CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`207620Orig1s000
`
`STATISTICAL REVIEW(S)
`
`
`
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`
`
`

`

`
`
`US. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Oflice of Biostatistics
`
`STATISTICAL REVIEW AND EVALUATION
`
`CLINICAL STUDIES
`
`NDA/BLA #:
`
`NDA 207-620
`
`Supplement #:
`
`Drug Name:
`
`Indication(s):
`
`Applicant:
`
`Date(s):
`
`LCZ696 (sacubitril/valsartan combination)
`
`(m4)
`
`Novartis
`
`12/17/2014
`
`Review Priority:
`
`Priority
`
`Biometrics Division:
`
`DBI
`
`Statistical Reviewer:
`
`John Lawrence, Ph D
`
`Concurring Reviewers:
`
`Jim Hung, Ph D
`
`Medical Division:
`
`Cardiorenal.
`
`Clinical Team:
`
`Kimberly Smith MD, Tzu-Yun McDowell MD, Aliza Thompson
`MD
`
`Project Manager:
`
`Alexis Childers
`
`Keywords:
`
`active control, Cox regression, combination products
`
`Reference ID: 3757898
`
`

`

`Table of Contents
`EXECUTIVE SUMMARY ......................................................................................................................................... 5
`INTRODUCTION ....................................................................................................................................................... 6
`1.1
`OVERVIEW ...................................................................................................................................................... 6
`1.2
`DATA SOURCES .............................................................................................................................................. 6
`STATISTICAL EVALUATION ................................................................................................................................ 7
`1.3
`DATA AND ANALYSIS QUALITY ..................................................................................................................... 7
`1.4
`EVALUATION OF EFFICACY ............................................................................................................................ 7
`1.4.1
`Study Design and Endpoints .................................................................................................................. 7
`1.4.2
`Statistical Methodologies ....................................................................................................................... 8
`1.4.3
`Patient Disposition, Demographic and Baseline Characteristics.......................................................... 9
`1.4.4
`Results and Conclusions ...................................................................................................................... 11
`1.5
`EVALUATION OF SAFETY .............................................................................................................................. 17
`1.6
`BENEFIT-RISK ASSESSMENT (OPTIONAL) ..................................................................................................... 17
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ..................................................................................... 17
`1.7
`GENDER, RACE, AGE, AND GEOGRAPHIC REGION ........................................................................................ 17
`1.8
`OTHER SPECIAL/SUBGROUP POPULATIONS .................................................................................................. 18
`SUMMARY AND CONCLUSIONS ........................................................................................................................ 19
`1.9
`STATISTICAL ISSUES ..................................................................................................................................... 19
`1.10 COLLECTIVE EVIDENCE ................................................................................................................................ 19
`1.11 CONCLUSIONS AND RECOMMENDATIONS ..................................................................................................... 19
`1.12 LABELING RECOMMENDATIONS (AS APPLICABLE) ........................................................................................ 20
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`Reference ID: 3757898
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`2
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`

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`LIST OF TABLES
`
`
`Table 1 List of all studies included in analysis .............................................................................................................. 6
`Table 2 Reasons for treatment discontinuation. ........................................................................................................... 10
`Table 3 Patient demographic and baseline characteristics ........................................................................................... 11
`Table 4 Adjudicated Primary Endpoint Analysis (CV death or HF hospitalization) .................................................. 12
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`3
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`Reference ID: 3757898
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`

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`LIST OF FIGURES
`
`Figure 1 Weights for alpha relocation in the sequentially rejective multiple test procedure for the secondary
`hypotheses ..................................................................................................................................................................... 9
`Figure 2 Proportion of subjects included in primary analysis over time in the study. ................................................. 13
`Figure 3 Kaplan-Meier estimates of event rates over time. ......................................................................................... 14
`Figure 4 Log{-log(survival)) plot for primary endpoint (Time is shown on the log-scale on the x-axis, log(-
`log(estimated survival)) on the y-axis). ....................................................................................................................... 15
`Figure 5 Kaplan-Meier estimates of all-cause mortality rates (secondary endpoint). .................................................. 16
`Figure 6 High dose/warfarin results for subgroups defined by gender, race, age, and geographic region. ................. 18
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`Reference ID: 3757898
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`4
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`

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`EXECUTIVE SUMMARY
`
`
`There was only one phase 3 trial for this indication in the submission. The study drug is a
`combination of valsartan and sacubitril. Both valsartan (a component of the combination study
`drug) and enalapril (the active control) are approved for the treatment of heart failure, but there
`has never been a study comparing valsartan monotherapy to enalapril. According to their
`respective labels, enalapril has a mortality effect compared to placebo, but valsartan has no
`mortality effect compared to placebo (where subjects were on the background therapy
`recommended by their physicians and 93% of the subjects were on ACE-inhibitor therapy, of
`which enalapril is one such therapy). In the trial, the combination was effective compared to the
`control on two endpoints: time to first heart failure hospitalization or CV death (primary
`endpoint) and time to all-cause mortality (a secondary endpoint). There is no way to know from
`this trial whether both components in the combination contribute to both or either of the claimed
`effects. From the valsartan label, it may be reasonable to infer that the valsartan component does
`not contribute to the claimed mortality effect; valsartan had no effect compared to placebo in the
`Val-HeFT trial when ACE-inhibitors were a background therapy, so it is not likely that valsartan
`would be more effective than an ACE-inhibitor in a head-to-head comparison. Although
`valsartan alone reduced HF hospitalization compared to placebo in the Val-HeFT trial, it is
`unknown whether both components contribute to the combined effect of valsartan/sacubitril
`compared to enalapril on the composite primary endpoint in this trial.
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`Reference ID: 3757898
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`5
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`

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`INTRODUCTION
`
`
`1.1 Overview
`
`
`Table 1 List of all studies included in analysis
`
`Phase
`Treatment
`Follow-
`and
`Period
`up
`Period
`Design
`Phase 3 Up to 51
`Up to 51
`months
`months
`(median
`(median
`of 27
`of 27
`months)
`months)
`
`Study
`CLCZ696B2314
`
` # of
`Subjects per
`Arm
`4209
`(LCZ696),
`4233
`(enalapril)
`
`Study Population
`
`patients with CHF (NYHA
`class II - IV), age 18 years
`or older, LVEF ≤ 35%, B-
`type natriuretic peptide
`(BNP) ≥ 150 pg/ml (or N-
`terminal prohormone B-
`type natriuretic
`peptide [NT-proBNP] ≥
`600 pg/ml) or BNP ≥ 100
`pg/mL (or NT-proBNP ≥
`400 pg/ml) and a
`hospitalization for HF
`within the last 12 months.
`
`Source: Study Report.
`
`
`
`1.2 Data Sources
`
`Electronic datasets and Study Reports:
`
`\\CDSESUB1\EVSPROD\NDA207620\207620.enx
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`\\cdsesub1\evsprod\NDA207620\0002\m5\datasets\lcz696b2314\analysis\legacy\datasets
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`Reference ID: 3757898
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`6
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`

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`STATISTICAL EVALUATION
`
`
`1.3 Data and Analysis Quality
`
`Both the data quality or analysis quality were very good to excellent. The largest file in the
`submission was about 640 MB. This file, although large, was not too large for me to open on my
`workstation. In the data analysis, appropriate adjustments were made for multiple comparisons of
`different endpoints and sequential testing of these endpoints at different time points (interim
`monitoring).
`
`1.4 Evaluation of Efficacy
`
`
`1.4.1 Study Design and Endpoints
`
`
`
`This was an active controlled trial without placebo. Although the active control has an effect
`described in the label, the trial was designed to show superiority to the active control and there
`was no non-inferiority testing planned. Unblinded ACEI or ARB concomitant therapy was not
`permitted in the trial.
`
`The study population consisted of patients with CHF (NYHA class II - IV), aged 18 years or
`older with LVEF ≤ 40%, changed to ≤ 35% by Protocol Amendment 1. Patients eligible for
`inclusion in the study had to have B-type natriuretic peptide (BNP) ≥ 150 pg/ml (or N-terminal
`prohormone B-type natriuretic peptide [NT-proBNP] ≥ 600 pg/ml) or BNP ≥ 100 pg/mL (or NT-
`proBNP ≥ 400 pg/ml) and a hospitalization for HF within the last 12 months. Eligible patients
`were to have been on an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin
`receptor blocker (ARB), at a stable dose of at least 10 mg/day of enalapril or equivalent for at
`least 4 weeks prior to Visit 1. Patients were to have been treated with a β-blocker, unless
`contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1. An
`aldosterone antagonist was also to have been considered in all patients if indicated.
`
` A
`
` total of 8442 patients were randomized (4209 patients to LCZ696 and 4233 patients to
`enalapril). Forty-three patients were excluded from the efficacy analysis due to site closure for
`serious GCP violations (37 patients) or due to misrandomization (6 patients). Thus, the full
`analysis set (FAS) included 8399 patients (4187 patients in the LCZ696 group and 4212 patients
`in the enalapril group).
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`Reference ID: 3757898
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`7
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`

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`The primary endpoint was the time to first heart failure hospitalization or CV death. There were
`4 secondary endpoints: i) time to all-cause death; ii) change from baseline (CFB) (randomization
`visit) in the clinical summary score for HF symptoms and physical limitations (as assessed by
`KCCQ) at 8 months; iii) time to new onset of atrial fibrillation; iv) time to first occurrence of
`either (1) a 50% decline in eGFR relative to baseline, (2) >30 mL/min/1.73 m2 decline in eGFR
`relative to baseline to a value below 60 mL/min/1.73 m2, or (3) reaching ESRD.
`
`
`1.4.2 Statistical Methodologies
`
`For the primary composite endpoint and the three time-to event secondary endpoints, time to
`event was analyzed using a Cox regression model with terms for treatment and region. For the
`remaining secondary endpoint- change in KCCQ score- a repeated measures ANCOVA analysis
`was used with terms for treatment, region, and time point (Months 4 and 8).
`
`The study was designed to have approximately 2410 primary endpoint events and 1229 CV-
`death events if the study reached the maximum study duration. Three interim analyses were
`planned at 1/3, 1/2 and 2/3 of information time (i.e. approximately 804, 1205 and 1607 patients,
`respectively, with a primary event). However, some adjustment to the frequency and time for
`interim analyses was made to coincide with the DMC meetings. Appropriate statistical
`adjustments for the interim analyses actually performed were made to control the overall type-I
`error of 0.025 (one-sided). For each IA, the analysis dataset comprised all patients who were
`randomized before the cutoff date. The Haybittle-Peto type of boundary was used for the interim
`efficacy analyses to assess superiority. The interim efficacy analysis with the boundary spent
`approximately an alpha of 0.0001 (one-sided) at the first IA and 0.001 (one-sided and nominal)
`at the second and third interim analyses.
`
`Whatever time point the study stopped, if the primary endpoint was statistically significant, then
`the secondary endpoints were to be tested using the same alpha as used for the primary endpoint.
`The testing of the four secondary endpoints was to be done using the Bonferroni-Holm's method
`as shown in the graph in Figure 1.
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`Reference ID: 3757898
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`

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`Figure 1 Weights for alpha relocation in the sequentially rejective multiple test procedure for the secondary
`hypotheses
`
`
`
`
`
`Source: Figure 9-2 of Study Report.
`
`
`
`
`1.4.3 Patient Disposition, Demographic and Baseline Characteristics
`
`
`
`The reasons for treatment discontinuation are shown in Table 2 and the baseline and demographic
`characteristics are shown in Table 3. The first table shows that very few subjects were lost to
`follow-up except for those who died. However, about 30% of the subjects stopped double-blind
`treatment before the end of the study. A strength of the trial is that there is very little loss to
`follow-up and subjects were followed after stopping study drug. In Table 3, it is seen that the
`average age was about 64 years, 78% were male, 66% were Caucasian. There were no significant
`differences in the demographics between groups.
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`Reference ID: 3757898
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`9
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`

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`Table 2 Reasons for treatment discontinuation.
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`Source: Table 10-3 of Study Report.
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`Reference ID: 3757898
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`10
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`

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`Table 3 Patient demographic and baseline characteristics
`
`
`Source: Table 11-3 of Study Report.
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`
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`1.4.4 Results and Conclusions
`
`The trial was stopped at the third interim analysis by the DMC because the efficacy boundary
`was crossed. The combination was superior to the control on the primary endpoint. The results
`are shown in Table 4. The p-value was less than 0.0001, which was statistically significant and
`smaller than the boundary pre-specified by the Haybittle-Peto rule (0.001). The first composite
`outcome event was CV death in 377 patients and 459 patients in the LCZ696 group and the
`
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`11
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`Reference ID: 3757898
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`

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`enalapril group, respectively. This can be found by subtracting the number of patients where the
`first event was HF hospitalization from the total number of primary endpoint events.
`
`
`
`Table 4 Adjudicated Primary Endpoint Analysis (CV death or HF hospitalization)
`
`
`n: Total number of events included in the analysis; N: Total number of patients included in the analysis.
`(1) EAIR (Exposure-adjusted incidence rate per 100 patient years)= n/T: T(100 years): total up-toevent/
`censoring duration-time summarized over patients in the respective treatment group.
`Source: Table 11-4 of Study Report and confirmed by FDA.
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`Reference ID: 3757898
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`12
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`
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`Figure 2 shows the estimated proportion of subjects remaining in the analysis over time. These are
`Kaplan-Meier type estimates using the reverse Kaplan-Meier method (Altman, D. G., et al. "Review
`of survival analyses published in cancer journals." British Journal of Cancer 72.2 (1995): 511.). There are
`two curves in the figure, but they are nearly identical. This figure is for the time to followup and
`not for the time on double-blind treatment.
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`Figure 2 Proportion of subjects included in primary analysis over time in the study.
`
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`Source: FDA analysis.
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`Reference ID: 3757898
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`13
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`

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`Next, in Figure 3,the Kaplan-Meier estimates for the primary endpoint are shown. This shows the
`
`estimate of the proportion of people with a primary endpoint event.
`
`Figure 3 Kaplan-Meier estimates of event rates over time.
`
`BEST AVAILABLE COPY
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`
`In Figure 4, the complimentary log-log survival plots are shown. These two curves are
`
`approximately straight lines and approximately parallel. This suggests that the time to events can
`
`be approximately modelled by the parametric Weibull survival family and that the propopl’tinal
`
`hazards assumption is not clearly violated.
`
`Reference ID: 3757898
`
`14
`
`

`

`Figure 4 Log{-log(survival)) plot for primary endpoint (Time is shown on the log-scale on the x-
`axis, log(-log(estimated survival)) on the y-axis).
`
`Source: FDA analysis
`
`
`Of the 4 secondary endpoints, only all-cause mortality was statistically significant. The Kaplan-
`Meier curves are shown in Figure 5. The p-value in the figure is a two-sided p-value. This p-value
`is significant because the one-sided p-value was to be compared to 0.8*0.001 to determine
`whether it is significant (the one-sided p-value 0.0005 was smaller than 0.0008).
`
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`Reference ID: 3757898
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`15
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`

`

`
`
`
`Figure 5 Kaplan-Meier estimates of all-cause mortality rates (secondary endpoint).
`
`
`
`
`
`Source: Study report Figure 11-4
`
`
`The dose of valsartan in the LCZ696 combination is equivalent to 160 mg of valsartan
`administered bid. Valsartan is an ARB (angiotensin receptor blocker) approved with a heart
`failure indication in the label on the basis of the Val-HeFT trial. In that trial, valsartan was
`compared to placebo where everyone in the trial was encouraged to be on the background
`therapy as chosen by their physician (93% were on a background of ACE-inhibition therapy). In
`the overall population, there was no mortality effect, but a 13% reduction in heart failure
`morbidity (defined as all-cause mortality, sudden death with resuscitation, hospitalization for
`heart failure, and the need for intravenous inotropic or vasodilatory drugs for at least 4 hours)
`including a 27% reduction in heart failure hospitalization (decrease from 18% to 14%). Here, the
`combination was compared to enalapril 10 mg twice daily. Enalpril is approved for treatment of
`symptomatic
` heart failure. In the trial for symptomatic patient (SOLVD-
`Treatment), the use of enalapril was associated with an 11% reduction in all-cause mortality and
`a 30% reduction in hospitalization for heart failure compared to placebo. In that study, the dose
`of enalapril was titrated up to a maximum of 10 mg twice daily if the patient did not have
`symptomatic hypotension or worsening renal function. The FDA label recommends a
`maintenance dose of 2.5 to 20 mg daily in two divided doses with a maximum recommended
`dose of 40 mg daily (in two divided doses). In the only trial where 40 mg daily dose was studied,
`most patients did not tolerate this dose.
`
`
`
`16
`
`Reference ID: 3757898
`
`(b) (4)
`
`

`

`In the trial, the combination was effective compared to the control on two endpoints: time to first
`heart failure hospitalization or CV death (primary endpoint) and time to all-cause mortality (a
`secondary endpoint). There is no way to know from this trial whether both components in the
`combination contribute to both or either of the claimed effects. From the valsartan label, it may
`be reasonable to infer that the valsartan component does not contribute to the claimed mortality
`effect; valsartan had no effect compared to placebo in the Val-HeFT trial when ACE-inhibitors
`were a background therapy, so it is not likely that valsartan would be more effective than
`enalapril in a head-to-head comparison. Although valsartan alone reduced HF hospitalization
`compared to placebo in the Val-HeFT trial, it is unknown whether both components contribute to
`the combined effect of valsartan/sacubitril compared to enalapril on the composite primary
`endpoint in this trial. More thought should have been taken to design a trial that would show both
`components contribute to the claimed effect. Certainly, a design with three treatment arms
`(valsartan alone, sacubitril alone, and the combination) where everyone was on a background per
`the physician's judgment (as done in Val-HeFT) would have been ethical (or, at least as ethical as
`the trial actually done) and if the combination were superior to both monotherapy arms, would
`have proven that both components contribute to the claimed effects. Another alternative trial
`designs might also be considered is a three arm trial with: i) valsartan with ACE allowed; ii)
`sacubitril with ACE allowed; iii) combination with no ACE allowed. This trial may not be
`ethical, but if the combination was superior to the other two arms, then both components would
`be proven to contribute to the claimed effects. I don't know if it is ethical to have arms ii) or iii)
`despite the fact that arm iii) was an arm actually used in the trial reviewed here.
`
`
`
`1.5 Evaluation of Safety
`
`See clinical review.
`
`
`1.6 Benefit-Risk Assessment (Optional)
`
`See clinical review.
`
`
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`1.7 Gender, Race, Age, and Geographic Region
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`
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`Reference ID: 3757898
`
`17
`
`

`

`The results comparing the high dose to warfarin for these subgroups for the primary endpoint are
`shown in Figure 6. There were no significant interactions.
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`Figure 6 High dose/warfarin results for subgroups defined by gender, race, age, and geographic region.
`
`
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`Source: Figure 11-6 of Study Report.
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`1.8 Other Special/Subgroup Populations
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`NA.
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`Reference ID: 3757898
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`
`
`18
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`

`

`SUMMARY AND CONCLUSIONS
`
`
`1.9 Statistical Issues
`
`Because of limitations in the study design, it is not possible to know whether both components
`contribute to the claimed effects and this should be clearly stated in the label if this combination
`is approved. One-sided testing and p-values were used sometimes in the Study Report
`
`. Two-sided p-values should be used throughout the label. P-values for the
`primary endpoint and the all-cause mortality endpoint were statistically significant and can be
`shown in the label. The components of the primary endpoint can be described in two ways. First
`by splitting the number of patients with the primary endpoint into mutually exclusive subsets, i.e.
`377+537=914 in the LCZ696 arm and 459+658=1117 in the enalapril arm. Second, as shown in
`Table 4 by any time in the trial, whether it was the first event or not. The number of HF
`hospitalization events in both ways of counting will be identical, by definition. But, that is not
`obvious to everyone and both should be reported in the label for clarity.
`
`
`1.10 Collective Evidence
`
`NA
`
`
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`1.11 Conclusions and Recommendations
`
`I don't think the combination should be approved. I don't want to prevent people from being able
`to purchase the components either since the combination was better than enalapril on all-cause
`mortality. I think there is a case for approving the sacubitril component with an indication for
`reducing CV mortality only. The most logical explanation for the observed mortality benefit is
`that sacubitril reduces mortality. It remains unknown whether the entire benefit on HF
`hospitalization could be explained by the valsartan component. We cannot force the company to
`manufacture or market sacubitril monotherapy, but that should be left to the company to decide.
`It is unfair to force people to buy the combination if they want to take only one component when
`there is no evidence that both components contribute to the claimed effect. Valsartan is approved
`for heart failure already and available to the public. People might reasonably choose to buy
`valsartan and sacubitril or they might also choose sacubitril alone or with an ACE or another
`ARB. Approving sacubitril as monotherapy is a less extreme option than approving the
`combination because approving the combination means we believe both components contribute
`to the mortality effect.
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`
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`Reference ID: 3757898
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`19
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`(b) (4)
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`

`

`
`
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`1.12 Labeling Recommendations (as applicable)
`
`Because of limitations in the study design, it is not possible to know whether both components
`contribute to the claimed effects and this should be clearly stated in the label if this combination
`is approved. One-sided testing and p-values were used sometimes in the Study Report
`
`. Two-sided p-values should be used throughout the label. P-values for the
`primary endpoint and the all-cause mortality endpoint were statistically significant and can be
`shown in the label. The components of the primary endpoint can be described in two ways. First
`by splitting the number of patients with the primary endpoint into mutually exclusive subsets, i.e.
`377+537=914 in the LCZ696 arm and 459+658=1117 in the enalapril arm. Second, as shown in
`Table 4 by any time in the trial, whether it was the first event or not. The number of HF
`hospitalization events in both ways of counting will be identical, by definition. But, that is not
`obvious to everyone and both should be reported in the label for clarity.
`
`
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`
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`Reference ID: 3757898
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`20
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`(b) (4)
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`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN P LAWRENCE
`05/18/2015
`
`KOOROS MAHJOOB
`05/20/2015
`
`Reference ID: 3757898
`
`

`

`
`
`US. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Oflice of Biostatistics
`
`STATISTICAL REVIEW AND EVALUATION
`
`CARCINOGENICITY STUDIES
`
`NDA/BLA #:
`
`Drug Name:
`
`Indication(s):
`
`NDA 207620/5—0001 (IND 104628)
`
`LCZ696 (sacubitr‘il/valsartan) Tablets (AHU377)
`
`Treatment of heart failure (NYHA class II—IV)
`
`(m4)
`
`Applicant:
`
`Novartis Pharmaceuticals Canada Inc.
`
`385 boul. Bouchard, Dorval, Quebec, H95 1A9, Canada
`
`Laboratory
`
`(hm)
`
`Date(s):
`
`Received 10/29/2014
`
`Documents Reviewed:
`
`Study pcs—r0870373 (rats) and Study pcs-r0870374 (mice) reports
`and electronic datasets submitted with the electronic submission on
`
`Novartis Pharmaceuticals Corporation (Novartis)
`
`Review Priority:
`
`Priority Review
`
`10/29/2014 (via 5-0001).
`
`Biometrics Division:
`
`Division of Biometrics VI
`
`Statistical Reviewer:
`
`Feng Zhou, M.S.
`
`Concurring Reviewers:
`
`Mohammad Atiar Rahman, Ph. D.
`
`Team Leader:
`
`Karl Lin, Ph.D.
`
`Medical Division:
`
`Division of Cardio—Renal Products
`
`Pharmacology Team:
`
`William Link, Ph.D; Al DeFelice, Ph.D
`
`Project Manager:
`
`Alexis Childers, Senior Regulatory health Project hIanager
`
`Keywords:
`
`Carcinogenicity, Dose response
`
`Reference ID: 3757737
`
`

`

`NDA 207620 ● AHU377 ● Novartis ● Carcinogenicity Study
`
` Page 2 of 21
`
`Table of Contents
`
`1
`
`2
`
`SUMMARY........................................................................................................................................... 3
`
`BACKGROUND................................................................................................................................... 3
`
`3
`
`RAT STUDY ......................................................................................................................................... 4
`3.1
`SPONSOR’S ANALYSES .................................................................................................................... 4
`3.1.1
`Survival Analysis .................................................................................................................... 4
`3.1.2
`Tumor Data Analysis.............................................................................................................. 5
`3.2
`REVIEWER’S ANALYSES.................................................................................................................. 6
`3.2.1
`Survival Analysis .................................................................................................................... 6
`3.2.2
`Tumor Data Analysis.............................................................................................................. 7
`4 MOUSE STUDY................................................................................................................................... 8
`4.1
`SPONSOR’S ANALYSES .................................................................................................................... 9
`4.1.1
`Survival Analysis .................................................................................................................... 9
`4.1.2
`Tumor Data Analysis.............................................................................................................. 9
`4.2
`REVIEWER’S ANALYSES.................................................................................................................10
`4.2.1
`Survival Analysis ...................................................................................................................10
`4.2.2
`Tumor Data Analysis.............................................................................................................10
`CONCLUSION....................................................................................................................................10
`
`5
`
`6
`
`7
`
`APPENDIX ..........................................................................................................................................12
`Table 1A: Intercurrent Mortality – Male Rats ................................................................................................12
`Table 1B: Intercurrent Mortality - Female Rats ...............................................................................................12
`Table 2A: Intercurrent Mortality - Male Mice.................................................................................................12
`Table 2B: Intercurrent Mortality – Female Mice ..............................................................................................12
`Table 3A: Intercurrent Mortality Comparison – Male Rats ...............................................................................13
`Table 3B: Intercurrent Mortality Comparison – Female Rats..............................................................................13
`Table 4A: Intercurrent Mortality Comparison – Male Mice...............................................................................13
`Table 4B: Intercurrent Mortality Comparison – Female Mice..............................................................................13
`Table 5A: Tumor Rates and P-Values for Dose Response Relationship and Pairwise Comparisons – Male Rats..........14
`Table 5B: Tumor Rates and P-Values for Dose Response Relationship and Pairwise Comparisons – Female Rats........15
`Table 6A: Tumor Rates and P-Values for Dose Response Relationship and Pairwise Comparisons – Male Mice..........16
`Table 6B: Tumor Rates and P-Values for Dose Response Relationship and Pairwise Comparisons – Female Mice........18
`Figure 1A: Kaplan-Meier Survival Functions for Male Rats...............................................................................19
`Figure 1B: Kaplan-Meier Survival Functions for Female Rats.............................................................................20
`Figure 2A: Kaplan-Meier Survival Functions for Male Mice ..............................................................................20
`Figure 2B: Kaplan-Meier Survival Functions for Female Mice.............................................................................21
`REFERENCES ....................................................................................................................................21
`
`File Name: NDA207620Carcin.doc
`
`Reference ID: 3757737
`
`

`

`NDA 207620 ● AHU377 ● Novartis ● Carcinogenicity Study
`
` Page 3 of 21
`
`1
`
`Summary
`
`This review evaluates statistically the tumori