Topic of Timely Interest-Decision Criteria for Negative QT Assessment Using Exposure Response Analysis of Data From Early-Phase Clinical Studies: Letter to the Editor.

Borje Darpo,Jiang Liu,Norman Stockbridge,Georg Ferber,Christine Garnett

doi:10.1177/2168479015596022

Abstract

There are ongoing discussions of the possibility of replacing the thorough QT (TQT) study with QT assessment in early phase clinical studies and the subject is currently under consideration by the International Conference of Harmonisation E14 Discussion Group. For small molecules, early studies are typically performed in healthy subjects with a good range of doses of the new chemical entity (NCE), and they often generate plasma concentrations of the parent compound and metabolites in substantial excess of the therapeutic levels later determined in development in patients. Phase 1 studies are often conducted in clinical units with the same level of strict experimental control as TQT studies and are therefore well suited to generate electrocardiogram (ECG) data of good quality using modern techniques with serial ECGs. If the effects of an NCE on ECG parameters can be evaluated using data from these studies with the same high level of confidence as from a TQT study, this would represent a more resource-efficient approach and would also come with the advantage of learning about adverse ECG effects early in clinical development.

Highlights

A prospective study was recently designed and conducted in close collaboration between FDA, industry, and cardiac safety experts to validate the concept of detecting and excluding druginduced QT effects by applying ER analysis to ECG data from a small, phase 1 study.[2]
The highest levels do exceed the levels seen with therapeutic doses, but the ER relationship provides an early indication of the likelihood of a significant QT effect
Using ER analysis at this stage identifies a range of concentrations that will not produce a QTc prolongation of concern and provides early information on what higher doses are likely to do. (2) Only later in development, when the pharmacokinetic (PK) profile of the new chemical entity (NCE) has been well characterized in the targeted patient population, can it become known that the achieved plasma concentrations in the phase 1 study exceed the highest possible therapeutic levels

Summary

Introduction

A prospective study was recently designed and conducted in close collaboration between FDA, industry, and cardiac safety experts to validate the concept of detecting and excluding druginduced QT effects by applying ER analysis to ECG data from a small, phase 1 study.[2]. The criterion above is based on a tiered approach with 2 steps: (1) ECG data are generated from early-phase clinical study(ies), which generally examine the full range of doses that could later be used in clinical studies.

Results

Conclusion