Very large treatment effects in randomised trials as an empirical marker to indicate whether subsequent trials are necessary: meta-epidemiological assessment

Objective To examine whether a very large effect (VLE; defined as a relative risk of ≤0.2 or ≥5) in a randomised trial could be an empirical marker that subsequent trials are unnecessary.Design Meta-epidemiological assessment of existing published data on randomised trials.Data sources Cochrane Database of Systematic Reviews (2010, issue 7) with data on subsequent large trials updated to 2015, issue 12.Eligibility criteria All binary outcome forest plots were selected, which contained an index randomised trial with a VLE that was nominally statistically significant (PResults Of 3082 reviews yielding 85 002 forest plots, only 44 (0.05%) satisfied the inclusion criteria. Index trials were generally small, with a median sample of 99 (median 14 events). Few index trials were rated at low risk of bias (9 of 44; 20%). The relative risk was closer to the null in the subsequent large trials in 43 of 44 cases. Subsequent large trial data failed to find a statistically significant (PConclusions The frequency of VLEs followed by a large trial is vanishingly small, and where they occur they do not appear to be a reliable marker for a benefit that is reproducible and directly actionable. An empirical rule using a VLE in a randomised controlled trial as a marker that further trials are unnecessary would be neither practical nor useful. Caution should be taken when interpreting small studies with very large treatment effects.