The Department of Health asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using teriflunomide in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see section 9) and the public. This document should be read along with the evidence base (the evaluation report).

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using teriflunomide in the NHS in England and Wales.

For further details, see the Guides to the technology appraisal process.

The key dates for this appraisal are:

Closing date for comments: 9 October 2013

Second Appraisal Committee meeting: 22 October 2013

Details of membership of the Appraisal Committee are given in section 8, and a list of the sources of evidence used in the preparation of this document is given in section 9.

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

1   Appraisal Committee’s preliminary recommendations

1.1  The Committee is minded not to recommend teriflunomide 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:

• Revised probabilistic analyses that:

-     use ‘all years’ mixed treatment comparison data adjusted for baseline annualised relapse rates

-     incorporate the inputs used in the Evidence Review Group’s (ERG’s) preferred scenario in which:

à      trial data are used to estimate the initial Expanded Disability Status Scale (EDSS) distribution and the natural history of progression

à      the ERG’s amended calculation of secondary progressive multiple sclerosis conversion is used

à      non-health costs are excluded (if non-health costs related to personal social services can be clearly identified, these can be included), with a sensitivity analysis including all non-health costs and,

à      utilities are derived from the trials, using the differences observed in the Orme et al. (2007) study to extrapolate the higher EDSS state values

-     include waning of treatment effect, with 75% treatment effect after 2 years and 50% treatment effect after 5 years

-     present probabilistic incremental cost-effectiveness ratios (ICERs) in a fully incremental analysis and as pairwise comparisons

• include pairwise comparisons for the probabilistic cost-effectiveness estimates for plausible treatment sequencing, reflecting UK clinical practice. For example:

-     teriflunomide, Rebif-44 (interferon beta-1a, 44 micrograms) and fingolimod compared with Rebif-44, fingolimod and no disease-modifying therapy

-     teriflunomide, Rebif-44 and glatiramer acetate compared with Rebif-44, glatiramer acetate and no disease-modifying therapy

• Pairwise comparisons for the probabilistic cost-effectiveness estimates for the current active treatment (all beta interferons, 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   Teriflunomide (Aubagio, Genzyme) is an immunomodulatory disease-modifying therapy. It has a UK marketing authorisation for ‘the treatment of adult patients with relapsing–remitting multiple sclerosis’. It is anti-inflammatory and works by blocking proliferation of stimulated lymphocytes. The exact mechanism of action for teriflunomide is not fully understood. It is thought to reduce the number of activated lymphocytes, which would cause inflammation, and damage myelin in the central nervous system. Teriflunomide is administered as a 14 mg oral tablet taken once daily.

2.2  The summary of product characteristics lists the following adverse effects for teriflunomide: diarrhoea, alopecia, nausea and increased levels of alanine aminotransferase. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3  The manufacturer has stated that the list price of teriflunomide is £1037.84 per 28‑tablet pack (excluding VAT). The length of teriflunomide treatment may vary because it is anticipated to be a long-term treatment for a chronic condition and would be stopped based on a joint decision between the patient and clinician. The manufacturer has estimated the annual cost of teriflunomide to be £13,529 per patient per year. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of teriflunomide 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 the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.

3  The manufacturer’s submission

The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of teriflunomide and a review of this submission by the Evidence Review Group (ERG; section 9).

Clinical effectiveness

3.1   The manufacturer provided clinical-effectiveness evidence, identified through systematic review, from:

• 3 phase III randomised controlled clinical trials: TEMSO (n=1088, 108 weeks follow-up), TENERE (n=324, follow up between 48 and 118 weeks) and TOWER (n=1169, follow up between 48 and 154 weeks)
• a phase II trial: Study 2001 (n=179, 36 weeks)
• 2 extension studies: to Study 2001 (n=147, median 7.1 years follow-up) and to TEMSO (n=742).

TEMSO, TOWER, and Study 2001 compared the effectiveness of teriflunomide (7 mg or 14 mg once daily) with placebo. After completion of the core study for TEMSO and Study 2001, patients could enter the extension phases of the studies. Those who were originally randomised to teriflunomide continued their assigned treatment and those receiving placebo were re-allocated to teriflunomide 7 mg or 14 mg. TENERE compared the effectiveness of teriflunomide (7 mg or 14 mg once daily) with Rebif-44 (interferon beta‑1a) 3 times a week. Each of the phase III multicentre trials included sites in the UK. The manufacturer also provided a meta-analysis of the placebo-controlled studies (Study 2001, TEMSO and TOWER).

3.2  The inclusion criteria of TEMSO, TOWER and Study 2001 specified the number of previous relapses before study entry. For TEMSO and TOWER, this was at least 1 relapse in the previous year, or at least 2 in the previous 2 years. For Study 2001, this was 1 relapse in the previous year or 2 in the previous 3 years. The phase III trials included people with an Expanded Disability Status Scale (EDSS) score between 0 and 5.5, whereas Study 2001 and the extension studies had a range of between 0 and 6.0 (where 6.0 represents a significant change in walking ability).

3.3   The primary outcome of TEMSO and TOWER was annualised relapse rate. The primary outcome of TENERE was time to failure (which included treatment failure and discontinuation), and the primary outcome of Study 2001 was combined unique active (new and persisting) lesions per MRI scan. The trial outcomes presented by the manufacturer included annualised relapse rate, severity of relapse (inferred from hospitalisation), disability (EDSS score, 3‑month sustained accumulation of disability [SAD], and 6‑month SAD), freedom from disease activity, mortality, adverse events and discontinuation rate. The manufacturer’s meta-analysis of the placebo-controlled trials included 5 outcomes: annualised relapse rate, proportion of relapse-free patients, 3‑month SAD, all-cause discontinuations and discontinuations because of adverse events. The intention-to-treat populations were used for analyses of clinical trial data.

3.4  The manufacturer provided data from Study 2001, TEMSO, TOWER and a meta-analysis, which compared the 14 mg dose of teriflunomide with placebo. These data showed that teriflunomide was associated with a statistically significant reduction in adjusted annualised relapse rate (adjusted for treatment, EDSS score at baseline and geographic region) compared with placebo in the TEMSO trial (teriflunomide 0.37 [95% confidence interval {CI} 0.31 to 0.44], placebo 0.54 [95% CI 0.47 to 0.62], 31.5% relative risk reduction, p<0.001), the TOWER trial (teriflunomide 0.32 [95% CI 0.27 to 0.38], placebo not stated, relative risk 0.637 [95% CI 0.512 to 0.793], p=0.0001) and the meta-analysis (relative risk compared with placebo: 0.66 [95% CI 0.59 to 0.75]). Teriflunomide reduced the point estimate for the annualised relapse rate compared with placebo in Study 2001, but this was not statistically significant. TEMSO showed that statistically significantly fewer people receiving teriflunomide had 3-month SAD than those receiving placebo (teriflunomide: 20.2% [95% CI 15.6 to 24.7], placebo: 27.3% [95% CI 22.3 to 32.3], hazard ratio [HR] 0.70 [95% CI 0.51 to 0.97]). TOWER showed lower rates of 3-month SAD with teriflunomide than placebo at 48 weeks (teriflunomide: 7.8%, placebo: 14.2%) and at 132 weeks (teriflunomide: 15.8%, placebo: 21.0%). The meta-analysis of TEMSO and TOWER (Study 2001 was not included in this analysis) estimated a statistically significantly lower risk of 3-month SAD for teriflunomide compared with placebo (HR 0.694, 95% CI 0.544 to 0.886). Teriflunomide did not statistically significantly reduce 6 month SAD compared with placebo in TEMSO (HR 0.749; 95% CI 0.505 to 1.111) or TOWER (HR 0.843; 95% CI 0.533 to 1.334). No statistically significant differences in EDSS change from baseline were observed in the TEMSO and Study 2001 trials. Changes in EDSS from TOWER were provided commercially in confidence by the manufacturer and therefore cannot be presented here. The manufacturer also provided health-related quality-of-life data. Changes in fatigue and health-related quality of life (measured using SF-36 and EQ-5D) were not statistically significantly different between teriflunomide and placebo in the individual trials.

3.5  The primary outcome of TENERE was time to failure, defined as confirmed relapse or treatment discontinuation with teriflunomide 14 mg compared with Rebif-44. Of those receiving teriflunomide, 37.8% experienced failure compared with 42.4% in the Rebif-44 group. For the adjusted annualised response rate, no statistically significant differences between teriflunomide and Rebif-44 were reported in the TENERE study (0.259 compared with 0.216, respectively; p=0.59). SAD data were provided from TENERE in confidence and cannot be reported here. In TENERE, the Treatment Satisfaction Questionnaire for Medication was used to assess health-related quality of life. At week 48 the global satisfaction score was statistically significantly higher with teriflunomide than Rebif-44 (higher score indicates better satisfaction; 68.818 compared with 60.975, p=0.0162).

3.6   The manufacturer undertook a mixed treatment comparison (MTC) that compared teriflunomide with each of the treatments in the decision problem (beta interferons, glatiramer acetate, natalizumab and fingolimod). The base-case MTC included 30 clinical trials, which recruited patients from the year 2000 onwards, and included at least 80% of patients with relapsing–remitting multiple sclerosis. A separate ‘all years’ analysis was also provided, which included studies that recruited patients before 2000. The year 2000 was justified by the manufacturer as an appropriate cut-off point because of changes in diagnostic criteria used in multiple sclerosis trials, which coincided with a reduction in annualised relapse rates at diagnosis. After 2000, the McDonald criteria were used, which identify multiple sclerosis earlier than the previously used Poser criteria. The outcomes presented in the MTCs included annualised relapse rate, proportion of relapse-free patients, 3-month SAD, all-cause discontinuation rate, and discontinuation rate because of adverse events. The MTCs used a Bayesian random effects model. The results from the base-case MTC (post-2000) are discussed for each comparator separately in sections 3.7 and 3.8. The results for the ‘all years’ MTC were provided academically in confidence and cannot be presented.

3.7   The manufacturer provided data from the base-case MTC (post-2000) on the clinical effectiveness of teriflunomide 14 mg compared with all the disease-modifying therapies including the interferons Rebif-44, Betaferon (interferon beta-1b) and Avonex (interferon beta-1a) and glatiramer acetate (see section 3.8 for the natalizumab and fingolimod results). For the adjusted annualised response rate, no statistically significant differences were observed between teriflunomide and Rebif-44 (rate ratio: 1.06 [95% CI 0.84 to 1.35]), Betaferon (relative risk 0.98, 95% CI 0.73 to 1.31), Avonex (relative risk 0.86, 95% CI 0.69 to 1.05) or glatiramer acetate (relative risk 1.05, 95% CI 0.83 to 1.31). The base-case MTC (post-2000) also suggested no statistically significant difference in 3-month SAD between teriflunomide and Rebif-44 (HR 0.90, 95% CI 0.54 to 1.45), Betaferon (HR 0.58, 95% CI 0.30 to 1.12), Avonex (HR 0.77, 95% CI 0.50 to 1.24) or glatiramer acetate (HR 0.76, 95% CI 0.45 to 1.30). The manufacturer also presented data for the following outcomes: proportion of patients who were relapse-free, all-cause discontinuation and discontinuation because of adverse events. However, these data are marked as academic in confidence by the manufacturer and cannot be presented here.

3.8  The base-case MTC (post-2000) was also used to compare the clinical effectiveness of teriflunomide against fingolimod and natalizumab. Teriflunomide was associated with a statistically significantly higher annualised relapse rate compared with fingolimod (rate ratio 1.45 [95% CI 1.17 to 1.80]) and natalizumab (rate ratio 2.12 [95% CI 1.63 to 2.75]). There was no statistically significant difference in 3-month SAD between teriflunomide and fingolimod or natalizumab. The manufacturer also presented data for the following outcomes: proportion of patients who were relapse-free, all-cause discontinuation and discontinuation because of adverse events. However, these data are marked as academic in confidence by the manufacturer and cannot be presented here.

3.9  The manufacturer conducted 2 separate indirect comparisons of teriflunomide for the subgroups of patients with highly active multiple sclerosis and rapidly evolving severe multiple sclerosis in TEMSO. The outcomes presented included annualised relapse rate and 3-month SAD. The 95% confidence intervals were not provided for these indirect treatment comparisons. The results of these were provided commercially in confidence and therefore cannot be presented here.

3.10  The manufacturer stated that almost all patients treated with teriflunomide reported at least 1 adverse effect. However, for most of the events, the incidence was similar to placebo. Rates of discontinuation because of adverse events were higher for teriflunomide compared with placebo. The manufacturer provided results from the base-case MTC (post-2000) for all cause discontinuations and discontinuations because of adverse effects; however these were presented as academic in confidence and cannot be reported here. In addition, the manufacturer carried out a comparison of adverse events between teriflunomide and Rebif, the results of which are commercial in confidence and therefore cannot be presented here. The following adverse effects were associated with teriflunomide: diarrhoea, nausea, vomiting, increased levels of alanine aminotransferase, parathesias and dysesthesias, infections and alopecia.

Cost effectiveness

3.11   The manufacturer submitted an economic model to evaluate the cost effectiveness of teriflunomide. In addition, it conducted a systematic literature review that identified 2 cost-effectiveness studies for relapsing–remitting multiple sclerosis to inform parameters used in the model.

3.12  The manufacturer’s model was presented as a multistate Markov model. The model contained 20 health states that were defined by disability level (EDSS scores 0–9), and the type of multiple sclerosis (relapsing–remitting multiple sclerosis or secondary progressive multiple sclerosis). Patients with relapsing–remitting multiple sclerosis entered the model in relapsing–remitting multiple sclerosis states 0–7. In each cycle, patients could remain in the same state, progress to a worse state (patients could not regress to a better state), transfer to a secondary progressive multiple sclerosis health state, or die. Health states for secondary progressive multiple sclerosis were included to represent the clinical progression of relapsing–remitting multiple sclerosis. It was assumed that when progressing from relapsing–remitting multiple sclerosis to a secondary progressive multiple sclerosis state, the patient’s disease would also progress by 1 EDSS state. In addition, in each cycle patients could withdraw from treatment, stop treatment after reaching the EDSS limit for which a disease-modifying treatment is allowed (EDSS 6), or experience relapse and adverse events. The probability of death depended on the EDSS state, age and sex. The transition probabilities, discontinuation rates, relapse rates and adverse event rates throughout the model were based on data from the base-case MTC (post-2000) (treatment effect on progression, treatment effect on relapses, hospitalisation because of relapse, withdrawal, and adverse events), or taken from the literature (natural disease progression, demographic profile of patients entering the model, natural relapse rates, mortality). Treatment effects on disability and relapse were assumed to be constant over time, that is, there was no waning of treatment and once patients stop receiving treatment they continue to benefit as they will be at a better EDSS state than they would have been without the treatment, and the EDSS state determines disability and relapse. The patients then followed the natural history of progression. The EDSS state determined progression and relapse rates, and therefore the patients in the model continued to benefit from treatment throughout the course of the model because receiving treatment meant they stayed in a better EDSS state for longer. In the base case, patients stopped treatment if their relapsing–remitting multiple sclerosis progressed to secondary progressive multiple sclerosis, or progressed to an EDSS state greater than 6. In the manufacturer’s sensitivity analyses, treatment could be continued in secondary progressive multiple sclerosis but the treatment effect was reduced by 50% when the condition progressed to secondary progressive multiple sclerosis. It was assumed that withdrawal rates would not persist over the whole period of the model and therefore after 2 years the rate was estimated to decrease by 50% (based on clinical opinion). The cycle length was 1 year, and the time horizon was lifetime, assumed to be 50 years with a mean starting age of 38 years (based on the UK risk-sharing scheme cohort). The manufacturer stated that the analyses used an NHS and personal and social services perspective and applied a 3.5% discount rate on costs and health effects.

3.13   The manufacturer’s base-case analyses compared teriflunomide with a blended comparator of Rebif-22 (interferon beta-1a [22 micrograms]), Rebif-44, Avonex, Betaferon and glatiramer acetate. The blended comparator was calculated as the weighted average of the clinical efficacy, and cost–utility inputs on the basis of UK market share data. The manufacturer also conducted a full incremental analysis, comparing teriflunomide with the individual treatments: glatiramer acetate, Rebif-22, Rebif-44, Avonex, Betaferon and aggregated Rebif. Treatment sequencing was considered in scenario analyses (see section 3.18). The manufacturer provided separate analyses of teriflunomide compared with fingolimod and natalizumab for the relapsing–remitting multiple sclerosis, and for the rapidly evolving severe multiple sclerosis and highly active multiple sclerosis subgroups (see section 3.20).

3.14  The model applied health state utility values to each of the EDSS states. The utility values in the manufacturer’s model were taken from Orme et al. (2007), which was a UK survey of health-related quality of life (measured using EQ-5D) in people with multiple sclerosis. The utility values ranged from 0.870 (EDSS 0) to a state worse than death, −0.195 (EDSS 9), in the relapsing–remitting multiple sclerosis health states. EDSS state 8 also had a negative utility value indicating a state worse than death. The secondary progressive multiple sclerosis health states were the values from the relapsing–remitting multiple sclerosis health states minus 0.045. The manufacturer collected EQ-5D data in the TEMSO study but did not apply these data in the model on the basis that this study was an international study and may not be representative of the UK population. In addition to the utility values in each EDSS state, disutilities were applied to each EDSS state for relapse, caregiving and adverse events. The disutilities associated with relapse were estimated using a UK study (Orme et al. 2007) and a US study (Prosser et al. 2003). The UK disutility of relapse taken from Orme et al. was assumed to correlate to relapse without hospitalisation. The difference in utility observed between relapses with or without hospitalisation in the Prosser study was then used to estimate the disutility of relapse with hospitalisation (−0.0297, −0.0089 without hospitalisation). Disutility values taken from a study by Gani et al. (2008) were applied for caregivers and took into account the time spent caring for the patient (which was taken from Orme et al.). A different value was estimated for each EDSS state and ranged from 0 (EDSS 0) to −0.140 (EDSS 9). The disutility values for adverse events were taken from the published literature. A value was derived for each event and adjusted for time, according to the treatment, to estimate a treatment-specific annual disutility value, these included nausea (−0.0001), diarrhoea (−0.0004), hair thinning (−0.0070), fatigue (−0.0004), headache (−0.0002), immediate post-injection systemic reactions (−0.0001), arthralgia (−0.0034) and influenza-like symptoms (−0.0005).

3.15  The model used NHS reference costs and the Payment by Results tariff to estimate the costs of administration, monitoring and adverse events associated with each treatment. The manufacturer assumed that teriflunomide was not associated with administration costs because it is an oral treatment. In addition, some costs were derived from the literature; health-state costs (including direct medical costs and direct non-medical costs) were derived from Tyas et al. (2007). These costs differed across the EDSS states and ranged from £336 (EDSS 0) to £19,704 (EDSS 9) for direct medical costs, and from £5335 (EDSS 0) to £20,811 (EDSS 8) and £12,915 (EDSS 9) for non-medical costs. The cost associated with relapse was sourced from Dee et al. (2012): £845 without hospitalisation and £6164 with hospitalisation. The resource use and costs applied in the model were validated by the manufacturer’s clinical experts. Fingolimod is available to the NHS with a simple discount through a patient access scheme agreed with the Department of Health. However, the magnitude of this discount was not known by the manufacturer and therefore was not applied in the base-case analysis (but was explored in the sensitivity analysis, using a range of discounts).

3.16  Teriflunomide dominated the blended comparator in the base case (incremental costs: −£5491; incremental QALYs: 0.201)), that is, it was less expensive and more effective. The cost-effectiveness acceptability curve provided by the manufacturer showed a 63% probability of teriflunomide being cost effective if the maximum acceptable ICER was £20,000 per QALY gained.

3.17  The manufacturer conducted one-way sensitivity analyses, which showed that the cost effectiveness of teriflunomide was most sensitive to the blended comparator hazard ratio for disability progression, the teriflunomide hazard ratio for disability progression, the blended comparator withdrawal rate, disease costs, the teriflunomide annual relapse rates, and the blended comparator annual relapse rates. For each of the analyses, teriflunomide continued to dominate the blended comparator, except when the hazard ratios for disability progression were varied. Teriflunomide was dominated by the blended comparator when the lower 95% confidence interval for the blended comparator disability progression hazard ratio was applied (reducing the progression risk with the blended comparator). When applying the upper 95% confidence interval for the teriflunomide disability progression hazard ratio (increasing the progression risk with teriflunomide), the ICER for teriflunomide compared with the blended comparator was £20,613 per QALY gained.

3.18  The manufacturer conducted scenario analyses that explored likely treatment sequences, based on clinical opinion. The model enabled a sequence of 2 treatments after teriflunomide or the blended comparator. Treatments that were included as second and third line were the blended comparator, fingolimod, natalizumab or best supportive care. As part of these analyses, the manufacturer applied 2 possible patient access scheme prices for fingolimod (£11,000 and £13,000), as well as the list price. Teriflunomide dominated the blended comparator in all scenarios, irrespective of the size of patient access scheme discount for fingolimod. The manufacturer conducted further scenario analyses including using the ‘all years’ MTC for clinical data, using different sources of costs and utilities, and using the EDSS distribution, patient population and proportion of relapses from the clinical trials. Teriflunomide dominated the blended comparator for all scenarios.

3.19   The manufacturer also presented an incremental analysis in which teriflunomide was compared with the individual comparators (glatiramer acetate, Rebif-22, Rebif-44, Avonex and Betaferon). In the base case, teriflunomide dominated all the comparators. The manufacturer also conducted incremental analysis for the following scenarios: the ‘all years’ MTC data; the ‘all years’ MTC values without Bornstein et al. (this study was excluded because it did not use EDSS); and the base case MTC (post-2000) values including treatment in secondary progressive multiple sclerosis. Teriflunomide dominated each of the individual comparators for most of the scenarios, with the following exceptions: the ‘all years’ MTC (£86,866 per QALY gained for teriflunomide compared with glatiramer acetate [incremental costs: £3573; incremental QALYs: 0.041]); the ‘all years’ MTC without Bornstein et al. (£21,062 per QALY gained for teriflunomide compared with glatiramer acetate [incremental costs: £2641; incremental QALYs: 0.125], and £301,857 per QALY gained for Rebif‑22 compared with teriflunomide [incremental costs: £4130; incremental QALYs: 0.130]); and the base-case MTC (post 2000) with secondary progressive multiple sclerosis treatment (£105,604 per QALY gained for Rebif-44 compared with teriflunomide [incremental costs: £11,709; incremental QALYs: 0.111]).

3.20  The manufacturer presented cost-effectiveness results for 2 subgroups: teriflunomide compared with fingolimod in the subgroup of people with highly active relapsing-remitting multiple sclerosis, and teriflunomide compared with natalizumab in the subgroup of people with rapidly evolving severe relapsing-remitting multiple sclerosis. For the first subgroup, teriflunomide dominated fingolimod when the fingolimod list price was used (incremental cost savings: £35,084; incremental QALYs: 0.746) and when it was assumed fingolimod cost £11,000 per year (incremental cost savings: £67,826; incremental QALYs: 0.725). For the second subgroup, teriflunomide was associated with an ICER of £63,107 (incremental cost savings: £30,133; incremental QALYs: −0.477) saved per QALY lost compared with natalizumab.

Evidence Review Group comments

3.21  The ERG reviewed the decision problem presented by the manufacturer, and commented that it was in line with the scope, with the exception of the population. The ERG noted that secondary progressive multiple sclerosis and primary progressive multiple sclerosis populations were not presented in the manufacturer’s submission because the marketing authorisation for teriflunomide was limited to relapsing–remitting multiple sclerosis.

3.22  The ERG considered the generalisability of the placebo-controlled clinical trials to UK clinical practice. It noted that although most of the patients in the trials had relapsing–remitting multiple sclerosis (at least 87%), the trials also included people with primary progressive multiple sclerosis and secondary progressive multiple sclerosis. The ERG noted that Study 2001 used the Poser rather than McDonald criteria to diagnose patients with multiple sclerosis, and stated that the McDonald criteria were more in keeping with current clinical practice. However, it concluded that overall, the differences were not large and that the trial populations can be considered generalisable to the UK population with relapsing–remitting multiple sclerosis who would be receiving a disease-modifying therapy.

3.23  The ERG commented that all placebo-controlled clinical trials were short considering the generally long duration of multiple sclerosis and infrequency of relapses, and therefore may not adequately capture differences in relapse rates. Of particular note, Study 2001 lasted only 36 weeks. The ERG noted that the European Medicines Agency suggests that a trial duration of at least 2 years is needed to accurately assess relapses and disability progression. Furthermore, the ERG noted that quality-of-life and mortality data were limited to 2-year follow-up and supplemented by longer-term extension studies, which were not placebo-controlled and therefore did not account for the natural history of the disease.

3.24   The ERG noted that the TEMSO and TOWER trials reported 3-month SAD and that the European Medicines Agency recommends the use of 6-month SAD data. The ERG commented that 6-month SAD would be preferable to 3-month SAD because there remains a possibility of recovery from disability at 3 months. The ERG noted that the manufacturer provided evidence that a large proportion of patients in both groups of the trials did not have persistent disability (that is, their disability regressed). The ERG commented that meta-analysis of 6-month SAD was not provided by the manufacturer.

3.25  The ERG commented that a random effects model chosen by the manufacturer for meta-analyses of the placebo-controlled trials may not have been appropriate because of the small number of studies (2 or 3 in each analysis). The ERG noted that there were some differences between Study 2001 and the phase III trials TEMSO and TOWER. It also noted that a higher proportion of patients in Study 2001 received previous disease-modifying therapies compared with TEMSO and TOWER. It noted that Study 2001, as a proof of concept study, was small (61 patients per treatment arm) and just 36 weeks long, so relapse rates may not have been robust. Furthermore, it noted that EDSS scores were higher and more patients stopped treatment in the teriflunomide arm of Study 2001 than in the other trials. The ERG stated that these differences suggested that the studies were too heterogeneous to pool the results of Study 2001 with TOWER and TEMSO. It noted that Study 2001 was excluded from the 3-month SAD meta-analysis because of the short duration of this trial. The ERG commented that it was questionable whether Study 2001 should have been included in the analyses for the other outcomes because of its short duration and the differences between the arms in previous treatment.

3.26 The ERG noted that the TENERE trial may not have been adequately powered to detect statistically significant differences in all investigated outcomes. It commented that because TENERE was not a double-blind trial, there may be bias in the evaluation of the primary outcome (which relies on patient-reported symptoms). The ERG also noted that there were some differences in patient baseline characteristics between the 2 treatment arms, which make the results of the trial difficult to interpret (details were provided commercial in confidence and therefore cannot be presented here).

3.27  The ERG noted that the base-case MTC (post-2000) included all of the relevant comparators. Informal checks for consistency by the ERG did not identify major problems, but the ERG commented that comparison of Betaferon with placebo showed different results in the base-case MTC (post-2000) to those from the TENERE study, in terms of 3-month SAD. They noted the base-case MTC (post-2000) data indicated Betaferon was associated with a higher 3-month SAD than placebo. The 3 month SAD from the TENERE were provided commercially in confidence and cannot be presented here. In addition, the ERG stated that the difference was quite large between the direct comparison and the base-case MTC (post-2000) (HR 0.90, 95% CI 0.54 to 1.45) for the effect of teriflunomide on 3-month SAD compared to Rebif-44 (the direct comparison was provided commercially in confidence and cannot be presented here). The ERG noted that this inconsistency may have contributed to the favourable results for teriflunomide compared with the beta interferons generated by the MTC (particularly for the base-case analysis). It also noted that the results of the ‘all years’ MTC were more consistent with the direct trial results. The ERG commented that the relative effect of teriflunomide on 3-month SAD was a key driver in the economic model.

3.28  The ERG’s major criticism of the manufacturer’s MTC was that pre-2000 trials were excluded in the base-case analysis. It acknowledged the reasons given by the manufacturer (change in diagnostic criteria in 2000 from Poser to McDonald, and identification of patients earlier in the disease course). However, the ERG noted that the base-case MTC (post-2000) included 5 studies that had used the earlier Poser criteria. The ERG considered that a more appropriate approach would have been to conduct an ‘all years’ MTC with baseline relapse rate included as a covariate because it would have included all the trial data but would have accounted for any heterogeneity in baseline annualised relapsed rates. The ERG noted that the impact of the 2000 cut-off date was that all but 1 of the placebo-controlled trials of beta interferons and glatiramer acetate were excluded. It commented that although the manufacturer’s concerns about including older trials were justified to some extent, neither the base case nor the ‘all years’ analysis were optimal, and that omission of the placebo-controlled beta interferon trials from the base-case analysis reduced the reliability of the results.

3.29  The ERG reviewed the trials that were included in the MTC and noted that some were short, in both the base case and the ‘all years’ networks. For example, the network for the outcome of annualised relapse rate included 11 trials of less than or equal to 12 months’ duration. The network for the outcome of 3-month SAD included 3 trials of less than or equal to 12 months duration. The ERG again commented that 12 months is a short duration for assessing infrequent events such as multiple sclerosis relapse or confirmed progression. However, the ERG did not re-run the MTC analyses after excluding these trials of shorter duration. It commented that it was unclear what impact this may have, especially considering outcomes such as relapse and SAD.

3.30  The ERG reviewed the clinical-effectiveness evidence provided for the subgroups of people with highly active or rapidly evolving severe relapsing-remitting multiple sclerosis. It commented that the results were of limited value, because of factors provided by the manufacturer that were commercial in confidence.

3.31  The ERG noted that the manufacturer’s submission did not include a synthesis of adverse event data that could be readily checked against supporting tables. Furthermore, the relatively short duration of the placebo-controlled trials limited the assessment of any differences in mortality and less frequently reported adverse events. The ERG commented further that although a greater number of patients in the Rebif-44 arm in the TENERE trial stopped treatment because of adverse events, this should be interpreted in the light of differences in baseline characteristics (the details of which were provided commercial in confidence and therefore cannot be presented here). The ERG commented that the impact of this difference is unknown.

3.32  The ERG reviewed the manufacturer’s economic model and systematic review. It commented that the manufacturer undertook a comprehensive, well-rounded systematic literature review. During clarification, an error was identified in the manufacturer’s model, which was corrected throughout the ERG analyses.

3.33  The ERG conducted some sensitivity analyses to determine the key areas of uncertainty in the manufacturer’s model. It identified the following as having the most impact and conducted scenario analyses to explore them further:

• the choice of comparator (see section 3.34)
• the natural history and the rate of transition to secondary progressive multiple sclerosis (see section 3.35)
• the rate of progression (see section 3.36)
• the health-related quality of life associated with the more severe health states (see section 3.38).

3.34  The ERG noted the use of a blended comparator in the base case of the manufacturer’s model. It regarded this as inappropriate because it noted that it does not meet the NICE methods guide reference case, which needs ‘best practice’ to be used as the comparator. In addition, the manufacturer’s method for calculating the blended comparator, which used a weighted average of each individual treatment outcome as model inputs, was considered by the ERG to be inappropriate, because the outcomes of the average treatment effects are not the same as the average outcomes of the treatments because of the correlation between the costs and QALYs in the model. To address this, the ERG weighted the costs and QALYs for each individual treatment, the results of which are commercial in confidence by the manufacturer and therefore cannot be presented here. Overall, the ERG considered that the use of a blended comparator hides the effects of changes in the model because the different individual treatments may have different treatment effects compared with placebo.

3.35  The ERG reviewed how disability progression was captured in the manufacturer’s model. It noted that the model used the London Ontario data set (published in 1989) for predicting the initial distribution of EDSS and natural history progression of relapsing–remitting multiple sclerosis without treatment. The ERG stated that previous NICE technology appraisals have questioned the applicability of the London Ontario data set because of changes in multiple sclerosis care and because it did not collect data on patients whose disease regressed to a better EDSS state over time. The ERG noted that a substantial proportion of patients in the TEMSO trial who experienced SAD later improved. It also considered that the initial EDSS states and transition probabilities were taken from a population with more severe disease than the first-line population in which teriflunomide is expected to be used. The ERG therefore conducted analyses to explore each of the following:

• Using the initial EDSS distribution from the TEMSO and TOWER trials.
• Using the TEMSO and TOWER data to estimate disability progression in 2 analyses: patients with relapsing–remitting multiple sclerosis, and patients with secondary progressive multiple sclerosis.
• Using alternative rates of conversion from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis based on the London Ontario data set, calculated by the ERG.

With the patient access scheme discount was applied, teriflunomide dominated Rebif and the blended comparator for each of these disability progression scenarios.

3.36   The ERG noted that the effect of treatment on disability progression was estimated from the manufacturer’s base-case MTC (post 2000), and stated that these data were not robust because a large number of studies were excluded (by selecting only studies post-2000) and because of the heterogeneity across the included studies (see sections 3.27 to 3.29). The ERG highlighted the following concerns:

• Betaferon was estimated to be less effective at slowing disability progression compared with best supportive care.
• The estimate of 3‑month SAD for teriflunomide compared with Rebif-44 from the base-case MTC (post-2000) appeared to be more favourable towards teriflunomide compared with the direct head-to-head evidence in TENERE.
• The blended comparator masked treatment effects and subsequently favoured teriflunomide compared with each of the beta interferons individually.

3.37  The ERG conducted scenario analyses to explore the impact of different treatment effects. Firstly, it used the TENERE trial data, rather than MTC data, to estimate the relative treatment effect for teriflunomide compared with Rebif-44. Secondly, it tested the assumption that there was no difference in treatment effect between teriflunomide and Rebif-44. Finally the ‘all years’ MTC data were used to estimate the relative treatment effect of teriflunomide. Applying the patient access scheme price in these exploratory analyses, teriflunomide dominated the blended comparator or Rebif-44 in all scenarios.

3.38  The ERG commented on the utility values used in the model. It noted that the manufacturer’s base case used values derived from a 2005 UK multiple sclerosis survey (Orme et al. 2007), which have been criticised in previous NICE technology appraisals because of the low response rates, selection bias, unrepresentative population and patient-reported level of severity. The ERG noted that the TEMSO trial had collected health-related quality-of-life data using EQ-5D, although only for EDSS states 0–6. The ERG noted that the utility values from TEMSO were higher for all EDSS states than the estimates taken from Orme et al., which were the lowest values identified in the manufacturer’s literature review. The ERG considered the utility values from TEMSO to be more applicable to the treatment population because TEMSO better reflected patients who are likely to receive teriflunomide as a first-line treatment for relapsing–remitting multiple sclerosis. The ERG therefore explored 4 scenarios using alternative utility values:

• TEMSO data for EDSS state 0–6, and health-related quality-of-life data from Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 127) for EDSS states 7–9.
• TEMSO data for EDSS states 0–6, and an average of 4 studies for states 7–9.
• An average of 4 studies used for all EDSS states.
• TEMSO data for EDSS states 0–6, and the differences between states 7–9 observed in Orme et al. used to calculate states 7–9 from the TEMSO data.

Applying the patient access scheme price, teriflunomide dominated the blended comparator and Rebif-44 in all scenarios. The ERG considered that scenario 4 was the most representative of patients being treated with teriflunomide because it used utility data from the TEMSO trial (EDSS 0–6) for the baseline estimates of health-related quality of life and estimated utility differences between EDSS states 7–9 from a large UK-based survey (Orme et al.).

3.39  The ERG reviewed the costs included in the manufacturer’s model. It commented that there was uncertainty surrounding which costs were included in some of the sources used, particularly the direct non-health costs for the EDSS states. Furthermore, it noted that one source of costs (Karampampa et al. 2012, used in sensitivity analyses) included informal care costs such as productivity losses of the working caregivers, and that these do not meet the NICE reference case.  When the ERG investigated the impact of excluding non-health costs, teriflunomide still dominated the blended comparator and Rebif-44 when the patient access scheme discount was included.

3.40  The ERG presented an exploratory analysis comprising all of its preferred parameters, as follows:

• trial distribution of initial EDSS
• trial estimates of natural history
• ERG calculation of secondary progressive multiple sclerosis conversion
• treatment effects from the ‘all years’ MTC
• trial-based health-related quality of life data using the differences observed in the Orme et al. 2007 study to extrapolate the higher EDSS state values
• exclusion of non-health costs.

The resulting ICERs were similar to those in the manufacturer’s base case, although the total QALYs were higher and the total costs lower for each intervention. The ERG noted that the increase in total QALYs was because the EDSS states were less severe at the start of treatment, the model allows for improvements in disability (EDSS), and because utility values were derived from the trials (for EDSS states 0–6). The decrease in total costs was largely explained by the exclusion of non-health costs. The results of the ERG’s probabilistic analysis suggested that teriflunomide is more effective and more costly than glatiramer acetate, resulting in an ICER of £107,148 per QALY gained. However, teriflunomide dominated Rebif-44 and the blended comparator. Because of the uncertainty associated with the manufacturer’s MTC, the ERG also presented its preferred analysis using the manufacturer’s base-case MTC (post 2000), rather than the ‘all years’ MTC. As described in sections 3.27 to 3.29, by using the base-case MTC (post-2000) rather than direct trial results, Betaferon is less effective (in terms of 3-month SAD) than placebo. In addition, the hazard ratios comparing teriflunomide with each of the comparators are lower in the base case MTC (post-2000), and therefore more favourable to teriflunomide. The ERG’s deterministic analysis resulted in an ICER of £6266 per QALY gained for teriflunomide compared with glatiramer acetate, and teriflunomide dominated all other comparators.

3.41 The ERG noted the treatment becomes more cost effective if more patients stop treatment, and suggested that this is counterintuitive. The ERG conducted exploratory analyses to test for logical consistency and external validation of the manufacturer’s model. The ERG compared the change in QALYs, the change in costs and the ICERs compared with treatment without a disease-modifying therapy presented in previous NICE technology appraisals (Beta interferon and glatiramer acetate for the treatment of multiple sclerosis [NICE technology appraisal guidance 32], Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis [NICE technology appraisal guidance 127], and Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis [NICE technology appraisal guidance 254]). It noted that the manufacturer’s model estimated ICERs for the interferons and glatiramer acetate compared with treatment without disease-modifying therapy that were considerably higher than those presented for the UK risk-sharing scheme (Avonex: £175, 918 per QALY gained, Betaferon: dominated by treatment without disease-modifying treatment, Rebif-22: £82,098 per QALY gained, Rebif-44: £79,310 per QALY gained, glatiramer acetate: £142,703 per QALY gained), and that the ICER for teriflunomide compared with treatment without disease-modifying therapy was substantially lower than these ICERs.

3.42  The ERG commented on the subgroup analyses that compared teriflunomide with fingolimod and natalizumab for highly active relapsing-remitting and rapidly evolving severe relapsing-remitting multiple sclerosis, respectively. It did not consider the subgroup analyses to be reliable because of the very small number of patients included in each of the teriflunomide groups, and because the relative risks and hazard ratios were calculated from the specified subgroups combined with the natural history of the full relapsing–remitting multiple sclerosis population. The ERG also noted that, although the manufacturer stated that the patient population in the model was based on patients for whom beta interferons and glatiramer acetate were the appropriate comparators (that is, not in people with rapidly evolving severe or highly active relapsing-remitting multiple sclerosis), the manufacturer did not provide subgroup analyses that excluded people with rapidly evolving severe or highly active relapsing-remitting multiple sclerosis. Furthermore, it stated that only results from the TEMSO trial were used to calculate the teriflunomide effects. The ERG used the manufacturer’s corrected model, and assumed that teriflunomide in people with rapidly evolving severe or highly active relapsing-remitting multiple sclerosis has the same effectiveness as in the full relapsing–remitting multiple sclerosis population, to calculate the ICERs for teriflunomide in people with rapidly evolving severe or highly active relapsing remitting multiple sclerosis populations (that is, compared with natalizumab and fingolimod respectively). The patient access scheme price for fingolimod was not applied. When the patient access scheme for teriflunomide was included, teriflunomide was associated with a lower cost than both natalizumab and fingolimod, but also fewer QALYs.

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

4   Consideration of the evidence

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

4.1   The Committee heard from the clinical specialists and patient experts about the nature of the condition. It was aware that relapsing–remitting multiple sclerosis is a chronic, disabling, neurological condition that, as it progresses, can be life altering and have a substantial negative impact on quality of life and activities of daily living. The patient experts emphasised that, as the disease progresses, this can lead to the loss of independence and have implications for employment. The Committee heard from a patient expert that only 25% of people with multiple sclerosis are employed 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 do not work. The patient experts emphasised the importance of having access to new treatments that could reduce the number of relapses and therefore slow the accumulation of 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 wellbeing. A patient expert described experiencing 2 or 3 days of feeling very unwell from flu-like symptoms after injecting treatment, followed by 3 days of dreading the next injection, and commented that they had taken time off work because of the side effects of treatment. The Committee heard from the patient experts that some people find it difficult to inject because of the stigma attached with taking an injection. It also heard that because teriflunomide is given orally and has a different side-effect profile than currently available treatments, it would be very beneficial. The Committee understood that any delay in relapse and progression of disability or relief from using injectable treatments would have a positive impact on the lives of people with multiple sclerosis and their families.

4.2  The Committee discussed the management of relapsing–remitting multiple sclerosis and considered the likely position of teriflunomide in the treatment pathway for adults with this condition. It heard from the clinical specialists that 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, Extavia] or glatiramer acetate), in line with the Association for British Neurologists’ guidelines. The Committee heard from the clinical specialists that in UK clinical practice treatment varies and that there is no clear first-line treatment. The clinical specialists explained that the choice of whether to take glatiramer acetate or beta interferon, and which beta interferon to take, was a decision made between the clinician and the patient; taking into consideration the route and schedule of administration, the side-effect profile and how the drug is stored. The Committee was aware that beta interferons and glatiramer acetate were not recommended in Beta interferon and glatiramer acetate for the treatment of multiple sclerosis (NICE technology appraisal guidance 32). However, it acknowledged that after this guidance was issued, the Department of Health agreed a risk-sharing scheme with manufacturers through which disease-modifying treatments for multiple sclerosis can be provided to patients in the NHS at a level that the Department of Health considers to be cost effective, and that use of disease-modifying therapies has become firmly established practice in the NHS. The Committee was aware that the role of disease-modifying therapies decreases as a patient’s Expanded Disability Status Scale (EDSS) score increases, and stopping treatment is determined by the accumulation of disability (reaching EDSS 7) or by the development of secondary progressive multiple sclerosis. The Committee heard from the clinical specialists that in clinical practice, teriflunomide would be considered as a first-line treatment option alongside glatiramer acetate and the beta interferons, and would be used in line with the Association for British Neurologists’ guidelines, and that it would be stopped if the person’s condition converted to secondary progressive multiple sclerosis, or reached EDSS state 7.

4.3 The Committee discussed the management of rapidly evolving severe and highly active multiple sclerosis. It was aware that, in Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 127), natalizumab is recommended for treating people with rapidly evolving severe relapsing–remitting multiple sclerosis. The Committee heard from the clinical specialists that more aggressive disease is difficult to identify in the first 2 years of onset, but for these people natalizumab would be considered the most appropriate first-line treatment option. The Committee was aware that Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 254) recommends fingolimod for treating highly active relapsing–remitting multiple sclerosis in adults following previous treatment with beta interferon. It understood that in line with its marketing authorisation, fingolimod could not be considered as a first-line treatment or as a second-line treatment after natalizumab or glatiramer acetate. The clinical specialists highlighted to the Committee that because of the lack of treatment options for patients with rapidly evolving severe multiple sclerosis and highly active multiple sclerosis, teriflunomide may be considered as an option for these patients, but it would not be used routinely.

Clinical effectiveness

4.4 The Committee discussed the clinical-effectiveness evidence from the trials. The Committee understood that the marketing authorisation included all people with relapsing-remitting multiple sclerosis, but that the trials included people who had one relapse in the last year or two in the last two years, and therefore were patients with more severe relapsing-remitting multiple sclerosis than the general population with relapsing-remitting multiple sclerosis. It heard from the clinical specialists that the trial populations broadly represented patients who would be offered beta interferon or glatiramer acetate in the UK, in line with the Association of British Neurologists’ guidelines. The Committee therefore concluded that the trial populations appropriately represented the decision problem as these would be the people who would receive treatment with disease modifying treatment in the UK. The Committee agreed that there was sufficient evidence to conclude that compared with placebo, teriflunomide statistically significantly reduced annualised relapse rates in both the TEMSO and TOWER trials and the meta-analyses (see section 3.4), and  that the proportion of people who experienced 3-month sustained accumulation of disability (SAD) was reduced with teriflunomide compared with placebo and that this difference was statistically significant in the TEMSO trial and in the meta-analysis (see section 3.4). The Committee agreed, however, that there was no statistically significant difference between teriflunomide and placebo in 6-month SAD in either of the placebo controlled trials (see section 3.4). Furthermore they agreed that the TENERE trials and the mixed treatment comparison (MTC) showed that there was very little difference in effectiveness between teriflunomide and the beta interferons or glatiramer acetate (see sections 3.5 to 3.7). The Committee concluded that teriflunomide was clinically effective in reducing relapse rates compared with placebo, and that it may have a beneficial impact on accumulation of disability.

4.5 The Committee discussed the appropriateness of reporting 3-month SAD rather than 6-month SAD. It heard from the clinical specialists that recovery from relapse may continue for up to 12 months, but on average, recovery from the disabling effects of a relapse will be seen within 3 or 4 months. The clinical specialists stated that 6-month SAD is therefore a more appropriate outcome measure than 3-month SAD for measuring disability progression. The Committee was also aware that sustained disability progression confirmed for 6 months 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 was aware that most of the multiple sclerosis trials measured 3-month SAD. It acknowledged that this outcome had been considered in previous multiple sclerosis appraisals and that it therefore should be considered in its decision-making. The Committee concluded however that although sustained disability progression confirmed for 6 months provides a more robust indication of the treatment effect when measuring disability progression, in light of the lack of 6 month SAD data available, 3 month SAD data should be considered.

4.6  The Committee discussed the MTC presented by the manufacturer that compared teriflunomide with the beta interferons and glatiramer acetate. It noted that the manufacturer had presented a base-case MTC, which had excluded trials that recruited patients before the year 2000 (‘post-2000’), and one that included all trials (‘all years’) (see section 3.6). The Committee acknowledged that trials were excluded because of changes in diagnostic criteria, which has resulted, in part, in changes in baseline relapse rates over time, but were concerned that important trials were excluded as a result of the cut-off date, including all trials comparing beta interferons with placebo (see section 3.28). The Committee agreed that a MTC should include all available evidence, and that in this case adjusting the MTC for baseline relapse rates would account for any differences in relapse rates between trials. The Committee concluded that an ‘all years’ MTC, adjusted for baseline relapse rates, is needed to compare the effectiveness of teriflunomide with beta interferons and glatiramer acetate.

4.7  The Committee discussed the TENERE trial which did not show any statistically significant differences in annualised relapse rate between teriflunomide and the active comparator Rebif-44 (interferon beta-1a, 44 micrograms) (see section 3.5). The Committee heard from the manufacturer that the primary outcome of the trial was time to failure and that the trial was not a non-inferiority or equivalence trial. It had been powered to test the hypothesis that people will stay on an oral drug with a different side-effect profile longer than on an injectable drug. The Committee noted that the TENERE trial was designed to show the benefits of an oral drug and had not been designed to compare the effectiveness of teriflunomide with Rebif. Therefore, the Committee concluded that the effectiveness of teriflunomide compared with Rebif-44 was still uncertain.

4.8  The Committee discussed the evidence for the effectiveness of teriflunomide in patients with rapidly evolving severe relapsing–remitting multiple sclerosis or highly active relapsing–remitting multiple sclerosis. The Committee agreed with the ERG that the evidence was insufficient to make any conclusions about the clinical effectiveness of teriflunomide compared with natalizumab and fingolimod in the respective subgroups. It noted that the clinical specialists confirmed that teriflunomide would not be routinely used in people with aggressive disease (see section 4.3). The Committee concluded that the evidence presented by the manufacturer was insufficient to make recommendations for teriflunomide in these subgroups.

4.9  The Committee was aware of the adverse effects associated with teriflunomide (see section 3.10). The Committee discussed the risk of teratogenicity with teriflunomide, and the long ‘washout’ period (2 years) needed for women to have stopped treatment before trying to conceive. It agreed that this was a particular concern because multiple sclerosis affects women of childbearing age. The Committee recognised, however, that none of the disease-modifying drugs are recommended in pregnancy, and therefore it was a concern for all the multiple sclerosis treatments (although the washout period with teriflunomide is longer). The Committee considered this a notable concern, but concluded that no additional monitoring for teriflunomide would be needed over that already given for treatment with the disease-modifying therapies and therefore it would not need to be reflected in the modelling for teriflunomide.

Cost effectiveness

4.10 The Committee discussed the manufacturer’s modelling assumptions, the incremental cost-effectiveness ratios (ICERs) estimated in the manufacturer’s economic model, and the ERG’s critique and exploratory analyses. The Committee understood that the manufacturer had submitted a model structurally similarly to models used in previous NICE technology appraisals. It noted that the manufacturer had used a blended comparator of beta interferons and glatiramer acetate in the base case, but had also presented incremental analyses, and that the ERG had presented incremental analyses of its preferred scenarios. The Committee noted the ERG’s reservations of using a blended comparator, because the outcomes of the average treatment effects are not the same as the average outcomes of the treatments and because the true incremental effect of a new treatment may be obscured or exaggerated (see section 3.34). The Committee concluded that an incremental approach including all comparators individually was more appropriate.

4.11 The Committee noted that the main driver of the manufacturer’s model was disease progression, and that this was estimated using 3-month SAD data derived from the manufacturer’s base-case MTC (post-2000). The Committee was concerned that this approach excluded all trials comparing beta interferons with placebo (see sections 3.28). The Committee recognised that the baseline relapse rates had changed over time. However, it agreed that all relevant data available should be included in the analyses, and that the data could be adjusted to account for the change in baseline relapse rate over time. The Committee concluded that the ‘all years’ MTC, adjusted for baseline relapse rates, was needed to determine the cost effectiveness of teriflunomide in relapsing–remitting multiple sclerosis.

4.12  The Committee discussed how the manufacturer modelled the natural history of multiple sclerosis using the London Ontario data set. The Committee noted the inherent limitations associated with using the London Ontario data set 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. It agreed 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 also heard from the clinical specialists that once patients are in higher EDSS states, relapses were less likely to occur; therefore the possibility for patients to move to lower EDSS states was less plausible. The Committee concluded that using trial data was a more appropriate way to model the natural history of disease currently experienced in the UK as done by the ERG with sensitivity analyses using the placebo arm of the trial data to model the natural history of multiple sclerosis.

4.13 The Committee heard from the clinical specialists that the health-related quality of life of people with multiple sclerosis was more closely related to EDSS state than to the clinical form of multiple sclerosis (that is, relapsing–remitting or secondary progressive). The clinical specialists stated that it is difficult to clearly identify when the condition becomes secondary progressive multiple sclerosis, and so it is also difficult to gauge its impact on health-related quality of life. The Committee was concerned that the manufacturer had used utility values from Orme et al. (2007), rather than EQ-5D data collected directly from the trials (see section 3.14). The Committee acknowledged that utility values and progression to secondary progressive multiple sclerosis were not key drivers of the model, but concluded that an approach incorporating trial-derived utility values, when possible, would be appropriate.

4.14  The Committee discussed the disutility values incorporated in the model to reflect caregiver disutility, as in previous multiple sclerosis appraisals, and considered this to be appropriate. The Committee noted that the disutility values for adverse events included in the model were small (see section 3.14). However, it understood that the disutility values did not have a large impact on the ICERs and therefore concluded that it did not need to consider the disutility values in the model further.

4.15 The Committee considered that the duration of treatment benefit on disease progression remained constant over time in the manufacturer’s model, that is, there was no option for the treatment benefit to decrease over time. It recognised that the long-term benefit was largely unknown but that it had a large impact on the outputs of the model. The Committee heard from the clinical specialists that they could not be confident that the treatment effect would not wane. The Committee noted that the manufacturer had not conducted any sensitivity analyses to explore this, and that waning of treatment effect was included in Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis (NICE technology appraisal guidance 254). The Committee concluded that it would be necessary to understand the impact of waning of treatment effect on the ICERs for teriflunomide and considered that an appropriate approach would be to assume that the treatment effect decreased to 75% at 2 years and 50% at 5 years.

4.16  The Committee considered the cost data used in the manufacturer’s base case and the ERG’s comments on these, particularly with regard to the inclusion of non-health costs (see section 3.39). It was concerned that the non-health costs contributed to a high proportion of the costs in the model, and it was unclear what proportion of these costs would include personal social services, and therefore would be appropriately included in the NICE reference case. The Committee understood that removing all non-health costs was an appropriate, albeit conservative, approach to adjusting the model’s cost inputs to follow NICE’s preferred perspective for analyses, unless it was possible to specify which non-health costs were in line with the reference case. The Committee agreed that given the large proportion of costs in the model that were non-health costs, it was important to understand the impact of these on the ICER. It therefore concluded that it would be beneficial to be presented with analyses both with and without the non-health costs, and the proportion of non-health costs in line with the reference case (if available).

4.17  The Committee discussed the exploratory analyses presented by the ERG, taking into account its preferred scenarios. The Committee agreed that it was more appropriate to use trial data to determine the initial EDSS distribution and the natural history progression (see section 3.35) because this was representative of the relevant patient population, and enabled patients to move to a better EDSS state. The Committee agreed with the approach to calculating secondary progressive multiple sclerosisconversion. It agreed that the utility values should be derived from the trials where possible, and using values from Orme et al. (2007) to calculate the higher EDSS states. Finally, the Committee agreed that conservatively removing non-health costs from the total costs was an appropriate base case approach (see section 4.16).

4.18  The Committee acknowledged that the manufacturer had presented analyses that included the realistic assumption that people would receive more than 1 disease-modifying therapy (treatment sequencing). The model enabled a sequence of 2 treatments after teriflunomide or the blended comparator. Treatments that were included as second and third line were the blended comparator, fingolimod, natalizumab or best supportive care. The Committee recognised that no specific treatment sequence was standard practice in the NHS. However, it agreed that it was important to establish how sensitive the ICERs were to the inclusion of more than 1 treatment. Because the Committee had agreed that it was not appropriate to use a blended comparator, it concluded that the effect on cost effectiveness of sequencing without a blended comparator needed to be explored.

4.19 The Committee noted the ERGs concern about the external validity of the manufacturer’s model (see section 3.41). The Committee was concerned that the ICERs estimated by the ERG for the currently available treatments (interferons and glatiramer acetate) compared with treatment without disease modifying therapies were higher than in the risk sharing scheme. However, the Committee was reassured that the ICER for teriflunomide compared with treatment without disease modifying therapies was lower than that for the interferons and glatiramer acetate. 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 cost effectiveness of current active treatments (all beta interferons, glatiramer acetate) compared with treatment without disease modifying therapies were to those in the NHS risk-sharing scheme for multiple sclerosis.

4.20  The Committee considered the ICERs presented by the manufacturer and the ERG. It agreed with the ERG’s preferred scenario (see section 4.17), with the exception that the Committee would have preferred the ‘all years’ MTC to be adjusted for baseline relapse rate. The Committee acknowledged that the incremental analysis gave an ICER for teriflunomide of £107,000 per quality-adjusted life year (QALY) gained compared with glatiramer acetate, using the ERG’s favoured scenario (without the baseline adjustment for relapse rate), and that teriflunomide dominated the beta interferons. The Committee recognised that making 1 change to the ERG’s most plausible scenario, by using the base-case MTC (post 2000) rather than the ‘all years’ MTC, reduced the ICER compared with glatiramer acetate to £6000 per QALY gained, and that teriflunomide continued to dominate the beta interferons. The Committee acknowledged that the most plausible ICER was very uncertain, but may lie in the range of £6000 to £107,000 per QALY gained. Therefore the Committee was minded not to recommend teriflunomide 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:

• Revised probabilistic analyses that:

-     use ‘all years’ MTC data adjusted for baseline annualised relapse rates

-     incorporate the inputs used in the ERG preferred scenario in which:

à      trial data are used to estimate the initial EDSS distribution and the natural history of progression

à      the ERG’s amended calculation of secondary progressive multiple sclerosis conversion is used

à      non-health costs are excluded (if non-health costs related to personal social services can be clearly identified, these can be included), with a sensitivity analysis including all non-health costs and

à      utilities are derived from the trials, using the differences observed in the Orme et al. (2007) study to extrapolate the higher EDSS state values

-     include waning of treatment effect, with 75% treatment effect after 2 years and 50% treatment effect after 5 years.

-     present probabilistic ICERs in a fully incremental analysis and as pairwise comparisons

• include pairwise comparisons for the probabilistic cost-effectiveness estimates for plausible treatment sequencing, reflecting UK clinical practice. For example:

-     teriflunomide, Rebif-44 and fingolimod compared with Rebif-44, fingolimod and no disease-modifying therapy

-     teriflunomide, Rebif-44 and glatiramer acetate compared with Rebif-44, glatiramer acetate and no disease-modifying therapy

• Pairwise comparisons for the probabilistic cost-effectiveness estimates for the current active treatment (all beta interferons, 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

4.21  The Committee discussed whether teriflunomide was innovative. It recognised the limitations of the current treatments in terms of their side-effect profile and administration methods and agreed that an oral treatment, with a different side-effect profile, would be beneficial for people with relapsing–remitting multiple sclerosis. The Committee discussed if there were health-related benefits associated with an oral treatment that were not captured in the modelling. The manufacturer’s economic model assigned different disutilities for treatment-specific adverse events, including injection site reactions. Therefore, some of the benefits of oral treatment had been captured, but possibly not all. The Committee concluded that teriflunomide was innovative but that additional health-related quality-of-life benefits related to the oral treatment may not have been captured fully, and that the ICER may decrease when the benefits oral treatment were taken into consideration.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title:		Section
Key conclusion
The Committee is minded not to recommend teriflunomide 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
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee was aware that relapsing–remitting multiple sclerosis is a chronic, disabling, neurological condition that, as it progresses, can be life altering and have a substantial negative impact on quality of life and activities of daily living. The Committee understood that current treatments all need to be injected, and can be associated with unpleasant side effects. The Committee concluded that any delay in relapse and progression of disability or relief from using injectable treatments would have a positive impact on the lives of people with multiple sclerosis and their families.	4.1
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 agreed that as an oral treatment, teriflunomide offered a step change for treating relapsing-remitting multiple sclerosis which could have a substantial impact on the quality of life for people with relapsing-remitting multiple sclerosis. It concluded that the quality of life benefits of an oral treatment were not fully captured in the QALY.	4.1, 4.21
What is the position of the treatment in the pathway of care for the condition?		Teriflunomide would be considered as a first-line treatment option alongside glatiramer acetate and the beta interferons, and would be used in line with the Association for British Neurologists’ guidelines, and that it would be stopped if the person’s condition converted to secondary progressive multiple sclerosis, or reached EDSS state 7.	4.2
Adverse reactions		The Committee understood that teriflunomide is associated with diarrhoea, nausea, vomiting, increased levels of alanine aminotransferase, parathesias and dysesthesias, infections and alopecia. The Committee discussed the risk of teratogenicity with teriflunomide, and the long ‘washout’ period (2 years) needed for women to have stopped treatment before trying to conceive. It agreed that this was a particular concern because multiple sclerosis affects women of childbearing age. The Committee considered this a notable concern, but concluded that no additional monitoring for teriflunomide would be needed over that already given for treatment with the disease-modifying therapies and therefore it would not need to be reflected in the modelling for teriflunomide.	3.10, 4.9
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The manufacturer provided evidence from 3 phase III clinical trials, a phase II clinical trial, a meta-analyses and a mixed treatment comparison. 2 of the phase III clinical trials, and the phase II clinical trial, compared the effectiveness of teriflunomide with placebo and were well conducted. The other phase III clinical trial compared the effectiveness of teriflunomide with Rebif-44 and was not powered to detect statistically significant differences in all the outcomes. The ERG noted that there were differences in baseline characteristics that make the results of the trial difficult to interpret. The ERG commented that a random effects model, chosen by the manufacturer for the meta-analyses, may not have been appropriate because of the small number of trials included, and stated that the studies may be too heterogenous to pool Study 2001 with TOWER and TEMSO. The ERG stated that the MTC was inclusive, and that informal checks for consistency did not identify any major problems. It however stated that it was not appropriate to exclude trials with patient recruitment prior to the year 2000 (as the manufacturer had done for the base case MTC), and commented that an ‘all years’ MTC was more appropriate.	3.1, 3.26, 3.25, 3.28
Relevance to general clinical practice in the NHS		The Committee heard from the clinical specialists that in clinical practice, teriflunomide would be considered as a first-line treatment option alongside glatiramer acetate and the beta interferons, and would be used in line with the Association for British Neurologists’ guidelines, and that it would be stopped if the person’s condition converted to secondary progressive multiple sclerosis, or reached EDSS state 7.	4.2
Uncertainties generated by the evidence		The Committee agreed that all evidence should be included and therefore an ‘all years’ MTC adjusted for baseline relapse rates would be more appropriate.  The Committee was aware that although a statistically significant improvement in 3-month SAD was observed with teriflunomide, this was not seen for 6-month SAD. The Committee concluded that teriflunomide may have a beneficial impact on accumulation of disability. The Committee noted that the TENERE trial was designed to show the benefits of an oral drug and had not been designed to compare the effectiveness of teriflunomide with Rebif. Therefore, the Committee concluded that the effectiveness of teriflunomide compared with Rebif-44 was still uncertain. The Committee agreed there was insufficient evidence to make recommendations for teriflunomide for people with rapidly evolving severe relapsing–remitting multiple sclerosis or highly active relapsing–remitting multiple sclerosis	4.4, 4.5, 4.6, 4.7, 4.8
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee agreed there was insufficient evidence to make recommendations for teriflunomide for people with rapidly evolving severe relapsing–remitting multiple sclerosis or highly active relapsing–remitting multiple sclerosis	4.8
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee concluded that teriflunomide was clinically effective in reducing relapse rates compared with placebo, and that it may have a beneficial impact on accumulation of disability. It agreed that the TENERE trials and the mixed treatment comparison (MTC) showed that there was very little difference in effectiveness between teriflunomide and the beta interferons or glatiramer acetate.	4.4
Evidence for cost effectiveness
Availability and nature of evidence		The manufacturer provided a de novo economic model which the Committee understood to be structurally similarly to models used in previous NICE technology appraisals.	4.10
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee recognised the uncertainty of using a blended comparator and agreed that an incremental approach including all comparators individually was more appropriate. The Committee noted the ERGs concern about the external validity of the manufacturer’s model, and agreed that to ensure the manufacturer’s economic model was appropriate for decision-making, the manufacturer needed to test for externally validity by showing how similar the cost effectiveness estimates of current active treatments (all beta interferons, glatiramer acetate) compared with treatment without disease modifying therapies were to those in the NHS risk-sharing scheme for multiple sclerosis. The Committee agreed with the most plausible scenario presented by the ERG, in that the Committee agreed that it was more appropriate to use trial data to determine the initial EDSS distribution and the natural history progression because this was representative of the relevant patient population, and enabled patients to move to a better EDSS state. The Committee agreed with the approach to calculating secondary progressive multiple sclerosis conversion. It agreed that the utility values should be derived from the trials where possible, and using values from Orme et al. (2007) to calculate the higher EDSS states. Finally, the Committee agreed that conservatively removing non-health costs from the total costs was an appropriate base case approach, unless non-health costs related to personal social services can be clearly identified. They commented that sensitivity analysis including all non-health costs would be informative. The Committee agreed that an ‘all years’ MTC adjusted for baseline annualised relapse rates should be used. The Committee agreed that it would be necessary to understand the impact of waning of treatment effect on the ICERs for teriflunomide and considered that an appropriate approach would be to assume that the treatment effect decreased to 75% at 2 years and 50% at 5 years. The Committee concluded that the effect on cost effectiveness of sequencing without a blended comparator needed to be explored.	3.35, 4.6, 4.10, 4.15 4.16, 4.19, 4.20,
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The Committee agreed that as an oral treatment, teriflunomide offered a step change for treating relapsing-remitting multiple sclerosis which could have a substantial impact on the quality of life for people with relapsing-remitting multiple sclerosis. It concluded that the quality of life benefits of an oral treatment were not fully captured in the QALY.	4.1, 4.21
Are there specific groups of people for whom the technology is particularly cost effective?		No
What are the key drivers of cost effectiveness?		The Committee was aware that the key drivers of the economic model were the choice of comparator, disease progression, the natural history, the rate of transition to secondary progressive multiple sclerosis, and health related quality of life associated with more severe health states.	3.33
Most likely cost-effectiveness estimate (given as an ICER)		The Committee acknowledged that the most plausible ICER was very uncertain, but may lie in the range of £6000 to £107,000 per QALY gained compared with glatiramer. Therefore the Committee was minded not to recommend teriflunomide for treating adults with relapsing–remitting multiple sclerosis as a cost-effective use of NHS resources.	4.20
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer of teriflunomide 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 the discount is commercial in confidence.	2.3
End-of-life considerations		Not applicable
Equalities considerations and social value judgements		No potential equality considerations were raised.

 

5  Implementation

5.1 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

• 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

NICE is developing the following guidance (details available from www.nice.org.uk):

• Dimethyl fumarate for treating relapsing–remitting multiple sclerosis. NICE technology appraisal. Publication expected January 2014.
• 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 October 2014.

7   Proposed date for review of guidance

NICE proposes that the guidance on this technology is considered for review by the Guidance Executive when the review of NICE Technology Appraisal 32, NICE Technology Appraisal 127, and NICE Technology Appraisal 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.

Ken Stein
Vice Chair, Appraisal Committee
September 2013

8  Appraisal Committee members 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 and Outcomes Research, Merck Sharp & Dohme

Dr Sanjeev Patel

Consultant Physician and 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.

Melinda Goodall

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:

• Fayter D, Spackman E, Epstein D et al., Teriflunomide for treating relapsing forms of 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:

• Genzyme

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
• Biogen

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 teriflunomide by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Waqar Rashid, Consultant and Honorary Clinical Senior Lecturer in Neurology, Brighton and Sussex University Hospitals NHS Trust, nominated by the Multiple Sclerosis Society - clinical specialist
• Professor Neil Scolding, Consultant Neurologist, Bristol, nominated by the Association of British Neurologists - clinical specialist
• Nick Rijke, Director of Policy and Research, the Multiple Sclerosis Society, nominated by the Multiple Sclerosis Society - patient expert
• Joanne Thomson, nominated by the Multiple Sclerosis Trust - 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.

• Genzyme