The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy Report commissioned by: NHS R&D HTA Programme On behalf of: The National Institute for Clinical Excellence Produced by: West Midlands Health Technology Assessment Collaboration, Department of Public Health and Epidemiology, The University of Birmingham Authors: alphabetical Prof Stirling Bryan Senior health economist# Dr Martin Connock Systematic reviewerà Dr Carole Cummins Paediatric trials adviser† Emma Frew Health economist# Anne Fry-Smith Information specialistà Beti-Wynn Jones Systematic reviewer‡ Prof Alain Li Wan Po Pharmacological adviser†† Josie Sandercock Senior reviewerà à Department of Public Health and Epidemiology, The University of Birmingham. # Health Economics Facility, Health Services Management Centre, The University of Birmingham. † Institute of Child Health, Whittal Street, Birmingham. †† Centre for Evidence-Based Pharmacotherapy, Aston University, Birmingham. ‡ Department of Medicine Management, Keele University Correspondence to: J. Sandercock, Tel 0121-414-2247. Email [email protected] M. Connock, Tel 0121-414-7507. Email [email protected] West Midlands Health Technology Collaboration, Department of Public Health and Epidemiology, The University of Birmingham, Edgbaston, Birmingham B15 2TT. FAX 0121- 414-7878 Date completed: February 2003 Expiry Date: Expiry date Newer Drugs for Children with Epilepsy PUBLICATION INFORMATION How to reference this publication: Connock M, Frew E, Jones B, Bryan S, Cummins C, Fry-Smith A, Li Wan Po A, Sandercock J. The clinical effectiveness and cost effectiveness of newer drugs for children with epilepsy. Birmingham: West Midlands Health Technology Collaboration, University of Birmingham, February 2003 ABOUT “HOME UNIT” The West Midlands Health Technology Assessment Collaboration (WMHTAC) produces rapid systematic reviews about the effectiveness of healthcare interventions and technologies, in response to requests from West Midlands Health Authorities or the HTA programme. Reviews usually take 3-6 months and aim to give a timely and accurate analysis of the quality, strength and direction of the available evidence, generating an economic analysis (where possible a cost-utility analysis) of the intervention. CONTRIBUTIONS OF AUTHORS Josie Sandercock Directed the review, assisted with the review of effectiveness, contributed to development of the decision-analytic model, wrote sections of the report Martin Connock Led the review of effectiveness, extracted data, wrote sections of the report Stirling Bryan Helped direct review, assessed industry models, conceived, developed and analysed decision-analytic model, wrote sections of the report Beti-Wynn Jones Developed and piloted data extraction form, extracted data, wrote sections of the report Emma Frew Assessed industry models, conceived, developed and analysed model, wrote sections of the report Anne Fry-Smith Performed literature searches, wrote sections of report Carole Cummins Wrote sections of the report, advised on paediatric aspects of the report Alain Li Wan Po Wrote sections of report, advised on pharmacology CONFLICTS OF INTEREST: Source of funding This report was commissioned by the NHS R&D HTA programme. Relationship of reviewer(s) with sponsor No members of the review team or the units to which they belong at the University of Birmingham, University of Aston , or Birmingham Children’s Hospital have any pecuniary relationship with sponsors, specific or non-specific. ACKNOWLEDGEMENTS We gratefully acknowledge the assistance of the following: Dr William Whitehouse, Dr Tim Betts, Professor David Chadwick, Dr Tony Johnson, Dr Richard Appleton, Dr Helen Cross, Dr Colin Ferrie, Dr Robert Smith, Dr John Gibbs, Professor Frank Besag, Dr Pelham Barton, Janine Dretzke. 2 Newer Drugs for Children with Epilepsy CONTENTS 1. AIM OF THE REVIEW.................................................................................. 13 “Newer” drugs for epilepsy ............................................................................... 14 2. BACKGROUND .............................................................................................. 15 2.1 Description of underlying health problem................................................. 15 2.1.1 Nature of condition ............................................................................ 15 2.1.2 Epilepsy in children ........................................................................... 17 2.1.3 Diagnosis............................................................................................ 20 2.1.4 Aetiology and pathology.................................................................... 21 2.1.5 Epidemiology..................................................................................... 23 2.1.6 Prognosis............................................................................................ 24 2.1.7 Significance in terms of ill-health............................................................ 25 2.2 Current service provision........................................................................... 26 2.2.1 Goals of service provision. ................................................................ 26 2.2.2 Standards of current service provision............................................... 27 2.2.3 Current service provision................................................................... 28 2.2.4 Treatment with anti-epileptic drugs (AEDs) ..................................... 29 2.2.5 Non AED treatments.......................................................................... 32 2.3 Description of new intervention ................................................................ 35 2.3.1 Mechanism of action.......................................................................... 35 3. EFFECTIVENESS........................................................................................... 37 3.1 Methods for reviewing effectiveness......................................................... 37 3.1.1 Search strategy................................................................................... 37 3.1.2 Inclusion and exclusion criteria ......................................................... 38 3.1.3 Data extraction strategy ..................................................................... 38 3.1.4 Quality assessment strategy ............................................................... 38 3.2 Results........................................................................................................ 39 3.2.1 Number and types of studies identified ............................................. 39 3.2.2 Mixed age studies .............................................................................. 41 3.2.3 Partial seizures (with or without secondary generalisation) .............. 43 3.2.4 Partial and generalised seizures (mixed population) ......................... 65 3.2.5 Generalised seizures.......................................................................... 70 3.2.6 Lennox-Gastaut syndrome................................................................. 74 3.2.7 Infantile spasms (West’s syndrome).................................................. 80 3.2.8 Absence Epilepsy............................................................................... 88 3.2.9 BECTS ............................................................................................... 91 3.2.10 Mixed population............................................................................... 93 3.2.11 Summary of RCT evidence................................................................ 97 3.2.12 Ongoing Trials................................................................................... 98 4. ECONOMIC ANALYSIS OF NEWER ANTI-EPILEPTIC DRUGS IN CHILDREN.............................................................................................................. 99 4.1 Summary .................................................................................................... 99 4.1.1 Commentary on company submissions that modelled childhood epilepsy. ............................................................................................................ 99 4.1.2 Summary of the Birmingham epilepsy model ................................... 99 4.2 Introduction.............................................................................................. 100 3 Newer Drugs for Children with Epilepsy 4.3 Systematic review of existing economic analyses................................... 100 4.3.1 Review of submission models ......................................................... 100 4.4 Birmingham economic analysis............................................................... 103 4.4.1 Overview of decision–analytic model ............................................. 103 4.4.2 Summary of model parameters ........................................................ 106 4.4.3 Drug sequences compared in the analysis ....................................... 107 4.4.4 Quality of life for children with epilepsy......................................... 109 4.4.5 Costs associated with care for children with epilepsy ..................... 111 4.4.6 Time spent in each model outcome ................................................. 113 4.4.7 Drug-specific proportions (for main outcome states) ...................... 118 4.4.8 Proportions moving into secondary model states ............................ 122 4.4.9 Methods of analysis ........................................................................