CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`213801Orig1s000
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`STATISTICAL REVIEW(S)
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
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`S T A T I S T I C A L R E V I E W A N D E VA L U A T I O N
`CLINICAL STUDIES
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`
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`NDA Serial Number:
`Drug Name:
`
`Indication(s):
`
`Applicant:
`Date(s):
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`213801
`Myrbetriq Granules (Mirabegron for extended release oral
`suspension)
`Treatment of neurogenic detrusor overactivity (NDO) in pediatric
`patients aged 3 years and older
`Astellas Pharma Global Development, INC.
`Receipt Date: 09/28/2020
`PDUFA Date: 03/28/2021
`Priority
`
`Biometrics Division:
`Division of Biometrics IV
`Statistical Reviewer:
`Jia Guo, Ph.D.
`Concurring Reviewers: Daphne Lin, Ph.D. Acting Team Leader, Deputy Director
`
`
`Medical Division:
`Division of Urology, Obstetrics and Gynecology (DUOG)
`Clinical Team:
`Elena Boley, M.D., Clinical Reviewer
`Mark Hirsch, M.D., Clinical Team Leader
`Project Manager:
`Nenita Crisostomo
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`Keywords: Change from Baseline
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`Review Priority:
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`Reference ID: 4760723
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`Table of Contents
`1 EXECUTIVE SUMMARY ................................................................................................................................. 4
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`2
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`3
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`INTRODUCTION ............................................................................................................................................... 5
`2.1
`OVERVIEW ...................................................................................................................................................... 5
`2.2
`DATA SOURCES .............................................................................................................................................. 5
`STATISTICAL EVALUATION ........................................................................................................................ 6
`3.1
`DATA AND ANALYSIS QUALITY ..................................................................................................................... 6
`3.2
`EVALUATION OF EFFICACY ............................................................................................................................ 6
`3.2.1
`Study Design and Endpoints .................................................................................................................. 6
`3.2.2
`Statistical Methodologies ....................................................................................................................... 7
`3.2.3
`Subject Disposition, Demographic and Baseline Characteristics ......................................................... 8
`3.2.4
`Results and Conclusions ........................................................................................................................ 8
`3.3
`EVALUATION OF SAFETY .............................................................................................................................. 11
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ............................................................................. 11
`4.1
`GENDER, RACE, AGE, AND GEOGRAPHIC REGION ........................................................................................ 11
`4.2
`OTHER SPECIAL/SUBGROUP POPULATIONS .................................................................................................. 13
`SUMMARY AND CONCLUSIONS ................................................................................................................ 13
`5.1
`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE ....................................................................................... 13
`5.2
`CONCLUSIONS AND RECOMMENDATIONS ..................................................................................................... 13
`6 APPENDICES .................................................................................................................................................... 14
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`4
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`5
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`Reference ID: 4760723
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`LIST OF TABLES
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`Table 1: List of all Studies included in the Statistical Review .......................................................................................................... 5
`Table 2: Summary of Subject Disposition and Analysis Sets ........................................................................................................... 8
`Table 3: Change from Baseline in Maximum Cystometric Capacity (mL) (FAS) ............................................................................ 9
`Table 4: Change from Baseline to Week 24 in Bladder Compliance (mL/cm H2O) (FAS) .............................................................. 9
`Table 5: Change from Baseline to Week 24 in Number of Overactive Detrusor Contractions (> 15 cm H2O) Until End of Bladder-
`filling (FAS) ..................................................................................................................................................................................... 9
`Table 6: Change from Baseline to Week 24 in Bladder Volume until First Detrusor Contraction > 15 cm H2O ........................... 10
`Table 7: Change from Baseline to Week 24 in Maximum Catheterized Daytime Volume (mL) (FAS) ......................................... 10
`Table 8: Change from Baseline to Week 24 in Mean Number of Leakage Episodes per 24 Hours (FAS) ..................................... 11
`Table 9: Subgroup Analysis of Change from Baseline to Week 24 (LOCF) in Maximum Cystometric Capacity (mL) by Gender
`(FAS) .............................................................................................................................................................................................. 12
`Table 10: Change from Baseline to Week 24 in Maximum Cystometric Capacity (mL) at Week 24 (LOCF) ............................... 12
`Table 11: Summary of Demographics and Baseline Characteristics (SAF) .................................................................................... 14
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`Reference ID: 4760723
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`3
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`

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`1 EXECUTIVE SUMMARY
`
`Myrbetriq® 25 mg and 50 mg tablets (Mirabegron) is currently approved under NDA 202611 for
`treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency,
`and urinary frequency in adults. A Written Request (WR) for the use of mirabegron in treatment
`of neurogenic detrusor overactivity (NDO) in pediatric patients was issued under NDA 202611
`on 18 March 2016.
`
`In this submission, the Applicant submitted the safety and efficacy data from one study to fulfill
`the WR and seek approval of mirabegron for NDO in pediatric patients. This review is to
`evaluate from a statistical perspective if the submitted information supports this claim.
`
`The study was a multinational, multi-center, open-label, single arm phase 3 study with a 12-week
`dose titration period followed by 40 weeks of treatment with fixed dose in subjects between 3 to
`18 years old.
`
`The primary efficacy endpoint was the change from baseline in maximum cystometric capacity
`(MCC) during treatment period at week 24 (measured in mL). It was summarized using
`descriptive statistics and the mean change from baseline estimate, together with 95% CI. The
`lower bound of the two-sided 95% CI was assessed to see if it excluded 0. Due to lack of a
`control group, the interpretation of the results is descriptive in nature. Secondary efficacy
`endpoints based on urodynamics and patient diary were also evaluated in a similar way as the
`primary efficacy endpoint.
`
`In children (3-12 years old), the MCC was increased by 72.1 mL (SD: 87.1, 95% CI 45.3 to
`98.9); in adolescents (12-18 years old), the MCC was increased by 113.2 mL (SD: 83.0, 95% CI
`79.0 to 147.5);
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`The study demonstrated that there is clinical benefit of mirabegron in treatment of NDO in
`pediatric subjects.
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`Reference ID: 4760723
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`INTRODUCTION
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`2
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`2.1 Overview
`
`The Applicant, Astellas Pharma Global Development INC., submitted an original New Drug
`Application (NDA 213801) for mirabegron granules oral suspension for treatment of neurogenic
`detrusor overactivity (NDO) in pediatric subjects.
`
`According to the Applicant,
`“mirabegron acts to relieve the symptoms of overactive bladder via its agonist effects on beta-
`3 adrenoceptors resulting in bladder smooth-muscle relaxation and increased bladder
`compliance.”
`
`
`Mirabegron (25mg and 50 mg tablets) is currently approved in the US under NDA 202611 for
`treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency,
`and urinary frequency in adults. A Written Request (WR) for the use of mirabegron in treatment
`of neurogenic detrusor overactivity (NDO) in pediatric subjects was issued under NDA 202611
`on 18 Mar 2016.
`
`The statistical review for this NDA is based on one open-label, single arm phase 3 studies, 178-
`cl-206a, which is briefly summarized in Table 1.
`
`
`Table 1: List of all Studies included in the Statistical Review
`Phase and Design
`Treatment
` # of Subjects per Arm
`Period
`Titration: 12 weeks
`Fixed dose: 40 weeks
`
`Study
`
`178-cl-206a
`
`Phase 3, open label,
`baseline controlled,
`multicenter
`
`Enrolled: 91 subjects
`
`Completed: 70 subjects
`
`
`Study Population
`
`pediatric subjects with
`NDO aged 3-18 years
`old
`
`Source: Statistical reviewer’s summary.
`
`2.2 Data Sources
`
`The study protocols, reports, data and additional information were submitted electronically, and
`are located in the Electronic Document Room at \\cdsesub1\evsprod\NDA213801 under
`submission dates 09/28/2020, 12/22/2020, 12/24/2020, 2/11/2021, 2/19/2021, 3/08/2021, and
`3/09/2021.
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`Reference ID: 4760723
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`3 STATISTICAL EVALUATION
`
`3.1 Data and Analysis Quality
`
`The Applicant submitted both tabulation data and analysis data for the study. Data sets were
`complete and documented. Statistical analysis programs were submitted.
`
`The statistical analyses of efficacy endpoints were carried out following the pre-specified
`statistical analysis plan with some exceptions.
`
`It was noted that the Applicant conducted an ad-hoc analysis for a secondary efficacy endpoint,
`i.e. mean number of leakage episodes, excluding a subject with data error and imputing subjects
`who did not report any leakage episodes during the visit with a “0” leakage episode for that visit.
`In the response to FDA’s information request on the justification of the above imputation
`approach, the Applicant clarified that in the ediary, a subject was asked, whether he/she had any
`leakage episodes between catheterizations (Y/N). If “Yes”, the next ediary screen asked for the
`number of leakages or to check a box for “I Don’t Know”. The subject should provide either a
`number or checkmark to continue. If “No”, then no number is recorded and the ediary continues
`to the next module. However, the Applicant found that the imputation rule did not entirely follow
`the above logic in the ediary when constructing the analysis dataset. The Applicant submitted the
`updated dataset for this endpoint considering the logic in the ediary and reanalyzed it following
`FDA’s recommendation on missing data imputation.
`
`3.2 Evaluation of Efficacy
`
`3.2.1 Study Design and Endpoints
`
`Study 178-cl-206a was a phase 3, open-label, baseline-controlled, multicenter study to assess the
`efficacy, safety and pharmacokinetics, of mirabegron in 3 to <18 years old children with NDO.
`
`The study consisted 3 periods:
`• Pretreatment period: for a maximum of 28 days before baseline, including screening,
`washout (if applicable) and baseline;
`• Efficacy treatment period: beginning the day after baseline and continuing to visit 8/week 24;
`• Long-term safety period: beginning after visit 8/week 24 and continuing to visit 10/week 52
`(end of study [EOS]), or to the end of treatment (EOT).
`
`At visit 4/week 2, visit 5/week 4 or visit 6/week 8, subjects must be up-titrated to the pediatric
`equivalent dose of 50 mg in adults (PED50), based on the given dose titration criteria. At visit
`8/week 24, efficacy was assessed. For long-term safety evaluation, following visit 8/week 24,
`subjects stayed on their individual dose level until visit 10/week 52 (EOT/EOS).
`
`The primary efficacy endpoint was the change from baseline to week 24 in maximum
`cystometric capacity (MCC) measured in mL based on the urodynamic data. The secondary
`efficacy endpoints of clinical interest were as follows.
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`Reference ID: 4760723
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`Changes from baseline to week 24 in:
`• Bladder compliance (mL/cm H2O);
`• Number of overactive detrusor contractions (> 15 cmH2O) until leakage or end of bladder-
`filling;
`• Bladder volume prior to first detrusor contraction > 15 cmH2O;
`• Maximum catheterized volume per day;
`• Mean number of leakage episodes per day;
`
`3.2.2 Statistical Methodologies
`
`The Applicant pre-defined the following analysis sets in the study protocol,
`
`Safety Analysis Set (SAF): all subjects who took at least one dose of study drug. The SAF was
`used for summaries of demographic and baseline characteristics and all safety and tolerability
`related variables.
`
`Full Analysis Set (FAS): all subjects who took at least one dose of study drug and provided both
`valid baseline and at least one post-baseline value for the primary efficacy endpoint (MCC). The
`FAS was used for analyses of efficacy data.
`
`Per Protocol Set (PPS): all subjects of the FAS who fulfilled the protocol in terms of their
`eligibility, interventions and outcome assessments, and for whom MCC measurements at
`baseline/visit 3 and at visit 8 (week 24) were reported.
`
`Analysis of primary efficacy endpoint
`MCC and changes from baseline in MCC at visit 8/week 24 were summarized using descriptive
`statistics for all subjects in the FAS. Missing MCC observations at visit 8/week 24 were imputed
`using the last observation carried forward (LOCF) method. Mean change from baseline
`estimates, together with 95% CIs were provided. The lower bound of the two-sided 95% CI was
`assessed to see if it excluded 0.
`
`The primary analysis was conducted in children (3 to <12 years old) and adolescents (12 to <18
`years old) as well.
`
`The Applicant also conducted the following analyses of the primary efficacy endpoint including
`the analysis with LOCF for the PPS;
`•
`•
`the analysis without LOCF for the FAS and PPS;
`•
`the analysis using BOCF for all enrolled subjects;
`•
`the sensitivity analysis using repeated measures ANCOVA in the FAS and PPS;
`•
`the sensitivity analysis using the Wilcoxon signed-rank test, with or without LOCF in the
`FAS.
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`Reference ID: 4760723
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`Analysis of secondary efficacy endpoints
`Each of the secondary efficacy endpoints was summarized with descriptive statistics. The mean
`change from baseline estimate together with 95% CI was provided. All analyses of secondary
`endpoints were conducted for subjects in the FAS.
`
`The bladder volume (mL) until the first detrusor contraction (>15 cm H2O) was imputed using
`MCC if no contraction occurred. No imputation was done for other secondary efficacy
`endpoints.
`
`3.2.3 Subject Disposition, Demographic and Baseline Characteristics
`
`Subject Disposition
`The disposition of study subjects and the analysis sets are summarized for the study (Table 2). A
`total of 113 subjects were screened and 91 subjects were enrolled. 86 subjects received treatment
`and 16 subjects discontinued the study drug.
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`
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`Table 2: Summary of Subject Disposition and Analysis Sets
`Children
`Adolescents
`3 to <12 years old
`12 to <18 years old
`n (%)
`n (%)
`69
`44
`56
`35
`55 (100%)
`31 (100%)
`12 (21.8%)
`4 (12.9%)
`
`
`Total
`n (%)
`113
`91
`86 (100%)
`16 (18.6%)
`
`3 (3.5%)
`13 (15.1%)
`86 (94.5%)
`68 (74.7%)
`60 (65.9%)
`
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`
`
`0
`4 (12.9%)
`31 (88.6%)
`25 (71.4%)
`22 (62.9%)
`
`Screened
`Enrolled
`Received study drug
` Treatment discontinuation1
` Primary reasons for discontinuation 1
`3 (5.5%)
`Adverse event
`9 (16.4%)
`Other
`55 (98.2%)
`Safety analysis set
`43 (76.8%)
`Full analysis set
`38 (67.9%)
`Per protocol set
` Source: Tables 12.1.1.4.4 and Table 3 in study report.
`The percentage is calculated using number of treated as the denominator.
`1
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`Demographics and Baseline Characteristics
`In the SAF, among all subjects (age 3 to < 18 years old), approximately half were female
`(54.7%); most were White (72.1%) and 3 (3.5%) subjects were Hispanic or Latino. The mean
`age (SD) was 10.1 (3.7) years and the mean weight (SD) was 37.45 (16.90) kg. There were more
`children than adolescents in this study (55 and 31, respectively in the SAF). The mean age (SD)
`and weight (SD) for children was 7.9 (2.5) years and 29.83 (13.41) kg. The mean age (SD) and
`weight (SD) for adolescents was 14.0 (1.7) years and 50.96 (13.78) kg. The demographic and
`baseline characteristics are summarized for each age group as shown in Table 11 (Appendix).
`
`3.2.4 Results and Conclusions
`
`Maximum Cystometric Capacity
`The analysis results for the primary efficacy endpoints are shown in Table 3. At week 24, both
`children and adolescents had increase in MCC compared with baseline with a mean (SD) of 72.1
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`Reference ID: 4760723
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`(87.1) mL and 113.2 (83.0) mL, respectively. The corresponding 95% CIs are (45.3, 98.9) and
`(79.0, 147.5) with lower bounds are all above 0.
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`Statistic
`
`Table 3: Change from Baseline in Maximum Cystometric Capacity (mL) (FAS)
`Children
`Adolescents
`All Subjects
`(3 to < 12 Years)
`(3 to < 18 Years)
`(12 to < 18 Years)
`n = 43
`n = 25
`n = 68
`158.6 (94.5)
`238.9 (99.1)
`188.2 (103.2)
`Baseline Mean (SD)
`230.7 (129.2)
`352.1 (125.2)
`275.4 (139.9)
`Week 24 Mean (SD)
`72.1 (87.1)
`113.2 (83.0)
`87.2 (87.3)
` Mean Change from Baseline (SD)
`(45.3, 98.9)
`(79.0, 147.5)
`(66.1, 108.3)
` 95% CI
` Source: Table 9 in study report. FAS: full analysis set; LOCF: last observation carried forward;
`
`Sensitivity analysis results are consistent with the primary analysis results.
`
`Bladder Compliance
`At week 24, the mean change in bladder compliance from baseline was 14.6 (95% CI: -0.3, 29.5)
`mL/cm H2O in children, and 13.6 mL/cm H2O (95% CI: 6.7, 20.4) in adolescents.
`
`
`
`Statistic
`
`Table 4: Change from Baseline to Week 24 in Bladder Compliance (mL/cm H2O) (FAS)
`Children
`Adolescents
`All Subjects
`(3 to < 12 Years)
`(3 to < 18 Years)
`(12 to < 18 Years)
`n = 25
`n = 43
`n = 68
`
`
`
`Baseline
`33
`21
`54
` n
`16.0 (55.8)
`11.1 (10.7)
`14.1 (43.9)
` Mean (SD)
`
`
`
`
`Week 24
`30.6 (54.2)
`24.7 (15.2)
`28.3 (42.3)
` Mean (SD)
`14.6 (42.1)
`13.6 (15.0)
`14.2 (34.0)
` Mean Change from Baseline (SD)
`(-0.3, 29.5)
` (6.7, 20.4)
` (4.9, 23.5)
` 95% CI
` Source: Table 12.3.3.1, Table 12.3.3.2 in study report and FDA reviewer’s analysis.
`
`Number of Overactive Detrusor Contractions (> 15 cm H2O) Until End of Bladder-filling
`At week 24, the mean change in number of overactive detrusor contractions (> 15 cmH2O) from
`baseline was -1.9 (95% CI: -3.3, -0.4) in children and -0.8 (95% CI: -2.5, 0.9) in adolescents.
`
`
`Table 5: Change from Baseline to Week 24 in Number of Overactive Detrusor Contractions (> 15 cm H2O)
`Until End of Bladder-filling (FAS)
`Adolescents
`Children
`(3 to < 12 Years)
`(12 to < 18 Years)
`n = 25
`n = 43
`
`
`Baseline
`36
`22
` n
`3.0 (4.0)
`2.1 (3.1)
` Mean (SD)
`
`
`
`Week 24
`1.1 (2.2)
`1.5 (2.4)
` Mean (SD)
`
`-1.9 (4.2)
`-0.8 (3.9)
` Mean Change from Baseline (SD)
` 95% CI
`(-3.3, -0.4)
` (-2.5, 0.9)
` Source: Table 12.3.4.2 in study report and FDA reviewer’s analysis.
`
`
`All Subjects
`(3 to < 18 Years)
`n = 68
`
`58
`2.7 (3.7)
`
`1.2 (2.3)
`-1.4 (4.1)
` (-2.5, -0.4)
`
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`Statistic
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`Reference ID: 4760723
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`Bladder Volume until First Detrusor Contraction > 15 cm H2O
`At week 24, the mean change in bladder volume until first detrusor contraction > 15 cm H2O was
`93.1 (95% CI: 64.1, 122.1) mL compared with baseline in children, and 121.3 (95% CI: 53.8,
`188.8) mL in adolescents.
`
`Table 6: Change from Baseline to Week 24 in Bladder Volume until First Detrusor Contraction > 15 cm H2O
`
`Adolescents
`All Subjects
`Children
`Statistic
`(3 to < 18 Years)
`(3 to < 12 Years)
`(12 to < 18 Years)
`n = 43
`n = 25
`n = 68
`
`
`
`Baseline
`38
`24
`62
` n
`114.8 (82.9)
`177.4 (117.3)
`139.0 (101.5)
` Mean (SD)
`
`
`
`
`Week 24
`38
`24
`62
` n
`207.9 (97.8)
`298.7 (144.4)
`243.0 (125.1)
` Mean (SD)
`
`93.1 (88.1)
`121.3 (159.8)
`104.0 (120.6)
` Mean Change from Baseline (SD)
` 95% CI
`(64.1, 122.1)
`(53.8, 188.8)
`(73.4, 134.6)
` Source: Table 12.3.6.3 submitted on 3/8/20201.
`
`Maximum Catheterized Volume per day
`At week 24, the mean change in maximum catheterized volume per day compared to baseline
`was 49.9 mL (95% CI: 17.1, 82.6) in children and 84.4 mL (95% CI: 31.6, 137.1) in adolescents.
`
`Table 7: Change from Baseline to Week 24 in Maximum Catheterized Daytime Volume (mL) (FAS)
`
`Children
`Adolescents
`All Subjects
`Statistic
`(3 to < 12 Years)
`(3 to < 18 Years)
`(12 to < 18 Years)
`n = 25
`n = 43
`n = 68
`
`
`
`Baseline
`41
`23
`64
` n
`304.1 (109.4)
`360.0 (111.4)
`324.2 (112.5)
` Mean (SD)
`
`
`
`
`Week 24
`41
`23
`64
` n
`354.0 (104.5)
`450.0 (146.6)
`386.4 (128.2)
` Mean (SD)
`
`49.9 (103.7)
`84.4 (122.0)
`62.3 (110.9)
` Mean Change from Baseline (SD)
` 95% CI
`(17.1, 82.6)
`(31.6, 137.1)
`(34.6, 90.0)
` Source: Table 12.3.8.2 in study report and FDA reviewer’s analysis.
`
`Mean Number of Leakage Episodes per 24 Hours
`The Applicant identified that subject
` entered the weight of the leakages in the
`ediary instead of the number of leakage episodes, which resulted that this subject had values that
`were 10-fold higher than those of the other subjects.
`
`In the study report, the Applicant conducted an ad-hoc analysis excluding this subject and
`imputing subjects who did not report any leakage episodes during the visit with a “0” leakage
`episode for that visit. The reviewer found this imputation approach is NOT appropriate because
`it is impossible to differentiate scenarios between missing leakage episodes and no leakage
`episodes using the data itself. Such best-scenario imputation approach might introduce strong
`bias toward positive treatment effect.
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`10
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`Reference ID: 4760723
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`(b) (6)
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`

`

`In the response to FDA’s information request on the justification of the above imputation
`approach, the Applicant clarified the logic in the ediary. In the ediary, the subject was asked,
`whether he/she had any leakage episodes between catheterizations (Y/N). If “Yes”, the next
`ediary screen asked for the number of leakages or to check a box for “I Don’t Know”. The
`subject had to provide either the number of leakages or checkmark to continue. If “No”, then no
`number was recorded and the ediary continued to the next module. The Applicant found that
`imputation approach did not entirely follow this logic when constructing the analysis dataset.
`
`Following FDA’s recommendation that if “no leakage episode” was confirmed, then number of
`leakages should be set as 0; if leakage occurred, but number of leakage episodes was not
`reported, then number of leakages should be set as missing, the Applicant submitted updated
`dataset for this endpoint and reanalyzed it.
`
`At week 24, the mean number of leakage episodes per day decreased by -2.0 (95% CI: -3.2, -0.7)
`and -1.0 (95% CI: -1.5, -0.5) from baseline in children and adolescents respectively (Table 8).
`
`Table 8: Change from Baseline to Week 24 in Mean Number of Leakage Episodes per 24 Hours (FAS)
`Children
`Adolescents
`All Subjects
`(3 to < 12 Years)
`(3 to < 18 Years)
`(12 to < 18 Years)
`N = 43
`N = 25
`N = 68
`
`
`
`Baseline
`26
`21
`47
` n
`2.8 (3.7)
`1.8 (1.7)
`2.3 (3.0)
` Mean (SD)
`
`
`
`Week 24
`26
`21
`47
` n
`0.8 (1.3)
`0.8 (1.1)
`0.8 (1.2)
` Mean (SD)
`-2.0 (3.2)
`-1.0 (1.1)
`-1.5 (2.5)
`
` Mean Change from Baseline (SD)
`(-2.3, -0.8)
`(-3.2, -0.7)
`(-1.5, -0.5)
` 95% CI
` Source: Table 12.3.11.16 submitted on 12/22/2020; FDA reviewer’s analysis. Subject
` was excluded.
`
`
`3.3 Evaluation of Safety
`
`Refer to the clinical reviewer’s report for evaluation of safety data.
`
`
`
`Statistic
`
` 4
`
` FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`
`4.1
`
` Gender, Race, Age, and Geographic Region
`
`Efficacy of mirabegron was also explored by subgroups defined by gender (female, male), race
`(White, Asian) descriptively.
`
`MCC and change from baseline in MCC are summarized by gender for all subjects and for
`children and adolescents respectively in the FAS (see Table 9). In both male and female subjects,
`there was an increase in the MCC at week 24 comparing to baseline.
`
`
`
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`Reference ID: 4760723
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`(b) (6)
`
`

`

`Statistic
`
`Baseline
` n
` Mean (SD)
`Week 24 (LOCF)
` Mean (SD)
` Mean Change from Baseline (SD)
` 95% CI
`
`Baseline
` n
` Mean (SD)
`Week 24 (LOCF)
` Mean (SD)
` Mean Change from Baseline (SD)
` 95% CI
`
`Female
`
`
`36
`175.1 (95.9)
`
`244.8 (115.8)
`69.7 (87.7)
`(40.1, 99.4)
`
`
`26
`149.1 (83.9)
`
`207.0 (90.9)
`57.9 (87.8)
`(22.4, 93.3)
`
`
`10
`242.6 (83.9)
`
`343.1 (119.6)
`100.5 (83.9)
`(40.5, 160.6)
`
`Table 9: Subgroup Analysis of Change from Baseline to Week 24 (LOCF) in Maximum Cystometric Capacity
`(mL) by Gender (FAS)
`Male
`All Subjects
`
`32
`202.9 (110.4)
`
`309.7 (157.6)
`106.9 (83.9)
`(76.6, 137.1)
`Children (3 to <12 Years)
`
`17
`173.2 (109.8)
`
`267.1 (169.1)
`93.8 (83.9)
`(50.7, 137.0)
`Adolescents (12 to < 18 Years)
`
`Baseline
`15
` N
`236.5 (104.5)
` Mean (SD)
`
`Week 24 (LOCF)
`358.1 (132.6)
` Mean (SD)
`121.7 (84.2)
` Mean Change from Baseline (SD)
`(75.0, 168.3)
` 95% CI
`Source: Table 16 in study report and FDA reviewer’s analysis.
`
`In both White and Asian subjects, there was an increase in the MCC at week 24 comparing to
`baseline for the overall population. Within children and adolescents respectively, Asian subjects
`seems to have less improvement from baseline compared to White subjects. However, the
`number of Asian subjects was limited, no definitive conclusion can be drawn.
`
`
`Table 10: Change from Baseline to Week 24 in Maximum Cystometric Capacity (mL) at Week 24 (LOCF)
`by Race (FAS)
`White
` All Subjects
`
`49
`189.9 (109.0)
`
`294.7 (149.0)
`104.8 (89.8)
`(79.0, 130.6)
`Children (3 to <12 Years)
`
`31
`162.6 (99.5)
`
`Statistic
`
`Baseline
` n
` Mean (SD)
`Week 24
` Mean (SD)
` Mean Change from Baseline (SD)
` 95% CI
`
`Baseline
` n
` Mean (SD)
`
`Asian
`
`
`19
`183.7 (88.9)
`
`225.5 (99.8)
`41.8 (62.0)
`(12.0, 71.7)
`
`
`12
`148.3 (83.4)
`
`
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`

`

`
`251.3 (142.4)
`88.7 (91.7)
`(55.0, 122.3)
`Adolescents (12 to < 18 Years)
`Baseline
`
` N
`18
` Mean (SD)
`236.8 (111.3)
`Week 24 (LOCF)
`
` Mean (SD)
`369.4 (132.5)
` Mean Change from Baseline (SD)
`132.6 (81.5)
`
`
` 95% CI
`(92.0, 173.1)
` Source: Table 17 in study report and FDA reviewer’s analysis.
`
`4.2 Other Special/Subgroup Populations
`
`The Applicant also conducted subgroup analysis by drug formulation (oral suspension vs. tablet).
`However, this subgroup is highly confounded by age. In the FAS set, 70% (30 out of 43) of
`children took suspension formulation and 88% (22 out of 25) of adolescents took tablet
`formulation. Therefore, this subgroup analysis can’t provide supportive information to evaluate
`if there is differential effect due to formulation after adjusting for the age groups.
`
` 5
`
` SUMMARY AND CONCLUSIONS
`
`5.1 Statistical Issues and Collective Evidence
`
`The Applicant submitted an open-label, single-arm, phase 3 study to evaluate the efficacy and
`safety of mirabegron in pediatric subjects and to fulfill the written request. The study had
`limitations due to lack of control group for ethical reason. Therefore, the evaluation of the
`treatment effect on efficacy is descriptive in nature.
`
`The primary and secondary efficacy endpoints based on the urodynamic assessments and patient
`diaries demonstrated improvement at week 24 compared to baseline in general.
`
`5.2 Conclusions and Recommendations
`
`The purpose of this review is to evaluate the efficacy data in support of mirabegron in the
`treatment of NDO in pediatric patients. Based on reviewer’s analyses, the submitted study
`demonstrated clinical benefit for this indication in pediatric patients.
`
`
`
`
`Reference ID: 4760723
`
`13
`
`
`177.6 (64.3)
`29.3 (56.9)
`(-6.9, 65.4)
`
` 7
`
`
`244.3 (64.7)
`
`307.7 (99.1)
`63.4 (68.7)
`(-0.1, 127.0)
`
`Week 24 (LOCF)
` Mean (SD)
` Mean Change from Baseline (SD)
` 95% CI
`
`

`

`6 APPENDICES
`
`
`22 (40.0%)
`33 (60.0%)
`
`7.9 (2.5)
`9.0
`3 - 11
`
`40 (72.7%)
`0
`13 (23.6%)
`0
`0
`2 (3.6%)
`
`1 (1.8%)
`54 (98.2%)
`
`55
`29.83 (13.41)
`28.00
`12.6 – 69.7
`
`55
`124.77 (18.69)
`128.00
`92.1 – 160.0
`
`55
`18.18 (3.94)
`17.10
`11.9 – 27.2
`
`17 (54.8%)
`14 (45.2%)
`
`14.0 (1.7)
`14.0
`12 - 17
`
`22 (71.0%)
`0
`7 (22.6%)
`1 (3.2%)
`0
`1 (3.2%)
`
`2 (6.5%)
`29 (93.5%)
`
`31
`50.96 (13.78)
`47.50
`28.2 – 78.5
`
`31
`152.91 (12.06)
`152.00
`120.0 – 178.0
`
`31
`21.96 (6.02)
`19.80
`10.5 – 33.3
`
`Table 11: Summary of Demographics and Baseline Characteristics (SAF)
`
`
`Children
`Adolescents
`(12 to < 18 Years)
`(3 to < 12 Years)
`n = 55
`n = 31
`
`
`Parameter
`Category/
`Statistics
`Sex, n (%)
`Male
`Female
`Age, years†
`Mean (SD)
`Median
`Min - Max
`Race, n (%)
`White
`Black/African American
`Asian
`American Indian/Alaska Native
`Native Hawaiian/Pacific Islander
`Other
`Ethnicity, n (%)
`Hispanic or Latino
`Not Hispanic or Latino
`Weight, kg‡
`n
`Mean (SD)
`Median
`Min – Max
`Height, cm‡
`n
`Mean (SD)
`Median
`Min – Max
`BMI, kg/m2‡
`n
`Mean (SD)
`Median
`Min – Max
`Source: Table 5 in study report.
`All subjects who received ≥ 1 dose of study drug (SAF).
`BMI: body mass index; eCRF: electronic case report form; Max: maximum; Min: minimum; SAF: safety
`analysis set.
`† Age at screening was calculated as (date of last informed consent given at screening - date of birth +1)/365.25.
`If the date of birth was not given, the age at screening was equal to the value recorded on the demographics
`page of the eCRF (an integer number of years) plus 0.5.
`‡ BMI = weight (kg)/ [height (m2)]. Height and weight were assessed at screening.
`
`
`
`
`All Subjects
`(3 to < 18 Years)
`n = 86
`
`39 (45.3%)
`47 (54.7%)
`
`10.1 (3.7)
`10.0
`3 – 17
`
`62 (72.1%)
`0
`20 (23.3%)
`1 (1.2%)
`0
`3 (3.5%)
`
`3 (3.5%)
`83 (96.5%)
`
`86
`37.45 (16.90)
`35.85
`12.6 – 78.5
`
`86
`134.91 (21.40)
`138.75
`92.1 – 178.0
`
`86
`19.55 (5.10)
`18.35
`10.5 – 33.3
`
`14
`
`
`
`Reference ID: 4760723
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`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`JIA GUO
`03/11/2021 02:02:54 PM
`
`TSAE YUN D LIN
`03/11/2021 03:07:11 PM
`
`Reference ID: 4760723
`
`