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

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA:
`
`203,168
`
`Submission Date(s):
`
`June 7, 2012
`
`Brand Name
`
`Prolensa
`
`Generic Name
`
`Bromfenac ophthalmic solution 0.07%
`
`Primary Reviewer
`
`Yoriko Harigaya, PharmD.
`
`Team Leader
`
`Philip Colangelo, Pharm.D., PhD.
`
`0CP Division
`
`Division of Clinical Pharmacology 4
`
`0ND Division
`
`Division of Transplant and Ophthalmology Products
`
`Applicant
`
`ISTA Pharmaceuticals, Inc.
`
`Relevant IND(s)
`
`60,295
`
`Submission Type
`
`Original Submission: Standard Review
`
`Formulation; Strength(s) Bromfenac ophthahnic solution 0.07%
`
`Indication
`
`Treatment of inflammation and pain associated with cataract
`extraction
`
`
`
`1. EXECUTIVE SUMNIARY
`
`The sponsor submitted an original New Drug Application (NDA) for Prolensa®
`(bromfenac ophthahnic solution 0.07%) on June 7, 2012. Prolensa®, administered once
`daily (QD), is a non-steroidal anti-inflammatory drug (NSAID) studied in clinical trials
`for the treatment of postoperative inflammation and the reduction of ocular pain in
`subjects who have undergone cataract surgery. The proposed dosage and route of
`administration for Prolensa® for this indication is as follows: instill one drop of
`bromfenac ophthahnic solution 0.07% into the affected eye once daily beginning 1 day
`prior to surgery, continued on the day of surgery, and through the first 14 days post-
`surgery.
`
`This ProlensaD formulation (0.07%) differs from the currently marketed bromfenac
`ophthalmic solution 0.09% product (BromdayO) in the amounts of bromfenac sodilnn and
`its target pH.
`mm
`The indication is the same as the currently marketed
`product, Bromday (bromfenac ophthalmic solution 0.09%), administered QD. sNDA
`21,664 for Bromday® was approved by the Agency on October 16, 2010 with a change in
`dosage regimen from the previously approved (March 24, 2005) twice-a-day (BID)
`dosing for Xibrom® (bromfenac sodium ophthalmic solution 0.1%) following cataract
`extraction surgery to QD dosing beginning 1 day prior to cataract surgery, continue on
`the day of surgery, and for 14 days after cataract surgery.
`
`Reference ID: 3263614
`
`

`

`No new clinical pharmacology data was presented in this supplement. Thus, no review is
`needed for this NDA submission. For information of the pharmacokinetic (PK)
`characteristics of Xibrom® (bromfenac sodium ophthalmic solution 0.1% BID), please
`refer to the Office of Clinical Pharmacology review of the original NDA 21,664 (by Dr.
`Lei Zhang dated March 8, 2005). For the efficacy study information of Bromday®
`(formerly XiDay®) (bromfenac ophthalmic solution 0.09% QD), please refer to the Office
`of Clinical Pharmacology review of the NDA 21,664 / SE2-013 (by Dr. Kimberly L.
`Bergman dated July 12, 2010).
`
`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.
`
`1.1 Recommendation
`From a Clinical Pharmacology perspective, the application is acceptable. No new clinical
`pharmacology data was presented in this supplement.
`
`1.2 Labeling Recommendations
`Please refer to Section 2 for detailed labeling recommendations.
`
`1.3 Phase 4 Requirements
`No Phase IV study recommendation.
`
`1.4 Summary of Important Clinical Pharmacology Findings
`No additional pharmacological studies were conducted for this NDA.
`
`2. LABELING RECOMMENDATIONS
`In the current submission (NDA 203,162 dated June 7, 2012), the applicant has proposed
`no changes to the already existing Clinical Pharmacology section in the approved label
`for Xibrom® and Bromday®. The labeling proposed for this supplement is acceptable
`from a clinical pharmacology perspective (see proposed labeling below), and there are no
`labeling revisions / edits to be sent to the sponsor.
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`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 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.
`
`Reference ID: 3263614
`
`2
`
`

`

`12.3 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
`other routes of administration, the systemic concentration of bromfenac is estimated
`to be below the limit of quantification (50 ng/mL) at steady-state in humans.
`
`Reference ID: 3263614
`
`3
`
`

`

`3. OCP Filing and Review Form
`Office of Clinical Pharmacology
`
`New Drug Application Filing and Review Form
`
`General Information About the Submission
`Information
`
`203,168
`IV
`DTOP
`Yoriko Harigaya, Pharm.D.
`
`Brand Name
`Generic Name
`Drug Class
`Indication(s)
`
`
`
`NDA/BLA Number
`OCP Division (I, II, III, IV, V)
`Medical Division
`OCP Reviewer
`
`OCP Team Leader
`
`Pharmacometrics Reviewer
`Date of Submission
`Estimated Due Date of OCP Review
`
`Philip M. Colangelo, Pharm.D.,
`Ph.D.
`N/A
`June 7, 2012
`March 7, 2012
`
`Dosage Form
`
`Dosing Regimen
`Route of Administration
`Sponsor
`
`Medical Division Due Date
`
`PDUFA Due Date
`
`N/A
`April 7, 2013
`
`Priority Classification
`
`
`Information
`Prolensa
`Bromfenac
`NSAID
`Treatment of
`inflammation and pain
`associated with cataract
`extraction
`Ophthalmic solution
`
`Once daily dose
`Topical
`ISTA Pharmaceuticals,
`Inc.
`Standard
`
`
`
`
`STUDY TYPE
`Table of Contents present and sufficient to
`locate reports, tables, data, etc.
`Tabular Listing of All Human Studies
`HPK Summary
`Labeling
`Reference Bioanalytical and Analytical
`Methods
`I. Clinical Pharmacology
` Mass balance:
`
` Isozyme characterization:
` Blood/plasma ratio:
` Plasma protein binding:
` Pharmacokinetics (e.g., Phase I) -
`
`Healthy Volunteers-
`
`Patients-
`
`single dose:
`multiple dose:
`
`single dose:
`multiple dose:
`
`Reference ID: 3263614
`
`Clin. Pharm. and Biopharm. Information
`“X” if included
`Number of
`Number of
`at filing
`studies
`studies
`submitted
`reviewed
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`Critical Comments If any
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`Refer to the OCP review of
`the original NDA 21,664 by
`Dr. Lei Zhang (Mar. 8, 2005)
`and Efficacy Supplement by
`Dr. Kimberly L. Bergman
`(July 12, 2010)
`
`
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`
`Refer to the OCP review of
`the original NDA 21,664 by
`Dr. Lei Zhang (Mar. 8, 2005)
`and Efficacy Supplement by
`Dr. Kimberly L. Bergman
`(July 12, 2010)
`
`4
`
`

`

` Dose proportionality -
`fasting / non-fasting single dose:
`fasting / non-fasting multiple dose:
` Drug-drug interaction studies -
`In-vivo effects on primary drug:
`In-vivo effects of primary drug:
`In-vitro:
`
` Subpopulation studies -
`
` PD -
`
` PK/PD -
`
` Population Analyses -
`
`Phase 1 and/or 2, proof of concept:
`Phase 3 clinical trial:
`
`ethnicity:
`gender:
`pediatrics:
`geriatrics:
`renal impairment:
`hepatic impairment:
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`Phase 2:
`Phase 3:
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`Data rich:
`Data sparse:
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`II. Biopharmaceutics
` Absolute bioavailability
` Relative bioavailability -
`
`solution as reference:
`alternate formulation as reference:
` Bioequivalence studies -
`traditional design; single / multi dose:
`replicate design; single / multi dose:
` Food-drug interaction studies
` Bio-waiver request based on BCS
` BCS class
` Dissolution study to evaluate alcohol induced
` dose-dumping
`III. Other CPB Studies
` Genotype/phenotype studies
` Chronopharmacokinetics
` Pediatric development plan
` Literature References
`Total Number of Studies
`
`
`Reference ID: 3263614
`
`5
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`YORIKO HARIGAYA
`02/19/2013
`
`PHILIP M COLANGELO
`02/19/2013
`
`Reference ID: 3263614
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
`
`Office of Clinical Pharmacology
`New Drug Application Filing and Review Form
`
`General Information About the Submission
`
`
`NDA/BLA Number
`OCP Division (I, II, III, IV, V)
`Medical Division
`OCP Reviewer
`
`Information
`203,168
`IV
`DTOP
`Yoriko Harigaya, Pharm.D.
`
`
`
`Brand Name
`Generic Name
`Drug Class
`Indication(s)
`
`OCP Team Leader
`
`Pharmacometrics Reviewer
`Date of Submission
`Estimated Due Date of OCP Review
`
`Philip M. Colangelo, Pharm.D.,
`Ph.D.
`N/A
`June 7, 2012
`March 7, 2012
`
`Dosage Form
`
`Dosing Regimen
`Route of Administration
`Sponsor
`
`Medical Division Due Date
`
`PDUFA Due Date
`
`N/A
`April 7, 2013
`
`Priority Classification
`
`
`Information
`Prolensa
`Bromfenac
`NSAID
`Treatment of
`inflammation and pain
`associated with cataract
`extraction
`Ophthalmic solution
`
`Once daily dose
`Topical
`ISTA Pharmaceuticals,
`Inc.
`Standard
`
`
`
`
`STUDY TYPE
`Table of Contents present and sufficient to
`locate reports, tables, data, etc.
`Tabular Listing of All Human Studies
`HPK Summary
`Labeling
`Reference Bioanalytical and Analytical
`Methods
`I. Clinical Pharmacology
` Mass balance:
`
` Isozyme characterization:
` Blood/plasma ratio:
` Plasma protein binding:
` Pharmacokinetics (e.g., Phase I) -
`
`(cid:42)(cid:71)(cid:67)(cid:78)(cid:86)(cid:74)(cid:91) (cid:56)(cid:81)(cid:78)(cid:87)(cid:80)(cid:86)(cid:71)(cid:71)(cid:84)(cid:85)(cid:15)
`
`Patients-
`
`single dose:
`multiple dose:
`
`single dose:
`
`Clin. Pharm. and Biopharm. Information
`“X” if included
`Number of
`Number of
`at filing
`studies
`studies
`submitted
`reviewed
`
`
`
`
`
`
`
`
`Critical Comments If any
`
`
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`X
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`Refer to the OCP review of
`the original NDA 21,664 by
`Dr. Lei Zhang (Mar. 8, 2005)
`and Efficacy Supplement by
`Dr. Kimberly L. Bergman
`(Dec. 18, 2009)
`
`
`
`
`
`
`
`
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`
`
`
`
`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
`NDA_BLA or Supplement 090808
`Reference ID: 3167645
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
`
`multiple dose:
`
`X
`
`
`
`
`
` Dose proportionality -
`fasting / non-fasting single dose:
`fasting / non-fasting multiple dose:
` Drug-drug interaction studies -
`In-vivo effects on primary drug:
`In-vivo effects of primary drug:
`In-vitro:
`
` Subpopulation studies -
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`
`Refer to the OCP review of
`the original NDA 21,664 by
`Dr. Lei Zhang (Mar. 8, 2005)
`and Efficacy Supplement by
`Dr. Kimberly L. Bergman
`(Dec. 18, 2009)
`
`
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`ethnicity:
`gender:
`pediatrics:
`geriatrics:
`renal impairment:
`hepatic impairment:
`
`Phase 2:
`Phase 3:
`
`Data rich:
`Data sparse:
`
` PD -
`
` PK/PD -
`
` Population Analyses -
`
`Phase 1 and/or 2, proof of concept:
`Phase 3 clinical trial:
`
`II. Biopharmaceutics
` Absolute bioavailability
` Relative bioavailability -
`
`solution as reference:
`alternate formulation as reference:
` Bioequivalence studies -
`traditional design; single / multi dose:
`replicate design; single / multi dose:
` Food-drug interaction studies
` Bio-waiver request based on BCS
` BCS class
` Dissolution study to evaluate alcohol induced
` dose-dumping
`III. Other CPB Studies
` Genotype/phenotype studies
` Chronopharmacokinetics
` Pediatric development plan
` Literature References
`Total Number of Studies
`
`
`On initial review of the NDA/BLA application for filing:
`
`Content Parameter
`Criteria for Refusal to File (RTF)
`1 Has the applicant submitted bioequivalence data comparing to-be-
`marketed product(s) and those used in the pivotal clinical trials?
`2 Has the applicant provided metabolism and drug-drug interaction
`information?
`
`Yes No N/A Comment
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`X
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`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
`NDA_BLA or Supplement 090808
`Reference ID: 3167645
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
`
`3 Has the sponsor submitted bioavailability data satisfying the CFR
`requirements?
`4 Did the sponsor submit data to allow the evaluation of the validity of
`the analytical assay?
`5 Has a rationale for dose selection been submitted?
`6
`Is the clinical pharmacology and biopharmaceutics section of the NDA
`organized, indexed and paginated in a manner to allow substantive
`review to begin?
`Is the clinical pharmacology and biopharmaceutics section of the NDA
`legible so that a substantive review can begin?
`Is the electronic submission searchable, does it have appropriate
`hyperlinks and do the hyperlinks work?
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`7
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`Criteria for Assessing Quality of an NDA (Preliminary Assessment of Quality)
` Data
`9 Are the data sets, as requested during pre-submission discussions,
`submitted in the appropriate format (e.g., CDISC)?
`If applicable, are the pharmacogenomic data sets submitted in the
`appropriate format?
` Studies and Analyses
`11
`Is the appropriate pharmacokinetic information submitted?
`12 Has the applicant made an appropriate attempt to determine reasonable
`dose individualization strategies for this product (i.e., appropriately
`designed and analyzed dose-ranging or pivotal studies)?
`13 Are the appropriate exposure-response (for desired and undesired
`effects) analyses conducted and submitted as described in the
`Exposure-Response guidance?
`Is there an adequate attempt by the applicant to use exposure-response
`relationships in order to assess the need for dose adjustments for
`intrinsic/extrinsic factors that might affect the pharmacokinetic or
`pharmacodynamics?
`15 Are the pediatric exclusivity studies adequately designed to
`demonstrate effectiveness, if the drug is indeed effective?
`16 Did the applicant submit all the pediatric exclusivity data, as described
`in the WR?
`Is there adequate information on the pharmacokinetics and exposure-
`response in the clinical pharmacology section of the label?
` General
`18 Are the clinical pharmacology and biopharmaceutics studies of
`appropriate design and breadth of investigation to meet basic
`requirements for approvability of this product?
`19 Was the translation (of study reports or other study information) from
`another language needed and provided in this submission?
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`IS THE CLINICAL PHARMACOLOGY SECTION OF THE APPLICATION FILEABLE?
`Yes
`
`If the NDA/BLA is not fileable from the clinical pharmacology perspective, state the reasons and provide
`comments to be sent to the Applicant.
`
`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
`NDA_BLA or Supplement 090808
`Reference ID: 3167645
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
` FILING FORM/CHECKLIST FOR NDA/BLA or Supplement
`
`N/A
`
`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-day letter.
`There are no potential review issues to be forwarded to the applicant for the 74 day letter from a clinical
`pharmacology perspective.
`
`Reviewing Clinical Pharmacologist
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`Team Leader/Supervisor
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`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
`NDA_BLA or Supplement 090808
`Reference ID: 3167645
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`YORIKO HARIGAYA
`07/31/2012
`
`PHILIP M COLANGELO
`08/01/2012
`
`Reference ID: 3167645
`
`