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submissions used a variety of analytic methods, comparators and outcomes. A majority of the evaluations were based on CMAs which assumed equality of benefits and did not fully consider uncertainty in outcomes, or were CEAs that used a variety of outcome measures and therefore could not be compared. A small number of CUAs were conducted; these considered only a limited number of alternative treatments and trial results and did not fully consider uncertainty, especially in the extrapolation of the results of short-term trial data to longer periods of treatment.

Given the limitations in submitted and previously published economic evaluations, an integrated CEA was conducted. This analysis incorporated available information on the costs and effects associated with the various newer and older epileptic drugs and allowed direct comparisons to be made despite the limited number and scope of ‘head-to-head’ trials. To allow the cost-

effectiveness of the various AEDs under

consideration to be compared with therapies for other conditions, a CUA was undertaken. The integrated CEA extrapolated from the individual short-term clinical trials to allow direct comparisons to be made between the various treatments based on predicted long-term benefits and costs. In order to allow these comparisons, data from a variety of sources were combined in the analysis and a number of assumptions were required. These are summarised below and should be borne in mind when considering the results of the analysis.

The first assumption relates to outcomes. AEDs may alter the intensity, frequency and pattern of occurrence of epileptic seizures. The impact of drug treatment on the QoL experienced by a patient will be a complex function of these various effects. The integrated economic analysis was limited to those reported clinical trial outcomes, seizure freedom and 50% reduction in seizure frequency that were common to all drugs and which could be interpreted in light of the available quality of life evidence. The estimates of the impact of seizure control on utility were based on a single small study.467An estimate of uncertainty was made based on the observed study data, but this does not account for potential variability between studies. As these utility estimates were common to all treatments being considered, the effect of this uncertainty on the estimates of differences in cost-effectiveness between treatments is likely to be limited.

A second assumption is that, in the absence of specific comparative long-term clinical trial data, we estimated the short-term effectiveness based on specific clinical trial data and the longer term effectiveness based on generic open-label study data. Although an estimate of uncertainty based on the observed trial data was incorporated in the analysis, no account was made of uncertainty arising from potential variability between studies and drugs. The generalisability of the clinical trial data should also be considered when reviewing the results of the analysis

A third assumption is that, in the absence of direct ‘head to head’ comparisons between all the drugs included in the analysis, estimates of relative short-term effectiveness were based on data resulting from indirect comparisons which were incorporated into a statistical model. When making direct comparisons based on such indirect comparisons, it is not possible to exclude the effects of systematic differences between studies on the estimates of effectiveness. Although an

estimate of uncertainty based on the observed differences between trials was incorporated in the analysis, uncertainty due to potential unobserved differences was not. To an extent, the effects of unobserved heterogeneity cannot be excluded from standard meta-analysis, and this form of evidence synthesis was felt to produce the best estimates of relative efficacy, which were required for the incremental CEA, based on the available clinical trial data.

A fourth assumption is that, owing to a lack of detailed observational and experimental data, our analysis included the use of a limited range of healthcare resource items, and the unit costs were assumed to be common to all drugs investigated. Most of the serious AEs are known to be rare so this should not affect the validity of any

conclusions drawn. VGB and PHT were excluded from the analysis as it was felt that the side-effect profile of VGB and the narrow therapeutic index of PHT would not be adequately accounted for in the analysis.

A fifth assumption is that, given the lack of data regarding the mean dose of the AEDs used in normal practice, the uncertainty in dose was modelled based on plausible assumptions. A gamma distribution based on the maximum and minimum recommended dose in the BNF was used to reflect uncertainty. As, in general, the various treatments were found to have similar efficacy, the CEA will be sensitive to the assumptions drawn regarding drug price. 132

Finally, in the absence of sufficient specific data, the safety of the various drugs during pregnancy was not considered in our analysis.

Although it is important for these assumptions to be explicit and to be considered in interpreting results, the objective of the integrated analysis was to provide the most reasonable synthesis of available evidence and to quantify the uncertainty associated with existing evidence. The analysis of the treatment of patients experiencing partial seizures indicated that the various drugs used in monotherapy for newly diagnosed patients produced similar health benefits and that the newer AEDs were more expensive. Consequently, older AEDs were found most likely to be cost- effective. It is important to bear in mind that there is a great deal of uncertainty in this conclusion owing to the imprecision in the estimate of benefits. As the threshold willingness to pay increases above £30,000, it is not possible to determine which is the most cost-effective AED with any great degree of certainty. It is also possible that, even at low values of the willingness to pay per QALY, the newer AEDs may be cost- effective as monotherapy for the treatment of patients who have failed to respond to older AEDs. There were insufficient clinical trial data regarding the treatment of refractory patients to evaluate this.

The very limited trial data regarding monotherapy for refractory patients with partial seizures

indicated that LTG, VPA and CBZ had similar effectiveness and that LTG was more expensive. The CEA indicated that CBZ was the most cost- effective treatment. However, LTG or VPA monotherapy may be cost-effective for patients who have failed to respond to CBZ. There were insufficient data on the use of other alternative newer or older AEDs for patients who are refractory to specific drugs to allow this to be investigated further.

The analysis of combination therapy for refractory patients with partial seizures indicated that the newer treatments were more effective and more costly than continuing with the patients’ existing therapy alone. At low values of the threshold willingness to pay, combination therapy with newer AEDs was found not to be cost-effective. Combination therapy may be cost-effective, however, given a threshold willingness to pay for a QALY of £20,000 or more, provided that patients are discontinued from adjunctive drugs should they prove to be unsuccessful. The precise value depends on which treatment options would be

appropriate for an individual patient based on their previous treatment history. Sensitivity analysis showed it is not cost-effective to retain patients on an adjunctive therapy if seizure control proves to be inadequate. The analysis indicates that there was a great deal of uncertainty in this conclusion owing to the lack of precision in the estimate of treatment benefits. Although OXC had the greatest probability of being cost-effective compared with other adjunctive AEDs, the estimate for its effectiveness was based only on a single clinical trial.

The analysis of the treatment of patients

experiencing generalised seizures indicated that LTG and VPA had similar efficacy and that treatment with VPA was less costly. The incremental analysis suggested that treatment with VPA was cost-effective compared with treatment with LTG. LTG monotherapy may be cost-effective, however, if VPA is contraindicated, or if patients have failed to respond to previous VPA treatment. There were insufficient data available to consider other alternative newer or older AEDs. The analysis indicated that TPM might be cost-effective when used as an adjunctive therapy, with an estimated ICER of £34,500 compared with continuing current treatment alone. The analysis did, however, indicate that there was a great deal of uncertainty in this estimate.

The integrated economic analysis presented may form the basis of further evaluations as more clinical trial evidence becomes available. In addition, value of information methods based on this model may provide a useful framework for setting priorities for future research in this area and for appropriately designing trials.