics improved treatment
`
`0 Required frequency of long-acting parenteral antipsychotic
`
`adherence, recent trials cast doubt upon
`
`administration ranges from weekly to quarterly.
`
`0 Administration of a long-acting antipsychotic requires a trained
`clinician for administration and post-injection monitoring.
`. Adherence to depot antipsychotics is relatively easy to monitor, as
`clinicians know when they administered the injection.
`o FDA-approved oral formulations of antipsychotic drugs include
`chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine,
`perchloroperazine, thioridazine, thiothixene, trifluoperazine,
`
`aripiprazole, asenapine, clozapine, illoperidone, lurasidone,
`
`olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone.
`
`this assertion. Newer trials suggest
`
`parentally administered depot
`BHtipSYChOtiCS merely delay "0"-
`adherence.
`The advantage 0f using long-acting
`BHtiPSYChOthS is the predictable timeframe
`in WhiCh clinicians 30d caregivers know
`repeat closing is required.
`
`o Abilify Mycite provides a means of tracking oral aripiprazole ingestion.
`
`Potential for improved adherence to oral
`
`0 Long-term adherence to oral antipsychotic drugs is poor.
`
`aripiprazole is possible with Abilify Mycite
`
`0 Many patients struggling with adherence to antipsychotic drugs
`
`use.
`
`cannot receive or refuse to receive long-acting antipsychotic drugs.
`
`Adverse effects associated with oral
`
`
`
`CDER Clinical Review Template 2015 Edition
`
`12
`
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
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`Reference ID: 41 73048
`
`Approval will likely spur future innovation
`
`aripiprazole are time-limited whereas
`
`adverse events associated with long-acting
`
`antipsychotics are prolonged.
`
`

`

`Clinical Review
`
`Daniel J. Lee, MD.
`MBA 207202
`
`aripiprazole + MIND1 system (Abilify Mycite)
`
`m Evidence and Uncertainties
`
`Conclusions and Reasons
`
`of similar drug tracking technology.
`
`Potential for improved communication
`
`between patients and clinicians regarding
`
`treatment is possible with Abilify Mycite.
`
`system is recommended.
`
`0 Individuals with active symptoms of schizophrenia, bipolar disorder,
`
`Usage errors increase the likelihood of
`
`and major depressive disorder are more likely to use Abilify Mycite
`
`incorrectly.
`
`patients experiencing wearable sensor-
`related adverse events and overdose.
`
`0 Minor, self-limited adverse events associated with the wearable
`
`Significant harm from usage errors is
`
`sensor were common in the three repeat-dose clinical trials,
`
`unlikely. Aripiprazole is relatively non-toxic
`
`accounting for 32%, 34%, and 64% of reported adverse events.
`
`0 Rare, severe dermatologic reactions requiring days to weeks to
`
`resolve occurred.
`
`in overdose and patients will presumably
`remove the wearable sensor if an adverse
`
`event occurs.
`
`0 Infections accounted for a higher than predicted 9%, 11%, and 18% of
`
`Rates of infection in repeat-dose trials are
`
`reported adverse events in the three repeat-dose trials. Infection
`
`explainable by high rates of concomitant
`
`rates are not reported in initial placebo-controlled published
`
`antipsychotic use. It is likely that Abilify
`
`aripiprazole tablet clinical trials; rates are assumed to be <2%. Raw
`
`Mycite is not associated with a higher rate
`
`data from these initial trials is contained in unavailable paper records.
`
`of infection than is present with
`
`0 The longest Abilify Mycite trial was 16 weeks in length.
`
`An open-label, longitudinal post-marketing
`
`aripiprazole.
`
`0 The generalizability of the applicant’s two-day simulated use trial to
`
`real-world Abilify Mycite use over time is unknown.
`
`0 While the overwhelming majority of tablets are detected within an
`
`hour or less post—ingestion, a delay of up to four hours in transmission
`
`of data from aripiprazole + IEM tablet to the Mycite mobile
`
`application and clinician/caregiver web-portal occurred in outlying
`cases.
`
`trial evaluating rates of correct MIND1 use,
`rates of wearable sensor-related adverse
`
`events, rates of MIND1-related overdose,
`
`rates of MIND1 adherence, and rates of
`
`infection in individuals using the MIND1
`
`CDER Clinical Review Template 2015 Edition
`
`13
`
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 41 73048
`
`

`

`Clinical Review
`
`Daniel J. Lee, MD.
`NDA 207202
`
`aripiprazole + MIND1 system (Abilify Mycite)
`
`m Evidence and Uncertainties
`
`Conclusions and Reasons
`
`0 Correct Abilify Mycite use in the simulated use trial was 66%.
`
`The Division recommended specific criteria
`
`0 Combining individuals who correctly used the product with individuals
`
`for wearable sensor discontinuationIn
`
`that failed in ways that did not undermine aripiprazole tablet
`
`labeling.
`
`resolve occurred.
`
`ingestion, 86% of enrolled participants derived benefit from ingesting
`
`Specific language cautioning against ”real-
`
`aripiprazole as prescribed.
`
`time” use of Abilify Mycite'IS incorporated
`
`0 Minor, self-limited wearable sensor-related adverse events occurred
`
`into labeling.
`
`frequently in Abilify Mycite clinical trials.
`
`0 Rare, severe dermatologic reactions requiring days to weeks to
`
`CDER Clinical Review Template 2015 Edition
`
`14
`
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 41 73048
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`
`2 Therapeutic Context
`
`
`
`Analysis of Condition
`
`Please see Section 1.3 Risk Benefit Assessment for condition details pertaining to this
`application.
`
`
`
`Analysis of Current Treatment Options
`
`Please see Section 1.3 Risk Benefit Assessment for current treatment details pertaining to this
`application.
`
`Table 1: Summary of FDA-Approved Long-Acting Antipsychotics
`
`Product (s) Name
`
`Relevant Indication
`
`Dosing/
`Administration
`
`haloperidol decanoate
`
`Schizophrenia
`
`50mg or 100mg injection monthly
`
`fluphenazine decanoate
`
`Schizophrenia
`
`12.5mg to 100mg injection monthly
`
`risperidone
`
`paliperidone palmitate
`(1-month formulation)
`paliperidone palmitate
`(3-month formulation)
`aripiprazole
`
`aripiprazole lauroxil
`
`Schizophrenia and Bipolar I
`Disorder
`Schizophrenia and
`Schizoaffective Disorder
`Schizophrenia
`
`Schizophrenia and Bipolar I
`Disorder
`Schizophrenia
`
`
`
`
`
`olanzapine pamoate
`
`Schizophrenia
`
`12.5mg, 25mg, 37.5mg, or 50mg
`injection every two weeks
`39mg, 78mg, 117mg, 156mg, or 234mg
`injection monthly
`273mg, 410mg, 546mg, or 819mg
`injection quarterly
`300mg or 400mg injection monthly
`
`441mg, 662mg, or 882mg injection
`monthly; 882mg injection every six
`weeks; 1064mg injection every two
`months
`150mg-300mg injection every two
`weeks; 405mg injection monthly
`
`Source: Reviewer Constructed
`
`3 Regulatory Background
`
` U.S. Regulatory Actions and Marketing History
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`15
`
`Reference ID: 4173048
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`Approved aripiprazole formulations include oral tablets, oral solution, oral disintegrating
`tablets, intramuscular injectable, and multiple formulations of extended-release injectable.
`
`Aripiprazole Indications by Year Granted
`
`
`
`Schizophrenia
`
`
`
`
`
`
`Acute bipolar disorder
`
`
`
`
`
`Bipolar disorder maintenance
`
`
`
`
`Adjunctive treatment of bipolar disorder
`
`Adjunctive treatment of major depressive disorder
`
`Irritability in children with autism
`
`
`
`Agitation associated with bipolar I mania and schizophrenia
`
`2002
`2004
`2004
`2004
`2007
`2009
`2009
`
`
`
`
`
`
`
`
`
`
`
`Summary of Pre-Submission/Submission Regulatory Activity
`
`During the original review cycle, reviewers identified several quality deficiencies. The Division
`issued a Complete Response letter, dated April 26, 2016. In Trial #316-13-206b, reviewers
`noted data for placebo only, significant non-detection of dosing 30 minutes following ingestion,
`
` Reviewers observed wide variability in time to data transmission from the wearable
`sensor to the Cloud server and mobile application. As no transmission times involved the fed
`state, reviewers did not know if food influenced variability for transmission times. Together,
`these concerns formed the basis for the Complete Response action.
`
`In the Complete Response letter, FDA required the Applicant undertake a trial designed
`similarly to Trial #316-13-206b “unambiguously testing the to-be-marketed formulation under
`real world conditions.” FDA also asked that the Applicant incorporate safeguards
`. The Complete Response
` from the mobile application as an alternative
`
`letter offered removal of the
`way to satisfy this requirement.
`
`
`
`Following the Complete Response letter, the Applicant submitted a human factors protocol for
`FDA review on September 19, 2016. The FDA completed an a priori review of the protocol on
`December 23, 2016. After receiving feedback on the protocol, the Applicant conducted a 35
`participant, two-day simulated use trial (DC-001576) at three U.S. sites from February 21, 2017,
`to March 3, 2017. The Applicant also removed the
` from the mobile
`application.
`
`
`
`Foreign Regulatory Actions and Marketing History
`
`Not applicable.
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: April 9, 2015 for initial rollout (NME/original BLA reviews)
`
`16
`
`Reference ID: 4173048
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Daniel J. Lee, M.D.
`NDA 207202
`aripiprazole + MIND1 system (Abilify Mycite)
`
`
`4 Significant Issues from Other Review Disciplines Pertinent to Clinical
`Conclusions on Efficacy and Safety
`
`
`
`Office of Scientific Investigations (OSI)
`
`FDA conducted no inspections in response to re-submission of this application.
`
`
`
`Product Quality
`
`From the perspective of product quality, the Applicant adequately responded to all deficiencies
`laid out in the Complete Response letter.
`
`
`
`Clinical Microbiology
`
`Not applicable.
`
`
`
`
`Nonclinical Pharmacology/Toxicology
`
`Not applicable.
`
`
`
`
`Clinical Pharmacology
`
`Not applicable.
`
` Mechanism of Action
`
`Aripiprazole is a dihydroquinolinone antipsychotic with no psychoactive metabolites.
`Pharmacologically, aripiprazole exhibits partial affinity at D2 and 5HT1A, antagonism activity at
`5HT2A, and affinity at D3, D4, 5HT2C, 5HT7, α-1, and H1.
`
` Pharmacodynamics
`
`The Applicant successfully demonstrated bioequivalence between approved oral aripiprazole
`tablets (the reference product) and oral aripiprazole tablets with embedded IEM in the original
`submission dated Jun 26, 2015.
`
` Pharmacokinetics
`
`The Applicant successfully demonstrated bioequivalence between approved oral aripiprazole
`tablets (the reference product) and oral aripiprazole tablets with embedded IEM in the original
`submission dated Jun 2