Some practical problems in implementing randomization.

ABSTRACT

BACKGROUND: While often theoretically simple, implementing randomization to treatment in a masked, but confirmable, fashion can prove difficult in practice. PURPOSE: At least three categories of problems occur in randomization (1) bad judgment in the choice of method, (2) design and programming errors in implementing the method, and (3) human error during the conduct of the trial. This article focuses on these latter two types of errors, dealing operationally with what can go wrong after trial designers have selected the allocation method. RESULTS: We offer several case studies and corresponding recommendations for lessening the frequency of problems in allocating treatment or for mitigating the consequences of errors. Recommendations include (1) reviewing the randomization schedule before starting a trial, (2) being especially cautious of systems that use on-demand random number generators, (3) drafting unambiguous randomization specifications, (4) performing thorough testing before entering a randomization system into production, (5) maintaining a dataset that captures the values investigators used to randomize participants, thereby allowing the process of treatment allocation to be reproduced and verified, (6) resisting the urge to correct errors that occur in individual treatment assignments, (7) preventing inadvertent unmasking to treatment assignments in kit allocations, and (8) checking a sample of study drug kits to allow detection of errors in drug packaging and labeling. LIMITATIONS: Although we performed a literature search of documented randomization errors, the examples that we provide and the resultant recommendations are based largely on our own experience in industry-sponsored clinical trials. We do not know how representative our experience is or how common errors of the type we have seen occur. CONCLUSIONS: Our experience underscores the importance of verifying the integrity of the treatment allocation process before and during a trial. Clinical Trials 2010; 7 235-245. http//ctj.sagepub.com.