ReviewDrug safety2012
Early investigation of QTc liability: the role of multiple ascending dose (MAD) study.
Review in Drug safety, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 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
16 citing papers in PubMed.
- Evaluation of the Effect of Contezolid (MRX-I) on the Corrected QT Interval in a Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study in Healthy Chinese Volunteers.Antimicrobial agents and chemotherapy · 2020Trial
- Comparison of Digital 12-Lead ECG and Digital 12-Lead Holter ECG Recordings in Healthy Male Subjects: Results from a Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc · 2016Trial
- Can an early phase clinical pharmacology study replace a thorough QT study? Experience with a novel H3-receptor antagonist/inverse agonist.European journal of clinical pharmacology · 2016Trial
- Establishing assay sensitivity in QT studies: experience with the use of moxifloxacin in an early phase clinical pharmacology study and comparison with its effect in a thorough QT study.European journal of clinical pharmacology · 2015Trial
- Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study.British journal of clinical pharmacology · 2015Trial
- Exposure-response analysis of adverse events associated with molibresib and its active metabolites in patients with solid tumors.CPT: pharmacometrics & systems pharmacology · 2022Article
- Cardiac risk assessment based on early Phase I data and PK-QTc analysis is concordant with the outcome of thorough QTc trials: an assessment based on eleven drug candidates.Journal of pharmacokinetics and pharmacodynamics · 2019Article
- Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies.British journal of pharmacology · 2017Article
- Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14.Drug safety · 2015Article
- Detection of QTc effects in small studies--implications for replacing the thorough QT study.Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc · 2015Article
- ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies.British journal of clinical pharmacology · 2015Article
- The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling Simulation Study.BioMed research international · 2015Article
- Evaluating the Use of Linear Mixed-Effect Models for Inference of the Concentration-QTc Slope Estimate as a Surrogate for a Biological QTc Model.CPT: pharmacometrics & systems pharmacology · 2015Article
- Replacing the thorough QT study: reflections of a baby in the bath water.British journal of clinical pharmacology · 2014Article
- The IQ-CSRC prospective clinical Phase 1 study: "Can early QT assessment using exposure response analysis replace the thorough QT study?".Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc · 2014Review
- Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval).Drug safety · 2013Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The International Conference on Harmonization (ICH) guidance note E14 requires a thorough QT (TQT) study to characterize proactively the potential of a new drug to affect cardiac repolarization, as determined by prolongation of the corrected QT (QTc) interval. A typical TQT study is reviewed herein with a discussion on various practical issues concerning the use of a supratherapeutic dose, establishing assay sensitivity, the application of QT rate-correction methods, and restricting analyses of ECGs and plasma samples to key timepoints. We then discuss, and provide examples of, how multiple ascending dose (MAD) study protocols can be modified to integrate robust ECG monitoring and analyses to gather key information provided by a TQT study. Among the main advantages of this approach are the ability to study the ECG effects of a wide range of doses to the maximum tolerated doses, eliminating routine analyses at unnecessary timepoints, making early go-no-go decisions, making phase II studies more efficient and, if necessary, being able to implement rigorous ECG monitoring in populations and pivotal studies of regulatory interest. If clear evidence for the presence or absence of QTc effect is found, the data from a modified MAD study may support a request for a waiver from the requirement to conduct a TQT study. In the event that a TQT study is considered unnecessary, there are obvious significant savings without compromising collection of vital safety data.
Indexed as
Identifiers
22845313What 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.