NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Single Technology Appraisal (STA) Belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus GlaxoSmithKline Specification for manufacturer/sponsor submission of evidence 13 April 2011 Belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus Page 1 of 373 Contents Abbreviations ................................................... Error! Bookmark not defined. Executive summary ........................................................................................ 14 Section A – Decision problem ........................................................................ 33 1 Description of technology under assessment ......................................... 33 2 Context ................................................................................................... 39 3 Equity and equality ................................................................................. 52 4 Statement of the decision problem ......................................................... 53 Section B – Clinical and cost effectiveness .................................................... 59 5 Clinical evidence ..................................................................................... 60 6 Cost effectiveness ................................................................................ 170 Section C – Implementation ......................................................................... 310 7 Assessment of factors relevant to the NHS and other parties............... 310 8 References (See Section 10) 9 Appendices ........................................................................................... 315 10 References ........................................................................................... 316 Belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus Page 2 of 373 List of tables and figures Please include a list of all tables and figures here with relevant page references. Table 1.1. Ongoing long-term continuation studies.........................................35 Table 1.2. Unit costs of technology being appraised......................................36 Table 2.1. ACR classification criteria for SLE.................................................40 Table 2.2. Eligible patient population and proposed subgroup………………44 Table 4.1. Statement of the decision problem.................................................54 Table 5.1. Eligibility criteria used in search strategy.......................................61 Table 5.2. Linked publications on belimumab.................................................64 Table 5.3. Linked publications on competitor products...................................64 Table 5.4. List of relevant RCTs......................................................................65 Table 5.5. List of relevant non-RCTs..............................................................69 Table 5.6. Comparative summary of methodology of the RCTs.....................70 Table 5.7. Eligibility criteria in the RCTs.........................................................74 Table 5.8. Selected demographic characteristics in Phase 3 trials.................76 Table 5.9. Selected baseline disease characteristics in Phase 3 trials...........78 Table 5.10. Selected baseline serological characteristics in Phase 3 trials....80 Table 5.11. Selected baseline concomitant medications in Phase 3 trials......82 Table 5.12. Primary and secondary outcomes of the RCTs...........................84 Table 5.13. Summary of statistical analyses in RCTs.....................................91 Table 5.14. Quality assessment results for RCTs.........................................100 Table 5.15. Primary efficacy endpoint (SRI) at Week 52 (dropout = failure)...........................................................................................................105 Table 5.16. Components of the SRI at Week 52 (adjusted)..........................110 Table 5.17. SELENA-SLEDAI mean and mean percent reduction from baseline at Week 52......................................................................................113 Table 5.18. PGA mean percent change and change from baseline at Week 24 and Week 52.................................................................................................115 Table 5.19 SF-36 PCS score change from baseline at Week 24 and Week 52 (LOCF)..........................................................................................................117 Table 5.20. Prednisone reduction by ≥ 25% from baseline to ≤ 7.5mg/day during Weeks 40 through 52 – Phase 3 trials...............................................120 Table 5.21. Primary response at Week 52 by race subgroup – Pooled Total Population.....................................................................................................139 Table 5.22. Primary response at Week 52 by black race – Pooled Total Population.....................................................................................................140 Table 5.23. Summary of methodology of the non-RCTs...............................149 Table 5.24. Eligibility criteria in the non-RCTs..............................................150 Table 5.25. Characteristics of participants in the non-RCTs across randomised groups.......................................................................................150 Table 5.26. Primary and secondary outcomes of the non-RCTs..................151 Table 5.27. Completion status in LBSL99, by protocol study year................152 Table 5.28. Number of subjects with AEs (IV SLE CRD)..............................156 Table 5.29. Most common (> 10% in any treatment group) adverse events by MedDRA preferred term (IV SLE CRD)........................................................156 Belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus Page 3 of 373 Table 5.30. Most frequent (≥ 1% in any treatment group) serious adverse events by preferred term (IV SLE CRD)........................................................158 Table 5.31. All infusion and hypersensitivity reactions1 summary (IV SLE CRD).............................................................................................................159 Table 5.32. All infection adverse event summary (IV SLE CRD)..................161 Table 5.33. Infections of special interest by category (IV SLE CRD)............162 Table 6.1. Key features of analysis...............................................................180 Table 6.2. Baseline patient demographics - Pooled total population............189 Table 6.3. Baseline disease activity parameters based on BLISS trials – Pooled total population..................................................................................190 Table 6.4: Baseline individual SDI item scores simulated from the BLISS trials – Pooled total population...............................................................................191 Table 6.5. Linear regression explaining change in SELENA-SEDAI score at week 52 - Pooled total population.................................................................193 Table 6.6. Probabilities of treatment continuation at 24 weeks for different baseline SS scores – Pooled total population...............................................196 Table 6.7. Baseline characteristics of Johns Hopkins cohort used for data analysis.........................................................................................................198 Table 6.8. Overview of assumptions made in the model with respect to SS score.............................................................................................................199 Table 6.9. Coefficient results for the linear regression model predicting change in mean SLEDAI – Johns Hopkins Cohort....................................................200 Table 6.10. The distribution of annual AMS scores in the Johns Hopkins cohort............................................................................................................202 Table 6.11. Linear regression model explaining average steroid dose per year (mg/day) based on SLEDAI score (model input) - Johns Hopkins cohort.....207 Table 6.12. Weibull survival model explaining risk of death with AMS included and item involvement effects removed - JH cohort.......................................209 Table 6.13. Standardised Mortality Ratios for SLE patients stratified by age groups according to Bernatsky et al (2006)..................................................210 Table 6.14. Organ damage time to event models and corresponding covariates from Johns Hopkins cohort analysis............................................212 Table 6.15. Johns Hopkins characteristics imputed in simulation model......213 Table 6.16. Average SLICC scores per organ - based on all recordings in Johns Hopkins cohort....................................................................................214 Table 6.17. Natural discontinuation and probability of treatment continuation in base case - Total pooled population.........................................................216 Table 6.18. Descriptive statistics of EQ-5D data – Pooled total population......................................................................................................224 Table 6.19. Summary of quality-of-life values for cost-effectiveness analysis.........................................................................................................228