`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205834Orig1s000
`
`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 #:
`Supplement #:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`
`Review Priority:
`
`205834
`0000
`Sofosbuvir and Ledipasvir fixed-dose combination
`Treatment of chronic hepatitis C for adults
`Gilead Sciences, Inc.
`Original NDA Submitted Date: February 10, 2014
`PDUFA date: October 10, 2014
`Priority
`
`Biometrics Division:
`Statistical Reviewer:
`Concurring Reviewers:
`Medical Division:
`Clinical Team:
`Project Manager:
`
`DB4
`Karen Qi, Ph.D.
`Fraser Smith, Ph.D.
`Antiviral
`Sarah Connelly, MD
`Linda Onaga, M.P.H.
`
`Keywords:
`one-sample binomial test, Clopper-Person exact confidence interval, Zelen’s exact test,
`stratified Cochran-Mantel-Haenszel test, exact confident interval based on inverting a two-
`sided test, hepatitis C
`
`Reference ID: 3539966
`
`1
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`

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`Table of Contents
`EXECUTIVE SUMMARY .................................................................................................................................... 5
`
`INTRODUCTION .................................................................................................................................................. 6
`2.1
`OVERVIEW......................................................................................................................................................... 6
`2.2
`DATA SOURCES ................................................................................................................................................. 7
`STATISTICAL EVALUATION ........................................................................................................................... 7
`3.1
`DATA AND ANALYSIS QUALITY ........................................................................................................................ 7
`3.2
`EVALUATION OF EFFICACY ............................................................................................................................... 8
`3.2.1
`ION-1 and ION-3...................................................................................................................................... 8
`3.2.2
`ION-2...................................................................................................................................................... 18
`3.3
`EVALUATION OF SAFETY................................................................................................................................. 25
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ................................................................................ 25
`4.1
`SUBGROUP ANALYSES FOR SVR12 RATE........................................................................................................ 25
`4.1.1
`Gender, Race, Age, and Geographic Region .......................................................................................... 25
`4.1.2
`Baseline Characteristics......................................................................................................................... 26
`4.2
`SUBGROUP ANALYSES FOR RELAPSE RATE ..................................................................................................... 26
`4.2.1
`Subgroup Analyses for Relapse Rate in TN Subjects in ION-3 Study..................................................... 26
`4.2.2
`Subgroup Analyses for Relapse Rate in TE Subjects in ION-2 Study ..................................................... 31
`SUMMARY AND CONCLUSIONS ................................................................................................................... 36
`5.1
`STATISTICAL ISSUES........................................................................................................................................ 36
`5.2
`COLLECTIVE EVIDENCE................................................................................................................................... 36
`5.3
`CONCLUSIONS AND RECOMMENDATIONS ........................................................................................................ 37
`APPENDICES....................................................................................................................................................... 38
`
`1
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`2
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`3
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`4
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`5
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`6
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`Reference ID: 3539966
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`LIST OF TABLES
`
`Table 1: List of Studies Reviewed in Report.................................................................................................................... 7
`Table 2: Patient Disposition in ION-1 and ION-3 .......................................................................................................... 12
`Table 3: Patient Demographics and Baseline HCV Disease Characteristics in ION-1 and ION-3 (All Treated)........... 13
`Table 4: Applicant’s Results for Primary Efficacy Endpoint of SVR12 Rate in ION-1 and ION-3 (All Treated)......... 14
`Table 5: Applicant’s Results for Inter Group Comparison of SVR12 Rates in ION-3 (All Treated)............................. 14
`Table 6: Reviewer’s Results for Primary Efficacy Endpoint of SVR12 Rate in ION-1 and ION-3 (All Treated) ......... 15
`Table 7: Reviewer’s Results for Inter Group Comparison of SVR12 Rates in ION-3 (All Treated) ............................. 15
`Table 8: Reviewer’s Results for Relapse Rates in ION-1 and ION-3 (All Treated)....................................................... 16
`Table 9: Reviewer’s Results for SVR Rates in ION-1 and ION-3 (All Treated)............................................................ 17
`Table 10: Applicant’s Results for Concordance between SVR12 and SVR12 in Part A of ION-1 (All Treated).......... 17
`Table 11: Reviewer’s Results for Comparison of Relapse Rates Between Different Treatment Durations in ION-3 (All
`Treated)........................................................................................................................................................................... 18
`Table 12: Patient Disposition in ION-2 .......................................................................................................................... 19
`Table 13: Applicant’s Results for Demographics and Baseline Characteristics in ION-2 (All Treated)........................ 20
`Table 14: Applicant’s Results for Primary Efficacy Endpoint of SVR12 Rate in ION-2 (All Treated)......................... 22
`Table 15: Reviewer’s Results for Relapse Rates in ION-2 (All Treated)....................................................................... 23
`Table 16: Reviewer’s Results for SVR Rates in ION-2 (All Treated)............................................................................ 23
`Table 17: Applicant’s Results for Concordance between SVR12 and SVR12 in ION-2 (All Treated).......................... 23
`Table 18: Reviewer’s Results for SVR12 and Relapse Rates in ION-2 (All Treated).................................................... 24
`Table 19: Reviewer’s Results for Comparison of Relapse Rates between Different Treatment Durations in ION-2 (All
`Treated)........................................................................................................................................................................... 25
`Table 20: Reviewer’s Results for Subgroup Relapse Rates for 8-Week Treatment Arms in ION-3 (All Treated) ........ 27
`Table 21: Reviewer’s Results for Relapse Rates by Baseline Viral Load for 8-Week and 12-Week Regimens in ION-3
`(All Treated) ................................................................................................................................................................... 28
`Table 22: Reviewer’s Results for Subgroup Relapse Rates for 8-Week and 12-Week Regimens in ION-3 (All Treated)
`........................................................................................................................................................................................ 29
`Table 23: Reviewer’s Results for Relapse Rates by Early Viral Response with Positive Predictive Values and Negative
`Predictive Values in ION-3 (All Treated)....................................................................................................................... 30
`Table 24: Reviewer’s Results for Relapse Rates by Early Viral Response in ION-3 (All Treated)............................... 31
`Table 25: Reviewer’s Results for Subgroup Relapse Rate in ION-2 (All Treated)........................................................ 31
`Table 26: Reviewer’s Results for Subgroup Relapse Rates for 8-Week and 12-Week Regimens in ION-2 (All Treated)
`........................................................................................................................................................................................ 33
`Table 27: Reviewer’s Results for Relapse Rates by Early Viral Response with Positive Predictive Values and Negative
`Predictive Values in ION-3 (All Treated)....................................................................................................................... 34
`Table 28: Reviewer’s Results for Relapse Rates by Early Viral Response for All Subjects in ION-2 (All Treated)..... 35
`Table 29: Reviewer’s Results for Relapse Rates by Early Viral Response for Cirrhotic Subjects in ION-2 (All Treated)
`........................................................................................................................................................................................ 35
`Table 30: Reviewer’s Results for Relapse Rates by Early Viral Response for Non-Cirrhotic Subjects in ION-2 (All
`Treated)........................................................................................................................................................................... 36
`Table 31: Reviewer’s Results for SVR12 Rates by Demographics in ION-1 and ION-3 (All Treated)......................... 38
`Table 32: Reviewer’s Results for SVR12 Rates by Baseline Characteristics in ION-1 and ION-3 (All Treated).......... 39
`Table 33: Reviewer’s Results for SVR12 Rates by Demographics in ION-2 (All Treated)........................................... 40
`Table 34: Reviewer’s Results for SVR12 Rates by Baseline Characteristics in ION-2 (All Treated)............................ 41
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`Reference ID: 3539966
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`LIST OF FIGURES
`
`Figure 1: Reviewer’s Results for On-Treatment Virologic Response by Treatment Groups in ION-1 and ION-3 (All
`Treated, NC=F)............................................................................................................................................................... 16
`Figure 2: Reviewer’s Results for On-Treatment Virologic Response by Treatment Groups in ION-2 (All Treated,
`NC=F)............................................................................................................................................................................. 22
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`Reference ID: 3539966
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`1 EXECUTIVE SUMMARY
`
`Gilead submitted three Phase 3 trials to support the regimens containing Sofosbuvir 400 mg and
`Ledipasvir 90 mg fixed-dose combination (SOF/LDV) tablet administered once daily in the
`treatment of subjects infected with genotype (GT) 1 hepatitis C virus (HCV). The three trials
`studied regimens of different durations of SOF/LDV with or without combined use of Ribavirin
`(RBV) in either GT1 treatment-naïve (TN) or GT1 treatment-experienced (TE) subjects. All of the
`trials had the same primary efficacy endpoint which was the SVR12 rate defined as the proportion
`of subjects who had HCV RNA below the lower of quantitation (LLOQ) 12 weeks after the end of
`treatment.
`
`The ION-1 study (i.e., Study GS-US-337-0102) evaluated four regimens in cirrhotic and non-
`cirrhotic GT1 TN subjects. The four regimens were 12 weeks of SOF/LDV, 12 weeks of
`SOF/LDV with RBV, 24 weeks of SOF/LDV, 24 weeks of SOF/LDV with RBV. In the pre-NDA
`meeting in June of 2013, the Antiviral Division agreed with the applicant that the efficacy data for
`the two 24-week arms in the study would not be necessary in this NDA submission if the two 12-
`week arms were able to achieve SVR rates ≥ 90% in subjects with and without cirrhosis separately.
`Based on this agreeable criterion, the applicant only summarized the efficacy results for the two
`12-week arms in the ION-1 study in the NDA. The study demonstrated that the SVR12 rate for the
`12-week SOF/LDV treatment either without or with RBV was greater than 97% in GT1 TN
`subjects including cirrhotic and non-cirrhotic subjects, which was statistically significantly
`superior to the pre-specified 60% historical rate. Only one relapse occurred in the two regimens.
`The use of RBV appeared not to affect the SVR12 rate.
`
`The ION-3 study (i.e., Study GS-US-337-0108) also included GT1 TN subjects. It differed from
`the ION-1 study mainly in patient population and treatment durations. The study only enrolled
`non-cirrhotic GT1 TN subjects. The three treatment arms in the study were 8 weeks of SOF/LDV,
`8 weeks of SOF/LDV plus RBV, and 12 weeks of SOF/LDV. All the three arms resulted in at
`least 93% SVR12 rates in non-cirrhotic GT1 TN subjects which were statistically significantly
`greater than the pre-specified 60% historical rate. The use of RBV again did not show to have an
`impact on SVR12 rate in the study. No statistically significant difference in SVR12 rates was
`found between the 8-week and 12-week treatment durations. The main reason that the subjects did
`not achieve SVR12 was relapse in the 8-week regimens but was discontinuation of study in the 12-
`week regimen. Relapse was one of the key pre-specified secondary efficacy endpoints. The
`relapse rate for 8 weeks of SOF/LDV without RBV (5%) was similar to the rate for 8 weeks of
`SOF/LDV with RBV (4%), which suggested that the use of RBV did not have an impact on
`relapse. The exploratory analyses to compare the pooled relapse rate for 8 weeks SOF/LDV with
`and without RBV versus 12 weeks of SOF/LDV revealed that the 12-week duration reduced the
`relapse rate by approximately 3% (95% CI: 0.2%, 6.0%) in comparison to the 8-week duration.
`Meanwhile, the safety review performed by the medical officer, Dr. Sarah Connelly, concluded
`that the 8 weeks and 12 weeks of SOF/LDV had similar safety profiles.
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`Based on the collective evidence in the ION-1 and ION-3 studies, the statistical reviewer
`concluded that the 12 weeks of SOF/LDV was a better regimen for treatment of GT1 TN cirrhotic
`and non-cirrhotic subjects.
`
`The ION-2 study (i.e., Study GS-US-337-109) included cirrhotic and non-cirrhotic GT1 TE
`subjects where the same four regimens as in the ION-1 study were investigated. The study showed
`that the 12 weeks of SOF/LDV without or with RBV led to approximately 94% to 96% SVR12
`rates and 24 weeks of SOF/LDV without or with RBV had the SVR12 rates as high as 99%. All of
`the SVR12 rates were statistically significantly superior to the pre-specified 25% historical rate.
`Also, the relapse rates for the two 12-week regimens were 4% to 6%, whereas no relapse occurred
`in the two 24-week treatment regimens. The difference in SVR12 rates between the 12-week and
`24-week regimens were almost entirely explained by the relapse rate. The study again suggested
`that the use of the RBV had a minimal impact on the SVR12 and relapse rates. The pre-specified
`subgroup analysis defined by the baseline cirrhotic status demonstrated that there was an obviously
`numerical trend that the treatment for 24 weeks resulted in a higher SVR12 rate than the treatment
`for 12 weeks in the cirrhotic subjects but the two treatment durations had comparable SVR12 rates
`in the non-cirrhotic subjects. Further exploratory analyses for the relapse rate led to the consistent
`results that the longer treatment duration had approximately 16% lower relapse rates than the
`shorter treatment duration in the cirrhotic subjects but was only 2% lower in the non-cirrhotic
`subjects. The statistical reviewer concluded that 12 weeks of SOF/LDV regimen was sufficient for
`the non-cirrhotic GT1 TE subjects while 24 weeks of SOF/LDV regimen was optimal for the
`cirrhotic GT1 TE subjects.
`
`There was no major statistical issue identified in the submission.
`
`2
`
`INTRODUCTION
`
`2.1 Overview
`
`SOF is a novel nucleotide analogue inhibitor of HCV NS5B protein to prevent viral replication. In
`2013, the FDA approved SOF in combination with Peg-IFN and RBV for 12 weeks to treat GT1
`and GT4 subjects and SOF in combination with RBV to treat GT2 and GT3 subjects. Peg-IFN is
`well known to have many side effects. The 12-week SOF+PegIFN+RBV regimen in GT1 subjects
`shortened the PegIFN treatment duration compared with the old standard of care which usually
`required 48 weeks of PegIFN, and therefore had a better safety profile. However, there is a need to
`develop safer PegIFN-free treatment regimens. LDV is a novel HCV NS5A inhibitor which has
`demonstrated potent anti-HCV activity against GT1a and GT1b HCV infection. The SOF/LDV
`tablet combines these two HCV-specific direct-acting antiviral agents into a single tablet.
`According to the applicant, the early phase studies showed that the SOF/LDV resulted in 90%
`SVR12 rates in GT1 subjects without any significant safety concern.
`
`SOF/LDV was shown to be effective. Also, it was Peg-IFN-free and could be RBV-free, and was
`a single tablet more convenient for patients. Therefore, the regimen is considered to be
`breakthrough therapy. In this NDA, the applicant submitted the interim clinical study reports for
`
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`three pivotal studies to support SOF/LDV in both TN and TE GT1 subjects with and without
`cirrhosis. The NDA was granted a priority review.
`
`The statistical reviewer focused on reviewing the efficacy of the three studies in this review report.
`The summaries of the key elements in the study design in each study are displayed in Table 1.
`
`Table 1: List of Studies Reviewed in Report
`Patient
`Treatment arms/
`population
`Sample size
`
`cirrhotic or non-
`cirrhotic TN
`subjects with
`genotype 1 (GT1)
`HCV infection
`
`12-week LDV/SOF, n=214
`12-week LDV/SOF +RBV, n=217
`(24-week LDV/SOF, n=2171)
`(24-week LDV/SOF+RBV, n=2171)
`
`non-cirrhotic TN
`subjects with GT1
`HCV infection
`
`8-week SOF/LDV, n=215
`8-week SOF/LDV+RBV, n=216
`12-week SOF/LDV, n=216
`
`cirrhotic or non-
`cirrhotic TE subjects
`with chronic GT1
`HCV infection
`
`12-week SOF/LDV, n=109
`12-week SOF/LDV+RBV, n=111
`24-week SOF/LDV, n=109
`24-week SOF/LDV+RBV, n=111
`
`Primary efficacy
`endpoint/
`hypothesis
`The primary efficacy
`hypothesis was that the
`primary efficacy endpoint of
`the SVR12 rate in each
`treatment arm was superior to
`the historical rate of 60%.
`same as ION-1
`
`The primary efficacy
`hypothesis was that the
`primary efficacy endpoint of
`the SVR12 rate in each
`treatment arm was superior to
`the historical rate of 25%.
`
`Study
`number
`
`ION-1 (GS-
`US-337-
`0102)
`
`ION-3 (GS-
`US-337-
`0108)
`
`ION-2 (GS-
`US-337-
`0109)
`
`Design
`
`phase 3,
`multicenter,
`randomized,
`open-label
`
`phase 3,
`multicenter,
`randomized,
`open-label
`phase 3,
`multicenter,
`randomized,
`open-label
`
`1not included in this NDA
`
`2.2 Data Sources
`
`The datasets were initially submitted electronically and are located in
`\\CDSESUB1\evsprod\NDA205834\0000. The updated SVR12 data for two subjects in the ION-3
`study is located in \\CDSESUB1\evsprod\NDA205834\0015. The updated SVR12 data for three
`subjects in the ION-2 study is located in \\CDSESUB1\evsprod\NDA205834\0019.
`
`3 STATISTICAL EVALUATION
`
`3.1 Data and Analysis Quality
`
`Overall the quality of the data in this NDA submission was good. In the initial submission, the
`applicant did not provide the SVR12 data for five subjects (three in the ION-1 study and two in the
`ION-3 study) since they did not reach the post-treatment Week 12 visit at the time of the data lock
`for the clinical reports. The applicant submitted the data upon the Division’s request during the
`course of the review.
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`3.2 Evaluation of Efficacy
`
`Both ION-1 and ION-3 studies recruited TN subjects, and the ION-2 study enrolled TE subjects.
`The reviewer will present the review results for the ION-1 and ION-3 studies together and the
`ION-2 study separately in Section 3.2.
`
`3.2.1 ION-1 and ION-3
`
`3.2.1.1 Study Design and Endpoints
`
`Both ION-1 and ION-3 studies were phase 3, multicenter, randomized, open-label trials to evaluate
`the efficacy and safety of use of SOF/LDV FDC with or without RBV for different durations in the
`GT1 TN subjects. The ION-1 study consisted of four treatment groups, namely, 12-week
`SOF/LDV, 12-week SOF/LDV+RBV, 24-week SOF/LDV, 24-week SOF/LDV+RBV; while the
`ION-3 study included three arms, namely, 8-week SOF/LDV, 8-week SOF/LDV+RBV, 12-week
`SOF/LDV. Eligible subjects were equally randomized into the treatment groups in both studies.
`All subjects were to complete the post-treatment Week 4 and 12 visits regardless of their treatment
`duration. Subjects who had HCV RNA < LLOQ at the post-treatment Week 12 visit were also to
`complete the post-treatment Week 24 visit unless a confirmed viral relapse occurred. After
`completing the current studies, subjects could enroll into either the SVR Registry Study (i.e., GS-
`US-248-0122) if they achieved SVR24 or the Sequence Registry Study (i.e., GS-US-248-0123) if
`they did not achieve SVR24.
`
`Of note, in the pre-NDA meeting in June of 2013, the Division agreed with the applicant that the
`efficacy data for 24-week arms in the ION-1 study would not be necessary in this NDA submission
`if the two 12-week arms were able to achieve an SVR12 rate ≥ 90% in subjects with and without
`cirrhosis separately. Therefore this review report focuses on the two 12-week arms in the study.
`
`In addition to the different treatment arms, there were the following three main differences in the
`study design for the two studies.
`
`1) The two studies had different TN patient populations. The ION-1 study enrolled both cirrhotic
`and non-cirrhotic subjects. Among the treated subjects in the two 12-week arms in the study,
`approximately 15% of them had cirrhosis at baseline. On the other hand, the ION-3 study
`recruited non-cirrhotic subjects only. Also, the ION-1 study recruited subjects both in the US
`and Europe. Approximately 42% to 46% of the treated subjects in the two 12-week treatment
`groups in the study were from Europe. In contrast, the subjects in the ION-3 study were all
`from the US sites.
`
`2) Since the ION-1 study enrolled the cirrhotic subjects, the stratification factors in the
`randomization included both genotype (1a or 1b) and cirrhotic status (presence or absence).
`Genotype was the only stratification factor that was used in the randomization procedure for
`the ION-3 study.
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`3) There were two parts in subject enrollment in the ION-1 study. Part A planned to randomize
`approximately 50 subjects in each arm (i.e., 25% of the planned sample size). Enrollment was
`halted once Part A was fully enrolled. After all subjects in the two 12-week arms completed
`post-treatment Week 4, an interim analysis was planned to be conducted by the external data
`monitoring committee to determine whether to terminate or continue the two 12-week
`regimens. The interim analysis calculated the conditional power based on the SVR4 rates for
`the two 12-week arms. If the conditional power was less than 5%, the two 12-week arms
`would be discontinued. If the conditional power was equal to or greater than 5%, Part B would
`start to enroll and randomize approximately 600 additional subjects into all four treatment
`groups.
`
`The HCV viral load was assessed every two weeks until the end of the treatment for the five arms
`in the ION-1 and ION-3 studies. The HCV viral load was measured at 4 and 12 weeks after the
`end of the treatment to obtain the sustained virologic responses.
`
`The primary efficacy endpoint in both studies was the proportion of subjects achieving SVR12.
`Also, the two studies had the same primary hypothesis which was that the SVR12 rate in each
`treatment arm was superior to the historical control rate of 60%.
`
`The secondary efficacy endpoints included the following:
`
`1) on-treatment virologic failure and relapse defined as follows:
`
`
`
`
`
`−
`−
`−
`−
`
`on-treatment virologic failure:
`
`Breakthrough: HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ
`while on treatment, confirmed with 2 consecutive values (note, second confirmation
`value can be post-treatment), or last available on-treatment measurement with no
`subsequent follow up values
`
`Rebound: > 1 log10IU/ml increase in HCV RNA from nadir while on treatment,
`confirmed with 2 consecutive values (note, second confirmation value can be post-
`treatment), or last available measurement with no subsequent follow up value
`
`Non-response: HCV RNA persistently ≥ LLOQ through 8 weeks of treatment
`
`Relapse:
`
`HCV RNA ≥ LLOQ during the post-treatment period having achieved HCV RNA <
`LLOQ at the last observed on-treatment HCV RNA measurement, confirmed with
`consecutive values or last available post-treatment measurement
`
`2) SVR4 and SVR24 rates
`3)
`proportion of subjects with HCV RNA < LLOQ at each on-treatment visit
`
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`4) HCV RNA (log10 IU/mL) absolute value and change from baseline in HCV RNA through
`Week 8
`
`3.2.1.2 Statistical Methodologies
`
`A.
`
`Efficacy Analysis
`
`The efficacy analyses were performed among the subjects who were randomized and received at
`least one dose of study drugs. The applicant referred the efficacy analysis set as full analysis set,
`while the reviewer referred to them as All Treated in this report. The two-sided one-sample
`binomial test was used to evaluate whether the SVR12 rate was superior to the 60% historical rate
`in each treatment group. Also, the exact confidence interval (CI) for the SVR12 rate was
`constructed for each treatment arm using the Clopper-Pearson method.
`
`In the ION-1 study, the applicant’s justification for the 60% historical rate as follows:
`
` A historical SVR rate of approximately 65% was calculated from the telaprevir (ADVANCE study) and
`boceprevir (SPRINT2 study) data after adjusting for the expected proportion of subjects with cirrhosis
`(approximately 20%) in this study.
`
` A 5% trade-off in efficacy exchanged for an expected improved safety profile and shorter duration of
`treatment. The weighted average of the telaprevir and boceprevir data was estimated to be approximately 70%
`in non-cirrhotic subjects and 44% in cirrhotic subjects. The SVR rate for the historical control in this study
`(ie, a patient population of 80% noncirrhotics and 20% cirrhotics) was then calculated to be approximately
`65% (ie, 0.8 × 70% + 0.2 ×44%).
`
`In the ION-3 study, the applicant derived the 60% historical rate as follows:
`
`The basis for this 60% SVR null rate was derived from the historical SVR rate calculated from the telaprevir
`(ADVANCE study) and boceprevir (SPRINT2 study) data after adjusting for a 5% trade-off in efficacy exchanged
`for an expected improved safety profile and shorter duration of treatment. The weighted average of the telaprevir
`and boceprevir data was estimated to be approximately 70% in noncirrhotic subjects. With an estimated minimum
`of 8% subjects being IFN ineligible (based on enrollment data from the GS-US-337-0102 study [ION-1]), and
`assuming a 5% response rate in these subjects, the adjusted rate is estimated to be approximately 65% (70%*0.92
`+ 5%*0.08 = 64.8%). As noted above, the 60% null SVR rate is obtained after allowing for a 5% trade-off in
`efficacy exchanged for an expected improved safety profile and shorter treatment duration.
`
`The Division agreed with the 60% historical rate in both studies because it was close to the upper
`bound of the 95% CI of the highest SVR rate for PEG+RBV treatment for GT1 subjects in the
`historical trial. Of note, the 60% historical rate was previously used in the NEUTRINO study to
`assess the efficacy of 12 weeks of SOF+PEG+RBV treatment in GT1 TN subjects.
`
`In the ION-1 study, the type I error was controlled using Bonferroni correction method. The
`Bonferroni correction method not only ensured a strong control of family-wise type I error rate at
`the 0.05 level, but also ensured strong controls of individual type I error rate at the 0.0125 level for
`comparison of the SVR12 rate in each treatment group against the historical rate of 60%. In the
`
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`ION-3 study, the SVR12 rates in the three groups were tested following a sequential testing
`procedure. If the SVR12 rate for the 12-week SOF+RBV was statistically significant compared to
`the 60% historical rate at the 0.05 significance level, the SVR12 rates for the two 8-week groups
`were compared to the null rate of 60%, respectively, each at the 0.025 significance level.
`
`B.
`
`Visit Windows
`
`All available HCV RNA data were included in the efficacy analysis unless a subject started
`alternative HCV medication. The visit windows were pre-specified for all scheduled visits. A
`visit window was defined as half of the duration of time between the two consecutive study visits.
`The on-treatment visit windows were calculated from the first dose of study drug (i.e., study day =
`collection date – date of the first dose; +1 if the result is ≥0), while the off-treatment visit windows
`were from the last study drug dosing date (i.e., follow-up day = collection data – last dose date).
`
`C.
`
`Handling Missing Data or Dropouts
`
`The applicant described their approach to handling missing viral load data in the statistical analysis
`plans (SAPs) as follows:
`
`A missing data point for a given study visit may be due to any one of the following reasons:
`
`• A visit occurred but data were not collected or were unusable
`• A visit did not occur
`• A subject permanently discontinued from the study before reaching the window
`
`For analyses of categorical HCV RNA data, if a data point is missing and is preceded and followed in time by
`values that are “< LLOQ TND”, then the missing data point will be set to “< LLOQ TND”. If a data point is
`missing and preceded and followed by values that are “< LLOQ detected”, or preceded by “< LLOQ detected”
`and followed by “< LLOQ TND”, or preceded by “< LLOQ TND” and followed by “< LLOQ detected”, then the
`missing value will be set to “< LLOQ detected”; otherwise the data point will be termed a failure (ie,
`≥ LLOQ detected).
`
`Subjects with missing data due to premature discontinuation of the study will have missing data imputed up to the
`time of their last dose (for on-treatment displays). If study days associated with the last dosing date is greater than
`the lower bound of a visit window, and the value at the visit is missing, then the value will be imputed. If the
`study days associated with the last dosing date is less than the lower bound of a visit window then the on-
`treatment value at that visit will remain missing.
`
`If no HCV RNA values are obtained after the last dose of any study drug, the subject will be considered a
`treatment failure for SVR endpoints. However, success for SVR12 who have no further HCV RNA measurements
`collected will be counted as a success for SVR24 due to the high correlation between these 2 endpoints.
`
`For the analyses of continuous HCV RNA efficacy data, any subject with a missing value in a visit window that is
`bracketed by prior and subsequent values of “< LLOQ TND” or “< LLOQ detected” will be set to “< LLOQ
`TND” (ie, 24 IU/mL). No other imputation will be performed for continuous data.
`
`11
`
`Reference ID: 3539966
`
`

`

`3.2.1.3 Patient Disposition, Demographic and Baseline Characteristics
`
`Table 2 shows the patient disposition for the two 12-week treatment groups in the ION-1 study and
`all three treatment arms in the ION-3 study. Almost all randomized subjects in these arms were
`treated, and almost all treated subjects completed the full course of the assigned treatment.
`
`Table 2: Patient Disposition in ION-1 and ION-3
`ION-1
`SOF/LDV
`SOF/LDV
`12 Weeks
`+RBV
`12 Weeks
`218
`1
`217
`(100%)
`213
`(98.2%)
`
`217
`3
`214
`(100%)
`212
`(99.1%)
`
`SOF/LDV
`8 Weeks
`
`215
`0
`215
`(100%)
`215
`(100%)
`
`Randomized
`Never treated
`Treated
`
`Completed study treatment
`
`ION-3
`SOF/LDV
`+RBV
`8 Weeks
`216
`0
`216
`(100%)
`213
`(98.6%)
`
`3 (1.4%)
`1 (0.5%)
`0
`0
`0
`2 (0.9%)
`
`SOF/LDV
`12 Weeks
`
`216
`0
`216
`(100%)
`211
`(97.7%)
`
`5 (2.3%)
`2 (0.9%)
`0
`1 (0.5%)
`0
`2 (