Natalizumab for the treatment of adults with highly active relapsingremitting multiple sclerosis

# Guidance
Natalizumab is recommended as an option for the treatment only of rapidly evolving severe relapsingremitting multiple sclerosis (RES). RES is defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2 lesion load compared with a previous MRI.
People currently receiving natalizumab, but for whom treatment would not have been recommended according to section 1.1 of this guidance, should have the option to continue therapy until they and their clinicians consider it appropriate to stop.# The technology
Natalizumab (Tysabri, Biogen Idec and Elan Pharma International Ltd) has a marketing authorisation as a single disease-modifying therapy in highly active relapsingremitting multiple sclerosis for the following groups.
Patients with rapidly evolving severe relapsingremitting multiple sclerosis defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI. This patient group is referred to as the 'RES group'.
Patients with high disease activity despite treatment with beta interferon. This group is defined as patients who have failed to respond to a full and adequate course of a beta interferon. Patients should have had at least one relapse in the previous year while on therapy, and have at least nine T2-hyperintensive lesions in cranial MRI or at least one gadolinium-enhancing lesion. This patient group is referred to as the 'suboptimal therapy group'.
The use of natalizumab may be associated with infections, urticaria, headache, dizziness, vomiting, nausea, arthralgia, infusion reactions and hypersensitivity reactions. Natalizumab has also been associated with an increased risk of progressive multifocal leukoencephalopathy (PML). For full details of side effects and contraindications, see the summary of product characteristics.
Natalizumab is administered by intravenous infusion; the recommended dose is 300 mg every 28 days. Natalizumab costs 1130 per 300 mg vial (according to the manufacturer's submission), so over a year the cost of the drug is approximately 14,730 per patient. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer expects that monitoring for symptoms of immunogenicity (anti-natalizumab antibodies) and hypersensitivity will be needed.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of natalizumab and a review of this submission by the evidence review group (ERG) (appendix B).
In its submission, the manufacturer compared natalizumab with beta interferon, glatiramer acetate and best supportive care (that is, no active treatment) for both the RES and the suboptimal therapy groups. The two major clinical outcomes examined were disability progression, defined as an increase in the expanded disability status scale (EDSS) score sustained for 12 or 24 weeks at 2 years, and annualised relapse rate.
The manufacturer presented data from the multinational, double-blind, randomised AFFIRM study (n = 942), which compared natalizumab with placebo. The study comprised people with relapsingremitting multiple sclerosis, of which a subgroup had highly active relapsingremitting multiple sclerosis. A post hoc subgroup analysis of AFFIRM (n = 209) provided clinical data for the RES group. The marketing authorisation for the suboptimal therapy group was based on data from the SENTINEL study (n = 1171), which compared natalizumab and beta interferon with beta interferon alone. However, the combination of natalizumab with beta interferon is not included in the marketing authorisation for natalizumab because of concerns over the risk of PML, and data from the SENTINEL study were not presented by the manufacturer. Instead, the manufacturer assumed that the intention to treat (ITT) population from AFFIRM is a suitable proxy for the suboptimal therapy group. The manufacturer provided additional data from two phase II studies. The manufacturer did not identify any studies that compared natalizumab with beta interferon or glatiramer acetate.
The AFFIRM study demonstrated that natalizumab statistically significantly reduces the probability of sustained disability progression compared with placebo in both the ITT and RES populations. The hazard ratios (HRs) varied between 0.46 and 0.58 in the ITT population, depending on the measure of disability progression (increase in EDSS sustained for 24 and 12 weeks respectively), and between 0.36 and 0.47 in the RES group. In addition, natalizumab led to a reduction in relapse rate, with a relative risk reduction of 0.68 in the ITT population and 0.81 in the RES group. The manufacturer presented evidence that showed that, compared with placebo, natalizumab significantly improved health-related quality of life when measured with the SF36 instrument, although not when the MSQLI instrument was used.
Given the absence of study data comparing natalizumab directly with beta interferon and glatiramer acetate, the manufacturer carried out an indirect comparison. This adopted an existing method to compare the results of AFFIRM with systematic reviews of beta interferon and glatiramer acetate. The systematic reviews included people with relapsingremitting multiple sclerosis rather than highly active relapsingremitting multiple sclerosis and did not specifically examine the clinical effectiveness of the drugs in the RES or suboptimal therapy groups. Therefore, the manufacturer assumed that the treatment effect of beta interferon and glatiramer acetate in relapsingremitting multiple sclerosis was equivalent to that in the RES and suboptimal therapy groups. The results of the indirect analysis showed that natalizumab was associated with a statistically significant reduction in relapse rates compared with beta interferon and glatiramer acetate, with relative risks of 0.63 and 0.57 respectively for the ITT population and 0.49 and 0.43 respectively for the RES group. The results of the indirect analysis for disability progression were submitted to NICE in confidence.
The AFFIRM study showed that natalizumab is not associated with a higher incidence of adverse events than placebo. The indirect comparison performed by the manufacturer found no statistically significant differences in adverse events between natalizumab and glatiramer acetate. However, compared with beta interferon, natalizumab was found to be associated with a statistically significant reduction in the incidence of influenza-like symptoms and myalgia/arthralgia, with relative risks of 0.47 and 0.68 respectively.
The manufacturer presented a multistate Markov model based on the economic model developed by the School of Health and Related Research (ScHARR) at Sheffield that was used in 'Beta interferon and glatiramer acetate for the treatment of multiple sclerosis' (NICE technology appraisal 32). The manufacturer's model predicts disability progression and disease activity over a time horizon of 20 years using a series of 1-year cycles. The model took an NHS perspective for the majority of costs, but included carers' disutility in the base case.
The clinical data that populate the manufacturer's model come from the AFFIRM study and the systematic reviews of beta interferon and glatiramer acetate. Additional data on disability progression were derived from the London data set (a longitudinal study of more than 1000 people with relapsingremitting multiple sclerosis followed for a mean of 25 years). Data on costs and utilities (based on EQ-5D scores) associated with EDSS states were derived from a cross-sectional study (the UK MS survey) commissioned by the manufacturer. This survey included people with relapsingremitting, secondary progressive and primary progressive multiple sclerosis, and the results were based on 2048 responses (a 15.8% response rate).
The results of the manufacturer's analysis showed that the incremental cost-effectiveness ratios (ICERs) for the RES group compared with best supportive care, beta interferon and glatiramer acetate were 44,600, 32,000 and 34,600 per quality-adjusted life year (QALY) gained respectively. For the suboptimal therapy group the ICERs were 56,100, 43,400 and 44,300 per QALY gained respectively.
Sensitivity analysis demonstrated that the variables that had the greatest effect on the ICERs were the time horizon over which costs and outcomes are evaluated and changing the source of the disability progression data from AFFIRM to the London dataset. Extending the time horizon to 30 years, for example, reduced the ICERs for natalizumab versus beta interferon to 24,600 and 34,200 per QALY gained in the RES and suboptimal therapy groups respectively. In contrast, changing the source of the disability progression data from AFFIRM to the London Ontario dataset increased the ICERs to 42,300 and 55,300 per QALY gained for natalizumab versus beta interferon in the RES and suboptimal therapy groups respectively.
The ERG expressed a number of concerns about the manufacturer's submission. The ERG recognised the general uncertainty associated with indirect analyses and that the data for the comparators was derived from people with relapsingremitting multiple sclerosis rather than highly active relapsingremitting multiple sclerosis. The ERG stated that this might alter the conclusions of the analysis, although the magnitude and direction of any such effect was unknown.
The ERG recognised that the approach adopted by the manufacturer in its economic modelling was pragmatic given the absence of better quality data. However, it expressed concern about the extrapolation of 2-year data from the AFFIRM study to a 20-year time horizon. The ERG also expressed concern that the utility and cost data, which were based on the UK MS survey, were not exclusively derived from people with highly active relapsingremitting multiple sclerosis; in addition the survey may not have been representative because of the low response rate.
The ERG commented on the limitations of the EDSS instrument, which suffers from limited responsiveness and inter- and intra-rater variability. In addition, the ERG expressed concern that, although the transition probabilities in the manufacturer's model were based on data from AFFIRM, the model appeared to predict a higher rate of sustained disability progression at 2 years than reported in AFFIRM. The ERG stated that this might overestimate the effectiveness of natalizumab, and might therefore lead to more favourable ICERs in the model. The ERG also highlighted the limited evidence for the assumption in the manufacturer's model that natalizumab reduces progression from relapsingremitting multiple sclerosis to secondary progressive multiple sclerosis.
Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of natalizumab for highly active relapsingremitting multiple sclerosis, having considered evidence on the nature of the condition and the value placed on the benefits of natalizumab by people with multiple sclerosis, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.

# Clinical effectiveness
The Committee considered the data on the clinical effectiveness of natalizumab in the subgroup of people whose multiple sclerosis has failed to respond to treatment with beta interferon, that is, the suboptimal therapy group. It noted that the ITT population from the AFFIRM study, which showed that natalizumab significantly reduces relapse rate and delays disability progression compared with placebo, was used in the manufacturer's submission as a proxy for this group. The Committee was aware that the Sentinel study was used to inform the licence for the suboptimal therapy group but that the study considered the use of natalizumab in combination with beta interferon; this combination is not licensed because of safety concerns. The Committee noted that there is no direct evidence about the clinical effectiveness of natalizumab monotherapy in the suboptimal therapy group. In addition, the clinical experts confirmed that, although natalizumab may be used in this situation, there are no clinical study data to indicate how clinically effective it is in this group. The Committee therefore concluded that the clinical effectiveness of natalizumab in the suboptimal therapy group has not been fully established.
The Committee considered the data on the clinical effectiveness of natalizumab in the RES group. The Committee was aware that a post hoc analysis of the AFFIRM study population indicated that natalizumab significantly reduces relapse rate and delays disability progression compared with placebo in the RES group. It noted the results of an indirect analysis performed by the manufacturer showing that natalizumab reduces relapse rate more effectively than beta interferon or glatiramer acetate. The Committee also heard the views of the clinical and patient experts that natalizumab has a clinically important effect on disability progression in people with highly active forms of multiple sclerosis that has not been seen with other disease-modifying therapies. The Committee agreed that natalizumab is clinically effective in the RES group compared with placebo, beta interferon and glatiramer acetate.

# Cost effectiveness
Although the Committee had reservations about the data on the clinical effectiveness of natalizumab in the suboptimal therapy group (as indicated in section 4.2), it reviewed the manufacturer's cost-effectiveness analysis for this group and the ERG's comments. The Committee noted that the base case ICERs estimated by the manufacturer for the suboptimal therapy group were 43,400 per QALY gained or higher. It therefore concluded that natalizumab would not be a cost-effective use of NHS resources in this group of people.
The Committee noted that the base case ICERs estimated for the RES group by the manufacturer ranged from 32,000 per QALY gained (natalizumab compared with beta interferon) to 44,600 per QALY gained (natalizumab compared with best supportive care).
The Committee considered which of the comparators used in the manufacturer's cost-effectiveness analysis for the RES group best reflected current clinical practice. The Committee noted that, as described in NICE technology appraisal guidance 32, beta interferon and glatiramer acetate were not recommended by NICE for the treatment of multiple sclerosis on the basis of their cost effectiveness. However, it was aware that, following the Institute's assessment of beta interferon and glatiramer acetate, a risk sharing scheme had been set up by the Department of Health. This allowed the continued use of these technologies with the financial risk being shared between the NHS and the participating pharmaceutical companies. The Committee also noted the information from consultees that treatment with beta interferon is the current standard of practice in the RES group. It was persuaded, therefore, that the most appropriate comparator for determining cost effectiveness in the RES group is beta interferon.
The Committee noted the views of the ERG that the results of the manufacturer's economic model were associated with considerable uncertainty and that alternative assumptions would substantially increase or decrease the ICERs (see sections 3.9 and 3.12). However, the Committee concluded that the ICER of 32,000 per QALY for natalizumab compared with beta interferon presented by the manufacturer was more likely to be an overestimate. The Committee considered that, for a disease which presents in early life and has limited effect on life expectancy, a time horizon longer than 20 years would be appropriate, which would lower the ICER. In addition it was persuaded that the disutility of relapses may have been underestimated in the model. In addition, the Committee took into account the high degree of clinical need among people in the RES group and the innovative nature of the technology. The Committee therefore concluded that the use of natalizumab for people with RES would be a cost-effective use of NHS resources and that it should be recommended for use within the NHS for the treatment of people with RES.# Recommendations for further research
The Committee considered that further research into the clinical effectiveness of natalizumab for the treatment of highly active relapsingremitting multiple sclerosis in the suboptimal therapy group is needed.# Related guidance
NICE has issued the following related technology appraisal guidance and clinical guidelines.
Multiple sclerosis: management of multiple sclerosis in primary and secondary care. NICE clinical guideline 8 (2003).
Beta interferon and glatiramer acetate for the management of multiple sclerosis. NICE technology appraisal guidance 32 (2002).# Review of guidance
The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.
The guidance on this technology will be considered for review in 2013.
Andrew DillonChief ExecutiveAugust 2007# Appendix C. List of organisations involved in this appraisal
The following organisations accepted the invitation to participate in this appraisal. They are also invited to comment on the appraisal consultation document and supporting evidence. Consultee organisations have the opportunity to appeal against the final appraisal determination.
I) Professional/specialist, patient/carer groups and other organisations:
Association of British Neurologists
Multiple Sclerosis Society
Multiple Sclerosis Trust
Primary Care Neurology Society
Royal College of Nursing
Royal College of Physicians
UK Multiple Sclerosis Specialist Nurse Association
Department of Health
Oldham PCT
Welsh Assembly Government
II) Commentator organisations (without the right of appeal):
Amgen (mitoxantrone)
Biogen Idec UK (interferon beta-1a)
British National Formulary
Department of Health, Social Services and Public Safety for Northern Ireland
Medicines and Healthcare products Regulatory Agency (MHRA)
Multiple Sclerosis Group, University of Bristol
National Coordinating Centre for Health Technology Assessment
National Collaborating Centre for Chronic Conditions
NHS Quality Improvement Scotland
Peninsula Technology Assessment Group, University of Exeter
Schering Health Care (interferon beta-1b)
Serono (interferon beta-1a)
Teva Pharmaceuticals (glatiramer acetate)# Changes after publication
March 2014: implementation section updated to clarify that natalizumab is recommended as an option for treating highly active relapsingremitting multiple sclerosis. Additional minor maintenance update also carried out.
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
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 National Institute for Health and Clinical Excellence 2007. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.