Randomized phase II designs.

As the use of molecularly targeted agents, which are anticipated to increase overall survival (OS)and progression-free survival (PFS) but not necessarily tumor response, has increased in oncology, there has been a corresponding increase in the recommendation and use of randomized phase II designs. Such designs reduce the potential for bias, existent in comparisons with historical controls, but also substantially increase the sample size requirements. We review the principal statistical designs for historically controlled and randomized phase II trials, along with their advantages, disadvantages, and statistical design considerations. We review the arguments for and against the use of randomization in phase II studies, the situations in which the use of historical controls is preferred, and the situations in which the use of randomized designs is preferred. We review methods used to calculate predicted OS or PFS values from historical controls, adjusted so as to be appropriate for an experimental sample with particular prognostic characteristics. We show how adjustment of the type I and type II error bounds for randomized studies can facilitate the detection of appropriate target increases in median PFS or OS with sample sizes appropriate for phase II studies. Although there continue to be differences among investigators concerning the use of randomization versus historical controls in phase II trials, there is agreement that each approach will continue to be appropriate, and the optimal approach will depend upon the circumstances of the individual trial.