Can early Phase ECG assessment serve as an alternative for thorough QT studies? A review of the literature
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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.
References:
1. Darpo B, Benson C, Dota C et al. Results from the IQ-CSRC prospective study support replacement of the thorough QT study by
QT assessment in the early clinical phase. Clin Pharmacol Ther. 2015 Apr97(4):326-335
2. Ferber G, Lorch U, Täubel J. The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling
Simulation Study. Biomed Res Int. 20152015:293564
3. RM Lester, SM Azzam, C Erskine, J Olbertz Triplicate Ecgs Are Sufficient In Obtaining Precise Estimates Of Qtcf. Clinical
Pharmacology & Therapeutics 2016 Feb 99, 87-87
4. Darpo B, Garnett C, Benson CT et al. Cardiac Safety Research Consortium: can the thorough QT/QTc study be replaced by early
QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward.Am
Heart J. 2014 Sep168(3):262-272
Keywords:
exposure response analysis,
Early Phase ECG,
ER analysis,
TQT-study
Conference:
EUFEMED 2017, London, United Kingdom, 17 May - 19 May, 2017.
Presentation Type:
Poster
Topic:
EUFEMED 2017 CONFERENCE
Citation:
Berghmans
PN and
Serluppens
N
(2019). Can early Phase ECG assessment serve as an alternative for thorough QT studies? A review of the literature.
Front. Pharmacol.
Conference Abstract:
EUFEMED 2017.
doi: 10.3389/conf.fphar.2017.62.00020
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Received:
29 Aug 2017;
Published Online:
25 Jan 2019.
*
Correspondence:
Dr. Pieter-Jan N Berghmans, SGS, Life Science, Antwerp, Belgium, pieterjan.berghmans@sgs.com