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The IQ-CSRC Prospective Clinical Phase 1 Study: 'Can Early QT Assessment Using Exposure Response Analysis Replace the Thorough QT Study?'

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

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