title: 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.
abstract: The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. In February 2012, the Cardiac Safety Research Consortium held a think tank meeting at Food and Drug Administration's White Oak campus to discuss whether "QT assessment" can be performed as part of routine phase 1 studies. Based on these discussions, a group of experts convened to discuss how to improve the confidence in QT data from early clinical studies, for example, the First-Time-in-Human trial, through collection of serial electrocardiograms and pharmacokinetic samples and the use of exposure response analysis. Recommendations are given on how to design such "early electrocardiogram assessment," and the limitation of not having a pharmacologic-positive control in these studies is discussed. A research path is identified toward collecting evidence to replace or provide an alternative to the dedicated TQT study.
authors.affiliation: Karolinska Institutet, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden; iCardiac Technologies, Rochester, NY. Electronic address: borje.darpo@telia.com.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.affiliation: Certara, St Louis, MO.
authors.forename: Christine
authors.initials: C
authors.lastname: Garnett
authors.affiliation: Lilly Corporate Center, Eli Lilly & Co, Indianapolis, IN.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Benson
authors.affiliation: Global Clinical Pharmacology & Exploratory Development, Astellas Pharma Global, Development, Inc, Northbrook, IL.
authors.forename: James
authors.initials: J
authors.lastname: Keirns
authors.affiliation: Global PK/PD & Pharmacometrics, Lilly Research Laboratories, Eli Lilly & Co, Indianapolis, IN.
authors.forename: Derek
authors.initials: D
authors.lastname: Leishman
authors.affiliation: St Paul's Cardiac Electrophysiology, University of London, and Imperial College, London, United Kingdom.
authors.forename: Marek
authors.initials: M
authors.lastname: Malik
authors.affiliation: Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD.
authors.forename: Nitin
authors.initials: N
authors.lastname: Mehrotra
authors.affiliation: Medicines and Healthcare products Regulatory Agency, DoH, London, United Kingdom.
authors.forename: Krishna
authors.initials: K
authors.lastname: Prasad
authors.affiliation: Clinical Pharmacology, Global Innovative Pharma Business, Pfizer Inc, Groton, CT.
authors.forename: Steve
authors.initials: S
authors.lastname: Riley
authors.affiliation: Pharma Development Safety Risk Management, Roche TCRC, Inc, New York, NY.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Rodriguez
authors.affiliation: Stanford School of Medicine, Palo Alto, CA.
authors.forename: Philip
authors.initials: P
authors.lastname: Sager
authors.affiliation: Clinical Sciences, Bayer Healthcare, Inc. Whippany, NJ.
authors.forename: Nenad
authors.initials: N
authors.lastname: Sarapa
authors.affiliation: Safety Pharmacology Consultant, Sandwich, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Wallis
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000175:diagnosis; D004353:Drug Evaluation, Preclinical / Q000379:methods* / Q000592:standards; D004562:Electrocardiography; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000517:prevention & control; D018408:Patch-Clamp Techniques; D012107:Research Design
chemical_list: D000889:Anti-Arrhythmia Agents