Confidential – do not copy or circulate CONFIDENTIAL UNTIL PUBLISHED Evidence Review Group Report commissioned by the NIHR HTA Programme on behalf of NICE Reslizumab for treating asthma with elevated blood eosinophils inadequately controlled by inhaled corticosteroids Produced by Southampton Health Technology Assessments Centre Authors Keith Cooper, Senior Research Fellow, SHTAC Petra Harris, Research Fellow, SHTAC Micah Rose, Research Fellow, SHTAC Maria Chorozoglou, Senior Research Fellow, SHTAC Karen Pickett, Research Fellow, SHTAC Geoff Frampton, Senior Research Fellow, SHTAC Correspondence to Dr Geoff Frampton Southampton Health Technology Assessments Centre University of Southampton First Floor, Epsilon House Enterprise Road, Southampton Science park Southampton SO16 7NS www.southampton.ac.uk/shtac Date completed 11th October 2016. This version of the report includes corrections made by the ERG following the company’s factual inaccuracy check. These are indicated as underlined italicised text. Version 1 1 Confidential – do not copy or circulate Source of funding: This report was commissioned by the NIHR HTA Programme as project number 15/121/14 Declared competing interests of the authors None Acknowledgements We would like to thank Professor Anoop Chauhan (Consultant and Professor in Respiratory Medicine and Director of Research, Portsmouth Hospitals NHS Trust) for providing clinical advice to the ERG and for commenting on a draft of the report; and Professor Tim Harrison (Clinical Associate Professor and Honorary Consultant, Faculty of Medicine & Health Sciences, University of Nottingham and Nottingham City Hospital) and Professor Dr Tom Wilkinson (Consultant and Professor in Respiratory Medicine, University of Southampton and Southampton University Hospital NHS Foundation Trust) for commenting on a draft of the report. We also thank Professor Joanne Lord, Director, SHTAC, for acting as internal editor for the draft 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: Cooper K, Harris P, Rose M, Chorozoglou M, Pickett K, Frampton G. Reslizumab for treating asthma with elevated blood eosinophils inadequately controlled by inhaled corticosteroids: A Single Technology Appraisal. Southampton Health Technology Assessments Centre (SHTAC). 2016. Contributions of authors Keith Cooper (Senior Research Fellow) critically appraised the health economic systematic review, critically appraised the economic evaluation and drafted the report. Petra Harris (Research Fellow) critically appraised the clinical effectiveness systematic review and drafted the report. Micah Rose (Research Fellow) critically appraised the health economic systematic Version 1 2 Confidential – do not copy or circulate review, critically appraised the economic evaluation and drafted the report. Maria Chorozoglou (Senior Research Fellow) critically appraised the economic evaluation and drafted the report. Karen Pickett (Research Fellow) critically appraised the clinical effectiveness systematic review and drafted the report. Geoff Frampton (Senior Research Fellow) critically appraised the clinical effectiveness systematic review, drafted the report, project managed the review and is the project guarantor. Word count: 55,862 (including tables) XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX. Version 1 3 Confidential – do not copy or circulate TABLE OF CONTENTS 1 Introduction to the ERG Report ..........................................................................................23 2 BACKGROUND .................................................................................................................23 2.1 Summary & critique of the company’s description of the underlying health problem....23 2.2 Summary & critique of the company’s overview of current service provision ...............25 2.3 Summary & critique of the company’s definition of the decision problem ....................29 3 CLINICAL EFFECTIVENESS .............................................................................................34 3.1 Summary & critique of the company’s approach to systematic review.........................34 3.2 Overall summary statement of the company’s approach .............................................73 3.3 Direct treatment comparison results: reslizumab versus placebo ................................74 3.4 Indirect treatment comparison results: reslizumab versus omalizumab .......................96 3.5 Summary of clinical effectiveness evidence .............................................................. 110 4 COST EFFECTIVENESS ................................................................................................. 114 4.1 Overview of the company’s economic evaluation ...................................................... 114 4.2 Company’s review of published economic evaluations .............................................. 114 4.3 Critical appraisal of the company’s submitted economic evaluation .......................... 119 4.4 Additional work undertaken by the ERG .................................................................... 164 4.5 Conclusions on cost effectiveness ............................................................................ 169 5 Innovation ........................................................................................................................ 170 6 DISCUSSION .................................................................................................................. 171 6.1 Summary of clinical effectiveness issues .................................................................. 171 6.2 Summary of cost effectiveness issues ...................................................................... 172 7 REFERENCES ................................................................................................................ 173 LIST OF TABLES Table 1 Asthma treatment stepwise approach...........................................................................25 Table 2 GINA definition of asthma severity ...............................................................................27 Table 3 Technology being appraised (CS Table 2) ...................................................................31 Table 4 Overview of reslizumab RCTs included in the CS ........................................................41 Table 5 Baseline characteristics of the reslizumab trials included in the CS ..............................48 Table 6 Company and ERG assessments of trial quality ...........................................................53 Table 7 Analysis populations in the trials of reslizumab .............................................................59 Table 8 Overview of statistical approaches in the trials of reslizumab .......................................60 Table 9 Outcomes included in meta-analyses ...........................................................................64 Table 10 Quality assessment (CRD criteria) of CS review ........................................................73 Table 11 ACQ score: mean change from baseline at 16±1 weeks ............................................75 Table 12 Direct comparison meta-analysis: ACQ score change over 16±1 weeks ....................75 Table 13 Rate of clinical asthma exacerbations over 52 weeks .................................................77 Table 14 Exacerbations requiring systemic corticosteroids for ≥3 days over 52 weeks .............77 Table 15 Exacerbations requiring oral corticosteroids for ≥3 days over 52 weeks .....................78 Table 16 Exacerbations requiring hospitalisation and/or emergency room visit over 52 weeks .78 Table 17 Kaplan-Meier probability of not experiencing a clinical asthma exacerbation by week 52..............................................................................................................................................78 Table 18 Clinically significant exacerbations .............................................................................79 Table 19 Direct comparison meta-analysis: clinically significant exacerbations .........................80 Table 20 Patients hospitalised due to exacerbations up to 52 weeks ........................................80 Table 21 Direct comparison meta-analysis: patients hospitalised due to exacerbations up to 52 weeks .......................................................................................................................................81 Table 22 FEV1: mean change from baseline (L) at 16±1 weeks ...............................................81 Version 1 4 Confidential – do not copy or circulate Table 23 FEV1: mean change from baseline (L) at 52 weeks ...................................................82 Table 24 Direct comparison meta-analysis: FEV1 change over 16 and 52 weeks .....................82 Table 25 % predicted FEV1: mean change from baseline at 16±1 weeks .................................83 Table 26 % predicted FEV1: mean change from baseline at 52 weeks .....................................84 Table 27 FVC: mean change from baseline (L) at 16±1 weeks .................................................84 Table 28 FVC: mean change from baseline (L) at 52 weeks .....................................................84 Table 29 FEF25-75%: mean change from baseline (L/s) at 16