CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`206276Orig1s000
`
`STATISTICAL REVIEW(S)
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
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`S T A T I S T I C A L R E V I E W A N D E VA L U A T I O N
`CLINICAL STUDIES
`
`NDA/BLA #:
`Supplement #:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`
`NDA 206276
`0000
`Olopatadine Hydrochloride Ophthalmic Solution 0.77%
`Treatment of Itching Associated with Allergic Conjunctivitis
`Alcon
`Submitted: 07/30/2014
`PDUFA date: 01/30/2015
`Review Priority:
`Priority
`
`
`Biometrics Division:
`DBIV
`Statistical Reviewer:
`Yunfan Deng, Ph.D.
`Concurring Reviewers: Yan Wang, Ph.D.
`
`
`Medical Division:
`Division of Transplant and Ophthalmology Products
`Clinical Team:
`Wiley Chambers, MD, Deputy Division Director
`William Boyd, MD, Team Leader
`Project Manager:
`Lois Almoza
`
`
`Keywords: itching, redness, allergic conjunctivitis, superiority
`
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`Reference ID: 3681856
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`

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`3 
`
`Table of Contents
`1  EXECUTIVE SUMMARY ................................................................................................................................. 4 
`2 
`INTRODUCTION ............................................................................................................................................... 7 
`2.1 
`OVERVIEW ...................................................................................................................................................... 7 
`2.1.1 
`Drug Class and Indication ..................................................................................................................... 7 
`2.1.2 
`History of Drug Development ................................................................................................................ 7 
`2.1.3 
`Studies Reviewed ................................................................................................................................... 8 
`2.2 
`DATA SOURCES ............................................................................................................................................ 10 
`STATISTICAL EVALUATION ...................................................................................................................... 10 
`3.1 
`DATA AND ANALYSIS QUALITY ................................................................................................................... 10 
`3.2 
`EVALUATION OF EFFICACY .......................................................................................................................... 10 
`3.2.1 
`Study Design and Endpoints ................................................................................................................ 10 
`3.2.2 
`Statistical Methodologies ..................................................................................................................... 16 
`3.2.3 
`Patient Disposition, Demographic and Baseline Characteristics........................................................ 19 
`3.2.4 
`Results and Conclusions ...................................................................................................................... 22 
`3.2.4.1  Ocular Itching .................................................................................................................................................. 22 
`3.2.4.2 
`....................................................................... 29 
`EVALUATION OF SAFETY .............................................................................................................................. 32 
`3.3 
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ............................................................................. 34 
`4.1 
`AGE, GENDER, AND RACE ............................................................................................................................ 34 
`SUMMARY AND CONCLUSIONS ................................................................................................................ 39 
`5.1 
`STATISTICAL ISSUES ..................................................................................................................................... 39 
`5.2 
`COLLECTIVE EVIDENCE ................................................................................................................................ 42 
`5.3 
`CONCLUSIONS AND RECOMMENDATIONS ..................................................................................................... 44 
`5.4 
`LABELING RECOMMENDATIONS ................................................................................................................... 44 
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`4 
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`5 
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`Reference ID: 3681856
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`2
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`(b) (4)
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`LIST OF TABLES
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`Table 1: Analysis of Ocular Itching Scores for Studies C-10-126 and C-12-053 (ITT) ................................................ 6 
`Table 2: Key Information for Studies C-10-126 and C-12-053 ..................................................................................... 9 
`Table 3: Side by Side Comparison of the Design Elements of the C-10-126 and C-12-053 ....................................... 10 
`Table 4: Study C-10-126 Schedule of Assessment ...................................................................................................... 12 
`Table 5: Study C-12-053 Schedule of Assessment ...................................................................................................... 13 
`Table 6: Subjects’ Disposition for Studies C-10-126 and C-12-053 ........................................................................... 20 
`Table 7: Analysis Population for Studies C-10-126 and C-12-053 ............................................................................. 21 
`Table 8: Study C-10-126 Demographic and Baseline Characteristics (ITT) ............................................................... 21 
`Table 9: Study C-12-053 Demographic and Baseline Characteristics (ITT) ............................................................... 22 
`Table 10: Study C-10-126 Analysis of Ocular Itching Score (ITT) ............................................................................ 24 
`Table 11: Study C-12-053 Analysis of Ocular Itching Score (ITT) ............................................................................ 25 
`Table 12: Descriptive Statistics for Ocular Itching for Studies C-10-126 (ITT Observed) ......................................... 28 
`Table 13: Descriptive Statistics for Ocular Itching for Studies C-12-053 (ITT Observed) ......................................... 28 
`) ................................................................. 30 
`Table 14:
`) ................................................................. 30 
`Table 15:
`) ................................ 31 
`Table 16:
` ................................ 31 
`Table 17:
`Table 18: Summary of Treatment-Emergent Adverse Events of Studies C-10-126 (Safety Analysis Set) ................. 32 
`Table 19: Summary of Treatment-Emergent Adverse Events of Studies C-12-053 (Safety Analysis Set) ................. 33 
`Table 20: Summary of Treatment-Emergent Adverse Events of Studies C-10-128 (Safety Analysis Set) ................. 34 
`Table 21: Study C-10-126 Analysis of Ocular Itching Score (ITT) ............................................................................ 43 
`Table 22: Study C-12-053 Analysis of Ocular Itching Score (ITT) ............................................................................ 44 
`
`
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`LIST OF FIGURES
`
`Figure 1: Study C-10-126 Analysis of Ocular Itching Score (Olopatadine 0.77% vs. Vehicle, ITT) .......................... 25 
`Figure 2: Study C-10-126 Analysis of Ocular Itching Score (Olopatadine 0.77% vs. PATADAY, ITT) ................... 26 
`Figure 3: Study C-12-053 Analysis of Ocular Itching Score (Olopatadine 0.77% vs. Vehicle, ITT) .......................... 26 
`Figure 4: Study C-12-053 Analysis of Ocular Itching Score (Olopatadine 0.77% vs. PATANOL, ITT) ................... 27 
`Figure 5: Study C-12-053 Analysis of Ocular Itching Score (Olopatadine 0.77% vs. PATADAY, ITT) ................... 27 
`Figure 6: Forest Plots of Subgroup Analyses for Studies C-10-126 (Olopatadine 0.77% vs. Vehicle at Onset-of-
`action and 16-hour Duration) ....................................................................................................................................... 35 
`Figure 7: Forest Plots of Subgroup Analyses for Studies C-12-053 (Olopatadine 0.77% vs. Vehicle at Onset-of-
`action and 24-hour Duration) ....................................................................................................................................... 36 
`Figure 8: Forest Plots of Subgroup Analyses for Studies C-12-053 (Olopatadine 0.77% vs. PANANOL and
`Olopatadine 0.77% vs. PANADAY at 24-hour Duration) ........................................................................................... 38 
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`Reference ID: 3681856
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`3
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`1 EXECUTIVE SUMMARY
`
`The applicant (Alcon) seeks approval of Olopatadine Hydrochloride Ophthalmic Solution, 0.77%
`(Olopatadine HCI Solution, 0.77%, also referred to as Olopatadine 0.77% throughout this
`review) for the treatment of ocular itching associated with allergic conjunctivitis. In 1996,
`Olopatadine HCI Solution 0.1% (PATANOL®) was approved for twice daily dosing in the U.S
`for the treatment of the signs and symptoms of allergic conjunctivitis. A higher concentration
`formulation, Olopatadine HCI Solution 0.2% (PATADAY®) was also approved for dosing once
`per day in the U.S. for the treatment of ocular itching (but not redness) associated with allergic
`conjunctivitis since 2004. This submission is for a new formulation of olopatadine having a
`0.77% concentration of the active ingredient, olopatadine hydrochloride for dosing once daily.
`By increasing the concentration of olopatadine hydrochloride to 0.77%, the applicant intended to
`demonstrate that the new formulation would extend the benefit offered by Olopatadine, 0.2%
`(PATADAY®) while maintaining its safety. In order to support the approval of this new
`formulation, the applicant submitted two pivotal efficacy studies: Study C-10-126, and Study C-
`12-053.
`
`Studies C-10-126 and C-12-053 were similarly designed phase 3 studies. Both were multicenter,
`randomized, double-masked, active and vehicle controlled, parallel-group studies and used the
`conjunctival allergen challenge (CAC) model to evaluate the safety and efficacy of Olopatadine
`0.77% versus Vehicle or active comparators in the treatment of ocular itching associated with
`allergic conjunctivitis. Both studies were conducted in patients at least 18 years of age with a
`history of seasonal and/or perennial allergic conjunctivitis for at least 1 year prior to study entry
`and a positive allergic skin test within 24 months prior to study entry. Study C-10-126 had
`PATADAY and Vehicle as comparators. Study C-12-053 had PATADAY, PATANOL and
`Vehicle as comparators; however, PATANOL was dosed only once (instead of the approved
`twice-a-day regimen) at Visit 3A (the day before the 24-hour duration-of-action efficacy
`evaluation) and Visit 4.
`
`The primary efficacy variable for both studies was patient-evaluated ocular itching severity
`scores (assessed using a 0-4 scale with 0.5 unit increments: 0 = none, 4 = incapacitating itch). In
`Study C-10-126, the primary efficacy endpoints were patient-evaluated ocular itching at 3, 5, and
`7 minutes post-CAC at both Visits 4B (16-hour duration-of-action) and 5 (onset-of-action). In
`Study C-12-053, the primary efficacy endpoints were patient-evaluated ocular itching at 3, 5, and
`7 minutes post-CAC at both Visit 3B (24-hour duration-of-action) and Visit 4 (onset-of-action).
`
`The primary efficacy objectives for Study C-10-126 were to demonstrate the superiority of
`Olopatadine 0.77% compared to Vehicle for the treatment of ocular itching associated with
`allergic conjunctivitis at:
` Onset-of-action
` 16-hour duration-of-action
`
` secondary efficacy objective in this study was to
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`Reference ID: 3681856
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`(b) (4)
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`The primary efficacy objectives for Study C-12-053 were to demonstrate the superiority of
`Olopatadine 0.77% for the treatment of ocular itching compared to:
` Vehicle at the onset-of-action;
` Vehicle at 24-hour duration-of-action;
`
` PATADAY at 24-hour duration-of-action.
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`
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`Both studies used the intention-to-treat (ITT) set in the primary efficacy analysis, which included
`all randomized patients who received study medication. Patients were included in the ITT
`analysis set according to randomized treatment.
`
`In Study C-10-126, a total of 202 patients from three centers in the U.S. were randomized to the
`three treatment groups respectively: 66 in Olopatadine HCl Solution 0.77% group, 68 in
`PATADAY group, and 68 in Vehicle group. Sixteen patients discontinued leaving 186 (92.1%)
`patients completing the study.
`
`In Study C-12-053, a total of 345 patients from six centers in the U.S. were randomized to the
`four treatment groups respectively: 98 in Olopatadine HCl Solution 0.77% group, 99 in
`PATADAY group, 99 in PATNOL group, and 49 in Vehicle group. A total of 325 (94.2%)
`patients completed the study.
`
`Based on the efficacy results (Table 1):
`
`In both Study C-10-126 and Study C-12-053, Olopatadine 0.77% was superior to Vehicle
`for treating ocular itching associated with allergic conjunctivitis at onset-of-action, and
`24-hour duration-of-action.
`In Study C-10-126, at 24-hour duration-of-action, Olopatadine 0.77% was superior to
`PATADAY for the treatment of ocular itching associated with allergic conjunctivitis. In
`Study C-12-053, Olopatadine 0.77% was superior to PATADAY for ocular itching
`associated with allergic conjunctivitis at 24-hour duration-of-action at 2 (3 and 5 minutes)
`out of 3 post CAC time points. The point estimate for the treatment difference at 7
`minutes post-CAC was in favor of Olopatadine 0.77% but did not demonstrate statistical
`significance.
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`Although in Study C-12-053,
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`, the efficacy results were consistent
`between Study C-12-053 and Study C-10-126 and all in favor of Olopatadine 0.77%. In addition,
`in both studies, comparing with Vehicle, the ocular itching treatment effects of Olopatadine
`0.77% were highly significant (p-value<0.0001) at all three time points in the efficacy evaluation
`visits. Therefore, this reviewer concluded that there is enough evidence to support the efficacy of
`Olopatadine 0.77% for the treatment of ocular itching associated with allergic conjunctivitis and
`recommended its approval for this indication.
`
`The approved regimen for PATANOL was twice daily; however, in Study C-12-053, PATANOL
`was dosed only once (instead of the approved twice-a-day regimen) at each study visit day.
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`Reference ID: 3681856
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`
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`Vehicle
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`C-10-126
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`
` Onset Average
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` 3 mins
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` 5 mins
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` 7 mins
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` 16h Average
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` 3 mins
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` 5 mins
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` 7 mins
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` 24h Average
`
`Mean
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`Mean
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`0.46
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`0.36
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`0.53
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`0.48
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`0.75
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`0.70
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`0.79
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`0.75
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`1.04
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`0.54
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`0.39
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`0.61
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`0.61
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`0.96
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`0.87
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`1.04
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`0.98
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`1.48
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`
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`Difference
`(95% CI)
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`
`
`
`
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`Mean
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`1.98
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`1.90
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`2.06
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`1.97
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`2.20
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`2.20
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`2.27
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`2.13
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`2.55
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`Table 1: Analysis of Ocular Itching Scores* for Studies C-10-126 and C-12-053 (ITT)
`PATANOL Dosed Once¹
`
`Time
`Olopatadine,
`PATADAY
`(Olopatadine, 0.2%)
`Point
`0.77%
`(Olopatadine, 0.1%)
`(N = 66)
`(N = 68)
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`Mean
`Difference
`(95% CI)
`-0.08
`(-0.37, 0.21)
`-0.02
`(-0.31, 0.26)
`-0.08
`(-0.39, 0.22)
`-0.13
`(-0.44, 0.17)
`-0.21
`(-0.49, 0.07)
`-0.17
`(-0.44, 0.11)
`-0.24
`(-0.55, 0.07)
`-0.23
`(-0.54, 0.08)
`-0.44
`(-0.72, -0.16)
`-0.48
`(-0.76, -0.20)
`-0.42
`(-0.72, -0.12)
`-0.41
`(-0.72, -0.10)
`
`
`(N = 68)
`Difference
`(95% CI)
`-1.51
`(-1.81, -1.23)
`-1.54
`(-1.82, -1.25)
`-1.53
`(-1.84, -1.22)
`-1.49
`(-1.80, -1.18)
`-1.45
`(-1.73, -1.17)
`-1.50
`(-1.77, -1.23)
`-1.48
`(-1.79, -1.16)
`-1.38
`(-1.69, -1.07)
`-1.51
`(-1.79, -1.24)
`-1.61
`(-1.88, -1.33)
`-1.51
`(-1.81, -1.21)
`-1.41
`(-1.72, -1.11)
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`2.54
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`2.62
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`2.50
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`(N = 49)
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`1.91
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`1.91
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`1.99
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`1.82
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`2.27
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`2.30
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`2.37
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`(N = 99)
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`0.56
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`0.47
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`0.61
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`0.61
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`1.40
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`1.33
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`1.48
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`
`
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`
`
`
` 3 mins
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` 5 mins
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` 7 mins
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`0.93
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`1.10
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`1.09
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`1.41
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`1.52
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`1.50
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`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`C-12-053
` Onset
`
`
` Average
`
`(N = 98)
`0.52
`
`
`
`
`
`
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
` 24h Average
`
`
`
`
`
`
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
`0.38
`
`0.53
`
`0.65
`
`1.16
`
`1.01
`
`1.22
`
`(N = 99)
`-1.39
`-0.05
`(-1.62, -1.16)
`(-0.24, 0.14)
`-1.53
`-0.09
`(-1.76, -1.30)
`(-0.28, 0.09)
`-1.46
`-0.08
`(-1.71, -1.22)
`(-0.29, 0.12)
`-1.17
`0.04
`(-1.45, -0.90)
`(-0.18, 0.26)
`-1.11
`-0.24
`(-1.40, -0.82)
`(-0.48, -0.00)
`-1.29
`-0.31
`(-1.60, -0.97)
`(-0.57, -0.06)
`-1.15
`-0.26
`(-1.46, -0.84)
`(-0.51, -0.01)
`-0.89
`-0.16
`2.14
`1.41
`1.25
`(-1.22, -0.57)
`(-0.42, 0.11)
`* Mean score estimates, treatment differences and corresponding 95% confidence intervals (CIs) were based on analysis of repeated measures
`using a mixed model with itching scores from each eye (left or right) as the dependent variable and fixed effect terms for investigator, treatment,
`eye-type (left or right), time, and treatment-by-time interaction.
`¹ PATANOL was dosed only once (instead of the approved twice-a-day regimen) at Visit 3A (for 24-hour duration-of-action) and Visit 4 (onset-
`of-action).
`Source: Tables 2.7.3.2-2, 2.7.3.2-3, 2.7.3.2-7, 2.7.3.2-10, and 2.7.3.2-11 of Summary of Clinical Efficacy.
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`Reference ID: 3681856
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`(b) (4)
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`2 INTRODUCTION
`
`
`2.1 Overview
`
`2.1.1 Drug Class and Indication
`
`Olopatadine is an anti-allergic agent that exerts its effects through multiple different mechanisms
`of action, including selective antagonism of histamine H1 receptors, mast cell stabilization, and
`prevention of histamine induced inflammatory cytokine production by human conjunctival
`epithelial cells. Olopatadine is used in several prescription products around the world as a topical
`ocular eye drop, a topical nasal spray and as an oral medication.
`
`Allergic conjunctivitis is inflammation of the conjunctiva (the membrane covering the white part
`of the eye) due to allergy. Seasonal allergic conjunctivitis (SAC) and perennial allergic
`conjunctivitis (PAC) are the most common forms of allergic conjunctivitis and are caused by an
`IgE-mediated reaction to allergens such as grass, weed and tree pollens, dust mites, animal
`dander and molds. Signs and symptoms of allergic conjunctivitis include ocular itching, ocular
`redness, tearing, eyelid swelling and chemosis. The symptoms are due to release of histamine
`and other active substances by mast cells, which stimulate dilation of blood vessels, irritate nerve
`endings, and increase secretion of tears. Treatment of allergic conjunctivitis is by avoiding the
`allergen (e.g., avoiding grass in bloom during "hay fever season") and treatment with
`antihistamines, either topical (in the form of eye drops), or systemic (in the form of tablets).
`
`
`2.1.2 History of Drug Development
`
`Olopatadine is used in several prescription products around the world as a topical ocular eye
`drop, a topical nasal spray and as an oral medication. In 1996, PATANOL® (Olopatadine
`Hydrochloride Ophthalmic Solution 0.1%) was approved for twice daily dosing in the U.S for
`the treatment of the signs and symptoms of allergic conjunctivitis (both itching and redness). A
`higher concentration formulation, PATADAY® (Olopatadine Hydrochloride Ophthalmic
`Solution 0.2%) is also approved for dosing once per day in the U.S. for the treatment of ocular
`itching (but not redness) associated with allergic conjunctivitis since 2004.
`
`According to the applicant, as the aqueous solubility of olopatadine at neutral pH is a limiting
`factor in formulating olopatadine-containing ophthalmic solutions, a new formulation was
`developed to overcome this limitation. By increasing the concentration of olopatadine
`hydrochloride to 0.77%, the applicant wanted to demonstrate that the new formulation would
`extend the benefit offered by Olopatadine, 0.2% (PATADAY®) while maintaining its safety.
`
`The Phase 3 study protocols and analysis plans for the test product were submitted and reviewed
`under IND 60991.
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`Reference ID: 3681856
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`7
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`

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`During the pre-NDA meeting between the Agency and the applicant on 08/26/2013, regarding
`the applicant’s question of whether the Agency agree that inclusion of the comparative efficacy
`results in the package insert, the Agency’s response was:
`“The inclusion of two active control safety and efficacy studies which compare
`Olopatadine 0.77% and Pataday, as long as each study shows superiority over the active
`comparator(s) with appropriate multiplicity adjustment to control the overall Type I
`error rate, may allow comparative efficacy labeling claims.”
`
`
`In addition, regarding the on-going Study C-12-053 at that time, the statistical reviewer had the
`following review comment:
`“According to your statistical analysis plan (SAP), the success criterion for this study
`is that all co-primary hypotheses must be rejected at the 5% level; otherwise, the
`study would be considered as failure. However, if you also intent to claim the study to
`be successful when the test product is shown to be superior to the vehicle but not
`superior to the active controls, the protocol needs to address multiplicity issue due to
`having multiple pathways of claiming study success. To address this issue, we
`recommend you consider to use the Bonferroni correction or the following
`gatekeeping sequential testing approach:
`o Step 1: first test the treatment difference in the itching score between
`Olopatadine 0.77% and the vehicle at the onset of action using a significant
`level of 5% (2-sided). If the test is statistically significant, proceed to Step 2;
`otherwise no testing will be performed for the remaining three hypotheses.
`o Step 2: test the treatment difference in the itching score between Olopatadine
`0.77% and the vehicle at 24 hours duration of action using a significant level
`of 5% (2-sided). If the test is statistically significant, proceed to Step 3;
`otherwise no testing will be performed for the remaining two hypotheses.
`o Step 3: test the treatment difference in the itching score between Olopatadine
`0.77% and PATANOL at 24 hours duration of action using a significant level
`of 5% (2-sided). If the test is statistically significant, proceed to Step 4;
`otherwise no testing will be performed for the remaining hypothesis.
`o Step 4: test the treatment difference in the itching score between Olopatadine
`0.77% and PATADAY at 24 hours duration of action using a significant level
`of 5% (2-sided).”
`
`
`However, the applicant did not follow our recommendation and still proceeded with the success
`criterion for Study C-12-053 being that all four primary hypotheses must be rejected at the 5%
`level simultaneously.
`
`
`2.1.3 Studies Reviewed
`
`Olopatadine 0.77% clinical development plan included five clinical studies: two Phase 1 studies
`(Study C-10-127 and C-11-036), two pivotal Phase 3 safety and efficacy studies (Studies C-10-
`126 and C-12-053), and a six-week safety study (C-12-028).
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`Reference ID: 3681856
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`Study C-10-127 was a Phase 1, single center, randomized, double-masked, vehicle and active
`controlled, three-way crossover study conducted in healthy subjects 18 years of age or older to
`evaluate the comfort and safety of Olopatadine HCl Solution, 0.77%. This study is not included
`in the statistical review for this NDA.
`
`C-11-036 was a single center, randomized, double-masked, vehicle controlled, parallel-group
`safety and PK study conducted in healthy, adult, Japanese (at least 50%) and non-Japanese
`subjects. This study is not included in the statistical review for this NDA either.
`
`Study C-12-028, was a Phase 3, six week, multicenter, randomized, double-masked, vehicle-
`controlled, parallel-group study evaluating the safety of Olopatadine HCl Solution, 0.77%
`compared to Vehicle when administered once daily in both eyes for 6 weeks. Healthy subjects at
`least 2 years of age or older with asymptomatic eyes were randomized in a 2:1 ratio to
`Olopatadine HCl Solution, 0.77% or Vehicle respectively. Subjects younger than 6 years of age
`were randomized from 1 randomization schedule; subjects 6 years of age or older were
`randomized from another randomization schedule. All randomized subjects received 1 drop of
`either Olopatadine HCl Solution, 0.77% or Vehicle once daily in both eyes for 6 weeks. The
`safety data from this study is included in the statistical review for this NDA.
`
`This statistical review focused on the two pivotal Phase 3 safety and efficacy studies: Studies C-
`10-126 and C-12-053. Key information of these two studies and the safety study C-12-028 is
`presented in the following table.
`
`Table 2: Key Information for Studies C-10-126 and C-12-053
`
`Phase and
`Treatment
`Follow-up
`Design
`Period
`Period
`One drop per
`n/a
`Phase 3
`eye at each
`randomized
`study visit (Visit
`double
`masked active
`3A [Day 0], Visit
`4A [Day 14], and
`and vehicle
`Visit 5 [Day 21])
`control
`
`Study Population
`
`Adult patients (≥ 18
`years of age) with
`seasonal or perennial
`allergic conjunctivitis
`
`Adult patients (≥ 18
`years of age) with
`seasonal or perennial
`allergic conjunctivitis
`
`Safety relative to
`vehicle
`
`9
`
`C-10-126
`
`C-12-053
`
`n/a
`
`Phase 3
`randomized
`double
`masked active
`and vehicle
`control
`
`One drop per
`eye at each
`study visit
`(Visit 3A [Day
`0], and Visit 4
`[Day 14])
`
`C-12-028
`(6-Week
`Safety)
`
`
`Randomized
`Double
`Masked
`
`6 weeks on test
`or control
`article
`
`
`
`Reference ID: 3681856
`
` # of Subjects
`per Arm
`Vehicle – 68
`subjects
`Olopatadine
`0.77% – 66
`subjects
`Olopatadine
`0.2% – 68
`subjects
`Vehicle – 49
`Olopatadine
`0.77% – 98
`Olopatadine
`0.2%
`(PATADAY) –
`99
`Olopatadine
`0.1%
`(PATANOL) –
`99
`Vehicle – 169
`subjects
`Olopatadine
`
`

`

`0.77% – 330
`subjects
`
`Parallel
`Group
`Source: Table 2.7.3.1-1 of Summary of Clinical Efficacy.
`
`
`2.2 Data Sources
`
`The data sources for this review mainly came from the applicant’s study reports for studies C-10-
`126, and C-12-053. The study reports are available at:
`\\Cdsesub1\evsprod\NDA206276\0000\m5\53-clin-stud-rep\535-rep-effic-safety-stud\ocular-
`itching\5351-stud-rep-contr.
`
`The applicant submitted SAS datasets and program codes that were used to generate the study
`reports electronically; they are available at: \\Cdsesub1\evsprod\NDA206276\0000\m5\datasets.
`
`
` 3
`
` STATISTICAL EVALUATION
`
`
`3.1 Data and Analysis Quality
`
`Overall, the submitted data were in good quality with definition of each variable. Results of the
`primary and key secondary efficacy endpoints can be reproduced by the statistical reviewer with
`minor data manipulation. The statistical analysis plans (SAPs) for the two pivotal studies were
`submitted.
`
`
`3.2 Evaluation of Efficacy
`
`3.2.1 Study Design and Endpoints
`
`Studies C-10-126 and C-12-053 were two similarly designed phase 3 pivotal studies. Both
`studies were multicenter, randomized, double-masked, both active and vehicle controlled,
`parallel-group studies and used the conjunctival allergen challenge (CAC) model. The objective
`of these studies was to demonstrate the efficacy and safety of Olopatadine HCl Solution, 0.77%
`in patients with seasonal or perennial allergic conjunctivitis. A side by side comparison of the
`design elements of studies C-10-126 and C-12-053 is presented in the following table.
`
`Table 3: Side by Side Comparison of the Design Elements of Studies C-10-126 and C-12-053
`Study
`C-10-126
`C-12-053
`Design
`Phase 3, multi-Center, randomized, double-
`Phase 3, multi-Center, randomized,
`masked, parallel-group, vehicle and active
`double-masked, parallel-group, vehicle and
`controlled, efficacy and safety study
`active controlled, efficacy and safety study
`Allergic conjunctivitis
`Allergic conjunctivitis
`Vehicle
`Vehicle
`Olopatadine 0.77%
`Olopatadine 0.77%
`Olopatadine 0.2% (PATADAY)
`Olopatadine 0.2% (PATADAY)
`
`Olopatadine 0.1% (PATANOL)
`
`Indication
`Treatment Arms
`
`
`
`Reference ID: 3681856
`
`10
`
`

`

`Treatment
`Regimen
`Randomization
`No of Sites
`No of Patients
`
`1 dose (1 drop per eye) at each of Visits 3A,
`4A and 5
`1:1:1
`3 sites in US
`Vehicle – 68 subjects
`Olopatadine 0.77% – 66 subjects
`Olopatadine 0.2% – 68 subjects
`
`Study Population
`
`Visits
`
`1 dose (1 drop per eye) at each of Visits 3A
`and 4
`1:2:2:2
`6 sites in US
`Vehicle – 49
`Olopatadine 0.77% – 98
`Olopatadine 0.2% (PATADAY) – 99
`Olopatadine 0.1% (PATANOL) – 99
`Adult patients with history of allergic
`conjunctivitis
`5 Visits:
`Visit 1 (Day -21) – Screening
`Visit 2 (Day -14) – Confirmation CAC
`Visit 3A (Day 0) – Randomization
`Visit 3B (Day 1) – 24-hour duration CAC
`visit
`Visit 4 (Day 14) – Onset-of-action CAC
`visit
`
`Adult patients with history of allergic
`conjunctivitis
`7 Visits:
`Visit 1 (Day -21) – Screening
`Visit 2 (Day -14) – Confirmation CAC
`Visit 3A (Day 0) – Randomization
`Visit 3B (Day 1) – 24-hour duration CAC
`visit
`Visit 4A (Day 14)
`Visit 4B (Day 14 + 16 Hours) – 16-hour
`duration CAC visit
`Visit 5 (Day 21) – Onset-of-action CAC visit
`Source: Statistical Reviewer’s Summary.
`
`Both studies were conducted in patients at least 18 years of age with a history of seasonal and/or
`perennial allergic conjunctivitis for at least 1 year prior to study entry and a positive allergic skin
`test within 24 months prior to study entry. C-10-126 had PATADAY (Olopatadine HCI, 0.2%)
`and Vehicle as comparators, C-12-053 had PATADAY, PATANOL (Olopatadine HCI, 0.1%)
`and Vehicle as comparators. The randomization ratio in C-10-126 was 1:1:1 (Oloptadine HCl
`Solution, 0.77%: PATADAY: Vehicle) and in C-12-053, it was 2:2:2:1 (Oloptadine HCl
`Solution, 0.77%: PATADAY: PATANOL: Vehicle). Patients were evaluated for safety and
`efficacy during the visits conducted at
` Visit 1 (Day -21 ± 2 days; Screening – Titration CAC)
` Visit 2 (Day -14 ± 3 days; Confirmation CAC)
` Visit 3A (Day 0; Randomization & Test Article [TA] instillation)
` Visit 3B (Day 1; CAC 24 hours post TA instillation);
` For Study C-12-053:
`o Visit 4 (Day 14 ± 2 days; CAC 27 minutes post TA instillation)
` For Study C-10-126:
`o Visit 4A (Day 14 ± 2 days; TA instillation)
`o Visit 4B (on the Day after Visit 4A; CAC 16 hours post TA instillation)
`o and Visit 5 (Day 21 ± 3 days; CAC 27 minutes post TA instillation).
`
`
`In the DOSAGE and ADMINISTRATION part of the approved label for PATANOL dated April
`17th, 2003, it stated “The recommended dose is one drop in each affected eye two times per day
`at an interval of 6 to 8 hours.”
`
`Based on the study protocol for Study C-12-053, in Section 9.2 Usage (Page 405 of Study C-12-
`053 Study Report), the applicant stated “Patients will receive 1 dose of the assigned
`investigational product (Olopatadine HCl Solution, 0.77%, Vehicle, PATADAY or PATANOL) at
`Visits 3A and 4. A dose is defined as 1 drop per eye of study product instilled topically.” And in
`
`11
`
`Reference ID: 3681856
`
`

`

`the study report body, the applicant also mentioned at Section 9.4.5 SELECTION AND TIMING
`OF DOSE FOR EACH PATIENT (Page 66 of Study C-12-053 Study Report) that
`“Randomization occurred at Visit 3A via IRT. Patients received 1 dose of the assigned
`investigational product at Visits 3A and 4. A dose was defined as 1 drop per eye of study product
`instilled topically.”
`
`Therefore, this statistical reviewer concluded that the approved regimen for PATANOL was
`twice daily; however, in Study C-12-053 that comparing Olopatadine 0.77% with PATANOL at
`24-hour duration-of-action, PATANOL was dosed for only once (instead of the approved twice-
`a-day regimen) in the previous day visit (Visit 3A).
`
`Table 4: Study C-10-126 Schedule of Assessment
`
`1 If one has not been done within 24 months prior to Visit 1
`2 Females of childbearing potential only
`3 Prior to CAC and/or treatment instillation at all visits; also after all post-CAC assessments at Visit 5/Exit
`4 After all post-CAC assessments
`5 Pre-CAC and 3, 5, 7, 15 and 20 minutes post-CAC (window of +/- 1 min. for each time point)
`6 24 hours (+ 1hr) after treatment instillation
`7 16 hours (+ 1hr) after treatment instillation
`8 27 minutes (+/- 1min) after treatment instillation
`So