NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Mirabegron for the treatment of overactive bladder Submitted by Astellas Single technology appraisal (STA) October 2012 Contents List of Tables ................................................................................................................... 4 List of Figures ................................................................................................................ 10 Abbreviations ................................................................................................................ 12 Executive summary ....................................................................................................... 16 Section A – Decision problem ....................................................................................... 20 1 Description of technology under assessment ..................................................... 20 2 Context .............................................................................................................. 24 3 Equality .............................................................................................................. 29 3.1 Identification of equality issues ........................................................................ 29 4 Innovation .......................................................................................................... 30 5 Statement of the decision problem ..................................................................... 32 Section B – Clinical and cost effectiveness ................................................................... 34 6 Clinical evidence ................................................................................................ 34 6.1 Identification of studies .................................................................................... 36 6.2 Study selection ................................................................................................ 37 6.3 Summary of methodology of relevant RCTs .................................................... 42 6.4 Critical appraisal of relevant RCTs .................................................................. 63 6.5 Results of the relevant RCTs ........................................................................... 65 6.6 Meta-analysis .................................................................................................. 93 6.7 Indirect and mixed treatment comparisons .................................................... 116 6.8 Non-RCT evidence ........................................................................................ 144 6.9 Adverse events ............................................................................................. 152 6.10 Interpretation of clinical evidence .................................................................. 173 7 Cost-effectiveness ........................................................................................... 176 7.1 Published cost-effectiveness evaluations ...................................................... 176 7.2 De novo analysis ........................................................................................... 186 7.3 Clinical parameters and variables.................................................................. 194 7.4 Measurement and valuation of health effects ................................................ 206 7.5 Resource identification, measurement and valuation..................................... 219 7.6 Sensitivity analysis ........................................................................................ 221 7.7 Results .......................................................................................................... 226 7.8 Validation ...................................................................................................... 241 7.9 Subgroup analysis ......................................................................................... 241 7.10 Interpretation of economic evidence .............................................................. 243 Section C – Implementation ........................................................................................ 246 8 Assessment of factors relevant to the NHS and other parties .......................... 246 Mirabegron, Astellas 2 9 References ...................................................................................................... 249 10 Appendices ...................................................................................................... 257 10.1 Appendix 1 .................................................................................................... 257 10.2 Appendix 2: Search strategy for Section 6.1 (Identification of studies) .......... 282 10.3 Appendix 3: Quality assessment of RCT(s) (section 6.4) ............................... 287 10.4 Appendix 4: Search strategy for Section 6.7 (Indirect and mixed treatment comparisons) ................................................................................................ 291 10.5 Appendix 5: Quality assessment of comparator RCT(s) in Section 6.7 (Indirect and mixed treatment comparisons) ............................................................... 291 10.6 Appendix 6: Search strategy for Section 6.8 (Non-RCT evidence) ................ 300 10.7 Appendix 7: Quality assessment of non-RCT(s) in Section 6.8 (Non-RCT evidence) ...................................................................................................... 303 10.8 Appendix 8: Search strategy for Section 6.9 (Adverse events) ...................... 304 10.9 Appendix 9: Quality assessment of adverse event data in Section 6.9 (Adverse events) .......................................................................................................... 305 10.10 Appendix 10: Search strategy for cost-effectiveness studies (section 7.1) ..... 306 10.11 Appendix 11: Quality assessment of cost-effectiveness studies (section 7.1) 308 10.12 Appendix 12: Search strategy for Section 7.4 (Measurement and valuation of health effects) ............................................................................................... 311 10.13 Appendix 13: Resource identification, measurement and valuation (section 7.5) 316 10.14 Appendix 14: Summary of supporting RCTs for mirabegron .......................... 317 10.15 Appendix 15: Description of micturition diary and scales used to assess QoL and treatment satisfaction in mirabegron studies ........................................... 330 10.16 Appendix 16: Winbugs code used for MTC ................................................... 332 10.17 Appendix 17: Inconsistency assessment between direct and indirect evidence for each comparison ...................................................................................... 336 10.18 Appendix 18: Severity levels for micturitions and incontinence; model predictions and comparison with trial data ..................................................... 339 10.19 Appendix 19: Logistic regression models for symptom severity levels ........... 342 10.20 Appendix 20: Transition probabilities; micturitions and incontinence episodes 348 10.21 Appendix 21: Transition matrices for the previously treated subgroup ........... 350 10.22 Appendix 22: Model inputs ............................................................................ 352 Mirabegron, Astellas 3 List of Tables Table 1: Base-case cost-effectiveness results ............................................................... 18 Table 2: Base case results, general OAB population, mirabegron vs antimuscarinics, based on MTC results ................................................................................................... 19 Table 3: Cost-effectiveness results in subgroups .......................................................... 19 Table 4: Unit costs of technology being appraised ........................................................ 22 Table 5: List of data sources for mirabegron.................................................................. 40 Table 6: List of relevant RCTs ....................................................................................... 40 Table 7: List of relevant non-RCTs ................................................................................ 42 Table 8: Comparative summary of methodology of the primary RCTs ........................... 43 Table 9: Eligibility criteria of the primary RCTs .............................................................. 46 Table 10: Patient demographics of participants across randomised groups in the primary RCTs, FAS .................................................................................................................... 48 Table 11: OAB history in participants across randomised groups in the primary RCTs, FAS ............................................................................................................................... 50 Table 12: OAB-related baseline characteristics in participants across randomised groups in the primary RCTs, FAS .............................................................................................. 52 Table 13: Incontinence-related baseline characteristics in participants across randomised groups in the primary RCTs, FAS-I ................................................................................ 54 Table 14: Primary and secondary outcomes of the primary RCTs ................................. 56 Table 15: Summary of statistical analyses in the primary RCTs ...................................