REPORT STA Ciclosporin for treating dry eye disease This report was commissioned by the NIHR HTA Programme as project number 13/166/01 Completed 17 March 2015 Ciclosporin for treating dry eye disease Single Technology Appraisal: Evidence Review Group Report Page 1 of 91 Copyright 2015 Queen's Printer and Controller of HMSO. All rights reserved. Title: Ciclosporin for treating dry eye disease Produced by: Liverpool Reviews & Implementation Group (LRiG) Authors: Nigel Fleeman, Research Fellow (Clinical Effectiveness), LRiG, University of Liverpool Adrian Bagust, Professor (Health Economic Modelling), LRiG, University of Liverpool Sophie Beale, Research Associate (Decision Analysis), LRiG, University of Liverpool Angela Boland, Associate Director, LRiG, University of Liverpool Kerry Dwan, Research Fellow (Medical Statistician), LRiG, University of Liverpool Eleanor Kotas, Information Specialist, LRiG, University of Liverpool Joanne McEntee, North West Medicines Information Centre, Pharmacy Practice Unit, Liverpool Saj Ahmad Senior Clinical Lecturer, Department of Eye and Vision Science, University of Liverpool Correspondence to: Nigel Fleeman, Research Fellow, Liverpool Reviews and Implementation Group, University of Liverpool, Room 2.10, Whelan Building, The Quadrangle, Brownlow Hill, Liverpool L69 3GB Date completed: 17 March 2015 Source of funding: This report was commissioned by the NIHR HTA Programme as project number 13/166/01 Declared competing interests of the authors: None Acknowledgements: The authors would like to thank Romesh Angunawela, Consultant in Cornea Cataract and Refractive Surgery at Moorfields Eye Hospital who provided feedback on a final draft version of the report and Gareth Jones for administrative support. Ciclosporin for treating dry eye disease Single Technology Appraisal: Evidence Review Group Report Page 2 of 91 Copyright 2015 Queen's Printer and Controller of HMSO. All rights reserved. Rider on responsibility for report: The views expressed in this report are those of the authors and not necessarily those of the NIHR HTA Programme. Any errors are the responsibility of the authors. This report should be referenced as follows: Fleeman N, Bagust A, Beale S, Boland A, Dwan K, Kotas E, McEntee J, Ahmad S. Ciclosporin for treating dry eye disease: A Single Technology Appraisal. LRiG, University of Liverpool, 2015 Contributions of authors: Fleeman N Project lead, drafted background, critique of decision problem and clinical results sections and supervised the final report Bagust A Checking and validation of the economic model and critique Beale S Critical appraisal of clinical and economic evidence Boland A Critical appraisal of clinical and economic evidence Dwan K Critical appraisal of the statistical evidence Kotas E Cross checking of the submission search strategy McEntee J Critical appraisal of the submission Ahmad S Clinical advice and critical appraisal of the clinical sections of the company’s submission All authors read and commented on draft versions of the ERG report. Ciclosporin for treating dry eye disease Single Technology Appraisal: Evidence Review Group Report Page 3 of 91 Copyright 2015 Queen's Printer and Controller of HMSO. All rights reserved. Table of contents LIST OF ABBREVIATIONS ................................................................................................... 6 1 SUMMARY .................................................................................................................... 7 1.1 Critique of the decision problem in the company’s submission ................................ 7 1.2 Summary of clinical effectiveness evidence submitted by the company .................. 8 1.3 Summary of the ERG’s critique of clinical effectiveness evidence submitted........... 9 1.4 Summary of cost effectiveness evidence submitted by the company .................... 11 1.5 Summary of the ERG’s critique of cost effectiveness evidence submitted ............. 12 1.6 ERG commentary on the robustness of evidence submitted by the company ....... 13 1.7 Summary of exploratory and sensitivity analyses undertaken by the ERG ............ 14 2 BACKGROUND ........................................................................................................... 16 2.1 Critique of company’s description of underlying health problems .......................... 16 2.2 Critique of company’s overview of current service provision ................................. 19 3 CRITIQUE OF COMPANY’S DEFINITION OF DECISION PROBLEM ......................... 21 3.1 Population ............................................................................................................. 22 3.2 Intervention ........................................................................................................... 22 3.3 Comparators ......................................................................................................... 23 3.4 Outcomes ............................................................................................................. 24 3.5 Economic analysis ................................................................................................ 24 3.6 Subgroups ............................................................................................................ 25 4 CLINICAL EFFECTIVENESS ....................................................................................... 26 4.1 Critique of the methods of review(s) ...................................................................... 26 4.2 Critique of trials of the technology of interest, their analysis and interpretation (and any standard meta-analyses of these) ............................................................................. 29 4.3 Critique of the safety data ..................................................................................... 44 4.4 Critique of the health-related quality of life data .................................................... 46 4.5 Additional work on clinical effectiveness undertaken by ERG ............................... 47 4.6 Conclusions of the clinical effectiveness section ................................................... 48 5 COST EFFECTIVENESS ............................................................................................. 49 5.1 Introduction ........................................................................................................... 49 5.2 ERG comment on company’s review of cost effectiveness evidence .................... 49 5.3 ERG critique of the company’s literature review .................................................... 50 5.4 Summary and critique of company’s submitted economic evaluation by the ERG . 51 5.5 Detailed critique of the company’s economic model .............................................. 63 5.6 Conclusions of the cost effectiveness section ....................................................... 71 6 IMPACT ON THE ICER OF ADDITIONAL CLINICAL AND ECONOMIC ANALYSES UNDERTAKEN BY THE ERG ............................................................................................. 73 7 DISCUSSION .............................................................................................................. 75 8 OVERALL CONCLUSIONS ......................................................................................... 79 8.1 Implications for research ....................................................................................... 80 9 REFERENCES ............................................................................................................ 81 10 APPENDICES .......................................................................................................... 85 10.1 Appendix 1: LRiG search strategies ...................................................................... 85 10.2 Appendix 2: Additional data on adverse events ..................................................... 86 10.3 Appendix 3: Implementation of ERG decision model amendments ....................... 89 Ciclosporin for treating dry eye disease Single Technology Appraisal: Evidence Review Group Report Page 4 of 91 Copyright 2015 Queen's Printer and Controller of HMSO. All rights reserved. List of tables Table 1 Estimates for the prevalence of DED in UK twins (median age of 60 years) ........... 17 Table 2 NICE scope and company’s decision problem ........................................................ 21 Table 3 Eligibility criteria used for the company’s systematic review ................................... 27 Table 4 Summary of trial characteristics of SANSIKA and SICCANOVE ............................. 31 Table 5 Post-hoc analyses conducted in SANSIKA and severe DED populations in SICCANOVE ....................................................................................................................... 36 Table 6 Quality assessment results for SANSIKA and SICCANOVE ................................... 38 Table 7 Summary of Key findings from SANSIKA and SICCANOVE* ................................. 40 Table 8 Summary of whether efficacy results presented in CS were statistically significant in SANSIKA and post-hoc analyses in SICCANOVE (severe DED) ........................................ 41 Table 9 Key AEs highlighted by the company from SANSIKA and SICCANOVE ................ 45 Table 10 Economic evidence search inclusion criteria used by the company ...................... 50 Table 11 NICE Reference case checklist completed by ERG .............................................. 51 Table 12 Critical appraisal checklist