What can be learned from open direct comparative trials in multiple sclerosis?

Randomised, placebo-controlled, double-blind clinical trials are considered the "gold standard" for clinical research. A corollary of this is that data from observational open- label studies are viewed as having less validity, and as not providing accurate estimates of treatment effects. However, a number of systematic reviews have shown that well- designed observational studies are quantitatively or qualitatively similar to those measured in randomised controlled trials. Moreover, these observational studies performed under standard conditions of care provide useful reassurance that the findings of randomised controlled trials can be considered as broadly representative of the population at risk. Several such observational studies have been performed in multiple sclerosis in order to compare the effectiveness and tolerability of the different disease-modifying therapies available for the treatment of relapsing remitting disease. One of these was a prospective study conducted in 156 patients that compared the effects of high-dose interferon-beta and glatiramer acetate. This study indicated that the two treatments had similar efficacy on all measures evaluated. The effect sizes observed were very comparable to those observed in the pivotal trials of these two agents. This study predates by a decade a much larger randomised study which also failed to demonstrate a difference between the efficacy of high-dose interferon-beta and that of glatiramer acetate. Observational studies such as this can thus provide useful and reliable information on treatment effects and can be used for preliminary hypothesis testing at a fraction of the cost and constraints of pivotal trials. In the context of the increasing difficulty and expense of conducting randomised, placebo-controlled trials in multiple sclerosis, comparative studies using an open-label design or a rater-blinded design are likely to be increasingly employed in comparing existing and future therapies.