TA312
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Appraisal title: Alemtuzumab for treating relapsing–remitting multiple sclerosis
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Section
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Key conclusion
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Alemtuzumab is recommended as an option, within its marketing authorisation, for treating highly active relapsing–remitting multiple sclerosis in adults with:
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highly active disease despite a full and adequate course of treatment with at least 1 disease-modifying therapy or
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rapidly evolving severe relapsing–remitting multiple sclerosis defined by 2 or more disabling relapses in 1 year, and with 1 or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI.
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 £8,900 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).
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1.1
4.21
4.22
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Current practice
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Clinical need of patients, including the availability of alternative treatments
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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.
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4.2
4.4
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The technology
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Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
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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.
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4.6
4.24
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What is the position of the treatment in the pathway of care for the condition?
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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.
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4.4
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Adverse reactions
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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.
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4.6
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Evidence for clinical effectiveness
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Availability, nature and quality of evidence
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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.
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4.9
4.11
4.14
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Relevance to general clinical practice in the NHS
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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.
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4.13
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Uncertainties generated by the evidence
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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.
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4.11
4.12
4.14
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Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
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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.
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4.14
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Estimate of the size of the clinical effectiveness including strength of supporting evidence
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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.
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4.9
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Evidence for cost effectiveness
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Availability and nature of evidence
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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.
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4.22
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Uncertainties around and plausibility of assumptions and inputs in the economic model
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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.
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4.15
4.16
4.17
4.18
4.19
4.20
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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?
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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.
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4.16
4.24
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Are there specific groups of people for whom the technology is particularly cost effective?
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n/a
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n/a
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What are the key drivers of cost effectiveness?
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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.
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4.17
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Most likely cost-effectiveness estimate (given as an ICER)
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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 £8,900 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).
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4.21
4.22
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Additional factors taken into account
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Patient access schemes (PPRS)
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Not applicable
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n/a
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End-of-life considerations
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Not applicable
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n/a
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Equalities considerations and social value judgements
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No relevant equality considerations were raised during scoping or the appraisal.
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n/a
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