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Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults PDF

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This is a repository copy of Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: A systematic review and economic evaluation. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/59216/ Version: Published Version Article: Wilby, J, Kainth, A, Hawkins, N et al. (9 more authors) (2005) Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: A systematic review and economic evaluation. Health technology assessment. ISSN 2046-4924 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing Health Technology Assessment 2005; Vol. 9: No. 15 Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation J Wilby, A Kainth, N Hawkins, D Epstein, H McIntosh, C McDaid, A Mason, S Golder, S O’Meara, M Sculpher, M Drummond and C Forbes April 2005 Health Technology Assessment NHS R&D HTA Programme HTA HTA How to obtain copies of this and other HTA Programme reports. An electronic version of this publication, in Adobe Acrobat format, is available for downloading free of charge for personal use from the HTA website (http://www.ncchta.org). A fully searchable CD-ROM is also available (see below). Printed copies of HTA monographs cost £20 each (post and packing free in the UK) to both public and private sector purchasers from our Despatch Agents, York Publishing Services. 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Contact details are as follows: York Publishing Services Email: Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation 1 1 2 2 J Wilby, A Kainth, N Hawkins, D Epstein, 1 1 2 1 H McIntosh, C McDaid, A Mason, S Golder, 1 2 2 S O’Meara, M Sculpher, M Drummond and 1* C Forbes 1 Centre for Reviews and Dissemination, University of York, UK 2 Centre for Health Economics, University of York, UK *Corresponding author Declared competing interests of authors: Neil Hawkins has undertaken consultancy for GlaxoSmithKline in therapeutic areas unrelated to the treatment of epilepsy. Mark Sculpher has undertaken consultancy or reviewed research findings for Aventix and GlaxoSmithKline, but on products unrelated to epilepsy. Michael Drummond has served on an Advisory Board for Aventis Pharma Ltd, but not related to epilepsy. He has also undertaken consultancy from Pfizer and GlaxoSmithKline, but in fields unrelated to epilepsy. Published April 2005 This report should be referenced as follows: Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation. Health Technol Assess 2005;9(15). Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE and Science Citation Index Expanded (SciSearch®) and Current Contents®/Clinical Medicine. NHS R&D HTA Programme he research findings from the NHS R&D Health Technology Assessment (HTA) Programme directly Tinfluence key decision-making bodies such as the National Institute for Clinical Excellence (NICE) and the National Screening Committee (NSC) who rely on HTA outputs to help raise standards of care. HTA findings also help to improve the quality of the service in the NHS indirectly in that they form a key component of the ‘National Knowledge Service’ that is being developed to improve the evidence of clinical practice throughout the NHS. The HTA Programme was set up in 1993. Its role is to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS. ‘Health technologies’ are broadly defined to include all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care, rather than settings of care. The HTA programme commissions research only on topics where it has identified key gaps in the evidence needed by the NHS. Suggestions for topics are actively sought from people working in the NHS, the public, consumer groups and professional bodies such as Royal Colleges and NHS Trusts. Research suggestions are carefully considered by panels of independent experts (including consumers) whose advice results in a ranked list of recommended research priorities. The HTA Programme then commissions the research team best suited to undertake the work, in the manner most appropriate to find the relevant answers. Some projects may take only months, others need several years to answer the research questions adequately. They may involve synthesising existing evidence or designing a trial to produce new evidence where none currently exists. Additionally, through its Technology Assessment Report (TAR) call-off contract, the HTA Programme is able to commission bespoke reports, principally for NICE, but also for other policy customers, such as a National Clinical Director. TARs bring together evidence on key aspects of the use of specific technologies and usually have to be completed within a limited time period. Criteria for inclusion in the HTA monograph series Reports are published in the HTA monograph series if (1) they have resulted from work commissioned for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors. Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others. The research reported in this monograph was commissioned and funded by the HTA Programme on behalf of NICE as project number 01/50/01. The authors have been wholly responsible for all data collection, analysis and interpretation and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme, NICE or the Department of Health. Editor-in-Chief: Professor Tom Walley Series Editors: Dr Peter Davidson, Professor John Gabbay, Dr Chris Hyde, Dr Ruairidh Milne, Dr Rob Riemsma and Dr Ken Stein Managing Editors: Sally Bailey and Caroline Ciupek ISSN 1366-5278 © Queen’s Printer and Controller of HMSO 2005 This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to NCCHTA, Mailpoint 728, Boldrewood, University of Southampton, Southampton, SO16 7PX, UK. Published by Gray Publishing, Tunbridge Wells, Kent, on behalf of NCCHTA. Printed on acid-free paper in the UK by St Edmundsbury Press Ltd, Bury St Edmunds, Suffolk. T Health Technology Assessment 2005; Vol. 9: No. 15 Abstract Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation 1 1 2 2 1 1 2 J Wilby, A Kainth, N Hawkins, D Epstein, H McIntosh, C McDaid, A Mason, 1 1 2 2 1* S Golder, S O’Meara, M Sculpher, M Drummond and C Forbes 1 Centre for Reviews and Dissemination, University of York, UK 2 Centre for Health Economics, University of York, UK *Corresponding author Objectives: To examine the clinical effectiveness, people with intellectual disabilities or in pregnant tolerability and cost-effectiveness of gabapentin (GBP), women. There was very little evidence to assess the lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine effectiveness of AEDs in the elderly; no significant (OXC), tiagabine (TGB), topiramate (TPM) and differences were found between LTG and vigabatrin (VGB) for epilepsy in adults. carbamazepine monotherapy. Sixty-seven RCTs Data sources: Electronic databases. Internet compared adjunctive therapy with placebo, older AEDs resources. Pharmaceutical company submissions. or other newer AEDs. For newer AEDs versus Review methods: Selected studies were screened and placebo, a trend was observed in favour of newer quality assessed. Separate analyses assessed clinical drugs, and there was evidence of statistically significant effectiveness, serious, rare and long-term adverse differences in proportion of responders favouring events and cost-effectiveness. An integrated economic newer drugs. However, it was not possible to assess analysis incorporating information on costs and effects long-term effectiveness. Most trials were conducted in of newer and older antiepileptic drugs (AEDs) was patients with partial seizures. For newer AEDs versus performed to give direct comparisons of long-term older drugs, there was no evidence to assess the costs and benefits. effectiveness of LEV, LTG or OXC, and evidence for Results: A total of 212 studies were included in the other newer drugs was limited to single studies. Trials review. All included systematic reviews were Cochrane only included patients with partial seizures and follow- reviews and of good quality. The quality of randomised up was relatively short. There was no evidence to controlled trials (RCTs) was variable. Assessment was assess effectiveness of adjunctive LEV, OXC or TPM hampered by poor reporting of methods of versus other newer drugs, and there were no time to randomisation, allocation concealment and blinding. event or cognitive data. No studies assessed the Few of the non-randomised studies were of good effectiveness of adjunctive AEDs in the elderly or quality. The main weakness of the economic pregnant women. There was some evidence from one evaluations was inappropriate use of the cost- study (GBP versus LTG) that both drugs have some minimisation design. The included systematic reviews beneficial effect on behaviour in people with learning reported that newer AEDs were effective as adjunctive disabilities. Eighty RCTs reported the incidence of therapy compared to placebo. For newer versus older adverse events. There was no consistent or convincing drugs, data were available for all three monotherapy evidence to draw any conclusions concerning relative AEDs, although data for OXC and TPM were limited. safety and tolerability of newer AEDs compared with There was limited, poor-quality evidence of a significant each other, older AEDs or placebo. The integrated improvement in cognitive function with LTG and OXC economic analysis for monotherapy for newly compared with older AEDs. However, there were no diagnosed patients with partial seizures showed that consistent statistically significant differences in other older AEDs were more likely to be cost-effective, clinical outcomes, including proportion of seizure-free although there was considerable uncertainty in these patients. No studies assessed effectiveness of AEDs in results. The integrated analysis suggested that newer iii © Queen’s Printer and Controller of HMSO 2005. All rights reserved. Abstract AEDs used as adjunctive therapy for refractory patients seizures, thus limiting the applicability of the data. with partial seizures were more effective and more Newer AEDs, used as monotherapy, may be cost- costly than continuing with existing treatment alone. effective for the treatment of patients who have Combination therapy, involving new AEDs, may be experienced adverse events with older AEDs, who cost-effective at a threshold willingness to pay per have failed to respond to the older drugs, or where quality-adjusted life year (QALY) greater than £20,000, such drugs are contraindicated. The integrated depending on patients’ previous treatment history. economic analysis also suggested that newer AEDs There was, again, considerable uncertainty in these used as adjunctive therapy may be cost-effective results. There were few data available to determine compared with the continuing current treatment alone effectiveness of treatments for patients with given a QALY of about £20,000. There is a need for generalised seizures. LTG and VPA showed similar more direct comparisons of the different AEDs within health benefits when used as monotherapy. VPA was clinical trials, considering different treatment sequences less costly and was likely to be cost-effective. The within both monotherapy and adjunctive therapy. analysis indicated that TPM might be cost-effective Length of follow-up also needs to be considered. Trials when used as an adjunctive therapy, with an estimated are needed that recruit patients with either partial or incremental cost-effectiveness ratio of £34,500 generalised seizures; that investigate effectiveness and compared with continuing current treatment alone. cost-effectiveness in patients with generalised onset Conclusions: There was little good-quality evidence seizures and that investigate effectiveness in specific from clinical trials to support the use of newer populations of epilepsy patients, as well as studies monotherapy or adjunctive therapy AEDs over older evaluating cognitive outcomes to use more stringent drugs, or to support the use of one newer AED in testing protocols and to adopt a more consistent preference to another. In general, data relating to approach in assessing outcomes. Further research is clinical effectiveness, safety and tolerability failed to also required to assess the quality of life within trials of demonstrate consistent and statistically significant epilepsy therapy using preference-based measures of differences between the drugs. The exception was outcomes that generate cost-effectiveness data. Future comparisons between newer adjunctive AEDs and RCTs should use CONSORT guidelines; and placebo, where significant differences favoured newer observational data to provide information on the use of AEDs. However, trials often had relatively short-term AEDs in actual practice, including details of treatment treatment durations and often failed to limit sequences and doses. recruitment to either partial or generalised onset iv Health Technology Assessment 2005; Vol. 9: No. 15 Contents Glossary and list of abbreviations ............. vii Appendix 6 Details of the types of data extracted from systematic reviews and Executive summary .................................... xv clinical effectiveness studies ....................... 187 1 Objectives and background ....................... 1 Appendix 7 Quality assessment checklist Aim of the review ....................................... 1 used to assess the quality of systematic Background ................................................ 1 reviews ........................................................ 189 2 Methods ..................................................... 9 Appendix 8 Quality assessment checklists Assessment of clinical effectiveness ............ 9 used to assess the quality of RCTs ............. 191 Assessment of serious, rare and long-term adverse events studies ............... 11 Appendix 9 Details of the information Assessment of cost-effectiveness ................. 13 extracted from studies included in the Integrated economic evaluation ................ 14 assessment of serious, rare and long-term adverse events ............................................ 193 3 Results ........................................................ 15 Quantity of research available .................... 15 Appendix 10 Quality assessment checklists Quality of included studies ........................ 17 used to assess the quality of studies included Analysis ....................................................... 22 in the assessment of serious, rare and Integrated analysis of cost-effectiveness .... 105 long-term adverse events ........................... 195 4 Discussion ................................................... 127 Appendix 11 Details of the types of Clinical effectiveness and tolerability ........ 127 data extracted from cost-effectiveness Cost-effectiveness ....................................... 131 studies ......................................................... 197 Integrated economic model ....................... 131 Relevance to the NHS ................................ 133 Appendix 12 Quality assessment checklists Implications for further research ............... 134 used to assess the quality of economic Updating the review ................................... 134 evaluations .................................................. 199 5 Conclusions ................................................ 135 Appendix 13 Summary of the quality of studies included in the economic model or Acknowledgements .................................... 137 reason for exclusion ................................... 201 References .................................................. 139 Appendix 14 Details of RCTs included in the assessment of clinical effectiveness Appendix 1 List of peer reviewers ............ 159 (licensed and unlicensed) ........................... 205 Appendix 2 Search strategies .................... 161 Appendix 15 Links between included studies ......................................................... 221 Appendix 3 Details of studies excluded from this review referenced by industry Appendix 16 Details of non-English submissions or other review language studies meeting the inclusion bibliographies ............................................. 177 criteria but not included in the review ...... 225 Appendix 4 Details of QoL measures Appendix 17 Ongoing studies (adults) ..... 227 used in RCTs .............................................. 181 Appendix 18 Quality assessment of Appendix 5 Details of cognitive effectiveness studies: randomised measures used in RCTs .............................. 183 controlled trials .......................................... 229 v Contents Appendix 19 Summary of main quality Appendix 26 Extraction tables for studies issues of RCTs ............................................. 253 included in the assessment of cost-effectiveness ........................................ 779 Appendix 20 Serious, rare and long-term adverse events: quality assessment of Appendix 27 Review of cost, utility and included studies ......................................... 259 mortality data to use as input parameters in the Centre for Health Economics (CHE) Appendix 21 Quality assessment of model ......................................................... 803 cost-effectiveness studies ............................ 269 Appendix 28 S-plus code .......................... 811 Appendix 22 Extraction tables for systematic reviews included in the Health Technology Assessment reports assessment of effectiveness (n = 13) .......... 275 published to date ....................................... 819 Appendix 23 Extraction tables for Health Technology Assessment clinical effectiveness studies ....................... 297 Programme ................................................ 829 Appendix 24 Adverse events results tables .......................................................... 727 Appendix 25 Extraction tables for studies of serious, rare and long-term adverse events .......................................................... 745 vi Health Technology Assessment 2005; Vol. 9: No. 15 Glossary and list of abbreviations Technical terms and abbreviations are used throughout this report. The meaning is usually clear from the context, but a glossary is provided for the non-specialist reader. In some cases, usage differs in the literature, but the term has a constant meaning throughout this review. Glossary Absence seizurea Previously called ‘petit other diseases or conditions that could be mal’, this is a generalised seizure involving a affecting their outcomes. Any other such brief interruption of consciousness. The person condition is called a ‘co-morbidity’. may look blank and their eyelids may flutter. Complex partial seizurea Partial seizure in Adverse effectb Any untoward medical which the person’s awareness is impaired. The occurrence that may present during treatment person may show confused behaviour and with a pharmaceutical product but which does ‘automatisms’ such as lip-smacking, chewing, not necessarily have a causal relationship with undressing, picking up objects and wandering the treatment. aimlessly. The seizure usually lasts a few Adverse eventb A response to a drug which is minutes and the person has no memory of what has happened. This type of seizure often noxious and unintended, and which occurs at originates in the temporal lobe of the brain, in doses normally used in humans for the which case the person may be said to have prophylaxis, diagnosis or therapy of the temporal lobe epilepsy. However, complex disease, or for the modification of physiological partial seizures may also originate in other function. lobes (areas) of the brain. Ambylopiac Dimness of vision, without Confidence interval (CI) Quantifies the detectable organic lesion of the eye. uncertainty in measurement. Usually reported Amnesiac Pathological impairment of as 95% CI, that is, the range of values within memory. which one is 95% sure that the true value for Anorexiac Lack or loss of appetite for food. the whole population lies. Aphasiac Defect or loss of the power of Cost-benefit analysis (CBA) A form of economic evaluation where both costs and expression by speech, writing or signs or of benefits are expressed in the same units, comprehending spoken or written language, usually monetary units, that is, all of the health due to injury or disease of the brain centres. benefits (e.g. disability days avoided, life-years Astheniac Lack or loss of strength and gained, medical complications avoided) are energy, weakness. translated into monetary units. This type of Ataxiac Failure of muscular coordination; analysis is not widely used in the economic evaluation of drugs or technologies, as it is irregularity of muscular action. often difficult to determine the cost of health Atonic seizurea Generalised seizure involving benefits. a sudden loss of muscle tone so that the person Cost-consequences analysis (CCA) A form of falls to the ground. Recovery is rapid but there cost-effectiveness analysis where costs and may be injuries due to the fall. effectiveness (consequences) are presented Co-morbidity In a study looking at treatment separately and the decision-maker is left to for one disease or condition, some of the make their own view about the relative individuals with that disease will also have importance of these factors. continued vii © Queen’s Printer and Controller of HMSO 2005. All rights reserved.

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