Detection of Clinically Significant QTc Prolongation in Phase I Studies in Healthy Participants: Comparison of 2 Semiautomated QT Measurement Methods

Sarapa, Nenad; Francom, Steven F.; Azzam, Sara; Wickremasingha, Prachi; Tyl, Benoît

doi:10.1177/0091270008326717

Cited by 7 publications

(6 citation statements)

References 23 publications

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“…Evidently, automated measurement techniques, provided these are proven reliable for the detection of small QT changes, would represent an important opportunity to conduct TQT studies more efficiently, as both 'fully manual and manually adjudicated' techniques are laborious and resource intensive. The utility of fully or partially automated measurement techniques has been compared with manual techniques in a number of studies and these techniques have been shown to produce similar results when tested on drugs with a QT prolonging effect (Azie et al, 2004;Sarapa et al, 2004;Darpo et al, 2006a;Fosser et al, 2009;Sarapa et al, 2009a). It has also been shown that different techniques generate different absolute QT intervals (Kligfield et al, 2006;Kligfield et al, 2007), and that some automated techniques consistently demonstrate the same QTc effect measured as change from baseline as manual techniques.…”

Section: Emerging Methods For Qt Interval Measurementsmentioning

confidence: 99%

The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance

Darpö

2010

British J Pharmacology

134

148

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The ICH E14 guidance on how to clinically assess a new drug's liability to prolong the QT interval was adopted in May 2005. A centre-piece of the guidance was the establishment of one single trial, the 'thorough QT/QTcstudy', intended to confidently identify drugs that may cause QT prolongation. Initially perceived as a great challenge, this study has rapidly become a standard component of all clinical development programs for new molecular entities. The study is normally conducted in healthy volunteers, includes both a positive and a negative (placebo) control and is stringently powered to exclude an effect on the QTc interval exceeding 10 ms. The E14 guidance was intentionally not very prescriptive and allowed sponsors and service providers to explore new methodologies. This has allowed for a rapid development of new methods during the first years after the guidance's implementation, such as computer-assisted algorithms for QT measurements. Regulators have worked in close collaboration with pharmaceutical industry to set standards for the design and conduct of the 'thorough QT/QTc study', which therefore has evolved as a key component of cardiac safety assessment of new drugs. This paper summarizes the requirements on the 'thorough QT/QTc study' with emphasis on the standard that has evolved based on interactions between regulators and sponsors and the experience from a large number of completed studies.

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Section: Emerging Methods For Qt Interval Measurementsmentioning

confidence: 99%

The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance

Darpö

2010

British J Pharmacology

134

148

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“…Even though there appears to be a limitation to the extent that variability can be reduced with replicates of intervals measured with a semiautomated technique, this does not seem to hold true for other techniques, which do not blend computer-based and manually performed interval measurements. The utility of fully or partially automated measurement techniques has been compared with manual techniques in a number of studies, and these techniques have been shown to produce similar results when tested on drugs with a QT-prolonging effect (Azie et al 2004;Darpo et al 2006;Sarapa et al 2004Sarapa et al , 2009Fosser et al 2009). It has also been shown that different techniques generate different absolute QT intervals (Kligfield et al 2006(Kligfield et al , 2007 and that some automated techniques consistently demonstrate the same QTc effect measured as change from baseline as manual techniques.…”

Section: Ecg Recordings and Qt Interval Measurementsmentioning

confidence: 99%

Clinical ECG Assessment

Darpö

2015

Principles of Safety Pharmacology

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With the adoption of the ICH E14 guidance, the thorough QT/QTc (TQT) study has become the focus of clinical assessment of an NCE's effects on ECG parameters. The TQT study is used as a guide to the liability of a drug to cause proarrhythmias on the basis of delayed cardiac repolarization. Around 300 TQT studies have been performed since 2005 and through interactions between sponsors and regulators, especially FDA's Interdisciplinary Review Team (IRT) for QT studies. These studies can today be performed more effectively and with great confidence in the generated data. This chapter will discuss technical features and the design and analysis of TQT studies, how assay sensitivity is demonstrated, and examples from recently conducted studies. ECG assessment for drugs that cannot be safely given to healthy volunteers is also addressed, and examples from studies in cancer patients and in healthy volunteers with tyrosine kinase inhibitors are discussed. The TQT study is resource intensive and designed to solely evaluate whether an NCE prolongs the QTc interval. If data with similar confidence can be generated from other studies that are routinely performed as part of the clinical development, this would represent a more optimal use of human resources. Methods and approaches to increase the confidence in ECG data derived from "early QT assessment" in single-ascending/multiple-ascending dose studies are therefore discussed, and a path toward replacing the TQT study using these approaches will be outlined.

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“…21 The intervals can be measured on multiple leads acquired simultaneously, either by incorporating all representative complexes into a single global complex or by the superimposition of all representative complexes (SIRC). [22][23][24] Use of representative complexes is now more commonly accepted. A recent ICH E14 Q&A document describes the most commonly used methods but does not address their relative performance.…”

Section: P Rolongation Of Cardiac Repolarization Can Causementioning

confidence: 99%

“…Recently, semiautomated methods, in which a trained analyst adjusts fiducial points placed by an automated algorithm, have been advocated. [23][24][25] This approach combines the often accurate approximation of automated interval measurements and the precision of manual adjustments.…”

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confidence: 99%

Comparison of Semiautomated and Fully Automated Methods for QT Measurement During a Thorough QT/QTc Study: Variability and Sample Size Considerations

Tyl¹,

Kabbaj

Fassi³

et al. 2009

The Journal of Clinical Pharma

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This study compares the ability of 2 semiautomated methods with a fully automated method for QT measurement to minimize the sample size required to detect a moxifloxacin effect and exclude a placebo effect in a thorough QT/QTc study. The fully automated and 1 of 2 semiautomated methods used a global QT measurement in 12 leads, whereas the other semiautomated method used a tangent method on single lead raw complexes. Mean QTcF intervals were greater when measured on a global QT electrocardiogram than on raw complexes, but the mean magnitudes of DeltaQTcF were similar for all methods. The 3 methods detected a statistically significant increase in QTcF for moxifloxacin compared to placebo and were able to exclude a placebo effect on QTcF in all 62 participants. However, due to a smaller variability, the semiautomated methods allowed these detections with fewer than 20 participants, whereas the fully automated required at least 27 participants.

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Detection of Clinically Significant QTc Prolongation in Phase I Studies in Healthy Participants: Comparison of 2 Semiautomated QT Measurement Methods

Cited by 7 publications

References 23 publications

The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance

The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance

Clinical ECG Assessment

Comparison of Semiautomated and Fully Automated Methods for QT Measurement During a Thorough QT/QTc Study: Variability and Sample Size Considerations

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