Horizon Scanning Centre July Daclizumab High Yield Process for relapsing forms of multiple sclerosis first or second line

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1 Horizon Scanning Centre July 2014 Daclizumab High Yield Process for relapsing forms of multiple sclerosis first or second line SUMMARY NIHR HSC ID: 2635 This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. Daclizumab High Yield Process (DAC HYP) is intended to be used for the long-term first or second line treatment of relapsing forms of multiple sclerosis. If licensed, DAC HYP will offer an additional treatment option for this patient group. DAC HYP is a humanised monoclonal antibody that blocks the alpha subunit of the interleukin-2 (IL-2) receptor, CD25. DAC HYP is able to inhibit T cell expansion and reduce brain inflammation in MS patients, thereby reducing the severity of associated symptoms, and may also promote the proliferation of CD56 (bright) natural killer cells, which act to further inhibit T cell survival. Daclizumab, as Zenapax, was previously licensed for the prevention of acute organ rejection in de novo renal transplantation, but was withdrawn from the market by the developer. MS is the most common demyelinating disease in the UK, with a prevalence of around 0.16% (approximately 100,000), and around 2,500 people are diagnosed with the condition each year. Around three times as many women have MS as men. Approximately 35.5% of all MS patients will have relapsing-remitting disease (around 30,388) in England and an estimated 38.75% (11,775) of these will be eligible for drug treatment. MS has limited impact on longevity; however it causes considerable disability and impacts on employment and quality of life, with walking impairment being the most prominent disability, affecting up to 85% of MS patients. 1,218 deaths from MS were registered in England and Wales during Current pharmacological management of relapsing-remitting MS includes the first line use of disease-modifying therapies to reduce the frequency and severity of relapses. These include beta interferon in combination with glatiramer acetate (not recommended by NICE), fingolimod, alemtuzumab, teriflunomide and natalizumab amongst others. Chronic symptoms and disability are usually managed by speech-, physio- and occupational therapy, pharmacological or surgical treatments. DAC HYP is currently in an extension phase III clinical trial investigating its long term safety. This trial is expected to complete in December This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health., University of Birmingham nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Multiple sclerosis: relapsing forms first or second line. TECHNOLOGY DESCRIPTION Daclizumab high yield process (DAC HYP; BIIB019) is a humanised monoclonal antibody that blocks the alpha subunit of the interleukin-2 (IL-2) receptor, CD25. IL-2 signalling plays a central role in the activation of immune responses involving the accommodation of T cells, B cells and natural killer (NK) cells 1. In multiple sclerosis (MS), T cells become abnormally activated and produce demyelination of the nerves myelin sheath which disrupts the electrical signalling between nerve cells. CD25 is expressed at high levels on these T cells. Through binding to the CD25 epitope and masking of the IL-2 binding site, DAC HYP is able to inhibit T cell expansion and reduce brain inflammation in patients with MS, thereby reducing the severity of associated symptoms 1. In addition, DAC HYP may also promote the proliferation of CD56 (bright) natural killer cells, which act to further inhibit T cell survival 1. DAC HYP is intended to be used for the long-term first or second line treatment of relapsing forms of MS. In the phase III clinical trials, DAC HYP is administered subcutaneously (SC) at 150mg once every 4 weeks for up to 3 years. Daclizumab, as Zenapax, was launched in the UK and EU in 1999 for the prevention of acute organ rejection in de novo renal transplantation, but was withdrawn by the developer for commercial reasons in INNOVATION and/or ADVANTAGES If licensed, DAC HYP will offer an additional treatment option for patients with relapsing forms of MS. The company note that given the heterogeneous nature of MS and variability in individual response to existing therapies, there is a high unmet need to provide MS patients with new therapeutic options that treat the condition through novel mechanisms of action, that can be conveniently administered. DEVELOPER Biogen Idec and AbbVie. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND Multiple sclerosis is a chronic, neurodegenerative disorder with multifocal inflammatory demyelination affecting the brain, optic nerves, and spinal cord 2. Demyelination occurs when the immune system attacks and destroys the myelin sheath, the layer of protein covering individual nerve fibres that protects the nerve and allows rapid conduction of electrical 2

3 signals. Damage to the myelin sheath disrupts the transfer of these nerve signals causing a wide range of symptoms which vary between patients in severity and appearance, and can be unpredictable 3. The more common symptoms of MS include: fatigue (in around 80% of patients), pain, difficulty in walking, numbness of the face, body or extremities, disturbance to muscle tone including weakness or spasticity, visual problems such as blurred vision or eye pain on movement, dizziness and vertigo, bladder dysfunction (in at least 80% of patients), bowel incontinence and cognitive impairment 4. Relapsing-remitting MS (RRMS) affects approximately 80% of people at the time of diagnosis. It is characterised by periods of remission followed by relapses (bouts of central nervous system inflammation), which may or may not result in residual disability 2. Most people with RRMS will develop secondary progressive MS (SPMS) 2. Around 65% of people with RRMS develop SPMS within 15 years of diagnosis, which is characterised by more persistent or gradually increasing disability 2. Some patients with SPMS may still experience relapses, but will be unable to fully recover from their symptoms 3. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: Department of Health. Improving quality of life for people with long term conditions (2013). NHS England. 2013/14 NHS Standard Contract for Complex Disability Equipment: Alternative and Augmentative Communication/Communication Aids (All Ages). D01/S/b. NHS England. 2013/14 NHS Standard Contract for complex disability equipment: specialised wheelchair and seating services (all ages). D01/S/a. NHS England. 2013/14 NHS Standard Contract for neurosciences: specialised neurology (adult). D04/S/a. NHS England. Clinical Commissioning Policy: Disease Modifying Therapies for Patients with Multiple Sclerosis (MS). NHS ENGLAND/D04/P/b. May NHS England. Clinical Commissioning Policy Statement: Fampridine for Multiple Sclerosis (MS). NHSCB/D04/PS/c. April CLINICAL NEED and BURDEN OF DISEASE Multiple sclerosis is incurable and progressive in the majority of people, resulting in a low incidence but high prevalence 5. MS is the most common demyelinating disease in the UK, with a prevalence of around 0.16% 6 (approximately 100,000 2 ), and around 2,500 people are diagnosed with the condition each year 2. Around three times as many women have MS as men 7. Most patients are diagnosed between the ages of 20 and 40 years although it has the potential to occur in young children and older adults 7. Approximately 35.5% of all MS patients will have relapsing-remitting disease 6, equating to around 30,388 people in England and an estimated 38.75% (11,775) of these will be eligible for drug treatment 6. The incident population starting treatment for MS each year in England is approximately 1,600 people 8. MS has limited impact on longevity; however it causes considerable disability and impacts on employment and quality of life, with walking impairment being the most prominent disability, affecting up to 85% of MS patients 9. In , there were 38,080 admissions for MS (ICD10 G35) in England, resulting in 58,892 bed days and 40,418 finished consultant episodes 10. 1,218 deaths from MS (ICD10 G35) were registered in England and Wales during

4 PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal in development. Dimethyl fumarate for the treatment of relapsing-remitting multiple sclerosis (ID585). Expected August NICE technology appraisal in development. Laquinimod for treating relapsing-remitting multiple sclerosis (ID560). Suspended May NICE technology appraisal. Alemtuzumab for treating relapsing-remitting multiple sclerosis (TA312). May NICE technology appraisal. Teriflunomide for treating relapsing-remitting multiple sclerosis (TA303). January NICE technology appraisal. Fingolimod for the treatment of highly active relapsingremitting multiple sclerosis (TA254). April NICE technology appraisal. Natalizumab for the treatment of adults with highly active relapsing-remitting multiple sclerosis (TA127). August NICE technology appraisal. Beta interferon and glatiramer acetate for the treatment of multiple sclerosis (TA32). January NICE clinical guideline in development. Management of multiple sclerosis in primary and secondary care. Expected October NICE clinical guideline. Management of multiple sclerosis in primary and secondary care (CG8). November NICE interventional procedures guidance. Percutaneous venoplasty for chronic cerebrospinal venous insufficiency for multiple sclerosis (IPG420). March Other Guidance European Federation of Neurological Societies. EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses Association of British Neurologists. Revised (2009) guidelines for prescribing in multiple sclerosis Royal College of Physicians, National Council for Palliative Care, British Society of Rehabilitation Medicine. Long-term neurological conditions: management at the interface between neurology, rehabilitation and palliative care CURRENT TREATMENT OPTIONS Current pharmacological management of RRMS includes the first line use of diseasemodifying therapies (DMTs) to reduce the frequency and severity of relapses (some of which are also employed to treat SPMS 3 ). These include 2,15,16,17,18 : Beta interferon and glatiramer acetate, although these are not recommended by NICE 19. For second line treatment, patients who experienced an inadequate response to first line treatment can be treated with another beta interferon or glatiramer acetate, or a dose escalation of existing beta interferon treatment 2. Fingolimod for the treatment of highly active RRMS in adults who have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon 2,20. Alemtuzumab for treating adults with active RRMS 21. 4

5 Teriflunomide for treating adults with active RRMS where patients do not have highly active or rapidly evolving severe RRMS 22. Natalizumab for people with rapidly-evolving severe RRMS 2,23. Dimethyl fumerate for adults with relapsing-remitting MS (NICE technology appraisal expected August 2014) 24. Unlicensed immunosuppressants are sometimes used, including methotrexate, cyclophosphamide (not recommended by NICE 17 ) and azathioprine. Acute exacerbations are usually treated using corticosteroids. Chronic symptoms and disability are usually managed by speech-, physio- and occupational therapy, pharmacological or occasionally surgical treatments. EFFICACY and SAFETY Trial EXTEND, NCT , 205MS303, EudraCT Number: ; DAC HYP; phase III extension. DECIDE, NCT , 205MS301, EudraCT Number: ; DAC HYP and interferon beta-1a placebo vs interferon beta-1a and DAC HYP placebo; phase III. OBSERVE, NCT , 205MS302, EudraCT Number: ; DAC HYP; phase III. Sponsor Biogen Idec. Biogen Idec. Biogen Idec. Status Ongoing. Ongoing. Ongoing. Source of Trial registry 25. Trial registry 26. Trial registry 27. information Location EU (incl UK), USA, Canada and other EU (incl UK), USA, Canada and other countries. EU (not UK), USA and Russia. countries. Design Uncontrolled, single arm. Randomised, activecontrolled. Uncontrolled, single arm. Participants Schedule n=1,841 (planned); aged 18 yrs; relapsingremitting multiple sclerosis (RRMS); participation in study 205MS301 (NCT ) and completed the end of study visit (week 96 or later) without early discontinuation of allocated treatment. DAC HYP 150mg SC once every 4 weeks for up to 3 yrs. n=1,800 (planned); aged yrs; RRMS and cranial MRI demonstrating lesion(s) consistent with MS; baseline EDSS between 0.0 and 5.0. Patients excluded if they had: intolerance, contraindication or history of non-compliance with interferon beta-1a; MS relapse within 50 days and/or not stabilised by study start. Randomised to DAC HYP 150mg SC once every 4 weeks for 96 to 144 weeks and interferon beta-1a placebo; or interferon beta- 1a 30mg intramuscular (IM) injection once weekly for 96 to 144 weeks and DAC HYP placebo. n=135 (planned); aged yrs; RRMS and previous MRI showing lesion; baseline EDSS between 0.0 and 5.0; 1 or more clinical relapses within 2 yrs. DAC HYP 150mg SC prefilled 1ml syringe once every 4 weeks for 24 weeks followed by a 20 week washout period and then 4 weekly treatment for 3 yrs. 5

6 Follow-up Active treatment for up to 3 yrs, follow-up 6 yrs. Active treatment for up to 144 weeks, follow-up to 144 weeks. Active treatment 24 wks followed by 20 wk washout and further active treatment for 3 yrs, follow-up 6 mths. Primary outcome/s Secondary outcome/s Expected reporting date Adverse events (AEs); serious adverse events (SAEs). Clinically notable laboratory abnormalities; depression; anti-dac HYP binding and neutralising antibodies; relapse; sustained disability progression; patients free from disease activity; sustained improvement in disability; annualised relapse rate; total number of new or newly enlarging T2 hyperintensive lesions, gadolinium (gd) enhancing lesions and T1 hypointense lesions on MRI; MS functional composite score; expanded disability status scale (EDSS) score; MS impact scale 29 (MSIS-29) physical and psychological scores; EQ5D and EQVAS quality of life measures; direct health resource utilisation; treatment satisfaction; participant productivity assessed by health related productivity questionnaire. Study completion date reported as Dec Annualised relapse rate. Number of new or newly enlarging T2 hyperintensive lesions on MRI; proportion of subjects with sustained disability progression from baseline EDSS; proportion of subjects who are relapsefree; proportion of subjects with a 7.5 point worsening from baseline in MSIS-29 physical score. Safety measured by: incidence of anti-dac HYP binding and neutralising antibodies. Pharmacokinetics. - Study completion date reported as Feb Trial SELECTED, NCT , 205-MS- 203, EudraCT Number: ; DAC HYP; phase II extension. SELECTION, NCT , 205- MS202, EudraCT Number: ; DAC HYP; phase II extension. SELECT, NCT , 205-MS-201, EudraCT Number: ; DAC HYP vs placebo; phase II. Sponsor Biogen Idec. Biogen Idec. Biogen Idec. Status Ongoing. Published. Published. Source of Trial registry 28. Publication 29, trial Publication 31, trial registry 32. information registry 30. Location EU (incl UK), India, Russia and Ukraine. EU (incl UK), India, Russia and Ukraine. EU (incl UK), India, Russia and Ukraine. 6

7 Design Uncontrolled, single arm. Randomised. Randomised, placebocontrolled. Participants n=600 (planned); aged yrs; RRMS; participation in study 205MS202 (NCT ) for 52 weeks and compliant with previous study protocol. n=517; aged yrs; RRMS; participation in study 205MS201 (NCT ) for 52 weeks and compliant with previous study protocol. n=621; aged yrs; RRMS; EDSS baseline score of 5.0 or less; 1 confirmed MS relapse in previous 12 months or at least one new gadolinium-enhancing lesion on brain MRI in previous 6 weeks. Schedule Subjects receive DAC HYP 150mg SC every 4 weeks. Follow-up Active treatment for 3-6 yrs, follow-up 144 weeks. Primary outcome/s Secondary outcome/s Safety of DAC HYP, including AEs, laboratory evaluations, vital signs, physical examinations and immunogenicity. Durability of DAC HYP response measured by brain MRI (new gd enhancing lesions, new or newly enlarging T2 hyperintense lesions, volume of new T1 hypointense lesions, and volume of non gd enhancing T1 hypointense lesions on brain MRI). Previous placebo group - randomised to DAC HYP 150mg SC, or 300mg SC, every 4 weeks for 52 weeks. Previous DAC HYP 150mg SC treatment group randomised to washout (placebo DAC HYP) for 20 weeks followed by DAC HYP 150mg SC every 4 weeks for 32 weeks; or DAC HYP 150mg SC every 4 weeks for 52 weeks. Previous DAC HYP 300mg SC treatment group randomised to washout (placebo DAC HYP) for 20 weeks followed by DAC HYP 150mg SC every 4 weeks for 32 weeks; or DAC HYP 150mg SC every 4 weeks for 52 weeks. Active treatment for 32 or 52 weeks, follow-up to 52 weeks. Safety and immunogenicity of DAC HYP. Durability of DAC HYP response measured by relapse activity (annualised relapse rate and proportion of relapsed patients), disability progression (EDSS score), and MRI endpoints (new gd enhancing lesions, new or newly enlarging T2 hyperintense lesions, volume of new T1 hypointense lesions, Patients excluded if: MS relapse in previous 50 days and/or no stabilisation from relapse. Randomised to DAC HYP 150mg SC every 4 weeks for 48 weeks; or DAC HYP 300mg SC every 4 weeks for 48 weeks; or placebo. Active treatment for 48 weeks, follow-up 52 weeks. Annualised relapse rate. Brain MRI measures (number of gd-enhancing lesions); proportion of relapsing subjects; quality of life improvement on MSIS-29 physical score; brain MRI measures (number of new or newly-enlarging T2 hyperintense lesions). 7

8 volume of non gd enhancing T1 hypointense lesions). Key results - The number of patients with antidrug antibodies and neutralising antidrug antibodies varied by group: in the treatment initiation group neutralising antidrug antibodies were transient and those present at week 72 were not detectable at week 104; in the continuous treatment group no incident cases of neutralising antidrug antibodies were reported; in the washout and reinitiation group, 13 (11%) of 115 patients were positive for antidrug antibodies at week 72 and one (1%) was positive for neutralising antidrug antibodies at the end of the washout period. After 32 weeks of retreatment one (1%) of 114 patients was positive for antidrug antibodies and none for neutralising antidrug antibodies. Adverse effects (AEs) Expected reporting date - The number of AEs and SAEs was similar between the treatment initiation and continuous treatment groups. The most frequently reported AEs included MS relapse, nasopharyngitis and upper respiratory tract infection. One patient in the washout and re-initiation group (300mg DAC HYP) died of autoimmune hepatitis, a contributory role of DAC HYP could not be ruled out. Study completion date reported as Sept For DAC HYP 150mg and 300mg groups, respectively: annualised relapse rate at 52 weeks compared to placebo was significantly lower (p<0.001) in the treatment groups (0.21, 95% CI , 54% reduction), (0.23, 95% CI , 50% reduction). The proportion of AEs was similar between groups. The most frequently reported included MS relapse, nasopharyngitis, headache, upper respiratory tract infection, pharyngitis, oral herpes and rash. In the DAC HYP treated groups compared to placebo, there was an increased incidence of serious infections (2% vs 0%), serious cutaneous events (1% vs 0%) and elevations of alanine aminotransferase (ALT) and aspartate transaminase (AST) >5x upper limit of normal (4% vs <1%), respectively. One patient (150mg DAC HYP group) recovering from a serious rash died because of local complication of a psoas abscess. 8

9 ESTIMATED COST and IMPACT COST The cost of DAC HYP is not yet known. The costs of other selected treatments for RRMS are summarised below: Drug Dose Annual cost 33,34,35 Interferon beta-1a (Rebif) 44mg, SC, 3 times weekly. 8,942 a,35 Interferon beta-1a (Avonex) 30mg, IM, once weekly. 8,502 Fingolimod (Gilenya) 500mg daily. 19,110 Natalizumab (Tysabri) 300mg, IV, every 4 weeks. 14,690 Glatiramer acetate (Copaxone) 20mg daily. 5,823 a,35 Alemtuzumab (Lemtrada) 5 daily consecutive 12mg doses in year 1, followed by 3 daily consecutive 12mg doses 12 months later in year 2. Teriflunomide (Aubagio) 14mg once daily. 13,492 Yr 1 cost: 35,225 Yr 2 cost: 21, IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Other: Reduced symptoms or disability No impact identified Impact on Health and Social Care Services Increased use of existing services Re-organisation of existing services Other: the subcutaneous (SC) route of administration for DAC HYP should allow it to be easily applied alongside existing treatment. Decreased use of existing services Need for new services None identified Impact on Costs and Other Resource Use Increased drug treatment costs Other increase in costs: Other: uncertain unit cost compared to existing treatments Reduced drug treatment costs Other reduction in costs: SC 4 weekly regimen has the potential for reduced disease activity and disability. None identified Other Issues Clinical uncertainty or other research question identified: expert opinion suggests the field of DMTs for relapsing forms of MS is rapidly evolving with the approval of new therapies e.g. teriflunomide, alemtuzumab, and potentially dimethyl fumarate in the near future b. The current patient pathway is therefore not clear due to this new range of therapeutic options, none of which provide the optimal a Prices from Department of Health. Health Service Circular. Cost effective provision of disease modifying therapies for people with multiple sclerosis (HSC 2002/004). London: DOH; February b Expert personal opinion. 9

10 balance between therapeutic efficacy and side effects b. This balance is critical when treating patients with potent immunomodulators with a life-long neurological disease b. The usefulness of DAC-HYP and its place in the treatment of relapsing forms of MS will therefore depend on how well balanced it is in its efficacy vs its side effects. REFERENCES 1 Liu J, Wang LN, Zhan S & Xia Y. Daclizumab for relapsing remitting multiple sclerosis (Review). Cochrane Database of Systematic Reviews 2013;12:Art. No.:CD DOI: / CD pub4. 2 National Institute for Health and Clinical Excellence. Single Technology Appraisal: Dimethyl fumarate for the treatment of relapsing-remitting multiple sclerosis - Final scope. London: NICE; March NHS Choices. Multiple Sclerosis. Accessed 19 June National Multiple Sclerosis Society. Symptoms and Diagnosis. Accessed 19 June Hobart JC, Riazi A, Lamping DL. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome. Health Technology Assessment 2004; 8(9). 6 National Institute for Health and Care Excellence. Costing template: multiple sclerosis (relapsing) teriflunomide. TA303. London: NICE; January Multiple Sclerosis Society. What is MS? Accessed 19 June National Institute for Health and Care Excellence. Costing report: Implementing the NICE guidance on alemtuzumab for treating relapsing remitting multiple sclerosis (TA312). London: NICE; May Harris Interactive. Experiences with Multiple Sclerosis (MS): Perspectives of People with MS and MS Care Partners [poll]. Poll commissioned by: Acorda Therapeutics Inc and the National MS Society. March Health and Social Care Information Centre. Hospital episode statistics, admitted patient care, England Office for National Statistics. Mortality Statistics: Deaths Registered in England and Wales (Series DR), Sellebjerg F, Barnes D, Filippini G et al. EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses. European Handbook of Neurological Management: Volume 1 2nd edition. Blackwell Publishing Ltd Association of British Neurologists. Revised (2009) guidelines for prescribing in multiple sclerosis. London: ABN. November Royal College of Physicians, National Council for Palliative Care, British Society of Rehabilitation Medicine. Long-term neurological conditions: management at the interface between neurology, rehabilitation and palliative care. March National Collaborating Centre for Chronic Conditions (NCC-CC) at the Royal College of Physicians. Multiple Sclerosis: National clinical guideline for diagnosis and management in primary and secondary care. August Thompson AJ, Toosy AT, Ciccarelli O. Pharmacological management of symptoms in multiple sclerosis: current approaches and future directions. Lancet Neurology 2010;9(12): National Institute for Health and Clinical Excellence. Management of multiple sclerosis in primary and secondary care. Clinical guideline CG8. London: NICE; November Sellebjerg F, Barnes D, Filippini G et al. EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses. European Journal of Neurology 2005;12(12): National Institute for Health and Clinical Excellence. Multiple sclerosis - beta interferon and glatiramer acetate. Technology appraisal TA32. London: NICE; January National Institute for Health and Clinical Excellence. Fingolimod for the treatment of highly active relapsing-remitting multiple sclerosis. Technology appraisal TA254. London: NICE; April National Institute for Health and Care Excellence. Alemtuzumab for treating relapsing-remitting multiple sclerosis. Technology appraisal TA312. London: NICE; May

11 22 National Institute for Health and Care Excellence. Teriflunomide for treating relapsing-remitting multiple sclerosis. Technology appraisal TA303. London: NICE; January National Institute for Health and Clinical Excellence. Natalizumab for the treatment of adults with highly active relapsing-remitting multiple sclerosis. Technology appraisal TA127. London: NICE; August National Institute for Health and Care Excellence. Dimethyl fumarate for the treatment of relapsing-remitting multiple sclerosis. Technology appraisal in development (ID585). London: NICE; expected August ClinicalTrials.gov. Long-term extension study in participants with multiple sclerosis who have completed study 205MS301 (NCT ) to evaluate the safety and efficacy of BIIB019 (EXTEND). Accessed 20 June ClinicalTrials.gov. Efficacy and safety of Daclizumab High Yield Process versus interferon β 1a in patients with relapsing-remitting Multiple Sclerosis ((DECIDE)). Accessed 20 June ClinicalTrials.gov. An immunogenicity and pharmacokinetics (PK) study of DAC HYP prefilled syringe in relapsing remitting Multiple Sclerosis (RRMS) (OBSERVE). Accessed 20 June ClinicalTrials.gov. Safety and efficacy extension study of Daclizumab High Yield Process (DAC HYP) to treat relapsing remitting Multiple Sclerosis. Accessed 20 June Giovannoni G, Gold R, Selmaj K et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet 2014;13: ClinicalTrials.gov. Safety and efficacy extension study of Daclizumab High Yield Process (DAC HYP) in subjects with multiple sclerosis who have completed study 205MS201 (NCT ) to treat relapsing-remitting Multiple Sclerosis (SELECTION). Accessed 26 June Gold R, Giovannoni G, Selmaj K et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 2013;381: ClinicalTrials.gov. Safety and efficacy study of Daclizumab High Yield Process to treat relapsingremitting Multiple Sclerosis (SELECT). Accessed 26 June British National Formulary (BNF). Accessed 30 June National Institute for Health and Care Excellence. TA312 Multiple sclerosis (relapsing-remitting) alemtuzumab: costing template. London: NICE; May Department of Health. Health Service Circular. Cost effective provision of disease modifying therapies for people with multiple sclerosis (HSC 2002/004). London: DOH; February