CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
`
`APPLICA TION NUMBER:
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`
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`APPLICATION NUMBER:
`22-264
`22-264
`
`
`MEDICAL REVIEW(S)
`MEDICAL REVIEW§SQ
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`

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`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 22264-000
`Priority or Standard S (Resubmission)
`
`Submit Date(s) 03 February 2009
`Received Date(s) 04 February 2009
`PDUFA Goal Date 03 August 2009
`Division / Office DPP/ONE1
`
`Reviewer Name(s)
`Jing Zhang, MD, PhD
`Review Completion Date June 8, 2009
`
`Established Name Paliperidone Palmitate
`(Proposed) Trade Name Invega® SustennaTM
`Therapeutic Class Atypical Antipsychotic
`Applicant
`Johnson & Johnson
`
`Formulation(s) Long-Acting Injection
`Dosing Regimen Injection Every 4 Weeks
`Indication(s) Acute Treatment of
`Schizophrenia
`Intended Population(s) Adults
`
`
`
`Template Version: March 6, 2009
`
`

`

`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 7
`1.1 Recommendation on Regulatory Action ............................................................. 7
`1.2 Risk Benefit Assessment.................................................................................... 7
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 8
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 8
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 9
`2.1 Product Information ............................................................................................ 9
`2.2 Product Tables of Currently Available Treatments for Proposed Indication........ 9
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 10
`2.4
`Important Safety Issues with Consideration to Related Drugs.......................... 10
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 10
`2.6 Other Relevant Background Information .......................................................... 11
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 11
`3.1 Submission Quality and Integrity ...................................................................... 11
`3.2 Compliance with Good Clinical Practices ......................................................... 11
`3.3 Financial Disclosures........................................................................................ 11
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 12
`4.1 Chemistry Manufacturing and Controls ............................................................ 12
`4.2 Clinical Microbiology......................................................................................... 12
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 12
`4.4 Clinical Pharmacology...................................................................................... 12
`4.4.1 Mechanism of Action.................................................................................. 12
`4.4.2 Pharmacodynamics.................................................................................... 12
`4.4.3 Pharmacokinetics....................................................................................... 13
`5 SOURCES OF CLINICAL DATA............................................................................ 13
`5.1 Tables of Studies/Clinical Trials ....................................................................... 13
`5.2 Review Strategy ............................................................................................... 15
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 15
`6 REVIEW OF EFFICACY......................................................................................... 15
`Efficacy Summary...................................................................................................... 15
`A. Study PSY-3007 for the Acute Treatment of Schizophrenia in Adults.................. 15
`a. Rationale for Selection of Studies for Review ................................................... 15
`b. Study Summaries.............................................................................................. 16
`c. Crosscutting Issues........................................................................................... 26
`d. Efficacy Conclusion Regarding Schizophrenia Indication ................................. 35
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`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`7 REVIEW OF SAFETY............................................................................................. 35
`Safety Summary ........................................................................................................ 35
`7.1 Methods............................................................................................................ 36
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 36
`7.1.2 Categorization of Adverse Events.............................................................. 36
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 36
`7.2 Adequacy of Safety Assessments .................................................................... 37
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 37
`7.2.2 Explorations for Dose Response................................................................ 38
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 38
`7.2.4 Routine Clinical Testing ............................................................................. 38
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 38
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 38
`7.3 Major Safety Results ........................................................................................ 38
`7.3.1 Deaths........................................................................................................ 38
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 39
`7.3.3 Dropouts and/or Discontinuations .............................................................. 40
`7.3.4 Significant Adverse Events ........................................................................ 42
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 43
`7.4 Supportive Safety Results ................................................................................ 43
`7.4.1 Common Adverse Events .......................................................................... 43
`7.4.2 Laboratory Findings ................................................................................... 45
`7.4.3 Vital Signs.................................................................................................. 45
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 46
`7.4.5 Special Safety Studies/Clinical Trials......................................................... 47
`7.4.6
`Immunogenicity.......................................................................................... 47
`7.5 Other Safety Explorations................................................................................. 47
`7.5.1 Dose Dependency for Adverse Events ...................................................... 47
`7.5.2 Time Dependency for Adverse Events....................................................... 47
`7.5.3 Drug-Demographic Interactions ................................................................. 48
`7.5.4 Drug-Disease Interactions.......................................................................... 49
`7.5.5 Drug-Drug Interactions............................................................................... 49
`7.5.6 Other Safety Issues with Special Interests................................................. 49
`7.6 Additional Safety Evaluations ........................................................................... 53
`7.6.1 Human Carcinogenicity.............................................................................. 53
`7.6.2 Human Reproduction and Pregnancy Data................................................ 53
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 53
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 53
`7.7 Additional Submissions / Safety Issues............................................................ 54
`8 POSTMARKET EXPERIENCE............................................................................... 54
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`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`9 APPENDICES ........................................................................................................ 55
`9.1 Literature Review/References .......................................................................... 55
`9.2 Labeling Recommendations............................................................................. 55
`9.3 Advisory Committee Meeting............................................................................ 57
`
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`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`
`Table of Tables
`
`Table 1 Currently Available Antipsychotics for Treatment of Schizophrenia ................ 10
`Table 2 Brief Summary of Study PSY-3007 ................................................................. 14
`Table 3 Demographic and Baseline Characteristics (ITT)............................................ 21
`Table 4 Demographic and Baseline Characteristics by US and Non-US Regions (ITT)
`....................................................................................................................... 21
`Table 5 Diagnosis and Psychiatry History at Baseline (ITT)......................................... 22
`Table 6 Study Completion Withdrawal Information (all randomized)............................ 23
`Table 7 Benzodiazepine Received During the Double-Blind Phase............................. 24
`Table 8 Duration (Days) of Benzodiazepines (with at Least 10 Subjects in Total)
`Received During the Double-Blind Phase, ITT .............................................. 24
`Table 9 Change From Baseline to End Point in PANSS Total Score (LOCF, ITT)....... 26
`Table 10 Change From Baseline to Endpoint in PANSS Total Score—Pairwise
`Comparisons between Paliperidone Palitate Groups (LOCF, ITT) ................ 29
`Table 11 Change from Baseline to End Point in PSP (LOCF, ITT) .............................. 30
`Table 12 Placebo-Adjusted Effect Sizes (Reduction in PANSS Total Score) from Study
`PSY-3003, -3004, -3007, and SCH-201......................................................... 31
`Table 13 Placebo-Adjusted Effect Sizes (Reduction in PANSS Total Score) from Study
`PSY-3007, RIS-USA-121, and HGJZ............................................................. 32
`Table 14 Percentage of Subjects above 7.5 ng/mL on Trough Days 8 and 36, for
`Various Initiation Regimens ........................................................................... 34
`Table 15 Number of Injections of Double-Blind Study Medication (Safety Analysis Set)
`....................................................................................................................... 37
`Table 16 Duration (Days) of Exposure to Study Medication (Safety Analysis Set)....... 37
`Table 17 Treatment-Emergent Serious Adverse Events by MedDRA System Organ
`Class and Preferred Term (Safety Analysis Set) ........................................... 40
`Table 18 Treatment-Emergent Adverse Events Leading to Study Discontinuation by
`MedDRA System Organ Class and Preferred Term (Safety Analysis Set) .... 42
`Table 19 Treatment-Emergent Adverse Events in ≥ 2% of Subjects in Any Treatment
`Group by MedDRA System Organ Class and Preferred Term (Safety Analysis
`Set) ................................................................................................................ 44
`Table 20 Body Weight, BMI and Waist Measurement: Change from Baseline to
`Endpoint (Safety Analysis Set)....................................................................... 50
`Table 21 Treatment-Emergent Extrapyramidal Symptom Related Adverse Events by
`MedDRA Preferred Term (Safety Analysis Set)............................................. 51
`
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`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`
`Table of Figures
`
`Figure 1 Least-Squares Mean Changes in PANSS Total Score at Endpoint by Baseline
`BMI Group (ITT)............................................................................................. 28
`Figure 2 Least-Squares Mean Changes in PANSS Total Score at Endpoint by Baseline
`BMI Group and Region .................................................................................. 28
`
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`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`Based on the available data submitted to this New Drug Application (NDA) (including
`the data from this resubmission and from the original NDA), it is recommended that this
`NDA be granted an approval status.
`
`Several major labeling recommendations have been made. Please refer to section 9.2
`Labeling Recommendations for detailed comments. Final approval is contingent on
`satisfactory response to the agency’s recommendations and mutual agreement on
`labeling as well as the conclusions of the CMC, pharmacology/toxicology, and clinical
`pharmacology reviewers.
`
`1.2 Risk Benefit Assessment
`
`Schizophrenia is a severe mental disorder affected about 1% of population world wide.
`Because schizophrenia is a life-long disorder, compliance with medication treatment is
`crucial in schizophrenia treatment. Numerous typical and atypical antipsychotics have
`been approved by FDA for the treatment of schizophrenia in the USA. Compared with
`the oral preparations, only a few long-acting antipsychotic injections are available in the
`USA: two typical antipsychotics—haloperidol decanoate and fluphenazine decanoate,
`and one atypical antipsychotic—Risperidal Consta. It is important to have more long-
`acting injectable antipsychotics available to patients who have compliance issues. In
`this NDA (including original submission and re-submission), paliperidone palmitate has
`demonstrated its efficacy in acute and maintenance treatment of schizophrenia in study
`PSY-3003, -3004, -3007, SCH-201, and PSY-3001. Study PSY-3001, 3003, -3004, and
`SCH-201 had been submitted to the original NDA on 25 October 2007, and Jing Zhang,
`MD. PhD. is the primary medical reviewer of the original submission.
`
`The safety profile of paliperidone palmitate has been established by reviewing data from
`16 completed paliperidone palmitate clinical trials (5 phase 3, 1 phase 2 and 10 phase
`1) submitted to the original submission, and data from study PSY-3007, and the open-
`label extension phase of study PSY-3001 which were submitted to this resubmission.
`The safety evaluation demonstrated that the safety profile of paliperidone palmitate is
`similar to that of paliperidone ER, a marketed oral antipsychotic, for most parameters
`that were measured with the exception of injection site-related adverse events. No new
`or unexpected safety signals were identified.
`
`Considering schizophrenia is a severe, and highly disabilititing mental illness, it is
`believed that the benefit of having paliperidone palmitate available to schizophrenia
`
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`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`patients, especially to those who have appliance issues, justifies the risk of potential
`adverse events in the treatment.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`The safety profile of paliperidone palmitate is comparable to paliperidone ER, a
`marketed oral tablet formulation. No specific safety concern had been identified during
`the review. Risk Evaluation and Mitigation Strategies is not required at this time point.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`
`Long-Term Efficacy and Safety Study
`
`The sponsor already conducted a positive long-term, relapse prevention study (study
`PSY-3001), which includes an initial 33 week open-label period (including a 24 week
`stabilization phase); a randomized, double-blind, placebo-controlled phase with varied
`duration; and followed by an optional 52 week open label extension phase. Therefore,
`no additional Phase 4 commitments are required at this time point.
`
`Pediatric Study
`
`With respect to conduct pediatric trials with paliperidone palmitate under PREA, the
`sponsor requested a full pediatric waiver based on following reasons:
`
`• Lack of diagnostic stability earlier in the course of a psychotic illness in
`adolescence, and the need to finely titrate the dose of antipsychotic treatment in
`order to use the lowest possible dose while obtaining the best benefit-risk profile,
`make the use of an oral antipsychotic a more appropriate treatment choice than
`an long-acting injection (LAI) agent in this age group.
`
`
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`
`
`• Oral antipsychotics are the standard of care in adolescents with schizophrenia,
`and clinical guidelines recommend LAIs only in exceptional circumstances.
`
`• Needle phobia and anticipatory distress, combined with the perception that LAI
`treatment is punitive or coercive, are likely to adversely affect a collaborative
`therapeutic relationship with a health-care professional and thus negatively
`impact on treatment adherence.
`
`• Use of LAI atypical antipsychotic agents in adolescent patients is very limited,
`based on prescription data and postmarketing experience.
`
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`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`
`• For the reasons above, it would be impractical and unfeasible to recruit adequate
`numbers of adolescent patients with schizophrenia to successfully complete a
`clinical trial.
`
`
`
`
`
` 2
`
`• The pharmacokinetics of oral paliperidone ER has been documented to be
`relatively similar in adolescents and adults.
`
`• The pharmacokinetic (PK) profile of paliperidone palmitate in adolescents is
`expected to be relatively similar to the profile in adults so that additional studies
`in adolescents would not add value.
`
`
`In addition, the sponsor is presently conducting a pediatric program with paliperidone
`ER tablets following the terms of FDA’s written request. This program includes a PK
`study in adolescents, 10 to 17 years of age inclusive, (PALIOROS-PSZ-1001); a 6-week
`Phase 3 efficacy study including sparse PK sampling (R076477-PSZ-3001); and a long-
`term safety study (R076477-PSZ-3002). The efficacy and safety studies are currently
`ongoing. Upon completion of these studies, the sponsor should be able to extrapolate
`some useful PK, efficacy and safety information in pediatric population.
`
`The sponsor’s argument appears reasonable. It is recommended that a full waiver of
`pediatric studies with paliperidone palmitate covering age 0 to 17 for the indication of
`acute and maintenance treatment of schizophrenia to be granted.
`
` Introduction and Regulatory Background
`
`2.1 Product Information
`
`Paliperidone (9-hydroxy-risperidone, R076477) is a mono-aminergic antagonist that
`exhibits the characteristic dopamine type 2 (D2) and serotonin (5-hydroxytryptamine [5-
`HT]) type 2A (5HT2A) antagonism of the newer, or second-generation, antipsychotic
`drugs. Paliperidone is the major active metabolite of risperidone (R064766) and is a
`racemic mixture of enantiomers R078543 (+) and R078544 (-).
`
`2.2 Product Tables of Currently Available Treatments for Proposed
`Indications
`
`
`Table 1 summarizes currently available antipsychotics for treatment of schizophrenia.
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`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`
`
`Table 1 Currently Available Antipsychotics for Treatment of Schizophrenia
`Oral Preparations
`Long-Acting Injections
`haloperidol decanoate,
`Typical antipsychotics:
`chlopromazine, mesoridazine, thioridazine,
`fluphenazine decanoate,
`fluphenazine, perphenazine, trifluoperazine,
`Risperdal Consta.
`haloperidol, thiothixene, molindone, loxapine, pimozide.
`
`Atypical antipsychotics:
`Clozapine, risperidone, olanzapine, ziprasidone,
`quetiapine, aripiprazole, paliperidone, iloperidone.
`
`
`2.3 Availability of Proposed Active Ingredient in the United States
`INVEGA® (paliperidone) Extended-Release (ER) Tablets are approved in the U.S and
`the Europe for the treatment of schizophrenia. Paliperidone palmitate long-lasting
`injection has not been approved either in the U.S or Europe.
`
`2.4 Important Safety Issues with Consideration to Related Drugs
`
`Paliperidone is an active metabolite of risperidone, an approved atypical antipsychotic.
`An oral formulation of paliperidone (paliperidone ER) has been approved for marketing
`in the United States and the Europe. Similar to risperidone and paliparidone ER,
`paliperidone palmitate are associated with adverse events of increased serum prolactin
`levels, weight gain coupled with metabolic syndrome, and EPS-related adverse events.
`These safety issues have been addressed in the proposed labeling of paliperidone
`palmitate. There are has been no new safety issues generated on this topic from this
`submission.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`23 August 2000
`
`16 June 2004
`
`28 September 2004
`
`
`
`
`
`Preclinical-Clinical Meeting with FDA for R092670
`
`CMC/Biopharmaceutics EOP2 meeting with FDA
`
`Preclinical/Clinical EOP2 Meeting with FDA and post follow-
`up information
`
`
`
`
`
`EOP2 CMC/Biopharm Meeting with FDA
`
`EOP2 pre-Phase 3 meeting with FDA for bipolar disorder
`
`10
`
`
`12 October 2004
`
` December 2005
`
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`

`

`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`
`11 December 2006
`
`
`18 April 2007
`
` 7
`
` June 2007
`
`
`25 October 2007
`
`25 February 2008
`
`25 August 2008
`
`21 November 2008
`
` 3
`
`
`
` February 2009
`
`NDA 22264 re-submission
`
`Tele-conference with FDA regarding paliperidone palmitate
`injection
`
`
`
`
`
`
`
`
`
`
`
`Pre-NDA meeting with FDA
`
`CMC-Biopharmaceutics Pre-NDA meeting with FDA
`
`Original paliperidone palmitate NDA submission
`
`4-Month Safety Update
`
`Complete Response Letter from FDA
`
`Meeting with FDA to address the comments provided in the
`Complete Response Letter
`
`2.6 Other Relevant Background Information
`
`Paliperidone ER has not been withdrawn from the market worldwide for any reason.
`
` Ethics and Good Clinical Practices
`
` 3
`
`3.1 Submission Quality and Integrity
`
`During the course of the review, no problems with respect to data quality or integrity
`were identified.
`
`3.2 Compliance with Good Clinical Practices
`
`Study PSY-3007 was performed in accordance with the ethical principles that have their
`origin in the Declaration of Helsinki and that are consistent with ICH/Good Clinical
`Practice and applicable regulatory requirements.
`
`
`3.3 Financial Disclosures
`
`Janssen Products.
`
`, a sub-investigator at study site#
`
`, was a speaker for
`
`11
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`(b) (6)
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`

`

`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`
`
`
`
` only
`
`, MD, serve as sub-investigators at study site #
` and
`, MD are couples.
` disclosed following
` and
`financial arrangements/agreements: 1) received a $250,000 research grant to study
`neurogenesis in rats receiving antipsychotics; 2) received a $15,000 honoraria for
`ongoing consultation; 3) CME grants for the Department Grand Rounds Grants; 4)
`Grants for neurological test; and 5) received advisory board and speaker honoraria.
`
`Since study PSY-3007 was a multi-center, double-blind study, the site #
`enrolled patients out of the total of 636 subjects. It is less likely that those
`arrangements biased the study results.
`
` 4
`
` Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`4.1 Chemistry Manufacturing and Controls
`
`David Claffey, PhD., is the CMC reviewers for this submission. Please refer to his
`review for detailed CMC information.
`
`4.2 Clinical Microbiology
`
`No clinical microbiology study was deemed necessary.
`
`4.3 Preclinical Pharmacology/Toxicology
`
`Elzbieta Chalecka-Franaszek, PhD., is the pharmacology/toxicology reviewer for this
`submission. Please refer to her review for detailed pharmacology/toxicology information.
`
`4.4 Clinical Pharmacology
`
`4.4.1 Mechanism of Action
`
`Hao Zhu, PhD., is the primary clinical pharmacology reviewer for this submission.
`Please refer to his review for detailed clinical pharmacology information.
`
`4.4.2 Pharmacodynamics
`
`Hao Zhu, PhD., is the primary clinical pharmacology reviewer for this submission.
`Please refer to his review for detailed clinical pharmacology information.
`
`12
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
`
`(b) (6)
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`(b) (6)
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`(b) (6)
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`(b) (6)
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`(b)
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`

`

`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`4.4.3 Pharmacokinetics
`
`Hao Zhu, PhD., is the primary clinical pharmacology reviewer for this submission.
`Please refer to his review for detailed clinical pharmacology information.
`
` Sources of Clinical Data
`
` 5
`
`5.1 Tables of Studies/Clinical Trials
`
`PSY-3007 is the only study submitted to this resubmission. Table 2 summarizes study
`PSY-3007.
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`

`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`
`Table 2 Brief Summary of Study PSY-3007
`
`
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`

`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`
`5.2 Review Strategy
`
`Material reviewed in this review cycle includes Clinical Study Report from PSY-3007,
`Clinical Summary, Clinical Overview, Safety Update, and the proposed labeling. The
`efficacy review was performed in consultation with the statistical reviewer, Yeh-Fong
`Chen, PhD. Please refer to her review for more detailed pertinent efficacy information.
`
`5.3 Discussion of Individual Studies/Clinical Trials
`
`Study PSY-3007 provides additional efficacy and safety information with regards to
`paliperidone palmitate in acute treatment of schizophrenia. PSY-3007 also provided
`some clinical evidence that supports a high starting dose regimen (starting with 150 mg
`followed by a 100 mg 1 week later, both deltoid injections)
`
`
`
` 6
`
` Review of Efficacy
`Efficacy Summary
`
`All 3 doses of paliperidone palmitate tested in study PSY-3007—25 mg, 100 mg and
`150 mg eq.—were efficacious in adult subjects with schizophrenia who were
`experiencing acutely exacerbated schizophrenia as measured by change from baseline
`to end point in the PANSS total score. There was a dose response pattern in the
`primary efficacy endpoints—the PANSS total score.
`
`A. Study PSY-3007 for the Acute Treatment of Schizophrenia in Adults
`
`a. Rationale for Selection of Studies for Review
`
`In this resubmission, only one study—PSY-3007—was submitted. Study PSY-3007 is a
`13-week, randomized, double-blind, placebo-controlled, parallel-group, dose-response
`study to evaluate the efficacy and safety of 3 fixed doses, 25mg, 100 mg, and 150 mg
`eq. paliperidone palmitate, in subjects with schizophrenia. The primary endpoint of this
`study was the change in the Positive and Negative Syndrome Scale (PANSS) total
`score from baseline to the end of the double-blind treatment period. The key secondary
`endpoint was the change in the Personal and Social Performance Scale (PSP) from
`baseline to the end of the double-blind treatment period.
`
`The PANSS is a well known and validated rating scale used in numerous drug
`evaluation trials. The severity of neuropsychiatric symptoms of schizophrenia were
`
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`

`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`assessed using the 30-item PANSS scale which provides a total score (sum of the
`scores of all 30 items) and scores for 3 subscales, the positive subscale (7 items), the
`negative subscale (7 items), and the general psychopathology subscale (16 items),
`each rated on a scale of 1 (absent) to 7 (extreme).
`
`The Personal and Social Performance Scale (PSP), is a validated scale to help
`clinicians assess the global functioning of a patient with Schizophrenia, and to track the
`progress of functioning over time, through repeat use of the scale. The ratings are
`based on the outcome of a structured clinical interview, divided into 4 categories a)
`socially useful activities, b) personal and social relationships, c) self-care, and d)
`disturbing and aggressive behaviors.
`
`In general, study PSY-3007 is appropriately designed. The study length and the efficacy
`measures—the primary and the key secondary endpoints—are acceptable.
`
`b. Study Summaries
`
`i. Methods/Study Design/Analysis Plan
`
`Study PSY-3007 was a 13-week, randomized, double-blind, placebo-controlled, parallel-
`group, dose-response study to evaluate the efficacy and safety of 3 fixed doses—25mg,
`100 mg, and 150 mg eq.—of paliperidone palmitate in subjects with DSM-IV diagnosis
`of schizophrenia. The study included a screening period of up to 7 days and a 13-week
`double-blind treatment period.
`
`This study was conducted from 08 March 2007 to 24 March 2008 in 72 centers which
`include 33 US centers and 39 non-US centers. The non-US centers are located in
`Korea, Malaysia, Romania, Russia, Serbia, Taiwan, and Ukraine. Three hundred
`fourteen subjects (Intent to treat, ITT) are from US and 322 subjects (ITT) are from non-
`US regions.
`
`Overall Study Design
`
`Study PSY-3007 was a multicenter, randomized, double-blind, placebo-controlled,
`parallel-group, dose-response study designed to evaluate the efficacy and safety of 3
`fixed doses of paliperidone palmitate (25, 100, and 150 mg eq.) compared with placebo
`(randomization ratio 1:1:1:1). Study medication was administered as 4 doses: an initial
`i.m. injection of placebo or paliperidone palmitate 150 mg eq. followed by 3 fixed i.m.
`doses of placebo or paliperidone palmitate [25, 100, or 150 mg eq.] on Days 8, 36, and
`64. The initial dose of study medication was given in the deltoid muscle. Subsequent
`injections were given either in the deltoid or gluteal muscle at the discretion of the
`investigator.
`
`
`16
`
`

`

`Clinical Review
`Jing Zhang, MD., PhD.
`NDA 22264-000 (resubmission)
`Paliperidone Palmitate, INVEGA® SUSTENNATM
`
`The study included a screening period of up to 7 days and a 13-week double-blind
`treatment period. The screening period included a washout of disallowed psychotropic
`medications and oral tolerability testing for subjects without documented previous
`exposure to risperidone or paliperidone.
`
`It was planned that 644 men and women (161 in each of 4 treatment groups) aged 18
`years or older with a DSM-IV diagnosis of schizophrenia for at least one year and
`suffering from an acute episode (PANSS total score at screening between 70 and 120,
`inclusive) would be enrolled into this study. A total of 652 eligible subjects were
`randomized and received at least 1 dose of double-blind study medication (safety
`analysis set); 636 subjects had both baseline and post baseline efficacy data (intent-to-
`treat analysis set).
`
`Doses and Administration
`
`Paliperidone ER was supplied as a 6-mg capsule-shaped tablet for the oral tolerability
`test. Paliperidone palmitate was supplied as 25, 100, or 150 mg