Integration of ICH E14 Cardiac safety in First Time in Man and other Phase I healthy volunteer studies - Opportunities and Challenges
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1
Richmond Pharmacology Ltd., UK
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2
St George's University of London, Cardiovascular and Cell Sciences Research Institute, UK
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3
Statistik Georg Ferber GmbH, Switzerland
Background: The current FDA thinking manifested on the most recent Q&A document accepts the use of ECG data collected
from Phase I studies in conjunction with concentration-effect modelling to assess arrhythmogenic risk. The need to show
assay sensitivity is currently a major obstacle if a clinically relevant effect is to be excluded when supratherapeutic plasma
concentrations cannot be achieved.
Methods: ECG and Holter data from different Thorough QT and Phase I studies were used. Standardised meals were served in
all studies. Concentration-effect analyses based on QTc interval were performed. Sensitivity was confirmed by demonstrating
a significant shortening of QTcF after a standardised meal. Simulation work was used to assess stability and the power of effect
after start of the meal.
Results: Case studies will be presented to demonstrate that time-effect attributed to food is stable and meal-induced changes
on QTc are reproducible with a power greater than 80%. Intrasubject variability of the response suggests that this approach can
perform as well as moxifloxacin as the number of subjects showing QT-prolongation after food is comparable to the number of
QT-shortening cases with moxifloxacin.
Conclusions: This presentation describes what aspects and key design features can enhance the power of the analysis and
how increased efficiency can be attained in Phase I studies. Points to be considered in data analysis when determining assay
sensitivity will be detailed. The results on stability and the power of effect support the effective integration of the food effect on
QTc in a study to establish assay sensitivity.
Keywords:
Risk Management,
patient recruitment,
Exploratory clinical trials,
human pharmacology,
early phase drug development,
over-volunteering
Conference:
EUFEMED 2017, London, United Kingdom, 17 May - 19 May, 2017.
Presentation Type:
Poster
Topic:
EUFEMED 2017 CONFERENCE
Citation:
Täubel
J,
Fernandes
S and
Ferber
G
(2019). Integration of ICH E14 Cardiac safety in First Time in Man and other Phase I healthy volunteer studies - Opportunities and Challenges.
Front. Pharmacol.
Conference Abstract:
EUFEMED 2017.
doi: 10.3389/conf.fphar.2017.62.00009
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Received:
29 Aug 2017;
Published Online:
25 Jan 2019.
*
Correspondence:
Dr. Jörg Täubel, Richmond Pharmacology Ltd., London, UK, j.taubel@richmondpharmacology.com