Data from the industry-driven reliance pilot projects for Chemistry, Manufacturing and Controls (CMC) Post-approval Changes (PACs) as presented in this paper have indicated the potential to reduce review and approval timelines by 12–80
Randomized controlled trials (RCTs) remain the gold standard for evaluating medical interventions, yet they face persistent methodological challenges: patient dropout, inadequate sample sizes, premature termination, missing data, and the limitations of indirect treatment comparisons. The emergence of digital twin technology—computational patient representations that generate simulated clinical trajectories statistically indistinguishable from real-world data—offers a promising methodological complement to address these limitations. We synthesize evidence from key methodological literature, regulatory guidance (ICH E9(R1), FDA, EMA), and proof-of-concept studies across oncology, neurology, and Alzheimer’s disease. A taxonomy of in silico clinical trial approaches provides the organizational framework. This article is a narrative perspective rather than a systematic review; no predefined search strategy, database range, or inclusion/exclusion criteria were applied. Digital twins may provide complementary methodological approaches across nine trial challenges: model-based sensitivity analyses for missing (MNAR) outcomes; Bayesian and posterior predictive modeling of partially observed longitudinal outcomes; prognostic covariate adjustment and virtual augmentation to improve efficiency; prospective simulation of futility stopping rules; prospective calibration of efficacy stopping boundaries; individualized control-arm (ICA) construction; hybrid augmented and synthetic control strategies; pre-trial protocol optimization through in silico simulation; and population-adjusted indirect treatment comparison. Digital twins represent an emerging methodological ecosystem rather than isolated tools. Their methodological potential depends on consistent validation and explainability standards; frameworks for detecting algorithmic bias; clarification of regulatory acceptance criteria; and comprehensive data infrastructure addressing representativeness gaps. Digital twin approaches should be viewed as complementary to—not replacements for—established randomized trial methodology.
Orphan drug development faces substantial economic and operational challenges, particularly in small patient populations where conventional industry-sponsored trials (ISTs) may be difficult to conduct. In Japan, investigator-initiated trials (IITs) have been used to support the development of treatments for rare diseases and other areas of high unmet medical need; however, the characteristics of orphan drug approvals supported by IITs compared with those supported by ISTs have not been fully evaluated. This study analyzed pivotal trials supporting orphan drug approvals in Japan between 2015 and 2024 and compared the trial and regulatory characteristics of IIT- and IST-supported approvals. Among 1,269 drugs approved, 260 orphan drugs were included in the final analysis. IITs were used as pivotal trials in 11.2
Multi-regional clinical trials (MRCTs) have become the standard approach for new drug development in Japan. However, no standardized methodology exists to determine the appropriate number of Japanese patients for MRCTs, and factors associated with Japanese patient enrollment remain unclear. In this study, new drugs approved in Japan between January 2006 and December 2024 using clinical data packages including MRCTs were examined. For the targeted products, the proportions of Japanese patients (JP ratio) in the MRCTs were calculated, and their associations with potential explanatory variables were analyzed. Among the 1621 newly approved drugs, 453 met the inclusion criteria. The median JP ratio was 8.9
The ASEAN Joint Assessment (ASEAN JA) is a collaborative regulatory initiative among Southeast Asian nations designed to accelerate the approval of essential medicines by enabling simultaneous evaluation and work-sharing among its National Regulatory Authorities (NRAs). This procedure aims to enhance regulatory efficiency, build mutual trust, and facilitate faster patient access to innovative treatments across the region. This article describes a large-scale ASEAN JA application made in accordance with the published ASEAN JA procedures for the registration of a broad-spectrum anti-infective combination aztreonam and avibactam. This application involved six participating ASEAN NRAs and three observer NRAs, marking the largest ASEAN JA attempted to date. The joint assessment proceeded with coordinated timelines and culminated in a joint recommendation to support subsequent national authorization. The joint application supported earlier and more coordinated national submissions across ASEAN markets and showed reductions in approval lead times compared with standard national timelines. Notably, the final approved indications were not fully harmonized across NRAs; two NRA approved narrower indications than the EMA SmPC, while the remaining four NRAs were substantively aligned with the SmPC. Using one common dossier for multiple countries saved resources and reduced submission lag in ASEAN markets, thereby facilitating earlier access to critical medicines for patients in this part of the world. The ASEAN JA initiative reflects ASEAN’s commitment to regulatory cooperation while preserving national sovereign decision. Continued enhancements and formalization of ASEAN JA at the national level are expected to further improve access to innovative treatments in the region.
