J.C. Locklear

Best Practices for Network Meta-Analysis Methodology: Comparative Effectiveness of Interferon-Beta Therapies In Relapsing-Remitting Multiple Sclerosis

• Multiple sclerosis (MS), a chronic, recurrent infl ammatory disease, is characterized by infl ammatory attacks on central nervous system myelin. Patients with MS experience symptoms such as blurred vision, walking and coordination problems, bladder or bowel dysfunction, numbness, and cognitive impairment.1 • Approximately 85% of patients with MS have relapsing–remitting MS (RRMS), which is characterized by defi ned attacks or relapses that result in worsening of neurological function, with partial to complete recovery between attacks.2 • Treatment with disease-modifying drugs (DMDs), including interferon beta (IFN ) therapies, can reduce relapse rates and delay disability progression and is associated with improved clinical outcomes.3–5 • Numerous network meta-analyses (NMAs) have evaluated DMDs in RRMS; however, analyses vary in their inclusion criteria, methodology, and types of statistical syntheses.6–8 • A consensus array of inclusion and exclusion criteria, endpoints, and statistical models may identify potential best practices in synthesizing clinical evidence to guide clinical decisions in RRMS.

A Real-World Assessment of Annual Multiple Sclerosis Prevalence and Disease-Modifying Drug Treatment Rates Using an Administrative Claims Database

Objectives: Time to 12-week confirmed disability progression, measured by the Expanded Disability Status Scale (EDSS), is a key endpoint in RRMS trials. However, the EDSS has widely discussed limitations, and several therapies have shown inconsistent results for this endpoint in terms of statistical significance. Here we contextualize differences in 12-week confirmed disability progression results in the Phase 3 studies of gastro-resistant dimethyl fumarate (DMF), DEFINE and CONFIRM. MethOds: Time to 12-week confirmed disability progression at 2 years was a secondary endpoint in both studies; however, the studies were not powered to detect statistical significance for this endpoint. Patients had the option of discontinuing study treatment and initiating alternative therapy at any time due to 12-week confirmed disability progression or after completing 48 weeks of study treatment and experiencing one confirmed relapse after 24 weeks (DEFINE) or two confirmed relapses at any time (CONFIRM). Results: Although gastro-resistant DMF 240mg BID demonstrated consistent reductions on 12-week confirmed disability progression, statistical significance was achieved in DEFINE (p= 0.0050) but not CONFIRM (p= 0.2536). There was an apparent difference in the placebo rate of 12-week confirmed disability progression at 2 years (DEFINE, 27%; CONFIRM, 17%). In CONFIRM, a relatively higher percentage of placebo patients (4.1%) versus gastro-resistant DMF patients (1.7%) switched to alternative MS therapy or withdrew after the time of tentative disability progression without a subsequent EDSS assessment. Additionally, a relatively higher percentage of placebo patients who switched to alternative MS therapy had ≥ 2 relapses without 12-week confirmed disability progression prior to switch in CONFIRM (45%) compared with DEFINE (16%). cOnclusiOns: Relapse-based criteria for switching to alternative therapy may have contributed to the lower placebo progression rate and decreased assay sensitivity for this particular endpoint in CONFIRM. The totality of evidence needs to be taken into account when assessing a therapy’s effect on disability progression.