CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202514Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`Medical Officer Review of NDA 202514
`
`Review #2
`
`Jan
`
`31, 2012
`
`Recommended:
`
`William M. B0 (1, MD.
`Medical Officer Review
`
`NDA #
`202514
`
`A licant
`
`Merck Sh t & Dohme Co .
`
`13, 2012
`Jan .
`Date of Submissions
`
`PDUFA Goal Date
`March 13, 2012
`
`TpneofAlication
`Name
`
`1
`505 I
`Zio otan taflu rost o hthalmic solution 0.0015%
`
`Dosa _e forms / Stren_ h
`Proposed Indication(s)
`
`To ical o hthalmic solution
`Reduction of elevated intraocular pressure in patients with
`o o en-an - 1e {laucoma or ocular h ‘0 ertension
`Recommended for A 0 roval
`
`1. Introduction
`
`NDA 202514 for Zioptan (tafluprost ophthahnic 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
`“"9 processing validation protocol in your submission of October 27, 2011,
`(”"9
`(mofilling procedures using this revised
`(I!) (4)
`we cannot determine that the product is sterile
`
`validation protocol. In the absence
`and safe for use.
`
`W"
`To address this deficiency, provide a report describing three consecutive successful
`processing simulations
`M0 that you will use for manufacturing the product using the
`inspection and accounting procedures provided in the revised
`°’(°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 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
`“9‘" processing simulations
`(am) using the revised validation protocol
`submitted to the agency on 27 October 2011.
`“W’batches 10019, 10020, and 10021 were
`manufactured separately and batch 10019 had a sterile I
`
`(on)
`
`Reference ID: 3079942
`
`

`

`Medical Oflicer’s Review #2
`
`William M. Boyd, M.D.
`NDA 202514
`
`Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`F. A summaxyouhe three- is providedm
`
`Ta el
`
`ow.
`
`Table 1- Summary results from- processing simulation studies (Sponsor Table
`3.2.P.3.5-2452-ophsln:l 1)
`
`Batch
`Number
`
`Mfg.
`Dale
`
`24Nov20l I
`
`100l9
`l0020
`1002]
`
`20Nov20| |
`22NW20| I
`
`The revised! procedures were summarized in Module 3.5.5.2 and were consistent with data
`reviewed for
`'
`'
`' Microbiolo
`e Pro uct
`
`
`were filled
`
`This application is recommended for approval on the basis of product quality microbiology.
`
`3. Safety Update
`
`Per Merck, the safety data presented in the Safety Update in the January 13, 2012, resubmission, are
`consistent with those submitted to the original NDA and the Safety Update in May 2011. Therefore,
`Merck is not proposing any changes to the proposed package insert and proposed patient package
`insert previously submitted to the FDA.
`
`Currently, there are no ongoing clinical studies for tafluprost that are sponsored by Merck in the US or
`in any ex-US country. However, there are two ongoing ex-US/non- IND, post-marketing surveillance
`studies for tafluprost that are being sponsored by Merck’s development partner, Santen, in some of the
`countn'es where they hold the Marketing Authorization.
`
`
`
`Reference ID: 3079942
`
`

`

`Medical Officer‘s Review #2
`
`William M. Boyd, M.D.
`NDA 202514
`
`Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`Five of these ongoing (m4) studies are double masked. The sixth study is an open labeled long term
`safety study for the (mo in Japan that has approximately 42 patients exposed to tafluprost
`monotherapy during the four week open label randomization phase. The remaining two ongoing
`studies are post—marketing safety surveillance studies for tafluprost in Japan and Korea. In addition to
`these eight ongoing studies, the final Clinical Study Report of one completed study
`(no)
`study) is being submitted in this Safety Update.
`
`Table 2.7.4: 1
`
`Ongoing Studies to be Included in the Safety Update Report for Tafluprost
`
`Study Name
`
`Duration
`
`Enrollment Ratio
`
`N
`
`Treatment Arms and
`Randomization or
`
`Randomized or
`Entered
`
`Protocol
`ONGOING STUDIES
`
`247 currently
`enrolled
`
`Treatment Phase
`ongoing
`
`6 months 7primary Approximately 600
`Phase III,
`evaluation of
`patients will be enrolled
`randomized,
`efficacy at 3
`to this study: 220
`double-masked
`study to compare months; data
`patients (1 10/group)
`efficacy and
`beyond 3 months
`for the comparison of
`safe of the PF
`used to
`timolol '
`‘5) (”Stratum
`(5" .o tafluprost
`investigate long-
`1) and 380 patients
`0.0015% and
`term safety of the
`(l90/group) for the
`timolol
`0')(4)
`comparison oftafluprost
`0.5% eye drops
`“)(Wstratum 2).
`given as
`individual
`
`on»
`EU Non-inferiority
`study (m0
`
`00(4)
`EU PK study| (”(9
`
`Reference ID: 3079942
`
`
`
`6 months treatment Approximately 380
`( up to 4 week
`patients will be enrolled
`washout. 6 months
`to this study in 1:1 (5)“)
`treatment, 1—3
`vs concomitant taf and
`week post-study
`tim
`follow-up).
`
`Treatment Phase
`ongoing
`
`monotherapies
`Phase III,
`randomized,
`double-masked
`study to compare
`efficacy and
`$8chofthe PF
`| (b)( 0 those of
`tafluprost
`0.0015% and
`
`timolol 0.5% eye
`drops given
`concomitantly
`
`15 Final Enrollment Treatment Phase
`ongoing
`
`Duration of the
`Ph 1, single
`first, second and
`center, double-
`third treatment
`masked, 3-period
`crossover for PK, period are 7 days
`safety. and
`each (Day
`tolerability of
`l to Day 7); 4
`(b) “’75 PF taf and weeks between the
`PF tim
`treatment
`
`15 healthy volunteers
`will be randomized to
`ensure that at least 12
`healthy
`vollmteers randomized
`
`monotherapy
`
`Periods; post-study
`follow—up period
`of 1-3 weeks.
`
`

`

`Medical Officer‘s Review #2
`
`William M. Boyd, M.D.
`NDA 202514
`
`Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`Ongoing Studies to be Included in the Safety Update Report for Tafluprost (Cont)
`
`Treatment Arms and
`Randomization or
`Enrollment Ratio
`
`Randomized or
`Entered
`N
`
`4 week observation
`with Taf and 4
`week double-
`masked treatment
`
`period
`
`Approx 480
`subjects. 1 60 subjects
`pergroup in 1:1:1
`randomization to 00(4)
`‘5) (”or Taf/Tim
`concomitant
`administration
`
`4 week observation
`with tim and 4
`week double-
`masked treatment
`
`Approx 140 subjects
`(70 subjects per group)
`in 1:1 randomization to
`Tim or
`(5)“)
`
`period
`
`374 currently
`enrolled
`
`Treatment Phase
`
`ongoing
`
`138 currently
`enrolled
`
`Treatment Phase
`ongoing
`
`l 3 6 currently
`enrolled
`
`Treatment Phase
`
`ongoing
`
`4502 tafluprost PC
`
`Treatment Phase
`ongoing
`
`ongoing
`
`
`(5X4)
`
`Japanl “(firm
`
`(I!) (4)
`
`Japan Long Term
`Safety Study- (5)“)
`
`Post-approval
`regulatory
`commitment,
`open label study in
`Japan
`
`Post-approval
`regulatory
`commitment,
`open label study in
`Korea
`
`Study Name
`Phase 111 Double-
`masked
`comparative
`(5) (4)
`study r
`compared to Taf
`monotherapy and
`Tat/Tim given
`concomitantly
`Phase III Double—
`masked
`
`(I!) (4)
`
`comparative
`study
`compared to
`Timolol
`
`monotherapy in
`patients
`
`Phase III Long
`term Open Label
`study of
`(5)“)
`
`TAPROS
`ophthalmic
`solution 0.0015%
`
`Special Drug
`Use-results
`Survey
`(Investigation on
`Long-term Use)
`
`Post Marketing
`Surveillance on
`
`Safety and
`Efficacy of
`Tafluprost PC
`Eye Drops in
`Korean Patients
`in Accordance
`with
`“Regulation for
`Re-Examiuation
`
`of New Drugs,
`Etc."
`
`Approx 126 subjects
`(42 subjects per group
`for each observation
`
`period ophthalmic
`solution); 4 week open
`label period of pts
`randomized to Taf, Tim,
`or Tat/Tim concomitant
`administration; 52 wk
`treatment period of
`patients
`“M"
`
`All patients enrolled to
`tafluprost PC by
`centralized registration
`system (TAPROS is the
`marketed tafluprost in
`Japan).
`
`4 week open
`randomization: 52
`week open label
`treatment period
`
`Followed for 2, 12
`and 24 months,
`follow-up of 6
`months if
`discontinued
`TAPROS due to
`AE
`
`Visit for
`assessment at
`
`Week 4; total study
`duration 6 years
`alter product
`release.
`
`3000 or more Korean
`pts.
`
`550 talluprost PC
`
`Treatment Phase
`
`Taf= PF tafluprost 0.0015% (or PC tafluprost 0.0015% for Japan Studies)
`Tim = PF tim01010.5% (or PC tim01010.5% for Japan Studies)
`
`Reference ID: 3079942
`
`

`

`Medical Officer’s Review #2
`William M. Boyd, M.D.
`NDA 202514
`Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`)
`Study 77553
` study with 185 patients, was completed and summarized
`Study 77553, the Phase 3 open label
`in the original Safety Update (May 2011). The study was performed to assess changes in ocular
`symptoms and signs in patients with ocular hypertension or primary open-angle glaucoma who were
`switched from preserved latanoprost 0.005% eye drops to preservative-free tafluprost 0.0015% eye
`drops. The most frequent non-serious AEs were eye irritation N= 6 (3%), eye pain N= 5 (3%), and eye
`pruritus N= 5 (3%). Drug related ocular AEs were reported for 20 (10.9%) patients. The systemic AE
`of headache was reported most frequently (3%). There were no systemic AEs related to study drug, as
`determined by the investigators. There was one serious adverse event reported in this study for a
`patient with unstable angina. The patient was not discontinued from the study, the AE was not related
`to study drug (as determined by the investigator), and the patient recovered from the SAE. These AEs
`are consistent with the safety profile of tafluprost.
`
` (EU PK Study)
`Study
`A phase 1, randomized, double-masked, 3-period cross-over clinical study to compare the
` tafluprost
`pharmacokinetics, safety and tolerability of
`0.0015% and timolol 0.5% eye drops to those of preservative free tafluprost 0.0015% and timolol 0.5%
`eye drops in healthy volunteers
`
`As of the cut-off date of November 7, 2011, there have been no patient discontinuations and no serious
`adverse events reported for this PK study 201150.
`
` (EU Superiority Study)
`Study
`A phase 3, randomized, double-masked 6-month clinical study to compare the efficacy and safety of
`the preservative-free
` tafluprost 0.0015% and timolol 0.5% eye drops to
`those of tafluprost 0.0015% and timolol 0.5% eye drops given as individual monotherapies in patients
`with open angle glaucoma or ocular hypertension
`
`Study data remain masked since the study is ongoing, however preliminary review indicates of 247
`randomized patients, 12 patients have discontinued, 2 of which were due to AEs. Adverse events
`necessitating discontinuation from the study for 2 patients were: 1) non-serious AEs of ocular burning,
`facial redness, tingling of lips, dulling sensorium; all of which were considered as related to study
`medication by the investigator and the patient recovered. Study medication assignment remained
`masked. 2) a serious adverse event of vertiginous syndrome, considered as not related to study
`medication and the patient recovered. Study medication assignment remained masked.
`
`There were 5 SAEs reported for this study in the reporting timeframe: vertiginous syndrome; high IOP;
`TIA and Raynaud's syndrome; adenolymphoma, and anorectal /hemorrrhoidal pain; all were judged to
`be not related to study medication.
`
`
` (EU Non-Inferiority Study)
`A phase 3, randomized, double-masked 6-month clinical study to compare the efficacy and safety of
`the preservative-free
` tafluprost 0.0015% and timolol 0.5% eye drops to
`those of tafluprost 0.0015% and timolol 0.5% eye drops given concomitantly in patients with open
`angle glaucoma or ocular hypertension.
`
`
`
`
`Reference ID: 3079942
`
`
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Medical Officer‘s Review #2
`
`William M. Boyd, M.D.
`NDA 202514
`
`Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`Study data remain masked since the study is ongoing; of 401 randomized patients, 20 have
`discontinued, 9 of which were due to AEs. One patient who discontinued experienced 2 SAEs: a hiatal
`hernia and a cerebral infarction. There were 7 patients who discontinued due to ocular AEs.
`
`There were 10 SAEs reported for this study during the reporting timeframe: gastrointestinal ulcer
`bleeding , esophageal hemorrhage, parotid swelling, cerebral infarction, renal colic, gastric neoplasm,
`mechanical ileus, colonic polyp, arm fracture, tachycardia; all were judged to be not related to study
`medication.
`
`Appendix 2 .7.4: 2
`
`M“) (l-ZU Non-inferiority)
`Randomized Patients Who Discontinued Study
`as of l lNovZOl 1* (Ongoing)
`
`
`?:-'33O:53
`
`n5
`
`Female
`
`
`
`Female
`Ferrrale
`
`Female
`
`Female
`
`Female
`
`
`
`
`
`
`
`
`
`
`
` Male
`Female
`
`Female
`
`Male r-T-
`
`DOSE
`DOSE
`DOSE
`
`Reason for Discontinuation
`Photosensrtrve. Courrnrclrvrtrs
`Irritating oi‘tlre eye. dry eye. sensitivity to
`light,
`foreign body sensation in the eye.
`rrffv e elids. redness of the e elids
`According to patients
`complaint of
`moderate eye pain. redness ol'
`the eye.
`discomfort and irritation in the
`eye,
`atierrl has $10
`ed IP installation
`Exacerbation of ocular allergy
`
`Corrjunctivnl redness
`
`Dys uoea
`lI
`erseusitivity to dru
`Aller
`ie eou’tmctivilis
`Two SAEs; cerebral
`hernia
`Voluntary withdraw -
`Voluntary Withdraw -
`Voluntzu withdraw -
`Volunt- withdraw -
`
`infarction.
`
`Iliatal
`
`aticnt re t uest
`atrent re r uest
`aticul re uest
`atient reuest
`
`Patient unable/unwilling to follow dosing
`Patient unable/unwillin . to follow dosing
`’atrerrt unable/unwrllurg to follow dosing
`’atient unable/unwillin to follow dosin
`rnproper Entry
`
`lOP rrrrcorrtrolled as
`invesli alor,
`Note: no CRF data entered
`
`judged by
`
`the
`
`
`
`
`“.3oor1r5_
`Female Female
`
`
`
`
`
` Female
`
`
`
`lOP
`
`OTI IER/
`Misrarrdonri
`zalion
`(screen
`failure)
`
`* Listiuu as 01'07N0v2011 is not available
`
`Reference ID: 3079942
`
`

`

`Medical Officer‘s Review #2
`
`William M. Boyd, M.D.
`NDA 202514
`
`Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`M" Compared to Tafluprost Monotherapy and Tafluprost/Timolol
`(m4) (Japan
`Study
`Given Concomitantly Study)
`A double-masked study of DE-l 11 ophthalmic solution versus tafluprost ophthalmic solution 0.0015%
`alone and concomitant use of tafluprost ophthahnic solution 0.0015% plus timolol ophthalmic solution
`0.5% in patients with primary open angle glaucoma or ocular hypertension
`
`Of the 374 patients who are randomized in this study, only 1 patient has discontinued due to a non-
`serious ocular AE; the AE was punctate keratitis. There were no SAEs reported in this study at the
`time of the November 7, 2011, cut-off date.
`
`M" Compared to Timolol Monotherapy Study)
`(m4) (Japan
`Study
`(mo ophthalmic solution versus timolol ophthalmic solution 0.5% in
`A double—masked study of
`patients with primary open angle glaucoma or ocular hypertension
`
`Of the 138 patients who are randomized in this study, 3 patients have discontinued due to 6 non-
`serious ocular AEs including ocular hyperemia, eye irritation, eyelid edema, and adenoviral
`conjunctivitis. There was 1 SAE of large intestine carcinoma reported in this study at the time of the
`November 7, 2011, cut—off date.
`
`Appendix 2.7.4: 4
`
`Randomized Patients who Discontinued from
`Japan Study
`(”was ofO7N0v2011 (Ongoing)
`
`Protocol No.
`
`Subject 1]) Country
`
`.
`
`(b)(
`
`-m
`
`Japan
`
`Female
`
`WE...
`
`Discontinued
`date
`
`MedDRA-PI
`
`M“) Ocular ltypcractnia
`Eye irritation
`
`Eyelid oedema
`Ocular liypcractnia
`Adcnoviml
`conjtutctivitis
`Ocular lty’pemetuitt
`
`(m4) Long Term Study)
`(m4) (Japan
`Study
`A Phase 3 long-term open-label study of
`M0 ophthalmic solution in patients with open angle
`glaucoma or ocular hypertension
`
`Of the 126 patients who are randomized in this study, one patient discontinued due to a non-serious
`non-ocular AE of generalized rash.
`
`There were 2 patients with reported unrelated SAEs of cellulitis and uterine leiomyoma at the time of
`the November 7, 2011, cut—off date; these 2 patients were both in the run—in period of the study on
`either timolol or tafluprost and were not on the
`(0(4)
`
`Reference ID: 3079942
`
`

`

`Medical Officer’s Review #2
`William M. Boyd, M.D.
`NDA 202514
`Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`
`Post Approval Studies (Japan and Korea)
`The two remaining studies (post-approval regulatory commitment studies), are long-term open-label
`post-marketing surveillance studies ongoing in Japan (TAPROS) and Korea.
`
`Worldwide Adverse Experience (WAES) Database
`The Worldwide Adverse Experience (WAES) database was searched for spontaneous reports from
`healthcare providers for tafluprost received from 02-Mar-2011 through 07- Nov-2011.
`
`
`
`
`
`Reference ID: 3079942
`
`
`
`
`
`
`
`8
`
`

`

`Medical Officer’s Review #2
`William M. Boyd, M.D.
`NDA 202514
`Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`
`
`
`
`
`
`
`
`Summary Statement
`
`The safety results included in this Safety Update Report are consistent with those submitted in the
`original NDA submission and subsequent initial Safety Update. As a result, no changes have been
`made to the proposed package insert and the proposed patient package insert. The currently proposed
`labeling adequately represents the safety profile of tafluprost.
`
`
`
`
`
`
`
`Reference ID: 3079942
`
`
`
`9
`
`

`

`Medical Officer’s Review #2
`William M. Boyd, M.D.
`NDA 202514
`Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`4. 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 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.
`
`The package insert, patient package insert, carton and container labeling are located in the Appendix at
`the end of this review.
`
`
`5. Recommendations
`
`
`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.
`
`
`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: 3079942
`
`
`
`10
`
`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
`01/31/2012
`
`WILEY A CHAMBERS
`02/01/2012
`
`Reference ID: 3079942
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthahnic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`Summary Review for Regulatory Action
`
`See electronic sta u o date
`
`Renata Albrecht, MD
`Division of Trans 0 lant and 0 hthalmolo 3 Products1
`Division Director Summ. Review
`
`NDA 202514
`NDA Number
`
`Related IND
`IND 62,690 av1K-2452)
`Merck Sh. oe & Dohme Co .
`
`A licant Name
`
`erck
`
`1
`505 9
`A uplicationTe
`
`January 7, 2011 (standard review)
`Date of Original Submission
`PDUFA Goal Date
`November 7, 2011
`Zioptan '
`Proprietary Name /
`
`Tafluprost ophthahnic solution
`Established (USAN) Name
`Sterile ophthahnic solution
`Dosage Form
`0.0015% (15 micrograms/mL)
`Dosage Strength
`Preservative
`Preservative free
`
`
`
`Route of Administration
`
`Topical
`Dose
`One drop in affected eye or eyes once daily in the
`
`evening
`reduction of elevated intraocular pressure in open-angle
`glaucoma or ocular hypertension
`Foil pouch containing strip of 10 single-use LDPE
`amoule, containin 0.3 mL clear solution
`Com Iete Res onse
`
`Proposed Indication(s)
`
`How Supplied
`
`Action for A lication
`
`l The Office ofAntimicrobial Products was reorganized efl‘ective May 2011: specifically the Division of Special
`Pathogen and Transplant Products (DSPTP) and Division of Anti-Infective and Ophthalmology Products
`(DAIOP) were reorganized into the Division of Transplant and Ophthalmology Products (DTOP) and the
`Division of Anti-Infective Products (DAIP).
`
`Reference ID: 3040897
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`CDTL Review
`Deputy Director
`Statistical Review
`Carcinogenicity Assessment
`Committee (CAC)
`Pharmacology/Toxicology Review
`
`CMC – ONDQA, Division II,
`Branch V Review
`Product Quality Microbiology
`Review
`Clinical Pharmacology Review
`OSI/DGCPC
`
`OSE/DMEPA Proprietary Name
`
`OSE/DMEPA Labeling Review
`PI and carton/container
`OMP/Patient Package Labeling
`
`OPDP/DPP (formerly DDMAC)
`
`
`Names of discipline reviewers
`
`Lucious Lim, Bill Boyd, Wiley Chambers 9/28/2011
`Bill Boyd 11/7/2011
`Wiley Chambers 11/7/2011
`Yunfan Deng, Yan Wang 7/20/2011
`David Jacobson-Kram 5/6/2011
`
`James Wild, Wendelyn Schmidt 7/20/2011
`Abby Jacobs 7/25/2011
`Maotang Zhou, Rapti Madurawe 8/26/1011,
`10/24/2011, Terrance Ocheltree 11/7/2011
`Jessica Cole, Stephen Langille 9/30/2011, 11/4/2011
`David Hussong 11/4/2011
`Yongheng Zhang, Philip Colangelo 7/20/2011
`Kassa Ayalew, Susan Thompson, Jean Mulinde
`6/27/2011
`Denise Baugh, Todd Bridges, Carol Holquist
`4/15/2011 (Saflutan denied)
`Denise Baugh, Todd Bridges, Carol Holquist
`8/31/2011 (Zioptan acceptable)
`Denise Baugh, Todd Bridges, Carol Holquist
`8/24/2011
`Sharon Williams, Melissa Hulett and LaShawn
`Griffiths 11/3/2011
`Package insert: Christine Corser, 10/19/2011
`Patient Package insert: Adora Ndu 11/3/2011
`
`
`CDTL=Cross-Discipline Team Leader
`OND=Office of New Drugs
`OPDP/DPP=Office of Prescription Drug Promotion/Division of Professional Promotion, (formerly DDMAC=Division of Drug
`Marketing, Advertising and Communication)
`PMHT=Pediatric and Maternal Health Staff
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DDRE= Division of Drug Risk Evaluation
`DRISK=Division of Risk Management
`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)
`OMP = Office of Medical Policy
`
`
`
`
`Reference ID: 3040897
`
`2
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`Table of Contents:
`Table of Contents:........................................................................................................................3 
`1. Summary and Recommendations ........................................................................................4 
`1.1 Product Quality Microbiology Sterility Deficiencies: .......................................................4 
`1.2 Post-Marketing Studies:....................................................................................................6 
`1.3 Other Issues........................................................................................................................6 
`2.  Background..........................................................................................................................6 
`3.  CMC/Product Quality Microbiology ...................................................................................7 
`4.  Nonclinical Pharmacology/Toxicology ...............................................................................9 
`5.  Clinical Pharmacology/Biopharmaceutics.........................................................................10 
`6.  Clinical Microbiology/Immunology ..................................................................................11 
`7.  Clinical/Statistical-Efficacy ...............................................................................................11 
`7.1 Efficacy Results: .............................................................................................................14 
`7.2 Proposed Labeling Regarding Efficacy: .........................................................................19 
`7.3 Noninferiority Margin:....................................................................................................20 
`8.  Safety .................................................................................................................................21 
`8.1 Adverse reactions of special interest...............................................................................24 
`9.  Advisory Committee Meeting............................................................................................25 
`10. 
`Pediatrics........................................................................................................................25 
`11. 
`Other Relevant Regulatory Issues..................................................................................25 
`11.1 Compliance Inspection..................................................................................................25 
`11.2 Office of Scientific Investigation (OSI) Audits............................................................25 
`11.3 Debarment certification ................................................................................................26 
`11.4     Financial Disclosure ................................................................................................26 
`11.5 
`Other Regulatory Issues...........................................................................................26 
`12. 
`Labeling .........................................................................................................................26 
`13. 
`Decision/Action/Risk Benefit Assessment ....................................................................26 
`13.1 Regulatory Action.........................................................................................................26 
`13.2 Risk Benefit Assessment...............................................................................................27 
`13.3 Recommendation for Postmarketing Requirements (PMR) and Commitments (PMC)
`................................................................................................................................................27 
`
`
`
`Reference ID: 3040897
`
`3
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`1. Summary and Recommendations
`
`Based on the reviews of NDA 202514, I concur that the application should be issued a
`Complete Response at this time because of outstanding Product Quality Microbiology Sterility
`deficiencies as summarized in 1.1 below. Other reviewers have found the application
`acceptable for approval from the clinical, statistical, clinical pharmacology, toxicology
`(including carcinogenicity), and manufacturing perspective. The Office of Compliance has
`recommended that the manufacturing sites for the drug product are acceptable on October 13,
`2011 and the Office of Scientific Investigations has recommended that clinical data are
`acceptable to support the application. Labeling recommendations have been received from
`OSE/DMEPA for the carton and containers, and from DDMAC for product labeling; their
`recommendations have been incorporated. The Office of Medical Policy (0MP) and DDMAC
`have reviewed the patient package insert and their recommendations incorporated.
`
`Carton and container labeling has been finalized. Both the package insert and patient package
`insert are considered final by the review team, to the extent that they can be included with the
`action letter.
`
`Zioptan (tafluprost ophthahnic solution)2 0.0015% is a prostaglandin F201 analogue indicated
`for reduction of elevated intraocular pressure (IOP) in open-angle glaucoma or ocular
`hypertension in adult patients. The dosing regimen is 1 drop of tafluprost solution in the
`conjunctiva] sac given once daily in the evening in the affected eye or eyes. The product to-
`be—marketed is a preservative flee (PF), sterile, clear solution supplied in single-dose ampules.
`Phase 3 clinical trials included both the PF and preservative-containing (PC) formulations; the
`preservative is benzalkonium chloride. The efficacy of this new molecular entity was
`demonstrated in two Phase 3 clinical trials (Study 15-003 and 001) conducted in US and
`Europe comparing tafluprost to timolol, along with a bridging trial (Study 77550). Other
`Phase 1, 2 and 3 studies conducted during development were also included in the application.
`
`1.1 Product Quality Microbiology Sterility Deficiencies:
`
`According to Dr Jessica Cole, the Product Quality Microbiology Reviewers, there are
`microbiology deficiencies that need to be addressed before approval. Specifically, her review
`recommends that
`(l) the
`(m4) procedures are not adequate because existing procedures allow additional
`inspection of positive vials after incubation has begun and as such are not adequate to
`insure sufficient sterility assurance for this
`(but) processed sterile drug product. She
`notes that the
`(m4)
`
`the applicant
`
`She recommends
`
`2 The established name for ophthalmic products includes the active ingredient and the formulation as shown here.
`The concentration of the formulation is listed outside the parentheses and is not part of the established name.
`
`Reference ID: 3040897
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated inlIaocular pressure in open-angle glaucoma or ocular hypertension
`
`(5) (4)
`
`procedure or provide an adequate scientific justification
`(a) remove from the
`(b) (4)
`for the additional inspection/scrutiny of
`ampules compared to product-
`filled ampules.
`on» data (i.e., positive samples or failures, etc.), if
`(b) provide any relevant
`applicable, regarding the filling line proposed for tafluprost
`(c ) confirm that a single filling line is proposed for tafluprost
`(2) the submitted documentation does not include a full accounting and description of units
`from
`(5)“)
`‘
`lfldat
`llldl
`(5X4)
`processrng va 1
`1011 5
`es.
`
`the applicant
`(a) provide the number of units filled, rejected, incubated, inspected, and positive for
`growth for all
`ma) conducted on each filling line proposed for tafluprost.
`
`She recommends
`
`Following internal discussion and teleconferences with Merck, the question was raised
`whether the
`(m4) nms could be performed and submitted as a post-marketing
`commitment by the end of the first quarter in 2012. Merck agreed to such an approach.
`
`However, Dr. David Hussong, Associate Director for Quality Microbiology notes that
`“This would mean that approval of the application could permit marketing of product prior to a
`complete demonstration of sterile manufacturing capability. We wanted to allow the applicant
`the opportunity to complete the validation and begin drug manufacture as promptly as
`possible, and proposed that the approval would be conditioned upon a commitment to
`withhold shipment of product until the validation was complete. However, that condition
`cannot be enforced in a post-approval commitment. If the applicant chose to market the
`product and subsequently
`(I'm failed (in March or April), the following outcomes
`may occur and would need to be addressed.
`1. All marketed product could be recalled for lack of sterility assurance.
`2. Patients might be exposed to contaminated products. Bacteria capable of growing in
`the solution would have time to reach great populations.
`3. The Quality Assurance department may exercise its authority to investigate the cause
`of the failure and conclude there is no risk. Their conclusion may be subject to bias.
`Two of these outcomes are undesirable from a regulatory and safety perspective.
`Based on these considerations and the applicant’s lack of willingness to perform these studies
`in a more timely fashion, I conclude that the application should not be approved until three
`consecutive
`W" are completed successfully and reported to the application file.”
`
`To address the outstanding deficiency,
`processing
`Merck should provide a report describing three consecutive successful
`simulations on the filling line that will be used for manufacturing the product using the
`inspection and accounting procedures provided in the revised
`(5)“) processing validation
`protocol submitted in the October 27, 2011 amendment.
`
`(5) (4)
`
`Reference ID: 3040897
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated inlraocular pressure in open-angle glaucom