Randomization, balance, and the validity and efficiency of design-adaptive allocation methods

Few topics have stirred as much discussion and controversy as randomization. A reading of the literature suggests that clinical trialists generally feel randomization is necessary for valid inference, while biostatisticians using model-based inference often appear to prefer nearly optimal designs irrespective of any induced randomness. Dissection of the methods of treatment assignment shows that there are five basic approaches; pure randomizers, true randomizers, quasi-randomizers, permutation testers, and conventional modelers. Four of these have coherent design and analysis strategies, even though they are not mutually consistent, but the fifth and most prevalent approach (quasi-randomization) has little to recommend it. Design-adaptive allocation is defined, it is shown to provide valid inference, and a simulation indicates its efficiency advantage. In small studies, or large studies with many important prognostic covariates or analytic subgroups, design-adaptive allocation is an extremely attractive method of treatment assignment. (C) 2001 Elsevier Science B.V. All rights reserved.