• National Institute for Clinical Excellence (NICE). Newer drugs for epilepsy in adults. London (UK): National Institute for Clinical Excellence (NICE); 2004 Mar. 36 p. (Technology appraisal; no. 76).

This is the current release of the guideline.

Epilepsy

Assessment of Therapeutic Effectiveness
Treatment

Family Practice
Internal Medicine
Neurology

Advanced Practice Nurses
Physician Assistants
Physicians

To assess the clinical and cost-effectiveness of the newer antiepileptic drugs gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin for the management of epilepsy in people who have not benefited from treatment with the older antiepileptic drugs

Adults with epilepsy who have not benefited from treatment with the older antiepileptic drugs

1. Antiepileptic drug treatment as monotherapy or combination therapy:
   • Gabapentin
   • Lamotrigine
   • Levetiracetam
   • Oxcarbazepine
   • Tiagabine
   • Topiramate
   • Vigabatrin
2. Assessment of risks and benefits of drugs in women of child-bearing potential
3. Referral to specialists in persons with first seizure
4. Review of and monitoring of treatment

• Clinical effectiveness, primarily:
  • Proportion of seizure-free participants
  • Proportion of participants experiencing at least a 50% reduction in seizure frequency (i.e., responders)
  • Time to exit/withdrawal
  • Time to first seizure
  • All quality of life outcomes
  • All outcomes relating to cognitive function
  • Safety (incidence of adverse events, mortality rate) and tolerability (incidence of withdrawals)
• Cost-effectiveness

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Unpublished Data

A total of 8095 titles and abstracts were screened for relevance and full copies of 1098 studies were ordered and assessed for inclusion/exclusion. A total of 212 studies were included in the review: 13 systematic reviews, 101 effectiveness publications covering 88 randomised controlled trials, 88 non-randomised experimental studies and observational publications covering 77 studies, and 21 economic evaluations.

Expert Consensus

Not applicable

Meta-Analysis of Randomized Controlled Trials
Systematic Review with Evidence Tables

Assessment of Clinical Effectiveness

Data Extraction Strategy

Data relating to study design, participants, interventions and outcomes were extracted in a standardised manner into an Access database by one reviewer and independently checked for accuracy by a second reviewer. Details of the types of data extracted are listed in Appendix 6 of the assessment report.

Attempts were made where possible to contact authors for missing data. Data from studies with multiple publications were extracted and reported as a single study. Where studies reported cognitive/quality of life data and seizure frequency outcomes in separate publications, both publications were considered.

Quality Assessment Strategy

Systematic Reviews

To be included in the review of effectiveness, as previously mentioned, all systematic reviews were required to meet the criteria necessary for inclusion in the Database of Abstracts of Reviews of Effects (DARE). Refer to Appendix 7 of the assessment report for the list of criteria used to assess the quality of systematic reviews. These criteria assess the quality of the review and so any reviews meeting the inclusion criteria were judged to be of reasonable quality. Assessment of the criteria was performed by one reviewer and independently checked by a second reviewer. Disagreements were resolved through consensus and if necessary a third reviewer was consulted.

Randomised Controlled Trials (RCTs)

The quality of the individual RCTs was assessed using criteria adapted from those used in the publication 'Undertaking Systematic Reviews of Research on Effectiveness: CRD's Guidance for Carrying Out or Commissioning Reviews'. In addition quality issues specifically pertaining to crossover and equivalence trials, were applied where appropriate. Refer to Appendix 8 of the assessment report for the list of criteria used to assess the quality of the individual RCTs.

In each case the quality of the trials was assessed by one reviewer and independently checked by a second reviewer. Disagreements were resolved through consensus and if necessary a third reviewer was consulted.

Handling Company Submissions

Data submitted by drug manufacturers by the deadline of 6th September 2002 were included. Submissions were checked for unpublished studies and any additional relevant information in relation to already published studies. Unpublished studies were assessed according to the inclusion/exclusion criteria above. Data extraction and quality assessment were carried out as for published studies. No submissions were received from the manufacturers of gabapentin or vigabatrin.

Data Analysis

Systematic Reviews

Data identified from systematic reviews are summarised in table form and briefly discussed in relation to the requirements and findings of this current review.

Randomised Controlled Trials

Data from the randomised controlled trials were presented in tables and discussed in a narrative. Effect sizes (relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CIs)) were reported where appropriate. RRs and HRs were considered to be statistically significant if the range of the 95% CIs does not include 1. Data were only pooled statistically (fixed effects model) if studies were considered to be clinically and statistically (Q-statistic) homogeneous. Due to the low power of the Q-statistic where numbers of studies are small (i.e. less than 20), a p value of 0.10 was used as a threshold for statistical significance. Studies were only pooled using the fixed effects model if the Q-statistic was less than the degrees of freedom (df) and the associated p value greater than 0.10.

Assessment of Serious, Rare and Long-Term Adverse Events Studies

Data Extraction Strategy

One reviewer extracted data using a standardised data extraction form (see Appendix 9 of the assessment report). Adverse effects data were extracted in detail only for serious, rare and long-term effects, and for withdrawal or discontinuation of treatment due to adverse effects. Published sources were used for guidance on the nature of serious and rare events associated with the newer AEDs. Serious included death, life threatening, hospitalisation, disability, congenital abnormality, cancer and overdose. Both serious and rare included any effect defined as such in the study reports. Long term was defined as longer than 6 months.

Prescription event monitoring and prospective post-marketing surveillance studies were data extracted directly into summary tables by one reviewer.

Quality Assessment Strategy

Data on methodological quality were extracted by one reviewer using standardized data extraction forms. Cohort and case-control studies were assessed using criteria derived from Centre for Reviews & Dissemination (CRD) Report 4.17 (See Appendix 10 of the assessment report) RCTs, non-randomised and uncontrolled studies were assessed against the criteria used in the review of effectiveness (see Appendix 8 of the assessment report). Study design and methods of prescription event monitoring and prospective post-marketing surveillance studies were tabulated.

Handling Company Submissions

Data submitted by drug manufacturers by the deadline of 6th September 2002 was searched for relevant studies according to the aforementioned criteria. No submissions were received from the manufacturers of gabapentin or vigabatrin.

Data Analysis

Tables describing the included studies and a narrative summary were presented according for each drug.

Cost Effectiveness

Data Extraction Strategy

Data from each individual study were extracted into an Access database by one reviewer and checked by a second reviewer. Details of the categories of data extracted are presented in Appendix 11 of the original guideline document.

Quality Assessment Strategy

The quality of each published economic evaluation was assessed independently by two reviewers using the criteria listed in Appendix 12 of the assessment report. Appendix 13 of the assessment report lists the economic model with any associated quality issues. In both cases disagreements were resolved through discussion with a third reviewer if necessary.

Handling Company Submissions

Data submitted by drug manufacturers by the deadline of 6th September 2002 were included. Submissions were checked for unpublished economic evaluations and models. Such evaluations were subject to similar processes of study selection, data extraction, and data analysis as reported for published evaluations.

Data Analysis

Summary tables of the data within the included economic evaluations are presented along with a critical appraisal of the design and findings of each of the evaluations. In addition an overview and comparison of the models reported within the company submissions is presented, in order to assess the suitability of the evaluations for use in an integrated economic evaluation of all the newer AEDs.

Integrated Economic Evaluation

In order to determine the cost-effectiveness of the newer AEDs all of the relevant available treatments must be directly compared. As described in section 3.3 of the assessment report, none of the published evaluations or industry submissions represented a direct comparison of all of the newer and older AEDs specified in the scope for this review. Therefore a decision analytic model was developed which incorporated all of the available information on the cost-effectiveness of the various newer and older AEDs that allowed direct comparisons to be made. The details of the structure of this analytic model, the information used to parameterise it, and the results of the analysis are described in section 3.4 of the assessment report. In summary, a cost-utility analysis was performed; using quality-adjusted life years calculated using utility weights estimated from EQ-5D responses and UK public valuations, so that the cost-effectiveness of the newer AEDs could be compared to the cost-effectiveness of treatments for other conditions.

Expert Consensus

Considerations

Technology appraisal recommendations are based on a review of clinical and economic evidence.

Technology Appraisal Process

The National Institute for Health and Clinical Excellence (NICE) invites 'consultee' and 'commentator' organisations to take part in the appraisal process. Consultee organisations include national groups representing patients and carers, the bodies representing health professionals, and the manufacturers of the technology under review. Consultees are invited to submit evidence during the appraisal and to comment on the appraisal documents.

Commentator organisations include manufacturers of the products with which the technology is being compared, the National Health Service (NHS) Quality Improvement Scotland and research groups working in the area. They can comment on the evidence and other documents but are not asked to submit evidence themselves.

NICE then commissions an independent academic centre to review published evidence on the technology and prepare an 'assessment report'. Consultees and commentators are invited to comment on the report. The assessment report and the comments on it are then drawn together in a document called the evaluation report.

An independent Appraisal Committee then considers the evaluation report. It holds a meeting where it hears direct, spoken evidence from nominated clinical experts, patients, and carers. The Committee uses all the evidence to make its first recommendations, in a document called the 'appraisal consultation document' (ACD). NICE sends all the consultees and commentators a copy of this document and posts it on the NICE website. Further comments are invited from everyone taking part.

When the Committee meets again it considers any comments submitted on the ACD; then it prepares its final recommendations in a document called the 'final appraisal determination' (FAD). This is submitted to NICE for approval.

Consultees have a chance to appeal against the final recommendations in the FAD. If there are no appeals, the final recommendations become the basis of the guidance that NICE issues.

Who is on the Appraisal Committee?

NICE technology appraisal recommendations are prepared by an independent committee. This includes health professionals working in the NHS and people who are familiar with the issues affecting patients and carers. Although the Appraisal Committee seeks the views of organisations representing health professionals, patients, carers, manufacturers and government, its advice is independent of any vested interests.

Not applicable

The evidence on cost effectiveness considered by the Committee included an integrated cost-effectiveness analysis developed by the Assessment Group and economic evaluations submitted by the manufacturers of five of the drugs (lamotrigine, levetiracetam, oxcarbazepine, tiagabine and topiramate). The Assessment Group also provided a review of the published literature on the cost effectiveness of newer antiepileptic drugs.

See Section 4.2 of the original guideline document for a detailed discussion of the cost-effectiveness analysis.

External Peer Review

Consultee organizations from the following groups were invited to comment on the draft scope, Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination.

• Manufacturer/sponsors
• Professional/specialist and patient/carer groups
• Commentator organisations (without the right of appeal)

In addition, individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.

• The newer antiepileptic drugs gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin, within their licensed indications, are recommended for the management of epilepsy in people who have not benefited from treatment with the older antiepileptic drugs such as carbamazepine or sodium valproate, or for whom the older antiepileptic drugs are unsuitable because:
  • there are contraindications to the drugs
  • they could interact with other drugs the person is taking (notably oral contraceptives)
  • they are already known to be poorly tolerated by the individual
  • the person is a woman of childbearing potential (see below).
• It is recommended that people should be treated with a single antiepileptic drug (monotherapy) wherever possible. If the initial treatment is unsuccessful, then monotherapy using another drug can be tried. Caution is needed during the changeover period.
• It is recommended that combination therapy (adjunctive or 'add-on' therapy) should only be considered when attempts at monotherapy with antiepileptic drugs (see above) have not resulted in seizure freedom. If trials of combination therapy do not bring about worthwhile benefits, treatment should revert to the regimen (monotherapy or combination therapy) that has proved most acceptable to the patient, in terms of providing the best balance between effectiveness in reducing seizure frequency and tolerability of side effects.
• In women of childbearing potential, the possibility of interaction with oral contraceptives and the risk of the drugs causing harm to an unborn child should be discussed and an assessment made as to the risks and benefits of treatment with individual drugs. There are currently few data upon which to base a definitive assessment of the risks to the unborn child associated with the newer drugs. Specific caution is advised in the use of sodium valproate because of the risk of harm to the unborn child.
• It is recommended that all people having a first seizure should be seen as soon as possible by a specialist in the management of the epilepsies to ensure precise and early diagnosis and initiation of therapy as appropriate to their needs.
• Treatment should be reviewed at regular intervals to ensure that people with epilepsy are not maintained for long periods on treatment that is ineffective or poorly tolerated and that concordance with prescribed medication is maintained.
• The recommendations on choice of treatment and the importance of regular monitoring of effectiveness and tolerability are the same for specific groups such as older people and those with learning disabilities as for the general population.

None provided

Only randomised controlled trials and systematic reviews were included in the review of clinical effectiveness, and in addition non-randomised experimental studies and observational studies were included in the review of serious, rare and long-term adverse events.

Appropriate use of the newer epileptic drugs for the management of patients with epilepsy to decrease the frequency of attacks and improve quality of life

Adverse events associated with therapy, including the risk of the drugs causing harm to an unborn child and the possibility of interaction with oral contraceptives, For full details of side effects and contraindications, the reader is referred to the Summary of Product Characteristics for each antiepileptic drug.

For full details of contraindications, the reader is referred to the Summary of Product Characteristics for each antiepileptic drug.

This guidance represents the view of the Institute, which was arrived at after careful consideration of the available evidence. Health professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.

Implementation and Audit

• All clinicians with responsibility for treating adults with epilepsy should review their current practice and policies to take account of the guidance.
• Local guidelines, protocols or care pathways that refer to the care of adults with epilepsy should incorporate the guidance.
• To measure compliance locally with the guidance, the following criteria could be used and will be applicable to all individuals with epilepsy. Further details on suggestions for audit are presented in Appendix C of the original guideline document.
  • A person with epilepsy is treated with a newer antiepileptic drug in the following circumstances.
    • He or she has not benefited from treatment with the older antiepileptic drugs such as carbamazepine or sodium valproate.
  • Older antiepileptic drugs are unsuitable because:
    • there are contraindications to the drugs
    • they could interact with other drugs the person is taking (notably oral contraceptives)
    • they are already known to be poorly tolerated by the individual
    • the person is a woman of childbearing potential (see "Major Recommendations" field in this summary).
  • A person with epilepsy is ordinarily treated with a single antiepileptic drug. If treatment with a single antiepileptic drug (monotherapy) is unsuccessful, then the person is treated using another single antiepileptic drug, exercising caution during the changeover period.
  • A person with epilepsy is prescribed combination adjunctive) therapy only when attempts at monotherapy with antiepileptic drugs have not resulted in seizure freedom. If trials of adjunctive therapy do not bring about worthwhile benefits, the person's treatment is reverted to the regimen that has proved most acceptable to the patient in terms of its effectiveness in reducing seizure frequency and the tolerability of its side effects.
  • In women of childbearing potential, the risk of the drugs causing harm to an unborn child and the possibility of interaction with oral contraceptives are discussed between the woman and the responsible clinician and an assessment is made as to the risks and benefits of treatment with individual drugs.
  • A person who has had a first seizure is seen as soon as possible by a specialist in the management of epilepsies.
  • Treatment is reviewed at regular intervals.
• Local clinical audits also could include measurement of compliance with issues identified in the National Clinical Audit of Epilepsy-related Death and/or Improving Services for People with Epilepsy (the Department of Health response to the National Clinical Audit of Epilepsy-related Death), such as carrying out appropriate investigations to reach a diagnosis of epilepsy, supporting people who are having problems with their drug regimens, and shared-care arrangements. Local audits may be able to make use of data already being collected for registries on epilepsy.

Living with Illness

Effectiveness
Patient-centeredness
Safety

• National Institute for Clinical Excellence (NICE). Newer drugs for epilepsy in adults. London (UK): National Institute for Clinical Excellence (NICE); 2004 Mar. 36 p. (Technology appraisal; no. 76).

Not applicable: The guideline was not adapted from another source.

2004 Mar

National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.]

National Institute for Health and Clinical Excellence (NICE)

Appraisal Committee

Committee Members: Dr A E Ades, MRC Senior Scientist, MRC Health Services Research Collaboration, University of Bristol; Dr Tom Aslan, General Practitioner, Stockwell, London; Professor David Barnett (Chair) Professor of Clinical Pharmacology, University of Leicester; Professor Rosamund Bryar, Professor of Community and Primary Care Nursing, St Bartholomew School of Nursing and Midwifery; Dr Richard Cookson, Senior Lecturer, Health Economics, School of Health Policy and Practice, University of East Anglia, Norwich; Professor Terry Feest, Clinical Director & Consultant Nephrologist, Richard Bright Renal Unit, & Chair of UK Renal Registry, Bristol; Dr John Geddes, Consultant Psychiatrist, University Department of Psychiatrists, Oxford; Ms Bethan George, Interface Liaison Pharmacist, Tower Hamlets PCT and Royal London Hospital, Whitechapel; Mr John Goulston, Director of Finance, Barts and the London NHS Trust; Dr Terry John, General Practitioner, The Firs, London; Mr Muntzer Mughal, Consultant Surgeon, Lancashire Teaching Hospitals NHS Trust, Chorley; Judith Paget, Chief Executive, Caerphilly Local Health Board, Torfaen; Mr James Partridge, Lay Representative; Chief Executive, Changing Faces, London; Mrs Kathryn Roberts, Nurse Practitioner, Hyde, Cheshire; Professor Andrew Stevens (Vice-Chair) Professor of Public Health, University of Birmingham; Dr Cathryn Thomas, General Practitioner, & Senior Lecturer, Department of Primary Care & General Practice, University of Birmingham; Dr Norman Vetter Reader, Department of Epidemiology, Statistics and Public Health, College of Medicine, University of Wales, Cardiff; Dr David Winfield, Consultant Haematologist, Royal Hallamshire Hospital, Sheffield

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

This is the current release of the guideline.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.