The New S7B/E14 Question and Answer Draft Guidance for Industry: Contents and Commentary.

In August 2020, the International Council on Harmonisation (ICH) released a new draft document, which for the first time combined nonclinical (S7B) and clinical (E14) Questions and Answers (Q&As) into 1 document. FDA describes the revision as a "value proposition": if the human ether-à-go-go assay and the in vivo study are performed in a standardized way, the number of dedicated thorough QT (TQT) studies can be reduced. In this article, we describe and discuss the Q&As that relate to clinical ECG evaluation. If supported by negative standardized nonclinical assays, Q&A 5.1 will obviate the need for a TQT study in the case that a >2-fold exposure margin vs high clinical scenario cannot be obtained. Q&A 6.1 addresses drugs that are poorly tolerated in healthy subjects and cannot be studied at high doses or in placebo-controlled studies; it therefore mainly applies to oncology drugs. It will enable sponsors to claim that a new drug has a "low likelihood of proarrhythmic effects" in the case that the mean corrected QT effect is <10 milliseconds at the time of market application. The E14 2015 revision allowed application of concentration-corrected QT analysis on data from routinely performed clinical pharmacology studies, for example, the first-in-human study and the proportion of dedicated TQT studies has since steadily decreased. It can be foreseen that the proposed new revision will further reduce the number of TQT studies. To achieve harmonization across regulatory regions, it seems important to reach consensus within the International Council on Harmonisation group on the new threshold proposed in 6.1. For this purpose, the Implementation Working Group has asked for public comments.

Preclinical QT safety assessment: cross-species comparisons and human translation from an industry consortium.

INTRODUCTION: In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic. METHODS: Six pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3-100 mg/kg, p.o.) with telemetered ECGs (≥500 Hz) obtained for 20-24h post-dose. Individual probabilistic QT-RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc-RR relationships. Normalized moxifloxacin QTca responses (Veh Δ%/µM) were derived for 1h centered on the moxifloxacin Tmax. RESULTS: All QT-RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate-dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man. DISCUSSION: The current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the implementation of standardized QTc data presentation, QTc reference cycle lengths, and rate-correction coefficients can markedly improve the concordance of preclinical and clinical outcomes in most preclinical species.

The IQ-CSRC prospective clinical Phase 1 study: "Can early QT assessment using exposure response analysis replace the thorough QT study?".

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.

Characterization of the human QT interval: novel distribution-based assessment of the repolarization effects of moxifloxacin.

The authors have previously demonstrated rate-independent QT variability in the dog and cynomolgus monkey, where the QT associated with any RR was a normally distributed value that was accurately evaluated as the distribution mean. The present study investigated the rate-independent characteristics of the human QT. Digital electrocardiographs (1000 Hz) were collected for 24 hours in 51 patients (thorough QT study) and analyzed by computer. Distribution-based analysis was applied to the placebo and moxifloxacin (400 mg) arms to characterize the nature of the QT interval and to assess the efficacy of distribution-based analysis for QTc determination. Novel statistics using continuous means and bootstrapped 95% confidence intervals were developed to facilitate QT analysis. Machine-read QT values were compared with core laboratory semiautomated values for verification. RR intervals demonstrated repetitive protocol-dependent variations (50-250 milliseconds); QT intervals were normally distributed, spanning 60 to 100 milliseconds for each RR interval. Distribution-based analysis detected a moxifloxacin response identical to semiautomated analysis, but with reduced variability and improved statistical power, where n = 12 satisfied the ICH E14 criteria for a positive control. Distribution-based analysis has the potential to provide a universal method for clinical QT heart rate correction, enabling accurate detection of QT changes when limited numbers of volunteers are exposed to drug.