ArticleDrug safety2015
Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14.
Article in Drug safety, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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
31 citing papers in PubMed.
- Evaluation of the Effect of Loperamide on the Cardiac Repolarization Interval Using Exposure-Response Analysis.Clinical and translational science · 2025Trial
- Population pharmacokinetic/pharmacodynamic modeling of nifekalant injection with varies dosing plan in Chinese volunteers: a randomized, blind, placebo-controlled study.Journal of pharmacokinetics and pharmacodynamics · 2024Trial
- Abemaciclib does not increase the corrected QT interval in healthy participants.Clinical and translational science · 2023Trial
- First-in-Human Single-Ascending-Dose, Multiple-Dose, and Food Interaction Studies of NRD.E1, an Innovative Nonopioid Therapy for Painful Diabetic Peripheral Neuropathy.Clinical pharmacology in drug development · 2022Trial
- A randomized, double-blind, placebo- and positive-controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects.Clinical and translational science · 2021Trial
- Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study of the Effects of Tebipenem Pivoxil Hydrobromide on QT/QTc Intervals in Healthy Subjects.Antimicrobial agents and chemotherapy · 2021Trial
- PKPD and cardiac single cell modeling of a DDI study with a CYP3A4 substrate and itraconazole to quantify the effects on QT interval duration.Journal of pharmacokinetics and pharmacodynamics · 2020Trial
- No QTc Prolongation With Zanubrutinib: Results of Concentration-QTc Analysis From a Thorough QT Study in Healthy Subjects.Clinical and translational science · 2020Trial
- Trial
- Evaluation of the Cardiac Safety of Long-Acting Endectocide Moxidectin in a Randomized Concentration-QT Study.Clinical and translational science · 2018Trial
- Estimation of the Power of the Food Effect on QTc to Show Assay Sensitivity.Journal of clinical pharmacology · 2018Trial
- Lack of QT Prolongation for 2'-O-Methoxyethyl-Modified Antisense Oligonucleotides Based on Retrospective Exposure/Response Analysis of Ten Phase 1 Dose-Escalation Placebo-Controlled Studies in Healthy Subjects.Nucleic acid therapeutics · 2017Trial
- Detecting moxifloxacin-induced QTc prolongation in thorough QT and early clinical phase studies using a highly automated ECG analysis approach.British journal of pharmacology · 2016Trial
- Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.PloS one · 2016Trial
- Platform Assessment of Concentration-QTc Relationship Across GalNAc-siRNA Molecules.Clinical pharmacokinetics · 2026Article
- The evolving role of investigative toxicology in the pharmaceutical industry.Nature reviews. Drug discovery · 2023Review
- ECG Evaluation as Part of the Clinical Pharmacology Strategy in the Development of New Drugs: A Review of Current Practices and Opportunities Based on Five Case Studies.Journal of clinical pharmacology · 2022Review
- The New S7B/E14 Question and Answer Draft Guidance for Industry: Contents and Commentary.Journal of clinical pharmacology · 2021Review
- Collaborations between Clinical Pharmacologists in Japan and in the United States - Report from the IQ CPLG and JPMA CPTF Meeting in Tokyo, Japan.Clinical and translational science · 2021Review
- Application of Trial Simulation in the Design of a Prospective Study for Concentration-QTc Analysis in Support of a Thorough QT Study Waiver.The AAPS journal · 2020Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Exposure-response (ER) analysis has evolved as an important tool to evaluate the effect of a drug on cardiac repolarization, as reflected in the QTc interval. It has been suggested that careful electrocardiogram (ECG) evaluation in 'first-in-human' studies using ER analysis could replace or serve as an alternative to the E14 'thorough QT' study. This commentary shares and discusses the results of a recently conducted study with the objective to evaluate this approach. Six drugs with a well-characterized QT effect, five of which are known QT prolongers, were evaluated in a study design similar to a conventional single-ascending-dose study. Each drug was given to nine healthy subjects (six for placebo) in two dose levels, which for the positive drugs (ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide) were chosen with the intent to cause 10-12 ms and 15-20 ms QTc prolongation. Replicate 12-lead ECGs were extracted from continuous recordings pre-dose and serially after dosing and paired with drug concentration determinations. The ER criteria for the identification of a QT effect, a statistically significant positive ER slope and an effect above 10 ms, were met with all five positive drugs, and an effect exceeding 10 ms could be excluded at the supratherapeutic dose of the negative drug, levocetirizine. The study results thereby provided evidence to support that careful QT assessment in early phase clinical studies can be used as an alternative to the thorough QT study. Clinical and regulatory implications, as well as limitations of this approach, are discussed in the commentary.
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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.