title: The IQ-CSRC prospective clinical Phase 1 study: "Can early QT assessment using exposure response analysis replace the thorough QT study?".
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.
authors.affiliation: Karolinska Institutet, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden and iCardiac Technologies, Rochester, NY.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.forename: Nenad
authors.initials: N
authors.lastname: Sarapa
authors.forename: Christine
authors.initials: C
authors.lastname: Garnett
authors.forename: Charles
authors.initials: C
authors.lastname: Benson
authors.forename: Corina
authors.initials: C
authors.lastname: Dota
authors.forename: Georg
authors.initials: G
authors.lastname: Ferber
authors.forename: Venkateswar
authors.initials: V
authors.lastname: Jarugula
authors.forename: Lars
authors.initials: L
authors.lastname: Johannesen
authors.forename: James
authors.initials: J
authors.lastname: Keirns
authors.forename: Kevin
authors.initials: K
authors.lastname: Krudys
authors.forename: Catherine
authors.initials: C
authors.lastname: Ortemann-Renon
authors.forename: Steve
authors.initials: S
authors.lastname: Riley
authors.forename: Danise
authors.initials: D
authors.lastname: Rogers-Subramaniam
authors.forename: Norman
authors.initials: N
authors.lastname: Stockbridge
mesh_terms: D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004562:Electrocardiography / Q000187:drug effects* / Q000379:methods* / Q000706:statistics & numerical data; D006801:Humans; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012016:Reference Values; D012107:Research Design / Q000706:statistics & numerical data*
keywords: QTc interval; Thorough QT/QTc study; healthy volunteers; single-ascending-dose