title: Early QT assessment--how can our confidence in the data be improved?
abstract: Exposure-response (ER) analysis has emerged as an important tool to interpret QT data from thorough QT (TQT) studies and allows the prediction of effects in the targeted patient population. Recently, ER analysis has also been applied to data from early clinical pharmacology studies, such as single and multiple ascending dose studies, in which high plasma concentrations are often achieved. In line with this, there is an on-going discussion between sponsors, academicians and regulators on whether 'early QT assessment' can provide sufficiently high confidence in assessment of QT prolongation to replace the TQT study. In this article, we discuss how QT assessment can be applied to early clinical studies ('early QT assessment') and what we believe is needed to achieve the same high confidence in the data as we currently obtain from data from the TQT study. The power to exclude a QTc effect exceeding 10 ms in small sample sizes using ER analysis will be discussed and compared with time-matched analysis, as described in the ICH E14 guidance. Two examples of early QT assessment are shared; one negative and one positive, and the challenge in terms of demonstrating assay sensitivity in the absence of a pharmacological positive control will be discussed. Finally, we describe a recent research proposal, which may generate data to support the replacement of the TQT study with data from QT assessment in early phase 1 studies.
authors.affiliation: Karolinska Institutet, Department of Clinical Sciences, Danderyd's Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.forename: Christine
authors.initials: C
authors.lastname: Garnett
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*
keywords: Early QT assessment; PK/PD thorough QT study; QT; QT/QTc; healthy volunteers