Evidence-based mechanistic reasoning

[Extract] Systematic reviews of high quality randomized trials generally count as the ‘best evidence’.1 However, well-conducted randomized trials are sometimes unavailable,2,3, unfeasible,4 unethical5 or unnecessary.6,7 In such cases other forms of evidence must be considered. Many EBM proponents accept mechanistic reasoning (‘pathophysiologic rationale’) for generalizability,1,8 hypothesis generation,9 ruling out implausible hypotheses,10,1111 and for supporting efficacy in the absence of other ‘stronger’ forms of evidence. Yet because mechanistic reasoning has often led us astray,12,13 most EBM proponents are justifiably sceptical about using mechanistic reasoning as evidence for efficacy.

We suggest that the scepticism about the value of mechanistic reasoning should not extend to high quality mechanistic reasoning. Just as poor quality randomized trials (that are unblinded,14,15,16 underpowered or biased,17 that employ unconcealed allocation,15,16 or otherwise biased) will not provide high quality evidence for efficacy, so poor quality mechanistic reasoning will be unreliable. In this theoretical exploration we suggest that mechanistic reasoning involving a not incomplete inferential chain and that takes potential complexity into account can and should be used as evidence of efficacy. We support our rules for mechanistic evidence with three examples.