The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE, or the Institute) to conduct a single technology appraisal (STA) of natalizumab and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by consultees and by the representatives nominated by professional/specialist and patient/carer groups. The Committee has developed preliminary recommendations on the use of natalizumab.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk ). This document should be read in conjunction with the manufacturer’s submission and the evidence review group report, which are available from www.nice.org.uk

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

• The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘Guide to the single technology appraisal process’ (this document is available on the Institute’s website, www.nice.org.uk).
• The Appraisal Committee will meet again to consider the original evidence and this Appraisal Consultation Document in the light of the views of the formal consultees.
• At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
• After considering feedback from the consultation process, the Committee will prepare the Final Appraisal Determination (FAD) and submit it to the Institute.

Subject to any appeal by consultees, the FAD may be used as the basis for the Institute’s guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:
Closing date for comments: 23 April 2007
Second Appraisal Committee meeting: 8 May 2007

Details of membership of the Appraisal Committee are given in appendix A, a list of the sources of evidence used in the preparation of this document is given in appendix B, and a list of organisations involved in this appraisal is given in appendix C.

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.

Natalizumab is not recommended for the treatment of highly active relapsing–remitting multiple sclerosis.

People currently receiving natalizumab should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

Natalizumab (Tysabri, Biogen Idec) has a marketing authorisation as a single disease-modifying therapy in highly active relapsing–remitting multiple sclerosis for the following groups.

• RES group: people with rapidly evolving severe relapsing–remitting multiple sclerosis (RES), defined as two or more disabling relapses in 1 year, and with 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.
• Suboptimal therapy group: people whose condition has not responded to a full and adequate course of a beta interferon, who have had at least one relapse in the previous year while on therapy, and have at least nine T2-hyperintensive lesions on brain MRI or at least one gadolinium-enhancing lesion.

Natalizumab may be associated with infections, urticaria, headache, dizziness, vomiting, nausea, arthralgia, infusion reactions and hypersensitivity reactions. The use of natalizumab has been associated with an increased risk of progressive multifocal leukencephalopathy (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 ml vial (according to manufacturer’s submission), so over a year the cost of the drug is approximately £14,730. 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 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).

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. This study mainly comprised people with relapsing–remitting 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 an increased risk of PML, so 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, and between 0.36 and 0.47 in the RES group. In addition, natalizumab led to a reduction in relapses 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 improves health-related quality of life when measured with the SF-36 instrument, but 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 the methods described by Song and coworkers to compare the results of AFFIRM with systematic reviews of beta interferon and glatiramer acetate. The systematic reviews included people with relapsing–remitting multiple sclerosis rather than highly active relapsing–remitting 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 relapsing–remitting 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 trial showed that natalizumab is not associated with a higher incidence of adverse events compared with 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 used in ‘Beta interferon and glatiramer acetate for the treatment of multiple sclerosis’ (NICE technology appraisal 32), which was developed by the School of Health and Related Research (ScHARR) at Sheffield University. 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 AFFIRM and the systematic reviews of beta interferon and glatiramer acetate. Data on disability progression were also derived from the London Ontario data set (a longitudinal study of more than 1000 people with relapsing–remitting 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. The results of the UK MS survey were based on 2048 responses (representing 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 £45,000, £32,000 and £34,600 respectively. For the suboptimal therapy group, the ICERs were £56,100, £43,400 and £44,300 respectively. Sensitivity analysis demonstrated that the variables that had the greatest effect on the ICERs were the time horizon and changing the source of the disability progression data from AFFIRM to the London Ontario dataset.

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 relapsing–remitting multiple sclerosis rather than highly active relapsing–remitting multiple sclerosis. The ERG stated that this could alter the conclusions of the analysis, although the magnitude and direction of any such effect was unknown. The ERG also expressed concern that the utility and cost data, which were based on the MS UK survey, were not exclusively derived from people with highly active relapsing–remitting multiple sclerosis; in addition the survey may not have been representative given the low response rate.

The ERG recognised that the approach adopted by the manufacturer in its economic modelling was pragmatic given the absence of good quality data. However, it expressed concern about the extrapolation of 2-year data from the AFFIRM trial to a 20-year time horizon, and about the extrapolation of data collected on costs and utilities from the UK MS survey.

The ERG commented on the limitations of the EDSS instrument, which suffers from limited responsiveness and inter- and intra-rater variability. The ERG was concerned that, unlike in the ScHARR model, the manufacturer’s analysis allowed EDSS scores to improve and that the transition probabilities appeared high. The ERG also expressed concern that, although the transition probabilities in the model were based on data from AFFIRM, the model appeared to predict a higher rate of disability progression than in observed in AFFIRM. The ERG stated that this could overestimate the effectiveness of natalizumab, and could therefore lead to more favourable ICERs in the model.

Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/TA xxx [This will be available when the final guidance is issued]

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of natalizumab for highly active relapsing–remitting 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.

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 trial population indicated that natalizumab significantly reduces relapses and delays disability progression compared with placebo in this group. 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, relative to placebo, that has not been seen with other disease-modifying therapies used to treat the condition. The Committee agreed that natalizumab is clinically effective in the RES group, compared with placebo.

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 in 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 all greater than £43,400 per QALY and concluded that natalizumab is not 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 (natalizumab compared with beta interferon) to £44,600 per QALY (natalizumab compared with best supportive care). The Committee also noted the views of the ERG that the results of the manufacturer’s economic model were associated with considerable uncertainty. In particular, the Committee was concerned about the ERG’s opinion that the model predicted greater disability progression than suggested by the trial data, which could lead to an overestimate of the treatment benefit for natalizumab and an underestimate of the ICER.

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 beta interferon and glatiramer acetate were not recommended by NICE for the treatment of multiple sclerosis on the basis of their cost effectiveness, as described in NICE technology appraisal 32. Additionally the Committee was aware of the absence of any clinical trial data about the effectiveness of beta interferon in the RES group. It also heard from the clinical experts that, for people with highly active disease, beta interferon is not generally considered to be effective and is consequently not used as a long-term treatment. The Committee was persuaded, therefore, that in the RES group the most appropriate comparator is best supportive care and that use of other currently licensed disease-modifying drugs is of unproven effectiveness. The Committee therefore concluded that, based on the ICER of £44,600 per QALY for natalizumab versus best supportive care presented in the manufacturer’s economic analysis, natalizumab could not be considered a cost-effective use of NHS resources in this group.

For the suboptimal therapy group, the Committee concluded that the clinical effectiveness of natalizumab in the suboptimal therapy group has not been established. Furthermore, the Committee agreed that natalizumab has not been shown to be cost effective and that it should not be recommended for use in the NHS in this group of people.

For the RES group, the Committee accepted that natalizumab is clinically effective compared with placebo. The Committee also concluded that for this subgroup the appropriate comparator in current UK practice is best supportive care. Owing to the high incremental cost per QALY of natalizumab compared with best supportive care and the considerable uncertainty around the estimates, the Committee concluded that the economic case for natalizumab had not been made and that natalizumab could not therefore be recommended for use in the NHS in this group of people.

The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ‘Standards for better health’ issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals, normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.

'Healthcare Standards for Wales’ was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.

NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TA xxx ). [Note: tools will be available when the final guidance is issued]

Proposed recommendations for further research

The Committee considered that further research into the clinical effectiveness of natalizumab for the treatment of highly active relapsing–remitting multiple sclerosis in the suboptimal therapy group is needed.

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). Available from: www.nice.org.uk/CG008
• Beta interferon and glatiramer acetate for the management of multiple sclerosis. NICE technology appraisal guidance 32 (2002). Available from: www.nice.org.uk/TA032

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.

It is proposed that the guidance on this technology is considered for review in March 2010. The Institute would particularly welcome comment on this proposed date.

David Barnett

Chair, Appraisal Committee

March 2007

Appendix A. Appraisal Committee members and NICE team members

A. Appraisal Committee members

The Appraisal Committee is a standing advisory committee of the Institute. Its 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. The Appraisal Committee meets twice a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice-chair. Each branch considers its own list of technologies and ongoing topics are not moved between the branches.

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.

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Jeff Aronson
Reader in Clinical Pharmacology, Radcliffe Infirmary

Dr Darren Ashcroft
Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Professor Stirling Bryan
Director of the Health Economics Facility, University of Birmingham

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

Dr Mark Charkravarty
Head of Government Affairs and NHS Policy, Procter and Gamble Pharmaceuticals ( UK) Ltd

Professor Jack Dowie
Health Economist, London School of Hygiene and Tropical Medicine

Lynn Field
Nurse Director, Pan Birmingham Cancer Network

Professor Christopher Fowler
Professor of Surgical Education, University of London

Dr Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Ms Sally Gooch
Former Director of Nursing and Workforce Development, Mid Essex Hospitals Services NHS Trust

Mrs Barbara Greggains
Company Director, Greggains Management Limited

Mr Sanjay Gupta
FormerStroke Services Manager, Basildon and Thurrock Universities Hospitals NHS Trust

Dr Mike Laker
Medical Director, Newcastle Hospitals NHS Trust

Mr Terence Lewis
Mental Health Consultant, National Institute for Mental Health in England

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens University, Belfast

Dr Ruairidh Milne
Senior Lecturer in Health Technology Assessment, National Coordinating Centre for Health Technology

Dr Neil Milner
General Medical Practitioner, Tramways Medical Centre, Sheffield

Dr Rubin Minhas
General Practitioner, CHD Clinical Lead, Medway PCT

Dr John Pounsford
Consultant Physician, North Bristol NHS Trust

Dr Rosalind Ramsay
Consultant Psychiatrist, Adult Mental Health Services, Maudsley Hospital, London

Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Cliff Snelling
Lay member

Dr Ken Stein
Senior Lecturer, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, University of Birmingham `

B. NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Zoe Charles and Prashanth Kandaswamy
Technical Leads

Dr Elisabeth George
Technical Adviser

Reetan Patel
Project Manager

The following manufacturer/sponsor provided a submission for this appraisal:

• Biogen Idec UK and Elan Pharma International

The evidence review group (ERG) report for this appraisal was prepared by Peninsula Technology Assessment Group, University of Exeter:

• Ruth Garside, Colin Green, Martin Hoyle, et al. The effectiveness and cost effectiveness of natalizumab for multiple sclerosis: an evidence review of the submission from Biogen, 6 February 2007.

The following individuals were selected from clinical specialist and patient advocate nominations from the professional/specialist and patient/carer groups. They gave their expert personal view on natalizumab for the treatment of multiple sclerosis by providing written evidence to the Committee. They are invited to comment on the Appraisal Consultation Document (ACD).

• Professor David Miller, nominated as a clinical expert by the Association of British Neurologists
• Professor Alan Thompson, nominated as a clinical expert by the Multiple Sclerosis Society
• Megan Burgess, nominated as a clinical expert by the Royal College of Nursing
• Mrs Caroline Haynes, nominated as a patient expert by the MS Trust
• Mr Mark Priest, nominated as a patient expert by the MS Trust

The following organisations accepted the invitation to participate in this appraisal. They are also invited to comment on the Appraisal Consultation Document (ACD) and supporting evidence. Consultee organisations have the opportunity to appeal against the Final Appraisal Determination.

I 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 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 Ltd (glatiramer acetate)

The following individuals were selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee’s deliberations. They gave their expert personal view on ezetimibe by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD .

• Dr David Monkman, clinical expert, General Practitioner, nominated by the Primary Care Cardiovascular Society


• Dr Richard Wray, clinical expert, Consultant Cardiologist, nominated by the British Cardiovascular Society


• Dr Anthony S Weirzbicki, clinical expert, Consultant Chemical Pathologist, nominated by South Asian Health Foundation


• Mr Bruce Mayo, patient expert, nominated by HEART UK


• Mr Raymond Edwards, patient expert, nominated by HEART UK