FDA's insights: implementing new strategies for evaluating drug-induced QTc prolongation

Abstract

The questions and answers (Q&A) document for ICH E14/S7B provides the following advancements for QTc assessment: concentration-QTc modeling (C-QTc) as the primary analysis, accepting alternative approaches (Q&A 5.1 and 6.1) to thorough QT (TQT) studies, and incorporating an integrated nonclinical risk assessment as supporting evidence. Based on QT study reports reviewed by the FDA between 2016 and 2024, changes to the E14 guideline have resulted in a 34% decrease in the proportion of TQT studies, while the use of C-QTc analysis as the primary analysis has significantly increased. Studies using C-QTc instead of by-time analysis as the primary analysis reduced median sample sizes by 67%, 42%, and 35% for parallel, nested crossover, and crossover studies, respectively. The white paper C-QTc model was used for 60% of drugs that prolonged the QTc interval. From 2020 to 2024, reviews incorporating an integrated nonclinical risk assessment have also increased. The advancements in QTc assessments have streamlined QTc assessment and made clinical trials less resource-intensive. As the advancements continue to evolve the drug safety evaluation is likely to become even more adaptive and enable more precise and targeted QTc assessment.

Keywords: Electrocardiogram; ICH E14 guideline; QTc interval prolongation; Thorough QT study.

Fig. 1

Summary of 424 QT study reports reviewed by FDA between 2016 and 2024

Fig. 2

Percentage of TQT studies (Top) and studies following the 5.1 approach (bottom) by the year reviewed by FDA

Fig. 3

Percentage of analysis methods of TQT studies by the year study conducted

Fig. 4

Cumulative distribution of sample size by analysis methods and study designs