Dose Optimization During Drug Development: Whether and When To Optimize

Abstract The goal of dose optimization during drug development is to identify a dose that preserves clinical benefit with optimal tolerability. Traditionally, the maximum tolerated dose in a small phase 1 dose escalation study is used in the phase 2 trial assessing clinical activity of the agent. Although it is possible that this dose level could be altered in the phase 2 trial if an unexpected level of toxicity is seen, no formal dose optimization has routinely been incorporated into later stages of drug development. Recently it has been suggested that formal dose optimization (involving randomizing patients between two or more dose levels) be routinely performed early in drug development, even before it is known that the experimental therapy has any clinical activity at any dose level. We consider the relative merits of performing dose optimization earlier versus later in the drug development process and demonstrate that a considerable number of patients may be exposed to ineffective therapies unless dose optimization is delayed until after clinical activity or benefit of the new agent has been established. We conclude that patient and public health interests may be better served by conducting dose optimization after (or during) phase 3 evaluation, with some exceptions when dose optimization should be performed after activity shown in phase 2 evaluation.