How to Replace the TQT Study-The Use of Concentration-QTc Modeling to Exclude a Small Effect of a Novel Drug on QT Interval: Historical Perspective and Implementation.
B, D., G, F., SC, H., K, L., N, S., H, X., & R, K. (2026). How to Replace the TQT Study-The Use of Concentration-QTc Modeling to Exclude a Small Effect of a Novel Drug on QT Interval: Historical Perspective and Implementation.. Journal of clinical pharmacology. https://doi.org/10.1002/jcph.70237
B D, G F, SC H, K L, N S, H X, et al. How to Replace the TQT Study-The Use of Concentration-QTc Modeling to Exclude a Small Effect of a Novel Drug on QT Interval: Historical Perspective and Implementation.. Journal of clinical pharmacology. 2026; doi: 10.1002/jcph.70237
B D, G F, SC H, et al. How to Replace the TQT Study-The Use of Concentration-QTc Modeling to Exclude a Small Effect of a Novel Drug on QT Interval: Historical Perspective and Implementation.[J]. Journal of clinical pharmacology. 2026. DOI: 10.1002/jcph.70237.
@article{b2026,
author = {Darpo B and Ferber G and Hopkins SC and Litherland K and Sarapa N and Xue H and Kleiman R},
title = {How to Replace the TQT Study-The Use of Concentration-QTc Modeling to Exclude a Small Effect of a Novel Drug on QT Interval: Historical Perspective and Implementation.},
journal = {Journal of clinical pharmacology},
year = {2026},
doi = {10.1002/jcph.70237},
note = {PMID: 42405644},
}
TY - JOUR AU - Darpo B AU - Ferber G AU - Hopkins SC AU - Litherland K AU - Sarapa N AU - Xue H AU - Kleiman R TI - How to Replace the TQT Study-The Use of Concentration-QTc Modeling to Exclude a Small Effect of a Novel Drug on QT Interval: Historical Perspective and Implementation. T2 - Journal of clinical pharmacology PY - 2026 DO - 10.1002/jcph.70237 AN - PMID:42405644 ER -
The initial ICH E14 guidance described the thorough QT/QTc (TQT) study with the purpose of evaluating whether a new drug has effects on the QTc interval. Following its adoption, concentration-QTc (C-QTc) modeling was applied to data from TQT studies, and results were comparable with those based on a "by time point" analysis. In 2014, the IQ-CSRC study demonstrated that a small study in healthy subjects using C-QTc as the primary analysis could detect mild drug-induced QTc prolongation. The study led to the revision of the E14 guidance in 2015, allowing the use of C-QTc modeling to exclude a QTc effect at the threshold of concern, 10 ms. The 2015 revision was the starting point for the use of C-QTc modeling applied to data from first-in-human (FIH) studies with the intent to waive requests for a designated TQT study. The 2022 revision (S7B/E14 Q&A) brought non-clinical studies into the decision process for a "definitive" QT evaluation. In this manuscript, the emergence of C-QTc analysis applied to FIH studies with the intent to waive the TQT study is described, and a survey of FDA labels and reviews of approved drugs since 2015 is shared. The uptake has been modest, with only 30% of approved drugs for which a TQT study would be expected using this approach, while a TQT study has been conducted in ∼70% of development programs. It can be expected that the 2022 S7B/E14 revision will increase the number of programs for which a TQT study can be replaced.