Happy Djokoto1, Professor Jean-Michel Dogné1, Professor Flora T. Musuamba1,2
1Clinical Pharmacology and toxicology research unit, Faculty of medicine, University of Namur, , 2Federal Agency for Medicines and Health Products (FAMHP)
Introduction: The assessment of proarrhythmic risk associated with QT interval prolongation and Torsade de Pointes (TdP) is a regulatory requirement and a critical aspect of new drug development. To ensure a standardized approach, drug developers are encouraged to follow the guidelines established by the International Conference on Harmonization (ICH) E14. The 2015 revision of the ICH E14 Questions & Answers (Q&A) document [1] has dramatically modified the role of the thorough QT (TQT) studies, that were previously considered the gold standard for evaluating the QT prolongation potential of investigational drugs. Since this revision, concentration-QT (C-QT) modelling has been recognized as a viable alternative to TQT study. This approach offers several advantages over TQT studies, including ethical considerations, practical feasibility, cost-effectiveness, and regulatory flexibility. As a result, C-QT modelling is increasingly being used in regulatory submissions to assess QT liability without the need for a dedicated TQT study. Despite its advantages, approval by regulatory agencies should follow a thorough assessment of the quality of the data used in model development and validation, as well as the adequacy of the implementation and interpretation of the technical modelling and simulation. The present study provides a retrospective review of European Medicines Agency (EMA) scientific advice on C-QT modelling between January 2022 and January 2025, analysing cases where applicants explicitly sought regulatory feedback on their clinical QT assessment strategy. Objectives: The study aims to identify patterns in the regulatory acceptance and rejection of C-QT modelling, as well as to explore the rationale behind regulatory feedback. By examining the EMA’s stance on C-QT modelling over this period, this work offers insights into the current regulatory landscape, common mistakes made by applicants, and potential steps to enhance regulatory clarity and decision-making in the future. Methods: A search was conducted in scientific advices using Scientific Explorer, the AI tool developed within the EMA with the keywords “QT” and “QTc” for the period January 2022 January 2025. The final Scientific advice were reviewed and sections related to QT assessment extracted in an anonymised manner. To ensure a systematic and consistent review, a custom Python tool was developed. This tool allowed to analyse the extracted sections and assess their relevance for our research question. The sections where the keywords appeared, display the corresponding discussion for each occurrence, including the applicant’s question, their position, and the Committee for Medicinal Products for Human Use (CHMP) response were eventually retained. Explicit requests for regulatory feedback were identified. For unsupportive CHMP responses, an in-depth analysis of the discussion was conducted to determine the rationale behind the negative feedback. Results: A total of 253 cases were identified during the search in Scientific Explorer. These cases contained 1,735 questions, among which 70 explicitly requested feedback on QT assessment. From these, 13 cases received unsupportive responses from CHMP, with reasons classified into six categories: study design issues (4 cases), concerns with QTc interpretation (4 cases), insufficient exposure (3 cases), methodological issues (3 cases), unclear methodological reporting (3 cases), regulatory & compliance issues (2 cases), data gaps (2 cases). The most frequent reasons for rejection were study design issues and concerns with QTc interpretation, each occurring in 4 cases. These were followed by insufficient exposure ranges covered, methodological issues, and unclear methodological reporting, identified in 3 cases, each. Regulatory & compliance issues and data gaps were the least common reasons, each appearing in 2 cases. Conclusion: While the results of this study are encouraging, with only 18% of responses by regulators being unsupportive, it highlights key regulatory concerns surrounding the use of C-QT modelling as an alternative to the TQT study in drug development. Despite its advantages, regulatory acceptance is not guaranteed. The analysis of unsupportive responses showed that study design issues and concerns with QTc interpretation were the most common reasons for rejection, emphasizing the need for adequate study designs and robust QTc modelling approaches. These findings suggest that clearer regulatory guidance, improved methodological standardization, and early engagement with regulatory agencies could enhance the acceptance of C-QT modelling. Future efforts should focus on populating best practices for C-QT study design to ensure better alignment with regulatory expectations.
1. EMA. ICH guideline E14/S7B: clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential – questions and answers 2022.
Reference: PAGE 33 (2025) Abstr 11411 [www.page-meeting.org/?abstract=11411]
Poster: Drug/Disease Modelling - Safety