1 Appraisal Committee's preliminary recommendations

1.1 The Committee is minded not to recommend dimethyl fumarate within its marketing authorisation, that is, for treating adults with relapsing–remitting multiple sclerosis.

1.2 The Committee recommends that NICE requests further clarification and analyses from the manufacturer, which should be made available for the second Appraisal Committee meeting, and should include the following:

• Presentation of the results from the DEFINE and CONFIRM trials adjusted for baseline relapse rate only, for the following outcomes:
  
  - proportion of patients with relapse at 2 years
  
  - annualised relapse rate
  
  - sustained disability progression confirmed for 3 months at 2 years
  
  - sustained disability progression confirmed for 6 months at 2 years.
• Revised probabilistic analyses incorporating a scenario that includes:
  
  - revised mixed treatment comparison results adjusted for the baseline relapse rate
  
  - revised estimates for monitoring resource use and costs as preferred by the Evidence Review Group (ERG) in its exploratory analyses
  
  - a reduced cost of relapse estimate (£607.80) as preferred by the ERG in its exploratory analyses
  - non-health costs are excluded (if non-health costs related to personal social services can be identified, these can be included), with a sensitivity analysis that includes all non-health costs, and
  - pairwise comparisons and incremental analyses for the probabilistic cost-effectiveness estimates.
• Pairwise comparisons for the probabilistic cost-effectiveness estimates for several plausible treatment sequences reflecting UK clinical practice. For example:
  - 
  dimethyl fumarate, beta interferon, fingolimod compared with beta interferon, glatiramer acetate, fingolimod
  
  - dimethyl fumarate, beta interferon, glatiramer acetate compared with beta interferon, glatiramer acetate, fingolimod.
• Pairwise comparisons for the probabilistic cost-effectiveness estimates for the current active treatments (all beta interferons and glatiramer acetate) compared with no disease-modifying therapy to externally validate the manufacturer’s economic model by showing how similar these cost effectiveness estimates are to those in the NHS risk-sharing scheme for multiple sclerosis.

2 The technology

2.1 Dimethyl fumarate (Tecfidera, Biogen Idec) derives from fumaric acid, promotes anti-inflammatory activity and can inhibit expression of pro-inflammatory cytokines and adhesion molecules. Dimethyl fumarate has a UK marketing authorisation for ‘the treatment of adult patients with relapsing–remitting multiple sclerosis’.

2.2 The summary of product characteristics lists the following adverse reactions for dimethyl fumarate: 'gastroenteritis, lymphopenia, leucopenia, hypersensitivity, burning sensation, flushing, hot flush, diarrhoea, nausea, abdominal pain upper, abdominal pain, vomiting, dyspepsia, gastritis, gastrointestinal disorder, pruritus, rash, erythema, proteinuria, feeling hot, ketones measured in urine, albumin urine present, aspartate aminotransferase increased, alanine aminotransferase increased and white blood cell count decreased'. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3 Dimethyl fumarate is taken orally. The recommended dosage is 120 mg twice daily in the first week of treatment and 240 mg twice daily thereafter, and treatment continues as long as patients benefit clinically, or until they experience unacceptable adverse reactions. The frequency of flushing and gastrointestinal adverse reactions may be managed by temporarily (up to a month) reducing the dosage to 120 mg twice daily. The prices of a pack of 120‑mg tablets (14 tablets per pack) and 240‑mg tablets (56 tablets per pack) are £343 and £1373 respectively (excluding VAT; manufacturer’s submission). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of dimethyl fumarate has agreed a patient access scheme with the Department of Health, with a simple discount applied at the point of purchase or invoice. The level of 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 (section 8) considered evidence submitted by the manufacturer of dimethyl fumarate and a review of this submission by the Evidence Review Group (ERG; section 9).

Clinical effectiveness

3.1 The manufacturer conducted a systematic review of the literature to identify studies evaluating the clinical effectiveness and safety of dimethyl fumarate for treating adults with relapsing–remitting multiple sclerosis. It identified 2 phase III randomised controlled trials (RCTs): DEFINE and CONFIRM.

3.2 The DEFINE trial was an international multicentre (198 centres in 28 countries) double-blind phase III RCT in 1237 adults with relapsing–remitting multiple sclerosis. Patients were stratified by geographical region and randomised in a 1:1:1 ratio to dimethyl fumarate 240 mg twice daily (n=410), dimethyl fumarate 240 mg three times daily (n=416) or placebo (n=408). The CONFIRM trial was an international multicentre (200 centres in 28 countries) double-blind phase III RCT in 1430 adults with relapsing–remitting multiple sclerosis. Patients were stratified by geographical region and randomised in a 1:1:1:1 ratio to dimethyl fumarate 240 mg twice daily (n=359), dimethyl fumarate 240 mg three times daily (n=345), glatiramer acetate 20 mg once daily (n=350; open-label) or placebo (n=363). In both the DEFINE and CONFIRM trials, patients were treated for 96 weeks and had a follow-up visit at 100 weeks if they completed treatment. Patients stopped treatment if they did not tolerate the study drug or withdrew consent. For dimethyl fumarate, only data relating to the licensed dosage (240 mg twice daily) were presented in the manufacturer’s submission.

3.3 Patients were eligible for inclusion in the DEFINE and CONFIRM trials if they were aged between 18 and 55 years, had a diagnosis of relapsing–remitting multiple sclerosis confirmed by the McDonald criteria, had an Expanded Disability Status Scale (EDSS) score of between 0 and 5 inclusive (the EDSS ranges from 0 to 10 in 0.5‑unit increments, higher scores representing higher levels of disability) and had either had at least 1 relapse during the previous year and a previous MRI scan showing lesions consistent with multiple sclerosis, or had gadolinium-enhancing lesions on MRI scans done within 6 weeks of randomisation. The manufacturer noted there were no significant differences in baseline characteristics between the treatment groups of the DEFINE and CONFIRM trials. Most patients were white (79% in DEFINE, 84% in CONFIRM) and female (74% in DEFINE, 70% in CONFIRM). The mean age of patients was 38.5 years and 37.3 years in the DEFINE and CONFIRM trials respectively. In the DEFINE trial, 29 patients were treated at 7 UK centres. The CONFIRM trial did not include any UK centres.

3.4 The primary outcome measures in the trials were the proportion of patients with a relapse at 2 years (DEFINE) and the annualised relapse rate at 2 years (CONFIRM). Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting 24 hours or longer, and with new objective neurological findings. An intention-to-treat population was the primary population for the analysis of efficacy outcomes in both trials adjusted for age, EDSS score, number of relapses in the year before randomisation and geographical region using proportional hazards regression in the DEFINE trial, and negative binomial regression in the CONFIRM trial. In the DEFINE trial, the proportion of patients with a relapse at 2 years was 27% with dimethyl fumarate and 46% with placebo (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.40 to 0.66). In the CONFIRM trial, the annualised relapse rate at 2 years was 0.22 with dimethyl fumarate and 0.40 with placebo (relative risk [RR] 0.56, 95% CI 0.42 to 0.74), and 0.29 with glatiramer acetate (RR compared with dimethyl fumarate not reported). The CONFIRM trial was not powered to detect differences between dimethyl fumarate and glatiramer acetate (active comparator). The manufacturer performed a number of sensitivity analyses that supported the results of the primary efficacy analysis of the DEFINE and CONFIRM trials comparing dimethyl fumarate with placebo.

3.5 Secondary outcomes reported annualised relapse rate at 2 years (DEFINE), the proportion of patients with a relapse at 2 years (CONFIRM), and in both trials, progression of disability on the EDSS and MRI lesion number (in a subset of patients) at 2 years. In the DEFINE trial, the annualised relapse rate at 2 years was 0.17 with dimethyl fumarate and 0.36 with placebo (RR 0.47, 95% CI 0.37 to 0.61). In the CONFIRM trial, the proportion of patients with a relapse at 2 years was 29% with dimethyl fumarate and 41% with placebo (HR 0.66, 95% CI 0.51 to 0.86). Patients taking dimethyl fumarate had a reduced risk of disability progression sustained for 3 months at 2 years compared with those taking placebo in both the DEFINE trial (16% compared with 27%; HR 0.62, 95% CI 0.44 to 0.87) and the CONFIRM trial (13% compared with 17%; HR 0.79, 95% CI 0.52 to 1.19). The manufacturer suggested that the 3‑month disability progression results in the CONFIRM trial may have been affected by the fact that the proportion of patients censored (whose disability may or may not have progressed) was higher in the placebo arm than in the dimethyl fumarate arm. It explained that patients were censored if they withdrew from the study or switched treatments before 3‑month progression could be confirmed. An analysis of disability progression sustained for 6 months at 2 years comparing dimethyl fumarate with placebo in DEFINE (HR 0.77, 95% CI 0.52 to 1.14) and CONFIRM (HR 0.62, 95% CI 0.37 to 1.03) was presented in the European Public Assessment Report. The number of lesions was significantly reduced on T1- and T2‑weighted and gadolinium-enhancing MRI at 2 years with dimethyl fumarate compared with placebo in the DEFINE and CONFIRM trials.

3.6 The manufacturer presented results for the pre-specified subgroup analyses for the DEFINE and CONFIRM trials in its submission. It stated that the results (treatment effect) of these analyses were generally consistent with the results for the overall population. The DEFINE trial results were similar for treatment-naïve patients (proportion relapsed: HR 0.37, 95% CI 0.24 to 0.57; annualised relapse rate: RR 0.33, 95% CI 0.21 to 0.52; 3‑month disability progression at 2 years: HR 0.38, 95% CI 0.22 to 0.65) and treatment-experienced patients (proportion relapsed: HR 0.65, 95% CI 0.48 to 0.89; annualised relapse rate: RR 0.61, 95% CI 0.45 to 0.84; 3‑month disability progression at 2 years: HR 0.83, 95% CI 0.54 to 1.29), although disability progression was not statistically significantly reduced with dimethyl fumarate compared with placebo for the treatment-experienced subgroup. The manufacturer also noted that the CONFIRM trial results were similar for treatment-naïve patients (proportion relapsed: HR 0.73, 95% CI 0.51 to 1.05; annualised relapse rate: RR 0.64, 95% CI 0.44 to 0.95; 3‑month disability progression at 2 years: HR 0.56, 95% CI 0.30 to 1.03) and treatment-experienced patients (proportion relapsed: HR 0.57, 95% CI 0.38 to 0.84; annualised relapse rate: RR 0.47, 95% CI 0.31 to 0.69; 3‑month disability progression at 2 years: HR 1.07, 95% CI 0.60 to 1.89). No tests of interaction were presented by the manufacturer.

3.7 Both trials measured health-related quality of life using the global well-being Visual Analogue Scale (VAS; which assesses a patient’s global well-being on study treatment on a linear scale, with 0 as ‘poor’ and 100 as ‘excellent’), the Short Form 36 Health Survey (SF‑36) and the EuroQol‑5 dimensions survey (including the EQ‑5D descriptive system and the EQ VAS). In the DEFINE trial, patients randomised to dimethyl fumarate had a significantly better health-related quality of life compared with those randomised to placebo when measured by the mean change in: global well-being VAS from baseline (0.4 compared with −4.0; p=0.003), the physical component score of the SF‑36 from baseline (0.5 compared with −1.4; p=0.000), 6 of 8 SF‑36 subscales from baseline, and EQ VAS from baseline (−0.3 compared with −4.2; p<0.001). In the CONFIRM trial, patients randomised to dimethyl fumarate showed a significantly better health-related quality of life compared with those randomised to placebo when measured by the mean change in: global well-being VAS from baseline (0.3 compared with −3.9; p=0.000), the physical component score of the SF‑36 from baseline (0.5 compared with −0.7; p=0.022), and 3 of 8 SF‑36 subscales from baseline.

3.8 The manufacturer reported that the overall incidence of adverse reactions was similar in patients taking dimethyl fumarate and placebo respectively (96% compared with 95% in DEFINE, and 94% compared with 92% in CONFIRM). The most common adverse reactions reported for dimethyl fumarate compared with placebo were flushing (38% compared with 5% in DEFINE and 31% compared with 4% in CONFIRM), hot flush (8% compared with 2% in DEFINE and 5% compared with 2% in CONFIRM), upper abdominal pain (10% compared with 7% in DEFINE and 10% compared with 5% in CONFIRM), nausea (13% compared with 9% in DEFINE and 11% compared with 8% in CONFIRM) and vomiting (10% compared with 6% in DEFINE and 7% compared with 4% in CONFIRM). The manufacturer noted that most adverse reactions were mild to moderate in severity and that incidences were highest in the first month and decreased thereafter. The percentages of patients stopping treatment because of adverse reactions were 16% of those taking dimethyl fumarate and 13% of those taking placebo in the DEFINE trial, and 12% of those taking dimethyl fumarate and 10% of those taking placebo in the CONFIRM trial. The manufacturer reported that the incidence of serious adverse reactions was low in patients taking dimethyl fumarate and comparable to patients taking placebo (18% compared with 21% in DEFINE and 17% compared with 22% in CONFIRM).

3.9 The manufacturer presented the results of both a fixed-effects and a random-effects meta-analysis of the efficacy and safety outcomes of the DEFINE and CONFIRM trials. It estimated that dimethyl fumarate was statistically significantly better than placebo for all efficacy outcomes analysed including disability progression sustained for 3 months at 2 years and for 6 months at 2 years. The manufacturer’s meta-analysis also estimated that patients taking dimethyl fumarate experienced statistically significantly more gastrointestinal events, flushing and skin reactions compared with those taking placebo or glatiramer acetate. It estimated no statistically significant differences in the number of withdrawals for any reason between treatments, but that statistically significantly more patients taking dimethyl fumarate withdrew because of adverse reactions compared with those taking placebo or glatiramer acetate.

3.10 To estimate the relative effectiveness of dimethyl fumarate compared with the comparators defined in the scope, the manufacturer conducted a mixed treatment comparison of 27 trials using a fixed-effects frequentist approach that assessed outcomes including annualised relapse rate, proportion of relapsing patients at 24 months, and confirmed disability progression sustained for 3 months at 2 years and for 6 months at 2 years. The following comparators were included in the manufacturer’s mixed treatment comparison: beta interferon‑1a (Avonex, Rebif‑22 and Rebif‑44), beta interferon‑1b (Betaferon), glatiramer acetate, fingolimod, natalizumab and placebo.

3.11 The manufacturer presented results of the mixed treatment comparison unadjusted for covariates. The manufacturer undertook a covariate analysis that showed that the chosen covariates had little or no impact on the outcomes of interest, although the baseline relapse rate was found to be a significant covariate for the annualised relapsed rate outcome. The manufacturer’s unadjusted mixed treatment comparison suggested that dimethyl fumarate statistically significantly reduces annualised relapse rate and the proportion of patients with relapses at 2 years compared with placebo, glatiramer acetate and all beta interferons. The manufacturer’s mixed treatment comparison also suggested dimethyl fumarate statistically significantly reduces disability progression sustained for 3 months at 2 years compared with placebo. No statistically significant differences were estimated between dimethyl fumarate and any comparator, including placebo, for disability progression sustained for 6 months at 2 years. The manufacturer labelled the effect size and credible intervals from its mixed treatment comparison as academic in confidence, and therefore they cannot be presented here. The manufacturer stated that it had not explored the subgroups specified in the scope of the appraisal because they had not been analysed in most of the trials included in its mixed treatment comparison.

Cost effectiveness

3.12 The manufacturer did not identify any published studies of the cost effectiveness of dimethyl fumarate for treating adults with relapsing–remitting multiple sclerosis. It submitted a cohort-based Markov model that reflected the natural history of relapsing–remitting multiple sclerosis with a cycle length of 1 year and assumed a patient can be offered 1 of 8 treatments: dimethyl fumarate, a beta interferon‑1a treatment (Avonex, Rebif‑22 or Rebif‑44), beta interferon‑1b (Betaferon), glatiramer acetate, fingolimod or natalizumab. The manufacturer conducted the economic analysis from an NHS and personal social services perspective and chose a time horizon of 30 years. Costs and health effects were discounted at an annual rate of 3.5% and a half-cycle correction was applied.

3.13 The manufacturer’s model was structurally similar to models used in previous NICE technology appraisal guidance on treatments for multiple sclerosis: Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 254), 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 estimates disease progression through 21 states that are defined by EDSS scores (ranging from 0 to 9.5) and cover disability in 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 move to a higher or lower EDSS state or remain in the same state. Patients can also advance from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, but cannot subsequently move back to relapsing–remitting disease. Only patients with relapsing–remitting multiple sclerosis and an EDSS score of 6 or less are assumed to receive disease-modifying treatment in the model.

3.14 Patient baseline characteristics were pooled from the DEFINE and CONFIRM trials. The probabilities of changing EDSS state or having a relapse (fixed for each EDSS state) were based on natural history data (underlying disease progression) and trial data (disease progression with treatment). The manufacturer estimated the natural history of disability progression using the placebo arms of the DEFINE and CONFIRM trials up to and including an EDSS score of 7, and using a longitudinal dataset of patients with multiple sclerosis in London Ontario, Canada for EDSS scores of more than 7, because of the small number of observations for the more severe EDSS states in the trials. The Ontario longitudinal dataset was also used by the manufacturer to estimate the natural history of: (i) progressing from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis (by EDSS score) and (ii) progressing within the secondary progressive multiple sclerosis states. The pooled baseline trial data gave the natural history of relapses by EDSS score in patients with an EDSS score of up to and including 5. The natural history of relapses by EDSS score in patients with an EDSS score of more than 5 was estimated by the manufacturer using data from Patzold et al. (1982) and the UK Multiple Sclerosis Survey because the sample sizes of patients with an EDSS score of more than 5 from the trials were small.

3.15 To estimate the clinical effectiveness of each treatment compared with placebo on disability progression and annualised relapse rate, the manufacturer used results from its mixed treatment comparison. The manufacturer applied treatment effects only to patients with relapsing–remitting multiple sclerosis because it assumed that patients with secondary progressive multiple sclerosis stop treatment. The economic model did not allow patients to switch treatments, so they remained on their original treatment until progression to EDSS score of 7 or more, because of adverse reactions, or conversion to secondary progressive multiple sclerosis. In the absence of evidence, the manufacturer also chose to assume that the treatment has no effect on disease progression to secondary progressive multiple sclerosis. The manufacturer noted that this assumption was adopted in Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 254). The model assumed that the treatment effect diminishes over time (waning) to 75% after 2 years and to 50% after 5 years. The manufacturer explained that because of a lack of long-term data on the clinical effectiveness of dimethyl fumarate it applied a similar approach to that adopted by the Committee in NICE technology appraisal guidance 254. The manufacturer assumed that patients followed the natural history of disease progression after stopping treatment.

3.16 To estimate the probabilities for all-cause mortality in the multiple sclerosis population, the manufacturer took England and Wales national mortality data and adjusted for patients with multiple sclerosis by age and EDSS score using mortality multipliers from a Danish population diagnosed with multiple sclerosis from 1948 onward reported in Pokorski et al. (1997). Mortality was assumed to be the same in patients with relapsing–remitting multiple sclerosis and secondary progressive multiple sclerosis. The manufacturer presented the results of a scenario analysis that explored setting the rate of mortality in people with relapsing-remitting multiple sclerosis equal to the rate of mortality in the general population of England and Wales.

3.17 Resource use and costs in the economic model depended on a patient’s EDSS score, on whether they had relapsing–remitting multiple sclerosis or secondary progressive multiple sclerosis, and on whether they were in relapse. The unit costs for each of the drugs and their administration were taken from the ‘British National Formulary 64’ and ‘NHS Reference Costs 2011–2012’. The cost of dimethyl fumarate in the model included the patient access scheme. Resource use and costs associated with monitoring patients on treatment were based on the licensed indications presented in the summaries of product characteristics of the drugs. The manufacturer took resource-use data for managing the disease from a regression analysis of data from the UK Multiple Sclerosis Survey that included 115 different healthcare resources. The manufacturer estimated a mean annual cost for each EDSS score in patients with relapsing–remitting multiple sclerosis and patients with secondary progressive multiple sclerosis, and the mean cost per relapse independent of the clinical form of multiple sclerosis (that is, £2028 per relapse in people with relapsing–remitting multiple sclerosis and £2028 per relapse in people with secondary progressive multiple sclerosis).

3.18 To estimate health-related quality of life, the manufacturer used pooled EQ‑5D data (descriptive system) from the DEFINE and CONFIRM trials for the EDSS states for relapsing–remitting multiple sclerosis. The manufacturer estimated the utility values for secondary progressive multiple sclerosis using the differences between utility values for relapsing–remitting multiple sclerosis and secondary progressive multiple sclerosis from the UK Multiple Sclerosis Survey. The manufacturer also subtracted the difference between utility for relapse and no relapse for each EDSS state as reported in the UK Multiple Sclerosis Survey from its EQ‑5D trial data to estimate the utility values for patients with relapse. The manufacturer’s economic model also incorporated carer’s disutility for each EDSS score, in line with estimates from Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 254) and Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 127). The maximum disutility is assumed to be 0.14 for a carer of a person with multiple sclerosis with an EDSS score of 9.

3.19 The economic model included costs and disutility values associated with adverse reactions. The manufacturer only included adverse reactions reported in the trials when the incidence was 5% or higher, or when the absolute incidence in the dimethyl fumarate arm was 3% higher than in the placebo arm. The manufacturer took resource use and costs for each adverse reaction from published sources and validated them by clinical expert opinion. Disutility values were based on clinical expert opinion, published sources when available or the manufacturer’s assumption.

3.20 The manufacturer presented deterministic pairwise incremental cost-effectiveness ratios (ICERs) for dimethyl fumarate with the patient access scheme compared with each of the treatments included in its economic model. The manufacturer updated its economic model during the factual accuracy check of the ERG report to include the prices from the NHS risk-sharing scheme (described in section 4.3) for beta interferons and glatiramer acetate in its base-case analysis; therefore, the results presented in the original manufacturer’s submission have been superseded. Dimethyl fumarate dominated Avonex (that is, dimethyl fumarate gave more QALYs and cost less than Avonex): the manufacturer estimated incremental cost savings of £223 and 0.194 incremental QALYs gained. For dimethyl fumarate compared with Rebif‑22, the manufacturer estimated incremental costs of £6093 and 0.286 incremental QALYs gained with an ICER of £21,341 per QALY gained. For dimethyl fumarate compared with Rebif‑44, the manufacturer estimated incremental costs of £2592 and 0.163 incremental QALYs gained with an ICER of £15,909 per QALY gained. For dimethyl fumarate compared with Betaferon, dimethyl fumarate dominated Betaferon; the manufacturer estimated incremental cost savings of £2834 and 0.386 incremental QALYs gained. For dimethyl fumarate compared with glatiramer acetate, the manufacturer estimated incremental costs of £6516 and 0.331 incremental QALYs gained with an ICER of £19,716 per QALY gained. The patient access scheme price for fingolimod was not included in the manufacturer’s base-case analysis because it is not publicly available and the manufacturer of fingolimod did not provide the patient access scheme to the manufacturer of dimethyl fumarate. Assuming a 35% reduction in the list price of fingolimod, dimethyl fumarate dominated fingolimod: the manufacturer estimated incremental cost savings of £18,347 and 0.264 incremental QALYs gained. For dimethyl fumarate compared with natalizumab, the manufacturer estimated incremental cost savings of £46,256 and an incremental QALY loss of 0.103 leading to savings of £448,729 per QALY lost.

3.21 The manufacturer explored parameter and structural uncertainty in its economic model by presenting the results of univariate sensitivity analyses, 2‑way sensitivity analyses and scenario analyses. The results from the univariate sensitivity analyses suggested the manufacturer’s economic model was most sensitive to changes in the effect of treatment on the disability progression rate (ICERs increased when the effect of dimethyl fumarate was reduced by 20%, or the effect of the comparator was increased by 20%). The manufacturer commented that its scenario analyses indicated that its economic model is robust to most of the structural assumptions. The results from the scenario analyses were most sensitive to changes in the time horizon. In its scenario analyses, the manufacturer varied the price of fingolimod by reducing its list price in 5% increments. It estimated that dimethyl fumarate dominated fingolimod up to a 60% decrease in fingolimods list price.

3.22 The manufacturer also presented results from probabilistic analyses. Dimethyl fumarate dominated Betaferon and fingolimod (with a 35% reduction in the list price of fingolimod). For dimethyl fumarate compared with Rebif‑22, the manufacturer estimated an ICER of £30,898 per QALY gained. For dimethyl fumarate compared with Rebif‑44, the manufacturer estimated an ICER of £23,408 per QALY gained. For dimethyl fumarate compared with Avonex, the manufacturer estimated an ICER of £2573 per QALY gained. For dimethyl fumarate compared with glatiramer acetate, the manufacturer estimated an ICER of £30,331 per QALY gained. For dimethyl fumarate compared with natalizumab, the manufacturer estimated incremental cost savings and an incremental QALY loss leading to savings of £610,134 per QALY lost.

ERG comments on the clinical effectiveness

3.23 The ERG stated that the DEFINE and CONFIRM trials were of good quality and had a low risk of bias. The ERG commented that the trial populations more closely reflect people with relapsing–remitting multiple sclerosis who meet the Association of British Neurologists' (ABN) prescribing criteria for disease-modifying therapy (that is, adults with active relapsing disease defined as 2 or more clinically significant relapses in the previous 2 years) than people with relapsing–remitting multiple sclerosis in general. The ERG explained that:

• Patients in the NHS risk-sharing scheme (patients taking beta interferon or glatiramer acetate who need to meet the ABN prescribing criteria to be eligible for treatment) have a mean of 2.9 relapses in the previous 2 years whereas the ERG’s clinical advisors suggested that the annualised relapse rate in the whole population with relapsing–remitting multiple sclerosis generally is approximately 0.8.
• The baseline annualised relapse rates in the DEFINE and CONFIRM trials were 1.3 and 1.4 respectively (which reflected the inclusion criterion requiring patients to have 1 or more relapse in the year before randomisation).

Therefore, the ERG considered that the effectiveness of dimethyl fumarate for the whole of the prevalent relapsing–remitting multiple sclerosis population was unknown. However, the ERG commented that the trial populations were broadly representative of people with relapsing–remitting multiple sclerosis seen in UK clinical practice for age, sex and disease duration, and did not consider the differences between the trial populations and the UK clinical population to be clinically significant.

3.24 The ERG stated that 3‑month disability progression was used as an outcome measure in Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 254). However, this is not consistent with the European Medicines Agency's draft guideline that advises the use of 6‑month disability progression (because at 3 months the possibility of recovery exists). Because the manufacturer’s data for 6‑month sustained disability progression showed less clear evidence of benefit than the 3‑month sustained disability progression, the ERG concluded that some uncertainty remained regarding the effect of dimethyl fumarate on disability progression.

3.25 The ERG stated that the rates of adverse reactions and serious adverse reactions for patients taking dimethyl fumarate were similar to those for placebo. The ERG noted that higher incidences of flushing and gastrointestinal events were reported for dimethyl fumarate, but these appeared to be confined to the first months of treatment. It was unclear whether this was also the case for skin reactions. The ERG was aware that progressive multifocal leukoencephalopathy had occurred in 3 patients taking Fumaderm (dimethyl fumarate combined with 3 other fumaric acid esters) and 1 patient taking a compounded formulation of dimethyl fumarate and copper monomethyl fumarate. The ERG stated that if progressive multifocal leukoencephalopathy were considered to be an adverse reaction of dimethyl fumarate, guidance regarding when to stop treatment would be needed in clinical practice.

3.26 The ERG stated that the 2‑year duration of trials was short compared with:

• the duration of the disease
• the length of time people with relapsing–remitting multiple sclerosis would be expected to take disease-modifying therapy.

It therefore concluded that there was considerable uncertainty regarding the long-term efficacy and safety of dimethyl fumarate.

3.27 The ERG commented that the manufacturer’s mixed treatment comparison included all relevant trials. It noted that these trials appeared to be at low, or unclear, risk of bias although the manufacturer did not assess allocation concealment. The ERG stated that some networks were sparsely populated because of the number of outcomes analysed and the availability of data from the included trials. It also noted a moderate level of clinical and methodological heterogeneity between the trials included. This included differences in baseline characteristics such as mean EDSS score and the inclusion criteria regarding the number of relapses in the period before randomisation. For example, the mean or median relapse rate in the year before randomisation ranged between 1.0 and 2.4, which the ERG considered to be clinically meaningful. However, the ERG concluded the level of heterogeneity between trials was not sufficient to make the comparisons unreasonable.

3.28 The ERG stated that using a fixed-effects frequentist approach in the manufacturer’s mixed treatment comparison was likely to be appropriate for assessing most of the outcomes because the small number of trials comprising the networks did not allow an estimation of the between-study variance. However, a random-effects model may have been more appropriate for assessing the annualised relapse rate than a fixed-effects model because the network included a sufficient number of trials. The ERG noted that the estimated confidence intervals for the annualised relapse rate outcome may therefore have been slightly underestimated (that is, too narrow).

3.29 The ERG commented that the manufacturer did not address the relative effectiveness of dimethyl fumarate compared with fingolimod or natalizumab in the subgroups specified in the final scope. It acknowledged that the populations included in the trials were broader than those defined in the drugs’ marketing authorisations. However, the ERG concluded that because the manufacturer did not analyse patients with highly active relapsing–remitting multiple sclerosis or rapidly evolving severe relapsing–remitting multiple sclerosis, the relative effectiveness of dimethyl fumarate compared with fingolimod and natalizumab was unknown in these subgroups respectively.

ERG comments on the cost effectiveness

3.30 The ERG noted that the economic model structure adopted by the manufacturer was structurally similar to previous NICE technology appraisals of multiple sclerosis. It stated that including improvement to lower EDSS states reflected the actual experience of patients in the trials of dimethyl fumarate and the experience of people with relapsing–remitting multiple sclerosis generally. Although sustaining disability progression for 6 months may be more closely associated with permanent progression, the ERG noted that the use of 3‑month sustained disability progression outcome data in the manufacturer’s economic model was reasonable because patients' disease could improve to lower EDSS states. The ERG commented that the economic model predictions for the patients across the EDSS states seemed reasonable compared with the distribution of dimethyl fumarate patients across the EDSS states within the time period of the trials.

3.31 The ERG preferred the manufacturer’s ICERs calculated from the probabilistic sensitivity analysis to the deterministic ICERs because the economic model is non-linear. However, the ERG noted that the manufacturer had not assigned probability distributions to a number of parameters including the parameter accounting for treatment waning over time and the annual risk of stopping treatment. The ERG explained that these 2 parameters have a significant effect on the estimated ICERs because disease progression is the key driver of the economic model. The ERG noted that the main driver of the economic model was the hazard ratio of 3‑month disability progression but it did not explore any analyses around this parameter because it felt that the manufacturer’s mixed treatment comparison and probability distributions were adequate. However, the ERG stated that a fixed-effects mixed treatment comparison may underestimate the uncertainty in the treatment effect, and therefore the uncertainty in the cost-effectiveness estimates of dimethyl fumarate may also be underestimated. It concluded that although the probabilistic results were more meaningful and represented a less biased approximation of the ICER compared with deterministic results, the full impact of the uncertainty around the ICER had not been completely accounted for.

3.32 The ERG’s exploratory analyses resulted in base-case deterministic pairwise ICERs within £100 of those presented by the manufacturer during its factual accuracy check of the ERG report, and are therefore not presented here; for further details see the ERG addendum. The ERG also presented base-case incremental results using hazard ratios as the outcome measure for 3‑month disability progression at 2 years which showed  that:

• the deterministic ICER per QALY gained for dimethyl fumarate compared with Rebif‑22 was £21,414
• the probabilistic ICER per QALY gained for dimethyl fumarate compared with Rebif‑22 was £31,244.

The ERG undertook several further exploratory analyses (see sections 3.33 to 3.37). Because running probabilistic analyses in the manufacturer’s economic model was time consuming, the ERG only estimated deterministic pairwise ICERs.

3.33 The ERG considered that the resource-use estimates relating to neurology visits in the manufacturer’s economic model were too high in year 1 for beta interferons, too low in year 1 for natalizumab, and too low after year 1 for dimethyl fumarate and fingolimod. It also chose to explore a scenario assuming that the cost of a neurology visit was equal to the cost of visiting a neurologist specialist (£205) because the manufacturer assumed that the cost of a neurology visit was equal to the cost of a day-case admission (£590). The ERG also used alternative estimates for the inclusion of annual MRI scans for patients taking natalizumab and the inclusion of nurse visits for patients taking injectable treatments. Using these alternative monitoring resource assumptions, the ERG estimated that its base-case ICER increased from £21,414 to between £21,419 and £28,973 for dimethyl fumarate compared with Rebif‑22.

3.34 The ERG explored alternative assumptions around the rates of stopping treatment. Changing the rates of stopping treatment to 50% of the original relative risks of stopping treatment from those estimated in the mixed treatment comparison after 2 years and to 0% after 2 years of treatment increased the ERG’s estimated base-case ICER for dimethyl fumarate compared with Rebif‑22 from £21,414 to £23,278 and £23,292 per QALY gained respectively. The ICER for dimethyl fumarate compared with glatiramer acetate increased above £30,000 per QALY gained when using the lower confidence intervals of the relative risks of stopping treatment. The ERG commented that when patients stop their starting treatment in the manufacturer’s economic model they receive placebo or ‘best supportive care’, and then progress more quickly through the EDSS states. Switching from treatment to no treatment reduces costs to a greater extent than it reduces QALYs; if more patients stop treatment, the treatment becomes more cost effective. The ERG raised the concern that if best supportive care were specified in the scope as one of the comparators, the ICER for dimethyl fumarate compared with an active treatment would never be lower than the ICER for dimethyl fumarate compared with best supportive care. However, the ERG considered that in clinical practice patients who stop treatment because of adverse reactions will take another active treatment if an alternative (with a differing side-effect profile) is available.

3.35 The ERG considered that it was appropriate for the manufacturer to use utility values estimated from the trials of dimethyl fumarate. However, it noted that by using the utility values from the trials as a proxy for ‘people with relapsing–remitting multiple sclerosis without relapse’ in its economic model, the manufacturer may have underestimated the health-related quality of life of these patients because some of the patients included in the trials will have been in relapse. The ERG explored this uncertainty by incorporating into its exploratory analyses utility values from 2 other sources based on the UK Multiple Sclerosis Survey. These sources were the utility values reported in Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 127), which reported slightly higher utility values than the DEFINE and CONFIRM trials, and the utility values estimated from a multivariate linear regression analysis of the UK Multiple Sclerosis Survey in Orme et al. (2007). However, the ERG noted that only 35.5% of the UK Multiple Sclerosis Survey population had relapsing–remitting multiple sclerosis. It was also concerned about the utility values in all sources because the differences between secondary progressive multiple sclerosis and relapsing–remitting multiple sclerosis, and between relapse and no relapse were based on a population that did not entirely reflect the scope of the appraisal. For dimethyl fumarate compared with Rebif‑22, the ERG estimated that its base-case ICER changed from £21,414 to between £18,700 and £22,144 per QALY gained when using the utility values from Orme et al. (2007) and NICE technology appraisal guidance 127 respectively.

3.36 The ERG considered that using different EDSS state costs for people with relapsing–remitting multiple sclerosis and people with secondary progressive multiple sclerosis is appropriate. It was aware of 3 sources reporting costs by EDSS state that used the resource-use data from the UK Multiple Sclerosis Survey (including the source used in the manufacturer’s economic model). However, despite using the same resource-use data, the 3 sources estimated different costs. The ERG explained that the variation between estimates may be because each source used different unit costs and only 1 of the sources separated medical and non-medical costs. It stated it was unclear which of the 3 sources was the most appropriate but these differing estimates of EDSS state costs did not have a significant impact on the ICERs. For dimethyl fumarate compared with Rebif‑22, the ERG estimated that its base-case ICER changed from £21,414 to between £17,239 and £21,377 per QALY gained. The ERG judged the cost per relapse in the manufacturer’s economic model of £2028 to be too high after receiving advice from clinicians that only 20% of relapses need hospitalisation. When the ERG varied the cost per relapse to between £3039 and £280 the ICER changed from £21,414 to £18,660 and £26,074 per QALY gained respectively, for dimethyl fumarate compared with Rebif‑22.

3.37 Although the manufacturer did not include the relative risks of adverse reactions from its mixed treatment comparison in its economic model, the ERG stated that the manufacturer’s approach to estimating the incidence of adverse reactions was reasonable. Using the relative risk of adverse reactions from the manufacturer’s mixed treatment comparison, or assuming no adverse reactions, the ERG estimated that its base-case ICER changed from £21,414 to £26,683 or to £24,869 per QALY gained respectively, for dimethyl fumarate compared with Rebif‑22. The ERG also explored revised disutility values for influenza and flu-like symptoms because the manufacturer’s estimate seemed unreasonably high. Updating these disutility values had very little impact on the incremental cost-effectiveness results.

3.38 Full details of all the evidence are in the manufacturer’s submission and the ERG report.

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dimethyl fumarate, having considered evidence on the nature of relapsing–remitting multiple sclerosis and the value placed on the benefits of dimethyl fumarate 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 heard from the clinical specialists and patient experts about the nature of the condition. It heard that relapsing–remitting multiple sclerosis is a chronic, disabling, neurological condition that as it progresses often has a substantial negative impact on quality of life and activities of daily living. The patient experts emphasised that as the disease progresses patients can lose independence and the capacity for employment. The Committee heard from the patient experts that only 25% of patients with multiple sclerosis are in employment compared with 75% of the general population who are of working age, and that 80% of people who have had multiple sclerosis for 15 years or more are not working. The patient experts emphasised the importance of having access to new treatments that could reduce the number of relapses and delay disability. The Committee noted that the current first-line treatments for relapsing–remitting multiple sclerosis need to be injected and can be associated with unpleasant side effects (such as injection-site reactions or flu-like symptoms, fatigue and depression) and can significantly affect patients’ emotional well-being. The Committee heard from the patient experts that because dimethyl fumarate is taken orally, it would allow more flexibility and decrease discomfort compared with injectable treatments. The Committee heard further from the patient experts that people with relapsing–remitting multiple sclerosis may need to take corticosteroids, which in some instances are administered intravenously over several days, and considered that the anti-inflammatory effect of dimethyl fumarate could reduce the need for corticosteroids. The Committee understood that any delay in relapse and progression of disability, or relief from using injectable treatments and corticosteroids, would have a positive impact on the lives of people with multiple sclerosis and their families.

4.3 The Committee discussed the management of relapsing–remitting multiple sclerosis and considered the likely position of dimethyl fumarate in the treatment pathway for adults with this condition. The Committee heard from the clinical specialists that in general, as recommended in the Association for British Neurologists' guidelines, most patients who have had 2 relapses in the previous 2 years would be offered a disease-modifying therapy (one of the beta interferons [Avonex, Rebif, Betaferon or Extavia] or glatiramer acetate) and enrolled in the risk-sharing scheme that has been agreed between the Department of Health and the manufacturers. The Committee understood that the risk-sharing scheme was established by the Department of Health in 2002 after NICE judged beta interferons and glatiramer acetate not to be cost effective (Beta interferon and glatiramer acetate for the treatment of multiple sclerosis [NICE technology appraisal guidance 32]), and that the financial risk is shared between the NHS and the participating pharmaceutical companies. The Committee heard from the clinical specialists that the treatments prescribed in clinical practice in the UK vary because there is no single treatment pathway. The clinical specialists explained that clinicians and patients together choose a disease-modifying therapy taking into account lifestyle, the route and schedule of administration, the side-effect profile, and how the drug is stored. The clinical specialists explained that as it was a personal choice, there was not a preferred first-line treatment. However the clinical specialists stated there would be circumstances when a drug is not prescribed; for instance, beta interferon would be avoided in a patient with, or at risk of, depression. The Committee also heard from the clinical specialists that patients would be offered a different disease-modifying therapy if they experienced more frequent relapses, there was evidence of increased disease activity on MRI, or they had adverse reactions to the treatment. The Committee heard from the clinical specialists that dimethyl fumarate would be considered as a first-line treatment option, alongside beta interferons or glatiramer acetate, in people with relapsing–remitting multiple sclerosis eligible for active treatment under the Association for British Neurologists' guidelines. The clinical specialists also considered that dimethyl fumarate may provide a treatment option for people with relapsing–remitting multiple sclerosis previously treated with beta interferons or glatiramer acetate whose disease had failed to respond or who had experienced adverse reactions. The Committee understood from the clinical specialists that the role of disease-modifying therapies decreases as a patient’s Expanded Disability Status Scale (EDSS) score increases, and therefore disability and the development of secondary progressive multiple sclerosis determines when to stop treatment.

4.4 The Committee discussed the management of rapidly evolving severe relapsing-remitting multiple sclerosis and highly active relapsing-remitting multiple sclerosis. The Committee heard from the clinical specialists that people with more aggressive disease, that is, rapidly evolving severe, and highly active, relapsing-remitting multiple sclerosis, may be difficult to identify early in the course of the disease but if the prescribing clinician were confident that a patient had aggressive disease, then the clinician would offer the patient natalizumab or fingolimod rather than dimethyl fumarate. The Committee was aware that if a patient had received beta interferon as a first-line therapy, NICE recommends fingolimod as an option for the treatment of highly active relapsing–remitting multiple sclerosis in adults who have an unchanged relapse rate or ongoing severe relapses compared with the previous year (Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis’ [NICE technology appraisal guidance 254]). The Committee was also aware that NICE recommends natalizumab for the treatment of people with rapidly-evolving severe relapsing–remitting multiple sclerosis (‘Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis’ [NICE technology appraisal guidance 127]). Although dimethyl fumarate would not be offered to patients with rapidly evolving severe relapsing-remitting multiple sclerosis, the clinical specialists noted that because natalizumab is associated with progressive multifocal leukoencephalopathy, dimethyl fumarate could be considered as a first-line treatment option in people with rapidly evolving severe relapsing–remitting multiple sclerosis who are at a high risk of developing progressive multifocal leukoencephalopathy (such as those who test positive for John Cunningham virus).

Clinical effectiveness

4.5 The Committee discussed the clinical-effectiveness evidence from the DEFINE and CONFIRM trials. It heard from the clinical specialists that the trial populations broadly represent patients who would be offered beta interferon or glatiramer acetate in the UK, in line with the Association for British Neurologists' guidelines. The Committee noted that the trial populations had more severe relapsing-remitting multiple sclerosis than the population included in the marketing authorisation. The Committee noted that the 2 trials included different primary endpoints for measuring relapse, that is, the proportion of patients with relapse at 2 years in the DEFINE trial and the annualised relapse rate in the CONFIRM trial, and heard from the manufacturer that this was because the European Medicines Agency and the Food and Drug Administration agency preferred different approaches to measuring relapse. The Committee heard from the clinical specialists that the 2 endpoints have the same influence on clinical decisions. The Committee noted that the results presented from the manufacturer’s trials and meta-analysis showed that dimethyl fumarate statistically significantly reduced both the rate of relapses and the proportion of patients experiencing a relapse compared with placebo. The Committee discussed the manufacturer’s approaches to analysing the efficacy outcomes for the trials and mixed treatment comparison. It commented that the manufacturer had adjusted its trial results for factors including baseline age, baseline EDSS, baseline relapse rate and geographical region, but had not adjusted its mixed treatment comparison for these factors. The manufacturer was not able to tell the Committee whether the effect measures from CONFIRM and DEFINE were adjusted or unadjusted when included in the mixed treatment comparison. The Committee was aware that the manufacturer’s analytical plan pre-specified adjusting the trial results for baseline age, baseline EDSS and baseline relapse rate, but did not pre-specify adjusting for geographical region. The manufacturer was unable to confirm to the Committee why it chose to use different statistical approaches when analysing the results of the trials and the mixed treatment comparison. The Committee was aware that good statistical practice goes against adjusting for factors without justification, and post hoc. In addition, the Committee heard from the clinical specialists and patient experts that it is difficult to define a relapse because each relapse varies in nature and severity, and that it is the disability that follows, rather than the relapse itself, that has the greater impact on the patient’s health-related quality of life. The Committee acknowledged that confirming a relapse may include a degree of subjectivity. It also recognised that patients in the DEFINE and CONFIRM trials taking dimethyl fumarate experienced more flushing than patients taking placebo and this may have led to functional unblinding of the treatment arms. The Committee concluded that, overall, the evidence suggested that dimethyl fumarate reduces relapses in people with relapsing–remitting multiple sclerosis compared with placebo, but that the magnitude of the treatment effect was unclear because the manufacturer did not justify its pre-specified covariate adjustment, because it adjusted the results post-hoc for geographical region, because of the subjective nature of assessing the endpoint relapse, and because of the potential for functional unblinding.

4.6 The Committee was aware of another factor potentially affecting the magnitude of the treatment effect of dimethyl fumarate compared with placebo in that patients in the DEFINE and CONFIRM trials were eligible to switch to alternative active therapies for multiple sclerosis if they had 1 or more relapse or confirmed progression of disability for 3 months. The Committee acknowledged that a higher proportion of patients randomised to placebo (13%) switched to active treatment than patients randomised to dimethyl fumarate (6%). The Committee heard from the manufacturer that in its base-case efficacy analysis, it included only outcomes measured before patients switched treatment, but conducted a sensitivity analysis that included outcomes after patients switched treatment. The sensitivity analyses showed that the estimated treatment effect were robust for dimethyl fumarate compared with placebo. The Committee concluded that it was satisfied that switching to alternative treatments in the DEFINE and CONFIRM trials did not affect the estimated treatment effect of dimethyl fumarate compared with placebo as measured by the primary efficacy endpoints.

4.7 The Committee discussed the results of the manufacturer’s mixed treatment comparison. It understood that in response to clarification requests from the ERG, the manufacturer revised its estimates for the sustained disability progression outcomes, presenting the effect measure as hazard ratios rather than risk ratios as in its original submission. The Committee heard from the ERG that it preferred hazard ratios because they represent the instantaneous risk over the study period while risk ratios measure the cumulative risk over the entire study. The Committee concluded that it was more appropriate to measure outcomes measuring sustained disability progression using hazard ratios.

4.8 The Committee discussed the trials’ outcome measure of sustained disability progression. The Committee noted that the manufacturer's mixed treatment comparison suggested that compared with placebo, dimethyl fumarate reduced confirmed disability progression sustained for 3 months in the 2 years of the trials, but not disability progression sustained for 6 months at 2 years. The Committee heard from the clinical specialists that patients may not have permanent disability progression after a relapse that recovery may take up to 12 months, but on average people will recover within 3 or 4 months. The clinical specialists stated that sustained disability progression lasting for 6 months is a more appropriate outcome measure than disability progression lasting for 3 months, and it was preferred by the European Medicines Agency in its draft guideline for the clinical investigation of medicinal products for the treatment of multiple sclerosis. The Committee heard from the ERG that most trials of relapsing-remitting multiple sclerosis measure sustained disability progression lasting for 3 months, and the Committee agreed that it would consider it in its decision-making. However, the Committee concluded that sustained disability progression confirmed for 6 months provides a more robust indication of the treatment effect given that patients may recover from relapse, and therefore the effect of dimethyl fumarate on disability progression was uncertain.

4.9 The Committee was aware that the diagnostic criteria, clinical management and prognosis of multiple sclerosis have changed since the year 2000 (approximately). The Committee noted that the manufacturer included trials that were published before the year 2000 in its mixed treatment comparison and that the ERG observed differences among the baseline relapse rates of the trials of relapsing–remitting multiple sclerosis, which were likely to be clinically meaningful. The Committee concluded that, in order to compare the effectiveness of dimethyl fumarate with beta interferons and glatiramer acetate, it is necessary to present several additional analyses adjusted for baseline relapse rate, including:

• the results for the 'proportion of patients with relapse at 2 years' and 'annualised relapse rate' outcomes from the DEFINE and CONFIRM trials
• the results for 'sustained disability progression confirmed for 3 months at 2 years' and 'sustained disability progression confirmed for 6 months at 2 years' from the DEFINE and CONFIRM trials
• the results from its mixed treatment comparison for the efficacy outcomes

The Committee agreed that without these additional analyses it would not be able to reach a conclusion on the clinical effectiveness of dimethyl fumarate.

4.10 The Committee was aware that the manufacturer did not present any evidence for the effectiveness of dimethyl fumarate in patients with rapidly evolving severe relapsing–remitting multiple sclerosis or with highly active relapsing–remitting multiple sclerosis. The Committee was aware that it could not make conclusions about the effectiveness of dimethyl fumarate compared with natalizumab and with fingolimod in the respective subgroups. However, it noted that the clinical specialists confirmed that dimethyl fumarate would not be used routinely in people with aggressive disease (see section 4.4). The Committee concluded there was no evidence presented by the manufacturer to make recommendations for dimethyl fumarate in these subgroups.

4.11 The Committee considered the safety data from the DEFINE and CONFIRM trials, which showed that patients taking dimethyl fumarate experienced more flushing, gastrointestinal and skin reactions, particularly in the first months of treatment, than patients not taking dimethyl fumarate. The Committee heard from the manufacturer that most of these episodes were mild to moderate in severity and that approximately 4% of trial participants taking dimethyl fumarate discontinued the study drug because of flushing. It was also aware that episodes of progressive multifocal leukoencephalopathy were reported in patients taking Fumaderm or a compound formulation of dimethyl fumarate and copper monomethyl fumarate, but that no episodes of progressive multifocal leukoencephalopathy had been reported in patients taking dimethyl fumarate. The Committee concluded that, although dimethyl fumarate can lead to several different adverse reactions, it is generally well tolerated.

Cost effectiveness

4.12 The Committee discussed the incremental cost-effectiveness ratios (ICERs) estimated in the manufacturer’s economic model, the manufacturer’s modelling assumptions, and the ERG’s exploratory analyses. The Committee commented that the manufacturer had submitted a model structurally similarly to models used in previous NICE technology appraisals. The Committee concluded that it could consider only the ICERs for dimethyl fumarate compared with beta interferons and glatiramer acetate in its deliberations because of the lack of data for the subgroups for whom natalizumab and fingolimod have been recommended (see section 4.10).

4.13 The Committee discussed how the manufacturer modelled the natural history of multiple sclerosis. It commented that it was appropriate to allow modelled patients with relapsing–remitting multiple sclerosis to move to lower as well as to higher EDSS states, that is, to allow for the condition to both improve and get worse, which is in line with what is seen in clinical practice for the lower EDSS states. The Committee noted the inherent limitations associated with using the London Ontario dataset to model the natural history of disease, namely, that it allowed only for movement to higher EDSS states, and that it reflected a cohort from the 1970s and 1980s. However, the Committee understood that the manufacturer had used the London Ontario dataset to model the natural history of disease only for EDSS scores of 7 or more in patients with relapsing–remitting multiple sclerosis, for rates of progression to secondary progressive multiple sclerosis, and in patients with secondary progressive multiple sclerosis. The Committee also heard from the clinical specialists that once patients are in a higher EDSS state they are less likely to relapse, and therefore the possibility of moving to lower EDSS states is less plausible. The Committee recognised that the manufacturer had used the DEFINE and CONFIRM trial data to model the natural history of relapsing–remitting multiple sclerosis at lower EDSS states, that the model allowed patients to move to lower EDSS states, and that the trial population more closely reflected the population in UK clinical practice than did the population in the older London Ontario dataset, especially considering that the prognosis for people with multiple sclerosis has improved in the last 20 years. The Committee concluded that by using its trial data, the manufacturer had appropriately modelled the natural history of disease.

4.14 The Committee discussed the mortality data included in the manufacturer’s economic model. It was aware that the manufacturer had used mortality multipliers by EDSS score from Pokorski et al. (1997) in a Danish population diagnosed with multiple sclerosis from 1948 onwards. The Committee heard from the clinical specialists that they would anticipate that the relative risk of mortality in people with multiple sclerosis compared with the general population is lower than reported in this publication because the life expectancy of people with multiple sclerosis has improved. However, the Committee was aware that the manufacturer provided scenario analyses around the mortality rates that showed that this had little impact on the ICERs and therefore concluded that it did not need to consider the mortality rate in the model further.

4.15 The Committee noted that because the trials lasted 2 years, but the manufacturer assumed that patients would take dimethyl fumarate indefinitely, the manufacturer modelled a waning of treatment effect because of the uncertain longer-term benefits of dimethyl fumarate. The Committee heard from the clinical specialists that the manufacturer’s assumption seemed reasonable, but, given the uncertainty, they could not comment on the degree to which the drug’s effect might wane. However, the Committee recognised that the manufacturer had taken a more cautious approach to modelling the longer-term benefits of treatments in its base-case analysis than the approach recommended by the Committee in Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 254). The Committee concluded that a more cautious approach was appropriate.

4.16 The Committee discussed the assumption in the manufacturer’s economic model that people with relapsing–remitting multiple sclerosis do not switch to another active treatment when their disease does not respond, or when they experience adverse reactions. The Committee heard from the clinical specialists that, in clinical practice, people with relapsing–remitting multiple sclerosis are likely to take another treatment in these circumstances, and confirmed that people would choose a treatment with a differential side-effect profile for subsequent lines of therapy. The Committee therefore considered that the manufacturer’s assumption that prohibited treatment switching was not plausible because it did not reflect UK clinical practice. The Committee recognised that no specific treatment pathway currently exists in the NHS for patients with relapsing–remitting multiple sclerosis. However, the Committee agreed that it was important to establish how sensitive the ICERs were to differing sequences of pharmacological treatments. The Committee concluded that to inform its decision-making, the manufacturer needed to provide scenario analyses including sequencing different treatments to reflect UK clinical practice, in order to show the robustness of the manufacturer’s estimated ICERs.

4.17 The Committee understood from the ERG that, based on sensitivity analyses, the main drivers of the ICERs were the costs of treatment, how likely a patient was to experience disease progression (represented by the hazard ratios of sustained disability progression for 3 months at 2 years), the probability of stopping treatment, and the magnitude of the treatment waning effect. The Committee heard from the clinical specialists that the rate of discontinuing drugs is likely to be lower in the longer term than that observed in the 2‑year trials because patients are more likely to experience adverse reactions and discontinue treatment early in the treatment course. The Committee noted the ERG’s observation that in the manufacturer’s economic model, the sooner a patient stops treatment, the more cost effective the treatment appears. The ERG suggested that this creates counterintuitive results; if ‘best supportive care’ (where a patient does not receive a disease-modifying therapy) were one of the comparators included in the analyses, the ICER of any drug would never be lower than the ICER compared to ‘best supportive care’. The Committee asked the manufacturer whether it had externally validated its model specifically to see whether the ICERs for beta interferon or glatiramer acetate compared with no treatment reflected the estimates of cost effectiveness obtained in the risk-sharing scheme. The Committee heard that the manufacturer was not sure whether any external validation had taken place because the economic model had been developed by an external contractor. The Committee concluded that in order to ensure the manufacturer’s economic model was appropriate for decision-making, the manufacturer needed to externally validate the model by showing how similar the estimates for cost effectiveness for current active treatments (all beta interferons and glatiramer acetate) compared with no treatment in its model were to those in the NHS risk-sharing scheme for multiple sclerosis.

4.18 The Committee discussed the costs and resource-use values included in the manufacturer’s economic model. The Committee heard from the ERG that several publications were available that presented the annual costs of relapsing–remitting multiple sclerosis by EDSS state, and that although they were also based on the UK Multiple Sclerosis Survey, the annual costs by EDSS state varied considerably. The ERG explained to the Committee that each publication used different unit costs and different cost items, and that some of the cost items were non-medical (and therefore potentially not considered from the perspective of the NHS and personal social services), and so it was unclear whether these items met the NICE reference case, as detailed in NICE’s Guide to the methods of technology appraisal (2008). The Committee understood from the ERG that it was unable to judge the most appropriate data source for annual costs by EDSS state, and that an approach that removed non-medical costs was more plausible (unless the manufacturer could prove that the non-medical costs met the NICE reference case). The Committee was also aware that a number of the manufacturer’s assumptions related to monitoring patients did not reflect UK clinical practice, and that the ERG had used revised costs in its exploratory analysis. The ERG also commented to the Committee that in its exploratory analyses it had included a more realistic cost of hospitalisation for patients who relapse. The Committee concluded that to inform its decision-making, it needed additional analyses to reflect the uncertainty associated with cost and resource estimates included in the manufacturer’s economic model.

4.19 The Committee noted that the manufacturer had chosen EQ‑5D utility data collected from its clinical trials of dimethyl fumarate for people with relapsing–remitting multiple sclerosis without relapses, and adjusted these values for patients with secondary progressive multiple sclerosis and for patients experiencing a relapse using data from the UK Multiple Sclerosis Survey (see section 3.18). The Committee heard from the clinical specialists that the health-related quality of life of people with multiple sclerosis was more closely related to their EDSS score than to the clinical form of their multiple sclerosis (that is, relapsing–remitting or secondary progressive). The clinical specialists stated that it is difficult to clearly identify when a patient’s disease becomes secondary progressive multiple sclerosis, and therefore it is also difficult to gauge the relative health-related quality of life impacts of the different clinical forms of multiple sclerosis. The Committee acknowledged that the ERG’s exploratory analyses showed that using alternative utility values and alternative assumptions relating to the rate of conversion from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis had little impact on the ICERs. The Committee noted that the model included disutility to carers of people with relapsing–remitting multiple sclerosis that increased with increasing disability of the patient. The Committee was aware that carer disutility had featured in Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis’ (NICE technology appraisal guidance 254) and Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 127), and concluded that including these carer disutilities was appropriate. It noted that the ERG had updated the disutility of flu-like symptoms and influenza in its exploratory analyses of the manufacturer’s economic model but this had had little impact on the estimated ICERs. The Committee concluded that the results of the ICERs were robust to changes in these parameters, and considered that the EQ‑5D utility values from the trial represented the best evidence available because it more closely reflected the population with relapsing–remitting multiple sclerosis treated with disease modifying therapy in UK clinical practice.

4.20 The Committee noted that the manufacturer’s ICERs estimated from deterministic analyses were substantially lower than the ICERs estimated from probabilistic analyses. The Committee was aware that the ERG preferred probabilistic sensitivity analyses because of the non-linear nature of the manufacturer’s economic model (see section 3.31). The Committee understood that the ERG’s exploratory analyses used a deterministic approach because of the length of time needed to run probabilistic analyses. The Committee also understood that the manufacturer fitted distributions around additional parameters in its response to clarification but did not submit its updated economic model, meaning the ERG was unable to assess its validity. The Committee concluded that it preferred probabilistic ICERs presented within a fully incremental analysis and as pairwise comparisons, as defined in NICE’s Guide to the methods of technology appraisal (2008).

4.21 The Committee discussed the most plausible ICER for dimethyl fumarate in the group of people with relapsing–remitting multiple sclerosis whose disease is eligible for active treatment under the Association of British Neurologists guidelines (see section 4.3). The Committee acknowledged that the manufacturer had used the best available evidence to model the natural history of the disease, used EQ‑5D utility data as preferred by NICE in its Guide to the methods of technology appraisal (2008) and included waning of the treatment effect. However, the Committee agreed that considerable uncertainty remained in estimating the ICER using the manufacturer’s economic model, and that this prevented the Committee from recommending dimethyl fumarate. The Committee noted that the ERG’s base-case probabilistic ICER of approximately £31,000 compared with Rebif‑22 in a fully incremental analysis was a plausible ICER presented to the Committee. However, it was concerned that because of the counterintuitive result identified by the ERG, the estimates of the manufacturer’s economic model may not be externally valid (see section 4.17). The Committee was minded not to recommend dimethyl fumarate for treating adults with relapsing–remitting multiple sclerosis as a cost-effective use of NHS resources. The Committee requested the following further clarification and analyses from the manufacturer to address the issues identified:

• Presentation of the results from the DEFINE and CONFIRM trials adjusted for baseline relapse rate only, for the following outcomes:
  
  - proportion of patients with relapse at 2 years
  
  - annualised relapse rate
  
  - sustained disability progression confirmed for 3 months at 2 years
  
  - sustained disability progression confirmed for 6 months at 2 years.
• Revised probabilistic analyses incorporating a scenario that includes:
  
  - revised mixed treatment comparison results adjusted for the baseline relapse rate
  
  - revised estimates for monitoring resource use and costs as preferred by the ERG in its exploratory analyses
  
  -  reduced cost of relapse estimate (£607.80) as preferred by the ERG in its exploratory analyses
  
  -  non-health costs are excluded (if non-health costs related to personal social services can be identified, these can be included), with a sensitivity analysis that includes all non-health costs, and
  - pairwise comparisons and incremental analyses for the probabilistic cost-effectiveness estimates.
• Pairwise comparisons for the probabilistic cost-effectiveness estimates for several plausible treatment sequences reflecting UK clinical practice. For example:
  
  - dimethyl fumarate, beta interferon, fingolimod compared with beta interferon, glatiramer acetate, fingolimod
  
  - dimethyl fumarate, beta interferon, glatiramer acetate compared with beta interferon, glatiramer acetate, fingolimod.
• Pairwise comparisons for the probabilistic cost-effectiveness estimates for the current active treatments (all beta interferons and glatiramer acetate) compared with no disease-modifying therapy to externally validate the manufacturer’s economic model by showing how similar these cost effectiveness estimates are to those in the NHS risk-sharing scheme for multiple sclerosis.

4.22 The Committee discussed the innovative nature of dimethyl fumarate and whether the economic analysis had captured all changes in health-related quality of life. In its submission, the manufacturer stated that dimethyl fumarate was innovative because it is taken orally, and because its mechanism of action targets the nuclear factor erythroid-derived 2‑like 2 (Nrf2) pathway. The Committee recognised that a drug taken orally may give people with relapsing–remitting multiple sclerosis a valuable alternative to current first-line treatment options but acknowledged comments from professional and patient groups that its twice-daily administration schedule may lower adherence compared with once-daily options. The benefit related to being an oral drug was not captured in the analysis because the manufacturer’s economic model applied the same utility values to dimethyl fumarate as to beta interferons and glatiramer acetate. The Committee therefore acknowledged that dimethyl fumarate provides health-related quality of life benefits other than those captured in the QALY calculation for patients currently taking beta interferons and glatiramer acetate, and that the ICER may decrease when the benefits of oral treatment were taken into consideration. The Committee heard from the clinical specialists that little is known about what causes multiple sclerosis and therefore it could not advise the Committee whether dimethyl fumarate’s mechanism of action could be considered relevant to the pathophysiology of multiple sclerosis or innovative. The Committee concluded that the case for innovation made by the manufacturer did not change its current conclusion about the cost effectiveness of dimethyl fumarate.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Dimethyl fumarate for treating relapsing–remitting multiple sclerosis		Section
Key conclusion
The Committee is minded not to recommend dimethyl fumarate within its marketing authorisation, that is, for treating adults with relapsing–remitting multiple sclerosis. The Committee recommends that NICE requests further clarification and analyses from the manufacturer, which should be made available for the second Appraisal Committee meeting.			1.1, 1.2, 4.21
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee understood that any delay in relapse and progression of disability, or relief from using injectable treatments and corticosteroids, would have a positive impact on the lives of people with multiple sclerosis and their families. The Committee heard from the clinical specialists that, as recommended in the Association for British Neurologists' guidelines, most patients who have had 2 relapses in the previous 2 years would be offered a disease-modifying therapy and enrolled in the risk-sharing scheme.	4.2 4.3
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 recognised that a drug taken orally may give people with relapsing–remitting multiple sclerosis a valuable alternative to current first-line treatment options but acknowledged comments from professional and patient groups that its twice-daily administration schedule may lower adherence compared with once-daily options.	4.22
What is the position of the treatment in the pathway of care for the condition?		The Committee heard from the clinical specialists that dimethyl fumarate would be considered as a first-line treatment option, alongside beta interferons or glatiramer acetate, in people with relapsing–remitting multiple sclerosis eligible for active treatment under the Association for British Neurologists' guidelines.	4.3
Adverse reactions		The Committee considered that patients taking dimethyl fumarate experienced more flushing, gastrointestinal and skin reactions, particularly in the first months of treatment, than patients not taking dimethyl fumarate. The Committee concluded that, although dimethyl fumarate can lead to several different adverse reactions, it is generally well tolerated.	4.11
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee discussed the clinical-effectiveness evidence from 2 phase III randomised controlled trials: the DEFINE and CONFIRM trials.	4.5
Relevance to general clinical practice in the NHS		The Committee heard from the clinical specialists that the trial populations broadly represent patients who would be offered beta interferon or glatiramer acetate in the UK, in line with the Association for British Neurologists' guidelines.	4.5
Uncertainties generated by the evidence		The Committee concluded that, overall, the evidence suggested that dimethyl fumarate reduces relapses in people with relapsing–remitting multiple sclerosis compared with placebo, but that the magnitude of the treatment effect was unclear because the manufacturer did not justify its pre-specified covariate adjustment, because it adjusted the results post-hoc for geographical region, because of the subjective nature of assessing the endpoint relapse, and because of the potential for functional unblinding. The Committee concluded that, to compare the effectiveness of dimethyl fumarate with beta interferons and glatiramer acetate, it needed to present several additional analyses.	4.5 4.9
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee concluded there was no evidence presented by the manufacturer to make recommendations for dimethyl fumarate in rapidly evolving severe, and highly active, relapsing-remitting multiple sclerosis.	4.10
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee noted that the results presented showed that dimethyl fumarate reduced the rate of relapses and the proportion of patients experiencing a relapse compared with placebo. The Committee noted that the manufacturer's mixed treatment comparison suggested that compared with placebo, dimethyl fumarate reduced confirmed disability progression sustained for 3 months, but not disability progression sustained for 6 months.	4.5 4.8
Evidence for cost effectiveness
Availability and nature of evidence		The Committee commented that the manufacturer had submitted a model structurally similarly to models used in previous NICE technology appraisals.	4.12
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee considered that the manufacturer’s assumption that prohibited treatment switching was not plausible because it did not reflect UK clinical practice. The Committee noted that in the manufacturer’s economic model, the sooner a patient stops treatment, the more cost effective the treatment appears. The ERG suggested that this creates counterintuitive results. The Committee concluded that in order to ensure the manufacturer’s economic model was appropriate for decision-making, the manufacturer needed to externally validate its model. The Committee understood from the ERG that it was unable to judge the most appropriate data source for annual costs by EDSS state, and that an approach that removed non-medical costs was more plausible (unless the manufacturer could prove that the non-medical costs met the NICE reference case). The Committee was also aware that a number of the manufacturer’s assumptions related to monitoring patients did not reflect UK clinical practice. The ERG also commented to the Committee that in its exploratory analyses it had included a more realistic cost of hospitalisation for patients who relapse.	4.16 4.17 4.18
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 benefit related to being an oral drug was not captured in the analysis. The Committee acknowledged that the ICER may decrease when the benefits of oral treatment were taken into consideration.	4.22
Are there specific groups of people for whom the technology is particularly cost effective?		N/A	4.10, 4.12
What are the key drivers of cost effectiveness?		The main drivers of the ICERs were the costs of treatment, how likely a patient was to experience disease progression (represented by the hazard ratios of sustained disability progression for 3 months at 2 years), the probability of stopping treatment, and the magnitude of the treatment waning effect.	4.17
Most likely cost-effectiveness estimate (given as an ICER)		The Committee noted that the ERG’s base-case probabilistic ICER of approximately £31,000 compared with Rebif‑22 in a fully incremental analysis was a plausible ICER presented to the Committee. However, it was concerned that because of the counterintuitive result identified by the ERG, the estimates of the manufacturer’s economic model may not be externally valid. The Committee agreed that considerable uncertainty remained in estimating the ICER using the manufacturer’s economic model.	4.21
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer of dimethyl fumarate has agreed a patient access scheme with the Department of Health. This is a simple discount scheme, with the discount applied at the point of purchase or invoice. The level of discount is commercial in confidence.	2.3
End-of-life considerations		N/A	-
Equalities considerations and social value judgements		Potential equality issues raised during the appraisal were outside the remit of NICE technology appraisal guidance.	-

5 Implementation

5.1 Section 7(6) of the National Institute for Health and Care Excellence (Constitution and Functions) and the Health and Social Care Information Centre (Functions) Regulations 2013 requires clinical commissioning groups, NHS England and, with respect to their public health functions, local authorities to comply with the recommendations in this appraisal within 3 months of its date of publication.

5.2 NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] to help organisations put this guidance into practice (listed below). [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 Related NICE guidance

Details are correct at the time of consultation. Further information is available on the NICE website.

Published

• Teriflunomide for treating relapsing-remitting multiple sclerosis. NICE technology appraisal guidance 303 (2014).
• Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis. NICE technology appraisal guidance 254 (2012).
• Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis. NICE technology appraisal guidance 127 (2007).
• Management of multiple sclerosis in primary and secondary care. NICE clinical guideline 8 (2003).
• Beta interferon and glatiramer acetate for the treatment of multiple sclerosis. NICE technology appraisal guidance 32 (2002).

Under development

• Alemtuzumab for treating relapsing–remitting multiple sclerosis. NICE technology appraisal. Publication expected April 2014.
• Laquinimod for treating relapsing–remitting multiple sclerosis. NICE technology appraisal. Publication expected TBC.

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in when the review of NICE technology appraisal guidance 32, NICE technology appraisal guidance 127 and NICE technology appraisal guidance 254 has been published. NICE welcomes comment on this proposal. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Amanda Adler
Chair, Appraisal Committee
February 2014

8 Appraisal Committee members, guideline representatives and NICE project team

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 4 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

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

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

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

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

Mark Chapman
Health Economics and Market Access Manager, Medtronic UK

Professor Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Dr Neil Iosson
General Practitioner

Terence Lewis
Lay Member

Dr Miriam McCarthy
Consultant, Public Health, Public Health Agency

Professor Ruairidh Milne
Director of Strategy and Development and Director for Public Health Research at the National Institute for Health Research (NIHR) Evaluation, Trials and Studies Coordinating Centre at the University of Southampton

Dr Elizabeth Murray
Reader in Primary Care, University College London

Dr Peter Norrie
Principal Lecturer in Nursing, DeMontfort University

Christopher O’Regan
Head of Health Technology Assessment & Outcomes Research, Merck Sharp & Dohme

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

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Danielle Preedy
Lay Member

Dr John Rodriguez
Assistant Director of Public Health, NHS Eastern and Coastal Kent

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

Stephen Sharp
Senior Statistician, MRC Epidemiology Unit

Roderick Smith
Chief Finance Officer, Coastal West Sussex Clinical Commissioning Group

Cliff Snelling
Lay Member

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

Dr Nicky Welton
Senior Lecturer in Biostatistics/Health Technology Assessment, University of Bristol

NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Martyn Burke
Technical Lead

Joanna Richardson
Technical Adviser

Jeremy Powell
Project Manager

9 Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by the NHS Centre for Reviews and Dissemination and Centre for Health Economics, University of York:

• Norman G, Rice S, O'Connor J et al, Dimethyl fumarate for treating relapsing-remitting multiple sclerosis, July 2013

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:

• Biogen Idec

II. Professional/specialist and patient/carer groups:

• Association of British Neurologists
• Multiple Sclerosis Society
• Multiple Sclerosis Trust
• Primary Care Neurology Society
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• United Kingdom Clinical Pharmacy Association
• United Kingdom Multiple Sclerosis Specialist Nurse Association

III. Other consultees:

• Department of Health
• Welsh Government

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

• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland
• Novartis
• Teva

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

• Dr Jacqueline Palace, Consultant Neurologist and Honorary Senior Lecturer, Oxford University, nominated by Biogen Idec - clinical specialist
• Professor Neil Robertson, Professor of Neurology at Cardiff University and University Health Board, nominated by the Multiple Sclerosis Trust - clinical specilist
• Catherine John, nominated by the Multiple Sclerosis Trust, patient expert
• Nick Rijke, Director of Policy and Research, the Multiple Sclerosis Society, nominated by the Multiple Sclerosis Society - patient expert

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.

• Biogen Idec