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, is life altering and has a large 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 active 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, 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 active 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-label before it was licensed for active relapsing–remitting multiple sclerosis (alemtuzumab had a previous marketing authorisation for B-cell chronic lymphocytic leukaemia, but the manufacturer has withdrawn the product for that indication). The Committee heard from a patient expert who received alemtuzumab for active relapsing–remitting multiple sclerosis in 2006 and 2007, and who has not experienced any relapses since, with her health being better now than at the time of diagnosis. 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 active relapsing–remitting multiple sclerosis and their families.

4.4 The Committee considered alemtuzumab's place in the treatment pathway for active relapsing–remitting multiple sclerosis. The Committee heard from the clinical specialists that alemtuzumab would be considered as a first-line treatment option, alongside beta interferons or glatiramer acetate, for people with active relapsing–remitting multiple sclerosis eligible for treatment under the Association for British Neurologists' guidelines. The Committee heard from the clinical specialists that, while effective therapies should ideally be offered early in disease, offering effective treatments later in disease is even more important because these patients have a higher risk for more severe complications. The Committee also heard that, while alemtuzumab's marketing authorisation permits its use as a first-line treatment, it is more likely to be offered to people for whom other disease-modifying treatments have not been effective. However, the Committee heard from the patient expert that a patient should not have to experience more severe symptoms before being offered alemtuzumab. One clinical specialist emphasised that alemtuzumab is 'not for everybody', and that clinicians would offer alemtuzumab to patients who, among other characteristics, would be likely to comply with the required monitoring for adverse effects, and that approaches exist to estimate the likely compliance with monitoring. The Committee concluded that alemtuzumab is a valuable treatment option for selected patients with varying types and stages of active relapsing–remitting multiple sclerosis.

4.5 The Committee considered whether neurologists would offer patients treatment with alemtuzumab 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. People who have relapses within the third year would not, however, be offered retreatment because clinicians would consider alemtuzumab to be no longer effective in this situation. The Committee concluded that some patients whose disease initially responds to alemtuzumab but later relapses may be treated with alemtuzumab beyond the 2 treatment courses described in the marketing authorisation.

4.6 The Committee considered the advantages and disadvantages of alemtuzumab treatment. The clinical specialists described advantages to alemtuzumab treatment, including that it is highly effective, does not cause the flu-like symptoms associated with beta interferons, and does not need to be discontinued by patients planning a pregnancy, although the Committee was aware that effective contraceptive measures should be taken when receiving alemtuzumab and for 4 months following a course of treatment according to the summary of product characteristics. 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, according to their summary of product characteristics, must be stopped for a person to have children. The clinical specialists explained that the main disadvantages of alemtuzumab treatment are the possible serious adverse effects observed during the trials, including idiopathic thrombocytopenic purpura, kidney disease or failure, thyroid disease and death. The clinical specialists stated that thyroid disease is the most common complication, affecting one-third of patients with multiple sclerosis treated with alemtuzumab. In response to a comment made by a consultee that patients treated with alemtuzumab were at risk for papillary thyroid cancer, a clinical specialist suggested that this could be related to increased detection following routine screening as required by the marketing authorisation for alemtuzumab. The clinical specialists and the manufacturer explained that patients need monthly platelet and white cell counts and quarterly assessment of thyroid and renal function for 4 years after the last treatment, 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 because 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 Committee expressed concern about the methods used to ensure that people treated with alemtuzumab would comply with monitoring requirements. The Committee heard from the clinical specialists that there are standard monitoring systems in place at the specialist centres that administer alemtuzumab and patients are contacted by a variety of methods if they miss a monthly monitoring visit. The Committee was aware that even when adverse events related to alemtuzumab were identified during regular 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 and patient experts acknowledged the risk of renal disease for which some patients need renal replacement therapy but stated that people with active 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 is associated with significant benefits, but also significant harms, that some people with active relapsing–remitting multiple sclerosis are willing to accept the disadvantages of alemtuzumab treatment, and that adhering to the recommended monitoring schedule is important.

4.7 The Committee further considered the adverse effects associated with alemtuzumab. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency acknowledged that alemtuzumab had been shown to be effective in people with active relapsing–remitting multiple sclerosis, but that there were serious safety concerns evidenced by the fact that 7 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 relapsing–remitting multiple sclerosis 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. It concluded 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 related to alemtuzumab treatment.

4.8 The Committee discussed the information provided to patients for whom treatment with alemtuzumab is considered, and specifically the requirements for monitoring and risks associated with treatment with alemtuzumab. The Committee questioned whether those requirements and risks were being clearly communicated to patients considering alemtuzumab as a treatment option. The Committee heard from the clinical specialists that alemtuzumab would only be offered to people who were fully informed of the possible adverse effects of alemtuzumab and aware of the stringent monitoring requirements. The patient expert explained that she had been fully informed about the possible adverse effects and monitoring requirements for alemtuzumab before making the decision to enrol in the alemtuzumab trial and further information had been provided during the initial stages of treatment to help her recognise possible adverse reactions. The Committee was aware that the summary of product characteristics requires that a neurologist experienced in treating patients with multiple sclerosis supervises treatment with alemtuzumab, and states that specialists and equipment should be available to diagnose and manage the most frequent adverse reactions, especially autoimmune conditions and infections. The Committee was also aware that patients should be given a Patient Alert Card and Patient Guide and be informed about the risks of alemtuzumab. The Committee remained concerned that not all people offered alemtuzumab might understand the risks or comply with the monitoring requirements. The Committee concluded that there are monitoring processes in place based on evidence from patients who received alemtuzumab either in trial or clinical settings.

Clinical effectiveness

4.9 The Committee considered the clinical effectiveness of alemtuzumab in the relapsing–remitting multiple sclerosis population in the 3 trials comparing it with Rebif (44 micrograms) (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 is a more clinically effective treatment for active relapsing–remitting multiple sclerosis than Rebif (44 micrograms).

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 for people with active relapsing–remitting multiple sclerosis, 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 heard from the clinical specialists that patients may not have permanent disability progression after a relapse and that recovery may take up to 12 months, but on average people will recover within 3 or 4 months. The clinical specialists stated that sustained disability progression lasting for 6 months is a more appropriate outcome measure than disability progression lasting for 3 months. The Committee heard from the manufacturer that the main reason for why it initially 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 beta interferons. 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 for people with active relapsing–remitting multiple sclerosis. It noted that the manufacturer initially presented a base-case mixed treatment comparison excluding trials that recruited patients before the year 2000, and a separate 'all years' sensitivity analysis that included all trials (see section 3.7). The Committee acknowledged that earlier trials were excluded because of changes in diagnostic criteria, which 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. It was aware that the manufacturer presented a revised mixed treatment comparison including trials from 'all years' and adjusted for baseline relapse in its response to the Appraisal Consultation Document. The Committee concluded that it is 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 accounts for any differences in relapse rates between trials.

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, which was 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 whereas in CARE‑MS I the full dataset 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, 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 the pooling of trial results that had been analysed differently, and the fact that the manufacturer had not initially 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 is 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. However, it was aware that the manufacturer's revised mixed treatment comparison presented in its response to the appraisal consultation document included the results from intention-to-treat analyses of the CARE-MS I, CARE-MS II and CAMMS223 trials and concluded that in this case it had little impact on the results of the mixed treatment comparison.

4.13 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 a median of 7 years and a maximum of 12 years. The clinical specialists also stated that people who experience a relapse soon after treatment with alemtuzumab will probably be offered 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.

4.14 The Committee considered the clinical effectiveness of alemtuzumab in people with rapidly evolving severe relapsing-remitting multiple sclerosis or highly active relapsing-remitting multiple sclerosis despite beta interferon treatment, for which the relevant comparators would be natalizumab and fingolimod respectively. The Committee heard from a clinical specialist that alemtuzumab was probably more effective than fingolimod, and probably equally effective to natalizumab. However, compared with natalizumab, alemtuzumab was probably safer in pregnancy and in people testing positive to John Cunningham virus, which can lead to progressive multifocal leukoencephalopathy. The Committee commented that the clinical effectiveness of alemtuzumab in the rapidly evolving severe relapsing-remitting multiple sclerosis or highly active relapsing-remitting multiple sclerosis despite beta interferon treatment subgroups was not robustly demonstrated. It was aware that no trials exist that directly compare alemtuzumab with either natalizumab or fingolimod. The Committee understood that the mixed treatment comparisons required a number of links to compare alemtuzumab with either natalizumab or fingolimod, and that different trials defined the subgroups differently, and both these factors increased uncertainty. The Committee noted that the results of the mixed treatment comparison had shown that alemtuzumab was associated with a lower annualised relapse rate and 3 month sustained accumulation of disability than fingolimod for the subgroup of highly active relapsing-remitting multiple sclerosis despite beta interferon treatment, although these differences were not statistically significant. The Committee also noted that alemtuzumab treatment led to lower annualised relapse rates and lower 6‑month sustained accumulation of disability than natalizumab for the subgroup of rapidly evolving severe relapsing-remitting multiple sclerosis, although the difference was not statistically significant. The Committee noted that the CARE MS-II study comparing alemtuzumab with Rebif (44 micrograms) showed that alemtuzumab had a greater absolute treatment effect on 3‑month sustained accumulation of disability in people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment than that of fingolimod compared with placebo in the FREEDOM study. The Committee also noted that in the CAMMS223, CARE MS-I and II studies (that compared alemtuzumab with Rebif [44 micrograms]) alemtuzumab had a similar effect on 6‑month sustained accumulation of disability in people with rapidly evolving severe relapsing-remitting multiple sclerosis to that of natalizumab compared with placebo in the AFFIRM study. Acknowledging the uncertainty, the Committee was persuaded that alemtuzumab was at least as effective as fingolimod and natalizumab for people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing-remitting multiple sclerosis respectively.

Cost effectiveness

4.15 The Committee considered the QALYs accumulated over the course of the modelled time horizon, and the consequences 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 (see section 3.17). It further noted that the modelled life years for the comparator (Rebif [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 original economic model had poor face validity. The manufacturer could not explain the low total lifetime QALY values estimated within 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 commented that discounting alone was unlikely to explain the low number of lifetime QALYs accrued in the original economic model. The Committee concluded that it is appropriate for the economic modelling to allow 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 either improve or get worse) which is in line with what is seen in clinical practice for the lower EDSS states.

4.16 The Committee considered the health-related quality of life data used in the model. 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 concerned about the manufacturer's initial choice of values to reflect the disutility associated with some of the adverse effects. The clinical specialists agreed that, for example, it is not plausible that a patient with leukocytopenia would have no disutility. The Committee was also aware that a number of deaths were observed in the trials (see section 4.7) and noted that this needed to be reflected in the economic modelling. The Committee understood that in its response to the appraisal consultation document, the manufacturer had pooled EQ-5D-5L utility scores by EDSS state from CARE-MS I and CARE-MS II both at baseline and after 24 months of treatment and had accounted for the deaths observed in the trials in its economic modelling. The manufacturer explained that the difference in mean utility values between baseline and at 24 months in patients with the same EDSS scores did not show improved utility, as might have been expected. The Committee concluded that it is appropriate for the economic modelling to include the deaths observed in the trials and also the trial EQ-5D-5L data (which is more likely to capture the disutility of adverse events associated with alemtuzumab than the manufacturer's original approximations).

4.17 The Committee considered the manufacturer's assumption that the treatment effect from alemtuzumab would persist for many years after the last treatment. 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 life‑long. 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 initial 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 from alemtuzumab it is appropriate to incorporate a 3- and 5‑year waning effect into the model, and it was satisfied that the manufacturer's revised economic analyses adequately explored the sensitivity of the ICER to several scenarios which assumed that the effectiveness of alemtuzumab and its comparators waned over time.

4.18 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. The Committee concluded that it is appropriate to incorporate the time-dependent rate of re-treatment from the trials in the model and was satisfied that in its response to the Appraisal Consultation Document, the manufacturer had reflected this in its revised economic model.

4.19 The Committee considered the costs included in the economic model for alemtuzumab. The Committee noted that the manufacturer's original 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 original economic 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 3.30). The Committee commented that it would have been more appropriate for the manufacturer to incorporate the health state costs used by the ERG in their exploratory analyses (that only included direct 'medical' costs rather than both 'medical' and 'non-medical' costs) because this is more consistent with NICE's preferred methods as presented in its Guide to the methods of technology appraisal. It noted that the manufacturer did not initially include the costs associated with adverse effects of treatment including renal failure, renal transplantation, dialysis and death. The Committee concluded that it was satisfied that the manufacturer's revised analyses adequately addressed and explored all of these uncertainties associated with the costs included in the economic model.

4.20 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 because this was representative of the patient population likely to be treated with alemtuzumab in the UK. 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 natural history of disease (underlying progression without disease-modifying therapy) in people who would be treated with alemtuzumab in the UK. It concluded that it is 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 is appropriate to incorporate the rates of disease progression in the placebo group from the TOWER and TEMSO trials to reflect the natural history of the disease.

4.21 The Committee considered the manufacturer's revised base-case results submitted in response to consultation (see section 3.35). It was aware that for the active relapsing–remitting multiple sclerosis population, the manufacturer had incorporated all the Committee's preferred assumptions (see sections 3.33, 4.10–4.12 and 4.15–4.20). The Committee noted that when assuming that the effect of treatment decreased for alemtuzumab and not for the comparators, the ICER for alemtuzumab compared with glatiramer acetate was £24,500 per QALY gained and that if the model assumed that the effectiveness of both alemtuzumab and its comparators waned, the ICER for alemtuzumab compared with glatiramer acetate was £13,600 per QALY gained. The Committee concluded that alemtuzumab could be considered a cost-effective use of NHS resources for treating adults with active relapsing–remitting multiple sclerosis.

4.22 The Committee also considered the manufacturer's revised analyses for the subgroups characterised by highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing-remitting multiple sclerosis, submitted in response to consultation. The clinical specialists noted that the terms used to describe these subgroups of patients are not generally used in UK clinical practice. The Committee was aware that the manufacturer's mixed treatment comparisons for these subgroups had not generated statistically significantly effects for alemtuzumab compared with the relevant comparator (see section 4.14) and was associated with uncertainty. The Committee heard during consultation from the Association of British Neurologists that it would be impractical to recommend 'a potent drug with significant side effects for patients with modestly active disease but not patients whose future is most threatened by their disease'. The Committee also heard the clinical specialists confirm that it would be clinically counterintuitive to recommend alemtuzumab for the overall active relapsing–remitting multiple sclerosis population, but not recommend it for the highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and the rapidly evolving severe relapsing-remitting multiple sclerosis subgroups for whom the need for treatment options was even greater. The Committee noted that the approach taken by the ERG assumed equal efficacy between alemtuzumab and fingolimod or natalizumab using a midpoint of the hazard ratios for treatment compared with placebo and applied it to the manufacturer's revised economic model. It agreed that this was a pragmatic way to determine the relative clinical and cost effectiveness of alemtuzumab in these subgroups given the uncertainty. The Committee noted that the most plausible ICER for patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment was £8900 per QALY gained for alemtuzumab compared with fingolimod. The Committee noted that for patients with rapidly evolving severe relapsing-remitting multiple sclerosis, alemtuzumab dominated natalizumab (that is, less expensive and more effective). The Committee therefore concluded that alemtuzumab could be considered a cost-effective use of NHS resources for people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and for people with rapidly evolving severe relapsing-remitting multiple sclerosis.

4.23 The Committee considered the manufacturer's assumptions about when people should receive disease-modifying therapies such as alemtuzumab and how this was incorporated into the manufacturer's economic model. The Committee noted that only patients with active relapsing–remitting multiple sclerosis in an EDSS state of 0 to 7 entered the model and that treatment with alemtuzumab would stop when a patient progresses to EDSS 7 or upon secondary progressive multiple sclerosis. It acknowledged that these assumptions were based on the Association of British Neurologists' guideline for prescribing of disease modifying treatments in multiple sclerosis. The Committee agreed that the manufacturer presented an economic model that supported the use of alemtuzumab in people with active relapsing–remitting multiple sclerosis in an EDSS state less than 7.

4.24 The Committee discussed whether alemtuzumab can be considered an innovative treatment, providing a step change in the treatment of active 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 believed that it was a step change because it delayed disease progression. The Committee noted that alemtuzumab did provide a step change in the treatment of active 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. The Committee therefore concluded that no additional QALY gains should be attributed to alemtuzumab to account for these benefits.

Summary of Appraisal Committee's key conclusions

TA312

Appraisal title: Alemtuzumab for treating relapsing–remitting multiple sclerosis

Section

Key conclusion

Alemtuzumab is recommended as an option, within its marketing authorisation, for treating adults with active relapsing–remitting multiple sclerosis.

The Committee considered the manufacturer's revised base-case results submitted in response to consultation that incorporated all the Committee's preferred assumptions. The Committee concluded that the most plausible ICER for alemtuzumab compared with glatiramer acetate for people with active relapsing-remitting multiple sclerosis is likely to lie between £13,600 and £24,500 per QALY gained, and therefore alemtuzumab could be considered a cost-effective use of NHS resources for treating adults with active relapsing–remitting multiple sclerosis.

The Committee noted that the most plausible ICER for patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment was £8900 per QALY gained for alemtuzumab compared with fingolimod. The Committee noted that for patients with rapidly evolving severe relapsing-remitting multiple sclerosis, alemtuzumab dominated natalizumab (that is, less expensive and more effective).

1.1



4.21








4.22

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, is life altering and has a large negative impact on quality of life. Currently available first-line treatments for active relapsing–remitting multiple sclerosis need to be injected weekly or several times per week and can be associated with unpleasant side effects. 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.

The Committee heard from the clinical specialists that, while therapies should ideally be offered early in disease, offering treatments later in disease is also important because these patients have a higher risk for more severe complications.

4.2













4.4

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 clinical specialists described advantages, including that it is highly effective, does not cause the flu-like symptoms, and does not need to be discontinued by patients planning a pregnancy, although the Committee was aware that effective contraceptive measures should be taken when receiving alemtuzumab and for 4 months following a course of treatment according to the summary of product characteristics.

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.

4.6









4.24

What is the position of the treatment in the pathway of care for the condition?

The Committee heard from the clinical specialists that while alemtuzumab's marketing authorisation permits its use as a first-line treatment, it is more likely to be offered to people for whom other disease-modifying treatments have not been effective. One clinical specialist emphasised that alemtuzumab is 'not for everybody', and that clinicians would offer alemtuzumab to patients who, among other characteristics, would be likely to comply with the required monitoring. The Committee concluded that alemtuzumab is a valuable treatment option for selected patients with varying types and stages of active relapsing–remitting multiple sclerosis.

4.4







Adverse reactions

The clinical specialists explained that the main disadvantages of alemtuzumab treatment are the possible serious adverse effects, including idiopathic thrombocytopenic purpura, kidney disease or failure, thyroid disease and death. The Committee concluded that alemtuzumab is associated with significant benefits, but also significant harms, that some people with active relapsing–remitting multiple sclerosis are willing to accept the disadvantages of alemtuzumab treatment, and that adhering to the recommended monitoring schedule is important.

4.6

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 Rebif.

The Committee discussed the manufacturer's mixed treatment comparison comparing alemtuzumab with other disease-modifying treatments.

The Committee was aware that no trials exist that compare alemtuzumab with either natalizumab or fingolimod.

4.9




4.11



4.14

Relevance to general clinical practice in the NHS

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. The Committee concluded that for some people alemtuzumab might not provide long-term enduring effect and other treatments might be required.

4.13

Uncertainties generated by the evidence

The Committee concluded that it is more appropriate for the mixed treatment comparison to include all available evidence, and that adjusting for baseline relapse rates accounts for any differences between trials.

The Committee noted that in CAMMS223 and CARE‑MS II, the investigators used the per-protocol set to conduct the statistical analyses whereas in CARE‑MS I the full dataset 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 concluded that it is more appropriate to include the per-protocol analyses set for all 3 trials, adjusted for baseline EDSS states only.

The Committee commented that alemtuzumab's clinical effectiveness in the subgroups was not robust. It was aware that no trials exist that directly compare alemtuzumab with either natalizumab or fingolimod. The Committee understood that the mixed treatment comparisons required a number of links to compare alemtuzumab with either natalizumab or fingolimod, and that different trials defined the subgroups differently.

4.11





4.12










4.14

Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?

Acknowledging the uncertainty, the Committee was persuaded that alemtuzumab was at least as effective as fingolimod and natalizumab for people with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment and rapidly evolving severe relapsing-remitting multiple sclerosis respectively.

4.14

Estimate of the size of the clinical effectiveness including strength of supporting evidence

The Committee concluded that alemtuzumab is a clinically effective treatment in reducing relapse rates and has a beneficial impact on sustained accumulation of disability at 6 months compared with Rebif in people with active relapsing–remitting multiple sclerosis.

4.9

Evidence for cost effectiveness

Availability and nature of evidence

The Committee considered the manufacturer's revised base-case results submitted in response to consultation. It was aware the manufacturer had incorporated all the Committee's preferred assumptions.

4.22

Uncertainties around and plausibility of assumptions and inputs in the economic model

The Committee heard that the alemtuzumab trial data and other evidence suggested that people's EDSS states could improve and concluded that it is appropriate for the economic modelling to allow patients to move to lower as well as to higher EDSS states.

The Committee considered that the trials provided the most appropriate source of quality of life data because the trial population best reflects the population that would receive the treatment in clinical practice. A number of deaths were observed in the trials and this needed to be reflected in the economic modelling.

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.

In the trials 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, and the clinical specialists commented that further treatments were considered likely in clinical practice. The Committee concluded that it is appropriate to incorporate the time-dependent rate of re-treatment in the model.

The Committee concluded that it was more appropriate to remove the mid-cycle correction for the cost of alemtuzumab treatment, increase the number of monitoring and neurology visits to reflect any additional monitoring needed, only include health states costs that are likely to meet the NICE reference case and to include the costs associated with managing adverse effects in the economic modelling.

The Committee agreed that it was more appropriate for the manufacturer to use trial data to determine the initial EDSS distribution because this was representative of the patient population likely to be treated with alemtuzumab in the UK. The Committee was also aware that the manufacturer of alemtuzumab has collected data in patients randomised to placebo and concluded that this dataset would more accurately reflect the natural history of disease in people who would be treated with alemtuzumab in the UK.

4.15






4.16






4.17






4.18








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 manufacturer pooled EQ-5D-5L utility scores by EDSS state from CARE-MS I and CARE-MS II.

The Committee noted that alemtuzumab did provide a step change in the treatment of active relapsing–remitting multiple sclerosis. However, these benefits would already be captured through increased efficacy gains, both in survival gains and in quality of life gains.

4.16


4.24

Are there specific groups of people for whom the technology is particularly cost effective?

n/a

n/a

What are the key drivers of cost effectiveness?

The manufacturer's original assumption that the treatment effect from alemtuzumab would persist for many years after the last treatment. The Committee was satisfied that the manufacturer's revised economic analyses adequately explored the sensitivity of the ICER to several scenarios assuming that the effectiveness of alemtuzumab and its comparators waned over time.

4.17

Most likely cost-effectiveness estimate (given as an ICER)

The Committee concluded that the most plausible ICER for alemtuzumab compared with glatiramer acetate for people with active relapsing-remitting multiple sclerosis is likely to lie between £13,600 and £24,500 per QALY gained.

The Committee noted that the most plausible ICER for patients with highly active relapsing-remitting multiple sclerosis despite beta interferon treatment was £8900 per QALY gained for alemtuzumab compared with fingolimod. The Committee noted that for patients with rapidly evolving severe relapsing-remitting multiple sclerosis, alemtuzumab dominated natalizumab (that is, less expensive and more effective).

4.21





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

  • National Institute for Health and Care Excellence (NICE)