Concentration‐QTc Analysis as an Alternative to TQT Studies: Findings From QT Evaluation and Safety Labeling Decisions in Japan

Thorough QT (TQT) studies have long been the regulatory gold standard for evaluating QT prolongation risk. With the implementation of the ICH E14 Q&A updates, various alternatives to TQT studies, referred to as QT pathways, have gained attention. However, it remains unclear whether concentration-QTc (C-QTc) analysis or other QT pathways carry the same regulatory weight as TQT studies, particularly when making safety labeling decisions. To address this issue, we investigated the relationship between QT evaluation methods and QT prolongation-related safety labeling for 295 new active substances approved in Japan between 2015 and 2024. These substances were grouped based on their respective QT pathways, and the consistency between QT assessment results and the corresponding labeling outcomes was evaluated. C-QTc analyses showed strong concordance in labeling outcomes and Phase 3 QT evaluation results, supporting their regulatory acceptability comparable to that of TQT studies. In contrast, the Q&A 6.1 pathway, primarily used for oncology drugs and substances with poor tolerability, exhibited more frequent inconsistencies between clinical pharmacology QT evaluation results and safety labeling. There was a noticeable tendency to rely more heavily on Phase 3 QT evaluation results to support labeling decisions. These findings suggest that C-QTc analysis could be more broadly adopted in future regulatory submissions in Japan and highlight the importance of early strategic planning, including decisions on ECG monitoring and early dialogue with regulators, when utilizing the Q&A 6.1 pathway.