Have randomized controlled trials of neuroprotective drugs been underpowered? An illustration of three statistical principles

Background and Purpose-The results of phase III trials of neuroprotective d rugs for acute ischemic stroke have been disappointing. We examine the ques tion of whether these trials may have been underpowered. Methods-Computer simulations were based on the binomial distribution, Results-We illustrate that even small overestimates of the efficacy of an i ntervention can lead to a serious reduction in statistical power, that the use of data from phase II studies tends to lead to such overestimation, and that a minimum clinically important difference derived with cost-effective ness modeling techniques is considerably smaller than might be suggested by intuition. Conclusions-We recommend placing more emphasis on minimum clinically import ant differences when planning stroke trials, with these differences being d erived from an assessment of the public health impact obtained in conjuncti on with the use of epidemiological and cost-effectiveness models. Even smal l benefits, when averaged over a sufficiently large number of cases, will, in total, accrue to a large positive impact on the public health.