`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203168Orig1s000
`
`
`STATISTICAL REVIEW(S)
`
`
`

`

`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`
`S T A T I S T I C A L T E A M L E A D E R R E V I E W A N D E V A L U A T I O N
`CLINICAL STUDIES
`
`NDA/BLA #:
`
`Drug Name:
`Indication(s):
`
`Applicant:
`Date(s):
`
`Review Priority:
`
`Biometrics Division:
`
`Statistical Review Team
`
`NDA203168
`
`Bromfenac 0.07% Ophthalmic Solution
`Treatment of postoperative inflammation and reduction of ocular
`pain in patients who have undergone cataract surgery
`Bausch+Lomb
`Stamp date: June 6, 2012
`PDUFA date: April 7, 2013
`Standard
`
`DBIV
`Primary statistical reviewer: Abel Eshete, PhD
`Statistical Team Leader: Yan Wang, PhD
`Concurring Reviewers: Daphne Lin, PhD
`
`Ophthalmology
`Medical Reviewer: William Boyd, M.D.
`Michael Puglisi
`
`Keywords: anterior chamber cells, anterior chamber flare, ocular inflammation, ocular pain,
`cataract surgery.
`
`
`Medical Division:
`Clinical Team:
`Project Manager:
`
`Reference ID: 3287264
`
`

`

`Table of Contents
`INTRODUCTION/PURPOSE OF REVIEW....................................................................................................4
`1
`2 CURRENT NDA203168 PROLENSA (BROMFENAC OPHTHALMIC SOLUTION, 0.07% QD)...........4
`3 EFFICAY ANALYSIS EVALUATIONS OF 7 APPROVED NDAS FOR THE TREATMENT OF
`OCULAR INFLAMMATION AFTER CATARACT SURGERY..........................................................................8
`3.1
`NDA021664 XIBROM (BROMFENAC OPHTHALMIC SOLUTION, 0.09% BID) FOR THE TREATMENT OF
`POSTOPERATIVE INFLAMMATION IN PATIENTS WHO HAVE UNDERGONE CATARACT EXTRACTION ..............................9
`3.2
`NDA021862 NEVANAC (NEPAFENAC OPHTHALMIC SUSPENSION, 0.1% TID) FOR THE TREATMENT OF PAIN
`AND INFLAMMATION ASSOCIATED WITH CATARACT SURGERY .................................................................................12
`3.3
`NDA022212 DUREZOL (DIFLUPREDNATE OPHTHALMIC SOLUTION, 0.05% QID) FOR THE TREATMENT OF
`INFLAMMATION AND PAIN ASSOCIATED WITH CATARACT SURGERY .........................................................................15
`3.4
`NDA021664 BROMDAY (BROMFENAC OPHTHALMIC SOLUTION, 0.09% QD) FOR THE TREATMENT OF
`POSTOPERATIVE INFLAMMATION AND REDUCTION OF OCULAR PAIN IN PATIENTS WHO HAVE UNDERGONE CATARACT
`EXTRACTION.............................................................................................................................................................19
`3.5
`NDA200738 LOTEMAX (LOTEPREDNOL ETABONATE OPHTHALMIC OINTMENT, 0.5% QID) FOR THE
`TREATMENT OF POSTOPERATIVE INFLAMMATION AND PAIN FOLLOWING OCULAR SURGERY ....................................23
`3.6
`NDA202872 LOTEMAX (LOTEPREDNOL ETABONATE OPHTHALMIC GEL, 0.5% QID) FOR THE TREATMENT OF
`POSTOPERATIVE INFLAMMATION AND PAIN FOLLOWING OCULAR SURGERY.............................................................26
`3.7
`NDA203491 ILEVRO (NEPAFENAC OPHTHALMIC SUSPENSION, 0.3% QD) FOR THE TREATMENT OF PAIN AND
`INFLAMMATION ASSOCIATED WITH CATARACT SURGERY .........................................................................................28
`3.8
`SUMMARY OF FINDINGS ON THE 7 APPROVED NDAS...................................................................................30
`3.8.1
`Varied anterior chamber cell grade scores and flare scores were used to evaluate ocular
`inflammation........................................................................................................................................................30
`3.8.2
`Varied definitions were used to define “cleared ocular inflammation” ..............................................31
`3.8.3
`Every Approved NDA had subjects whose ocular inflammation was cleared by week 1 (days 7-8) but
`was not cleared at week 2 (days 14-15) post-surgery..........................................................................................32
`3.8.4
`Varied time points and analyses were used for the primary endpoint of cleared ocular inflammation
`33
`
`3.8.5
`Varied information on the efficacy endpoint and results for ocular inflammation were included in
`labeling 34
`4 RECOMMENDATIONS FOR THE CLINICAL STUDIES SECTION OF THE LABELING FOR THE
`CURRENT NDA203168 PROLENSA .....................................................................................................................35
`
`Reference ID: 3287264
`
`Page 2 of 37
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`

`

`LIST OF TABLES
`Table 2. 1 NDA203168: Applicant’s Efficacy Analysis Results of Phase 3 Studies.....................................................6
`Table 2. 2 NDA203168: Number of Subjects whose ocular inflammation was cleared (0 cell and no flare) at or prior
`to Day 8, but was not cleared (cell score or flare score >0) at Day 15 ..........................................................................7
`Table 2. 3 NDA203168: FDA’s Primary Statistical Reviewer’s Analysis Results of Phase 3 Studies .........................8
`Table 3.0 List of NDAs Approved in 2005-2012 for post-operative Inflammation after Cataract Surgery………….. 8
`Table 3.1. 1 NDA021664 Xibrom: CRF-defined Anterior Chamber Cell Score.........................................................10
`Table 3.1. 2 NDA021664 Xibrom: CRF-defined Anterior Chamber Flare Score .......................................................10
`Table 3.1. 3 NDA021664 Xibrom: Efficacy Results of Phase 3 Studies (Subjects who received a rescue therapy were
`treated as failures) (Randomized Population)..............................................................................................................11
`Table 3.1. 4 NDA021664 Xibrom: Efficacy Results of Phase 3 Studies (Subjects who received a rescue therapy were
`treated as successes if their ocular inflammation was cleared)....................................................................................11
`Table 3.1. 5 NDA021664 Xibrom: Number of subjects whose ocular inflammation was cleared (0 cell and no flare)
`at or prior to Day 8 but was not cleared at Day 15 (cell score or flare score > 0) .......................................................12
`Table 3.2. 1 NDA021862 Nevanac: Anterior Chamber Cell Score ………………………………………………….13
`Table 3.2. 2 NDA021862 Nevanac: Anterior Chamber Flare Score ...........................................................................13
`Table 3.2. 3 NDA021862 Nevanac: Efficacy Results of Phase 3 Studies (ITT population) .......................................13
`Table 3.2. 4 NDA021862 Nevanac: Number of subjects whose ocular inflammation was cleared (0 cell and no flare)
`at or prior to Day 7 but was not cleared (cell score or flare Score > 0) at Day 14.......................................................14
`Table 3.3. 1 NDA022212 Durezol: Anterior Chamber Cell Score..............................................................................15
`Table 3.3. 2 NDA022212 Durezol: Anterior Chamber Flare Score ............................................................................15
`Table 3.3. 3 NDA022212 Durezol: Applicant’s Efficacy Results of Comparing Durezol QID to Vehicle.................17
`Table 3.3. 4 NDA022212 Durezol: Applicant’s Efficacy Results of Comparing Durezol BID to Vehicle.................19
`Table 3.4. 1 NDA021664 Bromday: Applicant’s Efficacy Results of Phase 3 Studies (ITT Population) …………..21
`Table 3.4. 2 NDA021664 Bromday: Number of subjects whose ocular inflammation was cleared (0 cell and no flare)
`at or prior to Day 8 but was not cleared (cell score or flare score > 0) at Day 15 .......................................................22
`Table 3.4. 3 NDA021664 Bromday: FDA’s Analysis Results of Phase 3 Studies .....................................................22
`Table 3.5. 1 NDA200738 Lotemax Ointment: Anterior Chamber Flare Score ...........................................................23
`Table 3.5. 2 NDA200738 Lotemax Ointment: Efficacy Results of Phase 3 Studies (ITT Population).......................24
`Table 3.5. 3 NDA200738 Lotemax Ointment: Number of subjects whose ocular inflammation was cleared (0 cell
`count and no flare) at or prior to Day 8 but was not cleared (cell score or flare score > 0) at Day 15 ........................24
`Table 3.5. 4 NDA200738 Lotemax Ointment: Efficacy Results of Phase 3 Studies for the Endpoint of Achieving 0
`Cell ..............................................................................................................................................................................25
`Table 3.6. 1 NDA202872 Lotemax Gel: Efficacy Results of Phase 3 Studies (ITT Population) ................................26
`Table 3.6. 2 NDA202872 Lotemax Gel: Number of subjects whose ocular inflammation was cleared (0 cell) at or
`prior to Day 8 but was not cleared (cell score > 0) at Day 15 .....................................................................................27
`Table 3.6. 3 NDA202872 Lotemax Gel: Efficacy Results of Phase 3 Studies for the Endpoint of Achieving 0 Cell
`and 0 Flare Score .........................................................................................................................................................27
`Table 3.7. 1 NDA203491 Ilevro: Efficacy Results of Phase 3 Studies (Randomized Population)..............................28
`Table 3.7. 2 NDA203491 Ilevro: Number of subjects whose ocular inflammation was cleared (0 cell and no flare) at
`or prior to Day 7 but was not cleared (cell score or flare score > 0) at Day 14 ...........................................................29
`Table 3.8. 1: Anterior Chamber Cell Grade Scores in 7 Approved NDAs..................................................................30
`Table 3.8. 2: Anterior Chamber Cell Flare Scores in 7 Approved NDAs....................................................................31
`Table 3.8. 3: Definitions of Cleared Ocular Inflammation in 7 Approved NDAs.......................................................31
`Table 3.8. 4: Number of subjects whose ocular inflammation was cleared by week 1 (days 7-8) but was not cleared
`at week 2 (days 14-15) post-surgery in the 7 approved NDAs....................................................................................32
`Table 3.8. 5: Timing of Primary Endpoint in 7 Approved NDAs................................................................................33
`Table 3.8. 6: Information of Ocular Inflammation Presented in Labeling for 7 Approved NDAs..............................35
`
`
`Page 3 of 37
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`Reference ID: 3287264
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`

`

`Introduction/Purpose of Review
`
`1
`
`To provide support for the primary statistical reviewer’s recommendation for the labeling, this
`statistical team leader’s review evaluates the analysis of the primary efficacy endpoint of cleared
`ocular inflammation in the current NDA203168 and compares the analysis to seven previously
`approved NDAs for the indication of ocular inflammation after cataract surgery.
`
`Specifically, the focus of this review is on the examination of the definition of postoperative
`ocular inflammation, including its two components of “anterior chamber cell counts and grade
`scores” and “anterior chamber flare scores”, along with the way these individual components
`were defined and measured, and the determination on the clearance/resolution of ocular
`inflammation. In addition to the grade and evaluation of ocular inflammation, this review also
`examines how many time points were included in each application and which time points were
`considered important in the assessment of efficacy on ocular inflammation. Furthermore for
`each application, this review also examines whether there were subjects whose ocular
`inflammation was cleared by week 1 (days 7-8), but was subsequently not cleared at week 2
`(days 14-15) post-surgery, and how these subjects were treated in the analysis of the endpoint
`“cleared ocular inflammation” at days 14-15.
`
`The endpoint of pain resolution is generally a secondary endpoint in these approved NDAs.
`Information on this endpoint is included in this review for the sake of completeness; however,
`the statistical team leader has not specifically examined the scales that were scored to evaluate
`the presence of pain and the resolution of pain. Therefore, the data on pain resolution are taken
`directly from the clinical and/or statistical reviews. Because the Clinical Studies sections of
`labeling are presented in their entirety, this review includes whatever information on pain is
`included in labeling.
`
`The applicant’s and the primary reviewer’s analyses for the current NDA203168 are presented in
`Section 2; the analyses for the 7 approved NDAs are presented in Section 3; and Section 4
`concludes with the statistical review team’s recommendations for the drug labeling for the
`current NDA.
`
`
`2 Current NDA203168 Prolensa (bromfenac ophthalmic solution, 0.07% QD)
`
`In support of the efficacy claim, this NDA included two phase 3 studies in subjects who
`underwent cataract extraction with posterior chamber intraocular lens implantation. These two
`studies shared a common protocol and a statistical analysis plan and were conducted in the
`United States. Both studies were randomized, double-masked, multi-center, parallel, and vehicle
`(placebo)-controlled studies. The major difference between these two studies was: Study 1
`included 20 sites in the east region of the United States and Study 2 included 19 sites in the west
`region of the United States.
`
`Randomization occurred at the screening visit (1 to 8 days prior to surgery). In each study, 220
`patients were randomized to receive either bromfenac 0.07% or vehicle in a 1:1 ratio. Subjects
`
`Page 4 of 37
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`Reference ID: 3287264
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`

`self-instilled 1 drop of study drug (bromfenac 0.07% or vehicle) into the study (operative) eye
`once daily, beginning 1 day prior to surgery (Day 0), continued on the day of surgery and
`through the first 14 days post-surgery. Subjects were evaluated on Days 1, 3, 8, 15, 22 following
`surgery or 7 days after their last dose of the study drug if subjects prematurely discontinued the
`study drug. Ocular inflammation and pain were assessed at the screening visit and each post-
`surgery visit. Pain was evaluated by the pain score from the Ocular Comfort Grading
`Assessment (OCGA) recorded in the subject diary. Regarding the evaluation of ocular
`inflammation and the primary efficacy outcome of cleared ocular inflammation, the applicant’s
`statistical analysis plan (dated 04/26/2011) states the following:
`
`
`The primary efficacy outcome of cleared ocular inflammation is defined as the proportion of
`subjects that achieve a summed ocular inflammation score (SOIS) of grade 0 (0 cells and
`absence of flare) by Day 15. The SOIS is defined as the sum of the mean anterior chamber cells
`score and anterior flare score. The anterior chamber cell grade is determined twice per study
`visit, and is based on a manual count of cells using a slit lamp biomicroscopy. Between the two
`manual cell counts, the biomicroscopy is to be refocused off and back onto the anterior
`chamber, as a means of obtaining a more precise average estimate. The anterior chamber cell
`grade and flare grade are determined as follows:
`
`Grade
`
`0
`
`0.5
`
`1
`
`2
`
`3
`4
`
`Anterior Chamber Cells
`Manual Cell
`Recorded Cell
`Count
`Grade
`0
`0
`
`1-5 (trace)
`
`0.5
`
`6-15
`
`16-25
`
`26-50
`>50
`
`1
`
`2
`
`3
`4
`
`Anterior Chamber Flare
`
`Grade
`
`Flare
`
`0
`
`1
`
`2
`
`3
`
`4
`
`
`
`Complete absence
`
`Very slight (barely detectable)
`
`Moderate (iris and lens clear)
`
`Marked (iris and lens hazy)
`
`Intense (fibrin clot)
`
`
`
`
`
`
`
`
`The anterior chamber cell score at each study visit is defined as the average of both cell grades
`obtained. If only one grade was collected for any given visit, the cell score will be set to the
`single cell grade. An anterior chamber cell score of zero is achieved at any given study visit
`only if both cell grades are zero, or if only a single cell grade is recorded and was observed to
`be zero. In order to satisfy the primary endpoint of a SOIS of grade zero by Day 15, an anterior
`chamber cells score of grade zero and an anterior flare score of grade zero must be observed
`on any scheduled visit on or prior to the Day 15 visit. Each score will be documented on the
`CRF; the mean values for SOIS will be calculated at the data management level to maintain
`accuracy.
`
`
`The key secondary efficacy endpoint was the proportion of subjects who were pain free (“None”
`on the Ocular Comfort Assessment) at Day 1. The primary efficacy analysis was conducted on
`the ITT population (all randomized subjects). For both the primary and key secondary
`
`Reference ID: 3287264
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`Page 5 of 37
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`

`

`endpoints, the Fisher’s exact test was used to compare the treatment difference. Missing data
`were imputed using the Last Observation Carried Forward (LOCF) method. The comparisons of
`the endpoint of cleared ocular inflammation (0 cell and no flare) at multiple time points (Day 1,
`3, and 8) were adjusted for multiplicity using the Hochberg method.
`
`The applicant’s primary analysis results are presented in Table 2.1. Compared with vehicle, the
`bromfenac group had a statistically significantly higher proportion of subjects who had cleared
`ocular inflammation by Day 15 and a statistically significantly higher proportion of subjects who
`were pain free at Day 1. Compared with vehicle, after adjusting for multiplicity (due to testing
`the endpoint of ocular inflammation at 4 time points) using the protocol-defined Hochberg
`method, the bromfenac group also had a statistically significantly higher proportion of subjects
`who had cleared ocular inflammation by Day 8.
`
`
`Table 2. 1 NDA203168: Applicant’s Efficacy Analysis Results of Phase 3 Studies
`Proportion of Subjects with Cleared Ocular Inflammation
`(0 cell and no flare)
`
`Visit
`
`Day 8
`
`Bromfenac 0.07%
`QD
`
`Vehicle QD
`
`Difference (%)
`(Asymptotic 95% CI)
`
`30/112 (26.8%)
`
`8/108 (7.4%)
`
`19.4 (9.8, 28.9)
`
`Day 15 (primary*)
`
`54/112 (48.2%)
`
`18/108 (16.7%)
`
`31.5 (19.9, 43.2)
`
`Day 8
`
`36/110 (32.7%)
`
`18/110 (16.4%)
`
`16.4 (5.2, 27.5)
`
`
`
`Study
`
`Study 1
`
`Study 2
`
`Day 15 (primary*)
`
`17.3 (4.5, 30.0)
`35/ 110 (31.8%)
`54/ 110 (49.1%)
`Proportion of Subject who Were Pain Free
`(0 pain score)
`47 (43.5%)
`
`37.7 (25.9, 49.6)
`
`91 (81.3%)
`
`Study 1 Day 1
`
`20.9 (8.7, 33.1)
`61 (55.5%)
`84 (76.4%)
`Study 2 Day 1
`Data Source: Table 2 of the primary statistical review dated 04/01/2013 (the p-values presented in the table were adjusted p-
`values using the Hochberg method).
`*This is stated as primary endpoint; however, some subjects who did not have a cell score of Grade 0 (0 cell) at Day 15 were
`treated as successes in this analysis. The FDA statistical reviewer’s analysis in Table 2.3 treated these subjects as failures.
`
`As shown in Table 2.2, for the two studies combined, there were 15 subjects in both treatment
`groups whose ocular inflammation was cleared at or prior to Day 8 but was not cleared at Day
`15. Among them, 13 (87%) subjects had a cell score of Grade 0.5 (1-5 cells), and 2 (13%)
`subjects had a cell score of Grade 1 (6-15 cells). These 15 subjects were counted as successes in
`the applicant’s analysis in Table 2.1, although these subjects had a cell count in the range of 1-15
`cells at Day 15 and a cell count of 0 at baseline (screening visit).
`
`These 15 subjects were treated as failures in the FDA’s statistical reviewer’s analysis presented
`in Table 2.3. Compared with the applicant’s analysis, the statistical reviewer’s analysis yielded a
`lower success rate at Day 15 for both treatment groups: 45.5% vs. 48.2% in the bromfenac
`Page 6 of 37
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`Reference ID: 3287264
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`

`

`group, and 13.0% vs. 16.7% in the vehicle group in Study 1; 45.4% vs. 49.1% in the bromfenac
`group, and 27.3% vs. 31.8% in the vehicle group in Study 2. The treatment differences in the
`FDA’s analysis were similar to the applicant’s analysis at both Visit time points.
`
`The numbers of subjects who received a rescue therapy were: 40 (4 in the bromfenac group and
`36 in the vehicle group) in Study 1 and 41 (8 in the bromfenac group and 33 in the vehicle
`group) in Study 2. It should be noted that the applicant’s LOCF analysis has imputed failures for
`all subjects who received a rescue therapy except for 1 vehicle-treated subject in Study 2. This
`subject was treated as failure in the FDA’s analysis in Table 2.3.
`
`(b) (4)
`
`in the following section this review examines the analysis
`results for the NDAs that were submitted and approved since 2004 for the treatment of ocular
`inflammation afier cataract surgery.
`
`Table 2. 2 NDA203168: Number of Subjects whose ocular inflammation was cleared (0 cell and no
`flare at or urior to Dav 8 but was not cleared cell score or flare score >0 at Dav 15
`
`# of
`
`Cell Score at Day 15
`
`(0 cell)
`(1—5 cells)
`(($15 cells)
`(16—25 cells)
`(26—50 cells)
`(>50 cells)
`.-——————_
`mnnnnn
`mun-_“n
`“mun-“m-
`___—————
`“mun-“m-
`___UI-I-I-
`”nu-Inn“
`___—————
`__—-_-_-_-_-_
`”nun-“nu-
`“mu-“m-
`
`--
`
`Flare Score atDay 15
`
`
`
`Studv 1 _—————
`———--_-_-_
`————_‘--_-_
`___———-_-_
`-_—————
`__——.--_-_
`———-.--_-_
`——n—-‘--_-_
`Data Source: Calculated by the statistical review team.
`*Two subjects had “0“ cell score for the first grade and “0.5" cell score for the second grade and two subjects had
`“0.5“ cell score for both grades. ** One subject had a cell score of “1" for both grades and one subject had “1“ cell
`score for the first grade and “0“ cell score for the second grade.
`
`Reference ID: 3287264
`
`Page 7 of 37
`
`

`

`Table 2. 3 NDA203168: FDA’s Primary Statistical Reviewer’s Analysis Results of Phase 3 Studies
`Proportion of Subjects with Cleared Ocular Inflammation
`(0 cell and no flare)
`
`
`
`Study
`
`Study 1
`
`Study 2
`
`Visit
`
`Day 8
`
`Day 15
`
`Day 8
`
`Bromfenac 0.07%
`QD
`
`Vehicle QD
`
`Difference (%)
`(Asymptotic 95% CI)
`
`27/112 (24.1%)
`
`7/108 (6.5%)
`
`17.6 (8.4, 26.8)
`
`51/112 (45.5%)
`
`14/108 (13.0%)
`
`32.5 (21.4, 43.8)
`
`33/110 (30.0%)
`
`14/110 (12.7%)
`
`17.3 (6.7, 27.9)
`
`Day 15
`18.2 (5.7, 30.7)
`30*/ 110 (27.3%)
`50/ 110 (45.4%)
`Data Source: Table 1 from the primary statistical review dated 04/01/2013. Note: The adjusted p-values using the
`Hochberg method were < 0.05 for the treatment difference at both time points (Day 8 and Day 15).
`* One subject who received a rescue therapy was treated as failure in the FDA’ analysis and this subject was treated as
`success in the applicant’s analysis in Table 2.1.
`
`
`3 Efficay Analysis Evaluations of 7 Approved NDAs for the Treatment of
`Ocular Inflammation after Cataract Surgery
`
` A
`
` total of 7 NDAs (see Table 3.0) were submitted and approved for the treatment of ocular
`inflammation after cataract surgery since 2004. For each of these 7 NDAs, this review presents,
`in Section 3.1 through 3.7, the findings on how ocular inflammation was defined and analyzed
`and what information was included in the Clinical Studies section of the labeling. For each of
`these 7 NDAs, this review also examines whether there were subjects whose ocular inflammation
`was cleared by week 1 (days 7-8 ) but was not cleared at week 2 (days 14-15) post-surgery, and
`how these subjects were treated in the analysis for the endpoint of cleared ocular inflammation,
`as this is the difference in the applicant’s and the statistical reviewer’s analyses for the current
`NDA203168.
`
`Table 3.0: List of NDAs Approved in 2005-2012 for post-operative Inflammation after Cataract Surgery
`NDA
`Submitted Approved
`3.1 NDA021664 Xibrom (bromfenac ophthalmic solution, 0.09% BID)
`2004
`2005
`3.2 NDA021862 Nevanac (nepafenac ophthalmic suspension, 0.1% TID)
`2005
`2005
`3.3 NDA022212 Durezol (difluprednate ophthalmic emulsion, 0.05%)
`2007
`2008
`3.4 NDA021664 Bromday (bromfenac ophthalmic solution, 0.09% QD)
`2009
`2010
`2.5 NDA200738 Lotemax (loteprednol etabonate ophthalmic ointment, 0.5% QID)
`2009
`2010
`3.6 NDA202872 Lotemax (loteprednol etabonate ophthalmic gel, 0.5% QID)
`2011
`2012
`3.7 NDA203491 Ilevro (nepafenac ophthalmic suspension, 0.3% QD)
`2011
`2012
`
`
`Reference ID: 3287264
`
`Page 8 of 37
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`

`

`It is noted that the title for Section 3.1 through 3.7 contains the exact wordings of indication from
`the labeling of each approved drug.
`
`
`3.1 NDA021664 Xibrom (bromfenac ophthalmic solution, 0.09% BID) for the treatment
`of postoperative inflammation in patients who have undergone cataract extraction
`
`
`This NDA submission was a paper submission and only the datasets (with blank CRF) were
`submitted electronically. Thus, the statistical team leader does not have access to the study
`reports/protocols/analysis plans from this submission. The study designs/analysis plans
`discussed below are from the primary medical review by Dr. Jennifer Harris dated 03/14/2005.
`
`This NDA included two identically-designed, randomized, and double-masked phase 3 studies in
`subjects who underwent cataract extraction with posterior chamber intraocular lens implantation.
`One day after surgery, subjects were randomized to receive the test product or vehicle in a 2:1
`ratio. Subjects self-instilled study drug (test product or vehicle) into the study (operative) eye
`twice a day for 14 days, beginning 1 day after surgery. Anterior chamber cell score and flare
`score were used to assessed ocular inflammation at the screening visit (1 to 7 days prior to
`surgery) and each post-surgery visit: Day 1, 3, 8, 15, 22, and 29 or early exit visit.
`
`Regarding the definition of the original primary endpoint, the primary medical review (on page
`13) reported the following:
`
`
`The original primary efficacy endpoint for the phase 3 trials proposed by the sponsor was
`defined as a summed ocular inflammation score (i.e. cell+ flare) (cid:148) 1 within the 14-day
`treatment period. This is not considered an acceptable endpoint for the treatment of ocular
`inflammation since rebound is a common occurrence after anti-inflammatory drugs are
`discontinued. This endpoint did not address this concern or the sustainability of the effect
`after the active-treatment period.
`
`The agency requires a more rigorous definition of efficacy which required bromfenac to
`demonstrate both statistical and clinical significance in the reduction of summed ocular
`inflammation score, or reduction in anterior cells, as compared to vehicle. A decision was
`made to redefine the primary efficacy endpoint. The primary efficacy endpoint is defined as
`the sum of anterior chamber cell and flare equal to zero (based on a five-point scale for
`each) at Visit 4 (Day 15).
`
`
`Regarding the definition of the primary endpoint presented in the NDA submission, the primary
`medical review (on pages 15-16) reported the following:
`
`
`The primary efficacy outcome was the proportion of subjects in the ITT population with
`cleared ocular inflammation in the study eye at Visit 4 (Day 15 visit). Cleared ocular
`inflammation was defined as a summed ocular inflammation score (anterior chamber cell
`score plus flare score, each measured on a five-point scale) of zero. The anterior chamber cell
`and flare score was determined as follows:
`
`
`
`Reference ID: 3287264
`
`Page 9 of 37
`
`

`

`
`
`
`
`Grade
`0
`1
`2
`3
`4
`
`Cell Count
`Non-5 (trace)
`6-15
`16-25
`26-50
`>50
`
`
`
`
`
`Grade
`0
`1
`2
`3
`4
`
`Flare
`Complete absence
`Very slight
`Moderate
`Marked
`Intense
`
`
`Regarding the above cell grade scores, the primary medical review (on page 6) had the following
`comments:
`
`
`The grading scale used by ISTA to evaluate the clearance of inflammatory cells (component of
`the primary efficacy endpoint) is not the Division’s recommended grading scale. Using the
`sponsor’s scale can lead to misleading results since patients who are graded as having
`“cleared ocular inflammation” may in fact still have trace inflammatory cells in the anterior
`chamber. This may or may not have had any clinical relevance based on the types of cells that
`were present.
`
`
`Dr. Wiley Chambers also had concern regarding evaluation of clearance of ocular inflammation
`allowing presence of non-zero cells in his review dated 03/25/2005 (on page 2):
`
`
`The trials were designed to evaluate the clearance of post-operative inflammation following
`cataract surgery. Evaluation of clearance in these studies however, was not true clearance
`because evaluations demonstrating 1-5 cells per high power field (normally called trace
`inflammation) were counted as cleared.
`
`
`According to the blank CRF located at \\fdswa150\NONECTD\N21664\N_000\2004-05-
`24\CRT\DATASETS\ISTA-BR-CS-001, the chamber cell scores were recorded in the datasets as
`defined in Table 3.1.1 and the flare scores in Table 3.1.2 (same as in the current NDA203168):
`
` Table 3.1. 1 NDA021664 Xibrom: CRF-defined Anterior Chamber Cell Score
`Grade 0
`Grade 0.5
`Grade 1
`Grade 2
`Grade 3
`Grade 4
`
`0 cell
`
`1-5 cells
`
`6-15 cells
`
`16-25 cells
`
`26-50 cells
`
`> 50 cells
`
`Table 3.1. 2 NDA021664 Xibrom: CRF-defined Anterior Chamber Flare Score
`Grade 0
`Grade 1
`Grade 2
`Grade 3
`Grade 4
`Complete
`Very slight
`Moderate
`Marked
`Intense
`absence
`(barely detectable)
`(iris and lens clear)
`(iris and lens haze)
`(fibrin clot)
`
`
`According to the CRF, the anterior chamber cell counts were graded twice and both grades were
`recorded on the CRF at each visit. Based on the CRF data, this review conducted analyses for
`the proportion of subjects whose ocular inflammation was cleared (defined as “0 cell and no
`flare”) and the results are presented in Table 3.1.3 and Table 3.1.4.
`
`
`Page 10 of 37
`
`Reference ID: 3287264
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`

`

`The difference between these two analyses is: the analysis in Table 3.1.3 treated all subjects who
`received a rescue therapy as failures regardless of whether their ocular inflammation was cleared
`or not, whereas the analysis in Table 3.1.4 did not treat those subjects as failures if their ocular
`inflammation was cleared a given visit.
`
`
`Table 3.1. 3 NDA021664 Xibrom: Efficacy Results of Phase 3 Studies (Subjects who received a
`rescue therapy were treated as failures) (Randomized Population)
`Proportion of Subject with Cleared Ocular Inflammation
`(0 cell and no flare)
`
`
`
`Study
`
`Study 1
`
`Study 2
`
`Visit
`
`Day 8
`
`Xibrom 0.09% BID
`
`Vehicle BID
`
`64/198(32.3%)
`
`12/98 (12.2%)
`
`Difference
`(Asymptotic 95% CI)
`20.1 (10.9, 29.3)
`
`Day 15 (primary)
`
`113/198 (57.1%)
`
`23/98 (23.5%)
`
`33.6 (22.7, 44.5)
`
`Day 8
`
`60/158 (38.0%)
`
`11/73 (15.1%)
`
`22.9 (11.7, 34.1)
`
`30.5 (17.4, 43.6)
`23/73 (31.5%)
`98/158 (62.0%)
`Day 15 (primary)
`Data Source: Calculated by the statistical review team based on the submitted efficacy datasets for the Xibrom
`NDA021664. The submitted datasets are located at \\fdswa150\NONECTD\N21664\N_000\2004-05-24.
`
`
`Table 3.1. 4 NDA021664 Xibrom: Efficacy Results of Phase 3 Studies (Subjects who received a
`rescue therapy were treated as successes if their ocular inflammation was cleared)
`Proportion of Subject with Cleared Ocular Inflammation
`(0 cell and no flare)
`
`
`
`Study
`
`Study 1
`(ER)
`
`Study 2
`
`Visit
`
`Day 8
`
`Xibrom 0.09% BID
`
`Vehicle BID
`
`67/198(33.8%)
`
`13/98 (13.3%)
`
`Difference (%)
`(Asymptotic 95% CI)
`20.6 (11.2, 30.0)
`
`Day 15 (primary)
`
`124/198 (62.6%)
`
`39/98 (39.8%)
`
`22.8 (11.0, 34.6)
`
`Day 8
`
`61/158 (38.6%)
`
`16/73 (21.9%)
`
`16.7 (4.5, 28.8)
`
`35/73 (47.9%)
`
`17.9 (4.2, 31.5)
`
`104/158 (65.8%)
`Day 15 (primary)
`Data Source: Same as for Table 3.1.3.
`
`The numbers of subjects whose ocular inflammation was cleared (0 cell and no flare) at or prior
`to Day 8 but was not cleared at Day 15 are presented in Table 3.1.5. For the two studies
`combined, there were 19 subjects in both treatment groups whose ocular inflammation was
`cleared at or prior to Day 8 but was not cleared at Day 15. Among them, 5 (26%) subjects had a
`cell score of Grade 0.5 (1-5 cells), 3 (16%) subjects had a cell score of Grade 1 (6-15 cells), and
`the remaining 11 (58%) subjects had a cell score of Grade 0 but a non-zero score for flare. All of
`these 19 subjects were treated as failures at Day 15 in Table 3.1.3 and Table 3.1.4.
`
`
`Reference ID: 3287264
`
`Page 11 of 37
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`

`

`Table 3.1. 5 NDA021664 Xibrom: Number of subjects whose ocular inflammation was cleared (0
`cell and no flare) at or prior to Day 8 but was not cleared at Day 15 (cell score or flare score > 0)
`Cell Score at Day 15
`
`
`Study
`
`Study 1
`Study 2
`Pooled
`
`
`Total
`Number Grade 0
`(0 cell)
`6
`5
`11
`
`10
`9
`19
`
`Grade 0.5
`(1-5 cells)
`3
`2
`5
`
`Grade 3
`(26-50 cells)
`0
`0
`0
`
`Grade 4
`(>50 cells)
`0
`0
`0
`
`Grade 2
`Grade 1
`(16-25