An adaptive design for identifying the dose with the best efficacy/tolerability profile with application to a crossover dose-finding study.

ABSTRACT

Proof-of-concept in clinical trials has traditionally focused on the identification of a maximum tolerated dose with the assumption that the higher doses provide better efficacy. However, adverse events associated with a maximum tolerated dose may have a negative effect on efficacy. We present an efficient adaptive dose-finding strategy that concentrates patient assignments at and around the dose which has the best efficacy/tolerability profile based on a utility function. The strategy is applied within the setting of a crossover design. While the strategy may also be applied to parallel studies, a crossover design provides more power for a given sample size for comparisons between the optimal dose versus placebo and/or active control when it is reasonable to assume no carryover effects.