Background: Since the commercial introduction of disease-modifying drugs (DMDs) for the treatment of multiple sclerosis (MS), there have been numerous randomized placebo-controlled and head-to-head clinical trials assessing the efficacy and safety of these agents in relapsing-remitting MS (RRMS).
Scope: Recent trials in the past 10 years demonstrate that the characteristics and behavior of clinical trial populations in RRMS have changed. Here we review evidence from key published clinical trials of DMDs in RRMS that highlights the general shift in trial populations, and examine the implications of this shift for future trial design.
Findings: Populations in recent studies are characterized by lower clinical disease activity. This difference is apparent with regards to baseline patient characteristics and on-study behavior in terms of outcomes (e.g., relapse rates). The reasons for this shift are probably multifactorial and include study design, current treatment options, patient selection, and a possible change in the natural history of MS.
Conclusions: The variation among study designs makes it difficult to draw more extensive conclusions about changes in clinical trial populations. However, these recent changes undoubtedly will affect interpretation of recent study results, some of which based clinical and statistical assumptions on earlier trials. Furthermore, the shift in populations has major implications for the design of future studies: (1) assumptions regarding effect size and statistical powering must be based on comparable patient populations; (2) larger trials of longer duration may be needed, possibly with stopping criteria based on the number of actual events rather than a preset, fixed time point for the end of study; (3) the use of biomarkers to facilitate identification of subpopulations may be considered; and (4) enhanced measures of disease activity (e.g., composite outcomes) may help to identify effects in multiple relevant MS outcomes. Furthermore, trial design may need to be modified to study the effects of a medication in patients who are representative of the anticipated patient population. To ensure that the clinical trial experience of a drug is reflected in its eventual clinical use, 'real-life' observation study programmers should be conducted to continuously monitor its effects in relevant populations and in comparison with available therapies.