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 drugs for acute ischemic stroke have been disappointing. We examine the question of whether these trials may have been underpowered. Methods— Computer simulations were based upon the binomial distribution. Results— We illustrated that even small overestimates of the efficacy of an intervention can lead to a serious reduction in statistical power, that use of data from phase II studies tends to lead to such overestimation, and that a minimum clinically important difference derived using cost-effectiveness modeling techniques is considerably smaller than might be suggested by intuition. Conclusions— We recommend placing more emphasis on minimum clinically important differences when planning stroke trials, with these differences being derived from an assessment of public health impact obtained in conjunction with the use of epidemiologic and cost-effectiveness models. Even small benefits, when averaged over a sufficiently large number of cases, will, in total, accrue to a large positive impact on the public health.