`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`202514Orig1s000
`
`STATISTICAL REVIEW(S)
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
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`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES
`
`NDA/Serial Number:
`202514
`Drug Name:
`Preservative-Free Tafluprost 0.0015% Ophthalmic Solution
`Indication(s):
`Treatment of Elevated Intraocular Pressure (IOP)
`Applicant:
`Merck & Co., Inc.
`Date(s):
`Submitted: 01/07/2011
`PDUFA Date:
`11/07/2011
`Review Priority:
`Standard
`Biometrics Division:
`DBIV
`Statistical Reviewer:
`Yunfan Deng, Ph.D.
`Concurring Reviewer: Yan Wang, Ph.D.
`Medical Division:
`Division of Transplant and Ophthalmologic Drug Products
`Clinical Team:
`Lucious Lim, MD, Clinical Reviewer
`William Boyd, MD, Clinical Team Leader
`Constantine Markos
`
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`Project Manager:
`
`Keywords:
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`NDA, Non-inferiority, Elevated Intraocular Pressure
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`Reference ID: 2976454
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`TABLE OF CONTENTS
`
`LIST OF TABLES.......................................................................................................................................................3
`1. EXECUTIVE SUMMARY .................................................................................................................................4
`1.1 CONCLUSIONS AND RECOMMENDATIONS.........................................................................................................4
`1.2 BRIEF OVERVIEW OF CLINICAL STUDIES..........................................................................................................4
`1.3 STATISTICAL ISSUES AND FINDINGS.................................................................................................................6
`2.
`INTRODUCTION ...............................................................................................................................................9
`2.1 OVERVIEW .......................................................................................................................................................9
`2.2 APPLICATION HISTORY ....................................................................................................................................9
`2.3 DATA SOURCES..............................................................................................................................................10
`3. STATISTICAL EVALUATION ......................................................................................................................10
`3.1 EVALUATION OF EFFICACY ............................................................................................................................10
`3.1.1 Study Designs and Endpoints .....................................................................................................................10
`3.1.2 Patient Disposition, Demographic and Baseline Characteristics ................................................................13
`3.1.3 Statistical Methodologies............................................................................................................................19
`3.1.3.1 Studies 15-003, 001, and 74458.......................................................................................19
`3.1.3.2 Study 77550 .....................................................................................................................22
`3.1.4 Results and Conclusions .............................................................................................................................22
`3.2 EVALUATION OF SAFETY ...............................................................................................................................28
`4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ................................................................................30
`4.1 STUDY 15-003................................................................................................................................................30
`4.2 STUDY 001.....................................................................................................................................................32
`4.3 STUDY 74458.................................................................................................................................................33
`5. SUMMARY AND CONCLUSIONS ..................................................................................................................34
`5.1 STATISTICAL ISSUES AND COLLECTIVE EVIDENCE.........................................................................................34
`5.2 CONCLUSIONS AND RECOMMENDATIONS.......................................................................................................37
`APPENDIX A: DISCUSSION REGARDING THE CHOICE OF 1.5 MMHG NON-INFERIORITY
`MARGIN USING TIMOLOL (0.5% TWICE DAILY) AS THE ACTIVE COMPARATOR...........................38
`APPEDIX B: SUMMARY OF PHASE II STUDIES .............................................................................................43
`1. STUDY 15-001 (PHASE II DOSE-FINDING STUDY I) ..............................................................................................43
`2. STUDY 15-002 (PHASE II DOSE-FINDING STUDY II) .............................................................................................45
`3. STUDY 74457 (PHASE II STUDY; A PILOT LATANOPROST COMPARISON STUDY) .................................................47
`APPENDIX C: SUMMARY OF OTHER PHASE III STUDIES .........................................................................48
`1. STUDY 74460 .......................................................................................................................................................48
`2. STUDY 77552 .......................................................................................................................................................49
`SIGNATURES/DISTRIBUTION LIST...................................................................................................................51
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`Reference ID: 2976454
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`LIST OF TABLES
`
`Table 1: IOP Change from Baseline Analysis Results (FAS, LOCF, ANCOVA) ............................................................................ 6
`Table 2: IOP Change from Baseline for Study 77550 (FAS, LOCF, RM ANCOVA)...................................................................... 8
`Table 3: Summary of Key Design Elements for Studies 15-003, 001, and 74458 .......................................................................... 11
`Table 4: Summary of Key Design Elements for Studies 74460, 77550, and 77552 ....................................................................... 12
`Table 5: Study 15-003 Disposition of All Randomized Subjects.................................................................................................... 13
`Table 6: Study 15-003 Summary of Each Analysis Set .................................................................................................................. 13
`Table 7: Study 15-003 Demographic Characteristics...................................................................................................................... 13
`Table 8: Study 15-003 Baseline IOPs (in worst eye) ...................................................................................................................... 14
`Table 9: Study 15-003 Ocular Diagnosis........................................................................................................................................ 14
`Table 10: Study 001 Disposition of All Randomized Subjects....................................................................................................... 15
`Table 11: Study 001 Summary of Each Analysis Set ..................................................................................................................... 15
`Table 12: Study 001 Demographic Characteristics......................................................................................................................... 15
`Table 13: Study 001 Baseline IOPs (in worst eye) ......................................................................................................................... 16
`Table 14: Study 74458 Disposition of All Randomized Subjects................................................................................................... 16
`Table 15: Study 74458 Summary of Each Analysis Set.................................................................................................................. 17
`Table 16: Study 77548 Demographic Characteristics..................................................................................................................... 17
`Table 17: Study 74458 Baseline IOPs (in worst eye) ..................................................................................................................... 18
`Table 18: Study 77548 Ocular Diagnosis ....................................................................................................................................... 18
`Table 19: Study 77550 Ocular Diagnosis ....................................................................................................................................... 19
`Table 20: Study 77550 Baseline IOPs (in worst eye) ..................................................................................................................... 19
`Table 21: IOP Change from Baseline Analysis Results by Statistical Reviewer (FAS, LOCF, ANOCVA) .................................. 23
`Table 22: IOP Change from Baseline for Study 77550 (FAS, LOCF, RM ANCOVA).................................................................. 25
`Table 23: IOP Change from Baseline Sensitivity Analysis Results by Statistical Reviewer (FAS, Multiple Imputation, ANOCVA)
`........................................................................................................................................................................................................ 26
`Table 24: Ocular AEs Reported for More Than 5 subjects in either group for study 15-003 (Safety Population).......................... 29
`Table 25: Ocular AEs Reported for ≥ 4 subjects in either group for study 001 (Safety Population) .............................................. 29
`Table 26: Ocular AEs Reported for More Than 5 subjects in either group for study 74458 (Safety Population)........................... 29
`Table 27: Ocular AEs in Either Group for Study 77550 (Safety Population) ................................................................................. 30
`Table 28: Study 15-003 Summary Statistics for IOP (mmHg) by Previous Use of Prostaglandin and Ocular Diagnosis .............. 30
`Table 29: Study 15-003 Summary Statistics for IOP (mmHg) by Time Point and Subgroup at Week 12 (PP, Study Eye)............ 32
`Table 30: Study 74458 Summary Statistics for IOP (mmHg) by Previous Use of Prostaglandin and Ocular Diagnosis (PP, Study
`Eye) ................................................................................................................................................................................................ 33
`Table 31: IOP Change from Baseline Analysis Results by Statistical Reviewer (FAS, LOCF, ANOCVA) .................................. 34
`Table 32: IOP Change from Baseline for Study 77550 (FAS, LOCF, RM ANCOVA).................................................................. 36
`Table 33: Mean Change ± SD from Baseline in IOP (mmHg) in Study 15-001 ............................................................................. 38
`Table 34: Treatment Difference with 95% CI for Mean Change from Baseline in IOP (mmHg) for Study 15-001....................... 39
`Table 35: Mean Change from Baseline in IOP (mmHg) in Study 15-002 ...................................................................................... 40
`Table 36: Mean IOP Change from Baseline for Studies 15-003 and 001 ....................................................................................... 40
`Table 37: Combined IOP Change from Baseline for Placebo and Timolol at Each Time Point ..................................................... 42
`Table 38: Mean Diurnal IOP during the Treatment Period (mmHg) in Study 15-001 (ANOVA, PP Population, Observed)......... 44
`Table 39: Mean Change from Baseline in Diurnal IOP (mmHg) in Study 15-001 (ANOVA, PP Population, Observed).............. 44
`Table 40: Mean Change from Baseline in IOP (mmHg) on Day 28 in Study 15-001 (ANOVA, PP Population, Observed) ......... 44
`Table 41: IOP Values of Patients Treated with 0.0015% Tafluprost, 0.5% Timolol and 0.005% Latanoprost in Phase II Clinical
`Trial 15-002 (ANOVA, PP, Observed)........................................................................................................................................... 46
`Table 42: Mean Change from Baseline in IOP on Day 28 (mmHg) in Study 15-002 (ANOVA, PP, Observed Data) ................... 46
`Table 43: Study 74457 Summary of IOP Change from Baseline (mmHg) by Visit, and Time Point (PP, LOCF) ......................... 47
`Table 44: Study 74457 Analysis of IOP Change from Baseline (mmHg) by Visit, and Time Point (PP, ANCOVA, LOCF)........ 48
`Table 45: Study 74460 Summary of IOP Change from Baseline (mmHg) by Visit, and Time Point (PP, LOCF) ......................... 49
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`Reference ID: 2976454
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`EXECUTIVE SUMMARY
`
`Conclusions and Recommendations
`
`1.
`
`1.1
`
`In this submission, the Applicant seeks approval of preservative-free (PF) tafluprost 0.0015%
`ophthalmic solution administered once daily for the treatment of elevated intraocular pressure
`(IOP). The Applicant submitted three non-inferiority efficacy studies (two timolol non-inferiority
`studies [15-003 and 001] and one Latanoprost Non-Inferiority Study [74458]), and a study
`comparing the PC formulation and PF formulation (Study 77550).
`
`For study 15-003 comparing preservative-containing (PC) tafluprost with PC timolol, both PC
`tafluprost and the active comparator PC timolol showed IOP-lowering effect throughout the 12-
`month study period. Tafluprost reached the predetermined criteria for non-inferiority (1.5 mmHg)
`at each visit and time point using timolol as the active comparator.
`
`For study 001 comparing PF tafluprost versus PF timolol, both PF tafluprost and the active
`comparator (PF timolol) showed IOP-lowering effect throughout the 12 weeks of treatment. The
`IOP-lowering effect of PF tafluprost was within the 1.5 mmHg non-inferiority margin compared
`to PF timolol at all visits and time points.
`
`Study 77550 investigated the pharmacodynamics (as expressed in IOP) of the preserved and
`unpreserved formulation of tafluprost 0.0015% eye drops in patients with open-angle glaucoma
`or ocular hypertension. For both the preservative-containing and preserve-free formulation, a
`similar and clear IOP-lowering effect was seen already at week 1 and the IOP-lowering effect
`was sustained and similar for both formulations at week 4.
`
`For study 74458, both PC tafluprost and PC latanoprost reduced IOP throughout the 24 months
`treatment period. However, tafluprost did not reach the predetermined criterion for non-
`inferiority (1.5 mmHg) versus latanoprost.
`
`Using the non-inferiority margin of 1.5 mmHg, both studies 15-003 and 001 demonstrated non-
`inferiority of tafluprost 0.0015% to timolol 0.5% in reducing elevated intraocular pressure in
`patients with open angle glaucoma or ocular hypertension in both preservative-containing and
`preservative-free formulation. Study 77550 demonstrated that the IOP lowering effects for the
`PC formulation and the PF formulation were similar.
`
`Based on the totality of the evidence provided by these pivotal studies, we recommend the
`approval of PF tafluprost 0.0015% dosed once daily for the treatment of elevated intraocular
`pressure in patients with open glaucoma or ocular hypertension.
`
`
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`Brief Overview of Clinical Studies
`
`1.2
`
`The Phase III program consisted of three pivotal non-inferiority efficacy studies (two timolol
`non-inferiority studies [15-003 and 001] and one Latanoprost Non-Inferiority Study [74458]), an
`adjunctive therapy to timolol study (74460) examining the additive effect of tafluprost to timolol,
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`Reference ID: 2976454
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`and a study comparing the PC formulation and PF formulation (Study 77550). In addition, an
`open-label Phase IIIb clinical trial (Study 77552) investigated changes in ocular signs and
`symptoms when patients were switched from preservative-containing latanoprost to preservative-
`free tafluprost.
`
`The focus of this review will be the three pivotal non-inferiority efficacy studies and the bridging
`study that compared the PC formulation with the PF formulation.
`
`Study 15-003 was a randomized, double-masked, parallel group, multicenter, 12-month trial
`comparing the efficacy and safety of PC tafluprost 0.0015% with PC timolol 0.5%. A total of
`458 patients were randomized. At the start of the study, 267 were randomized to tafluprost, out
`of which 250 completed the first 6 months of treatment, and 240 completed 12 months of
`treatment. Of the 191 patients randomized to timolol, 168 completed the first 6 months, and 162
`completed 12 months of treatment. IOP was measured at 8AM, 10AM, and 16PM at baseline
`visit, Week 2, Week 6, Month 3, Month 6, and Month 12 visits; and at 8AM, and 10AM at
`Month 9 visit.
`
`Study 001 was a randomized, multi-center, active comparator-controlled, 12-week, double-
`masked clinical trial to compare the efficacy and safety of preservative-free (PF) tafluprost
`(0.0015%) and PF timolol 0.5%. A total of 643 patients were randomized, among which 320
`patients were randomized to tafluprost treatment and 306 completed the study. Of 323 patients
`randomized to timolol, 312 completed the study. IOP was measured at 8AM, 10AM, and 16PM
`at baseline visit, Week 2, Week 6, and Month 3 visits.
`
`Study 77550 was a randomized, investigator-masked, multicenter, cross-over phase III study on
`two formulations (preserved and unpreserved) of tafluprost 0.0015% eye drops in patients with
`open-angle glaucoma or ocular hypertension. The study consisted of two treatment periods:
`preserved followed by unpreserved formulation or unpreserved followed by preserved
`formulation of study medication tafluprost 0.0015% once daily. Duration of both treatment
`periods was four weeks, separated by a washout period of at least four weeks. A total of 43
`patients were randomized in the study. IOP was measured at 8AM, 12PM, 16PM, and 20PM at
`baseline visit, Week 1, and Week 4 visits of each treatment period.
`
`Study 74458 was a randomized, double-masked, active-controlled, parallel-group, 24-month,
`multinational, and multicenter trial comparing efficacy and safety of PC tafluprost 0.0015%
`comparing with PC latanoprost 0.005%. A total of 533 patients were randomized. At the start of
`the study 269 patients were randomized to tafluprost treatment, out of which 246 completed the
`first 6 months of treatment, 229 completed 12 months of treatment, and 185 completed 24
`months of treatment. Of the 264 patients randomized to latanoprost, 252 completing the first 6
`months, 247 completing 12 months, and 217 completed 24 months of treatment. IOP was
`measured at 8AM, 12PM, 16PM, and 20PM at baseline visit, Month 3, Month 6, Month 12,
`Month 18, and Month 24 visits; and at 8AM on Week 2, Week 6, Month 9 and Month 15 visit.
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`Reference ID: 2976454
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`1.3
`
`There are no major statistical issues for this submission. The choice of 1.5 mmHg as the non-
`inferiority (NI) margin using timolol as the active comparator for studies 15-003, 001, and 74458
`was recommended to the Applicant by the FDA clinical review team during the design stage of
`the study protocol; the statistical reviewer considered this margin reasonable (for a detailed
`discussion, please see Appendix A).
`
`The pre-defined primary analyses were slightly different for the three non-inferiority studies. In
`order to present the studies’ results in a uniform format, the statistical reviewer analyzed the IOP
`change from baseline by visit and time point for each study using an ANCOVA model. The
`ANCOVA model includes the treatment and baseline IOP as independent variables. The
`following table lists the statistical reviewer’s analyses results of IOP change from baseline at
`each time point at each visit through month 6 for all the three non-inferiority studies and the
`bridging study; these results were consistent with the Applicant’s analyses results.
`
`Table 1: IOP Change from Baseline Analysis Results (FAS, LOCF, ANCOVA)
`Study 15-003
`PC Timolol 0.5%
`(N=187)
`LSMean¹ (mmHg)
`
`-6.48
`-5.92
`-5.07
`
`-6.91
`-5.81
`-4.79
`
`-6.13
`-5.76
`-4.83
`
`-6.32
`-5.67
`-4.44
`
`-6.32
`-5.48
`
`-6.57
`-5.62
`-4.21
`
`PC Tafluprost 0.0015%
`(N=265)
`LS Mean¹ (mmHg)
`
`-6.97
`-6.13
`-5.41
`
`-7.07
`-5.82
`-5.26
`
`-6.62
`-5.79
`-5.21
`
`-6.52
`-5.56
`-5.23
`
`-7.07
`-5.78
`
`-6.53
`-5.43
`-4.84
`
`Difference (95% CI)¹
`(mmHg)
`
`-0.49 (-1.06, 0.09)
`-0.21 (-1.17, 0.75)
`-0.34 (-1.24, 0.56)
`
`-0.01 (-0.70, 0.68)
`-0.02 (-0.71, 0.69)
`-0.47 (-1.17, 0.23)
`
`-0.49 (-1.10, 0.12)
`-0.03 (-0.58, 0.53)
`-0.38 (-0.92, 0.16)
`
`-0.20 (-0.81, 0.41)
`0.11 (-0.49, 0.72)
`-0.79 (-1.32, -0.25)
`
`-0.76 (-1.36, -0.16)
`-0.30 (-0.89, 0.30)
`
`-0.05 (-0.67, 0.58)
`-0.19 (-0.84, 0.46)
`-0.62 (-1.19, -0.05)
`
`Statistical Issues and Findings
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`Visit / Time
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`Week 2
`8:00
`10:00
`16:00
`Week 6
`8:00
`10:00
`16:00
`Month 3
`8:00
`10:00
`16:00
`Month 6
`8:00
`10:00
`16:00
`Month 9
`8:00
`10:00
`Month 12
`8:00
`10:00
`16:00
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`Reference ID: 2976454
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`PF Tafluprost 0.0015%
`(N=316)
`LSMean¹ (mmHg)
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`-7.21
`-6.81
`-6.17
`
`-7.24
`-6.95
`-6.33
`
`-7.48
`-7.08
`-6.28
`
`PC Tafluprost 0.0015%
`(N=264)
`LSMean¹ (mmHg)
`
`-7.99
`
`-7.85
`
`-7.95
`-7.27
`-6.73
`-6.19
`
`-7.74
`-7.03
`-6.46
`-6.18
`
`-7.41
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`-7.17
`-6.89
`-6.02
`-5.62
`
`-7.43
`
`
`Study 001
`PF Timolol 0.5%
`(N=321)
`LSMean¹ (mmHg)
`
`-6.81
`-6.10
`-5.34
`
`-7.36
`-6.60
`-5.52
`
`-7.50
`-6.69
`-5.73
`
`Study 74458
`PC Latanoprost 0.5%
`(N=264)
`LSMean¹ (mmHg)
`
`-8.69
`
`-8.80
`
`-9.07
`-8.46
`-7.38
`-7.05
`
`-9.08
`-8.55
`-7.66
`-7.15
`
`-8.80
`
`-8.85
`-8.31
`-7.45
`-6.88
`
`-9.14
`
`
`Visit / Time
`
`
`Week 2
`8:00
`10:00
`16:00
`Week 6
`8:00
`10:00
`16:00
`Month 3
`8:00
`10:00
`16:00
`
`Visit / Time
`
`
`Week 2
`8:00
`Week 6
`8:00
`Month 3
`8:00
`12:00
`16:00
`20:00
`Month 6
`8:00
`12:00
`16:00
`20:00
`Month 9
`8:00
`Month 12
`8:00
`12:00
`16:00
`20:00
`Month 15
`8:00
`Month 18
`
`
`
`Difference (95% CI)¹
`(mmHg)
`
`-0.41 (-0.85, 0.04)
`-0.73 (-1.16, -0.29)
`-0.83 (-1.26, -0.40)
`
`0.12 (-0.32, 0.56)
`-0.36 (-0.80, 0.08)
`-0.81 (-1.26, -0.36)
`
`0.02 (-0.42, 0.47)
`-0.39 (-0.84, 0.05)
`-0.55 (-0.98, -0.11)
`
`Difference (95% CI)¹
`(mmHg)
`
`0.70 (0.21, 1.19)
`
`0.95 (0.44, 1.46)
`
`1.11 (0.57, 1.66)
`1.19 (0.71, 1.67)
`0.65 (0.18, 1.12)
`0.86 (0.43, 1.30)
`
`1.33 (0.75, 1.91)
`1.52 (1.00, 2.03)
`1.19 (0.71, 1.68)
`0.97 (0.52, 1.43)
`
`1.39 (0.80, 1.99)
`
`1.68 (1.05, 2.31)
`1.42 (0.87, 1.96)
`1.43 (0.90, 1.95)
`1.26 (0.72, 1.80)
`
`1.72 (1.09, 2.34)
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`Reference ID: 2976454
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`-9.06
`-8.22
`-7.45
`-6.94
`
`-8.84
`-8.24
`-7.19
`-6.84
`
`1.57 (0.92, 2.22)
`1.13 (0.58, 1.69)
`1.21 (0.67, 1.75)
`1.10 (0.54, 1.10)
`
`1.63 (0.97, 2.28)
`1.34 (0.76, 1.92)
`1.15 (0.59, 1.70)
`1.10 (0.53, 1.67)
`
`8:00
`-7.49
`12:00
`-7.09
`16:00
`-6.23
`20:00
`-5.84
`Month 24
`
`8:00
`-7.21
`12:00
`-6.91
`16:00
`-6.04
`20:00
`-5.74
`¹ Based on ANCOVA with terms for treatment and baseline IOP.
`
`For the crossover study 77550 comparing the preserved and unpreserved formulation of
`tafluprost 0.0015%, the Applicant used a repeated measurements analysis of covariance (RM
`ANCOVA) model to analyze the changes from baseline in the diurnal IOP at 4 weeks. The
`model included fixed effects for baseline IOP, sequence, period, treatment, time, sequence by
`time, period by time, and treatment by time. The difference (unpreserved vs. preserved tafluprost)
`at 4 weeks and a 95% confidence interval for the difference was estimated from the RM
`ANCOVA model using a contrast (over all four time points). The following table lists the
`Applicant’s analysis results for the bridging study 77550 comparing the preserved and
`unpreserved formulation of tafluprost 0.0015%.
`
`Table 2: IOP Change from Baseline for Study 77550 (FAS, LOCF, RM ANCOVA)
`Study 77550
`PC Tafluprost 0.0015%
`PF Tafluprost 0.0015%
`Difference (95% CI)¹
`(N=42)
`(N=43)
`
`(mmHg)
`Mean (mmHg)
`Mean (mmHg)
`Week 1
`
`
`
`8:00
`-0.32 (-0.96, 0.32)
`-6.14
`-6.77
`12:00
`-0.25 (-0.89, 0.40)
`-5.08
`-6.06
`16:00
`-0.39 (-1.03, 0.26)
`-5.50
`-5.69
`20:00
`-0.13 (-0.77, 0.52)
`-5.51
`-5.65
`Week 4
`
`
`
`8:00
`0.24 (-0.51, 0.98)
`-6.18
`-6.17
`12:00
`0.11 (-0.64, 0.86)
`-4.56
`-5.10
`16:00
`0.00 (-0.74, 0.75)
`-5.08
`-4.80
`20:00
`-0.30 (-1.04, 0.45)
`-4.56
`-4.80
`¹ Based on RM ANCOVA with terms for baseline IOP, sequence, period, treatment, time, sequence by time, period by time, and treatment by
`time.
`Source: Table 14.2.1.2 and Table 14.2.3.1 of Study 77550 Report.
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`Visit / Time
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`Reference ID: 2976454
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`INTRODUCTION
`
`2.
`
`2.1 Overview
`
`Tafluprost (AFP-168) is an analogue of prostaglandin F2α (PGF2 α) that is hydrolyzed by
`corneal esterases to become the biologically active metabolite, AFP-172. Preclinical ocular
`pharmacology studies in ocular normotensive and ocular hypertensive monkeys have
`demonstrated that topical ocular administration of tafluprost lowers IOP in a dose-dependent
`manner (SR2750, SR2557). In addition, an in vitro investigation has showed that the active
`metabolite of tafluprost, AFP-172, has greater affinity for the human prostanoid FP receptor
`(receptors of PGF2α) than latanoprost, PGF2α, or unoprostone (SR2710).
`
`In several phase I and phase II studies, Tafluprost concentrations of up to 0.005% have been
`generally well tolerated, with the most frequently reported adverse events for the 0.0015%
`concentration being ocular hyperemia, eye irritation, abnormal eye sensation, and eye pruritis.
`Based on the overall efficacy and safety results from these trials, the 0.0015% concentration has
`been selected for further clinical investigation.
`
`Tafluprost is available both as a preserved formulation and an unpreserved formulation. The
`preservative, benzalkonium chloride (BAK) may adversely affect
`the
`tolerability of
`prostaglandin analogues and contribute to the risk for developing symptoms of dry eyes. In
`addition, a subset of patients exhibit a delayed hypersensitivity reaction (allergy) to BAK. As no
`other prostaglandin analogues are available as unpreserved eye drops, preservative-free
`tafluprost has the potential to provide a currently unavailable treatment option for patients with
`glaucoma as an alternative to preservative containing formulations.
`
`To date, Tafluprost 0.0015% preservative free (PF) has been approved for reduction of elevated
`intraocular pressure in open angle glaucoma and ocular hypertension in 18 European countries.
`Preservative containing (PC) tafluprost has also been approved in Germany, Finland, Japan,
`Korea, and Georgia.
`
`In this submission, the Applicant is seeking the approval of the preservative free formulation.
`
`
`2.2 Application History
`
`Tafluprost was developed under the Sponsorship of Santen, Inc. since 2001. The referenced IND
`for this NDA is 62690. By November 2009, Merck acquired the product from Santen, Inc. and
`assumed Sponsorship for the product. Therefore, for the submitted clinical studies, other than
`study 001 was conducted under Merck’s Sponsorship, all the other studies were conducted by
`Santen, Inc.
`
`The choice of 1.5 mmHg as the non-inferiority margin using timolol as the active comparator for
`studies 15-003, 001, and 74458 was recommended to the Applicant by the FDA clinical review
`team during the design stage of the study protocol. During an internal meeting discussion for
`study 001 protocol, the statistical review team recommended that the Applicant should provide
`
`
`
`Reference ID: 2976454
`
`9
`
`

`

`justification for the chosen NI margin. However, the director of the medical team didn’t want to
`convey this recommendation to the Applicant and indicated that all the information needed for
`justifying the NI margin of 1.5 mmHG was available in FDA’s own database.
`
`
`2.3 Data Sources
`and datasets
`reports
`study
`The Applicant’s
`\\CDSESUB1\EVSPROD\NDA202514.
`
`
`3.
`
`3.1
`
`are
`
`available on
`
`the EDR
`
`at
`
`STATISTICAL EVALUATION
`
`Evaluation of Efficacy
`
`3.1.1 Study Designs and Endpoints
`
`Dose was explored in 2 dose-ranging studies (Studies 15-001 [Dose Finding I] and 15-002 [Dose
`Finding II]). The Applicant selected 0.0015% concentration for further development based on
`these two dose ranging studies. (For a detailed review of these two Phase II studies, please see
`Appendix B.)
`
`The Phase III program had three pivotal non-inferiority efficacy studies (two timolol non-
`inferiority studies [15-003 and 001] and one Latanoprost Non-Inferiority Study [74458]).
`
`These three Phase III non-inferiority studies were all double-masked, randomized, parallel group
`studies that included patients aged 18 years or older with open glaucoma or ocular hypertension.
`Patients were randomized to: PC Tafluprost 0.0015% once daily (q.d) or latanoprost 0.005% q.d.
`(1:1) for study 74458; PC Tafluprost 0.0015% q.d. or timolol 0.5% twice daily (b.i.d.) (3:2) for
`study 15-003; and PF tafluprost 0.0015% q.d. or timolol PF 0.5% b.i.d. (1:1) for Study 001.
`Study 001 had a 3-month double-masked treatment period and Studies 15-003 and 74458 had 6-
`month double-masked treatment periods; Studies 15-003 and 74458 were extended to 12 and 24
`months (double-masked treatment period), respectively to provide additional long term safety
`and tolerability data as well as supportive efficacy data.
`
`There were different primary outcome measures between the three pivotal trials. For Studies 15-
`003 and 74458, the protocol-specified primary outcome measure was the difference in diurnal
`IOP reduction at Month 6 from baseline. The protocol-specified primary outcome measure for
`Study 001 was mean IOP change from baseline at all 9 time points during the study (0800 hrs,
`1000 hrs, and 1600 hrs at Weeks 2, 6, and 12). The non-inferiority limit for all 3 studies was 1.5
`mmHg based on the upper limit of the 95% CI for the difference between groups (tafluprost -
`control).
`
`However, based on a recommendation communicated by FDA to Santen, efficacy analyses
`(ANOVA including term for treatment group) examining the two-sided 95% CI for the
`difference in IOP between treatments at each time point and visit up to Month 6 were performed
`for Studies 15-003, and 74458. These analyses were included in a protocol amendment prior to
`
`10
`
`Reference ID: 2976454
`
`

`

`unmasking of the data from each of the two studies mentioned above. For this analysis (Studies
`15-003 and 74458), non-inferiority was defined as the upper limit of the 95% CI being ≤1.5
`mmHg at all time points and ≤1.0 mmHg at a majority of time points.
`
`The following table summarizes the key design elements and primary endpoints for the three
`Phase III non-inferiority studies.
`
`Table 3: Summary of Key Design Elements for Studies 15-003, 001, and 74458
`Protocol Study Design
`Duration Treatment Arms
`Endpoints (as
`Endpoints (as
`defined in the
`requested by FDA)
`protocol)
`Change from
`baseline in diurnal
`IOP reduction at
`month 6 for the
`study eye
`
`PC Tafluprost
`0.0015% q.d.
`PC Timolol 0.5% b.i.d.
`
`Randomization Ratio:
`3:2
`
`PF Tafluprost 0.0015%
`q.d.
`PF Timolol 0.5% b.i.d.
`
`Randomization Ratio:
`1:1
`
`PC Tafluprost
`0.0015% q.d.
`Latanoprost 0.005%
`q.d.
`
`Randomization Ratio:
`1:1
`
`15-003
`
`12
`months
`
`Randomized, Active-
`controlled, Double-
`masked, parallel-
`group, multicenter,
`12-month trial
`
`001
`
`74458
`
`12
`weeks
`
`24
`months
`
`Randomized, Active-
`controlled, Double-
`masked, parallel-
`group, multicenter,
`12-week trial
`
`Randomized, Active-
`controlled, Double-
`masked, parallel-
`group, multicenter,
`24-month trial
`
`IOP at each time
`point at each visit
`through month 6
`
`Mean change from
`baseline in IOP at
`all 9 time points
`during the study
`(0800, 1000, 1600
`hrs at Weeks 2, 6,
`and 12) for the
`study eye
`Change from
`b