ReviewClinical pharmacology and therapeutics2021
Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective.
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 31 papers, 2 of them syntheses that pooled it.
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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.
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Who cites it
31 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- QT Prolongation Risk of Antibody-Drug Conjugates.Drug safety · 2026Pooled it
- Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes as an in vitro model in toxicology: strengths and weaknesses for hazard identification and risk characterization.Expert opinion on drug metabolism & toxicology · 2021Pooled it
- In silico modeling of methadone-related ion current effects to predict QT interval prolongation.Journal of pharmacokinetics and pharmacodynamics · 2026Article
- An Integrated Nonclinical and Clinical Risk Assessment of the Effects of Investigational ATRi Tuvusertib on QTc Interval in Patients With Solid Tumors.Clinical and translational science · 2026Article
- Lessons learned from QT prolongation risk assessment for antibody-drug conjugates in oncology.Journal of pharmacokinetics and pharmacodynamics · 2025Review
- Comparison of in silico predictions of action potential duration in response to inhibition of IKr and ICaL with new human ex vivo recordings.PLoS computational biology · 2025Article
- A comprehensive review of 20 years of progress in nonclinical QT evaluation and proarrhythmic assessment.Journal of pharmacokinetics and pharmacodynamics · 2025Review
- A three-dimensional high throughput assay identifies novel antibacterial molecules with activity against intracellular Shigella.npj antimicrobials and resistance · 2025Article
- 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
- TAK-994 mechanistic investigation into drug-induced liver injury.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Incorporating new approach methods (NAMs) data in dose-response assessments: The future is now!Journal of toxicology and environmental health. Part B, Critical reviews · 2025Review
- 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
- Association of anxiolytic drugs with Torsade de Pointes: a pharmacovigilance study of the Food and Drug Administration Adverse Event Reporting System.Journal of pharmaceutical policy and practice · 2024Article
- 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
Corrections and comments
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Authors and funding
34 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.
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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.