1 Appraisal Committee's preliminary recommendations

1.1 Fingolimod is not recommended for the treatment of highly active relapsing–remitting multiple sclerosis.

2 The technology

2.1 Fingolimod (Gilenya, Novartis Pharmaceuticals UK) is a sphingosine-1-phosphate receptor modulator that prevents lymphocytes from crossing the blood–brain barrier and causing damage to nerve cells in the brain and spinal cord. Fingolimod has a marketing authorisation as a single disease-modifying therapy in highly active relapsing–remitting multiple sclerosis for the following groups:

• Adults with high disease activity despite treatment with a beta interferon. These patients may be defined as ‘those who have failed to respond to a full and adequate course (normally at least one year of treatment) of beta-interferon. Patients should have had at least one relapse in the previous year while on therapy, and have at least nine T2-hyperintense lesions in cranial magneticresonance imaging (MRI) or at least one gadolinium-enhancing lesion. A “non-responder” could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year’.
• Adults with rapidly evolving severe relapsing–remitting multiple sclerosis defined by two or more disabling relapses in 1 year, and with one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

2.2 The most common adverse reactions to treatment with fingolimod include influenza virus infections, headaches, diarrhoea and elevated liver enzyme activity. The summary of product characteristics (SPC) states that ‘macular oedema with or without visual symptoms has been reported in 0.4% of patients treated with fingolimod 0.5 mg, occurring predominantly in the first 3–4 months of therapy. An ophthalmological evaluation is therefore recommended at 3–4 months after treatment initiation’. For full details of side effects and contraindications, see the SPC.

2.3 Fingolimod is given as a 0.5 mg oral dose once daily. The SPC states that ‘patients can switch directly from beta interferon or glatiramer acetate to fingolimod provided there are no signs of relevant treatment-related abnormalities’. The cost of fingolimod is £1470 for 28 capsules (excluding VAT; MIMS July 2011), which is equivalent to an annual cost of approximately £19,169 per person. The manufacturer of fingolimod has agreed a patient access scheme with the Department of Health, in which a discount on the list price of fingolimod is offered. The size of the discount is commercial-in-confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of fingolimod and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer presented three populations in its submission:

• population 1a, consisting of people with highly active relapsing–remitting multiple sclerosis with at least one relapse in the previous year while on treatment with beta interferon and at least nine T2-hyperintense lesions on a brain MRI or at least one gadolinium-enhancing lesion
• population 1b, consisting of people with highly active relapsing–remitting multiple sclerosis whose relapse rates have remained unchanged or have increased compared with the previous year despite treatment with beta interferon
• population 2, consisting of people with rapidly evolving severe relapsing–remitting multiple sclerosis defined by two or more disabling relapses in 1 year, and with one or more gadolinium-enhancing lesions on a brain MRI or a significant increase in T2 lesion load compared with a previous recent MRI.

The manufacturer’s original submission focused on population 1b, but demographic data were also provided for populations 1a and 2. The manufacturer’s base-case analysis considered the effect of fingolimod in population 1b relative to beta interferon-1a (Avonex). The outcomes defining effectiveness included the number of confirmed relapses during a 12-month period (annualised relapse rate), confirmed disability progression at 3 months, mortality, adverse reactions to treatment and health-related quality of life. 

3.2 The manufacturer undertook a systematic literature review and identified two randomised controlled trials, the FREEDOMS trial and the TRANSFORMS trial, which assessed the efficacy and safety of fingolimod in adults with relapsing–remitting multiple sclerosis. The FREEDOMS trial was a phase III, multicentre, double-blind trial in which 1272 adults with relapsing–remitting multiple sclerosis were randomised to receive daily doses of oral fingolimod 0.5 mg (425 patients), oral fingolimod 1.25 mg (429 patients) or placebo (418 patients) for 24 months. In the FREEDOMS trial, 90 patients treated with fingolimod 0.5 mg and 79 patients treated with placebo were considered by the manufacturer to meet the criteria for population 1b. The TRANSFORMS trial was a phase III, multicentre, double-blind trial in which 1292 adults with relapsing–remitting multiple sclerosis were randomised to receive oral fingolimod 0.5 mg (431 patients) or oral fingolimod 1.25 mg (426 patients) once a day, or intramuscular Avonex 30 micrograms (435 patients) once a week for 12 months. In the TRANSFORMS trial, 191 patients who were treated with fingolimod 0.5 mg and 183 patients who received Avonex met the criteria for population 1b in the decision problem. Only data relating to fingolimod 0.5 mg are presented in the remaining sections of this document.

3.3 Patients were eligible for inclusion in the FREEDOMS and TRANSFORMS trials if they had an Expanded Disability Status Scale (EDSS) score between 0 and 5.5 (the EDSS ranges from 0 to 10 with 0.5-unit increments representing higher levels of disability), and at least one documented relapse during the previous year or at least two documented relapses during the 2 years preceding study enrolment. The primary outcome of the trials was annualised relapse rate. Secondary outcomes included disability progression confirmed after 3 months, time to first relapse and radiological outcomes, such as the number of new or enlarged lesions. In the FREEDOMS study, patient-reported outcomes were assessed using the EuroQoL 5-dimension survey (EQ-5D). Quality-of-life data were collected in the TRANSFORMS trial using the Patient-Reported Indices for Multiple Sclerosis – Quality of life (PRIMUS–QoL), the Patient-Reported Indices for Multiple Sclerosis – Activities (PRIMUS–Activities) and the Unidimensional Fatigue Impact Scale (UFIS).

3.4 Results from the FREEDOMS and TRANSFORMS trials showed that the annualised relapse rates were statistically significantly reduced for all patients treated with fingolimod compared with placebo (0.18 compared with 0.40; p < 0.001) and those treated with fingolimod compared with Avonex (0.16 compared with 0.33; p < 0.001). The European Public Assessment Report stated that the results in the sub-populations with highly active disease were consistent with those obtained in the overall trial population. Treatment with fingolimod reduced the annualised relapse rates (primary outcome) for patients in population 1b in the manufacturer’s submission (see section 3.1), compared with placebo (0.21 compared with 0.54; p < 0.001) and for those who received fingolimod compared with Avonex (0.25 compared with 0.51; p < 0.001). In the TRANSFORMS trial, 94.1% of all patients treated with fingolimod had no disability progression after 3 months (95% confidence interval [CI] 91.8 to 96.3) compared with 92.1% of all patients treated with Avonex (95% CI 89.4 to 94.7); however, this difference was not statistically significant (p = 0.25). Among the whole population of the FREEDOMS trial, 82.3% of patients treated with fingolimod had no disability progression after 3 months compared with 75.9% of all patients treated with placebo (p = 0.03). No statistically significant difference in disability progression between the treatment groups was reported for population 1b.

3.5 Fingolimod was well tolerated by patients in the clinical trials. It was considered to have a comparable safety profile to placebo and to be associated with fewer adverse reactions than Avonex. The incidence of serious adverse reactions after treatment with fingolimod was low across both studies, with the most common being infections, macular oedema and transient atrioventricular block at treatment initiation. In the TRANSFORMS trial, adverse reactions leading to treatment discontinuation in population 1b were reported in 3.1% of patients treated with fingolimod compared with 1.6% of patients treated with Avonex. In the FREEDOMS trial, the rate of treatment discontinuation because of adverse reactions in population 1b was lower in patients receiving fingolimod (2.2%) compared with placebo (7.6%). There were no treatment-related deaths reported with fingolimod or Avonex treatment in the TRANSFORMS trial. In the FREEDOMS trial, no treatment-related deaths were reported among patients receiving fingolimod or placebo.

3.6 In the TRANSFORMS trial, patients who received fingolimod showed significantly less deterioration in their ability to perform daily activities according to the PRIMUS–Activities scale compared with patients receiving Avonex (change from baseline 0.08 in patients treated with fingolimod compared with 0.43 in patients treated with Avonex; p < 0.05). In addition, a slight, non-significant improvement in health-related quality of life, as measured on the PRIMUS–QoL scale, was observed in patients treated with either fingolimod or Avonex. After 6 months of treatment with fingolimod, patients showed a statistically significant improvement in UFIS score compared with patients treated with Avonex; however, at 12 months this difference between the groups was no longer statistically significant. In the FREEDOMS trial, no statistically significant changes from baseline for EQ-5D measures were observed in patients with relapsing–remitting multiple sclerosis treated with fingolimod or placebo.

3.7 To estimate the relative effectiveness of all of the comparators in the absence of direct evidence, the manufacturer conducted a mixed treatment comparison of 18 trials that assessed annualised relapse rates, disability progression and treatment discontinuation because of adverse reactions, for the following interventions: fingolimod, natalizumab, beta interferon-1a (Avonex, Rebif-22 and Rebif-44), beta interferon-1b (Betaferon), glatiramer acetate and placebo. The manufacturer acknowledged that although the populations in the included trials had a clinical diagnosis of relapsing–remitting multiple sclerosis, they did not meet the criteria for highly active disease described in the marketing authorisation for fingolimod. There was also considerable clinical heterogeneity between the trials with respect to permitted and actual prior use of disease-modifying treatments, treatment duration and the criteria used to define the trial endpoints. As a consequence of the heterogeneity across the trial populations and the differences between these populations and the populations described in the marketing authorisation for fingolimod, the manufacturer did not use the results of the mixed treatment comparison to inform the economic model. Instead, an indirect comparison using the TRANSFORMS and FREEDOMS trials provided an estimate of the relative efficacy of Avonex and placebo for population 1b in the model. 

3.8 The manufacturer undertook a systematic search but did not identify any economic evaluations of fingolimod for the treatment of relapsing–remitting multiple sclerosis. The manufacturer submitted a de novo economic model that is structurally similar to models used in previous NICE technology appraisal guidance on treatments for multiple sclerosis (‘Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis’ [NICE technology appraisal guidance 127] and ‘Beta interferon and glatiramer acetate for the treatment of multiple sclerosis’ [NICE technology appraisal guidance 32]). The model is based on a Markov cohort approach and estimates disease progression through 21 disability states that are defined by EDSS score (ranging from 0 to 10) and account for disability for patients with relapsing–remitting multiple sclerosis (10 states), patients with secondary progressive multiple sclerosis (10 states) and death. In each cycle of the model, a patient with relapsing–remitting multiple sclerosis can progress to a worse EDSS state or remain in the same state. Patients can also convert from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis; however once a patient reaches this point in the disease course they cannot convert back to relapsing–remitting disease. Only people with relapsing–remitting multiple sclerosis and an EDSS score of 6 or less are assumed to receive disease-modifying treatment in the model. People with an EDSS score greater than 6, or with secondary progressive multiple sclerosis, are assumed to receive best supportive care.

3.9 Disability progression rates in the model were defined in a natural history transition matrix and derived from a longitudinal data set from patients with multiple sclerosis in Ontario, Canada. The manufacturer excluded patients with less progressive forms of relapsing–remitting multiple sclerosis from the data set and adjusted the natural history transition matrices to represent patients for whom treatment with disease-modifying therapies would be suitable. The probability of relapse in each model cycle was determined using published sources to estimate the natural history of relapses by disease type and EDSS stage.  

3.10 All patients were individually followed through the model from treatment initiation for a maximum of 50 years. Probabilities for all-cause mortality for the general population were derived using current statistics for England and Wales, and were then adjusted for patients with multiple sclerosis using mortality ratios from published sources. A published equation was also used to predict the excess mortality for individual EDSS states.

3.11 The probabilities of annual relapse rate and disability progression for fingolimod treatment were calculated from the absolute incidences of these outcomes in the FREEDOMS trial. The corresponding placebo relative risk value for Avonex was calculated indirectly from the TRANSFORMS trial. The relative risks associated with disease progression and relapse were constant over the entire on-treatment period. Discontinuations because of adverse reactions were included in the model throughout the on-treatment period based on trial data. The relative risks for disease progression were not applied to patients with secondary progressive multiple sclerosis (who receive best supportive care in the model); instead, patients entering this disease state followed the natural history of the disease (as predicted by data from Ontario, Canada).

3.12 Although quality-of-life data were collected in the TRANSFORMS and FREEDOMS trials, the manufacturer did not use these to estimate utilities for the model. Instead, published EDSS-based EQ-5D scores were used, in line with those from NICE technology appraisal guidance 127 and 32. Health-related quality of life was assumed to remain constant over time for each EDSS score, but an adjustment was made to reflect the time since diagnosis and to account for relapses. Utility decrements attributable to adverse events were applied for the whole duration of the treatment period. The model also incorporated caregiver’s disutility for each EDSS score in the base case, in line with estimates from NICE technology appraisal guidance 127. The maximum disutility for a caregiver of a person with multiple sclerosis was assumed to be 0.14 (EDSS 9).

3.13 The resource costs included in the model were drug acquisition costs, administration and monitoring costs, and the cost of the disease, which included the cost of each EDSS state, the cost of relapse and the costs associated with serious adverse reactions. Costs associated with non-serious adverse reactions were not considered in the model. The model assumes that when patients discontinue treatment with disease-modifying therapy and receive best supportive care, the only costs incurred are the disease costs by EDSS states.

3.14 The base-case incremental cost-effectiveness ratio (ICER) for fingolimod compared with Avonex was £55,634 per QALY gained (incremental costs £50,084; incremental QALYs 0.90) for population 1b. Cost-effectiveness analyses for population 1a and population 2 (defined in section 3.1) were not provided by the manufacturer. One-way sensitivity analyses suggested that the ICER for fingolimod compared with Avonex was most sensitive to the relative risks of disease progression assumed for fingolimod and Avonex, and the relative risk of relapse for Avonex. Uncertainty in all other parameter values led to only small changes in the ICER. Results of a probabilistic sensitivity analysis showed that there was a 12% probability that the base-case ICER was less than £20,000 per QALY gained, and a 26% probability that it was less than £30,000 per QALY gained.

3.15 The manufacturer explored uncertainty in the model caused by structural assumptions, including possible waning of treatment effect and the assumed time horizon. When treatment efficacy was assumed to be reduced by 50% or 75% after the first 2 years of treatment, the ICER increased to £73,191 and £85,266 per QALY gained respectively. When the time horizon was shortened to 10 years and 20 years, the ICER increased to £97,159 and £64,280 per QALY gained respectively.

3.16 The manufacturer acknowledged that there was considerable overlap between the populations defined in the marketing authorisation for fingolimod, and provided an analysis for a subgroup of population 1b that excluded patients who also met the criteria for population 2 (that is, it excluded those with rapidly evolving severe multiple sclerosis). The relative treatment effects estimated from the trials for this subgroup were significantly different from those estimated for the whole of population 1b. In particular, the risk of disease progression with Avonex was estimated (by indirect comparison) to be higher than with placebo. The manufacturer’s ICER for fingolimod compared with Avonex in this subgroup was £18,741 per QALY gained (incremental costs £38,420; incremental QALYs 2.05). No sensitivity analyses were conducted for this subgroup.

3.17 In its response to the appraisal consultation document, the manufacturer included a patient access scheme which was agreed with the Department of Health, to apply a simple confidential discount to the list price of fingolimod. The manufacturer’s base-case ICER for fingolimod in population 1b reduced to £10,839 per QALY gained (incremental costs £9758; incremental QALYs 0.90) compared with Avonex when the discounted price of fingolimod was included in the model. The probabilistic ICER determined by the manufacturer including the patient access scheme was £15,825 per QALY gained. Probabilistic analyses suggested that there was a 58% chance that the ICER for fingolimod would be less than £30,000 per QALY gained when the discounted price was included.

3.18 Sensitivity analyses provided by the manufacturer in response to the appraisal consultation document suggested that the ICER for fingolimod compared with Rebif-44 was £27,774 per QALY gained (patient access scheme included). The manufacturer noted that the data to inform this analysis were from patients with relapsing–remitting multiple sclerosis, rather than from those who had a suboptimal response to disease-modifying therapy (that is population 1b), and therefore the true ICER for population 1b was likely to be lower. The manufacturer also compared fingolimod with Rebif-22 and Betaferon using adjusted data from the mixed treatment comparison. Efficacy rates for each treatment were scaled down by 13.25% to account for the fact that the clinical effects seen in the trials for people with relapsing–remitting multiple sclerosis were likely to be reduced in population 1b. The ICERs from this analysis for fingolimod were £23,587 per QALY gained compared with Rebif-22, and £27,660 per QALY gained compared with Betaferon (patient access scheme included).

3.19 The ERG considered that the TRANSFORMS and FREEDOMS trials were well designed to assess the efficacy of fingolimod in patients with relapsing–remitting multiple sclerosis. The ERG noted that the populations in the clinical trials were broader than those defined in the marketing authorisation for fingolimod, but considered that the manufacturer’s post-hoc subgroup analyses provided a reasonable approximation to the populations in the marketing authorisation. The ERG noted that population 1b comprised only 43.6% of patients in the TRANSFORMS trial and 19.7% of patients in the FREEDOMS trial. The ERG was concerned that because of the smaller number of patients, the power of the trials to assess fingolimod relative to the comparators in the populations covered by the marketing authorisation was reduced. However, the ERG noted that the SPC for fingolimod states that ‘further analyses of clinical trial data demonstrate consistent treatment effects in the highly active subgroups of relapsing remitting multiple sclerosis’. The ERG was also concerned that there was considerable overlap between the populations and requested separate analyses from the manufacturer for population 1a, population 2, and populations 1a and 1b with patients who also met the criteria for population 2 excluded. The manufacturer provided analyses only for population 1b with patients who also met the criteria for population 2 excluded.

3.20 The ERG was concerned by the manufacturer’s approach of using only Avonex as the comparator treatment for population 1b. The ERG noted that population 1b constitutes patients with highly active disease that has remained unchanged or worsened despite treatment with beta interferon. In the ERG’s view, a comparison with Avonex may represent continued use of a treatment that is suboptimal in this group of patients, and may also cause adverse reactions. The ERG also noted that the results from the manufacturer’s mixed treatment comparisons did not yield clear differences between the beta interferons in patients with relapsing–remitting multiple sclerosis in terms of disease progression and annualised relapse rates. It cautioned that a comparison solely with Avonex could underestimate the ICER of fingolimod and therefore reasoned that a comparison with best supportive care would have been more appropriate.

3.21 The ERG considered the additional cost-effectiveness analysis from the manufacturer for the subgroup consisting of population 1b without those who also met the criteria for population 2. The ERG noted that the ICER for fingolimod compared with Avonex was more favourable for this subgroup than for the whole of population 1b. The ERG considered that this difference was largely attributable to the revised relative efficacy estimates for Avonex from the manufacturer’s indirect comparison for this subgroup. This suggested that Avonex provides less benefit than placebo (that is, that Avonex was associated with an increased risk of disease progression compared with placebo).

3.22 The ERG was concerned about the resources and costs assumed in the manufacturer’s original model. The ERG was unclear why the costs associated with only some severe adverse reactions were included in the model, and why the costs associated with non-serious adverse reactions were not included. The ERG was also unclear whether costs associated with relapsing–remitting multiple sclerosis were different from those associated with secondary progressive multiple sclerosis. In addition, the ERG noted that the cost of relapse used in the model was significantly different from the cost from other data sources and in NICE technology appraisal guidance 127. In the ERG’s view, the manufacturer had not adequately justified the administrative and monitoring costs for fingolimod and Avonex. In particular, it was unclear why the manufacturer assumed that patients treated with Avonex would need two more neurology visits in the first year of treatment than patients who received fingolimod. The ERG noted that in response to consultation on the appraisal consultation document the manufacturer provided additional justification for the resource use and cost assumptions included in the model, and showed that alternative assumptions only slightly increased the ICER.

3.23  The ERG noted that although the manufacturer had included a probabilistic model in its original submission, the cost-effectiveness results presented in the original submission were deterministic. The ERG provided a probabilistic analysis for the manufacturer’s base case that gave an ICER of £69,787 per QALY gained for fingolimod compared with Avonex. This ICER was noted to be substantively higher than the manufacturer’s deterministic estimate of £55,634 per QALY gained.

3.24 The ERG noted that the manufacturer had presented adjusted hazard ratios in its original submission to describe the relative effect on disease progression of treatment with fingolimod compared with Avonex. However, these estimates were not employed in the model, and instead relative risks from unadjusted trial data were used. The ERG analysed the manufacturer’s base case (population 1b) using hazard ratios instead of relative risks and noted that the probabilistic ICER for fingolimod compared with best supportive care was £94,094 per QALY gained. In addition, Avonex was extendedly dominated by fingolimod and best supportive care (that is, Avonex was more expensive and less effective than either fingolimod or best supportive care). For population 1b, excluding those who also met the criteria for population 2, the ICER for fingolimod compared with best supportive care was £81,369 per QALY gained and Avonex was dominated by best supportive care (Avonex was less effective and more expensive). The ERG considered that this analysis provided further evidence that best supportive care rather than Avonex should have been considered as the primary comparator to fingolimod for population 1b. The ERG acknowledged that the manufacturer provided an additional analysis in response to the appraisal consultation document. In this analysis, hazard ratio values were applied as relative risks in the model, and this reduced the deterministic base-case ICER to £52,906 per QALY gained for population 1b. In the ERG’s view the manufacturer’s additional analyses did not address its initial concerns, because the hazard ratio values used should have been applied as hazard ratios, rather than relative risks, in the probabilistic (not the deterministic) model.

3.25 The ERG was concerned that the manufacturer provided insufficient justification in the original submission for choosing published EDSS-based EQ-5D scores rather than the trial outcomes to derive utility data. The ERG cautioned that although the published utility data had been used in previous NICE technology appraisal guidance on treatments for multiple sclerosis, these data had been criticised for coming from trials with low response rates, selection bias and unrepresentative populations. The ERG suggested that because the manufacturer’s base case targeted a very specific patient population (population 1b), it would have been more appropriate to use utility data for these patients, which were available directly from the FREEDOMS and TRANSFORMS trials. The ERG conducted an exploratory analysis to assess the impact of using the average utilities for each EDSS score in the trial (up to EDSS 6) and then using published sources to impute the missing utility data for EDSS scores of 7 and above. In this analysis, the probabilistic ICER for fingolimod compared with best supportive care in population 1b increased to £106,824 per QALY gained when the missing utility estimates for EDSS scores 7 to 10 were imputed using values from NICE technology appraisal guidance 127. Based on these results, the ERG cautioned that changing the utility values of only three EDSS scores has a significant impact on the ICER for fingolimod. The ERG acknowledged that in response to the appraisal consultation document the manufacturer provided an additional analysis in which utility data from the trials were used for EDSS states up to 6, and then data from a study by Orme et al. 2007 were used for the remaining 13 states. Using data from the FREEDOMS and TRANSFORMS trials reduced the manufacturer’s deterministic base-case ICER to £52,982 per QALY gained and £52,866 per QALY gained respectively. In its critique of the manufacturer’s original submission, the ERG had previously explored a number of alternative scenarios for incorporating trial utility data into the model, which were shown to increase the ICERs. The ERG cautioned that the model predictions are highly sensitive to the utility estimates and therefore it is important to fully justify the data sources and imputation methods used.

3.26 The ERG was concerned about the representativeness of the initial EDSS score distribution used in the original model. The ERG examined a number of scenarios and showed that the cost effectiveness of fingolimod varies depending on the initial distribution of patients across EDSS states. The ICER for fingolimod compared with best supportive care in population 1b was £78,338 per QALY gained when it was assumed that at all people enter the model with an EDSS score of 4, and £102,718 per QALY gained when all people enter the model with an EDSS score of 2. The ERG considered that its analyses highlighted that the model was highly sensitive to the initial population EDSS distribution assumed.

3.27 The ERG noted from market share data provided by the manufacturer that Rebif-44 is commonly prescribed in the NHS for the treatment of multiple sclerosis. The ERG conducted two exploratory analyses that included Rebif-44 as an additional comparator. The first analysis used direct evidence on the effectiveness of Rebif-44 and Avonex, and the second used the results from the mixed treatment comparison provided by the manufacturer. Deterministic results were calculated using relative risks from the direct evidence and showed that Rebif-44 dominated Avonex in population 1b and in the subgroup of population 1b that excluded patients who also met the criteria for population 2. However, for population 1b, Rebif-44 was dominated by best supportive care and extendedly dominated by fingolimod (that is, Rebif-44 was more expensive and less effective than either best supportive care or fingolimod). The ICER for fingolimod compared with best supportive care was £91,059 per QALY gained for population 1b, and £79,315 per QALY gained for population 1b without those who also met the criteria for population 2. When data from the manufacturer’s mixed treatment comparison were used instead, Avonex was dominated by Rebiff-44 for both populations. The ICER for fingolimod compared with best supportive care was £119,213 per QALY gained for population 1b and £119,746 per QALY gained for population 1b without those who also met the criteria for population 2.

3.28 The ERG noted that the baseline relapse rates in the manufacturer’s model were dependent on EDSS state but were then adjusted by the relative risk of relapse with a particular disease-modifying therapy compared with best supportive care. The ERG was concerned that these estimates for relative effect were taken from different data sets and therefore had no implicit correlation. In addition, the ERG cautioned that the impact of disease-modifying therapy could be double-counted in the model. To explore this, the ERG re-ran the original model and excluded all adjustments to direct treatment effects on relapse rates. For population 1b, the ICER for fingolimod compared with best supportive care increased to £112,294 per QALY gained compared with the ERG’s base-case estimate of £94,094 per QALY gained. Avonex was extendedly dominated by best supportive care and fingolimod. For population 1b without those who also met the criteria for population 2, the ICER for fingolimod compared with best supportive care was £98,019 per QALY gained compared with £81,369 per QALY gained in the ERG’s base case, and Avonex was dominated by best supportive care.

3.29 The ERG was concerned that the underlying progression rates predicted in the model were higher than the rates seen in the TRANSFORMS and FREEDOMS trials, but the manufacturer did not explain the differences between the model predictions and the trial observations. The ERG conducted four scenario analyses to examine the sensitivity of the manufacturer’s model to natural history progression rates. These included reducing natural history progression transitions by 50%, 25% and 10%, and increasing them by 10%. Reducing the natural history progression rates substantially increased the ICER for fingolimod compared with best supportive care. Assuming a 50% decrease in natural history progression rate increased the ICER to £252,147 per QALY gained for population 1b, and to £191,027 per QALY gained for population 1b without those who also met the criteria for population 2. The ERG considered that the model predictions were highly sensitive to the natural history progression data used in the model.

3.30 The ERG noted that the manufacturer’s base-case model assumed a constant and continued treatment effect in patients who receive disease-modifying therapy, as long as they remain on treatment, over the time horizon of the model. In the ERG’s view this assumption, which was informed by trials of only 12 months’ and 24 months’ duration, was optimistic. The ERG conducted an exploratory analysis (expanding on the manufacturer’s sensitivity analysis) to evaluate the possible waning of treatment effect over time. Treatment efficacy was modelled to wane by 50%, 75% or 100% of the original level after 2 years and 5 years. In all scenarios, the more the efficacy was reduced, the higher the ICER. This is because the costs of treatment are still incurred but less health benefit is obtained. When the treatment effect was assumed to wane after 2 years, the ICERs for fingolimod compared with best supportive care were £140,282 per QALY gained (50% efficacy reduction), £177,674 per QALY gained (75% efficacy reduction) and £249,735 per QALY gained (100% efficacy reduction). When it was assumed that the treatment effect does not wane until after 5 years, the ICERs for fingolimod compared with best supportive care were £114,532 per QALY gained for a 50% efficacy reduction, £131,135 per QALY gained for a 75% efficacy reduction and £143,869 per QALY gained for a 100% efficacy reduction.

3.31 The ERG reviewed the revised model provided by the manufacturer in response to the appraisal consultation document. It noted that the manufacturer only adjusted the drug acquisition cost in the model in line with the patient access scheme. The ERG noted that the manufacturer had not updated the model to reflect the assumptions that the Committee had considered to be most plausible during the first Committee meeting. The ERG ran the manufacturer’s updated model including the patient access scheme and produced a probabilistic base-case ICER for fingolimod compared with Avonex of £14,997 per QALY gained. The ERG also produced an incremental analysis using the manufacturer’s updated model which showed that the probabilistic ICER for fingolimod was £58,024 per QALY gained compared with best supportive care, and Avonex was extendedly dominated by fingolimod and best supportive care with an ICER of £176,357 per QALY gained. The ERG cautioned that despite the discounted drug acquisition cost, the remaining uncertainty in the model still remained.

3.32 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of fingolimod, having considered evidence on the nature of highly active relapsing–remitting multiple sclerosis and the value placed on the benefits of fingolimod by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee understood from the patient experts that multiple sclerosis is a chronic, disabling, neurological condition that has a substantial negative impact on quality of life and activities of daily living. The patient experts placed particular emphasis on loss of independence and implications for employment. They also described a significant impact on emotional wellbeing, which can lead to depression. The Committee understood that any delay or relief from these problems would have a positive impact on the lives of people with multiple sclerosis and their families. The Committee also heard from the patient experts that fingolimod would allow greater flexibility and decrease discomfort because it is given orally whereas other currently available treatments are administered by injection.

4.3 The Committee heard from the clinical specialists that treatment of relapsing–remitting multiple sclerosis is determined by the severity of the disease. This, in turn, is determined by the number and severity of relapses and by disability caused by the persistent effects of relapse or by the development of secondary progressive multiple sclerosis. For people with rapidly evolving severe relapsing–remitting multiple sclerosis (whose condition is described in section 3.1), natalizumab is often considered as a first-line treatment in line with NICE technology appraisal guidance 127. For people without rapidly evolving severe disease, a beta interferon or glatiramer acetate is routinely offered. The Committee heard from the clinical specialists that after a suboptimal response to the first disease-modifying treatment used, clinicians are likely to either offer a different beta interferon or glatiramer acetate, or offer the patient a higher dose of beta interferon (such as Rebif-44). The Committee also heard that clinicians are generally reluctant to stop treatment altogether after a suboptimal response. The Committee noted that beta interferons and glatiramer acetate were not recommended in NICE technology appraisal guidance 32. However, it acknowledged that after this guidance was issued, the Department of Health agreed a risk-sharing scheme with manufacturers through which disease-modifying treatments for multiple sclerosis can be provided to patients in the NHS, albeit at a level of cost effectiveness above what is considered an appropriate use of NHS resources as defined in the NICE ‘Guide to the methods of technology appraisal’.

4.4 The Committee considered the likely place of fingolimod in the treatment of relapsing–remitting multiple sclerosis. The Committee understood that although clinical practice varies among neurologists, many clinical specialists would consider fingolimod as a second or subsequent line of treatment for people with high disease activity despite treatment with beta interferon or glatiramer acetate. It heard from the clinical specialists that fingolimod would provide the greatest benefit to people with rapidly evolving severe relapsing–remitting multiple sclerosis, because they currently have very few treatment options. The Committee acknowledged the clinical specialists’ disappointment that a specific recommendation for the use of fingolimod in this population could not be made because the manufacturer did not include an analysis of fingolimod compared with natalizumab in this population.  

4.5 The Committee understood from the clinical specialists and patient experts that fingolimod is generally well tolerated and that the adverse reactions expected during treatment could be managed in routine clinical practice. One patient expert noted that she had received fingolimod without experiencing treatment-related adverse reactions.  

Clinical effectiveness

4.6 The Committee noted that only part of the population covered by the marketing authorisation for fingolimod was considered in the manufacturer’s submission, that is, people with highly active relapsing–remitting multiple sclerosis whose relapse rates have remained unchanged or have increased compared with the previous year despite treatment with beta interferon (population 1b). The Committee noted that the manufacturer’s reason for this was that this population represented the largest subgroup in the clinical trials of fingolimod. The Committee concluded that it could only make a recommendation on the use of fingolimod for the population presented in the manufacturer’s submission (that is population 1b). The Committee also noted that the manufacturer compared fingolimod with only one formulation of beta interferon (Avonex) in its base-case analysis, and that it included no other comparators from the decision problem. The Committee heard from the manufacturer that Avonex and Rebif are the most commonly prescribed forms of beta interferon in the NHS. The Committee acknowledged the concerns of the ERG that a beta interferon should not be the only comparator in an analysis for a patient group who have had a suboptimal response to prior beta interferon therapy, and that best supportive care should also be considered. The Committee concluded that limiting the analyses to comparisons with Avonex only was not appropriate, and instead comparisons with other beta interferons and best supportive care need to be included as a basis for any recommendations in this appraisal.

4.7 The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of fingolimod. It noted that the manufacturer derived data from two clinical trials that assessed the efficacy and safety of fingolimod compared with placebo over 24 months (FREEDOMS trial), and with beta interferon-1a (Avonex) over 12 months (TRANSFORMS trial) in adults with relapsing–remitting multiple sclerosis. The Committee noted that the populations in the FREEDOMS and TRANSFORMS trials were broader than those in the marketing authorisation for fingolimod and therefore after the trials finished the manufacturer had to identify subgroups that approximated the populations in the marketing authorisation. The Committee heard from the ERG that the subgroups identified by the manufacturer were reasonable approximations to the populations in the marketing authorisation but that the subgroups were not mutually exclusive. The Committee noted that in response to clarification the manufacturer provided revised analyses for people in population 1b who did not have rapidly evolving severe relapsing–remitting multiple sclerosis (that is population 1b, with people who also met the criteria for population 2 excluded). However, separate analyses were not provided for populations 1a or 2. The Committee was aware that NICE technology appraisal 127 recommends natalizumab as a treatment option for people with rapidly evolving severe relapsing–remitting multiple sclerosis (population 2 in the manufacturer’s submission), and therefore natalizumab would be a comparator for this group. The Committee also considered the manufacturer’s mixed treatment comparison, which assessed treatment effects between comparators in the absence of direct evidence. It heard from the manufacturer and the ERG that there was considerable heterogeneity between the studies and that none of the studies in the analysis included populations that closely and consistently match those described in the marketing authorisation for fingolimod. It also heard that the TRANSFORMS and FREEDOMS trials were not powered to assess the efficacy of fingolimod in the subgroups defined by the marketing authorisation. The Committee concluded that the available evidence shows that people with relapsing–remitting multiple sclerosis who are treated with fingolimod have lower relapse rates than people treated with Avonex or placebo. The Committee also agreed that fingolimod was shown to reduce disability progression in people with relapsing–remitting multiple sclerosis compared with placebo in the FREEDOMS trial; however, there was no significant impact on disability progression compared with Avonex in the TRANSFORMS trial. The Committee heard from the manufacturer that the European Medicines Agency had judged that the clinical trial data demonstrated consistent treatment effects with fingolimod in all of the subgroups with highly active disease covered by the marketing authorisation. The Committee concluded that the available evidence shows that fingolimod improves outcomes for the whole population in the clinical trials, and in those with highly active disease defined by the marketing authorisation.

4.8 The Committee discussed the health-related quality-of-life data from the FREEDOMS and TRANSFORMS trials. It noted that there were no statistically significant changes from baseline for EQ-5D measures observed for people with relapsing–remitting multiple sclerosis treated with fingolimod or placebo in the FREEDOMS trial, and that only a slight non-significant improvement in health-related quality of life according to the PRIMUS-QoL scale was observed for people treated with fingolimod or Avonex in the TRANSFORMS trial. The Committee heard from the clinical specialists that a patient’s quality of life may not be affected by treatment because multiple sclerosis is a chronic disease and its symptoms are often residual. The Committee concluded that it was therefore clinically plausible to see non-significant changes in health-related quality-of-life measures in the FREEDOMS and TRANSFORMS trials, but the impact of fingolimod on health-related quality of life remained uncertain.

Cost effectiveness

4.9 The Committee discussed the cost-effectiveness estimates from the manufacturer’s original economic model, the assumptions on which these were based, and the ERG’s critique and exploratory analyses. The Committee noted that the manufacturer provided a probabilistic Markov model that was structurally similar to other models used in previous NICE technology appraisal guidance on treatments for multiple sclerosis. Based on the manufacturer’s sensitivity analyses, the Committee concluded that the manufacturer’s deterministic base-case ICER for fingolimod compared with Avonex of £55,600 per QALY gained for population 1b was subject to considerable uncertainty. The Committee considered that a probabilistic ICER would have been more appropriate for the base-case analysis and noted that the ERG’s exploratory analysis to determine the probabilistic results for the manufacturer’s base case produced an ICER of £69,800 per QALY gained for fingolimod compared with Avonex.

4.10 The Committee noted the concerns of the clinical specialists that the model may not reflect the natural history of multiple sclerosis because it does not allow for improvement in EDSS scores. The Committee heard from the manufacturer that the ability to include improvements in EDSS scores had been intentionally removed from the model to produce a conservative estimate. The Committee heard from the clinical specialists that few people experience an improvement in EDSS score and therefore it concluded that the manufacturer’s approach was reasonable.  

4.11 The Committee considered the concerns of the ERG that the manufacturer’s original model had not been validated against the trial data or against other published studies, and that the methods used to derive some of the model parameters had not, in the ERG’s opinion, been adequately described in the manufacturer’s submission. The Committee heard from the ERG that the manufacturer had determined the effect of treatment on disease progression by using relative risks from unadjusted trial data, rather than from adjusted hazard ratios. When hazard ratios were used, Avonex was dominated by fingolimod in population 1b. The Committee agreed that this result further demonstrated the considerable uncertainty present in the assessment and further compounding issues surrounding the choice of comparator for the population of interest.  

4.12 The Committee noted that the manufacturer did not use utility data from the FREEDOMS or TRANSFORMS trials in the original model because the study populations included only people with an EDSS score up to 6, and therefore utility data for higher EDSS scores were not available. The Committee heard from the ERG that the manufacturer used EDSS-based EQ-5D scores from a published source instead, despite this study being criticised in technology appraisal guidance 127 for having low response rates, not representing the appropriate population and being prone to selection bias. The Committee agreed that because the manufacturer’s base case targeted a very specific group (population 1b), it would have been more appropriate to use utility data for that group, from the trials, where possible and to use data from other sources only for EDSS scores above 6. The Committee considered additional analyses from the manufacturer in response to the appraisal consultation document, which indicated that the base-case ICER for population 1b slightly decreased when utility data from the FREEDOMS and TRANSFORMS trials were used for EDSS states up to 6 and published data from Orme et al. (2007) were only used for EDSS scores above 6. The Committee concluded that the manufacturer’s revised approach to incorporating utility estimates in the model was reasonable.

4.13 The Committee considered exploratory analyses conducted by the ERG on the manufacturer’s original model, which compared fingolimod with best supportive care and Rebif-44. The Committee noted that these analyses were based on indirect comparisons of limited data and that in population 1b Avonex was dominated by Rebif-44. The Committee noted comments in response to the appraisal consultation document from the manufacturer which suggested that the data to inform the analysis of fingolimod compared with Rebif-44 were from patients with relapsing–remitting multiple sclerosis, rather than from those who had a suboptimal response to disease-modifying therapy (that is population 1b), and therefore the true ICER for population 1b may be lower. The Committee agreed that the choice of comparator was a key driver of cost effectiveness, and therefore it concluded that it was more appropriate to include best supportive care and Rebif-44 as comparators, and that this would substantively impact the ICERs for fingolimod in population 1b (see section 3.27).

4.14 The Committee was concerned about the assumption in the manufacturer’s model that the treatment effect observed for the duration of the trials (1 or 2 years) was maintained at the same level during the on-treatment periods. It noted that sensitivity analyses carried out by the manufacturer and the ERG showed that a reduction in the assumed duration of treatment effect increased the ICERs substantively (see sections 3.15 and 3.30). The Committee concluded that in the absence of long-term data, it would be prudent to assume some waning of treatment effect over time in the base-case analysis to inform the decision-making.  

4.15 The Committee heard from the manufacturer that disability progression rates in the model were derived from a longitudinal data set from a population with multiple sclerosis in Ontario, Canada. This data source was chosen because it has been considered previously in other NICE technology appraisal guidance on treatments for multiple sclerosis; however it was now considered old. The Committee heard from the clinical specialists that this may have given more rapid disability progression rates than those seen in the current UK patient population. However, the Committee noted that there are currently no alternative data sources available. The Committee noted that the manufacturer did not explain the divergence between model predictions and the trial observations for disease progression in its submission. It also considered the ERG’s exploratory analyses, which showed that the model predictions were highly sensitive to the natural history progression data used. The Committee concluded that the natural history disability progression data were a source of considerable uncertainty in the model, particularly without an adequate exploration of the directional effect of alternative assumptions on disability progression on the results.   

4.16 The Committee noted potential inaccuracies in some of the administration costs included in the manufacturer’s original model. In particular, it heard from the manufacturer that it was assumed that people treated with Avonex had more visits to a neurologist than people treated with fingolimod. The Committee heard from the clinical specialists that this assumption was probably not correct and that it is more plausible that people receiving fingolimod would have three visits during the first year of treatment, compared with two visits for people receiving Avonex. The Committee noted the manufacturer’s revised analyses submitted in response to the appraisal consultation document which corrected this assumption. It was persuaded that revising the costs in the model had a minimal impact on the ICER.

4.17 The Committee acknowledged that although the manufacturer had tried to address some of the concerns raised during the first Committee meeting, the manufacturer and the ERG still had divided opinions on the most appropriate methodological approaches to evaluate the cost effectiveness of fingolimod in population 1b. The Committee considered the manufacturer’s revised deterministic base-case ICER of £10,800 per QALY gained for fingolimod compared with Avonex, which included a confidential patient access scheme. The Committee noted the ERG’s concern that the manufacturer had only adjusted for the cost of fingolimod in the revised model, and had not amended the model to take account of any of the ERG’s or Committee’s previous concerns. The Committee noted that the ERG’s calculation of the probabilistic ICER for fingolimod compared with best supportive care was £58,000 per QALY gained, and that Avonex was extendedly dominated by fingolimod (patient access scheme included). The Committee acknowledged that the ERG’s analyses demonstrated that beta-interferon treatment may not be cost effective, but was mindful of the need to take account of current NHS practice when defining the appropriate comparator(s) for assessment.

4.18 The Committee heard from the ERG that its clinical advisers had estimated that approximately one-third of people with relapsing–remitting multiple sclerosis whose disease has a suboptimal response to beta-interferon treatment will receive best supportive care in the UK. The Committee heard from the clinical specialists at the meeting that this estimate was likely to be correct. The Committee therefore considered that best supportive care should be included as a comparator, together with a mix of beta interferons (with the proportions for the beta interferons determined based on market share data from the Prescriptions Pricing Authority). The Committee estimated that the ICER for fingolimod compared with a comparator made up of equal proportions of best supportive care, Avonex and Rebif-44 using the manufacturer’s revised model, would be approximately £40,000 per QALY gained (patient access scheme included). The Committee concluded this to be a starting point for its decision, and noted that using a probabilistic analysis (see section 4.9) and the following, more plausible assumptions, would increase  this ICER:

• Using utility data from the trials where available, and then published data from Orme et al. (2007) for the remaining EDSS states (see section 4.12). 
• More plausible assumptions regarding the long-term effectiveness of treatment (that is, when a 50% waning of treatment effect at 5 years is considered) (see section 4.14).
• An exploration of the directional effect on the ICER of using alternative assumptions on natural history disability progression (see section 4.15).  

4.19 The Committee noted that the most plausible ICER for fingolimod (that is, at least £40,000 per QALY gained) was higher than is normally considered an effective use of NHS resources and that the NICE ‘Guide to the methods of technology appraisal’ states that a strong case should be identified for an ICER that is higher than £30,000 per QALY gained. The Committee noted that in these circumstances the NICE ‘Guide to methods of technology appraisal’ states that judgements about the acceptability of the technology as an effective use of NHS resources will specifically take account of:

• any strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured
• whether the innovative nature of the technology may not have been adequately captured in the QALY measure.

4.20 The Committee discussed whether the assessment of the change in health-related quality of life had been inadequately captured in the economic analysis. It heard from the patient experts that people who receive fingolimod have fewer adverse reactions than those who receive beta-interferon therapy. In addition, treatment with fingolimod significantly reduces relapses and could allow people to lead an active and fulfilling life and contribute more fully to society. The Committee accepted that fingolimod is a valuable new therapy and that its mechanism of action and oral formulation were novel. The Committee recognised that including these factors in the manufacturer’s model could decrease the ICER, but the magnitude of this decrease was uncertain. The Committee was therefore not persuaded that these factors would decrease the most plausible ICER (higher than £40,000 per QALY gained, see section 4.19) to a level that could be considered a cost-effective use of NHS resources. Therefore, the Committee could not recommend fingolimod for the treatment of relapsing–remitting multiple sclerosis.

4.21 The Committee discussed whether it had received evidence of any groups of people for whom fingolimod could be considered a cost-effective use of NHS resources. It noted that an analysis of population 1b that excluded people who also met the criteria for population 2 (that is, a population in which people with rapidly evolving severe disease were excluded) had been provided by the manufacturer in response to a request for clarification. It noted that this analysis generated substantially lower ICERs than those for the whole of population 1b. The Committee was aware of reservations expressed by the manufacturer and the ERG about the small samples on which the subgroup analysis was based. The Committee agreed that the same concerns regarding the limitations of the manufacturer’s model and the impact these may have on the ICERs in the base case (population 1b) also applied to this subgroup. Therefore, the Committee could not recommend fingolimod as a treatment for the subgroup of population 1b that excluded people with rapidly evolving severe disease.

Summary of Appraisal Committee's key conclusions

TAXXX	Appraisal title: Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis		Section
Key conclusion
Fingolimod is not recommended for the treatment of highly active relapsing–remitting multiple sclerosis. The Committee accepted that fingolimod is a valuable new therapy and that its mechanism of action and oral formulation were novel. The Committee recognised that including these factors in the manufacturer’s model could decrease the ICER, but the magnitude of this decrease was uncertain. The Committee was therefore not persuaded that these factors would decrease the most plausible ICER (which is at least £40,000 per QALY gained) to a level that could be considered a cost-effective use of NHS resources.			1.1, 4.20
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee understood from the patient experts that multiple sclerosis is a chronic, disabling, neurological condition that has a substantial negative impact on quality of life and activities of daily living. The Committee understood that any delay or relief from these problems would have a positive impact on the lives of people with multiple sclerosis and their families.	4.2
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee heard from the patient experts that fingolimod would allow greater flexibility and decrease discomfort because it is given orally whereas other currently available treatments are administered by injection. The Committee accepted that fingolimod is a valuable new therapy and that its mechanism of action and oral formulation were novel.	4.2 4.20
What is the position of the treatment in the pathway of care for the condition?		The Committee understood that although clinical practice varies between neurologists, many clinical specialists would consider fingolimod as a second or subsequent line of treatment for people with high disease activity despite treatment with beta interferon or glatiramer acetate. The Committee heard from the clinical specialists that fingolimod would provide the greatest benefit to people with rapidly evolving severe relapsing–remitting multiple sclerosis, because they currently have very few treatment options. The Committee acknowledged the clinical specialists’ disappointment that a specific recommendation on the use of fingolimod in this population could not be made because the manufacturer’s submission did not include an analysis of fingolimod compared with natalizumab in this population.	4.4
Adverse reactions		The Committee understood from the clinical specialists and patient experts that fingolimod is generally well tolerated and that the adverse reactions expected during treatment could be managed in routine clinical practice.	4.5
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee noted that only part of the population in the marketing authorisation for fingolimod was considered in the manufacturer’s submission (population 1b). The Committee also noted that the manufacturer compared fingolimod with only one formulation of beta interferon (Avonex) in its base-case analysis, and that it included no other comparators from the decision problem. The Committee concluded that limiting the analyses to comparisons with Avonex only was not appropriate. The manufacturer derived data from two clinical trials that assessed the efficacy and safety of fingolimod compared with placebo over 24 months (FREEDOMS trial), and with beta interferon-1a over 12 months (TRANSFORMS trial) in adults with relapsing–remitting multiple sclerosis. In response to clarification the manufacturer provided revised analyses for people in population 1b who did not have rapidly evolving severe relapsing–remitting multiple sclerosis (that is population 1b, with people who also met the criteria for population 2 excluded). However, separate analyses were not provided for populations 1a or 2. The manufacturer also conducted a mixed treatment comparison, which assessed treatment effects between comparators in the absence of direct evidence.	4.6 4.7 4.7
Relevance to general clinical practice in the NHS		The populations in the clinical trials were broader than those in the marketing authorisation for fingolimod. The manufacturer identified subgroups after the trials had finished that approximated the populations in the marketing authorisation. The ERG noted that the populations were not mutually exclusive. The Committee heard from the manufacturer that the European Medicines Agency had judged that the clinical trial data demonstrated consistent treatment effects with fingolimod in all of the subgroups with highly active disease covered by the marketing authorisation. The Committee concluded that the available evidence shows that fingolimod improves outcomes for the whole population in the clinical trials, and in those with highly active disease defined by the marketing authorisation.	4.7
Uncertainties generated by the evidence		The Committee concluded that limiting the analyses to comparisons with Avonex only was not appropriate in this appraisal, and instead comparisons with other beta interferons and best supportive care need to be included. The Committee concluded that it was clinically plausible to see non-significant changes in health-related quality-of-life measures in the FREEDOMS and TRANSFORMS trials, but the impact of fingolimod on health-related quality of life remained uncertain.	4.6, 4.7 4.8
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		See section under cost effectiveness	-
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee considered that the available evidence shows that people who are treated with fingolimod have lower relapse rates compared with Avonex or placebo. The Committee also agreed that fingolimod was shown to reduce disability progression in comparison with placebo in the FREEDOMS trial; however, no significant impact on disability progression was shown in comparison with Avonex in the TRANSFORMS trial. There were no statistically significant changes from baseline for EQ-5D measures observed for people with relapsing–remitting multiple sclerosis treated with fingolimod or placebo in the FREEDOMS trial. Only a slight non-significant improvement in health-related quality of life according to the PRIMUS-QoL scale was observed for people treated with fingolimod or Avonex in the TRANSFORMS trial.	4.7, 4.8
Evidence for cost effectiveness
Availability and nature of evidence		The manufacturer provided a Markov model that was structurally similar to other models used in previous NICE technology appraisal guidance on treatments for multiple sclerosis.	4.9
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee noted the concerns of the clinical specialists that the model may not reflect the natural history of multiple sclerosis, because it did not allow for improvement in EDSS scores. The Committee concluded that the manufacturer’s approach was reasonable because few people experience an improvement in EDSS score in clinical practice.   In the ERG’s opinion, the manufacturer’s model had not been validated against the trial data or against other published studies, and the methods used to derive some of the model parameters had not been adequately described in the manufacturer’s submission. The Committee considered exploratory analyses from the ERG, which compared fingolimod with best supportive care and Rebif-44. The Committee agreed that the choice of comparator was a key driver of cost effectiveness, and therefore it concluded that it was more appropriate to include best supportive care and Rebif-44 as comparators, and that this would substantively impact the ICERs for fingolimod in population 1b.    The Committee was concerned about the assumption in the manufacturer’s model that the treatment effect observed for the duration of the trials (1 or 2 years) was maintained at the same level during the on-treatment periods. The Committee concluded that in the absence of long-term data, it would be prudent to assume some waning of treatment effect over time.   The Committee was concerned that the manufacturer had used an old data set to estimate disability progression rates in the model. It heard from the clinical specialists that this may have given more rapid disability progression rates than those seen in the current UK patient population. The Committee concluded that the natural history progression data were a source of considerable uncertainty in the model. The Committee noted potential inaccuracies in some of the administration costs included in the manufacturer’s original model. The Committee considered the manufacturer’s revised analyses submitted in response to the appraisal consultation document, which corrected these inaccuracies, and was persuaded that revising the costs in the model had a minimal impact on the ICER.	4.10 4.11 4.13 4.14 4.15 4.16
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The Committee noted that the manufacturer did not use utility data from the FREEDOMS or TRANSFORMS trials in the original model. Additional analyses from the manufacturer in response to the appraisal consultation document indicated the base-case ICER for population 1b slightly decreased when utility data from the FREEDOMS and TRANSFORMS trials were used for EDSS states up to 6 (and data from published sources were used for EDSS scores above 6). The Committee concluded that the manufacturer’s revised approach to incorporating utility estimates in the model was reasonable. The Committee accepted that fingolimod is a valuable new therapy and that its mechanism of action and oral formulation were novel. The Committee recognised that including these factors in the manufacturer’s model could decrease the ICER, but the magnitude of this decrease was uncertain.	4.12 4.20
Are there specific groups of people for whom the technology is particularly cost effective?		An analysis of population 1b that excluded people who also met the criteria for population 2 (that is, a population in which people with rapidly evolving severe disease were excluded) was provided by the manufacturer in response to a request for clarification. The Committee noted that this analysis generated substantially lower ICERs than those for the whole of population 1b. The Committee was aware of reservations expressed by the manufacturer and the ERG about the small samples on which the subgroup analysis was based. The Committee agreed that the same concerns regarding the limitations of the manufacturer’s model and the impact these may have on the ICERs in the base case (population 1b) also applied to this subgroup.	4.21
What are the key drivers of cost effectiveness?		One-way sensitivity analyses conducted by the manufacturer suggested that the ICER for fingolimod compared with Avonex was most sensitive to the relative risks of disease progression assumed for fingolimod and Avonex, and the relative risk of relapse for Avonex. The Committee noted that using a probabilistic analysis and the following, more plausible assumptions, would increase  this ICER: ·         Using utility data from the trials where available, and then published data from Orme et al. (2007) for the remaining EDSS states.   ·         More plausible assumptions regarding the long-term effectiveness of treatment (that is, when a 50% waning of treatment effect at 5 years is considered). ·         An exploration of the directional effect on the ICER of using alternative assumptions on natural history disability progression.	3.14 4.18
Most likely cost-effectiveness estimate (given as an ICER)		The Committee estimated that the ICER for fingolimod compared with a comparator made up of equal proportions of best supportive care, Avonex and Rebif-44, using the manufacturer’s revised model, would be approximately £40,000 per QALY gained (patient access scheme included). The Committee concluded this to be a starting point for its decision, and noted that this ICER was likely to increase once probabilistic results were calculated and more plausible assumptions were applied.	4.18
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer agreed a patient access scheme with the Department of Health in which a simple confidential discount was applied to the list price of fingolimod.	3.17
End-of-life considerations		Not applicable.	-
Equalities considerations and social value judgements		No equality issues were raised during the scoping exercise or during the course of the appraisal.	-

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Proposed recommendations for further research

6.1 The Committee recommends the development of patient registries for multiple sclerosis to capture long-term treatment-related outcomes.

7 Related NICE guidance

Published

• Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis. NICE technology appraisal guidance 127 (2007). Available from www.nice.org.uk/guidance/TA127
• Beta interferon and glatiramer acetate for the treatment of multiple sclerosis. NICE technology appraisal guidance 32 (2002). Available from www.nice.org.uk/guidance/TA32
• Multiple sclerosis: management of multiple sclerosis in primary and secondary care. NICE clinical guideline 8 (2003). Available from www.nice.org.uk/guidance/CG8

8 Proposed date for review of guidance

8.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in January 2015. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Ken Stein
Vice Chair, Appraisal Committee
October 2011

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month except in December, when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

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.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Amanda Adler (Chair)
Consultant Physician, Addenbrooke's Hospital, Cambridge

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Dr Michael Boscoe
Consultant Cardiothoracic Anaesthetist, Royal Brompton and Harefield NHS Foundation Trust

Professor John Cairns
Professor of Health Economics Public Health and Policy, London School of Hygiene and Tropical Medicine

Mr Mark Chapman
Health Economics and Market Access Manager, Medtronic UK

Professor Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Mrs Eleanor Grey
Lay member

Mr Sanjay Gupta
YPD Service Case Manager, Southwark Health and Social Care, Southwark Primary Care Trust

Mr Terence Lewis
Lay member

Dr Peter Norrie
Principal Lecturer in Nursing, DeMontfort University, Leicester

Dr Sanjeev Patel
Consultant Physician and Senior Lecturer in Rheumatology, St Helier University Hospital, Carshalton

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Casey Quinn
Lecturer in Health Economics, Division of Primary Care, University of Nottingham

Mr Alun Roebuck
Consultant Nurse in Critical and Acute Care, United Lincolnshire NHS Trust

Dr Florian Alexander Ruths
Consultant Psychiatrist and Cognitive Therapist at the Maudsley Hospital, London

Mr Navin Sewak
Primary Care Pharmacist, NHS Hammersmith and Fulham

Mr Roderick Smith
Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling
Lay member

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

B NICE project team

Each technology appraisal is assigned to a team which may consist of one or more health technology analysts, a technical adviser and a project manager. The technical analyst or technical adviser may act as the technical lead for the appraisal.

Fiona Rinaldi
Technical Lead

Jeremy Powell
Project Manager

 Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by the Centre for Review and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Assessment Group:

• Asaria M, Norman G, Hinde S et al. Fingolimod for the treatment of relapsing–remitting multiple sclerosis, Centre for Reviews and Dissemination/Centre for Health Economics, University of York, June 2011.

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Novartis Pharmaceuticals UK

II Professional/specialist and patient/carer groups:

• Association of British Neurologists
• Multiple Sclerosis Trust
• Multiple Sclerosis Society
• Royal College of Nursing
• Royal College of Physicians

III Other consultees:

• Department of Health
• NHS North Yorkshire and York
• NHS South Staffordshire
• Welsh Government

IV  Commentator organisations (did not provide written evidence and without the right of appeal):

• Bayer
• Biogen Idec
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland
• Medicines and Healthcare products Regulatory Agency
• Merk Serono
• Sanofi
• Teva UK

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on fingolimod by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Victoria Matthews, Multiple Sclerosis Specialist Nurse, MS Trust, nominated by the Royal College of Nursing – clinical specialist
• Professor Carolyn Young, Consultant Neurologist and Honorary Professor of Neurology, Walton Centre for Neurology and Neurosurgery, nominated by the Association of British Neurologists and the Royal College of Physicians – clinical specialist
• Elizabeth Kinder, nominated by the Multiple Sclerosis Society – patient expert
• Laura Weir, Head of Policy and Campaigns, Multiple Sclerosis Society, nominated by the Multiple Sclerosis Society – patient expert

Victoria Matthews, Carolyn Young and Laura Weir also attended the second Committee discussion.

D Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Novartis Pharmaceuticals UK