Assessment

Problem Is the problem a priority?
Judgement	Research evidence	Additional considerations
○ No ○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know	The Atlas of MS estimates there are 2.8 million people living with multiple sclerosis (MS). Of these, 11% have progressive forms of MS. There is unequal access to DMTs globally, with 14% of countries not having access to any on-label disease-modifying therapies (DMTs). Low income countries (LICs), lower middle income countries (LMICs) and upper middle countries (UMICs) are affected more than high income countries (HICs). Treatment options for people with progressive forms of MS are often limited, and DMT regulatory approvals and indications are sometimes restricted to active forms of PMS. Evidence for both on-label and off-label DMTs should be considered when considering essential medicines for MS. PICO 4: The Panel decided to review DMTs for active and/or progressing forms of progressive MS to consider the most appropriate treatment approach. PICO 5: The Panel decided to review DMTs for not active and not progressing or indeterminate forms of progressive MS to consider the most appropriate treatment approach. PICO 6: The Panel decided to review DMTs for active and/or progressing forms of progressive MS when there is a lack of treatment response to consider the most appropriate treatment approach. Panel members with COI for DMTs reviewed for PMS: Anthony Traboulsee, Jagannadha Avasarala, Carlos Navas, Maya Zeineddine, Riley Bove, Dina Jacobs, Shanthi Viswanathan, Bassem Yamout, Kathy Costello. Undetermined COI: Hans-Peter Hartung.
Desirable Effects How substantial are the desirable anticipated effects for each intervention?
Judgement	Research evidence	Additional considerations
Trivial: Small: Moderate: Fingolimod, Rituximab, Ocrelizumab, Glatiramer acetate, Immunoglobulins, Interferon Beta 1b, Natalizumab Large: Azathioprine, Interferon Beta 1a (Avonex Rebif), Methotrexate, Siponimod Varies: Don't know:	The evidence base on DMTs for progressive forms of multiple sclerosis (PMS) was retrieved through systematic reviews of the biomedical literature developed according to the Cochrane methodology. The search was performed on February 11, 2022. Included studies were randomised-controlled trials (RCT). Thirty treatments (with registered indications for MS, as well as non-licensed but used off-label in clinical practice) were included in a network metanalysis, compared vs placebo or vs any other DMT. Direct, pairwise comparisons were assessed assuming placebo as the common comparator. Among people with PMS, three populations were identified by the panel: with active PMS, with non-active PMS and with active PMS when there is a lack of treatment response (switching). We retrieved 23 RCTs (10,167 participants in total) eligible for analysis, one of which reported no outcomes of interest (Etemadifar 2019). No study included only people with non-active disease or people with active PMS and lack of treatment response. Eighteen RCTs included only people with active PMS, 3 RCTs included a mixed population and in 2 RCTs the PMS phenotype was not reported. We performed an overall analysis including all RCTs and a sensitivity analysis including only the 18 studies with active forms of PMS. However, such analysis could not include pivotal RCTs of treatments that were considered very important by the panel (among them the pivotal trial of the only DMT licensed for the treatment of primary progressive MS). Therefore the panel agreed in considering as the evidence base the analysis including all retrieved RCTs. The resulting heterogeneity was considered acceptable by the panel, given the limited proportion (17%) of participants included in trials with a mixed population. Among the desirable effects, most studies assessed disability and relapse at 24 months. No study assessed cognitive decline. Disability at 24 and 36 months was reported in 11 and 5 studies, respectively. Point estimates were mostly in favor of the intervention compared to placebo. However, the certainty in such estimates was lowered by imprecision. Frequency of relapse was reported at 12, 24 and 36 months in 1, 6 and 4 RCTs, respectively, with interferon beta products and azathioprine providing estimates significantly better than placebo, although with moderate to very low certainty due to imprecision. Interferon beta products, siponimod and fingolimod showed higher efficacy than placebo in regard to new gadolinium-enhancing T1-weighted MRI lesions and new or enlarging T2-weighted MRI lesions at 12, 24 and 36 months. Certainty in MRI outcomes was overall better than the other outcomes due to lower imprecision of the point estimates. Quality of life was assessed in three RCTs on interferon beta 1a, natalizumab and ocrelizumab, reporting point estimates favouring treatment vs placebo, although with moderate to low certainty due to imprecision.