Stratified randomization for clinical trials

Trialists argue about the usefulness of stratified randomization. For inves tigators designing trials and readers who use them, the argument has create d uncertainty regarding the importance of stratification In this paper, we review stratified randomization to summarize its purpose, indications, acco mplishments, and alternatives. In order to identify research papers, we per formed a Medline search for 1966-1997. The search yielded 33 articles that included original research on stratification or included stratification as the major focus. Additional resources included textbooks. Stratified random ization prevents imbalance between treatment groups for known factors that influence prognosis or treatment responsiveness. As a result, stratificatio n may prevent type I error and improve power for small trials (< 400 patien ts), but only when the stratification factors have a large effect on progno sis. Stratification has an important effect on sample size for active contr ol equivalence trials, but not for superiority trials. Theoretical benefits include facilitation of subgroup analysis and interim analysis. The maximu m desirable number of strata is unknown, but experts argue for keeping it s mall. Stratified randomization is important only for small trials in which treatment outcome may be affected by known clinical factors that have a lar ge effect on prognosis, large trials when interim analyses are planned with small numbers of patients, and trials designed to show the equivalence of two therapies. Once the decision to stratify is made, investigators need to chose factors carefully and account for them in the analysis. J CLIN EPIDE MIOL 52;1:19-26, 1999. (C) 1999 Elsevier Science Inc.