Objective To summarise comparisons of randomised clinical trials and non-randomised clinical trials, trials with adequately concealed random allocation versus inadequately concealed random allocation, and high quality trials versus low quality trials where the effect of randomisation could not be separated from the effects of other methodological manoeuvres.
Design Systematic review.
Selection criteria Cohorts or meta-analyses of clinical trials that included an empirical assessment of the relation between randomisation and estimates of effect.
Data sources Cochrane Review Methodology Database, Medline, SciSearch, bibliographies, hand searching of journals, personal communication with methodologists, and the reference lists of relevant articles.
Main outcome measures Relation between randomisation and estimates of effect.
Results Eleven studies that compared randomised controlled trials with non-randomised controlled trials (eight for evaluations of the same intervention and three across different interventions), two studies that compared trials with adequately concealed random allocation and inadequately concealed random allocation, and five studies that assessed the relation between quality scores and estimates of treatment effects, were identified. Failure to use random allocation and concealment of allocation were associated with relative increases in estimates of effects of 150% or more, relative decreases of up to 90%, inversion of the estimated effect and, in some cases, no difference. On average, failure to use randomisation or adequate concealment of allocation resulted in larger estimates of effect due to a poorer prognosis in non-randomly selected control groups compared with randomly selected control groups.
Conclusions Failure to use adequately concealed random allocation can distort the apparent effects of care in either direction, causing the effects to seem either larger or smaller than they really are. The size of these distortions can be as large as or larger than the size of the effects that are to be detected.
Key messagesEmpirical studies support using random allocation in clinical trials and ensuring that the allocation process is concealed—that is, that assignment is impervious to any influence by the people making the allocationThe effect of not using concealed random allocation can be as large or larger than the effects of worthwhile interventionsOn average, failure to use concealed random allocation results in overestimates of effect due to a poorer prognosis in non-randomly selected control groups compared with randomly selected control groups, but it can result in underestimates of effect, reverse the direction of effect, mask an effect, or give similar estimates of effectThe adequacy of allocation concealment may be a more sensitive measure of bias in clinical trials than scales used to assess the quality of clinical trialsIt is a paradox that the unpredictability of randomisation is the best protection against the unpredictability of the extent and direction of bias in clinical trials that are not properly randomised