CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203168Orig1s000
`
`OFFICE DIRECTOR MEMO
`
`
`
`
`

`

`Deputy Division Director Review of NDA 203168
`
`I_—
`
`A. meant
`
`June 6, 2012Date of Submission '
`
`PDUFA Goal Date
`A III 7 2013
`
`Name
`
`Prolensa romfenac ohthahnic solution 0.07%
`
`
`
`Dosage forms / Strength
`Proposed Indication(s)
`
`Topical ophthahnic solution, 0.07%
`
`Recommendation:
`
`Recommended for A roval
`
`1. Background
`
`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. The mechanism of its action is believed to be due to its ability to block
`prostaglandin synthesis by inhibiting cyclooxygenase (COX) 1 and 2.
`
`NDA 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 8-01) for the
`treatment of post-operative pain. A later supplement added a once a day dosing regimen starting the
`day before surgery. The product with once a day dosing was relabeled as Bromday (bromfenac
`ophthahnic sodium) 0.09% and was approved on 10/16/2010 (SE2 8-13).
`
`The chemical structure for bromfenac sodium sesquihydrate is:
`
`There are multiple topical ophthahnic drug products approved for the treatment of inflammation and
`pain following cataract extraction or ocular surgery including:
`
`2N
`
`CH2C02Na
`
`' 11/2H20
`
`Ketorolac tromethamine ophthahnic solution 0.45%, 0.5% (i.e., Acuvail, Acular)
`Rimexolone ophthahnic suspension 1% (i.e., Vexol)
`Bromfenac ophthahnic solution 0.09% (i.e., Xibrom, Bromday)
`Nepafenac ophthahnic suspension 0.1%, 0.3% (i.e., Nevanac, Ilevro)
`Loteprednol etabonate ophthahnic suspension 0.5% (i.e., Lotemax)
`Loteprednol ophthahnic ointment 0.5% (i.e., Lotemax)
`Loteprednol ophthahnic gel 0.5% (i.e., Lotemax)
`Difluprednate ophthahnic emulsion 0.05% (i.e., Durezol).
`
`Clinical studies for this new drug application were conducted under IND 060295.
`
`Reference ID: 3288405
`
`

`

`Deputy Division Director Review
`Wiley A. Chambers, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`
`2. Product Quality
`
`Page: 2
`
`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. 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 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.
`
`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).
`
`Sterility Assurance
` at the Bausch and Lomb Tampa, FL
`The drug product will be
`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.
`
`Quantitative Composition:
`
`Bromfenac sodium sesquihydrate
`Boric acid
`Sodium borate
`Sodium sulfite
`Edetate disodium (EDTA)
`Tyloxapol
`Benzalkonium chloride
`Povidone
`Sodium hydroxide
`Water for Injection
`
`Declared Function
`Active
`
`%w/v
`0.0805
`
`mg per mL
`0.805
`
`Preservative
`
`pH adjuster
`
`0.005
`
`0.05
`
`q.s. to pH 7.8
`
`q.s. to pH 7.8
`
`Reference ID: 3288405
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`

`

`Deputy Division Director Review
`Wiley A. Chambers, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`
`Page: 3
`
`Specification
`
`Clear, yellow solution
`A white plastic bottle with dropper tip and gray cap, with no
`significant discoloration or physical distortion
`
`Regulatory Specifications:
`Test
`Product Appearance
`
`Description: Container
`
`Identification
`(release only)
`
`Bromfenac Sodium Assay
`
`Bromfenac Impurities
`
`Impurity,
`Any Individual Specified Impurity
`
`Any Individual Unspecified Impurity
`
`pH
`
`Osmolality
`
`Benzalkonium Chloride1
`
`EDTA
`
`Sodium Sulfite
`
`Sterility
`Bacterial Endotoxins
`
`Particulate Matter
`(Microscopic Evaluation)
`
`Particulate Matter (Visual)
`Weight Loss
`(stability only)
`
`INSPECTIONS
`An “Acceptable” site recommendation from the Office of Compliance has been made.
`
`Reference ID: 3288405
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Deputy Division Director Review
`Wiley A. Chambers, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`
`Page: 4
`
`3. Nonclinical Pharmacology/Toxicology
`The Pharmacology/Toxicology Review of NDA 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 Cmax values are listed below.
`Consistent with this class of products, unlike humans, many of the animals did not tolerate high doses
`of NSAIDs. The applicant did not attempt to measure systemic absorption from ophthalmic dosing
`because the limit of the assay detection was 50 ng/mL.
`
`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).
`
`4. Clinical Pharmacology/Biopharmaceutics
`No new clinical pharmacology data was presented in this supplement. From a Clinical Pharmacology
`perspective, the application was considered acceptable.
`
`5. Clinical/Statistical - Efficacy
`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
`
`Reference ID: 3288405
`
`

`

`Deputy Division Director Review
`Wiley A. Chambers, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`
`Page: 5
`
`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.
`
`Analysis of Primary Endpoint(s)
`
`S00124-ER (LOCF; ITT Population)
`Bromfenac 0.07%
`N = 112
`
`Placebo
`N = 108
`
`P-value
`
`Cleared Ocular Inflammation
`0.4979
`0 (0.0%)
`2 (1.8%)
`Day 1
`0.1314
`1 (0.9%)
`7 (6.3%)
`Day 3
`0.0006
`8 (7.4%)
`30 (26.8%)
`Day 8
`<0.0001
`18 (16.7%)
`54 (48.2%)
`Day 15 (Primary Endpoint)
`0.1314
`57 (52.8%)
`74 (66.1%)
`Day 22
`p-value was for bromfenac 0.07% versus placebo and was from the Fisher’s exact test adjusted for multiple comparisons
`using Hochberg’s method.
`
`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 (LOCF; ITT Population)
`Bromfenac 0.07%
`N = 110
`
`Placebo
`N = 110
`
`P-value
`
`Cleared Ocular Inflammation 1
`4 (3.6%)
`3 (2.7%)
`>0.99992
`Day 1
`7 (6.4%)
`8 (7.3%)
`>0.99992
`Day 3
`18 (16.4%)
`36 (32.7%)
`0.03702
`Day 8
`0.01323
`35 (31.8%)
`54 (49.1%)
`Day 15 (Primary Endpoint)
`63 (57.3%)
`81 (73.6%)
`0.04702
`Day 22
`p-value was for bromfenac 0.07% versus placebo and was from the Fisher’s exact test adjusted for multiple comparisons
`using Hochberg’s method.
`
`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: 3288405
`
`

`

`Deputy Division Director Review
`Wiley A. Chambers, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`
`Page: 6
`
`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: 3288405
`
`

`

`Deputy Division Director Review
`Wiley A. Chambers, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`
`Page: 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: 3288405
`
`

`

`Deputy Division Director Review
`Wiley A. Chambers, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`
`Page: 8
`
`6. Safety
`The primary basis for establishing relative safety in this application comes from the clinical trials
`supporting the bromfenac ophthalmic solution, 0.9%. The trials conducted with the bromfenac
`ophthalmic solution 0.7% are consistent with the results of those earlier trials.
`
`The most commonly reported adverse reactions in seen clinical trials conducted with bromfenac
`ophthalmic solution, 0.7%, occurred in 3-8% of patients and included anterior chamber
`inflammation, eye pain, foreign body sensation, photophobia, and vision blurred.
`
`7. 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.
`
`8. Pediatrics
`PREA was not triggered for this application. 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.
`
`9. Other Relevant Regulatory Issues
`a.
`The Statistical Group has proposed to change the labeling to reflect one of the additional
`endpoints and not include the primary endpoint. The Ophthalmology Clinical Group,
`including myself, 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. We do 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.
`
`b.
`
`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,
`
`Reference ID: 3288405
`
`

`

`Deputy Division Director Review
`Wiley A. Chambers, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`
`Page: 9
`
`c.
`
`d.
`
`e.
`
`respectively. Identical protocols were not necessarily utilized in other NSAIDS, Phase 3
`trials and thus their Clinical Studies Sections differ in format.
`
`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.
`
`Financial disclosure information has been provided by the applicant for the covered
`clinical studies in this application. A review of the financial disclosure data does not
`indicate a potential impact on the clinical study results.
`
`A routine Office of Scientific Investigations (OSI) audit was requested. The data derived
`from both inspected sites are considered reliable. The classification of the Clinical
`Investigator inspection of Dr. Cacioppo is No Official Action Indicated (NAI). The
`classification of the Clinical Investigator inspection of Dr. Goldberg is Voluntary Action
`Indicated (VAI).
`
`10. Labeling
`NDA 203168, Prolensa (bromfenac ophthalmic solution) 0.07%, is recommended for approval
`for the treatment of postoperative inflammation and reduction of ocular pain in patients who
`have undergone cataract surgery.
`
`Carton and container labeling submitted on 3/18/13 and found in the Appendix of this review is
`acceptable. With the next scheduled printing, the cartons should be revised to include a more
`precise description of the active (i.e. bromfenac sodium sesquihydrate 0.0805%).
`
`The package insert submitted by the applicant on 4/2/2013 is found in the Appendix of this
`review. I do not agree with altering the endpoint from “the proportion of subjects who had
`complete clearance of ocular inflammation by day 15” to “complete clearance at Day 8 and Day
`15.” The proportion of subjects who had complete clearance of ocular inflammation by day 15 is
`an appropriate endpoint and was statistically significant. The percentage of patients who had
`complete clearance on a particular day, when adjusted for the multiplicity of the multiple
`additional endpoints was not statistically significant.
`
`Reference ID: 3288405
`
`11 Pages of Draft Labeling have been Withheld in Full as b4 (CCI/TS)
`immediately following this page.
`
`

`

`Deputy Division Director Review
`Wiley A. Chambers, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`
`11. Recommendations/Risk Benefit Assessment
`
`Page: 21
`
`NDA 203168, Prolensa (bromfenac ophthalmic solution) 0.07%, is recommended for approval
`for the treatment of postoperative inflammation and reduction of ocular pain in patients who
`have undergone cataract surgery. It is also recommended that the labeling be revised to
`remove the references to the outcome “at day 8 and at day 15.”
`
`Wiley A. Chambers, MD
`Deputy Division Director
`
`Reference ID: 3288405
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`WILEY A CHAMBERS
`04/05/2013
`
`Reference ID: 3288405
`
`