CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203168Orig1s000
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`
`
`
`

`

`Cross—Discipline Team Leader Review
`
`
`Date
`April 4, 2013
`From
`William M. B0 (1, MD.
`m_ Cross-Disci line Team Leader Review
`203168
`
`June 6, 2012
`Date of Submission
`
`PDUFA Goal Date
`April 7, 2013
`
`Bausch & Lomb, Inc.
`
`Recommended for A roval
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Prolensa (bromfenac ophthalmic solution) 0.07%
`
`Dosa _e forms / Stren_ h
`Proposed Indication(s)
`
`Recommended:
`
`To a ical o .hthalmic solution, 0.07%
`Treatment of postoperative inflammation and reduction of
`ocular pain in patients who have undergone cataract
`sure
`
`1. Introduction
`
`Bromfenac ophthalmic solution is a non-steroidal anti—inflammatory drug (NSAID) studied for
`the treatment of postoperative inflammation and the reduction of pain in subjects who have
`undergone cataract surgery. Bromfenac is a nonsteroidal anti-inflammatory drug (NSAID)
`that has anti-inflammatory activity. The mechanism of its action is thought to be due to its
`ability to block prostaglandin synthesis by inhibiting cyclooxygenase (COX) 1 and 2.
`
`NBA 21-664 Xibrom (bromfenac ophthahnic sodium) 0.09% was approved in March 2005
`(Original) for the treatment of post-operative ocular inflammation and in January of 2006 (SE1
`S-01) for the treatment of post-operative pain.
`
`Bromday (bromfenac ophthahnic sodium) 0.09%, the same drug product labeled for the same
`indication to be dosed once per day was approved on 10/16/2010 (SE2 8-13).
`
`The chemical structure for bromfenac sodium sesquihydrate is:
`
`0I
`
`I80c
`
`HzN
`
`CHzcozNa
`
`-11/2H20
`
`There are multiple ophthalmic topical drugs approved for inflammation and pain following
`cataract extraction or ocular surgery including:
`
`Reference ID: 3287805
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`Ketorolac tromethamine ophthalmic solution 0.45%, 0.5% (i.e., Acuvail, Acular)
`Rimexolone ophthalmic suspension 1% (i.e., Vexol)
`Bromfenac ophthalmic solution 0.09% (i.e., Xibrom, Bromday)
`Nepafenac ophthalmic suspension 0.1%, 0.3% (i.e., Nevanac, Ilevro)
`Loteprednol etabonate ophthalmic suspension 0.5% (i.e., Lotemax)
`Loteprednol ophthalmic ointment 0.5% (i.e., Lotemax)
`Loteprednol ophthalmic gel 0.5% (i.e., Lotemax)
`Difluprednate ophthalmic emulsion 0.05% (i.e., Durezol).
`
`Post-marketing experience with this class of drugs has shown that use of topical NSAIDs for
`more than 24 hours prior to surgery or use beyond 14 days post surgery may increase the risk
`for the occurrence and severity of corneal adverse events such as epithelial breakdown, corneal
`thinning, corneal erosion, corneal ulceration and corneal perforation which are potentially
`sight threatening. Class labeling addressing this issue has been added to all existing topical
`NSAID labels and will be contained in the label for this drug product.
`
`2. Background
`
`
`Clinical studies for this new drug application were conducted under IND 060295.
`
`On April 14, 2011, a Special Protocol Assessment – No Agreement letter was issued for the
`Phase 3 clinical protocol titled: Efficacy and Safety of Bromfenac Ophthalmic Solution vs.
`Placebo for the Treatment of Ocular Inflammation and Pain Associated with Cataract Surgery.
`
`On August 29, 2011, a Pre-NDA teleconference meeting was held to discuss bromfenac
`ophthalmic solution, 0.07% for treatment of ocular inflammation and pain associated with
`cataract surgery.
`
`In a submission dated August 20, 2012, the Agency was informed that Bausch and Lomb Inc.
`had acquired ISTA Pharmaceuticals, Inc. The contact information (address and phone
`numbers) for this NDA remained the same.
`
`3. Product Quality
`
`
`Each mL of Prolensa (bromfenac ophthalmic solution) 0.07% contains:
`
`Active: Each mL contains bromfenac sodium sesquihydrate 0.0805%, which is equivalent to
`bromfenac free acid 0.07%.
`Preservative: benzalkonium chloride 0.005%
`Inactives: boric acid, edetate disodium, povidone, sodium borate, sodium sulfite, tyloxapol,
`sodium hydroxide to adjust pH and water for injection, USP.
`
`Reference ID: 3287805
`
`2
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`From the original Product Quality Review dated 2/26/2013:
`
`DRUG SUBSTANCE:
`The Active Pharmaceutical Ingredient (API) in the drug product is bromfenac sodium drug
`substance. The same drug substance is used in the manufacture of the currently marketed
`bromfenac ophthalmic solution 0.09% formulation in this applicant’s original NDA 21-664,
`which was approved on 24 March 2005. The manufacturer and supplier, manufacturing
`process, test methods, specifications, and all other parameters are the same as those applied to
`the drug substance for the currently approved Xibrom/Bromday 0.09% formulation.
`
`DRUG PRODUCT:
`The drug product is a non-steroidal anti-inflammatory drug (NSAID) for topical ophthalmic
`use. It is supplied as a clear, yellow, sterile solution containing 0.07% bromfenac free acid and
`dispensed from a 7.5cc capacity white low density polyethylene (LDPE) bottle with a white
`linear
` tip, and grey
` screw cap. The drug product is supplied in trade sizes
`of 1.6 mL and 3 mL fill volumes and sample sizes of 0.6 mL and 0.8 mL fill volumes.
`
`Per a March 12, 2013, amendment to the NDA, the applicant states that the 3-mL fill size is
`necessary to complete the labeled dosing regimen for the elderly population (approximately
`45% of the subjects in the Prolensa clinical studies were >70 years of age) as significant
`wastage of drops has been documented. This is acceptable.
`
`The components of the container closure system used for bromfenac ophthalmic solution
`0.07% are identical to the marketed bromfenac ophthalmic solution 0.09% (NDA 21-664).
`
`QUANTITATIVE COMPOSITION:
`
`Declared Function
`
`Bromfenac sodium sesquihydrate Active
`Boric acid
`Sodium borate
`Sodium sulfite
`Edetate disodium (EDTA)
`Tyloxapol
`Benzalkonium chloride
`Povidone
`Sodium hydroxide
`Water for Injection
`
`Preservative
`
`pH adjuster
`
`
`
`Reference ID: 3287805
`
`%w/v
`0.0805
`
`mg per mL
`0.805
`
`0.005
`
`0.05
`
`q.s. to pH 7.8 q.s. to pH 7.8
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross-Discipline To- Leader Review
`William M. Boyd, M.D.
`NBA 203 168
`
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`REGULATORY SPECIFICATIONS:
`
`Table 1.
`
`Specifications for Bromfennc Ophthalmic Solution 0.07%
`
`Clmellow sermon
`A white plastic bottle with dropper tip and gray cap, with no
`significant discoloration or physical distortion
`
`.
`_
`.
`.
`mmphon' comm”
`
`Identification
`(release only)
`
`Bromfenac Sodirnn Assay
`
`Bromfenac Impurities
`
`-—
`
`Any Individual Unspecified Impurity
`—
`
`—
`
`Osmolality
`
`Benzalkonium Chlorida'
`
`Sodium Sulfite
`
`Bacterial Endotoxins
`
`Particulate Matter
`(Microscopic Evaluation)
`
`Particulate Matter (Visual)
`Weight Loss
`stabili
`on]
`
`In the above specification table, the applicant did not include Leachables testing during shelf-
`life. The approved 0.09% formulation (NDA 203-168) is also packaged in 7.5 cc plastic
`bottles (as one of the configurations) and labeled with same labels and adhesive. NBA 21-
`664/S-017 was recently approved (6/6/12), which allowed the elimination of ongoing
`leachables testing based on large body ofXibrom-specific historical data.
`
`Reference ID: 3287805
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203 168
`
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`INSPECTIONS:
`
`An “Acceptable” site recommendation from the Office of Compliance has been made.
`
`FDA CDER EES
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`
`Reference ID: 3287805
`
`

`

`Cross-Disc'mline Team Leader Review
`William M. Boyd, M.D.
`NDA 203 168
`
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
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`4. Nonclinical Pharmacology/Toxicology
`
`The Pharmacology/Toxicology Review ofNDA 20—535, Bromfenac tablets, pages 28—30
`includes pharmacokinetic parameters of oral administration for mice, rats, rabbits, dogs,
`cynomologus monkeys, rhesus monkeys and humans. The measured or estimated Cm values
`are listed below. The applicant did not attempt to measure systemic absorption from
`ophthalmic dosing because the limit of the assay detection was 50 ng/mL.
`
`Reference ID: 3287805
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`The estimated Cmax for a 0.9 mg/kg dose to a rat would be 4.4 mcg/mL (4400 ng/mL).
`Assuming a maximum human Cmax is the limit of detection or 50 ng/mL as described in the
`Agency proposed labeling, the multiple would be approximately 90 times.
`
`The estimated Cmax for a 0.3 mg/kg dose to a rat would be 1.4 mcg/mL (1400 ng/mL).
`Assuming a maximum human Cmax is the limit of detection or 50 ng/mL as described in the
`Agency proposed labeling, the multiple would be approximately 30 times.
`
`For mice, the Cmax for a 5.0 mg/kg dose was 16.9 mcg/mL (16,900 ng/mL). Assuming a
`maximum human Cmax is the limit of detection or 50 ng/mL as described in the Agency
`proposed labeling, the multiple would be approximately 340 times.
`
`For rabbits, the Cmax for a 7.5 mg/kg dose was 7.6 mcg/mL (7600 ng/mL). Assuming a
`maximum human Cmax is the limit of detection or 50 ng/mL as described in the Agency
`proposed labeling, the multiple would be approximately 150 times.
`
`Long-term carcinogenicity studies in rats and mice given oral doses of bromfenac up to 0.6
`mg/kg/day (30 times the recommended human ophthalmic dose [RHOD] assuming the
`systemic concentration is at the maximum limit of quantification[50 ng/mL]) and 5 mg/kg/day
`(340 times RHOD), respectively, revealed no significant increases in tumor incidence.
`
`Bromfenac did not show mutagenic potential in various mutagenicity studies, including the
`reverse mutation, chromosomal aberration, and micronucleus tests.
`
`Bromfenac did not impair fertility when administered orally to male and female rats at doses
`up to 0.9 mg/kg/day and 0.3 mg/kg/day, respectively (90 and 30 times RHOD, respectively).
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`From the original Clinical Pharmacology Review dated 2/29/2013:
`
`No new clinical pharmacology data was presented in this supplement. Thus, no review is
`needed for this NDA submission.
`
`The sponsor conducted two Phase 3 studies S00124-ER and S00124-WR evaluated the
`efficacy and safety of Prolensa vs. placebo for the treatment of ocular inflammation and pain
`associated with cataract surgery.
`
`From a Clinical Pharmacology perspective, the application is acceptable. No new clinical
`pharmacology data was presented in this supplement.
`
`Reference ID: 3287805
`
`7
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`6. Sterility Assurance
`
`
`From the original drug substance Product Quality Microbiology Review dated 1/22/2013:
`
`NDA 203168/N-000 is recommended for approval from the standpoint of product quality
`microbiology.
`
` at the Bausch and Lomb Tampa,
`The drug product will be
`FL facility. The applicant provided an adequate summary of the microbiological attributes of
`the drug product. The raw counts for preservative effectiveness testing were requested due to
`past issues with regard to preservative testing of other bromfenac ophthalmic formulations.
`The results of preservative testing were adequate.
`
`No product quality microbiology deficiencies were identified based upon the information
`provided.
`
`7. Clinical/Statistical - Efficacy
`
`From the original Medical Officer Review dated 3/22/2013:
`
`The two Phase 3 studies, S00124-ER and S00124-WR utilized the same protocol administered
`in the eastern and western regions of the United States, respectively.
`
`For both Phase 3 studies, the primary efficacy outcome was the proportion of subjects who had
`cleared ocular inflammation (SOIS of grade 0) by Day 15. The SOIS is defined as the sum of
`the mean anterior chamber cells score and anterior flare score.
`
`All analyses of efficacy were conducted on the ITT Population. The primary analyses were
`based on the ITT Population with the LOCF data.
`
`Reference ID: 3287805
`
`8
`
`(b) (4)
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`Analysis of Primary Endpoint(s)
`S00124-ER
`
`The proportion of subjects who had cleared ocular inflammation (SOIS Grade 0) by Day 8 and
`by Day 15 were significantly higher (p<0.001) in the bromfenac 0.07% group (27-48%)
`compared with the placebo group (7-17%).
`
`S00124-WR
`
`The proportion of subjects who had cleared ocular inflammation by Day 8 and by Day 15 was
`significantly higher (p<0.05) in the bromfenac 0.07% group (33-49%) compared with the
`placebo group (16-32%).
`
`Reference ID: 3287805
`
`9
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`Analysis of Secondary Endpoints(s)
`For both Phase 3 studies, the secondary efficacy outcome was the proportion of subjects who
`were free of ocular pain at Day 1.
`
`S00124-ER
`
`The proportion of subjects who were pain free was significantly higher in the bromfenac 0.07%
`than in the placebo group at Day 1 (81.3%, 91/112 versus 43.5%, 47/108; p<0.0001).
`
`S00124-WR
`
`The proportions of subjects who were pain free were significantly higher in the bromfenac
`0.07% than in the placebo group at Day 1 (76.4%, 84/110 versus 55.5%, 61/110; p=0.0017).
`
`Reference ID: 3287805
`
`10
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`Additional Efficacy Issues/Analyses: Cleared Cells at Each Visit
`The following table shows the proportion of subjects who had cleared inflammation at each visit
`(LOCF, Summed Ocular Inflammation Score: Grade 0).
`
`S00124-ER
`
`
`S00124-WR
`
`
`
`The percentage of patients that clear “at a particular day” is just one of many additional analyses;
`after adjustment for multiplicity, the differences “at day x” are not statistically significant in both
`trials.
`
`Reference ID: 3287805
`
`11
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`Summary Efficacy Statement
`
`Adequate and well controlled studies (S00124-ER and S00124-WR) support the efficacy of
`Prolensa (bromfenac ophthalmic solution) 0.07% for the treatment of postoperative
`inflammation and reduction of ocular pain in patients who have undergone cataract surgery.
`
`The proportion of subjects who had cleared ocular inflammation (SOIS Grade 0) by Day 8 and
`by Day 15 (specified primary endpoint) was significantly higher in the bromfenac 0.07%
`group compared with the placebo group in both Phase 3 trials.
`
`8. Safety
`
`From the original Medical Officer Review dated 3/22/2013:
`
`Exposure
`
`Reference ID: 3287805
`
`12
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`Subjects participating in studies S00124-ER and S00-124-WR were assigned to receive
`bromfenac 0.07% QD for a maximum of 16 days. The mean number of doses received in a
`pooled analysis was 14.6 (1.0 to 16.0).
`
`Disposition of Subjects
`
`
`The definition of “study completion” as defined in Table 4 (Section 10.1 of the CSRs) for
`S00124-ER and S00124-WR in the original NDA submission was not acceptable. Subjects
`who discontinued investigational product early and completed the final study visit should not
`be considered to have completed the study. Revised tables for study disposition were provided
`to the application S00124-ER and S00124-WR on March 13, 2013. See the following tables.
`
`
`
`Reference ID: 3287805
`
`13
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`S00124-ER
`
`S00124-WR
`
`
`
`The Agency asked the applicant to comment on the disparity between the S00124-ER (ER)
`and S00124-WR (WR) in the number of subjects discontinuing IP early due to an adverse
`event. Per the applicant’s submission dated March 2, 2013, it appears that the WR placebo
`group had a much higher IP-discontinuation rate due to counting signs and symptoms of ocular
`inflammation and pain as adverse events, whereas the ER placebo group had appeared to count
`many of these same signs and symptoms as IP discontinuations due to treatment failures.
`
`
`14
`
`Reference ID: 3287805
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`Per the applicant, these differences might be reflected in the differences in placebo rates for the
`efficacy endpoint of cleared ocular inflammation (WR 31.8% vs. ER 16.7%). See the Medical
`Officer’s review, Section 7.3.3, for more detail.
`
`The efficacy outcomes for the proportion of subjects with SOIS=0 by Day 15 with the
`investigational product were nearly identical in both groups (WR 49.1% vs. ER 48.2%). See
`the Medical Officer’s review, Section 7.3.3, for more detail.
`
`Thus, the applicant concluded that these differences in assessing reasons for discontinuing IP
`early between groups did not affect the overall study conclusions. This conclusion by the
`applicant is reasonable.
`
`Deaths
`
`There were no deaths in either Study S00124-ER or Study S00124-WR. No deaths were
`reported during any of the BromCom, QD-ER, QD-WR, and QDII clinical studies with
`bromfenac 0.09% QD or in the S00007 studies with bromfenac
` and bromfenac
`BID.
`
`Common Adverse Events
`
`
`
`Incidence of Adverse Events Affecting the Study Eye: Events with an Incidence of (cid:149) 1.5
`% in the Bromfenac 0.07% Group or Placebo Group (ITT Population)
`
`Bromfenac
`0.07%
`N = 112
`(ER)
`0 (0%)
`
`Bromfenac
`0.07%
`N = 110
`(WR)
`8 (7.3%)
`
`Placebo
`N = 108
`(ER)
`
`Placebo
`N = 110
`(WR)
`
`0 (0%)
`
`18 (16.4%)
`
`0 (0%)
`1 (0.9%)
`0 (0%)
`1 (0.9%)
`0 (0%)
`0 (0%)
`0 (0%)
`3 (2.7%)
`1 (0.9%)
`0 (0%)
`3 (2.7%)
`1 (0.9%)
`0 (0%)
`0 (0%)
`
`0 (0%)
`2 (1.8%)
`1 (0.9%)
`1 (0.9%)
`0 (0%)
`1 (0.9%)
`0 (0%)
`9 (8.2%)
`2 (1.8%)
`0 (0%)
`4 (3.6%)
`3 (2.7%)
`2 (1.8%)
`0 (0%)
`
`3 (2.8%)
`2 (1.9%)
`0 (0%)
`2 (1.9%)
`0 (0%)
`0 (0%)
`6 (5.6%)
`6 (5.6%)
`2 (1.9%)
`2 (1.9%)
`5 (4.6%)
`6 (5.6%)
`0 (0%)
`0 (0%)
`
`2 (1.8%)
`13 (11.8%)
`2 (1.8%)
`8 (7.3%)
`2 (1.8%)
`3 (2.7%)
`0 (0%)
`14 (12.7%)
`2 (1.8%)
`4 (3.6%)
`3 (2.7%)
`5 (4.5%)
`3 (2.7%)
`2 (1.8%)
`
`15
`
`
`
`Preferred Term
`
`Anterior chamber
`inflammation
`Vitreous floaters
`Conjunctival hyperemia
`Conjunctival edema
`Corneal edema
`Punctate keratitis
`Iritis
`Lacrimation increased
`Eye pain
`Eye pruritis
`Ocular hyperemia
`Foreign body sensation in eyes
`Photophobia
`Intraocular pressure increased
`Visual acuity reduced
`
`Reference ID: 3287805
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`Preferred Term
`
`Cystoid macular edema
`Diplopia
`Vision blurred
`
`Bromfenac
`0.07%
`N = 112
`(ER)
`0 (0%)
`0 (0%)
`0 (0%)
`
`Bromfenac
`0.07%
`N = 110
`(WR)
`0 (0%)
`0 (0%)
`4 (3.6%)
`
`Placebo
`N = 108
`(ER)
`
`0 (0%)
`0 (0%)
`2 (1.9%)
`
`Placebo
`N = 110
`(WR)
`
`2 (1.8%)
`2 (1.8%)
`2 (1.8%)
`
`More subjects were evaluated for efficacy than were evaluated for safety in both S00124-ER
`and S00124-WR.
`
`A reanalysis of the study data for S00124-ER and S00124-WR with the Safety Population
`defined as least as loosely as the Intent-to-Treat (ITT) Population (i.e. all randomized subjects,
`where subjects were to be analyzed in the group to which they were randomized) was
`requested by the Agency.
`
`The most commonly reported adverse reactions in seen 3-8% of bromfenac ophthalmic
`solution 0.7% treated patients were: anterior chamber inflammation, eye pain, foreign body
`sensation, photophobia, and vision blurred.
`
`Safety Summary Statement
`Adequate and well controlled studies have been previously conducted with higher
`concentrations of bromfenac ophthalmic solution (0.09%) under NDA 21-664, and these
`studies also support the support the safety of bromfenac ophthalmic solution 0.07% for the
`treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract surgery.
`
`Adequate and well controlled studies (S00124-ER and S00124-WR) support the safety of
`Prolensa (bromfenac ophthalmic solution) 0.07% for the treatment of postoperative
`inflammation and reduction of ocular pain in patients who have undergone cataract surgery.
`
`A 120 Day Safety Update was submitted on 10/9/2012. No new safety issues relating to
`Prolensa (bromfenac ophthalmic solution) 0.07% have been found.
`
`9. Advisory Committee Meeting
`
`
`No Advisory Committee Meeting was held. There were no new issues raised in the review of
`the application which were thought to benefit from an Advisory Committee Meeting.
`
`Reference ID: 3287805
`
`16
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`10.
`
`Pediatrics
`
`PREA was not triggered for this application, and thus this application was not presented at the
`Pediatric Review Committee (PeRC). Studies were waived for all pediatric age groups;
`cataract surgery is not performed on a substantial number of pediatric patients, and the use of
`topical NSAIDS in pediatric patients does not represent a meaningful therapeutic benefit over
`topical corticosteroids.
`
`Safety and effectiveness of Prolensa (bromfenac ophthalmic solution) 0.07% in pediatric
`patients have not been established.
`
`11.
`
`Other Relevant Regulatory Issues
`
`BIOSTATISTICS
`Per the original Biostatistics review dated 3/4/2013:
`
`The efficacy and safety data from two Phase 3 studies, S00124-WR and S00124-ER, were
`included in this NDA. The two studies shared a common protocol and a statistical analysis
`plan. Both studies were double-masked, placebo-controlled, and randomized (with a 1:1 ratio)
`studies conducted in the United States, with S00124-WR including study sites in the west
`region and S00124-ER in the east region.
`
`A total of 220 subjects were randomized in each study. The primary efficacy endpoint was the
`proportion of subjects with cleared ocular inflammation by Day 15, which was defined as the
`summed ocular inflammation score (SOIS) of Grade 0 (0 cells and absence of flare) at any post
`surgery visit prior to and including Day 15. The key secondary efficacy endpoint was the
`proportion of subjects who were pain free at Day 1.
`
`Compared to the placebo group, the bromfenac 0.07% group had a significantly higher
`proportion of subjects with cleared ocular inflammation by Day 15, defined as no cells and no
`flare, and a significantly higher proportion of subjects who were pain free at Day 1.
`
`Reference ID: 3287805
`
`17
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`Visit
`
`Day 1
`Day 3
`Day 8
`Day 15 (Primary Endpoint)
`Day 22
`
`1.8% (-0.6%, 4.4%)
`5.3 %( 0.5%, 10.2%)
`19.4% (9.8%, 28.9%)
`31.5% (19.9%, 43.2%)
`13.3% (0.4%, 26.2%)
`
`P-value
`
`0.4979
`0.1314
`0.0006
`<0.0001
`0.1314
`
`Table 1: Applicant’s Results for the Primary and Key Secondary Endpoints (S00124-ER)
`Percentage of Subjects with Cleared Ocular Inflammation
`Bromfenac 0.07%
`Placebo
`% difference
`(Asymptotic 95% CI)
`N=112
`N=108
`2 (1.8%)
`0 (0.0%)
`7 (6.3%)
`1 (0.9%)
`30 (26.8%)
`8 (7.4%)
`54 (48.2%)
`18 (16.7%)
`74 (66.1%)
`57 (52.8%)
`
`Percentage of Subjects Who Were Pain Free
`91 (81.3%)
`47 (43.5%)
`37.7 %( 25.9%, 49.6%) <0.0001
`
`Day 1 (Secondary
`Endpoint)
`Day 3
`33.8 %( 22.5%, 45.2%) <0.0001
`57 (52.8%)
`97 (86.6%)
`Day 8
`34.5% (24.2%, 44.8%)
`<0.0001
`64 (59.3%)
`105 (93.8%)
`Day 15
`25.3% (15.2%, 35.3%)
`<0.0001
`73 (67.6%)
`104 (92.9%)
` Source: Table 8 and 22 of the applicant’s study reports (CI was calculated by the reviewer using normal
`approximation)
`
`Table 2: Applicant’s Results for the Primary and Key Secondary Endpoints (S00124-WR)
`
`
`
`Visit
`
`Day 1
`Day 3
`Day 8
`Day 15 (Primary Endpoint)
`Day 22
`
`Day 1 (Secondary Endpoint)
`
`-0.91% (-5.5%, 3.7%)
`0.91 %( -5.7%, 7.6%)
`16.4% (5.2%, 27.5%)
`17.3% (4.5%, 30.0%)
`16.4% (4.0%, 28.7%)
`
`P-value
`
`>0.9999
`>0.9999
`0.0370
`0.0132
`0.0470
`
`0.0017
`
`Percentage of Subjects with Cleared Ocular Inflammation
`Bromfenac 0.07%
`Placebo
`% difference
`(Asymptotic 95% CI)
`N=110
`N=110
`3 (2.7%)
`4 (3.6%)
`8 (7.3%)
`7 (6.4%)
`36 (32.7%)
`18 (16.4%)
`54 (49.1%)
`35 (31.8%)
`81 (73.6%)
`63 (57.3%)
`
`Percentage of Subjects Who Were Pain Free
`84 (76.4%)
`61 (55.5%)
`20.9% (8.7%, 33.1%)
`
`Day 3
`33.6 %( 22.3%, 45.0%) <0.0001
`58 (52.7%)
`95 (86.4%)
`Day 8
`28.2% (17.5%, 38.9%)
`<0.0001
`68 (61.8%)
`99 (90.0%)
`Day 15
`23.6% (13.3%, 33.9%)
`<0.0001
`74 (67.3%)
`100 (90.9%)
` Source: Table 8 and 22 of the applicant’s study reports (CI was calculated by the reviewer using normal
`approximation)
`
`Reference ID: 3287805
`
`18
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`There were 15 subjects, who were treated as successes in the applicant’s primary efficacy
`analysis despite a non-zero score at Day15. The Biostatistics reviewer believes that the
`primary efficacy analysis should treat every subject who received a rescue therapy or did not
`have cleared ocular inflammation at Day 15 as a failure.
`
`Table 3: FDA Reviewer’s Results for the Percentage of Subjects
`with Cleared Ocular Inflammation by Visit
`
`
`
`
`
`Visit
`
`
`Day 1
`Day 3
`Day 8
`Day 15 (Primary Endpoint)
`Day 22
`
`
`Visit
`
`Day 1
`
` S00124-ER
`
`Bromfenac 0.07%
`N=112
`2 (1.8%)
`6 (5.4%)
`27 (24.1%)
`51(45.5%)
`63 (56.2%)
`
`Placebo
`N=108
`0 (0.0%)
`1 (0.9%)
`7 (6.5%)
`14 (13.0%)
`33 (30.6%)
`
` S00124-WR
`Bromfenac 0.07%
`Placebo
`N=110
`N=110
`
`% difference
`(Asymptotic 95% CI)
`
`P-value
`
`0.4979
`1.8% (-0.6%, 4.4%)
`0.2388
`4.4 %( -0.1%, 9.0%)
`0.0004
`17.6% (8.4%, 26.8%)
`32.5% (21.4%, 43.8%) <0.0001
`25.7% (13.0%, 38.3%)
`<0.0001
`
`% difference
`(Asymptotic 95% CI)
`
`P-value
`
`3 (2.7%)
`
`4 (3.6%)
`
`1.8% (-0.6%, 4.4%)
`
`>0.9999
`
`>0.9999
`0.91 %( -5.3%, 7.1%)
`6 (5.4%)
`7 (6.4%)
`Day 3
`0.0112
`17.3% (6.7%, 27.9%)
`14 (12.7%)
`33 (30.0%)
`Day 8
`Day 15 (Primary Endpoint)
`0.0076
`18.2% (5.7%, 30.7%)
`30 (27.3%)
`50 (45.4%)
`<0.0001
`24.5% (11.7%, 37.3%)
`40 (36.4%)
`67 (60.9%)
`Day 22
`Source: Reviewer’s analysis. Subjects who received a rescue therapy and subjects who achieved a zero score at
`earlier visits but had a non-zero score at Day 15 were set as failures.
`
`Note: The Ophthalmology Clinical Group does not agree with the proposed revision of the
`primary endpoint. Cleared ocular inflammation by Day 15, which was defined as the summed
`ocular inflammation score (SOIS) of Grade 0 (0 cells and absence of flare) at any post surgery
`visit prior to and including Day 15, is a precise and well-defined endpoint. Clinical does not
`agree that the 15 subjects (treated as successes in the applicant’s primary efficacy analysis
`despite a non-zero score at Day15) represent treatment failure as defined by the protocol or by
`clinical practice.
`
`
`Reference ID: 3287805
`
`19
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`OPDP
`Office of Prescription Drug Promotion (OPDP) completed a formal review of the package
`insert based on the substantially complete labeling from 3/20/13.
`OPDP’s suggestion to add “including Prolensa” at any mention of a general NSAID-risk in
`Section 5 of the package insert is not recommended. Section 5, as currently proposed in the
`substantially complete labeling, is clear that all topical NSAIDS carry the specified risks.
`
`OPDP’s suggestion to remove the statement regarding prostaglandins in animal models in
`Section 12.1 is not recommended. The statement in question is not speculative; this statement
`and its implications are clinically relevant and supported by substantial evidence for humans.
`
`OPDP’s suggestion to expand upon the primary efficacy endpoint in Section 14.1 is not
`recommended. The endpoint, proportion of subjects clearing ocular inflammation, is
`understood by prescribing ophthalmologists who would be performing cataract surgery and
`performing postoperative evaluations.
`
`OPDP’s suggestion to separate the efficacy results of the two trials in Section 14.1 is not
`recommended. The two Phase 3 studies, S00124-ER and S00124-WR utilized the same
`protocol administered in the eastern and western regions of the United States, respectively.
`Identical protocols were not necessarily utilized in other NSAIDS, Phase 3 trials and thus their
`Clinical Studies Sections differ in format.
`
`DMEPA
`The Division of Medication Error Prevention and Analysis (DMEPA) finalized a review of
`originally proposed proprietary name, Prolensa, on 3/4/2013. Their proprietary name risk
`assessment did not find the name vulnerable to confusion that would lead to medication errors
`and did not consider the name promotional.
`
`DMEPA finalized their review of the Prolensa carton and container labeling on 2/8/2013.
`Comments regarding suggested changes to the carton and container that were not supported by
`regulation were not transmitted to the applicant. Agency requested the following revisions to
`their carton and container labeling submitted by the applicant on 8/21/12:
`
`1) The prominence of "Sample" and "Sample - Not for Resale" should be increased on the
`0.6 mL and 0.8 mL carton and container professional sample configurations.
`
`2) The established name should be revised on the carton and container labels to a
`prominence commensurate with the proprietary name, as stated in 21 CFR
`201.10(g)(2). We suggest you either de-bold the proprietary name or bold the
`established name.
`
`3) Remove the trailing zero from the 3.0 mL trade size carton and container labeling and
`revise to read as "3 mL."
`
`Reference ID: 3287805
`
`20
`
`

`

`Cross-Discipline Team Leader Review
`William M. Boyd, M.D.
`NDA 203168
`
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`FINANCIAL DISCLOSURE
`
`Financial disclosure information has been provided by the applicant for the covered clinical
`studies in this application.
`
`A Form FDA 3454 certifying the absence of financial interests for primary and
`subinvestigators who supplied data used in clinical studies that support this application is
`provided. Table 2 lists those investigators requiring financial disclosure. A Form FDA 3455
`for each investigator with financial arrangements requiring financial disclosure is included. A
`review of the financial disclosure data does not indicate a potential impact on the clinical study
`results.
`
`Table 2.
`
`List of Investigators With Financial Interests Requiring Disclosure
`
`m Primary Investigators
`M ;
`mm
`
`$00124-VVR
`
`Study Number
`
`081
`
`A routine Office of Scientific Investigations (OSI) audit was requested.
`
`Per the 081 review dated 2/4/2013:
`
`One site from each study was chosen for inspecti