Improved up-and-down designs for phase I trials.

We consider several designs from the family of up-and-down rules for the sequential allocation of dose levels to subjects in a dose-response study. We show that an up-and-down design can be improved by using more information than the most recent response. For example, the k-in-a-row rule uses up to the k most recent responses. We introduce a new design, the Narayana rule, which uses a local estimate of the probability of toxicity calculated from all previous responses. For the Narayana rule, as the sample size gets large, the probability of assignment goes to zero for dose levels not among the two (or three) closest to the target. Different estimators of the target dose are compared. We find that the isotonic regression estimator is superior to other estimators for small to moderate sample sizes.