Mechanisms and direction of allocation bias in randomised clinical trials.

BACKGROUND: Selective allocation of patients into the compared groups of a randomised trial may cause allocation bias, but the mechanisms behind the bias and its directionality are incompletely understood. We therefore analysed the mechanisms and directionality of allocation bias in randomised clinical trials.

METHODS: Two systematic reviews and a theoretical analysis. We conducted one systematic review of empirical studies of motives/methods for deciphering patient allocation sequences; and another review of methods publications commenting on allocation bias. We theoretically analysed the mechanisms of allocation bias and hypothesised which main factors predicts its direction.

RESULTS: Three empirical studies addressed motives/methods for deciphering allocation sequences. Main motives included ensuring best care for patients and ensuring best outcome for the trial. Main methods included various manipulations with randomisation envelopes. Out of 57 methods publications 11 (19 %) mentioned explicitly that allocation bias can go in either direction. We hypothesised that the direction of allocation bias is mainly decided by the interaction between the patient allocators' motives and treatment preference.

CONCLUSION: Inadequate allocation concealment may exaggerate treatment effects in some trials while underestimate effects in others. Our hypothesis provides a theoretical overview of the main factors responsible for the direction of allocation bias.