Vasopressors and the search for the optimal trial design

Despite several advances in the care of critically ill patients, sepsis and septic shock continue to carry the largest burden of mortality and morbidity. Trials comparing vasopressors in shock have been disappointing and several key issues in methodology may need to be explored. There has been substantial progress in evolving adaptive trial methodology, however these have seldom been translated to clinical trials. This paper discusses some of the issues relevant to critical illness. To illustrate the potential contribution of adaptive trials we discuss fixed sample size design including event and time to event studies. We then explore group sequential and adaptive trial design, enrichment strategies and sample size re-estimation. An attractive feature of responsive adaptive designs is the flexibility to deal with unanticipated treatment effect size. If the observed effect size is larger than expected, early stopping is permitted. If the effect size is smaller than expected, sample size recalculation would be a reasonable choice in the face of an underpowered study. This allows for optimal efficiency in trial design. Reservations about adaptive trial design centre on issues of validity, feasibility and integrity of the study and are discussed in this paper. (C) 2011 Elsevier Inc. All rights reserved.