208135Orig1s000

CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 208135Orig1s000 STATISTICAL REVIEW(S) 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 S TATISTICAL R EVIEW AND E VALUATION CLINICAL STUDIES NDA/BLA #: 208135 Drug Name: Tetracaine Hydrochloride Ophthalmic Solution 0.5% (STERI-UNIT®) Indication(s): For procedures requiring a rapid and short acting ophthalmic anesthetic Applicant: Alcon research ltd Date(s): Stamp date: April 30, 2015 PDUFA date: February 29, 2016 Review Priority: Standard Biometrics Division: DBIV Statistical Reviewer: Abel Tilahun Eshete Concurring Reviewers: Yan Wang Medical Division: Ophthalmology Clinical Team: Medical Reviewer: Jennifer Harris Project Manager: Michael Puglisi Keywords: Topical anesthesia, Pain scores, Tetracaine . Reference ID: 3875889 Table of Contents 1 EXECUTIVE SUMMARY............................................................................................................................... 4 2 INTRODUCTION............................................................................................................................................. 6 2.1 OVERVIEW ................................................................................................................................................... 6 2.2 SUBMISSION HISTORY .................................................................................................................................. 6 2.3 DATA SOURCES AND QUALITY .................................................................................................................... 6 3 STATISTICAL EVALUATION ...................................................................................................................... 7 3.1 EVALUATION OF EFFICACY .......................................................................................................................... 7 3.2 EVALUATION OF SAFETY ............................................................................................................................. 9 4 SUMMARY AND CONCLUSIONS ............................................................................................................... 9 4.1 STATISTICAL ISSUES .................................................................................................................................... 9 4.2 CONCLUSIONS AND RECOMMENDATION ..................................................................................................... 10 5 APPENDIX ...................................................................................................................................................... 15 5.1 PUBLICATIONS EVALUATING TETRACAINE OPHTHALMIC SOLUTION 0.5% .................................................. 15 5.2 PUBLICATIONS EVALUATING TETRACAINE OPHTHALMIC SOLUTION 1%..................................................... 30 5.3 PUBLICATIONS EVALUATING COMBINATIONS OF TETRACAINE OPHTHALMIC SOLUTION 0.5% AND OTHER PRODUCTS .............................................................................................................................................................. 36 6 REFERENCES ................................................................................................................................................ 39 LIST OF TABLES Table 1: Publications evaluating analgesic efficacy of tetracaine ophthalmic solution 0.5% ................................... 10 Table 2: Summary of key findings from publication evaluating tetracaine 0.5% ..................................................... 11 Table 3: Safety summary from post-marketing data ................................................................................................. 13 (b) (4) .................................................................................... 16 Table 5: Patient demographics (Carden 1998) .......................................................................................................... 19 Table 6: Operative data (Carden 1998) .................................................................................................................... 19 Table 7: Anastasia data (Carden 1998) ..................................................................................................................... 20 Table 8: Modified children’s hospital of eastern Ontario pain scores (Kim 2003) ................................................... 22 Table 9 : Patient demographics (Kim 2003) ............................................................................................................. 22 Table 10: Anesthetic data summary (Kim 2003) ...................................................................................................... 22 Table 11 : Patient demographics and treatment summary (Moshirfar 2014) ............................................................ 26 Table 12 : Pain outcome summary (Moshirfar 2014) ............................................................................................... 27 Table 13 : Patient characteristics and anesthetic efficacy summary (Chalam 2009) ................................................ 28 Table 14: Summary of proportion of subjects with post-operative pain score <5 (MBPS) (Anninger 2007) ........... 35 Table 15: Summary of proportion of subjects with postoperative emergence behavioral score of 1 or 2 (Anninger 2007) ......................................................................................................................................................................... 36 Table 16 : Summary pain scores (Tsoumani 2010)................................................................................................... 37 Table 17 : Summary of demographic characteristics (Sanabria 2013) ...................................................................... 37 Table 18 : Summary of main outcome efficacy measures (Sanabria 2013) .............................................................. 38 Table 19: Publications evaluating analgesic efficacy of tetracaine ophthalmic solution 1% .................................... 38 Table 20: Summary of key findings from publication evaluating tetracaine 1% ...................................................... 38 LIST OF FIGURES (b) (4) ............................................................................ 15 Figure 2 : Summary of pain scores (Carden 1998) ................................................................................................... 20 Figure 3: Summary of pain scores (Mild versus Severe) (Carden 1998) .................................................................. 21 2 Reference ID: 3875889 Figure 4 : Comparison of average pain score among three anesthetics (Rifkin 2012) .............................................. 24 Figure 5 : Comparison of average pain score among subgroups made based on demographic and disease characteristics (Rifkin 2012) ..................................................................................................................................... 25 Figure 6 : Pain outcomes for photorefractive keratectomy (PKR) (Moshirfar 2014) ............................................... 27 Figure 7 : Pain outcomes for LASIK (Moshirfar 2014) ............................................................................................ 27 Figure 8 : Pain summary (Shafi 1998) ...................................................................................................................... 30 Figure 9 : Summary of discomfort measured by linear scale (Shafi 1998) ............................................................... 30 Figure 10 : Summary of total postoperative assessment scores (Watson 1991) ....................................................... 32 Figure 11: Summary of patients subjective pain and discomfort and score (Yu 2003) ........................................... 33 Figure 12: Summary of surgeon subjective pain and discomfort and score (Yu 2003) ............................................ 33 Figure 13: Summary of mean number of additional anesthetic drops (Yu 2003) ..................................................... 34 Figure 14 : Summary of maximum MBPS score (Anniniger 2007) ......................................................................... 36 3 Reference ID: 3875889 three publications (Havener 1983, McGee 2007, Weaver 2003) and a list of adverse event cases collected through pharmacovigilance through 31 December 2014. In the three publications, burning and numbing sensations and potential punctate corneal erosion were reported. A total of 143 adverse events, 47 of which were serious, were collected through the applicant’s pharmacovigilance. The most frequently reported adverse events in the applicant’s pharmacovigilance summary were eye irritation, eye pain, ocular discomfort, endophthalmitis and toxic anterior segment syndrome (Table 3). The authors in one study identified by this reviewer (Sha et al. 2010) stated that multiple administration of tetracaine is known to be associated with corneal epithelial toxicity and delayed epithelial healing. In conclusion, statistically significant lower average pain scores in the tetracaine 0.5% arm were reported in three studies. Although, the superiority results from two of these three studies were questionable from a statistical perspective, the observed efficacy results for tetracaine 0.5% were numerically better than the active control (proparacaine 0.5%). Similarly,

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