Randomized optimal selection design for dose optimization

ABSTRACT The US Food and Drug Administration (FDA) launched Project Optimus to shift the objective of dose selection from the maximum tolerated dose to the optimal biological dose (OBD), optimizing the benefit-risk tradeoff. One approach recommended by the FDA’s guidance is to conduct randomized trials comparing multiple doses. In this paper, using the selection design framework, we propose a Randomized Optimal SElection (ROSE) design, which minimizes sample size while ensuring the probability of correct selection of the OBD at pre-specified accuracy levels. The ROSE design is simple to implement, involving a straightforward comparison of the difference in response rates between two dose arms against a predetermined decision boundary. We further consider a two-stage ROSE design that allows for early selection of the OBD at the interim when there is sufficient evidence, further reducing the sample size. Simulation studies demonstrate that the ROSE design exhibits desirable operating characteristics in correctly identifying the OBD. A sample size of 15–40 patients per dosage arm typically results in a percentage of correct selection of the optimal dose ranging from 60% to 70%.