1 Appraisal Committee's preliminary recommendations

1.1 The Committee is minded not to recommend alemtuzumab within its marketing authorisation, that is, for treating adults with relapsing–remitting multiple sclerosis with active disease defined by clinical or imaging features.

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:

• sustained accumulation of disability lasting 6 months as a primary outcome measure in the mixed treatment comparison, and incorporating the results into the economic model
• an 'all years' mixed treatment comparison that is adjusted for baseline relapse rates
• the intention-to-treat analyses developed for the CAMMS223, CARE‑MS I and CARE‑MS II trials adjusted for baseline Expanded Disability Status Scale (EDSS) only (unadjusted for country or region)
• EQ‑5D data from the CARE‑MS I and CARE‑MS II trials
• an amendment to the model to allow improvements in patients’ EDSS states
• an amendment to the model incorporating the observed deaths from the trial data
• a reduction in efficacy for alemtuzumab starting at 3 or 5 years
• additional costs of other licensed relapsing-remitting multiple sclerosis treatments after alemtuzumab treatment failure
• a time-dependent re-treatment rate for alemtuzumab
• removing the mid-cycle correction for the costs of alemtuzumab
• increasing the number of monitoring and neurology visits for patients treated with alemtuzumab and additional monitoring after re-starting alemtuzumab treatment
• higher health state costs used in the Evidence Review Group’s analyses
• costs associated with adverse effects of treatment including renal failure, renal transplantation, dialysis, and death
• baseline characteristics from patients in the alemtuzumab trials instead of from the UK Risk Sharing Scheme, and rates of disease progression incorporating the characteristics of the placebo group from the TOWER and TEMSO trials instead of data from the London Ontario data set.

Both the individual impacts and the combined impact of all amendments on the probabilistic base-case incremental cost-effectiveness ratios (ICERs) for the active relapsing–remitting multiple sclerosis population should be presented. A fully incremental analysis, including beta interferons and glatiramer acetate as comparators, incorporating all the Committee’s requested amendments should be presented.

 

2 The technology

2.1 Alemtuzumab (Lemtrada, Genzyme) is an antibody that binds to cells of the immune system (B and T cells), causing their destruction. The way in which alemtuzumab slows the decline of relapsing–remitting multiple sclerosis is not fully understood. Alemtuzumab has a UK marketing authorisation for treating adults with relapsing–remitting multiple sclerosis with active disease defined by clinical or imaging features. The recommended dosage of alemtuzumab is 12 mg/day administered by intravenous infusion for 2 treatment courses. The initial treatment course lasts 5 consecutive days, followed 12 months later by the second treatment course of 3 consecutive days.

2.2 The summary of product characteristics lists the following adverse reactions for alemtuzumab: autoimmunity (idiopathic thrombocytopenic purpura, thyroid disorders, nephropathies [kidney diseases or damage], cytopenias [reduced blood cell numbers]), infusion-associated reactions, rash, headache, fever and respiratory tract infections. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3 The indicative price of alemtuzumab is £7,045 per 12mg vial which equates to £56,360 for the full course of treatment consisting of 5 daily consecutive 12 mg doses in year 1, followed by 3 daily consecutive 12 mg doses 12 months later in year 2. The price of alemtuzumab has not yet been agreed between the Department of Health and Genzyme. However, the Department of Health has exceptionally agreed for this indicative price to be used for the purpose of this appraisal. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer's submission

The Appraisal Committee’s remit was to appraise the clinical and cost effectiveness of alemtuzumab within its licensed indication for the treatment of relapsing–remitting multiple sclerosis. The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of alemtuzumab 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 by systematic review, from:

• 2 phase III randomised controlled clinical trials: CARE‑MS I (n=581, median follow-up of 2 years), and CARE‑MS II (n=1046, median follow-up of 2 years)
• 1 phase II trial: CAMMS223 (n=334, maximum follow-up of 3 years extended by a follow-up period of 4 years from final alemtuzumab dose)
• 1 extension study: CAMMS03409 (n=1322, median follow-up of 7.1 years), which enrolled people with relapsing–remitting multiple sclerosis from the CAMMS223, CARE‑MS I and CARE‑MS II trials. In this study, all patients received alemtuzumab as needed, regardless of prior treatment.

In addition, the manufacturer submitted a direct meta-analysis of the above-listed trials and a mixed treatment comparison to compare alemtuzumab with other disease-modifying treatments for relapsing–remitting multiple sclerosis (section 3.7).

3.2 CAMMS223, CARE‑MS I and CARE‑MS II compared the effectiveness of 12 mg alemtuzumab (with an additional arm receiving 24 mg per infusion in CAMMS223 only) with subcutaneous interferon beta‑1a (small initial doses, gradually increasing to 44 micrograms 3 times weekly). All 3 trials included sites in the UK. All 3 trials specified the number of previous relapses patients must have had before they could enrol. For CAMMS223 this was at least 2 relapses in the previous 2 years. For CARE‑MS I and CARE‑MS II this was at least 2 relapses within the previous 2 years, with at least 1 within the previous year. CARE‑MS I and CAMMS223 included patients with an Expanded Disability Status Scale (EDSS) score between 0 and 3 (in which 0 means no disability and no signs of impairment in any functional system and 3 means unimpaired walking, but either moderate disability in 1 functional system or mild disability in 3 or 4 functional systems). CARE‑MS II included patients with an EDSS score between 0 and 5 (in which 5 means disability severe enough to impair normal daily activities and the person’s ability to work a full day without special provisions, but they are still able to walk for 200 metres without aid or rest). All patients in CARE‑MS II had to have previously received disease-modifying treatment with beta interferon or glatiramer acetate for 6 months in the preceding 10 years (the inclusion criteria also specified that more than 1 multiple sclerosis relapse had to have occurred while receiving these treatments), while patients in CARE‑MS I and CAMMS223 did not.

3.3 The co-primary outcomes of the 3 trials were time to the onset of sustained accumulation of disability (specified as lasting for 6 months for CARE‑MS I and CARE‑MS II) and relapse rate. In the trials, patients were assessed quarterly using the EDSS to determine disability, and were assessed as needed for suspected relapses. Sustained accumulation of disability was defined as an increase lasting for 6 months of at least 1.5 points for people with a baseline EDSS score of 0, or 1.0 point for people with a baseline EDSS score of 1.0 or more. A relapse was defined as new or worsening neurological symptoms attributable to relapsing–remitting multiple sclerosis, lasting at least 48 hours, without fever, after at least 30 days of clinical stability, with an objective change on neurological examination. Data from CAMMS223 were analysed by intention to treat, and adjusted for country and baseline EDSS score, as prespecified in the statistical plan. In CARE‑MS I and CARE‑MS II only patients who had received at least 1 dose of trial medication were included in the analysis (that is, a modified intention-to-treat analysis). In CARE-MS II the analysis was also limited to patients who had followed the trial protocol (excluding patients who had not met all inclusion criteria). The results were adjusted for region.

3.4 In CARE‑MS I the rates of sustained accumulation of disability did not differ between people taking alemtuzumab and people taking subcutaneous interferon beta‑1a. In CARE‑MS II 13% of people in the alemtuzumab treatment group had sustained accumulation of disability lasting for 6 months, compared with 20% in the subcutaneous interferon beta‑1a group. This corresponded to a 42% improvement with alemtuzumab (HR 0.58, 95% confidence interval (CI) 0.38 to 0.87; p=008). In CAMMS223 alemtuzumab statistically significantly reduced the risk of sustained accumulation of disability by 75% compared with subcutaneous interferon beta‑1a (HR 0.25, 95% CI 0.11 to 0.57, p<0.001). A separate extended follow-up study of CAMMS223 showed that over 5 years, alemtuzumab reduced the risk of sustained accumulation of disability lasting for at least 6 months by 69% compared with subcutaneous interferon beta‑1a (HR 0.31, 95% CI 0.16 to 0.60, p = 0.0005).

3.5 Alemtuzumab reduced the relapse rate compared with subcutaneous interferon beta‑1a by 54.9% in CARE‑MS I (HR 0.45, 95% CI 0.32 to 0.63, p<0.0001), by 49.4% in CARE‑MS II (HR 0.51, 95% CI 0.39 to 0.65, p<0·0001) and by 69% in CAMMS223 (HR 0.31, 95% CI 0.18 to 0.52, p<0.001). The extended follow-up study of CAMMS223 showed that over 5 years, alemtuzumab lowered the rate of relapse by 66% compared with subcutaneous interferon beta‑1a (HR 0.34, 95% CI 0.20 to 0.57, p<0.0001).

3.6 The manufacturer presented data from CARE‑MS II and CAMMS223 (and its separate study extension) to compare alemtuzumab with subcutaneous interferon beta‑1a in a subgroup of people with rapidly evolving severe relapsing–remitting multiple sclerosis (size of subpopulation not available). The manufacturer pooled the results of the 12-mg and 24-mg alemtuzumab arms of CAMMS223, considering that results in each arm were sufficiently similar to allow this. The manufacturer stated that the analyses showed that the effectiveness of alemtuzumab compared with subcutaneous interferon beta‑1a in the rapidly evolving severe relapsing–remitting multiple sclerosis subgroup was comparable to or greater than that seen in the overall trial populations. The reduction of risk in sustained accumulation of disability lasting at least 6 months was 51% in CARE‑MS II (no p value reported) and 65% (p=0.036) in the pooled group of CAMMS223. The analysis also indicated a reduction in relapse rates of 56% (p=0.0018) in the rapidly evolving severe relapsing–remitting multiple sclerosis subgroup of CARE‑MS II and 81% (p<0.0001) in the pooled dose group of CAMMS223.

3.7 The manufacturer presented a mixed treatment comparison that compared alemtuzumab with each of the treatments in the decision problem (subcutaneous interferon beta‑1a, intramuscular interferon beta‑1a, interferon beta‑1b, glatiramer acetate, natalizumab and fingolimod). The manufacturer included 30 clinical trials identified in the systematic literature review, all of which recruited patients from the year 2000 onwards, and in which at least 80% of the patients had relapsing–remitting multiple sclerosis (the ‘base-case mixed treatment comparison’). The manufacturer justified the year 2000 as an appropriate cut-off point because annualised relapse rates have fallen in recent years and because the diagnostic criteria used in multiple sclerosis trials have changed. The manufacturer provided a separate ‘all years’ analysis that, in addition, included trials recruiting patients before the year 2000. The outcomes in the base-case mixed treatment comparison were annualised relapse rate, proportion of patients who were relapse free, sustained accumulation of disability lasting for 3 months, sustained accumulation of disability lasting for 6 months, discontinuation of treatment rate and discontinuation of treatment rate because of adverse events. In the base-case mixed treatment comparison, alemtuzumab led to statistically significantly lower annualised relapse rates than the interferons and glatiramer acetate. For the 3 month sustained accumulation of disability outcome, alemtuzumab was statistically significantly lower than the interferons, however the difference between alemtuzumab and glatiramer acetate was not statistically significant. For the 6 month sustained accumulation of disability outcome, alemtuzumab was statistically significantly lower than subcutaneous interferon beta‑1a (44 micrograms). While the point estimates for alemtuzumab compared with glatiramer acetate favoured alemtuzumab, the difference was not statistically significant. The detailed results of the mixed treatment comparison were considered confidential by the manufacturer and therefore cannot be reported here.

3.8 The manufacturer also carried out 2 separate mixed treatment comparisons of alemtuzumab for the subgroups of patients with highly active disease despite treatment with beta interferon (from CARE‑MS II) and rapidly evolving severe disease (from CARE‑MS I and II and CAMMS223). For the highly active disease despite beta-interferon subgroup, alemtuzumab had a lower annualised relapse rate than fingolimod, however the difference was not statistically significant. For the outcome of 3 month sustained accumulation of disability, alemtuzumab was lower than fingolimod but again the difference was not statistically significant. For the rapidly evolving severe disease subgroup, alemtuzumab had a lower annualised relapse rate than natalizumab, however the difference was not statistically significant. No difference was found between alemtuzumab and natalizumab in the effect on 3 month sustained accumulation of disability. Neither of the subgroup analyses included the outcome of 6 month sustained accumulation of disability. The detailed results of this mixed treatment comparison were considered confidential by the manufacturer and therefore cannot be reported here.

3.9 In a pooled analysis of CARE‑MS I, CARE‑MS II and CAMMS223 results, most patients reported at least 1 adverse event, the majority of which were mild or moderate in severity. The most common adverse events were headache, rash, fever and multiple sclerosis relapse. The incidence of serious adverse events as reported at the end of the trials from the European Public Assessment Report (EPAR) was 18.3% in both the alemtuzumab and comparator arms. Independent investigators considered that the adverse events were related to alemtuzumab in 7.1% of all patients receiving 12 mg alemtuzumab and to subcutaneous interferon beta‑1a in 1.6% of all patients receiving subcutaneous interferon beta‑1a. The most frequently reported serious adverse events associated with alemtuzumab were multiple sclerosis relapse (6.1%), pneumonia (0.4%), autoimmune thrombocytopenia (0.4%), gastroenteritis (0.4%), appendicitis (0.4%) and hives (0.4%). Four people developed idiopathic thrombocytopenic purpura. More thyroid-related adverse events were observed in the alemtuzumab arm of the trial (16.6%) than in the subcutaneous interferon beta‑1a arm (5.2%). Thyroid-related adverse events were observed in 36.2% (at 4 years) and 44.7% (at 8 years) of patients in the alemtuzumab 12 mg/day group. The highest incidence of thyroid-related adverse events was observed between 24 and 42 months after the first treatment cycle. Other serious adverse events observed throughout the clinical trials included infections and renal disease. With the exception of thyroid disorders, administering more than 2 treatment cycles of alemtuzumab did not result in increased frequencies of common adverse events or clinically important events which had not already been observed. Eight people died during the clinical trials; 7 of these people had received alemtuzumab, and the EPAR states that the investigator judged that 3 deaths were possibly or likely to have been related to alemtuzumab treatment.

3.10 The manufacturer assessed health-related quality of life during the phase II and III trials using the Short-Form Health Survey (SF‑36), the Functional Assessment of Multiple Sclerosis (FAMS) and the EuroQoL‑5D (EQ‑5D) questionnaire. In CAMMS223, patients were asked to complete the SF‑36 every 6 months for 3 years, but not the FAMS or EQ-5D. In CARE‑MS I and II, patients were asked to complete the SF‑36 at baseline, at month 12, at month 24, and at discontinuation of treatment. In CARE‑MS I and II, the FAMS and EQ‑5D were assessed at baseline and every 6 months thereafter until month 24 or at discontinuation of treatment. The results were provided by the manufacturer as commercial-in-confidence.

Cost effectiveness

3.11 To assess the cost effectiveness of alemtuzumab the manufacturer submitted a multi-state Markov model simulating the course of multiple sclerosis and the effect of treatment with alemtuzumab or the comparators defined in the decision problem (that is, subcutaneous interferon beta‑1a, intramuscular interferon beta‑1a, interferon beta‑1b, glatiramer acetate, natalizumab and fingolimod). The model incorporated health states for the type of multiple sclerosis (relapsing–remitting or secondary progressive) and for disease severity defined by the level of disability (EDSS scores ranging from 0 [normal neurological examination] to 9 [confined to bed]). Patients with relapsing–remitting multiple sclerosis entered the model in EDSS 0–7 (in which 7 means patients need a wheelchair to get around, although they can move themselves and get out of the wheelchair without help). EDSS 10 represented death from multiple sclerosis. In each cycle, patients remained in the same state, progressed to a worse state (moving to a better state was not possible), transferred to a state reflecting secondary progressive multiple sclerosis, or died. The model assumed that when a patient progressed from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, their EDSS score increased by 1 point. The cycle length was 1 year, and the time horizon was a lifetime time horizon, assumed to be 50 years. Patients entering the model had a mean age of 39.3 years, and there were approximately 3 times as many women as men. The analyses used an NHS and personal social services perspective and applied a 3.5% discount rate on costs and health effects. Most patients received only 2 courses of alemtuzumab, but the model included re-treatment for some patients in year 3, in years 6 to 9 and for year 10 or above (the re-treatment rates were presented as academic in confidence by the manufacturer and cannot be recorded here).

3.12 To estimate the rate of disease progression in people with relapsing–remitting multiple sclerosis, the manufacturer used a natural history transition matrix representing disability progression in people who are not receiving disease-modifying therapies. This transition matrix was then adjusted using relative treatment effects from the mixed treatment comparison. The manufacturer chose the London Ontario data set, a longitudinal observational study from 1989, to populate the natural history transition matrix. Since no data for patients with an EDSS state of 0 were available in this data set, the manufacturer obtained transition probabilities for an EDSS 0 from the placebo arms of 2 trials (TOWER and TEMSO) that compared teriflunomide with placebo for treating multiple sclerosis. The manufacturer based the population entering the model on the average demographic profile of patients in the UK Risk Sharing Scheme, in which 85.8% have relapsing–remitting multiple sclerosis, the mean EDSS of patients with relapsing–remitting multiple sclerosis is 3.1, and the mean EDSS of patients with secondary progressive multiple sclerosis is 5.5. However, the manufacturer used characteristics from the whole population from the Risk Sharing Scheme to inform the model, which represented a population comprised entirely of patients with relapsing–remitting multiple sclerosis.

3.13 To model the effect of treatment with alemtuzumab on relapsing–remitting multiple sclerosis, the manufacturer applied the hazard ratios for the outcome of disability sustained for 3 months from the base-case mixed treatment comparison (section 3.7) to the natural history matrix. Separately, the manufacturer considered treatment effects on relapse rate and severity (whether or not the relapse leads to hospitalisation). In the base case, the manufacturer assumed that patients discontinue treatment when they convert from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis, or progress to EDSS 7. After discontinuing treatment, patients were assumed to receive best supportive care only. The manufacturer’s model assumed that no patient who received alemtuzumab ever discontinued treatment, while patients could discontinue comparator treatments (and subsequently receive best supportive care). The manufacturer also assumed that the treatment effect of alemtuzumab did not change over time (even during years when patients did not receive alemtuzumab) until a patient reached EDSS 7 or converted to secondary progressive multiple sclerosis. On entering EDSS 7 the benefits of alemtuzumab stopped, independent of the number of courses of alemtuzumab given. In each cycle patients could stop using comparator treatments, discontinue treatment after reaching EDSS 7, or experience relapse or adverse events. The probability of death was dependent on the EDSS state (the higher the EDSS score, the higher the risk of death), age and sex.

3.14 The manufacturer’s model applied health state utility values to each of the EDSS states. Although the manufacturer collected EQ‑5D data in the CARE‑MS I and II trials, it did not use these data in the model as they were not available at the time of submission. Instead, the manufacturer obtained health state utility values from Orme et al. (2007), a UK survey of health-related quality of life in (EQ‑5D) in people with multiple sclerosis. Utility values decreased as EDSS scores increased, with the exception of the utility value for EDSS state 3, which was lower than EDSS 4. EDSS states 8 and 9 had negative utility values, indicating states that are considered to be worse being dead. The manufacturer applied disutilities for a relapse, to caregivers, and for adverse events. The manufacturer obtained the value for the disutility of relapse from Orme et al. (2007), and the value for the disutility of relapse leading to hospitalisation from a US study (Prosser et al. 2003). To estimate disutility to caregivers, the manufacturer used values taken from Gani et al. (2008), and to estimate the time spent caring for the patient, the manufacturer used Orme et al. (2007). Disutility values applied for each adverse event were annualised based on the published literature. The manufacturer also took into account how long each adverse event lasted, and whether it was specific to treatment. The adverse events included infusion-associated reactions, bronchitis, herpes zoster, urinary tract infections, autoimmune thyroid-related adverse events, nephropathies, idiopathic thrombocytopenic purpura, other cytopenias and vomiting.

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 monitoring of patients previously treated with alemtuzumab lasts for up to 12 years. The manufacturer derived some costs from the literature: health state costs (including direct medical costs and direct non-medical costs) from a UK study (Tyas et al. 2007), and the costs associated with relapse from a study from the Republic of Ireland (Dee et al. 2012). For a sensitivity analysis, the manufacturer used an alternative UK study (Karampampa et al. 2012) to derive health state costs, although the manufacturer provided only natural history costs aggregated for EDSS states 0–3, 4–6 and 7–9, rather than costs for individual EDSS states. The manufacturer validated the resource use and costs it applied in the model using clinical experts. The cost of one of the comparators, fingolimod, includes a simple discount patient access scheme agreed with the Department of Health. However, the manufacturer did not know how large the discount was, and therefore could not use it in its base-case analysis. Instead, the manufacturer explored different prices of fingolimod in sensitivity analyses, using a range of assumed discounts).

3.16 The manufacturer’s submission presented the total life years gained, the total quality-adjusted life years (QALYs) and the total costs resulting from the economic model for alemtuzumab and subcutaneous interferon beta‑1a (44 micrograms). Treatment with alemtuzumab was associated with 18.62 life years which equated to 4.03 QALYs, at a total cost of £499,347. Treatment with subcutaneous interferon beta‑1a (44 micrograms) was associated with 18.38 life years which equated to 2.85 QALYs, at a total cost of £489,354.

3.17 The manufacturer conducted a fully incremental analysis, calculating the incremental QALY gains and costs for all treatment options and ordered by increasing costs. The treatments included alemtuzumab, glatiramer acetate, subcutaneous interferon beta‑1a (22 micrograms), subcutaneous interferon beta‑1a (44 micrograms), intramuscular interferon beta‑1a, and interferon beta–1b. The manufacturer also included fingolimod and natalizumab in this analysis, although it acknowledged that these drugs have marketing authorisations only for use in highly active and rapidly evolving severe relapsing‑remitting multiple sclerosis. When compared in this incremental analysis, the probabilistic estimates of the incremental cost-effectiveness ratios (ICERs) suggested that:

• alemtuzumab dominated interferon beta–1b, fingolimod (without applying a patient access scheme discount), fingolimod (assuming a patient access scheme price of £13,000 per year), and natalizumab (a treatment dominates other treatments when it is less expensive and more effective)
• subcutaneous interferon beta‑1a (44 micrograms) and subcutaneous interferon beta‑1a (22 micrograms) were extendedly dominated by alemtuzumab (a treatment is extendedly dominated when its ICER is higher than that of the next, more effective, option when compared with a common baseline).
• The ICER for alemtuzumab compared with glatiramer acetate was £7017 per QALY gained. The manufacturer’s deterministic results were similar with an ICER of £8924 per QALY gained for alemtuzumab compared with glatiramer acetate.

3.18 Using the results of the subgroup mixed treatment comparisons (see section 3.8), the manufacturer compared alemtuzumab with fingolimod and with natalizumab for the highly active relapsing–remitting multiple sclerosis and the rapidly evolving severe subgroups, respectively. For both analyses, alemtuzumab dominated the respective comparator.

3.19 The manufacturer conducted one‑way sensitivity analyses, which showed that the cost effectiveness of alemtuzumab was most sensitive to the hazard ratios reflecting the comparative effectiveness of treatment compared with other disease-modifying drugs for sustained disability progression, disease costs, and the discontinuation rate of subcutaneous interferon beta‑1a (44 micrograms). Alemtuzumab continued to dominate all comparators except glatiramer acetate, except when the manufacturer varied the hazard ratios for disability progression. When the manufacturer applied the upper limit of the 95% confidence interval around the sustained accumulation of disability hazard ratio for alemtuzumab from the manufacturer’s mixed treatment comparison, the resulting ICER for alemtuzumab compared with subcutaneous interferon beta‑1a was £1,200,973 per QALY gained. With the lower limit of the 95% confidence interval, alemtuzumab dominated subcutaneous interferon beta‑1a (that is, had the lowest total treatment costs for the greatest clinical gain of all treatments in the analysis).

3.20 The manufacturer also tested how sensitive the results were to which mixed treatment comparison it used, by using the ‘all years’ data instead of the ‘base-case’ mixed treatment comparison and by only including trials in which 100% of patients had relapsing–remitting multiple sclerosis (rather than the base-case mixed treatment comparison, in which trials with at least 80% of patients with relapsing–remitting multiple sclerosis were included). When trials from ‘all years’ in which at least 80% of patients had relapsing–remitting multiple sclerosis were included, the deterministic ICER for alemtuzumab compared with glatiramer acetate increased from £8924 to £9982 per QALY gained. When the manufacturer included trials from all years in which the percentage of the population with relapsing–remitting multiple sclerosis was 100% the ICER for alemtuzumab compared with glatiramer acetate increased to £27,434 per QALY gained. When the manufacturer used the mixed treatment comparison including trials after the year 2000 in which 100% of patients had relapsing–remitting multiple sclerosis, the ICER for alemtuzumab compared with glatiramer acetate was £10,822 per QALY gained.

3.21 The manufacturer conducted a number of scenario analyses using subcutaneous interferon beta‑1a (44 micrograms) as the comparator, but not glatiramer acetate, with the justification that subcutaneous interferon beta‑1a (44 micrograms) was the standard treatment for active relapsing–remitting multiple sclerosis. In the best case scenario alemtuzumab dominated subcutaneous interferon beta‑1a and in the worst case scenario the ICER for alemtuzumab compared with subcutaneous interferon beta 1-a was £20,388 per QALY gained. The manufacturer developed other scenarios based on:

• sourcing the baseline characteristics from the CARE‑MS trials rather than from the UK Risk Sharing Scheme (the ICER for alemtuzumab compared with subcutaneous interferon beta‑1a was £869 per QALY gained)
• using costs related to the natural history of multiple sclerosis from Karampampa et al. (2012) rather than Tyas et al. (2007) (alemtuzumab dominated subcutaneous interferon beta‑1a)
• using natural history transition probabilities assuming that the population only included people with active relapsing–remitting multiple sclerosis, instead of all people with relapsing–remitting multiple sclerosis (the ICER for alemtuzumab compared with subcutaneous interferon beta‑1a was £8597 per QALY gained)
• assuming long-term waning of treatment effect by 25% or 50% after year 5 for all treatments, instead of assuming that the beneficial effect of alemtuzumab does not wane (the ICERs for alemtuzumab compared with subcutaneous interferon beta‑1a were £13,956 and £20,388 per QALY gained, respectively)
• assuming that treatment with alemtuzumab does not influence the probability of relapses or hospitalisation (the ICER for alemtuzumab compared with subcutaneous interferon beta‑1a was £14,517 per QALY gained)
• using the trial data (pooled CARE‑MS I and CARE‑MS II) for the transition probabilities instead of using values sourced from the literature (alemtuzumab dominated subcutaneous interferon beta‑1a).

Evidence Review Group comments

3.22 The ERG reviewed the manufacturer’s model and economic systematic review. The ERG commented that the structure of the economic model was appropriate for multiple sclerosis and consistent with previous economic evaluations of treatments for multiple sclerosis, and that the methods of analysis were appropriate and conformed to NICE methodological guidelines.

3.23 The ERG stated that the manufacturer systematically reviewed the literature to populate its transition matrix and reflect the natural history for disability progression for patients not receiving a disease-modifying treatment. The ERG did not find any data more appropriate than the London Ontario data identified by the manufacturer, but commented that the manufacturer did not fully explore the uncertainty around the natural history of multiple sclerosis. In light of previous technology appraisals, the ERG suggested that it would have more appropriate to explore alternative sources of data.

3.24 The ERG evaluated the results of the economic model outputs as compared with published literature. The ERG noted that the manufacturer compared the results at the end of year 2, but no further. As there was no validation beyond 2 years, uncertainty remains as to the validity of longer-term outcomes.

3.25 The ERG stated that the manufacturer had performed appropriate structural sensitivity analyses, but had not conducted a sensitivity analysis that varied the rate of disease progression for patients receiving best supportive care only, or the rate of progression from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis.

3.26 The ERG identified weaknesses and uncertainty in the manufacturer’s economic analysis. The ERG stated that basing the starting model population on the UK Risk Sharing Scheme instead of the clinical trial populations introduced uncertainty into the model, because these populations did not have the same baseline characteristics, particularly with regard to the distribution of initial EDSS states. The ERG commented that the conversion rate used for patients moving from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis in the model was too high, because it did not reflect the people receiving first-line treatment for relapsing–remitting multiple sclerosis. The ERG also stated that the London Ontario estimates for disease progression for patients not taking disease-modifying treatments did not allow EDSS scores to improve. Trial-based transition probabilities were available that allowed EDSS scores to improve, although the ERG commented that using the trial data could pose problems as it reflected a short period of time. The ERG explored the impact of changing these assumptions in their exploratory analyses.

Exploratory sensitivity analyses undertaken by the ERG

3.27 The ERG presented a ‘preferred’ base case that included alternative characteristics for the patient population, and a different progression rate from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis. The ERG also conducted a series of sensitivity analyses to test uncertainties.

3.28 In all its exploratory analyses, the ERG compared alemtuzumab with subcutaneous interferon beta‑1a (44 micrograms) (instead of glatiramer acetate as used in the manufacturer’s fully incremental analysis). The ERG made this change because subcutaneous interferon beta‑1a (44 micrograms) was the direct comparator in the clinical trials and was the most efficacious comparator in the manufacturer’s mixed treatment comparison. Using the baseline characteristics for the populations in CARE‑MS I and CARE‑MS II, the ERG calculated that the ICER for alemtuzumab compared with subcutaneous interferon beta‑1a (44 micrograms) would decrease from £8445 (manufacturer’s base case comparing alemtuzumab with subcutaneous interferon beta‑1a 44 micrograms) to £2869 per QALY gained. The ERG also applied a conversion rate of 15 years from relapsing–remitting multiple sclerosis to secondary progressive multiple sclerosis (instead of the 10–11 years used by the manufacturer), as used in the NICE technology appraisal on teriflunomide for treating relapsing–remitting multiple sclerosis (under development). This had the effect of reducing the ICER to £3100 per QALY gained for alemtuzumab compared with subcutaneous interferon beta‑1a (44 micrograms). The ERG’s preferred approach combining these 2 changes resulted in alemtuzumab dominating (being less costly and more effective than) subcutaneous interferon beta‑1a (44 micrograms), with a cost saving of £852 per QALY gained.

3.29 The ERG tested its preferred base case for alemtuzumab compared with subcutaneous interferon beta‑1a (44 micrograms) in sensitivity analyses, including:

• reducing by 50% the transition probabilities to more severe health states from the London Ontario dataset (alemtuzumab dominated subcutaneous interferon beta-1a)
• using quality-of-life utility values (upper and lower confidence intervals from the Orme et al. 2007 data used in the manufacturer’s model) (for both, alemtuzumab dominated subcutaneous interferon beta-1a)
• using disease health state costs from Karampampa et al. (2012) and Biogen et al. (2007) (alemtuzumab dominated subcutaneous interferon beta-1a for Karampampa et al.; for Biogen et al. the ICER for alemtuzumab compared with subcutaneous interferon beta‑1a was £4654 per QALY gained)
• reducing the cost of a relapse that results in hospitalisation from £6146 to £3039 (the ICER for alemtuzumab compared with subcutaneous interferon beta‑1a was £1013 per QALY gained)
• applying a waning of treatment effect for alemtuzumab of 75% for year 10 and beyond, or 75% from year 6 to year 9 and 50% from year 10 and beyond (the ICERs for alemtuzumab compared with subcutaneous interferon beta‑1a were £1815 and £7319 per QALY gained, respectively)
• varying the proportionof patients receiving additional alemtuzumab treatment at year 3 (60%) and years 5 and beyond (the ICER for alemtuzumab compared with subcutaneous interferon beta‑1a was £8336 per QALY gained)
• applying the results from the ‘all years’ mixed treatment comparison (alemtuzumab dominated subcutaneous interferon beta-1a)
• using the outcome of sustained accumulation of disability lasting for 6 months from the mixed treatment comparison (instead of 3 months) to calculate the disease transition probabilities (alemtuzumab dominated subcutaneous interferon beta-1a).

3.30 The ERG also explored the cost effectiveness of alemtuzumab for the treatment‑naive and treatment‑experienced subgroups separately, using the ERG preferred base case, the relative risk for annualised rate of relapse, and a sustained accumulation of disability lasting 3 months for alemtuzumab. Using the treatment-naive group data from CARE‑MS I, the ERG’s preferred base case (that is, where alemtuzumab dominated subcutaneous interferon beta‑1a [44 micrograms], section 3.28) changed to an ICER of £6392 per QALY gained for alemtuzumab compared with subcutaneous interferon beta‑1a (44 micrograms). When the ERG used the CAMMS223 data, alemtuzumab dominated subcutaneous interferon beta‑1a (44 micrograms). Alemtuzumab also dominated subcutaneous interferon beta‑1a (44 micrograms) when the ERG pooled data from the 2 trials. For the treatment-experienced group, using effectiveness data from CARE‑MS II, the ICER was £2854 per QALY gained for alemtuzumab compared with subcutaneous interferon beta‑1a (44 micrograms).

3.31 The ERG also carried out exploratory analyses for the subgroup with highly active relapsing–remitting multiple sclerosis despite interferon use, and the subgroup with rapidly evolving severe relapsing–remitting multiple sclerosis. In these analyses the ERG used its preferred base case for a slower progression to secondary progressive multiple sclerosis for the rapidly evolving severe relapsing–remitting multiple sclerosis subgroup, and different patient characteristics for the highly active relapsing–remitting multiple sclerosis subgroup. These changes had only minimal effect on the model results, and alemtuzumab continued to dominate fingolimod and natalizumab.

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

 

4 Consideration of the evidence

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

4.2 The Committee heard from the clinical specialists and patient experts about the nature of the condition. It 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 heard from clinical specialists that the currently available first-line treatments for relapsing–remitting multiple sclerosis need to be injected weekly or several times per week 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. The Committee concluded that any delay in relapse and progression of disability or reduction in the frequency of treatment would have a positive impact on the lives of people with multiple sclerosis and their families.

4.3 The Committee considered the impact of treating relapsing–remitting multiple sclerosis with alemtuzumab. The Committee was aware that patients in the UK may have participated in trials of alemtuzumab, or may have received alemtuzumab off-licence before it was licensed for relapsing–remitting multiple sclerosis (alemtuzumab had a previous marketing authorisation for B-cell chronic lymphocytic leukaemia, but the manufacturer had withdrawn the product). The Committee heard from a patient expert who received alemtuzumab for relapsing–remitting multiple sclerosis in 2006 and 2007, and who had, since then, not experienced any relapses, with her health being better now than at the time of diagnosis with multiple sclerosis. She also preferred alemtuzumab’s administration schedule (see section 2.1) to weekly or daily self-administered injections with beta interferons, which to her would have been a ‘constant reminder’ of her multiple sclerosis. She commented that the considerable impact on her family and their concern about relapse or accumulation of disability lessened once she had received alemtuzumab. The Committee concluded that alemtuzumab has the potential to benefit people with relapsing–remitting multiple sclerosis and their families.

4.4 The Committee considered alemtuzumab’s place in the treatment pathway for relapsing–remitting multiple sclerosis. The Committee heard from clinical specialists that alemtuzumab would be used instead of other disease-modifying therapies, in line with the marketing authorisation, and preferably offered to patients at an earlier rather than a later stage in the disease. The Committee also heard that alemtuzumab would be offered to people for whom other disease-modifying treatments have not been effective, including people with rapidly evolving severe relapsing–remitting multiple sclerosis who have previously received natalizumab and for whom there are no other treatment options currently recommended. One clinical specialist emphasised that alemtuzumab was ‘not for everybody’, and that clinicians would offer alemtuzumab to patients who, among other characteristics, would be likely to comply with lifelong monitoring for adverse effects.The Committee concluded that alemtuzumab would be a valuable treatment option for selected patients.

4.5 The Committee considered whether neurologists would offer patients treatment beyond the 2 annual cycles stipulated in the marketing authorisation. The clinical specialists acknowledged that some patients need more than the 2 initial annual cycles, and that clinicians would consider offering further courses of alemtuzumab to patients whose disease had relapsed. One clinical specialist stated that people who have no relapses in the third year following first treatment, but who subsequently relapse, would be considered for retreatment, but that people who have multiple relapses within the third year would not be offered retreatment as clinicians would consider alemtuzumab to be no longer effective in this situation. The Committee concluded that some patients would be treated with alemtuzumab beyond the recommended treatment time of 2 years in the marketing authorisation.

4.6 The Committee considered the long-term efficacy of alemtuzumab. The clinical specialists acknowledged that there was uncertainty regarding the effectiveness of alemtuzumab in the long term, and specifically for periods exceeding the duration of the follow-up studies to the clinical trials, which to date have followed some patients for up to 7 years. The clinical specialists also stated that people who experienced a relapse soon after being treated with alemtuzumab would probably go on to receive alternative treatment, which, for severe disease, could include bone marrow transplantation. One clinical specialist noted that in the trials, the number of people for whom alemtuzumab was no longer effective was small. The Committee concluded that for some people alemtuzumab might not provide long-term enduring effect and other treatments might be required.

4.7 The Committee considered the advantages and disadvantages of alemtuzumab treatment. The clinical specialists described advantages to alemtuzumab treatment, including that it was highly effective, it did not cause the flu-like symptoms associated with beta interferons, and it did not need to be discontinued by patients planning a pregnancy. This was seen as important, because multiple sclerosis affects women and men during the years when they are most likely to have children, and all other multiple sclerosis treatments must be stopped for a person to have children. The clinical specialists explained that the main disadvantages of alemtuzumab treatment were the possible serious adverse events observed during the trials, including idiopathic thrombocytopenic purpura, kidney disease or failure, thyroid disease, and death. The clinical specialists explained that patients need monthly platelet and white cell counts and quarterly assessment of renal function for the rest of their lives, and that patients are monitored even more often than this immediately after treatment with alemtuzumab. The clinical specialists stated that alemtuzumab permanently changes a person’s immune system as it alters the numbers, proportions and properties of some lymphocyte subsets, and acknowledged that ongoing monthly monitoring might be an obstacle for some patients, particularly for those who feel well. The patient expert explained that she had been given enough information during the initial stages of treatment to help her understand that monitoring would be essential to prevent adverse events. The Committee heard from a clinical specialist that even if blood samples are taken for the monitoring there could still be problems with follow up actions when the results are received. The clinical specialists commented that idiopathic thrombocytopenic purpura associated with alemtuzumab responds to treatment with corticosteroids and immunoglobulin G, and patients would be unlikely to need treatment with thrombopoietin agonists. The clinical specialists acknowledged the risk of renal disease for which some patients need renal replacement therapy but that people with relapsing–remitting multiple sclerosis may be willing to accept the risks of serious adverse events associated with alemtuzumab treatment, because the potential benefits to quality of life are considerable. The clinical specialists acknowledged uncertainty about how prior treatment with alemtuzumab might change the adverse event profile of other monoclonal antibodies used for the treatment of multiple sclerosis, such as natalizumab. The Committee concluded that alemtuzumab was associated with significant benefits, but also significant harms, that some people with relapsing–remitting multiple sclerosis are willing to accept the disadvantages of alemtuzumab treatment, and that adhering to the recommended monitoring schedule is important.

Clinical effectiveness

4.8 The Committee considered the clinical effectiveness of alemtuzumab in the relapsing–remitting multiple sclerosis population in the 3 trials (see section 3.2). On the basis of the improvements in sustained accumulation of disability at 6 months in the trials and in relapse rates, the Committee concluded that alemtuzumab was a more clinically effective treatment for relapsing–remitting multiple sclerosis than subcutaneous interferon beta‑1a.

4.9 The Committee considered the clinical effectiveness of alemtuzumab for rapidly evolving severe and highly active relapsing–remitting multiple sclerosis despite interferon, for which the relevant comparators would be natalizumab and fingolimod respectively. However, the Committee was aware that no trials exist that compare alemtuzumab with either natalizumab or fingolimod. Based on the mixed treatment comparison, the Committee was not persuaded that evidence of clinical effectiveness in these subgroups had been demonstrated and concluded that without further evidence suggesting otherwise, it could not support a recommendation for alemtuzumab in these populations.

4.10 The Committee discussed whether it was appropriate for the manufacturer to have used the sustained accumulation of disability lasting 3 months rather than 6 months in its mixed treatment comparison and modelling, given that the CARE‑MS I and II trials included 6‑month sustained accumulation of disability as one of the co-primary endpoints (the other being annualised relapse rate). The Committee was also aware that 6‑month disability is preferred by clinicians, and is a more specific measure of disease progression than disability that lasts for only 3 months. The Committee heard from the manufacturer that the main reason it chose to use the sustained accumulation of disability at 3 months in its mixed treatment comparison was that this would allow for comparison across trials that included 3-month but not 6‑month disability. However the Committee understood that the 6‑month disability outcome was reported for all but 1 of the interferons (interferon beta‑1b [250 micrograms]). On the basis of clinicians’ preference, the Committee concluded that it preferred sustained accumulation of disability lasting 6 months to be used as the primary outcome measure in the mixed treatment comparison.

4.11 The Committee discussed the manufacturer’s mixed treatment comparison comparing alemtuzumab with other disease-modifying treatments. It noted that the manufacturer had presented a base-case mixed treatment comparison excluding trials that recruited patients before the year 2000, and a sensitivity analysis that included all trials (‘all years’) (see section 3.7). The Committee acknowledged that earlier 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. In addition, the Committee was not convinced that the difference in the baseline rate of relapse would modify the relative effectiveness of alemtuzumab compared with other disease-modifying drugs. The Committee agreed that it would have been more appropriate for the mixed treatment comparison to include all available evidence, and that in this case adjusting the mixed treatment comparison for baseline relapse rates would account for any differences in relapse rates between trials. The Committee concluded that an ‘all years’ mixed treatment comparison, adjusted for baseline relapse rates, would be more appropriate for comparing the effectiveness of alemtuzumab with the comparators.

4.12 The Committee discussed the statistical analysis plan for the 3 alemtuzumab trials. The Committee noted that the statistical plan for CAMMS223 stipulated an intention-to-treat analysis adjusted for baseline Expanded Disability Status Scale (EDSS) score and country reflected in the final publication. The Committee noted that in CAMMS223 and CARE‑MS II, the investigators used the per-protocol set to conduct the statistical analyses unlike CARE‑MS I where the full data set was analysed, which included some patients who did not meet the specified inclusion criteria or who had not received treatment as specified in the clinical trial protocol. The Committee heard from a clinical specialist, and author of all 3 trials, who was aware that the results for the full analysis set were similar to those for the per-protocol set for CARE‑MS I. However, the Committee remained concerned about pooling trial results that had been analysed differently, and the fact that the manufacturer had not presented a sensitivity analysis demonstrating the impact this difference could have on the results of the mixed treatment comparison (and therefore on the economic modelling). The Committee concluded that it was more appropriate to include the per-protocol analyses set for all 3 trials, unadjusted for country or region and adjusted for baseline EDSS states only, to explore whether the results had any impact on the mixed treatment comparison.

4.13 The Committee was aware of the adverse effects associated with alemtuzumab. The Committee for Medicinal Products for Human Use of the European Medicines Agency acknowledged that alemtuzumab had been shown to be effective in people with relapsing–remitting multiple sclerosis, but that there were serious safety concerns evidenced by the fact that seven CHMP members had publicly disagreed with the majority decision. These dissenting members stated in the European Public Assessment Report for alemtuzumab that the benefits to risks balance could be considered acceptable in a limited indication in patients with RRMS with high disease activity defined by clinical and imaging features, but that they did not consider that the benefits outweighed the risks in a population with less active disease. The Committee took into account the view of a clinical specialist that the deaths that occurred during the clinical trials could have been avoided. However, it agreed that a clinical trial provides better opportunities for regular monitoring than could be achieved in clinical practice, and remained concerned about the deaths that were possibly or likely to have been related to alemtuzumab treatment. The Committee considered the number of deaths in the trials and the number of people with serious adverse events and concluded it was more appropriate for the manufacturer to include them fully in the modelling.

4.14 The Committee discussed whether alemtuzumab could be considered an innovative treatment, providing a step change in the treatment of relapsing–remitting multiple sclerosis and providing benefit not accounted for in the modelling. The Committee heard from the clinical specialists and patient expert that alemtuzumab has been a revolutionary treatment for some people, allowing them to live their lives as they had before being diagnosed with multiple sclerosis. The clinical specialists stated that it was a step change because it delayed disease progression. The Committee concluded that alemtuzumab did provide a step change in the treatment of relapsing–remitting multiple sclerosis. However, the Committee considered that these benefits would already be captured through increased efficacy gains, both in survival gains and in quality of life gains, in the quality-adjusted life year (QALY) gain. The Committee therefore concluded that no additional QALY gains should be attributed to alemtuzumab to account for these benefits.

Cost effectiveness

4.15 The Committee discussed the assumptions in the manufacturer’s base-case model, in particular:

• the total QALYs accumulated over the time horizon for all treatments, including mortality rates
• the source of the health-related quality of life data
• the duration of the effect of alemtuzumab treatment
• re-treatment rates with alemtuzumab
• costs relating to treatment monitoring, health state disease costs and costs of adverse effects associated with alemtuzumab
• the data sources for the baseline characteristics of modelled patients, and the figures depicting the rates of disease progression in patients not using disease-modifying treatments (the natural history of disease progression).

4.16 The Committee considered the QALYs accumulated over the course of the modelled time horizon, and in relation to this the consequence of assuming that people can only move to worse EDSS states (that is, a person’s condition can deteriorate or stay the same but not improve) regardless of treatment. The Committee noted that for the full time horizon, a person who received treatment with alemtuzumab would accrue just over 4 QALYs despite accruing 18 life years (section 3.16). It further noted that the modelled life years for the comparator (subcutaneous interferon beta‑1a [44 micrograms]) was also much higher than the corresponding number of modelled QALYs. The Committee considered this to be an implausibly low number of QALYs to be accrued by a person with multiple sclerosis over the course of their lifetime. It therefore reasoned that that the model had poor face validity. The manufacturer could not explain the low total lifetime QALY values estimated with the model nor did it explore what might have caused the model to do this. The ERG commented that it was probably because the manufacturer had used the London Ontario data to define the natural history of disease in the absence of disease-modifying therapies, which only allowed a person to progress towards further disability on the EDSS. The Committee heard that the alemtuzumab trial data and other evidence provided by the patient expert and the clinical specialists suggested that people’s EDSS states could improve. The Committee was aware that this would considerably affect the number of QALYs accrued by a modelled patient population over a lifetime. The Committee noted that EDSS states of 8 and above were associated with negative utility values, which would reduce lifetime QALYs accrued. The Committee concluded that discounting alone was unlikely to explain the low number of lifetime QALYs accrued in the modelling. The Committee was aware that the manufacturer used an observational study by Pokorski (1997) as a source of estimates of mortality for each EDSS state, but the Pokorski reference provided estimates not by EDSS states but by mild, moderate and severe disability, and included a Danish cohort enrolled from 1948 to 1976. The Committee was aware that death rates for patients with multiple sclerosis are likely to be lower now than they have been in the past. The Committee concluded that it would be more appropriate to explore the variables affecting the QALY gains observed, including amending the model to allow patients to improve with respect to disability (EDSS state), assuming a lower mortality rate. The Committee further concluded that this would change the incremental cost-effectiveness ratios (ICERs), although the direction and size of change could not be quantified without this exploration.

4.17 The Committee considered the health-related quality of life data used in the model. The Committee heard from the manufacturer that the EQ5D‑5L data from the CARE-MS trials were not made available for use in this appraisal and considered that the manufacturer had not provided an adequate reason for why this evidence was not available. The Committee considered that the trials would provide the most appropriate source of quality of life data for the analysis, because the trial population best reflects the population that would receive the treatment if it were available in clinical practice. The Committee was also concerned about the manufacturer’s choice of values to reflect the disutility associated with some of the adverse effects. Upon questioning, the clinical specialists agreed that, for example, a disutility of zero did not reflect the disutility that would be experienced by a patient with leukocytopenia. The Committee concluded that it would have been more appropriate for the analyses to include the trial data, which may have also provided more realistic values for the disutility of adverse events associated with alemtuzumab.

4.18 The Committee considered the manufacturer’s assumption that people who receive alemtuzumab experience no change in treatment effect years after their last treatment, meaning that the relative frequencies of relapse and of developing disability compared with people who continue to take beta interferon remain unchanged over time until they reach EDSS state 7. The Committee questioned whether a constant treatment effect was biologically plausible. In response, a clinical specialist stated that alemtuzumab permanently modifies a person’s immune system, which may be why alemtuzumab’s treatment effect might be lifelong. However, the clinical specialist stated that there were no data comparing immune markers in people whose disease does and does not progress after treatment with alemtuzumab. The clinical specialists also commented that the long-term benefit of alemtuzumab is unknown given the absence of long-term data, but that it would be reasonable to assume that alemtuzumab’s treatment effect might start to decrease between 3 and 5 years after treatment but that this, too, was uncertain. The Committee concluded that the manufacturer’s assumption of constant treatment effect throughout the course of a person’s multiple sclerosis up to EDSS state 7 or secondary progressive multiple sclerosis was not supported by data, and that the clinical specialists had suggested a maximum of 5 years before waning occurs. The Committee concluded that because of the uncertainty about the long term treatment effect, it was appropriate to incorporate into the model a 3- and 5‑year waning effect for alemtuzumab.

4.19 The Committee discussed re-treatment with alemtuzumab. It was aware from clinical specialists that, in CARE‑MS I, CARE‑MS II and CAMMS233, a further cycle of alemtuzumab was offered to patients if a relapse that lasted for at least 24 hours occurred after the second annual course of infusions. It also heard from clinical specialists that further treatments were considered likely in UK clinical practice. The Committee heard from the clinical specialists that in the trials, the percentage of people who needed a third course was greater than the percentage who needed a fourth course, and that the trend of fewer people needing successive courses lasted up to 7 years (the median follow-up time for which data were available). The Committee considered that this indicated a time-dependent rate of re-treatment, which had not been accurately reflected in the manufacturer’s model. The Committee therefore concluded that it would be more appropriate to incorporate a time-dependent rate of re-treatment in the model.

4.20 The Committee considered the costs included in the economic model for alemtuzumab. The Committee noted that the manufacturer’s economic model included a mid-cycle correction, although alemtuzumab is given at the start of the cycle. The Committee was also concerned that the number of visits to neurologists included in the manufacturer’s model for people receiving alemtuzumab was low. Although the ERG increased the number of visits to neurologists (and the additional related costs) to 4 in year 1 and 2 in subsequent years, it did not take into account that people receiving 3 or more courses of alemtuzumab treatment would need 4 visits in the first year of restarting treatment. The Committee noted from the ERG exploratory analyses that using alternative health states costs had a large impact on the cost effectiveness of alemtuzumab (see section 3.29). Therefore, the Committee concluded that it would have been more appropriate to incorporate the higher health state costs used by the ERG in their analyses. The Committee finally noted that the manufacturer did not include the costs associated with adverse effects of treatment, including renal failure, renal transplantation, dialysis, and death. The Committee concluded that to reduce the uncertainty related to the costs associated with these parameter inputs, it would be more appropriate to incorporate these adjustments into the economic analysis.

4.21 The Committee discussed the data sources chosen by the manufacturer to reflect the baseline characteristics of patients with relapsing–remitting multiple sclerosis and the natural history of disease progression for patients not taking disease-modifying therapies. The Committee agreed that it was more appropriate for the manufacturer to use trial data to determine the initial EDSS distribution (see section 4.16) because this was representative of the patient population likely to be treated with alemtuzumab in the UK. The Committee was aware that the London Ontario dataset is made up of a heterogeneous population with respect to (among other factors) former treatments, and that it does not capture the full spectrum of the disease. In addition, the London Ontario dataset does not capture data from patients whose EDSS improves, which potentially makes the progression to more severe states occur more quickly than would be the case in current clinical practice. The Committee was aware that the manufacturer of alemtuzumab also manufactures teriflunomide and has collected data in the TOWER and TEMSO trials, both of which include groups of patients randomised to placebo. It concluded that this dataset would more accurately reflect the progression of disease in people who would be treated with alemtuzumab in the UK. It concluded that it would be more appropriate to incorporate the baseline characteristics of patients in the alemtuzumab trials instead of using data from the UK Risk Sharing Scheme, and that it would be more appropriate to incorporate the placebo group from the TOWER and TEMSO trials in place of the London Ontario data for rates of disease progression.

4.22 The Committee discussed what preliminary recommendation it should develop for alemtuzumab. It considered that a recommendation could not be made for the highly active despite beta interferon and rapidly evolving severe subgroups (section 4.9). For the active relapsing-remitting multiple sclerosis population, the Committee was aware that the ICERs presented by the manufacturer, and those explored in one‑way sensitivity analyses by the ERG, were mostly below £10,000 per QALY gained. However it was also aware that in a worst case scenario where the upper limit of the 95% confidence interval around the sustained accumulation of disability hazard ratio for alemtuzumab from the manufacturer’s mixed treatment comparison was used, the ICER for alemtuzumab was over £1,200,000 per QALY gained. The Committee considered that the level of uncertainty regarding the assumptions in the manufacturer’s model, and the interdependence of these uncertainties, had not been adequately explored. The Committee was not persuaded that any of the analyses presented allowed it to determine the cost-effectiveness of alemtuzumab compared with other disease-modifying treatments. The Committee was minded not to recommend alemtuzumab for treating adults with relapsing–remitting multiple sclerosis as a cost-effective use of NHS resources. The Committee requested that the manufacturer provides further clarification and an incremental analysis using the Committee’s preferred assumptions as outlined in sections 4.15 to 4.21.

Summary of Appraisal Committee's key conclusions

TAXXX	Appraisal title: Alemtuzumab for treating relapsing–remitting multiple sclerosis		Section
Key conclusion
The Committee is minded not to recommend alemtuzumab, within its marketing authorisation, that is, for treating adults with relapsing–remitting multiple sclerosis with active disease defined by clinical or imaging features. 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 heard from clinical specialists that the currently available first-line treatments for relapsing–remitting multiple sclerosis need to be injected weekly or several times per week and can be associated with unpleasant side effects and can significantly affect patients’ emotional wellbeing.	4.2
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee was aware of alemtuzumab’s administration schedule (see section 2.1) and reduction in relapse rates in people with relapsing–remitting multiple sclerosis and considered this to be a step change in the treatment of relapsing–remitting multiple sclerosis.	4.3, 4.14
What is the position of the treatment in the pathway of care for the condition?		The Committee heard from clinical specialists that alemtuzumab would be used instead of other disease-modifying therapies, in line with the marketing authorisation, and preferably offered at an earlier rather than a later stage in the disease.	4.3
Adverse reactions		The Committee heard that the main serious adverse events observed during the trials included idiopathic thrombocytopenic purpura, kidney disease or failure, thyroid disease, and death. The Committee concluded that some people with relapsing–remitting multiple sclerosis are willing to accept the disadvantages of alemtuzumab treatment.	4.7
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee considered the clinical effectiveness of alemtuzumab in the relapsing–remitting multiple sclerosis population in the 3 trials comparing it with subcutaneous interferon beta‑1a. The Committee was aware that no trials exist that compare alemtuzumab with either natalizumab or fingolimod The Committee also noted that the evidence presented from the trials was a post hoc analysis.	4.8, 4.9
Relevance to general clinical practice in the NHS		The Committee heard from a clinical specialist that even if blood samples are taken for the monitoring there could still be problems with follow up actions when the results are received. The Committee took into account the view of a clinical specialist that the deaths that occurred during the clinical trials could have been avoided. However, it agreed that a clinical trial provides better opportunities for regular monitoring than could be achieved in clinical practice	4.7 4.13
Uncertainties generated by the evidence		The Committee concluded that some patients would be treated with alemtuzumab beyond the time period stipulated in the marketing authorisation. The Committee concluded that for some people alemtuzumab might not provide long-term enduring effect and other treatments might be required. The Committee concluded that an ‘all year’ mixed treatment comparison, adjusted for baseline relapse rates, would be more appropriate for comparing the effectiveness of alemtuzumab with the comparators.	4.5, 4.6, 4.11
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		Based on the mixed treatment comparison, the Committee was not convinced that evidence of the clinical effectiveness of alemtuzumab in the highly active and rapidly evolving severe relapsing-remitting multiple sclerosis subgroups had been demonstrated.	4.9
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee concluded that alemtuzumab was a clinically effective treatment in reducing relapse rates and had a beneficial impact on sustained accumulation of disability at 6 months compared with subcutaneous interferon beta‑1a in people with relapsing–remitting multiple sclerosis.	4.8
Evidence for cost effectiveness
Availability and nature of evidence		The Committee concluded that it preferred sustained accumulation of disability lasting 6 months to be used as the primary outcome measure in the mixed treatment comparison, as it was a co-primary outcome in the alemtuzumab clinical trials. The Committee concluded that an ‘all years’ mixed treatment comparison, adjusted for baseline relapse rates, would be more appropriate for comparing the effectiveness of alemtuzumab with the comparators as it would have been more appropriate for the mixed treatment comparison to include all available evidence.	4.10, 4.11
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee was concerned with the implausibly low number of quality-adjusted life years (QALYs) accumulated over the course of the modelled time horizon and concluded that discounting alone was unlikely to account for the low number of lifetime QALYs accrued in the modelling. The Committee was aware that this might be explained by the use of the London Ontario data which only allowed a person to progress towards further disability on the Expanded Disability Status Scale (EDSS). The Committee concluded that it would be more appropriate to explore the variables affecting the QALY gains observed, including amending the model to allow patients to improve with respect to disability (EDSS state), assuming a lower mortality rate. The Committee heard from the manufacturer that the EQ5D-5L data from the CARE-MS trials were not made available for use in this appraisal and considered that the manufacturer had not provided an adequate reason for why this evidence was not available. The Committee concluded that it would have been more appropriate for the analyses to include the trial data, which may have provided more realistic values for the disutility of adverse events associated with alemtuzumab. Although the Committee was aware that alemtuzumab permanently modifies a person’s immune system and that clinical specialists believed that it would be reasonable to assume that alemtuzumab’s treatment effect might start to decrease between 3 and 5 years after treatment, given the absence of long-term data, it concluded that the manufacturer’s assumption of full efficacy throughout the course of a person’s multiple sclerosis up to EDSS state 7 or secondary progressive multiple sclerosis was not supported by data, and that the clinical specialists had suggested a maximum of 5 years before waning occurs. The Committee considered that time-dependent re-treatment had not been accurately reflected in the manufacturer’s model. The Committee concluded that it would be more appropriate to incorporate a time-dependent rate of re-treatment in the model. The Committee noted that the manufacturer’s model included a mid-cycle correction, although alemtuzumab is given at the start of the cycle and that the number of neurology visits included in the model for people receiving alemtuzumab was low. The Committee also noted from the ERG exploratory analyses that using alternative health state costs had a large impact on the cost effectiveness of alemtuzumab and that the costs associated with adverse effects of treatment including renal failure, renal transplantation, dialysis, and death had not been included in the manufacturer’s economic model. The Committee concluded that use of trial data was more appropriate to incorporate the baseline characteristics of patients in the alemtuzumab trials instead of using data from the UK Risk Sharing Scheme, and that it would be more appropriate to incorporate the placebo group from the TOWER and TEMSO trials in place of the London Ontario data for rates of disease progression.	4.16, 4.17, 4.18, 4.19, 4.20, 4.21
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?		Although the Committee heard that alemtuzumab could be considered a step change in the treatment of relapsing–remitting multiple sclerosis, the Committee concluded that the health benefits provided by alemtuzumab would be captured through increased efficacy gains, both in survival gains and in quality of life gains, in the quality-adjusted life year (QALY) gain and therefore no additional QALY gains should be attributed to alemtuzumab.	4.14
Are there specific groups of people for whom the technology is particularly cost effective?		No specific Committee consideration.	n/a
What are the key drivers of cost effectiveness?		The Committee was aware that the key drivers of cost effectiveness for alemtuzumab are the hazard ratios for disability progression.	4.22
Most likely cost-effectiveness estimate (given as an ICER)		The Committee was not persuaded that any of the analyses presented allowed it to determine the cost-effectiveness of alemtuzumab compared with other disease-modifying treatments on which to base its decision.	4.22
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable	n/a
End-of-life considerations		Not applicable	n/a
Equalities considerations and social value judgements		No relevant equality considerations were raised during scoping or the appraisal.	n/a

 

 

5 Implementation

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

5.2 When NICE recommends a treatment ‘as an option’, the NHS must make sure it is available within the period set out in the paragraph above. This means that, if a patient has relapsing-remitting multiple sclerosis with active disease defined by clinical or imaging features and the doctor responsible for their care thinks that alemtuzumab is the right treatment, it should be available for use, in line with NICE’s recommendations.

5.3 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. Earliest anticipated date of publication January 2014.
• Teriflunomide for treating relapsing–remitting multiple sclerosis. NICE technology appraisal. Earliest anticipated date of publication January 2014.
• Laquinimod for treating relapsing–remitting multiple sclerosis. NICE technology appraisal. Earliest anticipated date of publication October 2014.

 

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in January 2016. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

 

Amanda Adler
Chair, Appraisal Committee
November 2013

8 Appraisal Committee members, guideline representatives and NICE project team

8.1 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, University of Exeter Medical School

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

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

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

Professor Peter Crome
Consultant Geriatrician and Professor of Geriatric Medicine, Keele University

John Dervan
Lay Member

Robert Hinchliffe
HEFCE Clinical Senior Lecturer in Vascular Surgery and Honorary Consultant Vascular Surgeon, St George's Vascular Institute

Professor Daniel Hochhauser
Consultant in Medical Oncology, UCL Cancer Institute

Anne Joshua
Associate Director of Pharmacy, NHS Direct

Terence Lewis
Lay Member

Dr Miriam McCarthy
Consultant, Public Health, Public Health Agency

Dr Elizabeth Murray
Reader in Primary Care, University College London

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

Professor Stephen Palmer
Professor of Health Economics, Centre for Health Economics, University of York

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

Dr Ann Richardson
Lay Member

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

Cliff Snelling
Lay Member

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

David Thomson
Lay Member

Dr Nerys Woolacott
Senior Research Fellow, Centre for Health Economics, University of York

8.2 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

Richard Diaz
Technical Lead

Joanne Holden
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 Southampton Health Technology Assessment Centre:

• Cooper K, Bryant J Harris P et al., Alemtuzumab for the treatment of relapsing–remitting multiple sclerosis, September 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
• NHS England
• Welsh Government

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

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

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

• Dr Alisdair Coles, University Lecturer and Honorary Consultant Neurologist, University of Cambridge, nominated by Genzyme – clinical specialist
• Sam Colhoun, Clinical Nurse Specialist in Multiple Sclerosis, UK MS Specialist Nurse Association , nominated by the UK MS Specialist Nurse Association (UKMSSNA) – clinical specialist
• Dr Richard Nicholas, Consultant Neurologist and Honorary Senior Lecturer, Imperial Healthcare NHS Trust, nominated by the Multiple Sclerosis Trust – clinical specialist
• Helen Burchmore, nominated by the Multiple Sclerosis Society – patient expert
• Nick Rijke, Director of Policy and Research, the MS Society, nominated by the Multiple Sclerosis Society – patient expert

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

• Genzyme