Evidence-based mechanistic reasoning

An evidential role for mechanisms Systematic reviews of high quality randomized trials generally count as the ‘best evidence’.1 How-ever, well-conducted randomized trials are some-times unavailable,2,3 unfeasible,4 unethical5 or unnecessary.6,7 In such cases other forms of evi-dence must be considered. Many EBM proponents accept mechanistic reasoning (‘pathophysiologic rationale’) for generalizability,1,8 hypothesis gener-ation,9 ruling out implausible hypotheses,10,11 and for supporting efficacy in the absence of other ‘stronger ’ forms of evidence. Yet because mechanis-tic reasoning has often led us astray,12,13 most EBM proponents are justifiably sceptical about using mechanistic reasoning as evidence for efficacy.