Tafamidis for Transthyretin Familial Polyneuropathy (TTR-FAP) Evidence Review Group assessment of manufacturer submission Produced by CRD/CHE Technology Assessment Group (Centre for Reviews and Dissemination/Centre for Health Economics), University of York Authors Rita Faria, Research Fellow; Simon Walker, Research Fellow; Stephen Palmer, Professor Centre for Health Economics Mark Corbett, Research Fellow; Lisa Stirk, Information Specialist; Catriona McDaid, Senior Research Fellow. Centre for Reviews & Dissemination Acknowledgements With thanks to Professor Philip Hawkins and Professor Mary Reilly who provided clinical advice to the ERG. With thanks to David Epstein for providing advice on the health economics. Date completed 16th July 2012 Declared competing interests of the authors None Page | 1 Table of Contents 1 SUMMARY ..................................................................................................................... 11 1.1 Scope of the Evidence Review Group assessment .................................................. 11 1.2 Scope of the manufacturer submission .................................................................... 11 1.3 Summary of submitted clinical effectiveness evidence ............................................ 11 1.4 Summary of submitted cost effectiveness evidence ................................................. 12 1.5 Summary of additional work undertaken by the ERG ............................................... 14 1.6 Commentary on the robustness of submitted evidence ........................................... 15 2 BACKGROUND .............................................................................................................. 20 2.1 Introduction.............................................................................................................. 20 2.2 Description of health problem .................................................................................. 20 2.2.1 Epidemiology .................................................................................................... 20 2.2.2 Clinical variability in TTR-FAP .......................................................................... 21 2.2.3 V30M mutation ................................................................................................. 21 2.2.4 Stages of disease progression in V30M ............................................................ 21 2.2.5 Heterogeneity within V30M populations ............................................................ 22 2.2.6 Non-V30M mutations ........................................................................................ 23 2.2.7 Applicability of Coutinho classification of disease stages to NonV30M and non- endemic V30M populations ............................................................................................ 23 2.3 Current treatment .................................................................................................... 24 2.3.1 Treatment of symptoms .................................................................................... 24 2.3.2 Liver transplantation ......................................................................................... 24 2.4 Tafamidis and treatments in development ............................................................... 26 3 THE DECISION PROBLEM ............................................................................................ 27 3.1 Population ............................................................................................................... 27 3.2 Intervention.............................................................................................................. 27 3.3 Comparators ............................................................................................................ 27 3.4 Outcomes ................................................................................................................ 28 3.5 Time frame .............................................................................................................. 28 3.6 Treatment strategies ................................................................................................ 28 4 CLINICAL EFFECTIVENESS ......................................................................................... 29 4.1 Overview of the manufacturer’s submission............................................................. 29 4.2 ERG systematic review............................................................................................ 30 4.3 Overview of included studies ................................................................................... 31 4.4 Randomised Controlled Trial (Fx-005) ..................................................................... 33 Page | 2 4.4.1 Objectives and methods ................................................................................... 33 4.4.2 Analyses ........................................................................................................... 33 4.4.3 Results ............................................................................................................. 36 4.4.4 Assessment of study quality ............................................................................. 43 4.4.5 FDA analyses of the RCT data ......................................................................... 48 4.5 Open-label extension study (Fx-006) ....................................................................... 49 4.5.1 Study details and main results .......................................................................... 49 4.6 Non-randomised studies .......................................................................................... 52 4.6.1 Pre-post study (Fx1A-201)................................................................................ 53 4.6.2 Case series ...................................................................................................... 55 4.7 Ongoing studies ...................................................................................................... 56 4.8 Generalisability of the study results ......................................................................... 56 4.9 Summary ................................................................................................................. 57 5 ECONOMIC EVALUATION ............................................................................................ 59 5.1. Overview of manufacturer’s economic evaluation .................................................... 59 5.1.1. Review of existing literature .............................................................................. 64 5.1.2. Reports of other Health Technology Assessment agencies on tafamidis .......... 64 5.1.3. Manufacturer’s ‘de novo’ economic evaluation ................................................. 64 5.2. Patient population .................................................................................................... 68 5.3. Natural history ......................................................................................................... 70 5.3.1 Disease severity and TQoL scores ................................................................... 70 5.3.2 Mortality ............................................................................................................ 77 5.3.3 Liver transplantation ......................................................................................... 81 5.4 Treatment effectiveness within the submission ........................................................ 84 5.5 Health related quality of life ..................................................................................... 88 5.5.1 HRQoL associated with TTR-FAP .................................................................... 88 5.5.2 HRQoL associated with liver transplantation .................................................... 92 5.5.3 HRQoL experienced by carers ......................................................................... 93 5.5.4 HRQoL: Final issues ......................................................................................... 93 5.6 Resources and costs ............................................................................................... 94 5.6.1 Acquisition costs of tafamidis ............................................................................ 94 5.6.2 Costs associated with healthcare resource use per disease stage ................... 95 5.6.3 Costs associated with healthcare resource use from liver transplantation ........ 96 5.6.4 Productivity costs accrued by patients and carers ............................................ 96 5.7 Sensitivity analyses ................................................................................................. 97 5.8 Model validation ...................................................................................................... 97 Page | 3 5.9 Results included in manufacturer’s submission ....................................................... 98 5.9.1 Base-case ........................................................................................................ 98 5.9.2 Sensitivity Analysis ........................................................................................... 99 5.9.3 Budget Impact considerations ........................................................................ 100 5.10 Summary of uncertainties and issues .................................................................... 103 6 ADDITIONAL