CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`205552Orig2s000
`
`STATISTICAL REVIEW(S)
`
`
`
`
`
`
`
`

`

`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
`
`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
`
`NDA 205552
`
`NDA/BLA #:
`Supplement #:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`
`Ibrutinib
`Relapsed or refractory Chronic Lymphocytic Leukemia
`Pharmacyclics
`Submission Date: May 31, 2013
`PDUFA due Date: February 28, 2014
`Review Completion Date: 31 January, 2014
`Priority
`Review Priority:
`Division of Biometrics V
`Biometrics Division:
`Yun Wang, PhD
`Statistical Reviewer:
`Concurring Reviewers: Lei Nie, PhD, Acting Team Leader
`Thomas Gwise, PhD, Deputy Division Director
`Office of Hematology and Oncology Product
`Nicole Verdun, MD
`Angelo De Claro, MD
`Diane Hanner, MPH
`
`Medical Division:
`Clinical Team:
`
`Project Manager:
`
`Keywords: Chronic Lymphocytic Leukemia, Overall Response Rate, Duration of Response;
`Single arm trial.
`
`Reference ID: 3445417
`
`

`

`Table of Contents
`EXECUTIVE SUMMARY .................................................................................................................................4
`
`1
`
`INTRODUCTION ...............................................................................................................................................4
`2
`2.1 OVERVIEW ............................................................................................................................. 4
`2.2 DATA SOURCES...................................................................................................................... 6
`3
`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 .........................................................7
`3.2.4
`Results and Conclusions ......................................................................................................................11
`EVALUATION OF SAFETY ..................................................................................................... 13
`3.3
`3.4 BENEFIT-RISK ASSESSMENT ................................................................................................. 13
`4
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS .............................................................................14
`4.1 GENDER, AGE, RACE AND REGION ...................................................................................... 14
`4.2 DEL17P STATUS .................................................................................................................. 15
`5
`SUMMARY AND CONCLUSIONS ................................................................................................................16
`5.1
`STATISTICAL ISSUES ............................................................................................................ 16
`5.2 COLLECTIVE EVIDENCE........................................................................................................ 16
`5.3 CONCLUSIONS AND RECOMMENDATIONS............................................................................. 16
`LABELING RECOMMENDATIONS ........................................................................................... 16
`5.4
`
`Reference ID: 3445417
`
`2
`
`

`

`LIST OF TABLES
`
`Table 1: List of all studies included in analysis.............................................................................. 5
`Table 2: Summary of treatment cohorts in Study PCYC-1102-CA ............................................... 7
`Table 3: Subject disposition, relapsed/refractory CLL patients treated with 420mg ..................... 8
`Table 4: Demographics and baseline characteristics, relapsed/refractory CLL patients treated
`with 420mg ..................................................................................................................................... 9
`Table 5: Baseline disease characteristics, relapsed/refractory CLL patients treated with 420mg 10
`Table 6: Results of ORR per IRC, relapsed/refractory CLL patients treated with 420mg........... 11
`Table 7: Results of ORR per investigator assessments, relapsed/refractory CLL patients treated
`with 420mg ................................................................................................................................... 12
`Table 8: Summary of OS analysis results, relapsed / refractory CLL patients treated with 420mg
`....................................................................................................................................................... 13
`Table 9: ORR per IRC – subgroup analyses by gender and age, relapsed / refractory CLL
`patients treated with 420mg.......................................................................................................... 14
`Table 10: ORR per IRC – subgroup analyses by del17p positiveness relapsed / refractory CLL
`patients treated with 420mg.......................................................................................................... 15
`
`Reference ID: 3445417
`
`3
`
`

`

`1 EXECUTIVE SUMMARY
`
`New drug application (NDA) 205552 submission was split into two separate submissions based
`on two different indications: original-1 submission for mantle cell lymphoma (MCL), and
`original-2 submission for chronic lymphocytic leukemia (CLL). FDA granted accelerated
`approval in November 2013 for MCL indication based on original-1 submission. This statistical
`review is for original-2 submission. In original-2 submission, the applicant seeks the approval of
`ibrutinib for treatment of relapsed or refractory CLL patients who received at least one prior
`regimen.
`This NDA original-2 submission is based on two clinical studies (Study PCYC-1102-CA and
`Study PCYC-04753) in 149 subjects in which ibrutinib was evaluated as a single agent at
`different doses for the treatment of CLL patients. PCYC-1102-CA is a Phase 1b/2 study of
`ibrutinib at two dose levels (420 mg or 840 mg) in 133 subjects with treatment-naïve or
`relapsed/refractory CLL/Small Lymphocytic Lymphoma (SLL). This statistical review only
`considers 48 subjects with relapsed/refractory CLL treated at dose of 420 mg, the targeted dose
`and indication the applicant seeks the approval for, in the Study PCYC-1102-CA. Study PCYC-
`04753 enrolled 16 CLL patients into different doses and only provided preliminary efficacy
`results of ibrutinib. Therefore, Study PCYC-04753 was not included in this statistical review.
`Study PCYC-1102-CA was designed as a nonrandomized study. Therefore, all statistical
`analyses were descriptive and no formal statistical comparisons were performed.
`In Study PCYC-1102-CA, the overall response rate (ORR) per independent review committee
`(IRC) assessments was 56.3% (95% CI [41.2%, 70.5%]) with median duration of response
`(DOR) not achieved yet (95% CI not evaluable).
`The response data from Study PCYC-1102-CA demonstrated some clinically meaningful
`treatment effect of ibrutinib for relapsed and refractory CLL patients. Top line results from Study
`PCYC-1112-CA, an ongoing randomized, multicenter, and open-label Phase 3 study of the
`ibrutinib versus ofatumumab in patients with relapsed or refractory CLL/SLL, showed
`significant improvement in PFS for ibrutinib compared to ofatumumb, which provided more
`evidence of clinical benefit of ibrutinib for refractor/relapsed CLL patients.
`
`INTRODUCTION
`2
`2.1 Overview
`Ibrutinib is a selective, irreversible small molecule inhibitor of Bruton’s tyrosine kinase (BTK)
`for the treatment of B-cell malignancies. By combining fast covalent binding to BTK with rapid
`in vivo elimination, ibrutinib provides a unique approach to improve selectivity for BTK in vivo
`relative to reversibly inhibited off-target kinases.
`The proposed indication submitted in this NDA original-2 application is for the treatment of
`patients with relapsed/refractory CLL who have received at least one prior regimen.
`Ofatumumab (Arzerra) is currently approved for treatment of patients with CLL based on an
`open-label, single-arm, multicenter study of 154 patients with relapsed or refractory CLL.
`4
`
`Reference ID: 3445417
`
`

`

`Patients with CLL refractory to fludarabine and alemtuzumab (n = 59) comprised the efficacy
`population. Overall response rate (complete response (CR), unconfirmed CR (CRu), and partial
`response) to ofatumumab for patients with CLL refractory to fludarabine and alemtuzumab was
`42% (99% CI: 26%-60%), with duration of response of 6.5 months (95% CI: 5.8 – 8.3 months);
`There was no complete response.
`Study PCYC-1102-CA was an open-label, nonrandomized, multi-center, Phase 1b/2 study of
`ibrutinib in subjects with treatment-naïve or relapsed/refractory CLL/SLL. Cohorts were defined
`by the disease population (treatment-naïve or relapsed/refractory) and by the ibrutinib dose level
`(420 mg or 840 mg). The primary efficacy endpoint is ORR per IRC using International
`Myeloma Working Group (IMWG) response criteria. The secondary efficacy endpoints are TTR,
`time to disease progression (TTP) and OS.
`A total of 133 patients with CLL/SLL were enrolled between 20 May 2010 and 18 April 2012
`from 8 sites in the US. The data cut-off date was 18 December 2012. Among the enrolled 133
`patients, only 48 relapsed/refractory CLL patients treated with at least one dose of ibrutinib 420
`mg were included in the efficacy analyses for CLL indication.
`The original protocol for Study PCYC-1102-CA was dated 11 March 2010, and the latest version
`was Amendment 5 dated 14 June 2012.
`Throughout this review, relapsed/refractory CLL patients received ibrutinib at dose of 420 mg
`daily are referred as “Relapsed/Refractory 420 mg” arm in the text, the tables/figures.
`
`PCYC-
`1102-CA
`
`TABLE 1: LIST OF ALL STUDIES INCLUDED IN ANALYSIS
`Study
`Phase and Design
`Treatment
`Period
`Treatment until
`completion of
`planned
`treatment
`duration,
`progressive
`disease
`(PD),
`death, or any
`other
`reason
`listed
`in
`the
`protocol
`for
`mandatory
`withdrawal.
`
`Phase 1b/2, open-
`label,
`nonrandomized,
`multi-center
`study
`designed to evaluate
`the
`efficacy
`and
`safety of
`ibritinib
`monotherapy
`(420
`mg or 840 mg daily)
`in
`subjects with
`treatment-naïve
`or
`relapsed/refractory
`CLL/SLL
`
`# of Subjects
`per Arm
`N=133
`
`Enrollment period
`Geographic region
`20 May 2010 –
`18 April 2012
`8 sites in the US
`
`Follow-up
`Period
`After treatment
`discontinuation,
`subjects were
`followed
`for
`PD
`quarterly
`until PD or start
`of further anti-
`CLL
`therapy,
`after
`that,
`patients will be
`followed
`for
`quarterly
`until
`survival
`death or study
`closure.
`
`5
`
`Reference ID: 3445417
`
`

`

`2.2 Data Sources
`Analysis datasets, SDTM tabulations, and software codes are located on network with network
`path: \\CDSESUB1\evsprod\NDA205552\205552.enx
`
`3 STATISTICAL EVALUATION
`This statistical evaluation is based on data from the Study PCYC-1102-CA.
`
`3.1 Data and Analysis Quality
`The overall response data for Study PCYC-1102-CA were derived and saved in analysis dataset
`“ADEFIRC”, “ADTTEIRC” for both IRC and investigator assessments. This NDA original-2
`application provided source data for deriving overall response from individual disease
`assessments. The statistical reviewer can verify overall response per IRC for most patients in
`Study PCYC-1102-CA. However the statistical and clinical reviewers determined that:
` Three partial responses (PR) claimed by the applicant for patients 123-401, 217-109, 217-401
`should be treated as non-responses due to lack of confirmation of the response.
` One PR claimed by the applicant for patient 217-112 should be treated as non-response due
`to undetectable tumor burden at baseline.
`Therefore, the number of PR derived by the FDA reviewers was 4 less than those derived by the
`applicant. The responses derived by the FDA reviewers were used in this statistical review.
`In addition, FDA reviewers determined that patient 032-108 with partial response progressed on
`January 10, 2012, instead of being censored on November 13, 2012 as the applicant claimed.
`
`3.2 Evaluation of Efficacy
`
`3.2.1 Study Design and Endpoints
`3.2.1.1 Study Design
`The Study PCYC-1102-CA is an open-label, nonrandomized, multi-center, Phase 1b/2 study of
`ibrutinib in subjects with treatment-naïve or relapsed/refractory CLL/SLL. The primary objective
`of the study was to determine the safety of a fixed-dose daily regimen of ibrutinib at 2 dose
`levels (420 mg and 840 mg) in subjects with CLL/SLL. Assessment of preliminary efficacy is
`one of the secondary objectives.
`There were 6 treatment cohorts in Study PCYC-1102-CA (Table 2). The sponsor considered a
`sample size of 12 to 24 subjects per cohort was sufficient to define the safety profile and
`pharmacokinetic characteristics of the 2 fixed-dose regimens of ibrutinib. No interim analysis
`was planned for any cohort.
`Reviewer’s comment: This statistical review for Study PCYC-1102-CA is based on data from
`CLL patients in cohort 1 and 4 only because that subset represents the targeted population and
`dose the Sponsor applied for approval in this submission.
`
`6
`
`Reference ID: 3445417
`
`

`

`TABLE 2: SUMMARY OF TREATMENT COHORTS IN STUDY PCYC-1102-CA
`
`Population
`Cohort
`Relapsed/refractory
`1
`Treatment-naïve ≥ 65 years
`2
`Relapsed/refractory
`3
`Relapsed/refractory high-risk
`4
`Treatment-naïve ≥ 65 years
`5
`Relapsed/refractory*
`6
`* Effects of fed-versus-fasted state.
`[Source: Study PCYC-1102-CA CSR Pages 19 Table 1]
`
`Ibrutinib Dose
`420 mg/day
`420 mg/day
`840 mg/day
`420 mg/day
`840 mg/day
`420 mg/day
`
`Planned Sample Size
`24
`24
`24
`24
`12
`16
`
`3.2.1.2 Efficacy Endpoints
`Safety, as measured by the incidence, severity, and drug-relatedness of clinical adverse events,
`was the primary endpoint.
`Overall response rate assessed by investigators was one of the secondary endpoints. ORR was
`defined as the percent of subjects who achieved either a partial response (PR) or complete
`response (CR), according to the International Workshop on Chronic Lymphocytic Leukemia
`(IWCLL) 2008 guidelines.
`Duration of response (DOR), measured from the time CR or PR was first recorded to the time
`when progressive disease was objectively documented, was one of the exploratory endpoints.
`
`3.2.2 Statistical Methodologies
`The overall response rate and the corresponding 95% exact confidence interval (CI) will be
`presented for CLL patients in cohort 1 and 4. Median duration of response and the corresponding
`95% CI calculated using Kaplan-Meier method will be presented as well.
`
`3.2.3 Subject Disposition, Demographic and Baseline Characteristics
`Study PCYC-1102-CA enrolled 133 subjects with naïve or relapsed/refractory CLL/SLL from 8
`sites in US, 27 to cohort 1, 26 to cohort 2, 34 to cohort 3, 25 to cohort 4, 5 to cohort 5, 16 to
`cohort 6. Please refer to Table 2 for description of cohort 1- 6. Only 49 subjects with
`relapsed/refractory CLL enrolled into cohort 1 and 4 were considered in this statistical review.
`One of 49 subjects never received any dose of ibrutinib and was excluded from all treated
`population.
`
`7
`
`Reference ID: 3445417
`
`

`

`Subject disposition
`In Study PCYC-1102-CA, at the time of study cutoff of 18 December 2012, all 48 subjects
`discontinued study treatment. The most common reason for discontinuation was completion of
`specified study treatment plan (72.9%). The second most common reason for treatment
`discontinuation was disease progression (8.3%). Twenty nine out of 35 patients who completed
`study-specified treatment plan were enrolled into extension Study PCYC-1103-CA for
`continuing treatment with ibrutinib.
`
`TABLE 3: SUBJECT DISPOSITION, RELAPSED/REFRACTORY CLL PATIENTS TREATED WITH 420MG
`Relapsed/refractory CLL 420 mg
`N=48
`n (%)
`48 (100)
`
` Subject discontinued study treatment
` Primary reason for discontinuation
` Completion of study treatment plan
` Disease progression
` Adverse event
` Subjects decision
` Physician’s decision
` Patient not compliant
` Withdrawal due to SCT
`SCT: stem-cell transplant
`[Source: Statistical reviewer’s analysis]
`
`35 (72.9)
`4 (8.3)
`3 (6.3)
`3 (6.3)
`1 (2.1)
`1 (2.1)
`1 (2.1)
`
`Reference ID: 3445417
`
`8
`
`

`

`Subject demographics and baseline disease characteristics
`Demographics and baseline characteristics for the 48 patients relapsed/ refractory CLL patients
`received 420 mg ibrutinib in Study PCYC-1102-CA are summarized in Table 4. Baseline disease
`characteristics are summarized in Table 5.
`
`TABLE 4: DEMOGRAPHICS AND BASELINE CHARACTERISTICS, RELAPSED/REFRACTORY CLL
`PATIENTS TREATED WITH 420MG
`
`Relapsed/refractory CLL 420 mg
`N=48
`
`63.9 (11.0)
`67.0 (37, 82)
`
`23 (47.9)
`25 (52.1)
`
`Age (years)
` Mean (SD)
` Median (Min, Max)
` Category, n (%)
` < 65
` ≥ 65
`Sex, n (%)
` Male
` Female
`Race, n (%)
` White
` Other
`ECOG performance Status, n (%)
`18 (37.5)
` 0
`30 (62.5)
` 1
`SD: standard deviation; ECOG: Eastern Cooperative Oncology Group
`[Source: Statistical reviewer’s analysis]
`
`34 (70.8)
`14 (29.2)
`
`45 (93.8)
`3 (6.2)
`
`Reference ID: 3445417
`
`9
`
`

`

`TABLE 5: BASELINE DISEASE CHARACTERISTICS, RELAPSED/REFRACTORY CLL PATIENTS TREATED
`WITH 420MG
`
`Relapsed/refractory CLL 420 mg
`N=48
`
`Time from diagnosis to first dose
`(Months)
` Mean (SD)
` Median (Min, Max)
`Tumor bulk (largest diameter), n
`(%)
` < 5 cm
` ≥ 5 cm
`Rai stage at baseline
` 0 – II
` III – IV
` Unknown
`Prior number of regimens
` Mean (SD)
`
` Median (Min, Max)
`
` Category, n (%)
` < 3
`
` ≥ 3
`
`Del 17p
`
` Positive
`
` Negative
`
` Unknown
`[Source: Statistical reviewer’s analysis]
`
`95.7 (62.9)
`80.1 (14.2, 283.0)
`
`26 (54.2)
`22 (45.8)
`
`19 (39.6)
`27 (56.2)
`2 (4.2)
`
`4.3 (2.7)
`
`4.0 (1.0, 12.0)
`
`18 (37.5)
`
`30 (62.5)
`
`18 (37.5)
`
`28 (58.3)
`
`2 (4.2)
`
`In Study PCYC-1102-CA, 1 patient had major eligibility criteria deviations defined in the study
`protocol.
`
`10
`
`Reference ID: 3445417
`
`

`

`3.2.4 Results and Conclusions
`3.2.4.1 Results of overall response
`The results of overall response per IRC for relapsed/ refractory CLL patients received 420 mg
`ibrutinib are summarized in Table 6. Overall response rate was 56.3%. Median duration of
`response was not reached yet.
`
`TABLE 6: RESULTS OF ORR PER IRC, RELAPSED/REFRACTORY CLL PATIENTS TREATED WITH
`420MG
`
`Overall response rate (CR + PR), n (%)
` Complete response (CR), n (%)
` Partial Response (PR), n (%)
`95% CI for ORR (%)
`Duration of response (DOR)
` Number of subjects progressed or died, n (%)
` Median DOR (Months)
`CI: confidence interval; NR: not evaluable.
`[Source: Statistical reviewer’s analysis]
`
`Relapsed/refractory CLL 420 mg
`N=48
`27 (56.3)
`0 (0)
`27 (56.3)
`(41.2, 70.5)
`N=27
`4 (14.8)
`NE
`
`Reviewer’s comment:
` The number of PR derived by the FDA reviewers based on IRC assessments was 4 less
`than those derived by the applicant.
` FDA reviewers determined that patient 032-108 with partial response, progressed on
`January 10, 2012, instead of being censored on November 13, 2012 as the applicant
`claimed.
`
`Reference ID: 3445417
`
`11
`
`

`

`The results of overall response per investigator assessments for relapsed/ refractory CLL patients
`received 420 mg ibrutinib are summarized in Table 7. Overall response rate was 77.1%. Median
`duration of response was not reached yet.
`
`TABLE 7: RESULTS OF ORR PER INVESTIGATOR ASSESSMENTS, RELAPSED/REFRACTORY CLL
`PATIENTS TREATED WITH 420MG
`
`Overall response rate (CR + PR), n (%)
` Complete response (CR), n (%)
` Partial Response (PR), n (%)
`95% CI for ORR (%)
`Duration of response (DOR)
` Number of subjects progressed or died, n (%)
` Median DOR (Months)
`CI: confidence interval; NR: not evaluable.
`[Source: Statistical reviewer’s analysis]
`
`Relapsed/refractory CLL 420 mg
`N=48
`37 (77.1)
`0 (0)
`37 (77.1)
`(62.7, 88.0)
`N=37
`3 (8.1)
`NE
`
`Reference ID: 3445417
`
`12
`
`

`

`3.2.4.2 Analysis results for other efficacy endpoints
`The analysis results of overall survival (OS) are summarized in Table 8 for relapsed/ refractory
`CLL patients received 420 mg ibrutinib in Study PCYC-1102-CA.
`
`TABLE 8: SUMMARY OF OS ANALYSIS RESULTS, RELAPSED / REFRACTORY CLL PATIENTS TREATED
`WITH 420MG
`Endpoints
`
`Statistic
`
`Relapsed/refractory CLL 420 mg
`N=48
`
`OS (Months)
`
`Number (%) of subjects censored
`Number of subjects died
`Median (95% CI)
`CI: confidence interval; NE: not evaluable; SD: standard deviation.
`[Source: Statistical reviewer’s analysis]
`
`44 (91.7)
`4 (8.3)
`NE
`
`Reviewer’s comment:
` Analysis results presented in Table 8 are exploratory because OS analysis is not
`interpretable in single-arm study.
`
`3.2.4.3 Conclusions for efficacy
`The Study PCYC-1102-CA demonstrated durable treatment benefit of ibrutinib for patients with
`relapsed and/or refractory chronic lymphocytic leukemia.
`
`3.3 Evaluation of Safety
`Please refer to clinical review of this application for safety results and conclusions for safety.
`
`3.4 Benefit-risk assessment
`Because the pivotal study supporting this NDA original-2 application was a single-arm study, the
`benefit/risk can not be assessed based on comparative analyses. Whether the submission
`demonstrated an overall favorable risk-benefit profile on ibrutinib is deferred to the clinical team
`reviewing this submission.
`
`Reference ID: 3445417
`
`13
`
`

`

`4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`4.1 Gender, Age, Race and Region
`Table 9 summarizes the subgroup analyses of ORR by gender, age for the Study PCYC-1102-
`CA. The ORR results by subgroups are consistent with the ORR results for all patients.
`
`TABLE 9: ORR PER IRC – SUBGROUP ANALYSES BY GENDER AND AGE, RELAPSED / REFRACTORY
`CLL PATIENTS TREATED WITH 420MG
`Subgroup Relapsed/refractory CLL 420 mg
`N=48
`
`Gender
`
` Male
`
` Female
`
`Age
`
` < 65 yrs
`
` ≥ 65 yrs
`
`r/n (%)
`
`(95% CI (%))
`
`19/34 (55.9)
`
`(37.9, 72.8)
`
`8/14 (57.1)
`
`(28.9, 82.3)
`
`12/23 (52.2)
`
`(30.6, 73.2)
`
`15/25 (60.0)
`
`(38.7, 78.9)
`
`r: number of response, n: number of subjects in a subgroup
`[Source: Statistical reviewer’s analysis]
`
`Reviewer’s comments:
` Most patients in Study PCYC-1102-CA were White, subgroup analyses of ORR by race
`were not performed.
` All patients in the Study PCYC-1102-CA were enrolled in United States; therefore results
`of ORR by region are not provided.
`
`14
`
`Reference ID: 3445417
`
`

`

`4.2 DEL17p status
`Results of overall response in patients with del17p positive status are summarized in Table 10.
`Overall response rate for patients with positive del17p was 44.4%. Median duration of response
`was not reached yet.
`
`TABLE 10: ORR PER IRC – SUBGROUP ANALYSES BY DEL17P POSITIVENESS RELAPSED /
`REFRACTORY CLL PATIENTS TREATED WITH 420MG
`
`Relapsed/refractory CLL 420 mg
`Del17p positive
`N=18
`8 (44.4)
`0 (0)
`8 (44.4)
`(21.5, 69.2)
`8
`1 (12.5)
`NE (12.0, NE)
`
`Overall response rate (CR + PR), n (%)
` Complete response (CR), n (%)
` Partial Response (PR), n (%)
`95% CI for ORR (%)
`Duration of response (DOR)
` Number of subjects progressed or died, n (%)
` Median DOR (Months)
`CI: confidence interval; NR: not reached yet.
`[Source: Statistical reviewer’s analysis]
`
`Reference ID: 3445417
`
`15
`
`

`

`5 SUMMARY AND CONCLUSIONS
`
`Statistical Issues
`5.1
`Study PCYC-1102-CA was single-arm study, no comparative evaluation of treatment effect of
`ibrutinib can be performed within the trial.
`
`5.2 Collective evidence
`Ibrutinib provided durable treatment effect for patients with relapsed or refractory chronic
`lymphocytic leukemia in Study PCYC-1102-CA.
`
`5.3 Conclusions and Recommendations
`This NDA original-2 application was based on one pivotal multicenter Phase I studies (PCYC-
`1102-CA) to evaluate the treatment effect of ibrutinib for patients with relapsed/refractory CCL.
`Study PCYC-1102-CA demonstrated durable overall response benefit of ibrutinib for relapsed or
`refractory chronic lymphocytic leukemia patients who received at least one prior regimen.
`However, because Study PCYC-1102-CA was a single-arm study, the treatment effects of
`ibrutinib can only be descriptively summarized and no comparative evaluation of treatment
`effect of ibrutinib can be performed within the trial. The final decision on the benefit-risk
`evaluation of ibrutinib is deferred to the clinical review team.
`
`5.4 Labeling recommendations
`
`The reviewer does not have any comment for the labeling.
`
`Reference ID: 3445417
`
`16
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`YUN WANG
`01/31/2014
`
`LEI NIE
`01/31/2014
`
`THOMAS E GWISE
`01/31/2014
`
`Reference ID: 3445417
`
`

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`
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`NDA Number: 205552
`Drug Name: Ibrutinib
`
`On initial overview of the NDA/BLA application for RTF:
`
`
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`STATISTICS FILING CHECKLIST FOR A NEW NDA/BLA
`
`Applicant: Pharmacyclics
`NDA/BLA Type: 505(b)(1)
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`Stamp Date: May 31, 2013
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`Comments
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`Yes No NA
`X
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`X
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`X
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`X
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`1
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`2
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`3
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`Content Parameter
`Index is sufficient to locate necessary reports, tables, data,
`etc.
`ISS, ISE, and complete study reports are available
`(including original protocols, subsequent amendments, etc.)
`Safety and efficacy were investigated for gender, racial,
`and geriatric subgroups investigated (if applicable).
`4 Data sets in EDR are accessible and do they conform to
`applicable guidances (e.g., existence of define.pdf file for
`data sets).
`
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`IS THE STATISTICAL SECTION OF THE APPLICATION FILEABLE? ____Yes____
`
`If the NDA/BLA is not fileable from the statistical perspective, state the reasons and provide
`comments to be sent to the Applicant.
`
`
`
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`File name: 5_Statistics Filing Checklist for a New NDA_BLA
`
`Reference ID: 3357631
`
`

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`STATISTICS FILING CHECKLIST FOR A NEW NDA/BLA
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`Yes No NA Comment
`
`
`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-
`day letter.
`
`Content Parameter (possible review concerns for
`74-day letter)
`Designs utilized are appropriate for the indications
`requested.
`Endpoints and methods of analysis are specified in the
`protocols/statistical analysis plans.
`Interim analyses (if present) were pre-specified in the
`protocol and appropriate adjustments in significance
`level made. DSMB meeting minutes and data are
`available.
`Appropriate references for novel statistical methodology
`(if present) are included.
`Safety data organized to permit analyses across clinical
`trials in the NDA/BLA.
`Investigation of effect of dropouts on statistical analyses
`as described by applicant appears adequate.
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`X
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`X
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`X
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`X
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`X
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`X
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`This NDA is based
`on single-arm trials
`with ORR as
`the
`primary
`endpoints.
`Any subject dropped
`out without response
`will be
`treated as
`non-responders.
`No investigation of
`effect of dropouts on
`statistical
`analysis
`will be performed.
`
`
`
`Comment:
`
`
`
` Yun Wang
`
`Reviewing Statistician
`
`
`Supervisor/Team Leader
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` August 6, 2013
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` Date
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`Date
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`File name: 5_Statistics Filing Checklist for a New NDA_BLA
`
`Reference ID: 3357631
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`YUN WANG
`08/14/2013
`
`LEI NIE
`08/14/2013
`
`Reference ID: 3357631
`
`