CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-192
`
`MEDICAL REVIEW '
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`
`Iloperidone
`
`CLINICAL REVIEW
`
`Application Type NDA
`Submission Number
`22-192
`
`Submission Code N
`
`Letter Date September 27, 2007
`Stamp Date September 27, 2007
`PDUFA Goal Date
`July 27, 2008
`'
`
`Reviewer(s) Name(s) Michelle M. Chuen, M.D.
`Review Completion Date
`June 13, 2008
`
`Iloperidone
`Established Name
`Trade Name None
`
`Therapeutic Class, Antipsychotic
`Applicant Vanda Pharmaceuticals Inc.
`
`Priority Designation
`
`S
`
`1, 2, 4, 6, 8, 10, and 12 mg Tablets
`Formulation
`12-24 mg/day administered BID
`Dosing Regimen
`Indication Schizophrenia
`Intended Population Adults with Schizophrenia
`
`

`

`Clinical Review
`
`Michelle M. Chuen, M.D.
`NDA #22-192
`Iloperidone
`
`'
`
`1
`
`2
`
`
`EXECUTIVE SUMMARY.................................................................................. .
`
`......5
`
`Table of Contents
`
`1 .1
`
`1.2
`
`1.1.1
`1.1.2
`1.1.3
`
`1.2.1
`1.2.2
`1.2.3
`1.2.4
`1.2.5
`1.2.6
`
`
`
`RECOMMENDATION ON REGULATORY ACTION ...................................................................... 5
`Risk Management Activity ........................................................................................
`Required Phase 4 Commitments ...................
`Other Phase 4 Requests .................................
`SUMMARY OF CLINICAL FINDINGS .....................
`Brief Overview of Clinical Program .............
`Efficacy .........................................................
`Safety .....................................................................................................................................................6
`Dosing Regimen and Administration.....................................................................................................7
`Drug-Drug Interactions ................................7
`Special Populations ................................................................................................................................7
`
`
`
`INTRODUCTION AND BACKGROUND ......................................................................................................7
`
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`
`PRODUCT INFORMATION ............................................................................................................................. 7
`CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS ............................................................................ 8
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES ................................................ 8
`IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS .......................................... 8
`
`PRESUBMISSION REGULATORY ACTIVITY ........................................................ 8
`
`OTHER RELEVANT BACKGROUND INFORMATION .......................................................................
`.. 12
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES .................................................... 12
`
`3.1
`3.2
`3.3
`3.4
`
`CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ........................................................................... 12
`ANIMAL PHARMACOLOGY/TOXICOLOGY ......................
`STATISTICAL REVIEW AND EVALUATION
`DSI CLINICAL SITE INSPECTIONS ..............................................................................................................
`
`
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY..................................................... 15
`
`4.1
`4.2
`4.3
`4.4
`4.5
`4.6
`
`SOURCES OF CLINICAL DATA .................................................................................................................... 15
`
`TABLES OF CLINICAL STUDIES .............
`REVIEW STRATEGY ...........................................................
`
`DATA QUALITY AND INTEGRITY .......................................
`
`COMPLIANCE WITH GOOD CLINICAL PRACTICES ...........
`
`FINANCIAL DISCLOSURES ..........................................................................................................................
`CLINICAL PHARMACOLOGY ...................................................................................................................23
`
`5.1 PHARMACOKINETICS .........................23
`
`5 .2
`PHARMACODYNAMICS .......................................................................................
`
`EXPOSURE-RESPONSE RELATIONSHIPS .....................................................................................................
`5.3
`
`6
`
`6.1
`
`INTEGRATED REVIEW OF EFFICACY .....
`
`
`
`INDICATION .....................
`6:1.1 Methods ........................................................
`
`General Discussion ofEndpoints....
`
`StudyDeSIgn ............................................
`
`Efficacy Findings ......................................................................................
`
`Clinical Microbiology .......
`
`Efficacy Conclusions ........................................................................................................................... 31
`
`6.1.2
`6.1.3
`6.1.4
`6.1.5
`6.1 .6
`
`INTEGRATED REVIEW OF SAFETY ........................................................................................................31
`
`2
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`
`Iloperidone
`
`7.1
`
`7.2
`
`
`
`
`
`METHODS AND FINDINGS .......................................................................................................................... 31
`
`Deaths ........................................................32
`7.1.1
`Other Serious Adverse Events ..................................................................................................43
`7.1.2
`
`Dropouts and Other Significant Adverse Events ...................................................................... 53
`7.1.3
`Other Search Strategies ...................................................
`....60
`7.1.4
`Common Adverse Events ...........
`....61
`7.1.5
`
`Less Common Adverse Events ............................................................................................................ 65
`7.1.6
`Laboratory Findings .............................................................................................................................65
`7.1.7
`Vital Signs ...............................
`'
`....70
`7.1.8
`
`....73
`Electrocardiograms (ECGS) .....
`7.1.9
`
`....75
`Immunogenicity ..................
`7.1.10
`
`....75
`Human Carcinogenicity ......
`7.1.11
`Special Safety Studies ................................................
`....75
`7.1.12
`Withdrawal Phenomena and/or Abuse Potential ........
`76
`7.1.13
`Human Reproduction and Pregnancy Data ................
`76
`7.1.14
`Assessment ofEffect on Growth................................
`....76
`7.1.15
`Overdose Experience .....................
`....76
`7.1.16
`
`Postmarketing Experience ..................‘. ............................................................................................77
`7.1.17
`ADEQUACY OF PATIENT EXPOSURE AND SAFETY ASSESSMENTS ..............................................................77
`Description of Primary Clinical Data Sources (Populations Exposed and Extent of Exposure) Used to
`7.2.1
`Evaluate Safety ..................................................................................................................................................77
`7.2.2
`Description of Secondary Clinical Data Sources Used to Evaluate Safety .........
`....81
`7.2.3
`Adequacy of Overall Clinical Experience ..........................................................
`....81
`7.2.4
`Adequacy of Routine Clinical Testing ................................................................
`....81
`7.2.5
`Adequacy of Metabohc Clearance, and Interaction Workup ............................................................. 82
`7.2.6
`Adequacy ofEvaluation for Potential Adverse Events for Any New Drug and Particularly for Drugs
`in the Class Represented by the New Drug; Recommendations for Further Study ............................................ 82
`'
`....82
`7.2.7
`Assessment of Quality and Completeness of Data .............................................
`
`Additional Submissions, Including Safety Update .............................................................................. 83
`7.2.8
`SUMMARY OF SELECTED DRUG-RELATED ADVERSE EVENTS, IMPORTANT LIMITATIONS OF DATA, AND
`7.3
`CONCLUSIONS ......................................................................................................................................................... 83
`7.4
`GENERAL METHODOLOGY .....................................................................
`. . . .85
`7.4.1
`Pooling Data across Studies to Estimate and Compare Incidence
`....85
`7.4.2
`Explorations for Predictive Factors ..................................................
`....85
`7.4.3
`Causality Determination ...................................................................................................................... 85
`
`8
`
`ADDITIONAL CLINICAL ISSUES ..............................................................................................................86
`
`8. 1
`8.2
`8.3
`8.4
`8.5
`8.6
`8.7
`8.8
`
`DOSING REGIMEN AND ADMINISTRATION ................................................................................................. 86
`
`DRUG-DRUG INTERACTIONS ..............................
`. 86
`SPECIAL POPULATIONS ..........................................................................................
`....86
`PEDIATRICS ...........................................................................................................
`....86
`
`ADVISORY COMMITTEE MEETING ......................
`....87
`LITERATURE REVIEW .............................................
`....87
`
`POSTMARKETING RISK MANAGEMENT PLAN ............
`....87
`
`OTHER RELEVANT MATERIALS ................................................................................................................. 87
`
`
`
`9
`
`OVERALL ASSESSMENT............................................................................................................................ 87
`
`9.]
`9.2
`9.3
`
`CONCLUSIONS ........................................................................................................................................... 87
`RECOMIVIENDATION ON REGULATORY ACTION ....................
`....88
`RECOMMENDATION ON POSTMARKETING ACTIONS .............
`....88
`Risk Management Activity .............................................
`....88
`Required Phase 4 Commitments .......................................................................................................... 88
`
`9.3.1
`9.3.2
`
`3
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22—192
`
`Iloperidone
`
`9.3.3
`9.4
`9.5
`
`Other Phase 4Requests...............................; ........................................................................................ 89
`
`LABELING REVIEW .................
`....89
`COMMENTS TO APPLICANT........................................................................................................................ 89
`
`10 APPENDICES ..................................................................................................................................................93
`
`10.1
`10.2
`10.3
`10.4
`10.5
`
`REVIEW OF INDIVIDUAL STUDY REPORTS .................................................................................................93
`
`.
`.
`LlNE-BY-LINE LABELING REVIEW..........................................................
`130
`
`APPENDIX TO INDIVIDUAL STUDY REPORTS .............................................................................. 131
`
`APPENDIX TO DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY (SECTION 4)....
`...... 177
`APPENDIX TO INTEGRATED REVIEW OF SAFETY (SECTION 7) .................................................................. 180
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`
`Iloperidone '
`
`1 EXECUTIVE SUMMARY
`
`1.1 Recommendation on Regulatory Action
`
`In accordance with 21 CFR 312.120, it is recommended that this application be granted Net
`Approvable status on the basis of insufficient information about the drug to determine whether
`the product is safe for use under the conditions prescribed, recommended, or suggested in its
`proposed labeling [314.125 (b)(4)]; and lack of substantial evidence consisting of adequate and
`well—controlled investigations that the drug product will have the effect it purports or is
`represented to have under the conditions of use prescribed, recommended, or suggested in its
`proposed labeling[314.125 (b)(5)].
`
`1.1.1 Risk Management Activity
`
`Since the undersigned reviewer is recommending a Not Approvable action, a risk management
`activity is not applicable.
`
`1.1.2 Required Phase 4 Commitments
`
`Since the undersigned reviewer is recommending a Not Approvable action, required phase 4
`commitments are not applicable.
`
`1.1.3 Other Phase 4 Requests
`
`Since the undersigned reviewer is recommending a Not Approvable action, other phase 4
`requests are not applicable.
`
`1.2 Summary of Clinical Findings
`
`1.2.1 Brief Overview of Clinical Program
`
`The efficacy of iloperidone in the treatment of adult patients with schizophrenia is based on
`Studies 3000, 3004, and 3005, which were randomized, double—blind, placebo- and active—
`controlled trials of about 6 weeks duration and Studies 3101 and B202, which were randomized,
`placebo-controlled trials of about 4 weeks duration. Studies 3000, 3101, and B202 were fixed-
`dose trials and Studies 3004 and 3005 were flexible~dose trials.
`
`The evaluation of the safety of iloperidone in schizophrenia is based on four short-term trials:
`two fixed dose trials (3000 and 3101) and two flexible dose trials (3004 and 3005). Deaths,
`serious adverse events and dropouts due to adverse events were examined for the remaining 34
`
`5
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`
`Iloperidone
`
`studies [Studies ILPBlO3, 1L05220105, 1L05220104, VP—VYV-683—1001, VP-VYV-683-1002,
`ILPB106, ILOS220110, ILPB101/ 101A, ILPB102, lLPBIOS, 1L05222301, ILPB203,
`1L05220112, ILPB200, ILPB201, 1L0522B210, 1L05220102, 1L05220103, 1105220107,
`1L05220108, 1L0522A0109, ILP2001$T,ILP2001LT, ILP3007P1, ILP3007P2, ILP3001,
`ILP3 002, ILP3003, ILOS222328, ILPB104, ILPB199, 1LPB205, ILPB303, and ILPB2021] and
`the extension phases of Studies 3000, 3004, and 3005 (ILP3000LT, ILP3004 LT, and ILP3005
`OLE).
`
`1.2.2 Efficacy
`
`There are 3 negative studies, 2 positive studies, and 3 studies in which an active comparator was
`found to be superior to iloperidone. Only one study showed an effect size of iloperidone
`comparable to the active comparator, with an 0C analysis corroborating the MMRM analysis at
`most time points for the active comparator, but not iloperidone. Thus, the sponsor has not
`provided substantial evidence that supports the claim of short-term efficacy for the use of
`iloperidone in schizophrenia.
`
`Of note, data from at least one of the Study 3101 sites was not considered to be reliable in
`support of this NDA, and 47% of the ITT patients in Study 3005 were contributed by sites where
`information on investigator financial interests were unobtainable.
`
`1.2.3 Safety
`
`Overall clinical experience is not adequate, with less than 64 patients and less than 22 patients
`having a duration of exposure for over 6 months and over 12 months, respectively, at the
`possibly effective dosage level of 24 mg/d. Thus, there is insufficient information to determine
`whether iloperidone is safe for use at this dose level.
`
`Moreover, the integrity of the sponsor’s existing safety data is questionable, given that an audit
`of patient CRFs, Narrative Summaries, and adverse event data listings revealed deficiencies in 7
`out of the 8 examined, in addition to multiple deficiencies and discrepancies in the safety
`database which were incidentally noted.
`
`Safety findings in the deaths, serious adverse events, and adverse events leading to dropout
`database include sudden deaths, seizures, arrhythmias, hypotension, syncope, priapism, and
`elevated creatine phosphokinase (CPK).
`
`Safety findings in the controlled database include QTc prolongation, orthostatic hypotension,
`weight gain, anemia, high prolactin, and tachycardia.
`.
`
`1 Note that, although Study ILPB202 (also referred to as B202) was a placebo-controlled trial, the sponsor did not
`include it in their primary safety database.
`
`6
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22—192
`Iloperidone
`
`1.2.4 Dosing Regimen and Administration
`
`-
`
`Study 3005 was a flexible dose study that examined nonoverlapping dose ranges of iloperidone
`(12 or 16 mg/d and 20 or 24 mg/d) versus placebo, administered on a twice-daily basis. Both
`dose groups produced a significant difference over placebo. For all dose groups, dosing for
`iloperidone began at 2 mg/d, and then increased to 4 mg/d, 8 mg/d, and 12 mg/d on Days 2, 3,
`and 4, respectively. At Day 5 and 6, the 20—24 mg/d dose group was increased to 16 mg/d and
`20 mg/d, respectively.
`
`Study 3101 was a fixed dose study of iloperidone that examined a dose of 24 mg/d of iloperidone
`versus placebo, administered on a twice—daily basis. This dose produced a significant difference
`over placebo. Dosing for iloperidone began at 2 mg/d, then increased to 4 mg/d, 8 mg/d, 12
`mg/d, 16 mg/d, 20 mg/d, and 24 mg/d on Days 2, 3, 4, 5, 6, and 7, respectively.
`
`1.2.5 Drug-Drug Interactions
`
`There were no serious adverse events that suggested drug-drug interactions. There were no
`drug-drug interaction studies in the submission.
`
`1.2.6 Special Populations
`
`The sponsor’s subset analyses to evaluate the effect of age, gender, and race on treatment
`response was not appropriate due to varying primary efficacy variables among the 4 pooled
`studies, and due to the inclusion of schizoaffective patients in the analyses. Please see Section
`6.1.4 for further details.
`
`2
`
`INTRODUCTION AND BACKGROUND
`
`2.1 Product Information
`
`Iloperidone is a new chemical entity proposed for the treatment of schizophrenia. Iloperidone
`belongs to the chemical class of piperidinyl-benzisoxazole derivatives and has high (nM) affinity
`for 5HT2A/NEa1/NEa2c/D2/D3/5HT1A receptors in humans and acts as an antagonist at selected
`dopaminergic, serotoninergic, and adrenergic receptors.
`
`The sponsor is seeking approval for treatment of adults with schizophrenia with a dosing
`regimen of 12 to 24 mg/day administered b1.(1. based on the results of 5 completed short—term
`fixed- and flexible-dose clinical studies.
`
`

`

`Clinical Review
`
`Michelle M. Chuen, M.D.
`NDA #22—192
`lloperidone
`
`2.2 Currently Available Treatment for Indications
`
`The 17 moieties approved and available in the U.S. for the treatment of schizophrenia2 are:
`chlorpromazine, prochlorperazine, perphenazine, trifluoperazine, thioridazine, fluphenazine,
`haloperidol, thiothixine, molindone, loxapine, clozapine, risperidone, olanzapine, quetiapine,
`ziprasidone, aripiprazole, and paliperidone. The 6 moieties that were approved but may no
`longer be available in the U.S. are: promazine, acetophenazine, propiomazine, piperacetazine,
`chlorprothixine, and mesoridazine.
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`lloperidone has not been approved for use in the United States.
`
`2.4
`
`Important Issues with Pharmacologically Related Products
`
`Some major safety issues related to atypical antipsychotics are increased mortality in elderly
`patients with dementia-related psychosis, suicidality in children and adolescents, clinical
`worsening and suicidality, neuroleptic malignant syndrome, tardive dyskinesia, hyperglycemia
`and diabetes mellitus.
`
`2.5 Presubmission Regulatory Activity
`
`On 2/27/01, the Executive Carcinogenicity Assessment Committee (CAC) agreed with the
`sponsor that direct carcinogenicity testing of the metabolite, P95, was not necessary as long as
`P95 was negative in a full battery of genotoxicity tests and that no unique toxicities (compared to
`the parent compound) or preneoplastic findings are observed in the 6-mo oral toxicity of P95.
`
`On 5/11/01, the Full CAC determined that the carcinogenic potential of iloperidone was
`adequately tested (assuming that the completed 2-year oral carcinogenicity studies in rat and
`mouse were adequate). Additional testing was recommended: two-week mouse data for pK
`rather than single dose of P95; additional carcinogenicity testing could be considered as a phase
`4. commitment.
`
`At a Pre—NDA meeting with Novartis on 6/28/01, it was noted that Study 3004 was positive
`while Studies 3000 and 3005 were negative. The sponsor was informed that, to preclude a
`refusal to file action, another positive study would be required.
`
`2 Per 5/8/08 email from Project Manager, Kim Updegraff.
`
`8
`
`

`

`Clinical Review
`
`, Michelle M. Chuen, M.D.
`NDA #22-192
`Iloperidone
`
`Another Pre-NDA meeting with Novartis was held on 11/1/01, during which the sponsor’s
`planned additional Phase 3 studies were discussed. Issues included the following:
`0 We recommended that the sponsor explore doses higher than 24 mg.
`0 We indicated several weaknesses in their proposed design, including focusing on the
`Tmax of the parent compound, ignoring metabolites; and not assessing the effects of a
`CYP 2D6 inhibitor and a CYP 3A4 inhibitor independently.
`0 We agreed to the use of quetiapine and ziprasidone as active controls.
`0 We suggested the sponsor provide further data to support the hypothesis that metabolite
`P95 is devoid of effects on cardiac repolarization.
`0 We recommended using both higher and lower dose groups to assess the potential for QT
`prolongation over the entire expected dose range.
`0 We suggested that the sponsor investigate the effects of iloperidone on fasting blood
`glucose.
`'
`
`0 We stated that the presence of two negative trials, two positive trials, and three trials in
`which active control appeared superior to iloperidone would not be a compelling data set
`for the approval of iloperidone.
`- We stated that if a study was powered to detect a very small effect, this would have to be
`evaluated in the context of previous data.
`
`At another End-of—Phase 2/Pre-NDA meeting on 11/7/02, Novartis agreed to develop an
`approach to collect data on the pharmacokinetics of iloperidone at higher doses (e.g., 30 or 32
`mg) in order to determine whether the plasma levels are comparable to those observed when 24
`mg is maximally inhibited.
`
`At a 4/28/05 Guidance meeting with Vanda, the sponsor was advised that a claim for a specific
`genetic subgroup would have to be prospectively demonstrated in two studies. The need to
`include active control arms in their efficacy trials, because of earlier findings in two trials of
`superiority of active comparators to iloperidone was discussed; The Division policy of requiring
`positive longer-term efficacy data at the time of submission of an NDA (responder status for at
`least 6 months before randomization, using a randomized withdrawal design) was also discussed.
`The sponsor was planning to developWT“
`{W_ .
`
`11(4)
`
`At a statistical meeting held 7/26/05, the Division agreed that missing data imputed by the LOCF
`approach may introduce biases. The Division stated that we do not consider analysis based on a
`2-part model appropriate, and that analysis via an MMRM may be acceptable, depending on
`whether or not data suggest violation of the MAR assumption. Also, the Division stated that, in
`addition to pre—specifying the primary analysis, the sponsor would need to pre-specify a number
`of sensitivity analyses to assess the impact of the missing data.
`
`At the 9/7/05 End-of-Phase II meeting, for Study 3101, the Division recommended the
`following:
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22— 1 92
`
`Iloperidone
`
`0
`
`0
`
`that the sponsor include several fixed doses of iloperidone for Study 3101, because it was not
`clear that dose response for efficacy had been clarified
`that the statistical analysis plan would need to identify clearly the primary outcome or
`outcomes, and details and sequences of testing, as well as what would be needed to declare
`the study positive
`that showing specificity (i.e., a negative finding in the genetic subgroup with the marker)
`would be insufficient to support a claim of specificity in the subgroup of interest
`V
`that they would need to have worked out all the details of a test kit that could- be approved
`and marketed simultaneously with the approval and marketing of iloperidone
`that they would need full specification of the MMRM model, as well as justification for its
`use in this setting, along with sensitivity analyses and verification of the MAR assumption
`confirmation that their ITT sample would also require baseline assessment
`0
`that they needed to submit a final SAP well before completion of the trial
`0
`The sponsor clarified that aninteraction term in the model would be used in exploratory
`analyses, and not for the primary model
`
`0
`
`9
`
`0
`
`In addition, we did not provide a definitive answer on whether or not longer-term efficacy data
`would be needed, and indicated that we would very likely take iloperidone to a PDAC, given the
`safety concerns with this drug. We also agreed with a waiver for iloperidone for patients below
`the age of 13, and a deferral for the assessment of the effects of iloperidone in patients between
`13 and 18 until assessments in adults have been completed.
`
`At a 7/11/06 Executive CAC meeting, the Executive CAC concluded that:
`0 The full potential for carcinogenicity of the P95 metabolite has not been adequately tested,
`and that a follow-up study in rats is appropriate
`0 The sponsor should conduct a carcinogenicity study of the P95 metabolite with regard to P95
`capacity for induction of hyperplasia and cellular proliferation in rats
`0 The 2-year carcinogenicity assessment was not accepted because its acceptance was
`contingent on the 6-month P95 study not showing a potential for cellular proliferation, which
`was not the case (it did show such a potential). The findings of the 6—month P95 study
`suggest a mechanism that could be relevant to tumorigenic activity in humans.
`
`At a 9/12/06 EOPII/Type B meeting, the issues discussed include the following regarding study
`3101:
`
`0 The sponsor agreed to use the commonly used MMRM approach as their primary analysis
`0 We conveyed that response profiles of the dropout patients were needed
`0 We conveyed that if there was any suspicion that the missing mechanism was non-ignorable
`during the Agency’s review, then MMRM may not be deemed appropriate
`0 The sponsor agreed to pre-specify a detailed non-parametric method in the SAP in case there
`was doubt about the normality assumption
`0 We stated that, in pooling small sites, the sponsor may need to set a lower limit of number of
`patients in each site to avoid having unstable efficacy results
`
`10
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`Iloperidone
`
`The sponsor clarified that the pre-specified subgroup for CNTF is the genotype FS63 Ter(-
`)/Ter(-). Thus, the step-down primary analysis was the comparison between 110 treated
`patients vs. placebo in those patients whose genotype is FS63 Ter(-)/Ter(-).
`The division noted that the study randomization did not account for stratification by patients’
`CNTF status, and that this comparison is only a descriptive summary and is not a randomized
`comparison. Dr. Laughren stated that the results of such a comparison could not be the basis
`for a claim in labeling.
`We asked the sponsor to provide data for justification regarding the diagnostic assay
`performance on sensitivity, specificity, and accuracy.
`We expressed concern for DNA samples being collected through the optional PG protocol,
`thus presenting many confounding factors, including potential differing characteristics
`between consented vs. non-consented patients. For example, early withdrawal patients might
`have consented initially at study randomization with different characteristics as compared to
`non-consented withdrawals. Unknown confounders that are implicit can introduce unknown
`bias that cannot be assessed. Such a patient selection process cannot yield a randomized
`comparison for confirmatory purpose.
`
`In a 11/17/06 Type B meeting/EOPII to discuss the SAP for Study 3101,
`The Division agreed with the baseline—as-a—covariate MMRM model proposed in the SAP.
`The Division agreed with the methodology proposed for pooling sites.
`We accepted the sponsor’s proposal for a randomization test based on the MMRM model
`with at least 1000 simulations to derive the p-value.
`We stated that the SAP for the primary objective appeared acceptable.
`The sponsor was told that if there goal was to include information based on the step-down
`primary objective into labeling, they would need to ensure the DNA sample quality for
`proper determination of genotyping results, and the sponsor agreed.
`The sponsor was asked to clearly state in the protocol that CNTF F63 Ter(-) genotype refers
`to FS63 Ter(-)/Ter(-).
`
`In a 2/1/07 Pre-NDA Type B Meeting, the following were among the issues discussed:
`We noted that the purpose of subroup analyses for efficacy would be to explore the
`consistency of treatment effect across subgroups, and that they are not intended for claims in
`any subgroup. The non-inferiority analysis would also be considered exploratory.
`We indicated that the sponsor’s plan to conduct MMRM analyses for sensitivity purposes
`would be acceptable.
`
`In a 3/28/07 Advice Letter, the Division agreed that Vanda be allowed to file an NDA while the
`additional P95 carcinogenicity study was underway, under the conditions that the P95 two-year
`carcinogenicity study in rats be initiated before an NDA was filed, and until the P95
`carcinogenicity assessment was completed, the product labeling must contain astrong statement
`describing the findings of hyperplasia seen in the 26-week rat study of the metabolite and
`indicate that this could progress to tumors with longer term treatment.
`
`11
`
`

`

`Clinical Review
`Michelle M. Chuen, M.D.
`NDA #22-192
`Iloperidone
`
`This NDA was submitted to the Agency on 9/27/07. The Filing Meeting was held on 11/9/07,
`and it was concluded that this supplement was fileable. The User Fee due date is 7/27/08.
`
`A 4-Month Safety Update to the NDA was submitted on 1/23/08.
`
`2.6 Other Relevant Background Information
`
`Although the sponsor states that iloperidone has not been approved or marketed in any country,
`the undersigned reviewer was unable to locate any information specifically on withdrawal of the
`product in other countries, or on submission of marketing authorization applications to foreign
`regulatory agencies.
`
`3 SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES
`
`3.1 CMC (and Product Microbiology, if Applicable)
`
`The sponsor claimed categorical exclusion from Environmental Assessment for this NDA. Per a
`5/13/08 email from Donghao Lu, Ph.D., CMC reviewer, all CMC concerns have been resolved.
`
`3.2 Animal Pharmacology/Toxicology
`
`At the time of completion of this review, neither a Pharmacology/Toxicology review nor a draft
`of the review was available. Per a 5/15/08 email from Sonia Tabacova, Ph.D., Pharm/Tox
`reviewer, there were no unexpected findings.
`
`3.3 Statistical Review and Evaluation
`
`Phillip Dinh, Ph.D., is the Statistical Reviewer for this NDA. His final review is pending as of
`5/13/08. Based on a draft of his review, he has indicated that efficacy for the schizophrenia
`subsample was demonstrated in Studies 3005 and 3101.
`
`3.4 DSI Clinical Site Inspections
`
`At the Filing Meeting on 11/9/07, Peiling Yang, PhD. Statistical Team Leader stated that she
`received a call from a .~WKMN who had some concerns
`regarding the sponsor’s data integrity. Dianne Tesch, DSI Consumer Safety Officer, contacted
`”MN Per Ms. Tesch’s 5/13/08 email, .—- had nothing specific regarding any of
`the sponsor’s study sites. ~=W , and -" mpression was
`that the sponsor would stop at nothing to get approval. However,
`..; lad no hard evidence or
`promising leads.
`
`b(6)
`
`_
`
`12
`
`

`

`Clinical Review
`
`Michelle M. Chuen, M.D.
`NDA #22—192
`Iloperidone
`
`The Division of Psychiatry Products selected 8 sites for inspection by the Division of Scientific
`Investigations (DSI). Five sites were from Study 3005 and 3 sites were from Study 3101. These
`sites are described in the table below, extracted from an 11/13/07 email from Dr. Phillip Dinh,
`Statistical Reviewer.
`
`Investigator
`
`Site
`
`
`Study 3005 Site
`number
`
`
`
`Study 3101 Site
`number
`
`
`Tram Tran-Johnson,
`Pharm. D.
`I
`
`Rick Mofsen, D.O.
`
`California
`
`Neuropsychopharmacology
`Clinical Research Institute
`
`# of sub'ects)
`# of sub'ects)
`
`
`
`002
`545
`
`
`(27 patients)
`(31 patients)
`
`
`
`San Diego, CA 92126
`
`USA
`Clinical Research, Inc.
`612
`014
`St. Louis, MO 63118
`(14 patients)
`(25 patients)
`USA
`'
`
`
`
`
`Saibal Nandy,
`D.P.M.,
`‘
`M.R.C.Ps ch.
`
`631 Prospect Drive SW
`Medicine Hat, AB TIA 4C2
`Canada
`
`907
`(8 patients)
`
`NA
`
`
`
`
`Miro Jakovljevic,
`Clinical Hospital Centre
`
`M.D.
`Rebro
`
`
`Zagreb, 10000
`
`
`
`Croatia
`
`Psychiatric Hospital Vrapce
`Zagreb, 1000