Multi-stakeholder Colloquium – Opportunities and Challenges in Multiple Sclerosis Management

European Neurological Review, 2016;11(1):41–7 DOI: http://doi.org/10.17925/ENR.2016.11.01.41

Abstract:

In Europe, despite recent therapeutic advances, there are many deficiencies in the management of multiple sclerosis (MS). Diagnostic and monitoring measures, guidelines, development of new treatments and best practice care are often suboptimal. These shortcomings were discussed at two MS multi-stakeholder colloquia that were convened in Brussels, Belgium in May 2014 and May 2015, and gathered experts from a range of different specialities to identify the key issues and propose means of tackling them. After considering all the testimony and discussion, the organising committee drew up a list of 10 calls to action, which included: increase awareness and understanding in the EU about the burden of MS; obtain better insights into the direct and indirect cost burden of MS; (re)define treatment goals and clinical study endpoints; develop new tools to better capture the total clinical burden of MS; develop a protocol to standardise magnetic resonance imaging (MRI); develop biomarkers of treatment response prediction and disability progression; integrate drug licensing and cost-effectiveness decision-making processes; develop separate European Medicines Agency guidelines for evaluating follow-on products of non-biological complex drugs and biologicals; implement a set of evidence-based standards of care and incentives to support people with MS to remain physically and mentally active. Addressing these ambitious calls to action requires cooperation from various health bodies and governments and some will require additional funding, but they are achievable and worthwhile. They would help minimise disease impact and would reduce disease progression and the consequent burden on people with MS, their caregivers, and on health budgets. These calls to action set out a strategy for future MS management and should be acted upon with urgency.
Keywords: Multiple sclerosis, diagnosis, improving management, stakeholders, treatment development, regulatory issues, funding, treatment access, guidelines
Disclosure: Patrick Vermersch has received consulting fees and honoraria from Bayer Schering, Biogen Idec, Merck-Serono, Novartis, Teva, Genzyme-Sanofi, Almirall and Roche. He has also received research support from Bayer Schering, Biogen Idec, Merck-Serono, and Teva. Ralf Gold has received research support and speaker‘s honoraria from Bayer Schering, Biogen, Chugai, ELAN, Merck Serono, Novartis, Roche, Sanofi-Genzyme and Teva and consulting honoraria from ZLB Behring, Baxter and Talecris. Chris Holloway has received honoraria or consultation fees from Teva. Alex Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and on the editorial board of the American Journal of Neuroradiology and Neuroradiology. He has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec, and has research agreements with Siemens AG. Gavin Giovannoni has received personal compensation for participating on advisory boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer Schering Healthcare, Biogen Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals. Mondher Toumi has provided consul ting through Aix Marseille University and through Creativ- Ceutical to most companies engaged in commercialising MS products: scientific board contribution, presentation in scientific meeting, strategic consulting.
Published Online: 20 April 2016
Acknowledgments: Medical writing assistance was provided by James Gilbart at Touch Medical Media, London and funded by Teva Pharmaceuticals Europe B.V. This article reports the proceedings of a sponsored satellite symposium and as such has not been subject to the journal’s usual peer-review process.
Received: January 22, 2016
Correspondence: Patrick Vermersch, University of Lille, CHU Lille, LIRIC INSERM U995, FHU IMMINENT, F-59000 Lille, France. E: patrick.vermersch@univ-lille2.fr
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Over the past two decades, advances in the availability of new treatments and understanding of the disease have significantly improved the prognosis for many people with multiple sclerosis (PwMS). Despite this, in Europe, various aspects of management, diagnosis and monitoring of MS, the availability of guidelines, the development of new treatments and the provision of best-practice care are frequently suboptimal. Full awareness of the disease and its total burden is often lacking and patients’ access to the most appropriate treatments is highly variable between different territories. Reasons for low adoption of innovations are complex and affected by cultural factors. In addition, the methods used to assess the disease and its progression have notable limitations, and the protocols for use of diagnostic techniques, such as magnetic resonance imaging (MRI) are inconsistent between different treatment centres. To address these shortcomings, multi-stakeholder

colloquia bring together healthcare professionals (HCPs), regulators, pharmacists, payers, economists and patient representatives. These gatherings of diverse disciplines enable valuable exchanges of views between sectors that infrequently interact. The colloquia were designed to initially identify and discuss the issues facing MS understanding and management in Europe and then to propose actions to address the issues identified. Based on this evidence, the scientific committee of the MS multi-stakeholder colloquia identified 10 key calls to action. Addressing all these calls will require cooperation and funding from governments, healthcare organisations and payers, and active support from HCPs and patient groups. Such worthwhile actions may ultimately eliminate disparities in MS care levels in different countries in Europe, they could reduce the burden on patients and caregivers burden and improve long-term outcomes.

1. Increase awareness and understanding in the European community of the burden of multiple sclerosis on patients and caregivers
In the general population, among legislators and some healthcare providers, the extent of MS and its impact on younger populations is not widely recognised or understood. This decreases understanding of the scale of the problem and can restrict resources allocated to managing the disease. Worldwide, there are 2–2.5 million people living with MS, which is equivalent to 30 cases/100,000, including 600,000 in Europe with 1,000,000 associated caregivers and family members.1 The prevalence of MS is higher in developed countries and at higher latitudes. Current data show that per 100,000 population, the rates are: 140 in Europe, 108 in North America, 2.1 in sub-Saharan Africa and 2.2 in Asia.2–4The mean age of onset of MS is 30 years5 – a time of maximum work productivity – resulting in years of lost earnings in addition to extensive medical and care costs. PwMS can live with the disease for many decades, necessitating long-term care and increasing dependence on others (Figure 1).

In PwMS, moderate disability (Expanded Disability Status Scale [EDSS] score of 3),which is often reached in a few years, reduces health-related quality of life (HRQoL) to 0.56 (EQ5D-5L). This is a poorer quality of life (QoL) status than patients’ experience with chronic ischaemic heart disease or noninsulin dependent diabetes mellitus.6,7 To help address some of these issues, various activities and initiatives of the European Multiple Sclerosis Platform (EMSP) are ongoing. These seek to improve public awareness of MS and increase understanding of the impact of MS for researchers and HCPs (Table 1).1,8–12

2. Obtain better insights into the direct and indirect (patient and caregiver) cost burden of multiple sclerosis
The economic impact of MS is high but the exact costs (both direct and indirect) are insufficiently studied; recent figures may be underestimates of the true impact of the disease. MS generally strikes in mid-life; data from studies conducted during the last decade indicate that it has a very high cost burden compared with other brain conditions such as stroke, dementia, Parkinson’s disease and epilepsy (Figure 2)13despite having a lower prevalence than some other brain disorders (e.g. anxiety, migraine, addiction etc.). An MS International Federation (MSIF) review estimated that in 15 countries worldwide, in 2010 the entire cost of the disease was $41,335 (€33,136)/patient/year ($69,118 [€55,410] in the US, equivalent to a total of $28 billion [€22.5 billion]).14 An earlier international study in 2005 estimated the total cost in Europe to be €12.5 billion ($16 billion). Of this, direct costs represented slightly more than half of the total cost (€6.0 billion [$7.5 billion]); informal care was estimated at €3.2 billion ($4 billion), and indirect costs due to morbidity was €3.2 billion ($4 billion).15

A systematic review of 17 studies conducted in Europe and the US published between 2006 and 2012, found that the annual average cost of MS per patient was $41,133 (€33,971) (in terms of US Dollar Purchasing

Power Parity).16 Meanwhile, the total direct and indirect costs of MS in Europe have been estimated to be €31,000/patient/year (Figure 3). Such estimates are not always comparable or reliable; methods to measure cost of disease are well established but are not applied in all territories and regions. Definitive data on MS economic impact and burden in different territories across Europe are much needed to justify the allocation of greater resources for managing the disease.

References:
1. European Multiple Sclerosis Platform, Defeating MS together - The European code of good practice in MS, 2014. Available at: www.emsp.org/attachments/article/253/EMSP_ Code_210x100mm-ScreenRGB_Bookmarked.pdf (accessed 22 July 2014).
2. World Health Organisation, Atlas of Multiple sclerosis resources in the world, 2008. Available at: www.who.int/ mental_health/neurology/Atlas_MS_WEB.pdf (accessed 4 July 2014).
3. Multiple Sclerosis International Federation, Atlas of MS 2013, 2013. Available at: http://www.msif.org/includes/documents/ cm_docs/2013/m/msif-atlas-of-ms-2013-report.pdf?f=1 (accessed 29 July 2014).
4. Milo R, Kahana E, Multiple sclerosis: geoepidemiology, genetics and the environment, Autoimmun Rev, 2010;9:A387–94.
5. Confavreux C, Vukusic S, [The natural history of multiple sclerosis], 2006;56:1313–20.
6. Kobelt G, Berg J, Lindgren P, et al., Costs and quality of life of patients with multiple sclerosis in Europe, J Neurol Neurosurg Psychiatry, 2006;77:918–26.
7. Orme M, Kerrigan J, Tyas D, et al., The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK, Value Health, 2007;10:54–60.
8. European Multiple Sclerosis Platform, MS Barometer 2013, 2013. Available at: www.emsp.org/tmp/ms_barometer_2013_ May_2014.pdf (accessed 21 July 2014).
9. European Multiple Sclerosis Platform, Under pressure - Living with MS in Europe, 2011. Available at: www. underpressureproject.eu/web/about-under-pressure-project (accessed 22 July 2014).
10. European Multiple Sclerosis Platform (EMSP), 2014. Available at: www.emsp.org/emsp (accessed 22 July 2014).
11. European Multiple Sclerosis Platform/International Organisation of MS Nurses/Rehabilitation in MS, MS Nurse Professional, 2014. Available at: www.msnursepro.org/index. aspx (accessed 22 July 2014).
12. European Multiple Sclerosis Platform, Believe and achive: The oppportunity that makes the difference, 2014. Available at: www.emsp.org/projects/believe-and-achieve (accessed 22 July 2014).
13. Andlin-Sobocki P, Jonsson B, Wittchen HU, et al., Cost of disorders of the brain in Europe, Eur J Neurol, 2005;12 (Suppl 1):1–27.
14. Multiple Sclerosis International Federation, Global Economic Impact of Multiple Sclerosis, 2010. Available at: www.msra. org.au/files/msra/docs/Economic%20Impact%20of%20 MS%20in%202010%20Full%20Report%20v2.pdf (accessed 17 October 2014).
15. Sobocki P, Pugliatti M, Lauer K, et al., Estimation of the cost of MS in Europe: extrapolations from a multinational cost study, Mult Scler, 2007;13:1054–64.
16. Kolasa K, How much is the cost of multiple sclerosissystematic literature review, Przegl Epidemiol, 2013;67:75–9, 157–60.
17. Preiningerova JL, Tur C, Ziemssen T, 2014, What are important treatment goals for multiple sclerosis patients and how to capture this by means of different attributes in clinical practice? First Pan-European Multi-stakeholder Colloquium. Exploring opportunities and challenges for improving multiple sclerosis management, Brussels, Belgium, Mirrors of Medicine, 2014:18 (abs. 13).
18. Rothwell PM, McDowell Z, Wong CK, et al., Doctors and patients don’t agree: cross sectional study of patients’ and doctors’ perceptions and assessments of disability in multiple sclerosis, BMJ, 1997;314:1580–3.
19. Johnson FR, Van Houtven G, Ozdemir S, et al., Multiple sclerosis patients’ benefit-risk preferences: serious adverse event risks versus treatment efficacy, J Neurol, 2009;256:554–62.
20. Vermersch P, Comi G, 2014, How to optimally measure treatment (Tx) success in patients with multiple sclerosis (MS)?, First Pan-European multi-stakeholder colloquium, Exploring opportunities and challenges for improving Multiple Sclerosis management, Brussels, Belgium, Mirrors of Medicine, 2014:12 (abs. 7).
21. Meyer-Moock S, Feng YS, Maeurer M, et al., Systematic literature review and validity evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients with multiple sclerosis, BMC Neurol, 2014;14:58.
22. Fischer JS, Rudick RA, Cutter GR, et al., The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force, Mult Scler, 1999;5:244–50.
23. Ravnborg M, Blinkenberg M, Sellebjerg F, et al., Responsiveness of the Multiple Sclerosis Impairment Scale in comparison with the Expanded Disability Status Scale, Mult Scler, 2005;11:81–4.
24. Cella DF, Dineen K, Arnason B, et al., Validation of the functional assessment of multiple sclerosis quality of life instrument, Neurology, 1996;47:129–39.
25. Kesselring J, Disease Progression in Multiple Sclerosis II. Methods for the Determination of Walking Impairment and Its Impact on Activities and Social Participation, European Neurological Review, 2010;5:61–8.
26. Thompson AJ, Hobart JC, Multiple sclerosis: assessment of disability and disability scales, J Neurol, 1998;245:189–96.
27. Benedict RH, Amato MP, Boringa J, et al., Brief International Cognitive Assessment for MS (BICAMS): international standards for validation, BMC Neurol, 2012;12:55.
28. Fisniku LK, Brex PA, Altmann DR, et al., Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis, Brain, 2008;131:808–17.
29. Sormani MP, Rovaris M, Comi G, et al., A composite score to predict short-term disease activity in patients with relapsingremitting MS, Neurology, 2007;69:1230–5.
30. Minneboo A, Barkhof F, Polman CH, et al., Infratentorial lesions predict long-term disability in patients with initial findings suggestive of multiple sclerosis, Arch Neurol, 2004;61:217–21.
31. Tintore M, Rovira A, Rio J, et al., Defining high, medium and low impact prognostic factors for developing multiple sclerosis, Brain, 2015;138:1863–74.
32. Kappos L, Polman CH, Freedman MS, et al., Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes, Neurology, 2006;67:1242–9.
33. Giorgio A, Stromillo ML, Bartolozzi ML, et al., Relevance of hypointense brain MRI lesions for long-term worsening of clinical disability in relapsing multiple sclerosis, Mult Scler, 2014;20:214–9.
34. Fisher E, Rudick RA, Simon JH, et al., Eight-year follow-up study of brain atrophy in patients with MS, Neurology, 2002;59:1412–20.
35. Minneboo A, Jasperse B, Barkhof F, et al., Predicting shortterm disability progression in early multiple sclerosis: added value of MRI parameters, J Neurol Neurosurg Psychiatry, 2008;79:917–23.
36. Popescu V, Agosta F, Hulst HE, et al., Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry, 2013;84:1082-91.
37. Comabella M, Montalban X, Body fluid biomarkers in multiple sclerosis, Lancet Neurol, 2014;13:113–26.
38. Avsar T, Korkmaz D, Tutuncu M, et al., Protein biomarkers for multiple sclerosis: semi-quantitative analysis of cerebrospinal fluid candidate protein biomarkers in different forms of multiple sclerosis, Mult Scler, 2012;18:1081–91.
39. Disanto G, Adiutori R, Dobson R, et al., Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome, J Neurol Neurosurg Psychiatry, 2015;doi:10.1136/jnnp-2014-309690.
40. Teunissen CE, Dijkstra C, Polman C, Biological markers in CSF and blood for axonal degeneration in multiple sclerosis, Lancet Neurol, 2005;4:32–41.
41. Teunissen CE, Khalil M, Neurofilaments as biomarkers in multiple sclerosis, Mult Scler, 2012;18:552–6.
42. Dobson R, Ramagopalan S, Davis A, et al., Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude, J Neurol Neurosurg Psychiatry, 2013;84:909–14.
43. Kuhle J, Disanto G, Dobson R, et al., Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study, Mult Scler, 2015;21:1013–24.
44. Goris A, Pauwels I, Gustavsen MW, et al., Genetic variants are major determinants of CSF antibody levels in multiple sclerosis, Brain, 2015;138:632–43.
45. Ferraro D, Simone AM, Bedin R, et al., Cerebrospinal fluid oligoclonal IgM bands predict early conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome, J Neuroimmunol, 2013;257:76–81.
46. Thangarajh M, Gomez-Rial J, Hedstrom AK, et al., Lipid-specific immunoglobulin M in CSF predicts adverse long-term outcome in multiple sclerosis, Mult Scler, 2008;14:1208–13.
47. Villar LM, Casanova B, Ouamara N, et al., Immunoglobulin M oligoclonal bands: biomarker of targetable inflammation in primary progressive multiple sclerosis, Ann Neurol, 2014;76:231–40.
48. Andersson M, Alvarez-Cermeno J, Bernardi G, et al., Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report, J Neurol Neurosurg Psychiatry, 1994;57:897–902.
49. Luque FA, Jaffe SL, Cerebrospinal fluid analysis in multiple sclerosis, Int Rev Neurobiol, 2007;79:341–56.
50. Katsavos S, Anagnostouli M, Biomarkers in Multiple Sclerosis: An Up-to-Date Overview, Mult Scler Int, 2013;2013:340508.
51. Ascherio A, Munger KL, White R, et al., Vitamin D as an early predictor of multiple sclerosis activity and progression, JAMA Neurol, 2014;71:306–14.
52. Calabresi PA, Giovannoni G, Confavreux C, et al., The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL, Neurology, 2007;69:1391–403.
53. Bloomgren G, Richman S, Hotermans C, et al., Risk of natalizumab-associated progressive multifocal leukoencephalopathy, N Engl J Med, 2012;366:1870–80.
54. Schwab N, Schneider-Hohendorf T, Posevitz V, et al., L-selectin is a possible biomarker for individual PML risk in natalizumabtreated MS patients, Neurology, 2013;81:865–71.
55. Azzopardi L, Thompson SA, Harding KE, et al., Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis, J Neurol Neurosurg Psychiatry, 2014;85:795–8.
56. Jones JL, Phuah CL, Cox AL, et al., IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H), J Clin Invest, 2009;119:2052–61.
57. Mullner N, Eichler HG, Current issues in drug regulation. In: Muller M (eds.), Clinical pharmacology: current topics and case studies, Vienna, Austria: Springer, 2010;19–32.
58. Ellis SJ, Bad decision NICE, Lancet, 2002;359:447.
59. European Federation of Pharmaceutical Industry Associations (EFPIA), Access to innovative treatments in multiple sclerosis in Europe, 2009. Available at: www.comparatorreports.se/ Access%20to%20MS%20treatments%20-%20October%20 2009.pdf (accessed 20 November 2014).
60. European Medicines Agency Evaluation of Medicines for Human Use CHMP Assessment report for Biferonex Procedure No. EMEA/H/C/000901 2009. Available at: www. ema.europa.eu/docs/en_GB/document_library/Application_ withdrawal_assessment_report/2010/01/WC500061394.pdf (accessed 11 Novemer 2014).
61. Bakshi S, Chalifa-Caspi V, Plaschkes I, et al., Gene expression analysis reveals functional pathways of glatiramer acetate activation, Expert Opin Ther Targets, 2013;17:351–62.
62. Towfic F, Funt JM, Fowler KD, et al., Comparing the biological impact of glatiramer acetate with the biological impact of a generic, PLoS One, 2014;9:e83757.
63. FDA - Public Hearing Non Biological Complex Drugs Working Group, Challenges for Non-Biological Complex Drugs (NBCDs), 2014. Available at: www.fda.gov/downloads/ForIndustry/ UserFees/GenericDrugUserFees/UCM398889.pdf (accessed 21 January 2016).
64. Holloway C, Mueller-Berghaus J, Lima BS, et al., Scientific considerations for complex drugs in light of established and emerging regulatory guidance, Ann N Y Acad Sci, 2012;1276:26–36.
65. Towfic F, Funt JM, Fowler KD, et al., Comparing the biological impact of innovative medicines with purported generics, Annals of Neurology, 2014; 9(1):e83757.
66. Generics and Biosimilars Initiative, Doctors’ survey reveals lack of confidence in biosimilars, 2015. Available at: www. gabionline.net/Reports/Doctors-survey-reveals-lack-ofconfidence- in-biosimilars (accessed 21 January 2016).
67. Crommelin DJ, Shah VP, Klebovich I, et al., The similarity question for biologicals and non-biological complex drugs, Eur J Pharm Sci, 2015;76:10–7.
68. Kozlowski S, Woodcock J, Midthun K, et al., Developing the nation’s biosimilars program, N Engl J Med, 2011;365:385–8.
69. Weise M, Bielsky MC, De Smet K, et al., Biosimilars: what clinicians should know, Blood, 2012;120:5111–7.
70. Pfleger CC, Flachs EM, Koch-Henriksen N, Social consequences of multiple sclerosis (1): early pension and temporary unemployment-a historical prospective cohort study, Mult Scler, 2010;16:121–6.
71. Goodworth MC, Stepleman L, Hibbard J, et al., Variables associated with patient activation in persons with multiple sclerosis, J Health Psychol, 2016;21:82–92.
72. Stepleman L, Rutter MC, Hibbard J, et al., Validation of the patient activation measure in a multiple sclerosis clinic sample and implications for care, Disabil Rehabil, 2010;32:1558–67.
73. Royal Collge of Surgeons/ Multiple Sclerosis Trust, The national audit of services for people with multiple sclerosis 2011. Available at: www.rcplondon.ac.uk/sites/default/files/ ms_audit_executive_summary_2011_1.pdf (accessed 2 July 2015).
74. Gallien P, Gich J, Sanchez-Dalmau BF, et al., Multidisciplinary management of multiple sclerosis symptoms, Eur Neurol2014;72 Suppl 1:20–5.
75. European Multiple Sclerosis Platform, European Register for Multiple Sclerosis (EUReMS), 2014. Available at: www.emsp. org/projects/eurems (accessed 22 July 2014).
76. Canto E, Tintore M, Villar LM, et al., Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes, Brain, 2015;138:918–31.
77. Modvig S, Degn M, Roed H, et al., Cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain predict multiple sclerosis development and disability after optic neuritis, Mult Scler, 2015;21:1761–70.
Keywords: Multiple sclerosis, diagnosis, improving management, stakeholders, treatment development, regulatory issues, funding, treatment access, guidelines