P219: Innovative Clinical Trial Designs in Japanese Regulatory Practice: Findings from PMDA Consultations and New Drug Review
Poster Presenter
Yukino Umeki
Reviewer (Biostatistics)
Pharmaceuticals and Medical Devices Agency (PMDA) Japan
Objectives
The objective of this study is to characterize the use of innovative clinical trial designs (e.g., adaptive designs, Bayesian methods, and external controls) in recent clinical trial consultations and reviews in Japan, and to summarize key considerations derived from these experiences.
Method
We reviewed PMDA consultation minutes and review reports for drugs and cellular and tissue-based products finalized in Japan between October 2024 and December 2025. We also summarized key considerations related to the use of innovative clinical trial designs identified in these cases.
Results
Within adaptive design proposals discussed during consultations, sample size adaptation and adaptive dose-selection designs were frequently proposed, with sample size adaptation being most frequent. These proposals were observed not only in development programs for rare diseases, but also in those for non-rare diseases. One approved product implemented response-adaptive randomization in an exploratory trial. Regulatory discussions focused on control of the type I error probability and adequacy of pre-specified simulation scenarios.
Bayesian methods were discussed for several purposes, including efficacy confirmation and futility assessment in pivotal trials. They were also proposed to evaluate efficacy in Japanese participants when pivotal trials were conducted overseas. Among approved products using the Bayesian methods, one used a Bayesian method for efficacy evaluation in a pivotal trial, one for dose-response assessment, and two for safety evaluation. Thus, Bayesian methods were applied across a range of contexts, including exploratory analyses and confirmatory evaluations of efficacy and safety. Key regulatory issues included justification of prior assumptions, their relevance to the target population, and transparency in decision criteria.
Utilization of external controls based on individual patient data (IPD) was primarily discussed in the development programs for rare diseases where randomized controlled trials were infeasible. Key regulatory considerations included data quality, participant selection and matching methods, adjustment for baseline characteristics, and pre-specification of the analysis plan. For two products, external controls were used in pivotal trials. Review reports discussed adequate adjustment for background factors and robustness of treatment effect estimate.
Conclusion
Ensuring statistical validity and transparency in design assumptions remains a fundamental regulatory requirement across all innovative clinical trial designs, including adaptive designs, Bayesian methods, and IPD-based external controls. The limited review period in our study and the operational complexity of implementing adaptive designs may partly explain the low prevalence of adaptive design trials among approved products identified in this review. Bayesian methods, which allow the incorporation of external information and support decision-making in small-sample settings, were primarily used in the development programs for rare disease. IPD-based external controls are expected to become a practical alternative to randomized controlled trials in rare disease settings; however, potential biases due to limited comparability between groups remain unavoidable, even when applying confounding-adjustment methods, and treatment effects should be interpreted cautiously. This review characterizes recent cases involving innovative clinical trial designs and outlines key regulatory considerations that may support their appropriate and scientifically sound use in future development programs. Despite increasing interest in innovative clinical trial designs, their implementation in pivotal trials remains limited, highlighting the need for early and proactive communications with regulatory authorities.
Note: The views expressed in this research are those of the authors and do not necessarily reflect the official views of the Pharmaceuticals and Medical Devices Agency.
