CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202514Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross-Discipline Team Leader Review of NDA 202514
`Review #2
`
`a.an
`William M. Boyd, M.D.
`Cross-Disci - line Team Leader Review
`
`NDA #
`202514
`
`30, 2012
`
`A licant
`
`Merck Sh u & Dohme Co .
`
`13, 2012
`Janu
`Date of Submission
`
`PDUFA Goal Date
`March 13, 2012
`
`Tp-eofA ulication
`Name
`
`1
`505 I
`Zio tan taflurost o hthahnic solution 0.0015%
`
`Recommended:
`
`Dosa _c forms / Stren_ h
`Proposed Indication(s)
`
`To ical o hthahnic solution
`Reduction of elevated intraocular pressure in patients with
`o en-an - le ' laucoma or ocular h p ertension
`Recommended for A o uroval
`
`1. Introduction
`
`NDA 202514 for Zioptan (tafluprost ophthalmic solution) 0.0015% received a Complete Response
`Letter dated November 7, 2011, which cited the following deficiency:
`
`Your NDA does not provide assurance of the sterility of the final drug product. While you have
`revised your
`out) processing validation protocol in your submission of October 27, 2011, M0
`filling procedures using this revised
`m4), we cannot determine that the product is sterile
`
`validation protocol. In the absence
`and safe for use.
`
`(on)
`To address this deficiency, provide a re 011 describing three consecutive successful
`processing simulations
`on) 0 that you will use for manufacturing the product using the
`inspection and accounting procedures provided in the revised
`(mo processing validation
`protocol submitted in the October 27, 2011, amendment.
`
`Merck submitted an amendment on January 13, 2012, which constituted a Complete Response.
`
`2. Sterility Assurance
`
`From the original Product Quality Microbiology Review finalized 1/18/2012:
`
`On 13 January 2011 the applicant filed a Class 1 resubmission with the requested data from 3
`consecutive
`“(0 processing simulations
`am) using the revised validation protocol
`submitted to the agency on 27 October 2011.
`M4) batches 10019, 10020, and 10021 were
`manufactured separately and batch 10019 had a sterile
`
`(mo
`
`Reference ID: 3078993
`
`

`

`CDTL Review #2
`
`William M. Boyd, M.D.
`NDA 2025 14
`
`Zioptan (tafluprost ophthalmic solution) 0.001596
`
`_.Ammmemree-ismovmedm
`
`Ta e1
`
`ow.
`
`Table 1- Summary results from- processing simulation studies (Sponsor Table
`3.2.P.3.5-2452—ophsln: l 1)
`
`Batch
`Number
`
`Mfg.
`Dale
`
`fl of Units
`Positive
`for
`Growth
`
`22NOV20| | 10021
`
`10019
`10020
`
`20Nov20l I
`
`24NOV2011
`
`The revised
`reviewed for
`
`procedures were summarized in Module 3.5.5.2 and were consistent with data
`t
`' Microbiolo Reviews #1 and #2. Briefl
`ules
`
`were filled with
`
`
`
`This application is recommended for approval on the basis ofproduct quality microbiology.
`
`3. Labeling
`
`NDA 202514, Zioptan (tafluprost ophthalmic solution) 0.0015% is recommended for approval for the
`reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension
`with the labeling found in this review.
`
`The labeling for Zioptan was finalized prior to the Complete Response letter dated November 7, 2011.
`
`In a January 18, 2012, teleconference with Merck, there was discussion regarding the inclusion of an
`additional statement in Section 16 (How Supplied/Storage and Handling) of the proposed package
`insert for Zioptan to maintain consistency between Cosopt PF labeling and Zioptan labeling. The only
`changes to the proposed Zioptan patient package insert were limited to the revision date, the copyright
`date and the component number.
`
`The revised package insert and revised patient package insert submitted on 1/23/2012 are acceptable.
`
`The carton and container labeling submitted on 11/4/2011 are acceptable.
`
`Reference ID: 3078993
`
`

`

`CDTL Review #2
`William M. Boyd, M.D.
`NDA 202514
`Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`The package insert, patient package insert, carton and container labeling are located in the Appendix at
`the end of this review.
`
`
`4. Recommendations/Risk Benefit Assessment
`
`
`RECOMMENDED REGULATORY ACTION:
`NDA 202514, Zioptan (tafluprost ophthalmic solution) 0.0015% is recommended for approval for the
`reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
`There is substantial evidence of safety and effectiveness consisting of adequate and well controlled
`studies which demonstrate that patients receiving Zioptan (tafluprost ophthalmic solution) 0.0015%
`experienced a statistically and clinically significant reduction in intraocular pressure. The data support
`Zioptan (tafluprost ophthalmic solution) 0.0015% administered once daily in the evening for the
`reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
`
`The most common ocular adverse reactions (pooled) were conjunctival hyperemia (10.7%) and ocular
`stinging/irritation (7.2%). The most common nonocular adverse reaction was headache (5.6%).
`
`
`RISK BENEFIT ASSESSMENT:
`Studies 15-003 and 001 demonstrate that the IOP lowering ability of tafluprost 0.0015% is not inferior
`to timolol 0.5%. Study 74458 had unequal baselines and is difficult to interpret. The safety profile of
`tafluprost 0.0015% is similar to other marketed topical prostaglandin analogues.
`
`The benefit of tafluprost 0.0015% for the treatment of elevated IOP in open-angle glaucoma or ocular
`hypertension has been demonstrated in this NDA application. The risk for using this drug is consistent
`with the currently marketed prostaglandin analogues.
`
`Pharmacology/Toxicology, CMC, Biostatistics, Clinical, Clinical Pharmacology, and Product Quality
`have recommended approval for this application.
`
`RECOMMENDATION FOR POSTMARKETING RISK MANAGEMENT ACTIVITIES:
`There are no risk management activities recommended beyond the routine monitoring and reporting of
`all adverse reactions.
`
`
`
`
`
`
`Reference ID: 3078993
`
`
`
`3
`
`17 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this
`page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILLIAM M BOYD
`01/30/2012
`
`WILEY A CHAMBERS
`02/01/2012
`
`Reference ID: 3078993
`
`