Review of methodological issues of clinical trials in multiple sclerosis.

There are currently six approved disease-modifying therapies available to the physician for the treatment of multiple sclerosis. Their efficacy on clinical and radiological parameters has been demonstrated in Phase III pivotal clinical trials over the past two decades. Perceptions of the relative potency of these treatments have been driven principally by the response measured relative to a placebo group. However, efficacy comparisons between trials is of limited value because of differences in study methodology, in characteristics of the patient populations included, in the behaviour of the placebo group during the trial and in the time at which the trial was conducted. Moreover, and most importantly, the assumption that the efficacy observed in clinical trial settings is the same as that achievable in everyday clinical practice is inevitably flawed. Impressions of the relative efficacy of two treatments may differ dramatically depending on whether absolute or relative differences with respect to placebo are compared. Randomised direct comparative trials are therefore the only objective way to evaluate the relative efficacy of two therapies. It is clear that between-treatment differences are difficult to quantify in short-term studies and require large numbers of patients. Long-term outcome is increasingly important to monitor in spite of the inherent methodological limitations in order to establish the safety profile of a potentially lifelong treatment. New disease-modifying treatments for multiple sclerosis will soon be available. Although these are eagerly awaited, their risk-benefit profile, and their place in therapy, will only be adequately understood once real-life and long-term use has been documented as well as it has been for current treatments. Over the last two decades, considerable advances have been made in the methodology of clinical trials in multiple sclerosis. Consensual standardised protocols have been designed and validated for Phase II and Phase III trials, with standardised definitions for short-term clinical and radiological outcome measures. The elaboration and implementation of this methodology were possible through international collaborations, and this has enabled extensive experience to be gained throughout the world. These trials have laid the foundation for an evidence-based medicine approach to the treatment of multiple sclerosis. Clinical trials in multiple sclerosis have to some extent become a victim of their own success, with more and more trials competing for a limited pool of patients and limited resources. Modern trials require large number of patients to generate adequate statistical power and this in turn entails recruitment in many countries across different continents. This increases the complexity and cost of the study, and contract research organisations now play a dominant role in the logistics and administration of these trials. The challenge in conducting trials on a global basis involving large numbers of countries is to ensure that this heterogeneity does not impinge on the reliability of the findings. This may happen due to differences in the patient populations included in different countries, access to or experience with methods in evaluation, for example certain magnetic resonance imaging (MRI) protocols, and also due to ethical considerations. In addition, whether disease-modifying treatments are reimbursed in a given country or not will influence what sort of patients are likely to get included in clinical trial protocols.