Can early Phase ECG assessment serve as an alternative for thorough QT studies? A review of the literature

Abstract

Event Abstract Back to Event Can early Phase ECG assessment serve as an alternative for thorough QT studies? A review of the literature Pieter-Jan N. Berghmans1* and Nina Serluppens1 1 SGS, Life Science, Belgium Background: In Phase I research, we often deal with the question whether Early Phase Exposure-Response (ER) QT analysis can replace Late Phase Thorough QT (TQT) studies. In response we performed a review of available literature. Methodology: Literature study, 22 articles were selected for review. Results: TQT-studies are recommended (cfr. 2005 ICH E14 guidelines) to assess potential of drugs to prolong QT interval. These stand-alone and large, expensive studies are carried out in Later Phase drug development. Incorporating QT-effect measurements in Early Phase with an ER analysis could be an alternative enhancing cost-efficiency. Current literature provides promising evidence for this Early Phase ECG approach. Several trials including 1 compound; and 1 trial including 6 compounds (IQ-CSRC trial) , each managed to correctly categorize (QT prolonging/ no QT prolonging) every single compound using a Phase I setup and ER QT-analysis Furthermore, we identified key characteristics to enhance statistical power (in a cost-efficient way): • Sample size: ≥ 9 subjects with supra therapeutic dose, ≥ 6 placebo subjects (common in SAD)2 • Triplicate ECG in 5 min interval3 • 6-8 ECG timepoints first 24h post-dose4 • Enough ECG timepoints around Tmax Conclusions: Literature provides supporting evidence to replace TQT studies with Early Phase ECG assessment. These data suggest that compounds with a clean pre-clinical profile and a robust negative Early Phase ER analysis, can waive the request for a later phase TQT study.