Abstract
Purpose
Drug loss in oncology therapies in Japan highlights the need to reduce operational and regulatory uncertainty in drug development. In oncology, regulatory requirements for Japanese Phase 1 studies that primarily assess tolerability in Japanese participants remain unclear. This lack of clarity may discourage sponsors from pursuing drug development in Japan, contributing to drug loss. We (1) characterized current practices of Japanese tolerability assessments through a landscape analysis and (2) identified factors associated with single-dose Japanese tolerability assessments.Methods
We analyzed Japanese tolerability assessments among new oncology drugs approved in Japan during fiscal years 2015-2024. Trial characteristics were summarized, including study type, tumor type, and number of dose levels evaluated. Multivariable Firth's logistic regression was used to identify factors associated with single-dose Japanese tolerability assessments among 71 drugs. Predicted probabilities were estimated for combinations of key factors.Results
Single-dose assessments were associated with (1) determination of the recommended phase 2 dose (RP2D) before the Japanese tolerability assessment, although a wide confidence interval suggested instability in this estimate, and (2) regulatory approval supported by multi-regional clinical trials (MRCTs) including Japan. Predicted probabilities showed an increase from 0.2% in the absence of both factors to 61.8% when both were present, although these estimates should be interpreted as exploratory.Conclusion
Incorporating a single-dose Japanese tolerability cohort within an MRCT after RP2D determination may represent one potential development strategy. This study may help better understand current Japanese tolerability assessment practices and potential development pathways for integrating Japan into global development programs.