DYNAMIC BALANCED RANDOMIZATION FOR CLINICAL-TRIALS

Common methods of treatment allocation for multi-centre and/or stratified randomized clinical trials can result in substantial differences between the number of patients allocated to each treatment arm. This can occur in the overall trial for a permuted block design or within individual institutions/strata when using a minimization scheme. This may lead to a bias in the result. Also, these procedures can be predictable, with the possibility of an investigator-introduced selection bias. An easily implemented method of randomization is proposed which attempts to overcome these problems by balancing treatment allocations both within strata and across the trial as a whole. The method keeps a running tally on total treatment allocation numbers at all stratification levels. When a patient accrues a hierarchical decision rule is applied, and the allocation is deterministic if certain pre-defined limits are exceeded, and random otherwise. The method is an extension of the big stick design of Soares and Wu, and is related to both Zelen's key number randomization methods and the schemes of Nordle and Brantmark. Simulation studies are used to demonstrate that major imbalances possible with other schemes do not occur using this method, and that the potential for selection bias is much reduced.