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`CENTER FOR DRUG EVALUATION AND
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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`RESEARCH
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`APPLICA TION NUMBER:
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`APPLICATION NUMBER:
`22-264
`22-264
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`STATISTICAL REVIEW(S)
`STATISTICAL REVIEW! S}
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` DEPARTMENT OF HEALTH AND HUMAN SERVICES
` PUBLIC HEALTH SERVICE
` FOOD AND DRUG ADMINISTRATION
` CENTER FOR DRUG EVALUATION AND RESEARCH
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` STATISTICAL REVIEW AND EVALUATION
` Clinical Studies
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`22-264 (N000)
`Invega SustennaTM (paliperidone palmitate)
`Schizophrenia
`Johnson & Johnson
`Date of Document: 2/03/2009
`PDUFA Due Date: 8/03/2009
`Standard
`Biometrics I, HFD-710
`Yeh-Fong Chen, Ph.D.
`Peiling Yang, Ph.D.
`James Hung, Ph.D.
`Division of Psychiatry Products, HFD-130
`Clinical Reviewer: Jing Zhang, M.D.
`Clinical Team Leader: Gwen Zornberg, M.D.
`Kimberly Updegraff
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`NDA/Serial Number:
`Drug Name:
`Indication:
`Applicant:
`Dates:
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`Review Priority:
`Biometrics Division:
`Statistical Reviewer:
`Concurring
`Reviewers:
`Medical Division:
`Clinical Team:
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`Project Manager:
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`1
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`(b) (4)
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`Table of Contents
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`1. EXECUTIVE SUMMARY ...................................................................................................................... 3
`1.1 CONCLUSIONS AND RECOMMENDATIONS ............................................................................... 3
`1.2 BRIEF OVERVIEW OF CLINICAL STUDIES.................................................................................. 3
`1.3 STATISTICAL ISSUES AND FINDINGS .......................................................................................... 4
`2. INTRODUCTION .................................................................................................................................... 4
`2.1 OVERVIEW......................................................................................................................................... 4
`2.2 DATA SOURCES ................................................................................................................................ 5
`3. STATISTICAL EVALUATION ............................................................................................................. 5
`3.1 EVALUATION OF EFFICACY .......................................................................................................... 5
`3.1.1 Description of Protocol R092670-PSY-3007................................................................................. 5
`3.1.1.1 Study Objectives...................................................................................................................................... 5
`3.1.1.2 Study Design............................................................................................................................................ 5
`3.1.1.3 Efficacy Endpoints and Analyses............................................................................................................. 6
`3.1.2 Efficacy Results for Study R092670-PSY-3007.............................................................................. 7
`3.1.2.1 Patient Population and Baseline Demographic Characteristics................................................................ 7
`3.1.2.2 Sponsor’s Results for Primary Efficacy Endpoint.................................................................................... 8
`3.1.2.3 Sponsor’s Results for Secondary Efficacy Endpoints.............................................................................. 9
`3.1.2.4 Statistical Reviewer’s Findings and Comments..................................................................................... 10
`3.2 EVALUATION OF SAFETY............................................................................................................. 11
`4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS.................................................................. 11
`4.1 GENDER, RACE AND AGE ............................................................................................................. 11
`4.2 OTHER SPECIAL/SUBGROUP POPULATIONS............................................................................ 12
`5. SUMMARY AND CONCLUSIONS..................................................................................................... 13
`5.1 STATISTICAL ISSUES AND COLLECTIVE EVIDENCE.............................................................. 13
`5.2 CONCLUSIONS AND RECOMMENDATIONS.............................................................................. 13
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`1. EXECUTIVE SUMMARY
`
`1.1 CONCLUSIONS AND RECOMMENDATIONS
`
`The statistical reviewer agreed that Study 3007 was a positive study, where all three
`doses (25, 100 and 150 mg eq.) showed statistically significant effects in comparison
`with placebo on the primary endpoint, PANSS total scores. However, the efficacy
`findings on the PSP scores have not been replicated; thus this reviewer suggests that these
`findings not be included in the label. In addition, although 150 mg eq. performed
`numerically better than 100 mg eq., the numerical advantage was small and statistically
`indistinguishable (p=0.59); thus, it remains unclear whether 150 mg eq. would have an
`additional beneficial effect.
`
`1.2 BRIEF OVERVIEW OF CLINICAL STUDIES
`
`In response to the complete response letter for the original NDA application for
`paliperidone palmitate as a treatment of schizophrenia in adult patients, the sponsor
`included an additional efficacy study (Study 3007), which was designed to confirm the
`efficacy and safety of the paliperidone palmitate 25 and 100 mg eq. doses previously
`observed in the Phase 3 studies R092670-PSY-3003 (100 mg eq. dose) and R092670-
`PSY-3004 (25 and 100 mg eq. doses), to explore the efficacy and safety of a higher dose
`(paliperidone palmitate 150 mg eq.) and to examine a new dosing regimen used to
`increase the initial exposure to paliperidone (initial dose of 150 mg eq. in the deltoid
`muscle followed by either deltoid or gluteal injections at the target dose).
`
`Study 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. Study
`medication was administered as 4 doses: an intial 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. Subsequent
`injections were given either in the deltoid or gluteal muscle at the discretion of the
`investigator. Randomized subjects were to remain in the study for 28 days after the last
`injection on Day 64 with the end of study visit scheduled for Day 92 during the double-
`blind period. The primary endpoint is the change in the PANSS total score (sum of the
`scores of all 30 PANSS items) from the start of the double-blind treatment period
`(baseline) to the end of the double-blind treatment period (Day 92 or last post baseline
`assessment). Secondary endpoints included the changes from baseline to the end of the
`double-blind treatment period (Day 92 or last post baseline assessment) in the PSP and
`the CGI-S scores, where PSP was designated as a key secondary endpoint.
`
`Based on statistically significant results shown on all three doses in comparison with
`placebo for the primary endpoint and on two higher doses for the key secondary
`endpoint, PSP scores, the sponsor concluded that paliperidone palmitate, injected at a
`dose of 150 mg eq. into the deltoid muscle followed by 3 i.m. injections at fixed doses of
`25 mg eq., 100 mg eq., or 150 mg eq. on Days 8, 36 and 64, was statistically significantly
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`more effective than placebo in improving the PANSS total score at end point in the 13-
`week double-blind study in subjects with schizophrenia. The sponsor even claimed that
`there was a dose response with respect to efficacy for the primary endpoint, with mean
`change in the PANSS total score at end point showing incrementally greater
`improvement across the 3 doses of paliperidone palmitate.
`
`1.3 STATISTICAL ISSUES AND FINDINGS
`
`The statistical reviewer basically confirmed the sponsor’s analysis results for Study 3007.
`It was agreed that data supported the efficacy of paliperidone palmitate as a treatment for
`adult patients with schizophrenia.
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`Regarding the sponsor’s dose response claim, although paliperidone palmitate 150 mg eq.
`seemed to perform numerically better than 100 mg eq. the observed difference between
`them appeared very small. With a p-value 0.59 for the comparison between these two
`treatment arms, it is not clear whether paliperidone palmitate 150 mg eq. would
`contribute any additional benefit.
`
`2. INTRODUCTION
`
`2.1 OVERVIEW
`
`Paliperidone palmitate is the palmitate ester of paliperidone. The original new drug
`application for paliperidone palmitate
` was submitted by the sponsor
`on October 25 of 2007 for the treatment of schizophrenia in adults. In that submission, 4
`phase 2/3 studies for subjects with acute psychosis were evaluated. It was determined that
`the efficacy of paliperidone palmitate (25 and 100 mg eq.) in treating patients with
`schizophrenia was demonstrated. However, due to some issues regarding the product
`quality, the NDA application was not approved.
`
`To promote the use of higher initiation doses of paliperidone palmitate in a new dosing
`regimen and also explore the efficacy and safety of a higher dose (paloperidone palmitate
`150 mg eq.), the sponsor conducted and included an additional efficacy study (Study
`3007) along with this NDA re-submission. The sponsor also included their exploration
`for the effects of BMI on pharmacokinetics, clinical efficacy and clinical safety in this
`submission. They concluded that no consistent clinically remarkable difference was
`observed among the 3 BMI categories (normal, overweight, and obese) with regard to the
`overall pattern and incidences of treatment-emergent adverse events. They further
`concluded that at the highest recommended dose of 150 mg eq. paliperidone palmitate
`was generally safe and well tolerated across all BMI categories, supporting the safety and
`tolerability of the recommended dosing regimen.
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`4
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`(b) (4)
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`(b) (4)
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`2.2 DATA SOURCES
`
`The sponsor’s submission including study clinical report and study data is stored in the
`CDER electronic document room (EDR) with the following link:
`\\CDSESUB1\EVSPROD\NDA022264\0026.
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`3. STATISTICAL EVALUATION
`
`3.1 EVALUATION OF EFFICACY
`
`3.1.1 Description of Protocol R092670-PSY-3007
`
`This study was titled “A Randomized, Double-Blind, Placebo-Controlled, Parallel-
`Group, Dose-Response Study to Evaluate the Efficacy and Safety of 3 Fixed Doses (25
`mg eq., 100 mg eq., and 150 mg eq.) of Paliperidone Palmitate in Subjects with
`Schizophrenia”. There were 72 centers in 8 countries participated in this study. The 8
`countries participating in the study included the United States (33 centers), Russia (11
`centers), Romania (8 centers), the Ukraine (5 centers), Taiwan (5 centers), the Republic
`of Korea (4 centers), Malaysia (4 centers), and Serbia (2 centers).
`
`3.1.1.1 Study Objectives
`
`The primary objectives of this study were to evaluate the efficacy and safety of 3 fixed
`doses of paliperidone palmitate (25, 100, and 150 mg eq.) administered i.m. after an
`initial dose of 150 mg eq. in the deltoid muscle followed by either deltoid or gluteal
`injections for a total of 13 weeks of treatment as compared with placebo in subjects
`with schizophrenia.
`
`The secondary objectives were to:
`
`
`• Assess the benefits in personal and social functioning (key secondary endpoint)
`associated with the use of paliperidone palmitate compared with placebo;
`• Assess the global improvement in severity of illness associated with the use of
`paliperidone palmitate compared with placebo;
`• Assess the dose-response and exposure-response relationships of paliperidone
`palmitate.
`
`
`3.1.1.2 Study Design
`
`Study R092670-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. 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
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`either in the deltoid or gluteal muscle at the discretion of the investigator. Randomized
`subjects were to remain in the study for 28 days after the last injection on Day 64 with the
`end of study visit scheduled for Day 92 during the double-blind period.
`
`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. The entire study, including the screening period, lasted approximately 14
`weeks.
`
`It was planned that approximately 644 subjects (161 in each of 4 treatment groups) aged
`18 years or older, with a Diagnostic and Statistical Manual of Mental Disorders, 4th
`Edition (DSM-IV) diagnosis of schizophrenia for at least one year before screening and
`severely symptomatic (Positive and Negative Syndrome Scale [PANSS] total score
`between 70 and 120, inclusive, at screening) would participate in the double-blind period
`of this study.
`
`At the beginning of the double-blind treatment period, eligible subjects were randomly
`assigned in equal numbers to 1 of 4 treatment groups: paliperidone palmitate 25, 100, or
`150 mg eq. or placebo. All subjects randomly assigned to active (paliperidone palmitate)
`treatment were given an injection of paliperidone palmitate 150 mg eq. in the deltoid
`muscle followed by 1 of 3 fixed doses of paliperidone palmitate (25, 100 or 150 mg eq.)
`on Days 8, 36, and 64. Subjects assigned to placebo received an injection of placebo in
`the deltoid muscle on Day 1, followed by injections of placebo on Days 8, 36, and 64 in
`either the deltoid or gluteal muscle. The choice of the injection site, deltoid or gluteal, for
`i.m. injections of study medication administered after Day 1 was at the discretion of the
`investigator.
`
`Subjects were considered to have completed the study if they completed all assessments
`on Day 92 (Visit 12) of the double-blind period. The 13-week duration of the double-
`blind treatment period was intended to evaluate the efficacy and safety of paliperidone
`palmitate at approximate steady-state levels using the new initial 150 mg eq. dose
`regimen.
`
`3.1.1.3 Efficacy Endpoints and Analyses
`
`Efficacy assessments included PANSS, CGI-S, the Personal and Social Performance
`(PSP) scale, and the Sleep Visual Analog Scale (VAS).
`
`The primary efficacy endpoint is the change in the PANSS total score (sum of the scores
`of all 30 PANSS items) from the start of the double-blind treatment period (baseline) to
`the end of the double-blind treatment period (Day 92 or last post baseline assessment).
`
`Secondary endpoints included the changes from baseline to the end of the double-blind
`treatment period (Day 92 or last post baseline assessment) in the PSP and the CGI-S
`scores, where the PSP score at endpoint (LOCF) was designated as a key secondary
`variable.
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`Other endpoints included change in the Sleep VAS scores, onset of therapeutic effect,
`responder rate, changes from baseline to the end of the double-blind treatment period in
`the PANSS subscales and shifts in PSP.
`
`For the change in PANSS total score at end point (LOCF), the least-squares (LS) means
`were estimated and compared between each active treatment group and placebo using an
`analysis of covariance (ANCOVA) model with treatment and country as factors, and
`baseline PANSS total score as a covariate. Dunnett’s test was applied to adjust for
`multiple testing of the 3 doses versus placebo.
`
`At end point, the interaction terms between treatment and country and between treatment
`and baseline PANSS total score were added to the primary ANCOVA model one at a
`time. If an interaction was observed to be statistically significant at the pre-specified 2-
`sided 0.10 significance level, then further evaluations were to be performed to assess and
`explain the nature of the interaction. Significant interactions were also to be examined
`using a 2-sided Gail-Simon test, with a 0.10 significance level. This is a likelihood ratio
`test for testing the presence of qualitative interaction (treatment effect is not consistent
`across subgroups).
`
`For each time point (both LOCF and observed case), descriptive statistics were produced
`on the PANSS total score and change from baseline. In addition, to explore the course of
`treatment effect over time, ANCOVA models on both LOCF and observed case data were
`performed for each time point using the same factors as mentioned above for the primary
`efficacy analysis.
`
`The analysis of the key secondary efficacy endpoint, the change in PSP score at end point
`(LOCF), was conducted by means of an ANCOVA model with treatment and country as
`factors, and the baseline PSP score as a covariate. The Dunnett-Bonferroni-based parallel
`gatekeeping approach (Xu et al. submitted) was used to adjust for multiple testing.
`
`3.1.2 Efficacy Results for Study R092670-PSY-3007
`
`3.1.2.1 Patient Population and Baseline Demographic Characteristics
`
`Table 3.1 shows number of patients randomized in each treatment group for different
`study populations and patient disposition. Table 3.2 shows the demographic and baseline
`characteristics for the intent-to-treat analysis set. As shown in the table, the baseline
`characteristics and baseline PANSS total score appear similar among the treatment
`groups.
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`Table 3.1 Number of Subjects Randomly Assigned to Each Treatment Group
`Reported are n (%)
`Placebo
`R092670
`R092670
`R092670
`(N=164)
`25 mg eq.
`100 mg eq.
`150 mg eq.
`(N=160)
`(N=160)
`(N=160)
`160 (100)
`165 (100)
`163 (100)
`160 (100)
`165 (100)
`163 (100)
`155 (97)
`161 (98)
`160 (98)
`83 (52)
`89 (54)
`90 (55)
`77 (48)
`76 (46)
`73 (45)
`31 (19)
`28 (17)
`23 (14)
`23 (14)
`28 (17)
`30 (18)
`10 (6)
`10 (6)
`13 (8)
`12 (8)
`6 (4)
`6 (4)
`0
`1 (1)
`0
`1 (1)
`3 (2)
`1 (1)
`
`Total
`(N=652)
`
`652 (100)
`652 (100)
`636 (98)
`333 (51)
`319 (49)
`127 (19)
`107 (16)
`44 (7)
`33 (5)
`1 (<1)
`7 (1)
`
`164 (100)
`All Randomized
`164 (100)
`Safety
`160 (98)
`Intent-to-Treat
`71 (43)
`Completed
`93 (57)
`Withdrawn
`45 (27)
` Lack of Efficacy
`26 (16)
` Subject Withdrew Consent
`11 (7)
` Adverse Event
`9 (5)
` Lost to Follow-Up
`0
` Pregnancy
`2 (1)
` Other
`Source: Sponsor’s Tables 4 and 5 in CSR
`
`Table 3.2 Demographic and Baseline Characteristics for ITT Analysis Set
`
`Placebo
`R092670
`R092670
`(N=160)
`25 mg eq.
`100 mg eq.
`(N=155)
`(N=161)
`
`
`39.5 (10.31)
`38.8 (10.37)
`
`
`111 (72)
`107 (66)
`44 (28)
`54 (34)
`
`
`86 (53)
`86 (55)
`51 (32)
`42 (27)
`22 (14)
`24 (15)
`0
`2 (1)
`
`
`2 (1)
`2 (1)
`80.8 (20.39)
`77.2 (18.32)
`173.1 (9.59)
`170.7 (9.79)
`
`
`86.9 (11.99)
`86.2 (10.77)
`
`R092670
`150 mg eq.
`(N=160)
`
`39.4 (10.59)
`
`103 (64)
`57 (36)
`
`84 (53)
`50 (31)
`22 (14)
`2 (1)
`
`2 (1)
`78.2 (16.78)
`171.2 (9.16)
`
`88.4 (11.70)
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`
`39.9 (10.98)
`
`106 (66)
`54 (34)
`
`87 (54)
`49 (31)
`24 (15)
`0
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` 0
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`Age (years) , Mean (SD)
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`Sex, n (%)
` Male
` Female
`Race, n (%)
` White
` Black
` Asian
` American Indian or
` Alaskan native
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` Other
`78.2 (17.19)
`Weight (kg), Mean (SD)
`170.5 (9.43)
`Height (cm), Mean (SD)
`
`Baseline PANSS Total,
`86.8 (10.31)
`Mean (SD)
`Source: Sponsor’s Tables 6 and 7 in CSR
`
`3.1.2.2 Sponsor’s Results for Primary Efficacy Endpoint
`
`Table 3.2 shows the sponsor’s analysis results for PANSS Total score. Based on the
`intent-to-treat LOCF analysis of the primary efficacy variable using Dunnett’s test to
`control for multiplicity, the improvement in all 3 paliperidone palmitate treatment groups
`reached statistical significance when compared with the placebo group.
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`Change from Baseline
`161
`155
`160
` N
`-11.6 (17.63)
`-8.0 (19.90)
`-2.9 (19.26)
` Mean (SD)
`-8.7 (2.00)
`-5.1 (2.01)
`
` Diff. of LS Means (SE)
`<0.0001
`0.0124
`
` P-Value (Unadjusted)
`<0.0001
`0.0335
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` P-Value (Dunnett’s Adjusted)
`(-12.62, -4.78)
`(-9.01,-1.10)
`
` 95% C.I. (Unadjusted)
`Source: Sponsor’s Table 17. Note: the sponsor did not report unadjusted p-values.
`
`The sponsor also performed some exploratory analyses for assessing palperidone
`palmitate dose response. Their results of the ANCOVA comparing mean change from
`baseline to endpoint in PANSS total score between the paliperidone palmitate groups are
`presented in Table 3.3. The sponsor claimed that there was a dose-response pattern with
`respect to the primary efficacy variable, with the mean decreases (improvement) in the
`PANSS total score at endpoint based on LOCF data.
`
`Table 3.3 Sponsor’s Pair-Wise Comparison Results for PANSS Total Score
`Total 30 item Positive and Negative Syndrome Scale
`R092670
`R092670
`25 mg eq.
`100 mg eq.
`(N=155)
`(N=161)
`
`
`
`
`
`R092670
`150 mg eq.
`(N=160)
`
`160
`-13.2 (18.48)
`-9.8 (2.00)
`<0.0001
`<0.0001
`(-13.71, -5.85)
`
`R092670
`150 mg eq.
`(N=160)
`
`-13.2 (18.48)
`0.019
`-4.7 (2.02)
`(-8.69; -0.77)
`0.588
`-1.1 (2.00)
`(-5.01; 2.85)
`
`Table 3.2 Analysis Results for PANSS Total Score on LOCF Data
`R092670
`Total 30 item Positive and
`Placebo
`R092670
`100 mg eq.
`Negative Syndrome Scale
`(N=160)
`25 mg eq.
`(N=161)
`(N=155)
`
`
`
`
`
`
`
`
`
`-8.0 (19.90)
`
`
`
`
`
`
`
`
`
`-11.6 (17.63)
`0.071
`-3.6 (2.01)
`(-7.60; 0.31)
`
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`9
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`Change from Baseline
` Mean (SD)
` Unadjusted P-value (minus R092670 25 mg eq. )
` Diff. of LS Means (SE)
` 95% CI
` Unadjusted P-value (minus R092670 100 mg eq.)
` Diff. of LS Means (SE)
` 95% CI
`Source: Sponsor’s Table 18.
`
`Note that for the primary endpoint, the sponsor also performed some sensitivity analyses
`including the worst rank analysis and two additional analyses based on longitudinal
`mixed effects model. All analysis results showed that three doses of paliperidone
`palmitate were all statistically significantly superior to placebo in improving the PANSS
`total scores.
`
`3.1.2.3 Sponsor’s Results for Secondary Efficacy Endpoints
`
`Key Secondary Endpoint: Change in PSP Scores
`
`Table 3.4 shows the sponsor’s analysis results for change from baseline to end point in
`the PSP score. The sponsor stated in the clinical study report that using the Dunnett-
`Bonferroni-based parallel gatekeeping procedure to adjust for multiplicity, the
`improvement in the paliperidone palmitate 100 and 150 mg eq. treatment groups reached
`statistical significance when compared with the placebo group. The paliperidone
`palmitate 25 mg eq. treatment group was not found to be statistically significantly
`superior to placebo (p=0.509).
`
`

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`Table 3.4 Sponsor’s Analysis Results for PSP Scores on LOCF Data
`Personal and Social Performance
`Placebo
`R092670
`R092670
`(N=160)
`25 mg eq.
`100 mg eq.
`(N=155)
`(N=161)
`
`
`
`157
`1.7 (15.60)
`
`
`
`
`
`
`
`153
`2.9 (15.29)
`1.0 (1.50)
`0.509
`0.509
`(-1.96, 3.95)
`
`
`
`156
`6.1 (13.59)
`4.4 (1.50)
`0.0036
`0.007
`(1.43, 7.31)
`
`
`
`R092670
`150 mg eq.
`(N=160)
`
`157
`8.3 (14.69)
`6.2 (1.49)
`<0.0001
`<0.001
`(3.26, 9.12)
`
`Change from Baseline
` N
` Mean (SD)
` Diff. of LS Means (SE)
` P-Value (Unadjusted)
` P-Valuea (D-B adjusted)
` 95% C.I. (Unadjusted)
`Source: Sponsor’s Table 19 in CSR
`a P-values were adjusted for multiplicity between PANSS Total Score and PSP, as well as different dose
`levels in comparison with placebo, using the Dunnett-Bonferroni-based parallel gate-keeping method.
`
`Secondary Efficacy Endpoint: Change in CGI-S Scores
`
`Table 3.5 shows the sponsor’s analysis results for the change from baseline to end point
`in CGI-S scores. Note that the sponsor analyzed the CGI-S scores based on the ranked
`data. As shown in the table, they concluded that the improvement in the paliperidone
`palmitate 100 and 150 mg eq. groups reached statistical significance when compared with
`the placebo group at nominal significance level of 0.05. The paliperidone palmitate 25
`mg eq. group was not statistically significantly superior to placebo. No multiplicity
`adjustment was applied for this analysis.
`
`Table 3.5 Sponsor’s Analysis Results for CGI-S Scores on LOCF Data
`Clinical Global Impression-
`Placebo
`R092670
`R092670
`Severity Scale (CGI-S)
`(N=160)
`25 mg eq.
`100 mg eq.
`(N=155)
`(N=161)
`
`R092670
`150 mg eq.
`(N=160)
`
`160
`-1.0 (-4;3)
`<0.0001
`
`
`
`Change from Baseline
` N
` Median (Range)
` P-Value (minus Placebo)a
`Source: Sponsor’s Table 20 in CSR
`a Based on analysis of covariance (ANCOVA) model on ranks with treatment (Placebo, R092670 25 mg
`eq., R092670 100 mg eq., R092670 150 mg eq.) and country as factors, and baseline value as a covariate.
`
`3.1.2.4 Statistical Reviewer’s Findings and Comments
`
`1. The statistical reviewer confirmed the sponsor’s analysis results for the primary
` endpoint and also two secondary endpoints. It was agreed that in comparison with
` placebo all three doses showed statistical significance on the primary endpoint and also
` the two higher doses showed statistically significant findings on the pre-specified key
`
` secondary endpoint.
`
`
`
`
`
`
`
`
`
`
`160
`0.0 (-3;2)
`
`
`
`
`154
`-1.0 (-3;2)
`0.140
`
`
`
`
`
`161
`-1.0 (-4;2)
`0.005
`
`
`
`
`
`10
`
`(b) (4)
`
`

`

`2. Although the sponsor claimed that Study 3007 showed a dose-response pattern, this
`reviewer would like to point out that the observed difference between R092670 100
`mg eq. and 150 mg eq. is small. It is not clear whether 150 mg eq. had any additional
`beneficial effect in comparison with 100 mg eq.
`
`
`3.2 EVALUATION OF SAFETY
`
`The evaluation of safety was not performed in this review. Please refer the clinical
`review for this evaluation.
`
`4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`4.1 GENDER, RACE AND AGE
`
`Tables 3.5 to 3.7 show this reviewer’s exploratory subgroup analysis by gender, race and
`age. As observed from the tables for these basic demographic factors, none of subgroups
`had any dose which performed worse than placebo.
`
`Table 3.5 FDA Results of Subgroup Analysis by Gender for PANSS Total Scores
`Change from Baseline to Endpoint in
`Placebo
`R092670
`R092670
`R092670
`PANSS Total Score
`
`25 mg eq.
`100 mg eq.
`150 mg eq.
`Male, N
`106
`111
`107
`103
` LS Mean Change (SE)
`-6.63 (2.15)
`-10.39 (2.03)
`-14.61 (2.17)
`-18.19 (2.12)
` Unadjusted P-Value (vs. Placebo)
`
`0.12
`0.0010
`<0.0001
`Female, N
`54
`44
`54
`57
` LS Mean Change (SE)
`-5.51 (2.85)
`-13.49 (3.17)
`-14.56 (2.76)
`-12.89 (2.91)
` Unadjusted P-Value (vs. Placebo)
`
`0.035
`0.011
`0.037
`
`Table 3.6 FDA Results of Subgroup Analysis by Race for PANSS Total Scores
`Change from Baseline to Endpoint in
`Placebo
`R092670
`R092670
`PANSS Total Score
`
`25 mg eq.
`100 mg eq.
`White, N
`87
`86
`86
` LS Mean Change (SE)
`-9.00 (2.22)
`-17.69 (2.22)
`-17.93 (2.19)
` Unadjusted P-Value (vs. Placebo)
`
`0.0014
`0.001
`Black, N
`49
`42
`51
` LS Mean Change (SE)
`-5.39 (2.17)
`-6.89 (2.33)
`-11.88 (2.13)
` Unadjusted P-Value (vs. Placebo)
`
`0.64
`0.04
`Asian, N
`24
`24
`22
` LS Mean Change (SE)
`-1.41 (6.91)
`-1.27 (7.67)
`-14.84 (7.88)
` Unadjusted P-Value (vs. Placebo)
`
`0.98
`0.06
`Other, N
`.
`3
`2
` LS Mean Change (SE)
`.
`-3.76 (9.26)
`3.03 (12.14)
` Unadjusted P-Value (vs. Placebo)
`.
`.
`.
`
`
`
`
`
`
`
`R092670
`150 mg eq.
`84
`-19.92 (2.25)
`<0.0001
`50
`-11.15 (2.14)
`0.06
`22
`-13.62 (7.96)
`0.09
`4
`-24.94 (8.27)
`.
`
`
`
`11
`
`

`

`R092670
`150 mg eq.
`81
`-17.39 (2.60)
`<0.0001
`79
`-14.12 (2.44)
`0.02
`
`Table 3.7 FDA Results of Subgroup Analysis by Age for PANSS Total Scores
`Change from Baseline to Endpoint in
`Placebo
`R092670
`R092670
`PANSS Total Score
`
`25 mg eq.
`100 mg eq.
`Age <40, N
`76
`79
`81
` LS Mean Change (SE)
`-4.26 (2.64)
`-11.56 (2.45)
`-16.40 (2.41)
` Unadjusted P-Value (vs. Placebo)
`
`0.014
`<0.0001
`Age≥40, N
`84
`76
`80
` LS Mean Change (SE)
`-7.35 (2.37)
`-10.79 (2.54)
`-12.90 (2.54)
` Unadjusted P-Value (vs. Placebo)
`
`0.22
`0.05
`
`
`4.2 OTHER SPECIAL/SUBGROUP POPULATIONS
`
`Tables 3.8 and 3.9 show this reviewer’s exploratory subgroup analysis results by the
`regional and weight factor. For the regional subgroup analyses, except 25 mg eq. of
`R092670 in Asia subgroup, all others showed that all doses performed numerically better
`than placebo. The observed drug effects from the North America seem to be smaller than
`those observed from the Eastern Europe. For the weight subgroup analyses, it is
`interesting to observe that in general the drug has stronger effect in patients with normal
`weight than those who are overweight or obese in comparison with placebo.
`Nevertheless, one should also note that the placebo responses among these three weight
`groups do not seem to be comparable.
`
`Table 3.8 FDA Results of Subgroup Analysis by Region for PANSS Total Scores
`Change from Baseline to Endpoint in
`Placebo
`R092670
`R092670
`R092670
`PANSS Total Score
`
`25 mg eq.
`100 mg eq.
`150 mg eq.
`North America, N
`80
`73
`79
`82
` LS Mean Change (SE)
`-5.32 (1.73)
`-7.86 (1.80)
`-8.94 (1.75)
`-11.96 (1.71)
` Unadjusted P-Value (vs. Placebo)
`
`0.31
`0.14
`0.01
`Eastern Europe, N
`57
`58
`60
`56
` LS Mean Change (SE)
`-8.80 (2.84)
`-19.63 (2.83)
`-22.61 (2.76)
`-21.89 (2.87)
` Unadjusted P-Value (vs. Placebo)
`
`0.002
`<0.0001
`0.0002
`Asia, N
`23
`24
`22
`22
` LS Mean Change (SE)
`2.43 (4.93)
`2.56 (4.80)
`-11.01 (5.05)
`-9.79 (5.08)
` Unadjusted P-Value (vs. Placebo)
`
`0.98
`0.06
`0.09
`
`Table 3.9 FDA Results of Subgroup Analysis by Weight for PANSS Total Scores
`Change from Baseline to Endpoint in
`Placebo
`R092670
`R092670
`R092670
`PANSS Total Score
`
`25 mg eq.
`100 mg eq.
`150 mg eq.
`Normal (BMI<25), N
`61
`73
`75
`69
` LS Mean Change (SE)
`-3.75 (3.05)
`-12.38 (2.83)
`-15.07 (2.79)
`-16.16 (2.93)
` Unadjusted P-Value (vs. Placebo)
`
`0.0101
`0.0007
`0.0003
`Overweight (25≤BMI<30), N
`59
`40
`53
`53
` LS Mean Change (SE)
`-7.78 (2.78)
`-8.05 (2.96)
`-17.19 (2.83)
`-21.14 (2.99)
` Unadjusted P-Value (vs. Placebo)
`
`0.9382
`0.0037
`<0.0001
`Obese (BMI≥30), N
`40
`42
`33
`38
` LS Mean Change (SE)
`-5.63 (4.22)
`-9.38 (4.03)
`-10.51 (4.56)
`-6.79 (4.16)
` Unadjusted P-Value (vs. Placebo)
`
`0.30
`0.21
`0.76
`
`
`
`
`
`
`
`12
`
`

`

`5. SUMMARY AND CONCLUSIONS
`
`5.1 STATISTICAL ISSUES AND COLLECTIVE EVIDENCE
`
`The statistical reviewer basically confirmed the sponsor’s analysis results for Study 3007.
`It was agreed that data supported the efficacy of paliperidone palmitate as a treatment for
`adult patients with schizophrenia.
`
`
`
`
`
`
`
`
`
`
` paliperidone palmitate 150 mg eq.
`seemed to perform numerically better than 100 mg eq. the observed difference between
`them appeared very small. With a p-value 0.59 for the comparison between these two
`treatment arms, it is not clear whether paliperidone palmitate 150 mg eq. would
`contribute any additional benefit.
`
`5.2 CONCLUSIONS AND RECOMMENDATIONS
`
`The statistical reviewer agreed that Study 3007 was a positive study, where all three
`doses (25, 100 and 150 mg eq.) showed statistically significant effects in comparison
`with placebo on the primary endpoint, PANSS total scores.
`
`
`
`
` In addition, although 150 mg eq. performed
`numerically better than 100 mg eq., the numerical advantage was small and statistically
`indistinguishable (p=0.59); thus, it remains unclear whether 150 mg eq. would have an
`additional beneficial effect.
`
`
` ____________________
` Yeh-Fong Chen, Ph.D.
` Mathematical Statistician
` cc: NDA 22-264
`HFD-130/Dr. Laughren
`HFD-130/Dr. Mathis
` HFD-130/Dr. Zornberg
` HFD-130/Dr. Zhang