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Ethical Use of Off-Label Disease-Modifying Therapies for Multiple Sclerosis

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Ethical Use of Off-Label Disease-Modifying Therapies for Multiple Sclerosis MSJ0010.1177/13524585211030207Multiple Sclerosis JournalJ Laurson-Doube, N Rijke 1030207research-article20212021 MULTIPLE SCLEROSIS MSJ JOURNAL Future Perspectives Multiple Sclerosis Journal Ethical use of off-label disease-modifying 1 –8 https://doi.org/10.1177/13524585211030207DOI: 10.1177/ therapies for multiple sclerosis https://doi.org/10.1177/1352458521103020713524585211030207 © The Author(s), 2021. Joanna Laurson-Doube , Nick Rijke, Anne Helme, Peer Baneke, Brenda Banwell, Article reuse guidelines: Shanthi Viswanathan , Bernhard Hemmer and Bassem Yamout sagepub.com/journals- permissions Abstract Correspondence to: J Laurson-Doube Background: Off-label disease-modifying therapies (DMTs) for multiple sclerosis (MS) are used in at Multiple Sclerosis International Federation, 3rd least 89 countries. There is a need for structured and transparent evidence-based guidelines to support Floor, Skyline House, 200 clinical decision-making, pharmaceutical policies and reimbursement decisions for off-label DMTs. Union Street, London SE1 0LX, UK. Objectives/Results: The authors put forward general principles for the ethical use of off-label DMTs for [email protected] treating MS and a process to assess existing evidence and develop recommendations for their use. Joanna Laurson-Doube Nick Rijke Conclusion: The principles and process are endorsed by the World Federation of Neurology (WFN), Anne Helme American Academy of Neurology (AAN), European Academy of Neurology (EAN), Americas Commit- Peer Baneke Multiple Sclerosis tee for Treatment and Research in Multiple Sclerosis (ACTRIMS), European Committee for Treatment International Federation, and Research in Multiple Sclerosis (ECTRIMS), Middle-East North Africa Committee for Treatment and London, UK Brenda Banwell Research in Multiple Sclerosis (MENACTRIMS) and Pan-Asian Committee for Treatment and Research Division of Neurology, in Multiple Sclerosis (PACTRIMS), and we have regularly consulted with the Brain Health Unit, Mental Children’s Hospital of Philadelphia, Perelman Health and Substance Use Department at the World Health Organization (WHO). School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Keywords: Disease-modifying therapies, access to treatment, off-label treatment, guideline Shanthi Viswanathan Department of Neurology, Hospital Kuala Lumpur, Date received: 21 April 2021; revised: 10 June 2021; accepted: 11 June 2021. Kuala Lumpur, Malaysia Bernhard Hemmer Department of Neurology, Introduction also used in practice for the treatment of MS, for exam- Klinikum rechts der Isar, Technische Universität All people with multiple sclerosis (MS) should have ple, azathioprine (has approval in Germany), rituximab, München, Munich, Germany/ access to effective, safe and affordable disease-modifying cladribine (non-oral forms), mitoxantrone (has approval Munich Cluster for Systems Neurology (SyNergy), therapies (DMTs). A range of DMTs is required for use in in the United States), methotrexate, leflunomide, fludara- Munich, Germany different clinical scenarios and personal circumstances, bine, cyclophosphamide, minocycline, mycophenolate Bassem Yamout but these are not always available or affordable.1,2 mofetil and intravenous immunoglobulin (IVIG). Some Department of Neurology- Nehmeh and Therese of these were used off-label before on-label DMTs came Tohmeh Multiple Sclerosis MSIF’s recent Atlas of MS survey showed that 72% on the market, but many are still used to treat MS. The Center, American University of Beirut, Beirut, Lebanon/ of countries have major barriers for accessing DMTs. amount and quality of clinical evidence supporting the Neurology Institute, Harley The countries were categorised according to the use of these DMTs varies greatly. Street Medical Center, Abu World Bank’s income groups for analysis: 70% of Dhabi, United Arab Emirates low-income countries and 60% of countries in the The drivers for off-label prescribing can be complex4 and WHO Africa region report no on-label MS DMTs are influenced by local health care infrastructure, access available for use (Figure 1(a)–(b)).3 The quality of to health insurance, and availability of innovator drugs, the data from these regions is variable and only a generics and biosimilars. In low-resource settings, off- proportion of countries were able to supply data for label prescribing is often driven by a lack of appropriate the Atlas, suggesting the percentages may be even options or cost5 (see Box 1). higher due to the lack of awareness of MS and exist- ing treatment options. On-label high-efficacy mono- A total of 89 countries (87%) use at least one off-label clonal antibodies are particularly poorly available DMT to treat MS. Rituximab and azathioprine were (Figure 1(c)).3 mentioned by most countries (Figure 2): 69% and 67%, respectively. There is lack of data on the scale, Despite 17 different on-label DMTs having marketing i.e., the number of people being treated with these authorisation for MS, a number of off-label DMTs are DMTs in each country. journals.sagepub.com/home/msj 1 Multiple Sclerosis Journal 00(0) (a) Percentage of countrieswithnoon-labelDMTsavailablefor usebyWorld Bankincomelevel 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% World (106) High Income (44) Upper Middle Lower Middle Low Income (10) Income (29) Income (23) (b) Percentage of countrieswithnoon-labelDMTsavailablefor usebyWHO worldregion 60% 50% 40% 30% 20% 10% 0% Africa (15) Americas (17) Eastern Europe (41) South-East Asia (6) Western Pacific (9) Mediterranean (18) 2 journals.sagepub.com/home/msj J Laurson-Doube, N Rijke et al. (c) Percentage of countrieswithnoon-label high-efficacy DMTs availablefor use (natalizumab, alemtuzumab, ocrelizumab) by World Bank income level Low Income (10) LowerMiddleIncome (23) Upper Middle Income (29) High Income (44) World (102) 0% 10% 2 30% 40% 50%60% 70%80% 90%100% Figure 1. The percentage of countries that do not have access to on-label DMTs for use, stratified for (a) income level and (b) region, as well as (c) the percentage of countries with no access to on-label high-efficacy DMTs according to income level. Total number of countries that supplied data for this question in the Atlas survey in parentheses (n = number of countries). Please note that we lack data from a number of countries around the world and that World Bank income classification comes with limitations of accuracy and heterogeneity within countries. Box 1. Case study from Malaysia. Clinical features of patient: A 24-year-old woman develops recurrent multifocal attacks of vertigo, unsteady gait, double vision and weakness of limbs. Neurologically, she has an internuclear ophthalmoplegia, ataxia of limbs and gait with pyramidal signs in the lower limbs and spastic paraparesis. She doesn’t recover well from her attacks and her EDSS within a short period of time increases to 5.0 due to attack-related disability. Her MRI of brain and spine shows multiple active lesions in the cortex, periventricular, juxtacortical, brainstem, cerebellar and spinal cord regions some of which are enhancing. She has a highly aggressive form of relapsing remitting multiple sclerosis with significant residual disability. Treatment options: Her clinical features warrant high-efficacy treatments such as fingolimod, alemtuzumab, natalizumab, ocrelizumab, cladribine or off-label rituximab. Personal circumstances: She is considered a non-resident due to her family circumstances, and therefore unable to access treatment through local hospital funding or non-governmental organisation support. She has no medical insurance coverage and has economic constraints. She paid for plasma exchange through a donation and was started on off-label therapy with azathioprine as this was the only treatment option she could afford (approximate prices in Malaysia in 2020: azathioprine €135/year vs rituximab €1430/year, fingolimod €13,240/ year, alemtuzumab €73,315/year and cladribine €18,330/year). In 2020, ocrelizumab and natalizumab were not available in Malaysia. journals.sagepub.com/home/msj 3 Multiple Sclerosis Journal 00(0) Percentage of countriesusing DMT Interferon-beta 1a (88) Interferon-beta 1b (82) Fingolimod (78) Teriflunomide (70) Rituximab (70) Natalizumab (69) Azathioprine (68) Ocrelizumab (66) Glatiramer acetate (65) Mitoxantrone (62) Dimethyl Fumarate (58) Alemtuzumab (56) Cladribine [oral] (52) Cyclophosphamide (49) Methotrexate (41) Peg-Interferon-beta 1a (37) Siponimod (11) Cladribine [IV] (10) Leflunomide (9) Minocycline (4) Off-label Fumaderm (4) On-label Mycophenolate mofetil (3) IV Immunoglobulin [IVIG] (3) Fludarabine (2) 0% 10% 20% 30% 40% 50% 60%70% 80% 90% 100% Figure 2. The percentage of countries that report using each DMT for MS. The number of countries for each DMT is in parentheses. Total number of countries that supplied data for this question in the Atlas survey is 102. Please note that mitoxantrone has regulatory approval in the United States and azathioprine in Germany. Principles and process tolerated, unsuitable for the best clinical out- There is a need to provide guidance for policymakers, come, unavailable or unaffordable. clinicians and people affected by MS to ensure the 3. Shared decision-making between persons with MS best possible health outcomes. The highest ethical and their health care professional is especially standard would be uniform access for all persons to a important when off-label DMTs are considered. range of evidence-based therapies. Using off-label 4. Appropriate information on health benefits and DMTs may thus be unethical
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