CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203168Orig1s000
`
`SUMMARY REVIEW
`
`
`
`PAGE 1 OF 22
`
`SENJU EXHIBIT 2153
`INNOPHARMA v SENJU
`IPR2015-00903
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract sm gery
`
`Summary Review for Regulatory Action
`
`Date
`Fr om
`
`Subject
`BLANumber
`R elated IND
`R elated NDA
`Review type
`Applicant N arne
`Date of Submission
`Date of Receipt
`PDUFA Goal Date
`Proprietary N arne I
`Established (USAN) Name
`Formulation
`Concentration
`Dosing R egimen
`
`Therapeutic Class
`Proposed Ind ication
`
`Action for NME
`
`See electronic stamp date
`Renata Albrecht, MD
`Division of Transplant and Ophthalmology Products
`Division Director Sunumny Review
`NDA 203 168
`IND 60295
`NDA 21664, NDA 20535
`Standard
`Bausch & Lomb, previously IST A
`June 5, 201 2
`June 7, 2012
`April 7, 2013
`Prolensa
`bromfenac
`Topical ophthalmic solution
`0.07%
`One drop in the affected eye one time daily beginning 1
`day prior to cataract surgery, continued on the day of
`surge1y , and tlu·ough the fu st 14 days of the post-
`operative period.
`Nonsteroidal anti-inflammatory agent
`For the treatment of postoperative inflammation and
`reduction of ocular pain in patients who have
`undergone cataract surge1y
`Approval
`
`Reference ID: 3289134
`
`1
`
`PAGE 2 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract surgery
`
`
`Names of discipline reviewers
`Material Reviewed/Consulted
`OND Action Package, including:
`
`Bill Boyd 3/20/2013
`Medical Officer Review
`Bill Boyd 4/5/2013
`CDTL Review
`Wiley Chambers 4/5/2013
`Deputy Director Review
`Abel Eshete, Yan Wang 3/4/2013
`Statistical Review
`Yan Wang, Daphne Lin 4/4/2013
`Team Leader Review
`Pharmacology/Toxicology Review Robeena Aziz, Lori Kotch 3/4/2013
`Clinical Pharmacology Review
`Yoriko Hayigaya, Philip Colangelo 2/19/2013
`ONDQA CMC Review
`Rao Kambhampati, Rapti Madurawe 2/26/2013, 4/4/2013
`Rapti Madurawe 4/5/2013
`Stephen Langille, Bryan Riley 1/22/2013
`Kassa Ayalew, Susan Leibenhaut, Susan Thompson
`2/4/2013, 2/20/2013
`Jung Lee, Zachary Oleszczuk, Carol Holquist 11/7/2012
`Carol Holquist 11/9/2012
`Jung Lee, Jamie Wilkins Parker 3/4/2013
`Jung Lee, Jamie Wilkins Parker, Carol Holquist 2/8/2013
`
`Quality Microbiology Review
`OSI/DGCPC
`
`OSE/DMEPA Proprietary Name
`Letter
`Final Review
`OSE/DMEPA Label, Labeling and
`Packaging Review
`OPDP/DPDP Review
`Pediatric Review Committee
`OND=Office of New Drugs
`CDTL=Cross-Discipline Team Leader
`ONDQA=Office of New Drug Quality Assessment
`OSI/DGCPC=Office of Scientific Investigations/Division of Good Clinical Practice Compliance
`(formerly Division of Scientific Investigation (DSI)
`OSE=Office of Surveillance and Epidemiology
`OMEPARM=Office of Medication Error Prevention and Risk Management
`DMEPA=Division of Medication Error Prevention and Analysis
`OPDP/DPDP=Office of Prescription Drug Promotion/Division of Professional Drug Promotion;
`formerly, DDMAC=Division of Drug Marketing, Advertising and Communication
`
`Christine Corser 3/20/2013
`This application did not trigger PREA
`
`
`Reference ID: 3289134
`
`2
`
`PAGE 3 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract surgery
`
`
`Table of Contents:
`
`
`Table of Contents: ................................................................................................... 3
`1.
`Summary and Recommendations ................................................................. 4
`1.1 Deficiencies ................................................................................................................... 5
`1.2
`Post-Marketing Studies: ................................................................................................ 5
`1.3 Other Issues ................................................................................................................... 5
`2.
`Background ................................................................................................... 5
`2.1 Application History ....................................................................................................... 5
`3.
`CMC/Product Quality Microbiology............................................................ 6
`4.
`Nonclinical Pharmacology/Toxicology ........................................................ 9
`5.
`Clinical Pharmacology/Biopharmaceutics ................................................. 10
`6.
`Clinical Microbiology/Immunology........................................................... 10
`7.
`Clinical/Statistical-Efficacy ........................................................................ 10
`7.1
`Phase 3 clinical trials ................................................................................................... 10
`8.
`Safety .......................................................................................................... 14
`8.1
`Post Marketing Experience ......................................................................................... 18
`9.
`Advisory Committee Meeting .................................................................... 18
`10.
`Pediatrics .................................................................................................... 18
`11. Other Relevant Regulatory Issues .............................................................. 18
`11.1
`Compliance Inspection - Facilities .......................................................................... 18
`11.2
`Office of Scientific Investigation (OSI) Audits ....................................................... 19
`11.3
`Debarment Certification .......................................................................................... 19
`11.4
`Financial Disclosure ................................................................................................ 19
`11.5
`Other Regulatory Issues........................................................................................... 19
`12. Labeling ...................................................................................................... 19
`13. Decision/Action/Risk Benefit Assessment ................................................. 19
`13.1
`Regulatory Action.................................................................................................... 19
`13.2
`Risk Benefit Assessment ......................................................................................... 20
`13.3
`Recommendation for other Postmarketing Requirements and Commitments ........ 20
`
`
`Reference ID: 3289134
`
`3
`
`PAGE 4 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract surgery
`
`
`
`1. Summary and Recommendations
`
`
`Bromfenac ophthalmic solution, 0.07% has been shown to be effective and safe for the
`treatment of pain and inflammation associated with cataract surgery based on two Phase 3
`trials showing superiority of the product to vehicle. The treatment regimen evaluated in these
`trials and recommended for approval is one drop in the affected eye one time daily beginning 1
`day prior to cataract surgery, continued on the day of surgery, and through the first 14 days of
`the post-operative period.
`
`
`Study
`
`Visit
`
`Bromfenac 0.07%
`
`Vehicle
`
` Key Efficacy Results of Phase 3 Studies in Prolensa NDA (ITT Population)
`Proportion of Subjects with Cleared Ocular Inflammation (0 cell and no flare)
`Difference (%)
`(Asymptotic 95% CI)
`17.6 (8.4, 26.8)
`
`Study 1
`
`Study 2
`
`
`
`Day 8
`
`27/112 (24.1%)
`
`7/108 (6.5%)
`
`Day 15
`
`51/112 (45.5%)
`
`14/108 (13.0%)
`
`32.5 (21.4, 43.8)
`
`Day 8
`
`33/110 (30.0%)
`
`14/110 (12.7%)
`
`17.3 (6.7, 27.9)
`
`Day 15
`
`50/ 110 (45.4%)
`
`30/ 110 (27.3%)
`
`18.2 (5.7, 30.7)
`
`Proportion of Subjects Who Were Pain Free
`
`Study 1 Day 1
`
`91/112 (81.3%)
`
`47/108 (43.5%)
`
`37.7 (25.9, 49.6)
`
`84/110 (76.4%)
`
`61/110 (55.5%)
`
`20.9 (8.7, 33.1)
`
`Study 2 Day 1
`
`The safety of the 0.07% bromfenac formulation was evaluated in 222 patients treated with this
`product and compared to 218 patients who received vehicle. This represents a new
`concentration of bromfenac. The safety of bromfenac 0.09% given twice daily (Xibrom) and
`once daily (Bromday) was evaluated in NDA 21-664 for the same indication(s).
`
`The labeling will include information on adverse reactions in these trials, and other safety
`information. The Warnings and Precautions includes information that the product contains
`sodium sulfite and may cause allergic reactions in susceptible people, NSAIDs may slow or
`delay healing, there is a potential cross-sensitivity with aspirin, increase bleeding time, and
`potential for keratitis and corneal erosion, ulceration and perforation. Common adverse
`reactions after cataract surgery associated with Prolensa use included anterior chamber
`inflammation, foreign body sensation, eye pain, photophobia, and blurred vision. These
`adverse reactions were reported in 3 to 8% of patients.
`
`All reviewers recommend approval. OSI recommends that clinical site data are considered
`reliable. As summarized in the CMC review, OC recommends that manufacturing facilities are
`
`
`Reference ID: 3289134
`
`4
`
`PAGE 5 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract smgery
`
`recommended acceptable. DMEPA considered the trade name Prolensa acceptable. Product
`labeling has been reviewed and is acceptable. The package insett is in PLR fotmat.
`
`The application will be issued an Approval letter.
`
`Deficiencies
`None
`
`Post-Marketing Studies:
`None
`
`1.1
`
`1.2
`
`1.3
`
`2. Background
`
`Bromfenac is a non-steroidal anti-inflammat01y dmg (NSAID). The active ingredient was ftrst
`approved March 24, 2005 as Xibrom (bromfenac ophthalmic solution) 0.09% under NDA
`21664 for the treatment of inflammation following cataract surgery. The sponsor was ISTA
`Phatmaceuticals, Inc. The recommended treatment regimen ofXibrom is one drop of
`XIBROM ophthalmic solution applied to the affected eye two times daily beginning 24 hours
`after cataract surgety and continuing through the ftrst 2 weeks of the postoperative period.
`Bromday was approved October 16, 2010 as Supplement 13 to NDA 21664, and established
`that one drop (instead of two drops) ofBromday ophthalmic solution 0.09% was safe and
`effective. The current product provides a lower concentration (0.07%) ofbromfenac.
`
`There are cunently a number ofNSAIDs and corticosteroids approved for the treatment of
`postoperative inflammation (and pain for some):
`• bromfenac sodium ophthalmic solution 0.09% (Xibrom, Bromday)
`• nepafenac ophthalmic solution 0.1% (Nevanac), nepafenac 0.3% (Ilevro)
`• ketorolac tromethamine ophthalmic solution 0.5% (Acular)
`• diclofenac sodium ophthalmic solution 0.1% (V oltru·en)
`•
`loteprednol etabonate ophthalmic solution, suspension and gel, each 0.5% (Lotemax)
`• difluprednate ophthalmic solution 0.05% (Durezol)
`rimexolone ophthalmic suspension 1% (V exol)
`•
`
`2.1
`
`Application History
`
`IND 60295 for bromfenac was originally submitted as a pre-IND on October 12, 2001 and as
`an lND for a 0.1% solution by ISTA on March 8, 2003 for the study of ophthalmic bromfenac.
`The 0.09% fotmulation was a
`roved under NDA 21664 in 2005.
`(bJ(~!
`the division
`~------~~-~~~~~~~~~~·--~--------~------~--~~
`recommended a 0.09% solution instead, due to concems about corneal toxicity issues and the
`
`Reference ID: 3289134
`
`5
`
`PAGE 6 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract smgery
`
`. - - - - - - - - - - - - - - - - - - - - - - - ,(b)(4!
`
`On May 29, 2008 a proposal to study the bromfenac 0.09% QD regimen was submitted and
`after the company conducted three trials, two of which showed the product was safe and
`effective, this regimen was approved in 2010 under NDA 21664/supplement 13.
`
`On Februruy 28, 2011, a SPA was submitted for bromfenac 0.07% for treatment of oculru·
`inflammation and pain associated with catru·act surge1y - no agreement on the protocol was
`reached with the Division. A No Agreement letter was issued April 14, 2011.
`
`The rationale for developing the 0.07% fmmulation was included in the Integrated Summary
`of Safety of this application (NDA 203168):
`
`The net effects of the changes led to a fonnulahon
`that maintains both safety and efficacy."
`. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -,(D)(4)
`
`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 surge1y.
`
`On August 20, 2012, ISTA notified the FDA they had been acquired by Bausch & Lomb
`Incorporated.
`
`3. CMC/Product Quality Microbiology
`
`For complete details, see the reviews by the product quality and quality microbiology
`reviewers. The following summary is excerpted from these reviews:
`
`The CMC reviewer noted that the manufacturer and supplier, manufacturing process, test
`methods, specifications, and all other parameters are the same for the 0.07% concentration as
`those used for the dmg substance in NDA 21664, bromfenac ophthalmic solution, 0.09%
`(Bausch & Lomb, fo1merly ISTA).
`
`The dmg product is manufactured by Bausch & Lomb Pharmaceuticals, Inc. (B,_&;.;.L~~.
`Tam a, FL and the rocess is summarized in the CMC review. The solution is
`
`Reference ID: 3289134
`
`6
`
`PAGE 7 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0 .07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract smgery
`
`-------------------------'(b)(4)
`
`<bH4
`(bll'll
`l filled into 7.5 mL size
`Bromfenac ophthalmic solution 0.07% is
`low-density eolyethf ene (LDPE white round bottles into w tch a"----.--~--~6!_<_.41
`controlled dropper tip is then insetied. It is capped and a
`!bH'~l seal is shrink-sealed over the cap and the neck of the
`":-ta_m_p_e_r---ev- i.-.d'e-n71t
`bottle. Labels coded with lot number and expiiy date are affixed to the bottle. The components
`of the container closure system used for bromfenac ophthalmic solution 0.07% at·e identical to
`the marketed bromfenac ophthalmic solution 0.09%.
`
`QC sampling and inspection is performed throughout the packaging operation. The product is
`then released for fmal distribution. The trade sizes for the dmg product are 1.6 mL and 3 mL
`fill volume per bottle. In addition, the applicant has submitted professional sample sizes of 0.6
`mL and 0.8 mL per 7.5 mL bottle. The applicant was asked why a 3mL bottle size was needed
`for the 16 drops of the treatment regimen and responded on March 4, 2013 that, "the 3-mL fill
`size ofProlensa™ takes into account the documented wastage in the elderly population to
`ensme evety patient is able to complete the labeled dosing regimen without compromising
`safety and efficacy." Publications to supp01t this rationale are summarized and included in
`the submission .
`
`The composition of the product is provided in the table below (applicant table from section
`3.2.P.l )
`
`Tablt> 1.
`
`Bromfenac Ophtbalmlc Solution 0.07% Quantltllllvt> Composition
`
`Com)Jonent
`
`Function
`
`Bromfenac 0.07%
`Formulation
`(%wlv)
`0.0805
`
`Amount /mL ~Batch
`Composition
`~(b)(4)
`-
`
`( mglmL)
`0.805
`
`(6)l.ill
`
`Active
`ingredient
`
`Bromfenac sodium
`sesquihydrate
`Boric acid
`~orlinm hornre
`Sodium sulfite
`Edctatc disodium (EDT A)
`Tyloxapol
`Benzalkonium chloride
`Povidone
`
`(b)(.fll
`
`I
`
`Sodium hydroxidel
`W.atcdodniec.tiOJ~'-~~~
`(b){4l
`
`Preservative
`
`0 .005
`
`0.05
`
`pH adjuster
`
`q.s. to pH 7.8
`
`q.s. to pH 7.8
`
`(b)(4)11
`
`., .. 1
`
`q.s. to pH 7.8 1
`
`7
`
`I
`
`Eqmvalent to 0.07 Vo bwmfenac free actd.
`0
`Only if necessary to adjust pH to 7. 8.
`
`Reference ID: 3289134
`
`PAGE 8 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract smgery
`
`The revised product specifications from the CMC review are listed in the following table
`
`T~ble- l.
`
`Spe-rifieiliOIU fer Eromfn:te Op.th<~lmi.: S~lution t .Oi%
`
`SpRili.-~tiom
`
`O ear, yellow soluti<>!l.
`A wlute l!hsttc bottle u.uh Wol>J)I>T tip a:o.d ~ cap. ";m n >
`significant discoloralton <>r physocai distorti<>n
`
`(6f(4J
`
`Tn 1
`Product Appe<!ranoe
`
`De~criptio:L. Co.nr.~in~
`
`Idmtifie.ation
`(releaso only)
`
`Bromfmac Sodium Assay
`
`Br<>mf..,..c lmpuruie,
`
`(b)(4j
`
`lm?urily~
`ADv ID.:Ii•-l:lu.al Sr1ied [mpwiry
`(b)(~
`
`Any llld.i~~ U ""pocilUd 1-"lpuriry
`
`pH
`
`Osmolality
`
`B~o:mUJD Chloricie:1
`
`EDTA
`
`Sodium Sulfite
`
`S teilit,.-
`Ba.eterial :EudotolO.DS
`
`Particulate Matter
`(MacroscopiC Ev a.hatlon)
`
`Particulate Matter (Vi..<ual)
`Weigh! Loss
`(subiliry ally)
`
`(b)l'll 'j
`
`Based on 12 months of real-time data, the expiration period granted is 12 months for the 0.8
`and 0.6 mL fill sizes. Based on 18 months of real-time data, the expiTation dating period
`granted is 22 months for the 1.6 and 3 mL fill sizes. The recommended label storage condition
`is 1 5°C-25°C (59°F-77°F).
`
`The applicant's request for exemption from enviTonmental assessment was considered
`acceptable (21 CFR 25.3 1(b)).
`
`Comments:
`The Product Quality and Microbiology Sterility reviewers recommend approval of the
`application from the CMC perspective. They conclude there is sufficient information to assure
`the identity, strength, purity, and qualityofthe drug product. The labels have adequat~ CMC
`4
`information as required,
`•.bl 1
`1
`
`Reference ID: 3289134
`
`8
`
`PAGE 9 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract surgery
`
`
` The establishment evaluation of the manufacturing and testing facilities was
`complete and the Office of Compliance issued an Overall Acceptable Recommendation. There
`are no post-marketing studies requested.
`
`
`4. Nonclinical Pharmacology/Toxicology
`For detailed information, see Pharmacology/Toxicology (P/T) reviews.
`
`There are no new pharmacology/toxicology (P/T) studies submitted in this application, the
`applicant refers to their applications, NDA 21664 (Xibrom and Bromday) and NDA 20535
`(Duract, bromfenac sodium capsules) for nonclinical information. The P/T reviewer
`recommended using mg/m2 exposure to calculate safety margins in patients receiving the
`topical solution in the labeling because AUC data were not provided. This approach showed
`that animal findings of embryolethality, maternal toxicity, delayed parturition, and delayed
`growth were seen at 80 to 4000 times the anticipated human exposure.
`
`The Deputy Director located tables of Cmax data for the oral animal studies in NDA 20535,
`and also noted the lower limit of detection for the assay was 50 ng/mL for bromfenac, and
`human testing showed values to be below this limit. Based on this information, he calculated
`the following:
`
`
`(cid:120) 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 (50 ng/mL) as described
`in the labeling, the multiple would be approximately 90 times.
`
`
`
`
`
`
`
`(cid:120) 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 (50 ng/mL) as described
`in the labeling, the multiple would be approximately 30 times.
`
`(cid:120) 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 (50 ng/mL) as described
`in the labeling, the multiple would be approximately 340 times.
`
`(cid:120) 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 (50 ng/mL) as described in the
`labeling, the multiple would be approximately 150 times.
`
`
`Comment:
`Although exposure comparisons are based on AUC, AUC information was not available for
`animal studies and not available in humans after topical application since values were below
`level of detection. Therefore, the Cmax comparison was used. As shown above, this approach
`yielded more conservative margins (30 to 340) compared to the mg/m2 approach (80 to 4000)
`and are acceptable for presenting the safety margins in the labeling. Therefore, the
`application is recommended for approval from a pharmacology/toxicology standpoint.
`Labeling recommendations have been finalized. The applicant asked for clarification on the
`animal to human plasma exposure calculations, and these were provided, including an
`
`
`Reference ID: 3289134
`
`9
`
`(b) (4)
`
`PAGE 10 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract surgery
`
`explanation that calculations were historically based on mg/kg comparison, and then mg/m2
`comparison and more recently based on comparison of exposures.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`For complete information, see clinical pharmacology review.
`
`There are no new PK studies submitted with this application, and the labeling of Section 12
`Clinical Pharmacology has the same information on mechanism of action and
`pharmacokinetics as NDA 21664. Specifically, based on information from bromfenac
`ophthalmic solution 0.09%, the company states that systemic absorption is estimated to be
`below the level of detection at steady state (50 ng/mL).
`
`Comment:
`The clinical pharmacolgoy reviewer recommends approval from the clinical pharmacology
`perspective; labeling is acceptable and no phase 4 studies are requested.
`
`
`6. Clinical Microbiology/Immunology
`Not applicable
`
`
`7. Clinical/Statistical-Efficacy
`
`Phase 3 clinical trials
`
`
`For complete details, see clinical and statistical reviews. The summary below is excerpted
`from these reviews, and additional information is taken from NDA 203168:
`
`7.1
`
`Two randomized, masked, vehicle (placebo) controlled trials, S00124-ER (ER)and S00124-
`WR (WR), were conducted in the “eastern” and “western” region of the United States,
`respectively. The same protocols and statistical analysis plan was used in each study. A total of
`220 patients were randomized 1:1 in each study; there were 20 sites that participated in Study
`ER and 19 sites in Study WR.
`
`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,
`measured on the ocular comfort grading assessment (ODGA). The ODGA rated 7 symptoms
`(eye pain, tearing, itching, foreign body sensation, photophobia [light sensitivity], eye
`discharge, and haziness) as 0=none, 1=mild, 2=moderate, and 3=severe.
`
`The primary efficacy analysis was conducted on the ITT population, defined as all randomized
`subjects. The Fisher’s exact test was used to compare the bromfenac 0.07% and the placebo
`groups with respect to the primary efficacy endpoint and the key secondary endpoint. Missing
`10
`
`Reference ID: 3289134
`
`PAGE 11 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract surgery
`
`data were imputed using the Last Observation Carried Forward (LOCF) method. The
`Hochberg’s method was used to adjust for multiple comparisons.
`
`Bromfenac ophthalmic solution 0.07% was superior to vehicle in both studies at Day 8 and
`Day 15, and significant when adjusted for multiple comparisons. More vehicle-treated
`patients than bromfenac-treated patients received rescue therapy. The applicant considered
`subjects who received rescue therapy as having missing data but imputed these as “failure”
`which is considered the appropriate way to categorize these patients.
`
`In addition, the applicant considered subjects who had non-zero cell and/or flare scores as
`successes at Day 15 if they has a Day 3 or Day 8 visit with zero cell and flare scores. While the
`ophthalmology reviewers agreed with this approach, the statistical reviewers did not (see
`Comments below). As summarized in the statistical reviews, patients who had zero scores on
`Day 3 or 8, but did not have a score of zero on Day 15 were considered as failures. There
`were a total of 15 patients in the two studies (out of 440), who met this outcome, and were
`approximately evenly distributed between the two studies and the two arms.
`
`The Tables below presents the FDA results and the applicant’s results for cleared ocular
`inflammation. It can be seen that both analyses lead to the interpretation of efficacy, The
`applicant’s analysis resulted in rates for the “by Day 15” analysis that were approximately 2%
`to 4% higher than in the FDA “at Day 15” analysis. Both FDA and the applicant agreed on the
`analysis of pain, which was evaluated on Day 1.
`
`FDA analysis:
`Proportion of Subjects with Cleared Ocular Inflammation (0 cells and no flare)
`Study
`Visit
`Bromfenac 0.7%
`Vehicle
`Difference (%)
`(Asymptotic 95% CI)
`17.6 (8.4, 26.8)
`32.5 (21.4, 43.8)
`17.3 (6.7, 27.9)
`18.2 (5.7, 30.7)
`
`7/108 (6.5%)
`14/108 (13.0%)
`14/110 (12.7%)
`30/110 (27.3%)
`
`27/112 (24.1%)
`S00124-ER At Day 8
`51/112 (45.5%)
`At Day 15
`33/110 (30.0%)
`S00124-WR At Day 8
`50/110 (45.5%)
`At Day 15
`Proportion of Subjects who Were Pain Free
`Study
`Visit
`Bromfenac 0.07%
`
`Vehicle
`
`Difference (%)
`(Asymptotic 95% CI)
`37.7 (25.9, 49.6)
`20.9 (8.7, 33.1)
`
`S00124-ER At Day 1
`S00124-WR At Day 1
`
`91/112 (81.3%)
`84/110 (76.4%)
`
`47/108 (43.5%)
`61/110 (55.5%)
`
`
`
`Applicant’s analysis:
`Proportion of Subjects with Cleared Ocular Inflammation (0 cells and no flare)
`Study
`Visit
`Bromfenac 0.7%
`Placebo
`Difference (%)
`(Asymptotic 95% CI)
`31.5 (19.9, 43.2)
`17.3 (4.5, 30.0)
`
`54/112 (48.2%)
`54/110 (49.1%)
`
`18/108 (16.7%)
`35/110 (31.8%)
`
`S00124-ER By Day 15
`S00124-WR By Day 15
`
`
`
`
`Reference ID: 3289134
`
`11
`
`PAGE 12 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract sm gery
`
`Proportion of Subjects who Wer e Pain Free
`Study
`Visit
`Bromfenac 0.07%
`
`Vehicle
`
`At Da_y I
`SOOI24-ER
`SOO I24-WR At Day I
`
`911112 {81.3%}
`84/1 10 (76.4%)
`
`47/ I08 (43.5%2
`6 I/1 10 (55.5%)
`
`Difference (%)
`(Asymptotic 95% en
`37.7 (25.9, 49.6}
`20.9 (8.7, 33.I)
`
`. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -·<bH'fl
`
`. An agreement had not been reached on the protocol - a No
`Agreement letter was issued in April 20I I for the SPA. However, the cmTent approach of
`repoliing results based on findings on the day of the visit is consistent with previous FDA
`approvals, based on examination ofNDAs for this indication and comments from various
`ophthalmology reviews for these products. In the review of the last 7 NDAs for the indication
`of inflammation after cataract sm ge1y , the analysis was based on the assessment "at" or "on"
`the day of evaluation in six of these seven NDAs (see below). The one exception had been
`Bromday (bromfenac 0.09%) approved in 20IO, which was also submitted by ISTA. In
`addition, "by" is defined as "dming the com se of "or "no later than," so the expectation would
`be that these patients were successes "dming the com se of Day I 5" or "no later than Day 15"
`and had zero scores for inflammation.
`
`The approach to using zero scores to determine success has been applied in the last 6 or 7
`NDAs for NSAID or steroid products. ISTA had been previously advised of this dming the
`development of their Xibrom product.
`
`Comment:
`A detailed summary of the analyses used to support the approval of the last 7 NSAID or
`steroid products for treatment of inflammation after cataract surgety, and tabular
`comparisons of the endpoints, the definitions, the timing of evaluations is included in the
`Statistical Team Leader Review.
`
`List of NDAs Approved in 2005-2012 for post-oper ative Inflammation after Catar act Surgery
`
`ND A
`3.1 NDA021664 Xibrom (bromfenac ophthahnic solution, 0.09% BID)
`3.2 NDA021862 Nevanac (nepafenac ophthalmic suspension, 0.1% TID)
`
`3.3 NDA022212 Durezol (diflupred.nate ophthalmic emulsion, 0.05%)
`
`3.4 NDA021664 Bromday (bromfenac ophthalmic solution, 0.09% QD)
`
`2.5 NDA200738 Lotemax (loteprednol eta bonate ophthahnic ointment, 0.5% QID)
`
`3.6 NDA202872 Lotemax (loteprednol etabonate ophthahnic gel, 0.5% QID)
`
`3.7 NDA203491 Ilevr o (nepafenac ophthahnic suspension, 0.3% QD)
`
`Submitted Approved
`2004
`2005
`
`2005
`
`2007
`
`2009
`
`2009
`
`2011
`
`2011
`
`2005
`
`2008
`
`2010
`
`2010
`
`2012
`
`2012
`
`<b><4
`X the ophthalmology reviewers recommended presenting
`~~~~~~~~.--~~~~
`data "by Day 15" where patients who had non-zero scores on day 15 were considered
`successes, this approach was inconsistent with 6 of the above 7 NDAs that present study
`results on or at the Day of the visit when the inflammation score was zero.
`
`Reference ID: 3289134
`
`12
`
`PAGE 13 OF 22
`
`

`
`NDA 203168 Prolensa (bromfenac ophthalmic solution) 0.07%
`Indication: For the treatment of postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract surgery
`
`The decision that success is based on a zero inflammation score is also consistent in that
`labeling for the majority (6 of 7) NDAs reports success as scores of 0 cell and flare, or 0 cell,
`in approved labeling. In fact, this interpretation was articulated by the MO at the time of the
`original Xibrom bromfenac 0.09% NDA 21-664 submission and review:
`
`
`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) ≤ 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. (MOR 3/14/2005, NDA 21664)
`
`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). (MOR 3/14/2005, NDA 21664)
`
`
`Similar comments are found in reviews by other reviewers for NSAID and steroid products for
`this indication about the cell counts, and interpretation of rescue therapy is also addressed:
`
`
`If a drug product is given on Day 15 to treat ocular inflammation, the drug product may be
`considered rescue treatment. (MOR, 3/21/2011, IND 60295)
`
` I
`
` disagree with the statement in the protocol, “Therefore if a subject completes the
`treatment Phase (i.e., all 16 days of IP treatment) any alternative treatment given to the
`subject thereafter is NOT a rescue medication.” If an alternative treatment is given to a
`subject at the end of treatment phase because the patient has not cleared his/her
`inflammation, the alternative treatment can be considered rescue treatment. (MOR
`4/14/2011, IND 60295)
`
`The latter statements indicate that patients who are non-zero scores at the end of treatment
`(e.g., Day 15) and require rescue therapy are not counted as successes, therefore, to count
`patients with non-zero scores as successes is inconsistent with past advice.
`
`Al