The growing need for alternative clinical trial designs for multiple sclerosis

Introduction Prior to the early 1980s, most multiple sclerosis (MS) clinical trials were observational, without appropriate controls and with little attention paid to the fluctuating natural history of MS. Consensus developed at a 1982 international conference on MS trials recommended that Phase 3 clinical trials for MS should be randomized, blinded, and placebo-controlled. The relative benefits and safety of multiple agents for relapsing forms of MS, “worsening” disease, “clinically isolated syndromes,” and symptomatic management have since been shown using such studies. MS clinical trials follow a pattern that begins with mechanistic (including preclinical) studies, continues into toxicity and safety studies (Phase 1), through preliminary and proof-of-concept exploratory studies (Phase 2) and then into registration studies (Phase 3). Biological and imaging markers have become standard primary outcomes in Phase 1 and 2 studies but have been restricted to secondary or exploratory outcomes in Phase 3 studies, as regulatory agencies continue to require evidence based on clinical outcomes for pivotal studies. The widespread use of disease-modifying treatments for MS since 1993 not only has changed short- and potentially long-term outcomes for people with MS, but has also altered the ability to undertake clinical trials using established approaches. Use of approved therapies for individuals with active disease has led to recruitment of subjects with less severe disease into new trials, oten resulting in subjects with less disease activity than in the past. This lower frequency of events in patients entered into contemporary clinical trials has rendered popular outcomes less sensitive to change over reasonable time-frames and thus has had an impact on the statistical power of studies.