Darpo, B, Sarapa, N, Garnett, C, Benson, C, Dota, C, Ferber, G, Jarugula, V, Johannesen, L, Keirns, J, Krudys, K, Ortemann-Renon, C, Riley, S, Rogers-Subramaniam, D and Stockbridge, N (2014) The IQ-CSRC Prospective Clinical Phase 1 Study: 'Can Early QT Assessment Using Exposure Response Analysis Replace the Thorough QT Study?'. ANNALS OF NONINVASIVE ELECTROCARDIOLOGY. pp. 70-81.

Abstract

A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure-response (ER) analysis of data generated from First-in-Man single ascending dose (SAD) studies. Six marketed drugs with well-characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo-controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study. Two doses (low and high) of each drug will be given on separate, consecutive days to 9 subjects. Six subjects will receive placebo. Data will be analyzed using linear mixed-effects ER models. Criteria for QT-positive drugs will be the demonstration of an upper bound (UB) of the 2-sided 90% confidence interval (CI) of the projected QTc effect at the peak plasma level of the lower dose above the threshold of regulatory concern (currently 10 ms) and a positive slope of ER relationship. The criterion for QT-negative drug will be an UB of the CI of the projected QTc effect of the higher dose <10 ms. It is expected that a successful outcome in this study will provide evidence supporting replacement of the TQT study with ECG assessments in standard early clinical development studies for a new chemical entity

Item Type:	Article
Additional Information:	NIBR author: Jarugula, V institute: NIBR contributor address: Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden, iCardiac Technol, Rochester, NY USA borje.darpo@telia.com; Bayer Healthcare Inc, Clin Sci, Whippany, NJ USA ; Certara, St Louis, MO USA ; Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA ; AstraZeneca R&D, Molndal, Sweden ; Stat Georg Ferber GmbH, CH-4125 Riehen, Switzerland ; Novartis Inst Biomed Res, Drug Metab & Pharmacokinet, E Hanover, NJ USA ; US FDA, Div Pharmacometr, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA, Karolinska Univ Hosp, Karolinska Inst, Dept Clin Physiol, Stockholm, Sweden ; Astellas Pharma Global Dev Inc, Global Clin Pharmacol & Exploratory Dev, Northbrook, IL USA ; US FDA, Div Pharmacometr, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA ; Clin & Exploratory Pharmacol, Bridgewater, MA USA ; Pfizer Inc, Specialty Care Business Unit, Clin Pharmacol, Groton, CT 06340 USA ; US FDA, Ctr Drug Evaluat & Res, Div Cardiovasc & Renal Prod, Silver Spring, MD USA ; Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden; iCardiac Technol, Rochester, NY USA; Darpo, B; Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22580