Immunomodulatory agents in multiple sclerosis: clinical trials and therapy

Introduction
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By Luca Durelli MD, Elisabetta Versino MD, and Marinella Clerico MD

Immunomodulatory agents are drugs that affect the immune system. -ed.

The fortunate combination of the utilization of MRI for monitoring disease progression in multiple sclerosis (Filippi and Miller 1996) coupled with increasing interest from pharmaceutical companies after the pilot trials with interferons (Jacobs et al 1986; Greenstein et al 1987) during the 1980s gave clinicians an opportunity to organize statistically powerful trials. This led to approval of the interferon betas for multiple sclerosis treatment, followed by other immunomodulatory therapies.

Clinical trials should fulfill standard criteria for methodological quality, assuring an objective estimate of treatment effects. The quality of clinical trials is now frequently evaluated according to the consolidated standards of reporting trials statement (Altman et al 2001). Adequate randomization eliminates selection bias; blinding prevents ascertainment bias. Randomization is the crucial component of high quality clinical trials (Altman et al 2001), particularly when testing drugs, such as interferons or immunosuppressants, with very well known side effects that can bias reliability of blinding (Rice et al 2001).

Evidence-based medicine principles allow clinically meaningful conclusions to be drawn from clinical trials and simplify the comparison of results from different trials (Sackett et al 1997). The relative effectiveness of a drug can be compared using both the risk ratio and risk reduction relative to the control group, as well as the number needed to treat. Evidence-based medicine compares risks of the disease event (adverse outcome) in the actively treated group to that in the placebo-treated group, which is considered to be the reference population. Risk ratio measures how large (or small) the risk of the adverse outcome is in the treated group relative to the control group. Risk reduction measures to what extent the active drug reduced the risk of the adverse outcome compared to the control, whereas the number needed to treat is the number of patients that must be treated to prevent 1 additional adverse outcome, if patients are treated with the placebo instead of the active drug. Importantly, evidence-based medicine measures are all calculated as proportion of the risk of the disease event in the control population of each trial, so they can be compared between trials.

The aim of this review is to evaluate quality of published randomized clinical trials in multiple sclerosis. We will evaluate trial internal validity to allow physicians to decide for themselves about the reliability of a published trial. A different issue is that of the external validity, or generalizability, of trial results—that is, the applicability of the results of a study to other populations, settings, or treatment variables (Juni et al 2001). External validity is a matter of judgment of each individual physician facing a single specific clinical case. Special circumstances like highly aggressive cases, pregnancy, coexistent medical problems, adverse effects necessitating a change in treatment, long-term remissions, and unrelenting progression despite treatment are not discussed in this review and must be individually evaluated.