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

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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
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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
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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,
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Contents®/Clinical Medicine.
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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.