The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance

Abstract

The ICH E14 guidance on how to clinically assess a new drug's liability to prolong the QT interval was adopted in May 2005. A centre-piece of the guidance was the establishment of one single trial, the 'thorough QT/QTc study', intended to confidently identify drugs that may cause QT prolongation. Initially perceived as a great challenge, this study has rapidly become a standard component of all clinical development programs for new molecular entities. The study is normally conducted in healthy volunteers, includes both a positive and a negative (placebo) control and is stringently powered to exclude an effect on the QTc interval exceeding 10 ms. The E14 guidance was intentionally not very prescriptive and allowed sponsors and service providers to explore new methodologies. This has allowed for a rapid development of new methods during the first years after the guidance's implementation, such as computer-assisted algorithms for QT measurements. Regulators have worked in close collaboration with pharmaceutical industry to set standards for the design and conduct of the 'thorough QT/QTc study', which therefore has evolved as a key component of cardiac safety assessment of new drugs. This paper summarizes the requirements on the 'thorough QT/QTc study' with emphasis on the standard that has evolved based on interactions between regulators and sponsors and the experience from a large number of completed studies.

Figure 1

Examples of the effect induced by moxifloxacin: Baseline-adjusted, placebo-corrected QTcF after oral dosing of 400 mg moxifloxacin in a TQT study, measured with an automated and a fully manual measurement technique. With both techniques a peak effect of approximately 14 ms was seen 2 h after dosing, at which time the lower bound of the confidence interval clearly exceeded 5 ms. With the automated technique, QTcF thereafter declined, whereas with the manual, a second peak was seen at 8 h. Bars represent two-sided 90% confidence interval. QTcF, QT heart rate corrected according to Fridericia; TQT, thorough QT/QTc.

Figure 2

Schematic outline of a ‘nested crossover’ design in a parallel TQT study. Panel A shows a parallel-designed TQT study with separate treatment group for a supra-therapeutic and a therapeutic dose of the NME, for placebo and for the positive control (PC), resulting in four groups. The NME and placebo are administered for 14 days (Day 1 through Day 14) and the primary assessment is performed on Day 14. In group 4, placebo is given on Day 1 through Day 13 and the PC (moxifloxacin, PC) on Day 14. QTc on Day 14 is baseline-adjusted by subtracting values on Day 0 in all groups. Four treatment groups with equal allocation results in 4 × 40 = 160 subjects. Panel B shows the ‘nested crossover’ design applied to the same example, in which the effect of the NME is evaluated after 14 days of dosing. In Group 1 and 2, the NME is given on Day 1 to Day 14. The joint placebo–PC treatment group (Group 3) is divided into two arms with half the subjects in each. In the PC/placebo arm, the PC is given on Day 1 followed by placebo to Day 15. In the placebo/PC arm (bottom), placebo is given on Day 1 to Day 14 and the PC on Day 15. NME, new molecular entity; PC, positive control; TQT, thorough QT/QTc.