ReviewClinical pharmacology and therapeutics2021
Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates).
Review in Clinical pharmacology and therapeutics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 93 citations in OpenAlex.
- Ten years of using key characteristics of human carcinogens to organize and evaluate mechanistic evidence in IARC Monographs on the identification of carcinogenic hazards to humans: Patterns and associations.Toxicological sciences : an official journal of the Society of Toxicology · 2024Pooled it
- Results of a Phase 1 Study Assessing the Effect of CIN-102, a Novel Formulation of the Dopamine Receptor Antagonist Domperidone Designed to Treat Gastroparesis, on Cardiac Repolarization in Healthy Volunteers.Clinical pharmacology in drug development · 2026Trial
- Impact of Daridorexant, a Dual Orexin Receptor Antagonist, on Cardiac Repolarization Following Bedtime Dosing: Results from a Thorough QT Study Using Concentration-QT Analysis.Clinical drug investigation · 2021Trial
- Motif-Level Graph Learning Enables Interpretable Prediction of Drug-Induced QT Prolongation via Cooperative Substructural Determinants.International journal of molecular sciences · 2026Article
- Computational modelling for improved translation of cardiac inotropic and lusitropic drug effects from rats to humans.Journal of pharmacological and toxicological methods · 2025Article
- A comprehensive review of 20 years of progress in nonclinical QT evaluation and proarrhythmic assessment.Journal of pharmacokinetics and pharmacodynamics · 2025Review
- Computational modelling of biological systems now and then: revisiting tools and visions from the beginning of the century.Philosophical transactions. Series A, Mathematical, physical, and engineering sciences · 2025Review
- Restraint-Based ECG and Arterial Pressure Assessment Do Not Reliably Detect Drug Induced QTc Prolongation and Hypotension: Evidence From Case Studies.Clinical and translational science · 2025Article
- A "one-step" approach to heart rate correction and statistical analysis applied to conscious dog QTc studies.Clinical and translational science · 2024Article
- The state of the art in secondary pharmacology and its impact on the safety of new medicines.Nature reviews. Drug discovery · 2024Review
- Article
- An In Silico Platform to Predict Cardiotoxicity Risk of Anti-tumor Drug Combination with hiPSC-CMs Based In Vitro Study.Pharmaceutical research · 2024Article
- Neural network emulation of the human ventricular cardiomyocyte action potential: a tool for more efficient computation in pharmacological studies.bioRxiv : the preprint server for biology · 2023Article
- The "One-Step" approach for QT analysis increases the sensitivity of nonclinical QTc analysis.Clinical and translational science · 2023Article
- The evolving role of investigative toxicology in the pharmaceutical industry.Nature reviews. Drug discovery · 2023Review
- Evaluation of levocetirizine in beagle dog and cynomolgus monkey telemetry assays: Defining the no QTc effect profile by timepoint and concentration-QTc analysis.Clinical and translational science · 2023Article
- How to Successfully Generate an Alternative Approach to a Thorough QT Study: GLPG1972 as an Example.Clinical pharmacology and therapeutics · 2023Article
- Predicting human cardiac QT alterations and pro-arrhythmic effects of compounds with a 3D beating heart-on-chip platform.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Methadone Blockade of Cardiac Inward Rectifier KJournal of the American Heart Association · 2022Article
- The Challenges of Predicting Drug-Induced QTc Prolongation in Humans.Toxicological sciences : an official journal of the Society of Toxicology · 2022Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
After multiple drugs were removed from the market secondary to drug-induced torsade de pointes (TdP) risk, the International Council for Harmonisation (ICH) released guidelines in 2005 that focused on the nonclinical (S7B) and clinical (E14) assessment of surrogate biomarkers for TdP. Recently, Vargas et al. published a pharmaceutical-industry perspective making the case that "double-negative" nonclinical data (negative in vitro hERG and in vivo heart-rate corrected QT (QTc) assays) are associated with such low probability of clinical QTc prolongation and TdP that potentially all double-negative drugs would not need detailed clinical QTc evaluation. Subsequently, the ICH released a new E14/S7B Draft Guideline containing Questions and Answers (Q&As) that defined ways that double-negative nonclinical data could be used to reduce the number of "Thorough QT" (TQT) studies and reach a low-risk determination when a TQT or equivalent could not be performed. We review the Vargas et al. proposal in the context of what was contained in the ICH E14/S7B Draft Guideline and what was proposed by the ICH E14/S7B working group for a "stage 2" of updates (potential expanded roles for nonclinical data and details for assessing TdP risk of QTc-prolonging drugs). Although we do not agree with the exact probability statistics in the Vargas et al. paper because of limitations in the underlying datasets, we show how more modest predictive value of individual assays could still result in low probability for TdP with double-negative findings. Furthermore, we expect that the predictive value of the nonclinical assays will improve with implementation of the new ICH E14/S7B Draft Guideline.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.