The impact of early phase trial design in the drug development process

Purpose: Many of the therapeutic agents that are being used currently were developed using the 3+3 decision rule for dose-finding. Over the past 30 years, several dose-finding designs have been proposed and evaluated, including the 'continual reassessment method' (CRM) and the 'Bayesian optimal interval design' (BOIN). This research investigates the role of the choice of an early phase design on the likelihood that drugs entering the drug development pipeline will have two successful phase III trials. Experimental Design: Using simulation, each agent in a population of hypothetical agents was tracked through the drug development process, from initial dose-finding to two confirmatory phase III trials. Varying the designs of the phase I, II, and III trials allows for an assessment of the effect of the choice of designs on the proportion of agents with successful phase III trials. Results: The results indicate that using the CRM or BOIN, rather than the 3+3 substantially enhances the proportion of effective agents that have successful phase III trials, with the CRM having a greater effect than BOIN. A larger phase II trial magnifies the effect of the phase I design. Conclusions:The results underscore the importance of the choice of the early phase designs. Use of the 3+3 results in fewer agents with successful phase III trials compared to the CRM or BOIN. The difference is more pronounced among highly effective agents. In addition, the results show the importance of a sufficiently powered phase II trial.

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