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

`

`
`
`CLINICAL REVIEW
`
`Indication(s)
`
`Application Type NDA
`Application Number(s) 203168
`Priority or Standard Standard
`
`
`Submit Date(s) June 6, 2012
`Received Date(s) June 7, 2012
`PDUFA Goal Date April 7, 2013
`Division / Office OAP/DTOP
`
`
`Reviewer Name(s) William M. Boyd, M.D.
`Review Completion Date March 20, 2013
`
`
`Established Name bromfenac ophthalmic solution
`0.07%
`(Proposed) Trade Name Prolensa
`Therapeutic Class nonsteroidal anti-inflammatory
`Applicant Bausch & Lomb, Inc.
`
`
`Formulation(s) bromfenac ophthalmic solution
`0.07%
`Dosing Regimen one drop into the affected eye
`once daily
`treatment of postoperative
`inflammation and reduction of
`ocular pain in patients who have
`undergone cataract surgery
`Intended Population(s) patients who have undergone
`cataract surgery
`
`
`
`Template Version: March 6, 2009
`
`
`
`
`
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 5
`1.1 Recommendation on Regulatory Action ............................................................. 5
`1.2 Risk Benefit Assessment.................................................................................... 5
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 5
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 5
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 5
`2.1 Product Information ............................................................................................ 6
`2.2 Tables of Currently Available Treatments for Proposed Indications ................... 6
`2.3 Availability of Proposed Active Ingredient in the United States .......................... 6
`2.4
`Important Safety Issues With Consideration to Related Drugs........................... 6
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ............ 6
`2.6 Other Relevant Background Information ............................................................ 7
`3 ETHICS AND GOOD CLINICAL PRACTICES......................................................... 7
`3.1 Submission Quality and Integrity ........................................................................ 7
`3.2 Compliance with Good Clinical Practices ........................................................... 8
`3.3 Financial Disclosures.......................................................................................... 8
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ........................................................................................................... 8
`4.1 Chemistry Manufacturing and Controls .............................................................. 9
`4.2 Clinical Microbiology......................................................................................... 10
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 10
`4.4 Clinical Pharmacology...................................................................................... 11
`4.4.1 Mechanism of Action.................................................................................. 11
`4.4.2 Pharmacodynamics/Pharmacokinetics ...................................................... 11
`5 SOURCES OF CLINICAL DATA............................................................................ 12
`5.1 Tables of Studies/Clinical Trials ....................................................................... 12
`5.2 Review Strategy ............................................................................................... 14
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 14
`6 REVIEW OF EFFICACY......................................................................................... 24
`6.1
`Indication .......................................................................................................... 24
`6.1.1 Methods ..................................................................................................... 24
`6.1.2 Demographics............................................................................................ 25
`6.1.3 Subject Disposition..................................................................................... 26
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 28
`6.1.5 Analysis of Secondary Endpoints(s) .......................................................... 30
`6.1.6 Other Endpoints ......................................................................................... 32
`6.1.7 Subpopulations .......................................................................................... 34
`
`2
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 34
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 34
`6.1.10 Additional Efficacy Issues/Analyses........................................................... 34
`7 REVIEW OF SAFETY............................................................................................. 35
`7.1 Methods............................................................................................................ 35
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 35
`7.1.2 Categorization of Adverse Events.............................................................. 35
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 36
`7.2 Adequacy of Safety Assessments .................................................................... 37
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 37
`7.2.2 Explorations for Dose Response................................................................ 38
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 38
`7.2.4 Routine Clinical Testing ............................................................................. 38
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 38
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 38
`7.3 Major Safety Results ........................................................................................ 39
`7.3.1 Deaths........................................................................................................ 39
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 39
`7.3.3 Dropouts and/or Discontinuations .............................................................. 40
`7.3.4 Significant Adverse Events ........................................................................ 46
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 46
`7.4 Supportive Safety Results ................................................................................ 47
`7.4.1 Common Adverse Events .......................................................................... 47
`7.4.2
`Laboratory Findings ................................................................................... 53
`7.4.3 Vital Signs .................................................................................................. 53
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 53
`7.4.5 Special Safety Studies/Clinical Trials......................................................... 53
`7.4.6
`Immunogenicity.......................................................................................... 53
`7.5 Other Safety Explorations................................................................................. 53
`7.5.1 Dose Dependency for Adverse Events ...................................................... 53
`7.5.2 Time Dependency for Adverse Events....................................................... 53
`7.5.3 Drug-Demographic Interactions ................................................................. 54
`7.5.4 Drug-Disease Interactions.......................................................................... 54
`7.5.5 Drug-Drug Interactions............................................................................... 54
`7.6 Additional Safety Evaluations ........................................................................... 54
`7.6.1 Human Carcinogenicity.............................................................................. 54
`7.6.2 Human Reproduction and Pregnancy Data................................................ 54
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 54
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 55
`7.7 Additional Submissions / Safety Issues............................................................ 55
`8 POSTMARKET EXPERIENCE............................................................................... 55
`
`3
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`9 APPENDICES ........................................................................................................ 56
`9.1
`Literature Review/References .......................................................................... 56
`9.2 Advisory Committee Meeting............................................................................ 56
`9.3
`Labeling Recommendations ............................................................................. 56
`
`
`
`4
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`1 Recommendations/Risk Benefit Assessment
`
`
`1.1 Recommendation on Regulatory Action
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1.2 Risk Benefit Assessment
`
`There is substantial evidence of effectiveness consisting of adequate and well
`controlled studies which demonstrate that Prolensa (bromfenac ophthalmic solution)
`0.07% is (1) statistically superior to placebo in the proportion of subjects who had
`cleared ocular inflammation in the study eye by Day 15 and (2) is statistically superior to
`placebo for the absence of pain on the first day post-op.
`
`The most commonly reported adverse reactions in seen 3-8% of bromfenac ophthalmic
`solution 0.7% treated patients were: anterior chamber inflammation, eye pain, and
`foreign body sensation.
`
`The benefits of using this drug product outweigh the risks for the above indication(s).
`
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`Risk evaluation and mitigation strategies are not recommended.
`
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`Postmarket requirements/commitments are not recommended.
`
` Introduction and Regulatory Background
`
` 2
`
`
`
`5
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`2.1 Product Information
`
`
`
`Proprietary Name:
`
`Established Name:
`
`Applicant:
`
`
`
`Chemical Class:
`
`Pharmacologic Category:
`Proposed Indication:
`
`Dosage Form and Route
`of Administration:
`
`
`
`
`
`Prolensa
`bromfenac ophthalmic solution 0.07%
`Bausch & Lomb, Inc.
`
`
`5S
`non-steroidal anti-inflammatory
`The treatment of ocular inflammation and pain
`following cataract surgery
`
`
`
`topical drops
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`There are multiple ophthalmic topical drugs approved for inflammation and pain
`following cataract extraction (i.e. surgery) including:
`
`Ketorolac tromethamine ophthalmic solution 0.45%, (i.e. Acuvail)
`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).
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Bromfenac ophthalmic solution 0.09% is currently marketed and is available in the
`United States.
`
`2.4 Important Safety Issues With Consideration to Related Drugs
`
`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.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`Clinical studies for this new drug application were conducted under IND 060295.
`
`6
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`
`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.
`
`2.6 Other Relevant Background Information
`
`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.
`
`NDA 21-664 Xibrom (bromfenac ophthalmic sodium) 0.09% BID 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.
`
`ISTA Pharmaceuticals, Inc. (ISTA) initiated development of bromfenac ophthalmic
`solution
`as a once-daily alternative to the currently marketed product. Data from
`this clinical development program demonstrated that the 0.09%
` QD dosing
`formulations were equivalent in terms of safety and efficacy. ISTA subsequently
`performed simultaneous Phase 3 studies comparing bromfenac ophthalmic solution
`0.09% QD to placebo (CL-S&E-0415081-P-ER [QD-ER] and CL-S&E-0415081-P-WR
`[QD-WR]). QD-WR showed statistical significance for the primary efficacy endpoint;
`however, QD-ER failed to show a statistically significant treatment effect in either the
`primary or secondary endpoints. ISTA initiated a third placebo-controlled Phase 3 study
`with bromfenac ophthalmic solution 0.09% QD (CL-S&E-1205081-P [QDII]) to confirm
`that bromfenac ophthalmic solution 0.09% QD was safe and effective in the subject
`population enrolled.
`
`Bromday (bromfenac ophthalmic sodium) 0.09% was approved on 10/16/2010 (SE2 S-
`13).
`
` Ethics and Good Clinical Practices
`
` 3
`
`3.1 Submission Quality and Integrity
`
`The submission was of sufficient quality to allow for a substantive review.
`
`7
`
`Reference ID: 3280872
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`
`William M. Boyd, M.D.
`NDA 203168
`
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`3.2 Compliance with Good Clinical Practices
`
`AII completed clinical studies in this submission were conducted in compliance with the
`Declaration of Helsinki, the International Conference on harmonization (ICH Good
`Clinical Practice (GCP) guidelines and the applicable governmental regulatory
`requirements.
`
`Two clinical investigator sites were inspected by the Office of Scientific Investigations
`(OSI) for this application. The data derived from both inspected sites are considered
`reliable.
`
`3.3 Financial Disclosures
`
`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 \Vith Financial Interests Requiring Disclosure
`
`Primary Investigators
`
`800124—ER
`
`Study Number
`
`sum 244$"R
`
`4 Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`
`William M. Boyd, M.D.
`NDA 203168
`
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`4.1 Chemistry Manufacturing and Controls
`
`Table l.
`
`Bronte-ac Ophthalmic Solution 0.07% Quantitative Composition
`
`Component
`
`Bromfennc 0.07%
`Formulation
`
`Bromfenac sodium
`sesquihydrate
`
`Active
`ingredient
`
`0.0805
`
`Amount lmL
`
`(ms/m)
`0.805
`
`Itch
`ornposition
`
`
`
`_oricacid
`
`Sodium sulfite
`
`Edema disodium (EDTA)
`Benza‘l'yloxapol ———- -
`
`Sodium hydroxide
`
`pH adjuster
`
`q.s. to pH 7.8
`
`qs. to pH 7.8
`
`(1.5. to pH 7.8
`
`2
`
`Equivalent to 0.07% bromfenac fi’ec acid.
`Only if necessary to adjust pH to 7.8.
`
`The drug product is a non-steroidal anti-inflammatory drug (NSAID) for topiwl
`ophthalmic use. It is supplied as a clear, yellow, sterile solution containing 0.07%
`bromfenac free acid and dispensed from a 7.5cc ca acity white low dens'
`
`screw
`
`polyethylene (LDPE) bottlewith a white limingItip, and grey
`
`e. In
`m per
`are 1.6 mL an
`u
`cap. The proposed trade sizes for the drug p
`addition, the applicant has proposed sample sizes of 0.6 mL and 0.8 mL per bottle.
`
`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).
`
`Reviewer’s Comments:
`
`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.
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`
`Vtfilliam M. Boyd, MD.
`MBA 203168
`
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`Tobi: l. Wrath-s tor Bronte-M: Ophthalmic Soluion 0.07%
`
`0...,me solution
`A white plastic bottle with dropper tip and any cap. with no
`significant disoolontion or physical distortion
`
`("’5“in only}
`
`Identification
`(releue only)
`
`BennlkonimnChloI-idc'
`
`EDTA
`
`Sodium Snlfilc
`
`Sterility
`Bacterial Enduoxins
`
`Mallet: Matter
`(Microscopic Evnlmtion)
`
`Particulate Matter (Visunl)
`Wendi! Loss
`
`4.2 Clinical Microbiology
`
`Not applicable to this review.
`
`4.3 Preclinical Phannacologyl'l'oxicology
`
`The estimated C..m for a 0.9 mg/kg dose to a rat would be 4.4 mchmL (4400 ngImL).
`Assuming a maximum human C...” is the limit of detection or 50 ngImL as described in
`the labeling, the multiple would be approximately 90 times.
`
`10
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`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 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 labeling,
`the multiple would be approximately 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 labeling,
`the multiple would be approximately 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).
`
`
`4.4 Clinical Pharmacology
`
`4.4.1 Mechanism of Action
`
`Bromfenac is a non-steroidal 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 1 and 2. Prostaglandins have
`been shown in many animal models to be mediators of certain kinds of intraocular
`inflammation. In studies performed in animal eyes, prostaglandins have been shown to
`produce disruption of the blood-aqueous humor barrier, vasodilation, increased vascular
`permeability, leukocytosis, and increased intraocular pressure.
`
`4.4.2 Pharmacodynamics/Pharmacokinetics
`
`The plasma concentration of bromfenac following ocular administration of 0.07%
`Prolensa (bromfenac ophthalmic solution) in humans is unknown. Based on the
`maximum proposed dose of one drop to the eye (0.035 mg) and PK information from
`
`11
`
`Reference ID: 3280872
`
`

`

`Cliniccl Review
`
`Vlfilliam M. Boyd, MD.
`MBA 203168
`
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`other routes of administration, the systemic concentration of bromfenac is estimated to
`be below the limit of quantification (50 nglmL) at steady-state in humans.
`
`5 Sources of Clinical Data
`
`5.1 Tables of Studies/Clinical Trials
`
`The double-masked, placebo controlled clinical trials utillzng bromfenac ophthalmic
`solution 0.7% dosed once daily in subjects undergoing mtaract surgery ($00124-ER
`and $00124~WR) form the primary efficacy and safety databases for this new drug
`product. These trials utilized the same protocol administered in the eastern and
`western regions of the United States, respectively.
`
`Following is the applicant's table of all bromfenac ophthalmic solution PK and safety
`and efficacy trials. This table includes all formulations and concentrations of bromfenac
`and their study report lowtions.
`
`Study
`Dunc III
`'lpr of
`Control
`
`Tat Pndudtl):
`Dong: [cu-cl:
`Ron: at
`M-Inhntlon
`
`Number
`of
`Sch ca:
`
`flccllly Slogan
`or Dhgnncln cf
`Sch cctc
`
`ncrclloc
`of
`Trcnlmccl
`
`Study
`SKI-I;
`Type of
`R A
`
`Typc of
`Stu
`
`Study
`ldenttlbr
`
`locum of
`Scdy
`It
`‘
`‘ rt
`
`Ohjrcflvcm of
`the St
`'
`
`- rt
`
`12
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`
`William M. Boyd, M.D.
`NDA 203168
`
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`man of
`
`Study
`
`Idunlflr
`
`a. Study
`
`03;,-We!
`Control
`
`l‘ut Prod"((3):
`Doug! Regimen;
`Route 0!
`Adfllunllon
`
`Number Hula-y s-opeu Dumb-
`oI'
`or Dhguolls of
`of
`Subject:
`Subject:
`Tirol-to!
`
`0.09%. l dnop BID
`
`SM!
`”alga and
`1w of
`Collml
`Doubl
`mashed.
`placebo-
`
`Ten We):
`Dong: Kg
`3
`Rule of
`Mlhunflol
`Boomfuuc
`
`ophthalmicsolulion
`0.09%. l dvopBID
`Bnmfemc
`qflulnlmic solution
`
`NI-ul'
`ol
`abject:
`
`"any s-ogccu
`or blag-ooh ol’
`SnMed:
`Subject: wit
`postoperative
`Innunnmlon one:
`
`Duration
`
`Tint-en!
`
`Study
`all":
`
`Report
`
`Em“
`'P‘“
`
`1‘ny of
`Study
`
`ISTA-BR-
`csool an:
`
`Mod 5. Vols
`-I3 cal-'31::
`
`Efficacy Ind
`solely (US
`Phase 3)
`
`ISTA-BI—
`csooI-wn
`
`16-27 CNS
`in Vols 53-66
`
`13
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`
`William M. Boyd, MD.
`MBA 203168
`
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`Type ol‘
`Study
`
`Study
`Idcatillcr
`
`[M‘bl cl’
`Study
`upon
`
`Objccllvea) of
`(it Study
`
`Study
`Dcal‘a aad
`Type of
`Coat»!
`
`felt 'Ndllflfl):
`Decay Rogl-aat
`Route of
`M-hlctntloa
`
`Numb"
`at
`Subhcta
`
`Ilcalthy Subject-
`or thoutu of
`Sabjoetc
`
`me stay
`Ellie-Cy
`
`sun-m
`
`.
`Subpas
`Broml’euc
`fitting and
`undcrpirg cataract
`ophthalnic solution
`salty (US
`sunny
`0.07% 1 deD
`Phase 3)
`.
`Sutyects
`Brumfnac
`Ell'tcccy Ind
`ophthahric solution m unduwim cataract
`“fist
`may (us
`a"?
`0.07% I drop OD
`surgery
`cZntrollcd
`Phase 3)
`cly
`PK = plum-counties: QID = four times daily: ED = two line: daily: OD - one lime daily; IOL = lnmoculcr lens
`
`
`
`Study
`Satan
`Type of
`Report
`
`r n R
`l6 days kau“
`“ 4”"
`
`cml‘m
`Full Repon
`
`Double-
`l
`1m».
`0“
`cam,“
`Double
`
`220
`
`5.2 Review Strategy
`
`The June 6, 2012, submission was submitted electronically. Subsequent amendments
`were also submitted in electronically. All study reports were reviewed. The included
`clinical study reports, literature review, and package insert formed the basis for the
`review of efficacy and safety for the proposed indications.
`
`A literature search conducted by this reviewer failed to identify any literature references
`which were contrary to the information provided or referenced by Bausch & Lomb, Inc.
`in this application for this indication.
`
`5.3 Discussion of Individual Studies/Clinical Trials
`
`The 2 Phase 3 studies, SOO124—ER and $00124-WR utilized the same protocol
`administered in the eastern and western regions of the United States, respectively.
`
`SOO124-ER and $00124-WR
`
`Methodology
`This was a multi-center (20 site SOO124—ER; 19 site SOO124—WR), randomized,
`
`14
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`double-masked, parallel-group, and placebo-controlled study. Subjects were screened
`for this study between 1 and 8 days prior to the initiation of dosing with the
`investigational product (IP). Subjects who signed the informed consent and met all
`inclusion/exclusion criteria were randomized to receive either bromfenac or placebo
`(1:1).
`
`Subjects were seen for evaluation on Days 1, 3±1, 8±1, 15±1 following cataract surgery.
`In addition, subjects were seen for a follow-up visit on Day 22 (+3) following surgery or 7
`days (+3) after their last dose of the IP if the subject prematurely discontinued the IP.
`
`Number of Subjects
`200 subjects were planned; 211 subjects were analyzed for safety; 220 subjects were
`analyzed for efficacy. (S00124-ER)
`
`200 subjects were planned; 205 subjects were analyzed for safety; 220 subjects were
`analyzed for efficacy. (S00124-WR)
`
`Reviewer’s Comments:
`
`More subjects were evaluated for efficacy than were evaluated for safety in both
`S00124-ER and S00124-WR. Safety analyses were to be conducted on the Safety
`Population, defined as all randomized subjects who received at least 1 dose of IP. All
`analyses of efficacy were to be conducted on the Intent-to-Treat (ITT) Population,
`defined as all randomized subjects, where subjects were to be analyzed in the group to
`which they were randomized.
`
`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.
`
`See Sections 6.1.3, 7.1.3, and 7.4.1 of this review for the results of this reanalysis.
`
`Inclusion Criteria
`Each subject had to meet the following criteria to be eligible for the study:
`
`1. Were male or female at least 18 years of age who were scheduled for unilateral
`cataract surgery (phacoemulsification or extracapsular) with PCIOL implantation and for
`whom no other ophthalmic surgical procedures (eg, relaxing incisions, iridectomy,
`conjunctival excisions, etc.) were to be conducted during the cataract surgery.
`2. Agreed not to have any other ocular surgical procedures in the study or fellow (non-
`study) eye within 15 days prior to the initiation of dosing with the IP and throughout the
`duration of the study.
`3. Had VA logMAR of 0.6 (ETDRS) or better in the fellow (non-study) eye.
`
`15
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`4. Were willing and able to return for all required study visits.
`5. Were willing and able to follow instructions from the study investigator and his/her
`staff.
`6. Had IOP (cid:149)5 mmHg and (cid:148)22 mmHg (in study eye) with or without anti-glaucoma
`therapy at the pre-operative screening visit (if >22 mmHg, adjust, if necessary, following
`documented pachymetry).
`7. Were willing and able to self administer the IP (or had a caregiver available to instill
`all doses of the IP).
`8. If a woman capable of becoming pregnant, agreed to have urine pregnancy testing
`performed at screening (must be negative) and agreed to use a medically acceptable
`form of birth control throughout the study duration and for at least 1 week prior to and
`after completion of the study. Women considered capable of becoming pregnant
`included all females who have experienced menarche and who had not experienced
`menopause (as defined by amenorrhea for greater than 12 consecutive months) or had
`not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
`bilateral oophorectomy).
`9. Had signed informed consent approved by Institutional Review Board or Independent
`Ethics Committee.
`
`Exclusion Criteria
`Subjects who met any of the following criteria were excluded from the study:
`
`1. Had known hypersensitivity to bromfenac or to any component of the IP (including
`“procedural” medications such as anesthetic and/or fluorescein drops, dilating drops,
`etc.).
`2. Used anterior capsule staining for capsulorhexis (i.e., trypan blue).
`3. Had a known hypersensitivity to the class of salicylates (i.e., acetylsalicylic acid or
`Aspirin) or to other NSAIDs.
`4. Had a known hypersensitivity to sulfites.
`5. Had intraocular inflammation (ie, any cells or flare in the anterior chamber as
`measured on slit lamp examination) or had ocular pain (greater than “None”) on the pain
`scale of the OCGA in either eye at the screening visit.
`6. Had any active or chronic/recurrent ocular or systemic disease that was uncontrolled
`and likely to affect wound healing (ie, diabetes mellitus, systemic connective tissue
`disease, severe atopic disease, etc.). Note: An uncontrolled disease was described by a
`change in disease severity or by a clinically significant change assessed by the
`investigator within the past 30 days prior to screening.
`7. Had a known uncontrolled systemic disease including bleeding disorder.
`8. Had taken any anticoagulants (i.e., Coumadin, Plavix, etc.) within 7 days of initiating
`dosing with the IP, or needed to take anticoagulant therapy (including aspirin at doses
`of more than 165 mg/day) during the study, or had any known or suspected bleeding
`tendencies.
`9. Had used within 7 days prior to initiation of dosing with the IP or throughout the
`duration of the study:
`
`16
`
`Reference ID: 3280872
`
`

`

`Clinical Review
`William M. Boyd, M.D.
`NDA 203168
`Prolensa (bromfenac ophthalmic solution) 0.7%
`
`• Ocular, topical, or systemic NSAIDs,
`• Ocular, topical, or systemic gentamicin,
`• Any form of opioid, narcotic, or any other pain relieving medication that could have
`interfered with the interpretation of the study results, eg, gabapentin, pregabalin, COX-2
`inhibitors. Note: Use of acetaminophen (up to 4,000 mg/day) during the study and/or an
`opioid during surgery (i.e., fentanyl) were allowed,
`• Immunomodulators (i.e., Restasis).
`10. Had used ocular, topical, inhaled, or oral corticosteroids within 15 days prior to the
`initiation of dosing with the IP or depo-corticosteroids within 45 days prior to initiation of
`dosing with the IP or throughout the duration of the study.
`11. Had used:
`• tamsulosin (Flomax),
`• silodosin (Rapaflo),
`• afluzoxin (Uroxatral), or
`• finasteride (Proscar or