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`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
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`
`
`APPLICATION NUMBER:
`22-228
`
`APPLICA TI0N NUMBER:
`
`STATISTICAL REVIEW(S)
`STATISTICAL REVIEW! S}
`
`
`22-228
`
`

`

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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
`
`S t a t i s t i c a l R e v i e w a n d E v a l u a t i o n
`Clinical Studies
`
`NDA/Serial Number:
`
` associated with allergic
`
`Drug Name:
`
`Indication(s):
`
`Applicant:
`Date(s):
`
`22,288 (original)
`
`Bepotastine besilate ophthalmic solution 1.5% and 1.0%
`(Bepreve)
`Treatment of itching
`conjunctivitis
`ISTA Pharmaceuticals, Inc.
`Stamp date: November 12, 2008
`PDUFA date: September 11, 2009
`Standard
`Review Priority:
`IV
`Biometrics Division:
`Mushfiqur Rashid, Ph.D.
`Statistical Reviewer:
`Yan Wang, Ph.D.
`Statistical Team Leader:
`Division of Anti-infective and Ophthalmology Products
`Medical Division:
`Sonal D. Wadhwa, M.D.
`Medical Reviewer(s)
`William Boyd, M.D.
`Medical Team Leader
`Raphael Rodriguez
`Project Manager:
`Keywords: Conjunctival Allergen Challenge Model, Ocular Itching, Conjunctival Redness.
`
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`1
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`(b) (4)
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`

`

`1 EXECUTIVE SUMMARY…………………………………………………………………………........3
`1.1 Conclusions and Recommendations…………………………………………………..3
`1.2 Brief Overview of Clinical Studies……………………………………………………3
`1.3 Statistical Issues and Findings………………………………………………………...4
`2 INTRODUCTION..................................................................................................................................... 6
`3 STATISTICAL EVALUATION…………………………………………………………………………7
`3.1Evaluation of Efficacy…………………………………………………………………7
`3.1.1 Introduction ........................................................................................................................................... 7
`3.1.2 Study Designs........................................................................................................................................ 7
`3.1.3 Efficacy Results................................................................................................................................... 18
`4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS................................................................... 27
`4.1 Examination of Subgroups……………………………………………………...........27
`5. SUMMARY AND CONCLUSIONS..................................................................................................... 27
`5.1 Statistical Issues and Collective Evidence…………………………………………...27
`5.2 Conclusions and Recommendations…………………………………………………28
`SIGNATURES/DISTRIBUTION LIST.................................................................................................... 30
`
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`2
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`

`

`1 EXECUTIVE SUMMARY
`
`
`
` 1.1 Conclusions and Recommendations
`
`In this NDA 22288 submission, the applicant is seeking approval for Bepotastine Besilate
`Ophthalmic Solution (Bepreve) as an eye drop treatment for ocular itching
`
`associated with allergic conjunctivitis. The applicant has submitted two phase 3
`conjunctival allergen challenge (CAC) studies: ISTA-BEPO-CS01 and CL-S&E-
`0409071-P. In addition, the applicant has submitted a safety study (CL-SAF-0405071-P).
`
`These studies have demonstrated that: (1) Both Bepreve 1.5% and Bepreve 1.0%
`achieved the pre-defined clinical and statistical significance in the primary endpoint of
`ocular itching; (2) Bepreve 1.5% had numerical advantage (in terms of point estimate of
`treatment effect) over Bepreve 1.0% in the primary endpoint of ocular itching; (3) Both
`Bepreve 1.5% and Bepreve 1.0% failed in the primary endpoint of conjunctival redness;
`(4) There were no serious ocular adverse events reported in patients dosed with either
`Bepreve 1.0% or 1.5%.
`
`It is recommended that Bepreve 1.5% be approved for the treatment of ocular itching
`associated with allergic conjunctivitis.
`
`
`1.2 Brief Overview of Clinical Studies
`
`Both the phase 3 CAC studies (ISTA-BEPO-CS01 and CL-S&E-0409071-P) were
`identical in design except that (1) study ISTA-BEPO-CS01 was a single centered whereas
`and CL-S&E-0409071-P was a multi-centered and (2) the multicenter trial included an
`assessment of ocular comfort.
`
`Both studies were double-masked, randomized, vehicle-controlled efficacy and safety
`studies. They evaluated the onset and duration of action of Bepreve 1.5% and Bepreve
`1.0% in patients with acute allergic conjunctivitis using the conjunctival allergen
`challenge (CAC) model of acute allergic conjunctivitis. Study subjects were randomized
`in a 1:1:1 ratio to one of there test agents (vehicle, Bepreve 1.0%, and Bepreve 1.5%). In
`Study ISTA-BEPO-CS01, 107 subjects from one US site were randomized: 36 in the
`Vehicle group, 36 in the Bepreve 1.0% group, and 35 in the Bepreve 1.5% group. In
`Study CL-S&E-0409071-P, 130 subjects from 5 US sites were randomized: 43 in the
`Vehicle group, 43 in the Bepreve 1.0% group, and 44 in the Bepreve 1.5% group.
`
`These two studies included 5 visits in a period over approximately 7 weeks: Visit 1 (Day
`-21) for an allergen titration CAC test, Visit 2 (Day -14) for an allergen confirmation
`CAC test, Visit 3A (Day 0) for randomization and the first instillation of the assigned test
`agent, Visit 3B (Day 1) for a duration of action CAC test 16 hours post instillation of test
`agent, Visit 4 (Day 14) for the second instillation of test agent and a duration of action
`CAC test 8 hours post instillation of test agent, and Visit 5 (Day 28) for the third
`
`
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`3
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`(b) (4)
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`

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`instillation of test agent and an onset of action CAC test 15 minutes post instillation of
`test agent.
`
`The primary objectives of both studies were to establish the efficacy and safety of
`Bepreve 1.0% and 1.5% compared with vehicle in alleviating the signs and symptoms of
`CAC-induced allergic conjunctivitis when dosed 15 minutes prior to a CAC (for onset of
`action), 8 hours prior to a CAC (for duration of action acceptable for a drug indicated for
`twice-daily dosing), or 16 hours prior to a CAC (for duration of action acceptable for a
`drug indicated for once-daily dosing) in subjects with a history of allergic conjunctivitis.
`
`The primary efficacy variables were subject-evaluated ocular itching at 3, 5, and 7
`minutes post CAC and investigator-evaluated conjunctival redness at 7, 15, and 20
`minutes post CAC.
`
`In order to demonstrate clinical significance for the primary endpoints (ocular itching and
`conjunctival redness) at a given visit, Bepreve 1.5% or Bepreve 1.0% must demonstrate
`clinical superiority over vehicle by at least 0.5 unit (point-estimate) for all time points
`and at least 1.0 unit (point-estimate) for the majority (2/3) of time points.
`
`Statistical significance was considered to have been demonstrated for Bepreve 1.5% or
`Bepreve 1.0% by showing statistical significance for the primary efficacy variables
`(ocular itching and conjunctival redness) at majority (2/3) of the time points at Visit 5
`(Day 28) and either at Visit 3B (Day 1) or at Visit 4 (Day 14).
`
`Efficacy of treatment with Bepreve 1.5% or Bepreve 1.0% was considered to have been
`demonstrated in each primary endpoint if both the clinical significancy and the statistical
`significancy were achieved at Visit 5 (Day 28) and either at Visit 3B (Day 1) or at Visit 4
`(Day 14).
`
`
`
`1.3 Statistical Issues and Findings
`
`The efficacy data from the two phase-3 CAC studies (ISTA-BEPO-CS01 and CL-S&E-
`0409071-P) demonstrated that both Bepreve 1.5% and Bepreve 1.0% achieved
`statistically significant reductions in the primary endpoint of ocular itching. However,
`both Bepreve 1.5% and Bepreve 1.0% did not show statistically significant reductions in
`the other primary endpoint of redness associated with allergic conjunctivitis.
`
`The efficacy data from Study ISTA-BEPO-CSO1 (single site trial) showed that only
`Bepreve 1.5% achieved clinical significance and statistical significance in treating ocular
`itching at all visits (Day 1, Day 14, and Day 28). Furthermore, in both studies, Bepreve
`1.5% had numerical advantage (in terms of the point estimate) over Bepreve 1.0% at
`Visit 4 (Day 14) and Visit 5 (Day 28). Therefore, Bepreve 1.5% is recommended as the
`more efficacious dose.
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`4
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`Robustness of the Efficacy Results for the Primary Endpoint of Ocular Itching:
`
`The primary efficacy analysis in the two phase 3 studies was based on the ITT population
`using the last observation carried forward (LOCF) method for imputing missing data.
`There are concerns in using LOCF method that can potentially bias the results. The
`applicant conducted sensitivity analyses using alternative population analysis sets (the PP
`population and the ITT population with observed data only). The sensitivity analysis
`results were consistent with those of the primary analysis. The applicant also conducted
`analyses using different imputation methods for missing data for the ITT population. The
`imputation methods were Monte Carlo Markov Chain (MCMC) imputation, and the Visit
`2 (Day -14: baseline) observations carried forward imputation. The treatment effect of
`Bepreve 1.5% and Bepreve 1.0% for the ocular itching indication continued to be
`significant according to the pre-defined clinical and statistical criteria. Furthermore, the
`sensitivity analysis results using multiple alternative statistical testing procedures (e.g., t-
`test, Wilcoxon rank sum test, etc.) were also consistent with the primary analysis results.
`
`In the two phase 3 studies, multiplicity adjustments (for controlling overall 0.05 type I
`error rate) were made because two concentrations of Bepreve were tested (1.0% and
`1.5%), multiple primary endpoints were assessed (ocular itching and conjunctival
`redness), and both studies only required that statistical significance be achieved at the
`onset of action of CAC test (Visit 5) and at 1 of the 2 durations of action CAC tests (8-
`hour or 16-hour). The requirements for statistical significance pre-specified in the
`protocol were p-value ≤ 0.00625 at the 8-hour (Day 14: Visit 4) and 16-hour duration
`(Day 1: Visit 3B) of CAC tests and p-value ≤ 0.0125 at the onset of action CAC test (Day
`28: Visit 5) for a majority (2/3) of time points. However, the multiplicity adjustments
`criteria applied in this submission do not adjust for the majority of the time points within
`a visit. In order to adjust multiplicity correctly for the majority (2/3) of time points, the
`proposed type I error rates 0.0125 and 0.00625 have to be divided by 3 because there are
`three different ways to win. Therefore, type I error rates will be 0.0042 and 0.0021 for
`Visit 5 (Day 28) and Visit 3B (Day 1) /Visit 4 (Day 14) respectively. With these type I
`error rate adjustments, the efficacy conclusions remain the same.
`
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`5
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` 2
`
`INTRODUCTION
`
`
`According to the applicant, bepotastine besilate is an anti-allergic drug possessing highly
`selective histamine H1 receptor antagonistic action and, in addition, inhibitory action on
`eosinophilic infiltration to inflammatory sites. It was originally developed in Japan by
`Ube Industries, Ltd. and Tanabe Seiyaku Co., Ltd. as a treatment for allergic rhinitis. An
`oral preparation of bepotastine besilate [Talion tablets, Mitsubishi Tanabe Pharma
`Corporation (formerly Tanabe Seiyaku Company, Ltd.)] was approved in Japan in July
`2000 as a treatment for allergic rhinitis (10mg po bid for up to 4 weeks). In January
`2002, the additional indication of pruritus/itching accompanying urticaria and other skin
`diseases was approved in Japan. Currently, Bepotastine is not an approved product in the
`U.S. for any indication. There are approved drugs for the proposed indications in the U.S.
`
`Bepotastine besilate was developed under IND 66,864. There was an end of phase 2/pre-
`Phase 3 meeting on August 15, 2007. The multicenter phase 3 study protocol (CL-S&E-
`0409071-P) was submitted to the Agency for review under special protocol assessments
`(SAP). The SPA responses for Study CL-S&E-040907-P were dated on July 23, 2007
`(SPA response) and December 3, 2007 (final response). The pre-NDA meeting was held
`on August 4, 2008..
`
`Data sets and all modules containing clinical study reports were submitted electronically.
`This reviewer focused on the review of the two phase 3 studies ISTA-BEPO-CS01 and
`CL-S&E-0409071-P. The full electronic path for the study results according to CDER
`EDR naming convention is as follows:
`
`\\CDSESUB1\EVSPROD\NDA022288\
`
`The data sets were adequately documented.
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`6
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` STATISTICAL EVALUATION
`
` 3
`
`
`
`3.1 Evaluation of Efficacy
`
`3.1.1 Introduction
`
`In this NDA, the applicant has submitted data from two Phase 3 studies (ISTA-BEPO-
`CS01 and CL-S&E-0409071-P) in patients with allergic conjunctivitis.
`
`
`3.1.2 Study Designs
`
`Studies ISTA-BEPO-CS01 and CL-S&E-0409071-P were identical in design except that
`1) study ISTA-BEPO-CS01 was a single centered whereas and CL-S&E-0409071-P was
`a multi-centered and 2) the multicenter trial included an assessment of ocular comfort.
`Both studies were double-masked, randomized, vehicle-controlled, evaluation of the
`onset and duration of action of Bepreve 1.5% and Bepreve 1.0% in the conjunctival
`allergen challenge (CAC) model of acute allergic conjunctivitis planned for patients with
`a demonstrated history of allergic conjunctivitis. Patients (≥ 10 years of age) who
`demonstrated history of allergic conjunctivitis were eligible for the study. This study
`consisted of a total of 5 visits, conducted over approximately 7 weeks.
`
`Subjects were evaluated during screening for a consistent allergic response to a defined
`allergen as judged by grades of 2.0 units or greater for ocular itching and for hyperemia
`in at least 2 out of the 3 vessel beds examined during two screening visits. At Visit 1
`(Day -21), allergen instilled in each eye of subjects was titrated for the induction of an
`ocular allergic response to obtain the lowest concentration of allergen that produced an
`allergic response. Any subject who met the criteria for an allergic response continued to
`Visit 2 (Day -14) at which time the allergen of the same identity and dose used in the
`previous visit was instilled in each subject eye and an ocular allergic response was
`confirmed. Itching at Visit 2 (Day -14) was subject-assessed at 3, 5, and 7 minutes post
`CAC. Redness was investigator-assessed at 7, 15, and 20 minutes post CAC. Only
`subjects who met the study criteria for a positive CAC reaction at Visits 1 and 2 were
`allowed to continue to Visit 3A (Day 0). At Visit 3A a computer-generated
`randomization list was used to assign the subjects (in 1:1:1 proportions) to one of three
`treatment groups (Bepreve 1.0%, Bepreve 1.5%, or vehicle).
`
`At Visits 3A (Day 0), 4 (Day 14), and 5 (Day 28), a trained technician instilled 1 drop of
`the assigned test agent into both eyes of each subject. CAC was performed, using the
`previously validated allergen dose for each subject at: 16 hours (duration-of-action
`acceptable for drugs intended to be dosed QD), 8 hours (duration-of-action acceptable for
`drugs intended to be dosed BID), or 15 minutes (onset of action) post test agent
`instillation during Visit 3A (Day 0), 4 (Day 14), and 5 (Day 28), respectively.
`
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`7
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`The test agents (Bepreve 1.0% or Bepreve 1.5% or vehicle) were dosed as one drop in
`each eye at each of Visits 3B, 4, and 5, always at the same concentration for an individual
`subject. Signs and symptoms of allergic conjunctivitis were then graded over a 20-
`minute period following the CAC. The severity of allergy symptoms was evaluated
`independently by subjects, using a self-reported standardized severity scale, and the
`severity of allergic signs independently by investigators. Using slit lamp biomicroscopy
`and accompanying photographic standards, investigators evaluated subjects’ allergic
`response using a 5-point scale, with 0.5 unit increments allowed, for ciliary hyperemia,
`conjunctival hyperemia, and episcleral hyperemia. Chemosis also was evaluated by
`investigators on a 5-point (nine-step) scale with 0.5 unit increments allowed.
`Investigators additionally evaluated mucous discharge, which was rated as either absent
`or present. All investigator evaluations were recorded for both eyes.
`
`Subject-evaluated assessments included both ocular and nasal allergic symptoms. Both
`the right and left eyes were independently evaluated for itching (using a 5-point scale
`with 0.5 unit increments allowed) and lid swelling (using a 4-point scale with whole unit
`increments only). Tearing was rated by subjects as either absent or present. Nasal
`symptoms were evaluated by subjects on a 5-point scale, with whole unit increments
`only, for rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion. Subject-
`evaluated assessments of ocular itching occurred at 3, 5, and 7 minutes post-allergen
`challenge. All other assessments, including investigator-evaluated assessments and
`subject-evaluated ocular and nasal symptom assessments, occurred at 7, 15, and 20
`minutes post-challenge.
`
`
`Inclusion/Exclusion Criteria:
`
`See clinical review for details.
`
`
`Study Schedule
`
`The first dose of the test agents was administered at Visit 3A (Day 0), 16 hours prior to a
`CAC, and the second dose was administered at Visit 4 (Day 14), 8 hours prior to a CAC.
`The last dose was administered at Visit 5 (Day 28), 15 minutes prior to a CAC. The
`detailed study schedules are summarized in the following table:
`
`
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`8
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`Table 1: Detailed Study Schedules
`
`Source: Clinical Study Report:CL-S & E-0409071-P, Page 29
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`9
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`Comparison of Study Designs:
`
`Table 2 provides a comparison of study designs in CAC studies ISTA-BEPO-CS01, C-
`S&E-0409071-P and CL-SAF-0405071-P:
`
`Table 2: Brief Summary of Clinical Studies
`Study
`Objective of the
`Study Design
`Identifier
`Study
`
`Healthy
`Subjects or
`Diagnosis of
`Patients
`CAC induced
`allergic
`conjunctivitis
`
`Duration of
`Treatment
`
`3 single doses
`received over a
`period of 7 weeks
`
`Test Products
`
`Number
`of
`Subjects
`
`Single center,
`double-masked,
`randomized
`vehicle-
`controlled ,
`CAC study
`
`107
`
`Bepotastine
`besilate
`ophthalmic
`solution 1.0%,
`1.5%, or vehicle
`one drop at Visit
`3A, Visit 4, and
`visit 5
`
`ISTA-
`BEPO-
`CS01
`
`Safety and
`Efficacy
`Phase 2/3
`
`CL-S&E-
`0409071-P
`
`Safety and
`Efficacy
`Phase 3
`
`CL-SAF-
`0405071-P
`
`Safety
`Phase 3
`
`Efficacy and safety
`of bepotastine
`besilate ophthalmic
`solution 1.0% and
`1.5% compared to
`vehicle in alleviating
`the signs and
`symptoms of CAC-
`induced allergic
`conjunctivitis at 15
`mins., 8 hours, and
`16 hours following
`mediation instillation
`Efficacy and safety
`of bepotastine
`ophthalmic solution
`1.0% and 1.5%
`compared to vehicle
`in alleviating the
`signs and symptoms
`of CAC-induced
`allergic conjunctivitis
`at 15 mins., 8 hours,
`and 16 hours
`Evaluate the safety of
`bepotastine besilate
`ophthalmic solution
`1.5% in healthy,
`normal volunteers
`
`
`
`
`
`
`
`
`
`
`
`
`
`Multi-center,
`double-masked,
`randomized,
`vehicle-
`controlled, CAC
`study
`
`Multi-center,
`randomized,
`double-masked,
`vehicle-
`controlled,
`parallel-group
`study
`
`Bepotastine
`besilate
`ophthalmic
`solution 1.0%,
`1.5%, or vehicle
`one drop at Visit
`3A, Visit 4, and
`visit 5
`
`Bepotastine
`besilate
`ophthalmic
`solution 1.5% or
`vehicle BID
`
`130
`
`CAC induced
`allergic
`conjunctivitis
`
`3 single doses
`received over a
`period of 7 weeks
`
`861
`
`Healthy
`
`Treatment BID
`for 6 weeks for all
`subjects and
`subjects which
`participated in
`measuring
`endothelial cell
`counts were
`followed for an
`additional 6
`weeks after
`stopping
`treatment
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`10
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`Primary Efficacy Variables:
`
`The primary efficacy variables were subject-evaluated ocular itching at 3, 5, and 7
`minutes post CAC and investigator-evaluated conjunctival redness at 7, 15, and 20
`minutes post CAC. Ocular itching and conjunctival redness scales were based on a 5-unit
`grading scale with half unit (one step) increments. The endpoint measurement was
`calculated by averaging the scores from both eyes of each subject.
`
`The Ocular Itching Assessment Grades are described as follows:
`
`Table 3: Ocular Itching Assessment Grades
`Grade
`Assessment
`
`0
`
`0.5
`
`1.0
`
`None
`
`An intermittent tickle sensation possible localized in the corner of the eye
`
`An intermittent tickle sensation involving more than just the corner of the eye
`
`Intermittent all-over itching sensation
`
`Moderate, diffuse continuous itch with desire to rub
`
`A severe itch with desire to rub
`
`Severe itch improved with minimal rubbing
`
`Incapacitating itch with an irresistible urge to rub
`
`
`1.5
`
`2.0
`
`3.0
`
`3.5
`
`4.0
`
`2.0
`
`3.0
`
`4.0
`
`
`
`
`The Conjunctival redness assessment grades are described in the following table:
`
`Table 4: Conjunctival redness assessment grades
`Grade
`Assessment
`
`0
`
`1.0
`
`None
`
`Mild-Slightly dilated blood vessels; color of vessels is typically pink; can be
`quadrantal
`Moderate-More apparent dilation of blood vessels; vessels color is more
`intense (redder); involves the majority of the vessels bed
`Severe-Numerous and obvious dilated blood vessels; in the absence of
`chemosis the color is deep red, may be less red or pink in presence of
`chemosis, is not quandrantic
`Extremely severe-Large, numerous, dilated blood vessels characterized by
`unusually severe deep red color, regardless of grade of chemosis, which
`involves the entire vessel bed
`
`
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`11
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`Secondary Efficacy Variables:
`
`The secondary efficacy variables were evaluated at 7, 15, and 20 minutes post CAC and
`included: investigator-evaluated ciliary redness, episcleral redness, and chemosis
`(0-4 unit scales, allowing half unit increments), and ocular mucous discharge (graded
`absent or present).
`
`Analysis Populations:
`
`The analysis populations are described in sections below:
`
`The ITT population was defined as all randomized subjects regardless of whether or not
`the subject received test agent. The PP population was defined as randomized subjects
`that had no significant protocol deviations or any incomplete patient data. The safety
`population was defined as all subjects who received at least one dose of test agent.
`
`Safety Endpoints:
`
`The safety variables for this study included:
`
` •
`
` Incidence and frequency of AEs (reported, elicited, and observed).
`
`• Physical examination [an assessment of general health, head, eyes, ears, nose, and
`throat (HEENT), heart, lungs, abdomen, neurologic evaluation, condition of
`extremities, back, skin, and vital signs] and pregnancy test (women of childbearing
`potential only) at Visit 1, Visit 4, and Visit 5.
`
` •
`
` Visual acuity using an ETDRS chart at the beginning of each study visit. For subjects
`< 10 years who were developmentally unable to use the ETDRS chart, a best attempt
`at visual acuity was made using the LEA symbols.
`
`
`• Slit lamp biomicroscopy conducted by the investigator at all study visits.
`
`• ECC conducted on subject’s age ≥10 years old at Visit 1 and Visit 5. All safety
`assessment performed at Visit 4 were repeated at Visit 5, in addition to ocular
`endothelial cell counts.
`
`
`• Intraocular pressure (IOP) conducted on subject’s age ≥10 years old (if possible), at
`Visit 1, Visit 4, and Visit 5.
`
`
`• DFE conducted by the investigator at Visit 1, Visit 4, and Visit 5. The presence or
`absence of clinically significant fundus abnormalities and vitreous pathology were
`evaluated by comparison to baseline (Visit 1) values using a 0-3 severity scale.
`
` Ocular comfort examinations.
`
`12
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` •
`
`
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`

`

`
`Sample Size Determination:
`
`In Study ISTA-BEPO-CS01, a sample size of 30 subjects in each treatment group was
`selected based on 90% power and 0.05 alpha (two-sided) to detect a difference in means
`of 1.00 unit (the difference between vehicle and one of the bepotastine besilate
`ophthalmic solution groups). The two-sample t-test was used assuming the common
`standard deviation of unity.
`
`In Study CL-S&E-0409071-P, a sample size of approximately 40 subjects was selected
`in each group based on 90% power and 0.05 alpha (two-sided) to detect a difference in
`means of 1.0 (the difference between vehicle and bepotastine besilate ophthalmic solution
`1.0% or the difference between vehicle and bepotastine besilate ophthalmic solution
`1.5%). The two-sample t-test was used assuming the common standard deviation of
`unity.
`
`
`Statistical Methods:
`In order to demonstrate clinical significance, bepotastine besilate ophthalmic solution
`(1.0% and 1.5%) must demonstrate clinical superiority over vehicle by at least 0.5 (point-
`estimate) unit (1-step) of a 5-point grading scale for all time points and at least 1.0 (point-
`estimate) unit (2 steps) for the majority of time points within a visit, measured for both
`ocular itching and conjunctival redness. Statistical significance was considered to have
`been demonstrated for bepotastine besilate ophthalmic solution (1.0% and 1.5%) by
`showing statistical significance for the primary efficacy variables (ocular itching and
`conjunctival redness) at majority (2/3) of the time points at Visit 5 (Day 28) and either at
`Visit 3B (Day 1) or Visit 4 (Day 14). Clinical efficacy was considered to have been
`demonstrated for bepotastine besilate ophthalmic solution (1.0% and 1.5%) by showing
`clinical and statistical significance for the primary efficacy variables, ocular itching and
`conjunctival redness, at Visit 5 (Day 28) and either at Visit 3B (Day 1) or Visit 4 (Day
`14).
`
`Hypothesis testing (using Wilcoxon rank sum test) was performed on the primary
`efficacy variables using a Wilcoxon rank sum test at each visit. The null hypotheses
`were:
`
` ●
`
` There is no difference in primary efficacy endpoints between bepotastine besilate
`ophthalmic solution 1.0% and vehicle at the majority of the time points
`
` ●
`
` There is no difference in primary efficacy endpoints between bepotastine besilate
`ophthalmic solution 1.5% and vehicle at the majority of the time points
`
`In the primary analysis, the missing data were imputed using the Last Observation
`Carried Forward (LOCF) method.
`
`
`
`
`
`13
`
`

`

`Sensitivity analyses on various study populations were performed to examine the
`robustness of the primary efficacy results: the per protocol (PP) population (observed
`data), the ITT population with observed data only, the ITT population with baseline
`values carried forward for imputation of missing, data and the ITT population with
`Monte Carlo Markov Chain (MCMC) imputation of missing data. Additional sensitivity
`analyses were also performed using two-sample t-test, Wilcoxon rank sum test for
`clustered data, and ANCOVA.
`
`Multiplicity adjustments (to control overall type I error rate of 0.05) were made because
`multiple concentrations of Bepreve were tested (1.0% and 1.5%), multiple primary
`endpoints were assessed (ocular itching and conjunctival redness), and both CAC trials
`only required that statistical significance be achieved at 1 of the 2 duration of action CAC
`tests (8-hour or 16-hour). The requirements for statistical significance therefore were p-
`value ≤ 0.00625 at the 8-hour and 16-hour duration of CAC tests and p-value ≤ 0.0125 at
`the onset of action CAC test for a majority of time points.
`
`Statistical Comments:
`The multiplicity adjustments criteria applied in this submission do not adjust for the
`majority of the time points within a visit. In order to adjust multiplicity correctly for the
`majority (2/3) of time points, the proposed type I error rates 0.0125 and 0.00625 have to
`be divided by 3 because there are three different ways to win. Therefore, type I error
`rates will be 0.0042 and 0.0021 for Visit 5 (Day 28) and Visit 3B (Day 1) /Visit 4 (Day
`14) respectively.
`
`Patient Disposition and Study populations
`
`In Study ISTA-BEPO-CSO1, a total of four subjects (one in vehicle group, three in the
`Bepotastine 1.5% group, and none in the Bepotastine 1.0% group) discontinued/
`withdrawn over the course of the study. The per-protocol (PP) population, defined prior
`to database lock as subjects who completed the study without any major protocol
`violation, was 101 subjects.
`study visit).
`
`In Study CL-S&E-0409071-P, a total of thirteen subjects (seven in the vehicle group, five
`in the Bepotastine 1.5% group, and one in the Bepotastine 1.0% group) discontinued/
`withdrawn over the course of the study. The remaining 117 subjects completed the study
`and comprised the PP population.
`The summary of the study population for both studies is presented in Tables 5-6.
`Table 5: Patient Disposition (Study ISTA-BEPO-CSO1)
`
`Bepreve
`Bepreve
`1.0%
`1.5%
`36
`36
`35
`Randomized
`36
`36
`35
`Safety Population
`36
`36
`35
`ITT Population with LOCF
`34
`35
`32
`PP Population
`Data source: Clinical Study Report: ISTA-BEPO-CS01, Page 108 (Table 14.1.1)
`
`Vehicle
`
`Total
`
`107
`107
`107
`101
`
`
`
`14
`
`

`

`
`Table 6: Patient Disposition (Study CL-S&E-0409071-P)
`
`Bepreve
`Bepreve 1.5%
`Vehicle Total
`1.0%
`
`44
`43
`44
`43
`
`130
`130
`
`43
`43
`
`Randomized
`Safety
`Population
`ITT Population
`with LOCF
`117
`36
`38
`43
`PP Population
`Data source: Clinical Study Report:CL-S & E-0409071-P, Page 155 (Table 14.1.1)
`
`44
`
`43
`
`43
`
`130
`
`Demographic and Baseline Characteristics at Entry:
`
`Baseline demographics for the intent-to-treat (ITT) population for Study ISTA-BEPO-
`CSO1 are presented in the following table:
`Table 7: Study ISTA-BEPO-CSO1: Demographics (ITT Population)
`Parameter
`Total Randomized
`Bepreve 1.0%
`Bepreve 1.5%
`Subjects (N=107)
`(N=36)
`(N=35)
`
`
`
`58
`22
`17
`
`Gender
` Male
`
` Female
`
`
`Age
` Mean
`
`Race
`
`49
`
`
`
`41.7
`
`
`
`14
`
`
`
`39.3
`
`
`
`18
`
`
`
`44.3
`
`
`
`99
`2
`
`2
`4
`
`
`10
`
`97
`
`35
`0
`
`0
`1
`
`
`2
`
`34
`
`31
`1
`
`0
`3
`
`
`4
`
`31
`
` Caucasian
` African-
`American
` Asian
` Other race
`
`Ethnicity
`
`
`Hispanic/Latino
` Not
`Hispanic/Latino
`
`
`
`
`
`
`
`Iris Color
`11
`11
`34
` Blue
`17
`15
`51
` Brown
`1
`3
`6
` Green
`6
`7
`16
` Hazel
`Data Source: Clinical Study Report: ISTA-BEPO-CS01, Page 110 (Table 14.1.3.1)
`
`
`
`Vehicle
`(N=36)
`
`19
`
`17
`
`
`
`40.9
`
`
`
`33
`1
`
`2
`0
`
`
`4
`
`32
`
`
`
`12
`19
`2
`3
`
`15
`
`

`

`It can be seen that demographics and other characteristics of subjects were well-balanced
`among the treatment groups for the ITT population. The applicant reported that pairwise
`comparison of demographics for bepotastine besilate ophthalmic solutions 1.0% and
`1.5% to vehicle revealed a lack of statistically significant differences with regards to age
`(p-value = 0.747 for 1.0%, p-value = 0.305 for 1.5%), gender (p-value = 0.634 for 1.0%,
`p-value = 0.814 for 1.5%), ethnicity (p-value = 0.674 for 1.0%, p-value = 1.000 for
`1.5%), eye color (p-value = 0.514 for 1.0%, p-value = 0.716 for 1.5%), or race (p-value =
`0.364 for 1.0%, p-value = 0.145 for 1.5%).
`
`Baseline demographics for the intent-to-treat (ITT) population for Study CL-S&E-
`0409071-P are presented in the following table:
`
`Table 8: Study CL-S&E-0409071-P: Demographics (ITT Population)
`Parameter
`Total
`Bepreve
`Bepreve 1.5%
`Vehicle
`Randomized
`1.0%
`(N=43)
`(N=43)
`Subjects
`(N=44)
`(N=130)
`
`
`
`Gender
`21
`25
`75
` Male
`22
`19
`55
` Female
`
`
`
`
`
`
`
`Age
`33.3
`34.8
`33.8
` Mean
`
`
`
`
`
`
`
`Race
`29
`33
`94
` Caucasian
`6
`2
`12
` African-American
`8
`8
`22
` Asian
`0
`1
`1
` American Indian
`0
`0
`1
` Other race
`
`
`
`
`
`
`
`Ethnicity
`0
`0
`2
` Hispanic/Latino
`43
`44
` Not Hispanic/Latino 128
`
`
`
`
`
`
`Iris Color
`
`38
`22
` Blue
`86
`34
`42
` Brown
`118
`10
`8
` Green
`28
`4
`16
` Hazel
`26
`0
`0
` Other
`2
`Data source: Clinical Study Report:CL-S & E-0409071-P, Page 157 (Table 14.1.3.1)
`
`It can be seen from the above table that demographics and other characteristics of
`subjects were well balanced among the treatment groups for the ITT population. The
`applicant reported that comparison of demographics for bepotastine besilate ophthalmic
`
`
`29
`14
`
`
`33.3
`
`
`32
`4
`6
`
`1
`
`
`2
`41
`
`
`26
`42
`10
`6
`2
`
`
`
`16
`
`

`

`solutions 1.0% and 1.5% to vehicle revealed a lack of statistically significant differences
`with regards to age (t-test; p-value 0.62 for 1.0%, p-value=1.0 for 1.5%), gender (Fisher’s
`exact test; p-value=0.378 for 1.0%, p-value=0.125 for 1.5%), ethnicity (Fisher’s exact
`test; p-value=0.24 for 1.0%, p-value=0.49 for 1.5%),