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Considerations in the design of clinical trials for relapsing multiple sclerosis

Richard Nicholas, Tim Friede

Trials in relapsing multiple sclerosis have been complicated by difficulties in defining the two principal significant clinical events (relapses and disability progression) that contribute to the devastating permanent neurological impairment characteristic of end-stage multiple sclerosis. There are further difficulties measuring the impact of these events, and the commonly used MRI end points used in Phase II studies have a complex relationship with both events and permanent neurological disability. Current designs favor the parallel-group, randomized, placebo-controlled study with annualized relapse rates as the principal clinical outcome in Phase III studies. As therapies have been developed, problems have arisen with changing trial populations with lower annualized relapse rates that vary both between studies and during the course of studies, making comparing therapies across studies difficult. Although novel designs have had very limited use thus far, active comparator trials, adaptive designs and targeted therapies/biomarkers have the potential to streamline therapy development in an increasingly crowded therapeutic marketplace.