Evidence Review Group’s Report Degarelix for treating advanced hormone-dependent prostate cancer Produced by School of Health and Related Research (ScHARR), The University of Sheffield Authors Lesley Uttley, Research Fellow, xxxxxxx xxx xxxxxxxxx xx xxxxxxxx xxxxxx xxxxx xx xxxxxx xxxxxx xxxxxxxx xxxxx Sophie Whyte, Research Fellow, xxxxxxx xxx xxxxxxxxx xx xxxxxxxx xxxxxx xxxxx xx xxxxxx xxxxxx xxxxxxxx xxxxx Timothy Gomersall, Research Associate, xxxxxxx xxx xxxxxxxxx xx xxxxxxxx xxxxxx xxxxx xx xxxxxx xxxxxx xxxxxxxx xxxxx Shijie Ren, Research Associate, xxxxxxx xxx xxxxxxxxx xx xxxxxxxx xxxxxx xxxxx xx xxxxxx xxxxxx xxxxxxxx xxxxx Ruth Wong, Information Specialist, xxxxxxx xxx xxxxxxxxx xx xxxxxxxx xxxxxx xxxxx xx xxxxxx xxxxxx xxxxxxxx xxxxx Paul Tappenden, Reader, ScHARR, xxxxxxx xxx xxxxxxxxx xx xxxxxxxx xxxxxx xxxxx xx xxxxxx xxxxxx xxxxxxxx xxxxx Noel Clarke, Professor of Urological Oncology, xxx xxxxxxx xxx xxxxxxxxx xxxxx xxxxxxx xxxx xxxxxxxx xxx xxx David Bottomley, Consultant Clinical Oncologist, xx xxxxx xxxxxxxx xxxxxxxx xxxxxxx xx xxxxx xxx xxx Derek Rosario, Senior Lecturer and Hon. Consultant Urologist, Department of Oncology, xxxxxxxxxx xx xxxxxxx xxxxxxx xxxx xxxxxxx xxxxxx Correspondence to Lesley Uttley, Research Fellow xxxxxxx xxx xxxxxxxxx xx xxxxxxxx xxxxxx xxxxx xx xxxxxx xxxxxx xxxxxxxx xxxxx Date completed 30.10.2013 Copyright 2013 Queen's Printer and Controller of HMSO. All rights reserved. Source of funding: This report was commissioned by the NIHR HTA Programme as project number 12/64/01. Declared competing interests of the authors Derek Rosario declared a personal pecuniary interest for the deliverance of a lecture on the topic of prostate biopsy at the STOP conference (11th to 13th October 2012) sponsored by Ferring Pharmaceuticals for which he received an honorarium. No other competing interests were declared by the clinical advisors to the ERG. Acknowledgements The authors wish to thank Nick Latimer and John Stevens for providing methodological and statistical advice; and also Gill Rooney, Programme Administrator, ScHARR, for her help in preparing and formatting the report. 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: Uttley, L., Whyte, S., Gomersall, T., Ren, S., Wong, R., Tappenden, P., Clarke, N., Bottomley, D., Rosario, D. Degarelix for treating advanced hormone-dependent prostate cancer: A single technology appraisal. ScHARR, University of Sheffield, 2013. Contributions of authors Lesley Uttley acted as project lead and systematic reviewer on this assessment; critiqued the manufacturer’s definition of the decision problem; led the critique of the clinical effectiveness methods and evidence and contributed to the writing of the report. Sophie Whyte acted as health economist on this assessment, critiqued the manufacturer’s economic evaluation and contributed to the writing of the report. Tim Gomersall also acted as a systematic reviewer, critiqued the description of the underlying health problem and contributed to the critique of the clinical effectiveness methods and writing of the report. Shijie Ren acted as the statistician on this assessment and contributed to the writing of the report. Ruth Wong critiqued the searches included in the manufacturer’s submission and contributed to the writing of the report. Paul Tappenden acted as a senior health economist on this assessment and critiqued the report. Noel Clarke, David Bottomley and Derek Rosario acted as clinical advisors on this assessment and provided input on the current treatment pathway and critiqued the evidence of the clinical effectiveness methods; reviewed and provided comments on the report. Copyright 2013 Queen's Printer and Controller of HMSO. All rights reserved. TABLE OF CONTENTS 1. Summary 1 1.1 Scope of the manufacturer submission 1 1.2 Summary of clinical effectiveness evidence submitted by the 2 manufacturer 1.3 Summary of the ERG’s critique of clinical effectiveness evidence 3 submitted 1.4 Summary of cost effectiveness submitted evidence by the 4 manufacturer 1.5 Summary of the ERG’s critique of cost effectiveness evidence 6 submitted 1.6 ERG commentary on the robustness of evidence submitted by the 7 manufacturer 1.7 Summary of additional work undertaken by the ERG 8 2. Background 10 2.1 Critique of manufacturer’s description of underlying health 10 problem 2.2 Critique of manufacturer’s overview of current service provision 11 3. Critique of manufacturer’s definition of decision problem 14 3.1 Population 15 3.2 Intervention 16 3.3 Comparators 17 3.4 Outcomes 19 3.5 Other relevant factors 20 4. Clinical Effectiveness 22 4.1 Critique of the methods used by the manufacturer to 22 systematically review clinical effectiveness evidence 4.2 Summary and critique of submitted clinical effectiveness evidence 33 for the intervention 4.3 Summary and critique of submitted evidence in the MTC 66 4.4 Summary and critique of submitted evidence in the MTC 71 4.5 Conclusions 80 5. Economic Evaluation 82 5.1 ERG comment on manufacturer’s review of cost-effectiveness 82 evidence 5.2 Summary and critique of manufacturer’s submitted economic evaluation by the ERG 5.3 Exploratory and sensitivity analyses undertaken by the ERG 113 5.4 Impact on the ICER of additional clinical and economic analyses 143 undertaken by the ERG 5.5 Conclusions of the cost effectiveness section 117 6. End of Life 120 7. Conclusions 121 7.1 Implications for research 121 8. Appendices 125 9. References 136 Copyright 2013 Queen's Printer and Controller of HMSO. All rights reserved. LIST OF TABLES & FIGURES Table 1 Decision problem as outlined in the final scope issued by NICE 14 and addressed in the manufacturers’ submission (based on pages 30-32 of MS but amended by ERG to reflect their opinion of the submission) Table 2 Table of outcomes specified in the NICE scope as included in the 19 assessment of clinical effectiveness in the MS Table 3 Inclusion criteria used for study selection as indicated in the MS 24 (Table 8; page 36) Table 4 Intervention and comparator groups in the included studies 25 Table 5 Summary Table of inclusion and exclusion criteria for the 27 included trials Table 6 Eight trials identified by the ERG with reasons provided by the 30 manufacturer for omission from the MS from the clarifications process Table 7 Four trials identified by the ERG stated by the manufacturer to 31 have “no results available yet” from the clarifications process. Table 8 Baseline participant characteristics from the 6 included RCTs 34 replicated from Appendix B of the MS Table 9 Number of patients and attrition reported across the six included 37 RCTS of degarelix Table 10 Summary table of main objectives of each of the 6 RCTs, 40 modified from Table 36 (Appendix B of the MS). Table 11 Main outcome measures in included randomised controlled trials 43 replicated from page 52 of the MS Table 12 Testosterone outcomes results reported from individual trials in 45 the MS Table 13 Kaplan–Meier estimated cumulative probability of testosterone 46 ≤0.5 ng/ml, combining data from CS21, CS28, CS30 and CS31 replicated from page 74 of the MS Table 14 Kaplan Meier estimated cumulative probability of testosterone 47 ≤0.5 ng/ml replicated from MS page 64 Table 15 Median percentage change in PSA levels across individual trials 47 Table 16 PSA progression in CS21 (PSA >20.ng/ml subgroup) and CS35 48 Table 17 Kaplan Meier analysis for the cumulative probability of 49 completing the study without PSA failure from Day 0 to Day 364: ITT analysis set replicated from page 69 of the MS Table 18 Post hoc exploratory subgroup analyses of PSA from trial CS21 50 Table 19 Mean change in total IPSS 51 Table 20 Death outcome results from included RCTS modified from page 52 71 of the MS Table 21 Quality of life measures measured and reported from included 53 RCTs extracted from pages 72/73 of the MS Table 22 Eight studies excluded from the MTC; taken from Table 16 of the 69 MS Table 23 Studies Included in the MTC; adapted from Table 16 of the MS 71 Table 24 Results of MTC of rates of hot flushes provided by the 79 Copyright 2013 Queen's Printer and Controller of HMSO. All rights reserved. manufacturer during the clarifications process following ERG request Table 25 Mortality – Odds ratios and 95% credible intervals relative 79 Table 26 Mortality – Hazard ratios and 95% credible intervals relative 79 Table 27 Eligibility criteria and rationale for each criterion [MS page 83 106;Table 20] Table 28 Summary list of other cost-effectiveness evaluations [MS table 84 21] Table 29 Comparison of MS with the NICE Reference Case checklist 86 Table 30 Summary of information presented within the MS on subgroups 91 included within the NICE scope Table 31 Modelling assumptions relating to treatment efficacy [Part of MS 95 Table 33] Table 32 Summary of quality-of-life values for cost-effectiveness analysis 98 [MS Table 41] Table 33 Model assumptions relating to utility data [Part of MS Table 33] 99 Table 34 Costs associated with each comparator including the drug cost, 102 administration costs and testing [Adapted from MS Table 43] Table 35 Summary of adverse event costs used within model [Adapted 102 from MS Table 51] Table 36 Costs associated with each of the model health states [Adapted 103 from MS Table 44] Table 37 Deterministic base case results [adapted from MS clarification 106 Table D6] Table 38 Results