4.1 Four randomised controlled trials (including a number of UK centres) in patients who fall within the diagnostic category of ALS have compared riluzole with placebo (a total of 1477 individuals). Three trials used riluzole at 100 mg/day and one used doses of 50, 100 and 200mg/day. Individuals were under 75 years, had a Forced Vital Capacity (FVC) ≥60% in three trials, with two of these also excluding patients who had suffered from MND for more than 5 years. The fourth trial recruited individuals who were older or who had a greater duration of disease (> 5 years) or who had a FVC<60%.
4.2 All trials used tracheostomy-free survival as a primary outcome. Most individuals (in all four trials) were prevalent, rather than incident cases.
4.3 The assessment report reviewed the results from all four of the trials identified and reported riluzole to be associated with a relative reduction in hazard ratio for tracheostomy-free survival at 18 months of 17% (i.e. hazard ratio of 0.88, 95% CI: 0.75- 1.02). There was some evidence of heterogeneity across the results of these four trials.
4.4 When data on functional status were combined, a small reduction in the rate of deterioration of functional status was observed, although the statistical methods used to calculate changes were questionable. Furthermore it is not clear whether the estimated differences obtained using these methods were clinically significant.
4.5 There was little evidence of a difference in adverse events between riluzole and placebo.
4.6 There is strong clinical support for the use of riluzole in forms of MND other than ALS but the current licensed indications limit its use to ALS alone. The inclusion criteria for the published clinical trials has been restricted to a diagnosis of the ALS form of MND alone.
4.7 Current estimates of the cost-effectiveness of riluzole must be viewed cautiously. Some of the key remaining uncertainties on benefits for the economic analysis concern the disease stage(s) in which the survival gain is experienced, the quality of life utility weights for ALS health states and the mean gain in life expectancy for individuals who take riluzole. Estimates from the two fully published trials suggest a gain in median tracheostomy free survival time of 2 months to 4 months. It is clear that riluzole is associated with a net increase in costs to the health service, though the magnitude of the increase is difficult to predict accurately.
4.8 Using a published Markov model and 18 month trial follow up data, the manufacturer's submission provided a base case cost per quality adjusted life year (cost/QALY) estimate of £18,000 to £29,000 for riluzole. Based on a re-analysis of this Markov model using an alternative, more conservative, estimate of time-dependant probabilities, the assessment report derived discounted cost per QALY estimates for riluzole of between approximately £34,000 to £43, 500. These later estimates are consistent with the results obtained by the assessment report authors when using Weibull and Gompertz models to extrapolate survival over time.
4.9 The Appraisal Committee considered the evidence of the clinical and cost effectiveness of this technology by reference to the Directions to the Institute issued by the Secretary of State. The Committee took account of the severity and relatively short life span of people with ALS and in particular, as directly reported to it, of the values which patients place on the extension of tracheostomy free survival time. With these considerations in mind, the Committee considered that the net increase in cost for the NHS of the use of riluzole in this indication was reasonable when set against the benefit, assessed as extended months of an acceptable (to patients) quality of life.
4.10 The documentation and opinion available to the Appraisals Committee is set out in Appendix B.