Impact of Dose-Escalation Design on the Safety and Development of Anticancer Drugs in Clinical Trials

Abstract

The operational characteristics of dose-escalation design in phase I studies have been studied using simulations; however, there is limited analysis regarding its effects on the results of clinical trials. We collected the data of 394 clinical trials involving dose-escalation studies for anticancer drugs submitted to the Pharmaceuticals and Medical Devices Agency between 2013 and 2022. We used the internal data of the PMDA and published papers and analyzed outcomes such as enrollment and drug development. We identified model-based designs and rule-based designs as the two primary designs. The median number of dose-limiting toxicity (DLT)-evaluated patients was higher for model-based designs than for rule-based designs. The proportion of rule-based designs was higher in Japanese trials and that of model-based designs was higher in multiregional clinical trials (MRCTs). The determined recommended phase II dose (RP2D) was consistent with the approved dose in all trials (13/13) involving model-based designs and in 84.0% (21/25) of trials involving rule-based designs, although it was not statistically significant. The proportion of progression to the next study phase was 50.0% (61/122) for rule-based designs and 56.3% (36/64) for model-based designs. Similar trends in these outcomes were observed when MRCTs and Japanese trials were examined separately. Model-based designs might require more DLT-evaluated patients; however, they might have different operational capabilities compared with rule-based designs, such as selecting an RP2D consistent with the approved dose. The results might help in selecting the optimal dose-escalation methods in future phase I trials.