Are Exposure Recommendations for QT Evaluation Being Fulfilled?

Abstract Pharmaceutical companies have several options to evaluate drug‐induced QT prolongation, often referred to as QT pathways, during clinical development. Current regulatory practices recommend achieving high clinical exposure (HCE) for conventional thorough QT (TQT) studies. An alternative to the TQT study, commonly known as the Q&A 5.1 pathway, recommends a two‐fold HCE as the exposure margin for concentration‐corrected QT (C‐QTc) analysis. To assess the impact of these recommendations, we analyzed the exposure margins of 166 new active substances approved in Japan since 2015. Among these, 28.3% of substances in conventional TQT studies (n = 92) did not achieve HCE, and 50.0% of substances in the C‐QTc analysis (n = 22) did not achieve two‐fold HCE. In the integrated risk assessment, C‐QTc analysis, often incorporated into first‐in‐human studies, is recommended to cover HCE for substances showing no QT prolongation risks in both in vitro and in vivo non‐clinical studies, and we analyzed whether the C max achieved in single‐ascending dose (SAD) and multiple‐ascending dose (MAD) studies reached HCE. The result showed that 51.1% and 47.7% of substances did not achieve HCE in SAD and MAD studies, respectively. Our findings highlight the need for dose‐ascending strategy targeting two‐fold therapeutic exposure to ensure HCE. Insufficient exposure may lead to failure to waive the TQT study, and delays in development timelines. To address these challenges, we propose strategies for optimizing early clinical study designs to meet the exposure recommendations and reduce the risk of additional requirements from the regulatory authorities at a later stage.