Detection of QTc Effects in Small Studies—Implications for Replacing the Thorough QT Study

Ferber, Georg; Zhou, Meijian; Darpö, Börje

doi:10.1111/anec.12227

Cited by 53 publications

(71 citation statements)

References 17 publications

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“…A large number of small studies with 6-18 subjects receiving active treatment and six receiving placebo was simulated with data from five TQT studies; three studies with moxifloxacin with mean peak DDQTcF effect of 12.5, 14.0, and 8.0 ms, one study with ketoconazole with a smaller QT effect (DDQTcF 7.6 ms), and one TQT study with a drug with a larger effect (DDQTcF 26 ms). A total of 1000 studies were simulated for each of five sample sizes of subjects on active treatment (n = 6, 9, 12, 15, and 18) for each study, i.e., a total of 25,000 studies [39]. The criterion for negative QT assessment was based on ER analysis and was the same as in this study, i.e., a QT effect (DDQTcF) exceeding 10 ms should be excluded.…”

Section: Lack Of Positive Controlmentioning

confidence: 99%

“…These simulations lend support to the claim that the risk of false-negative results is low when ER analysis is applied to data from small studies with drugs that have a threshold QT effect but call for confirmation from real-life studies. The rate of false positives is obviously also of interest, since a high rate would be ineffective from a resource perspective: this rate was below 20 % with nine subjects receiving active (six receiving placebo) and near or below 10 % with 12 subjects in the simulation study discussed above [39]. Which rate of false positives is acceptable will most likely vary among drug developers, since in these cases additional studies would be needed.…”

Section: Lack Of Positive Controlmentioning

confidence: 99%

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Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

et al. 2015

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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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Section: Lack Of Positive Controlmentioning

confidence: 99%

Section: Lack Of Positive Controlmentioning

confidence: 99%

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

et al. 2015

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“…Using subsampling simulation techniques and data from TQT studies, we were also able to confirm the ability of the method to control the rate of false-positives and falsenegatives with similar sample sizes [17].…”

Section: Alternatives To a Tqt Studymentioning

confidence: 72%

A Comparison of Methods for Thorough QT Analysis for the Assessment of Cardiac Safety

Ferber

Johannesen

2015

Pharm Med

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Ten years after the adoption of the E14 guideline of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) on ''The clinical evaluation of QT/ QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs'' the discussion of new methods for the clinical assessment of this potential has intensified in two arenas: more powerful methods of statistical analysis allow to reliably exclude a prolongation of the QT interval corrected for heart rate (QTc) of regulatory concern based on data from Phase I single or multiple ascending dose (SAD/MAD) studies and more specific biomarkers than the QTc interval itself have been established. Key PointsMethodology to replace the Thorough QT (TQT) study by ECG measurements obtained from routine Phase I studies has matured and has successfully been used to waive a TQT/QTc study.Novel ECG parameters, in particular J-T peak c are more specific to detect the presence of inward current block likely associated with a lower risk of torsade de pointes.

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“…Recent data from five thorough QT studies (Ferber et al, 2015) utilized access to continuous Holter recordings to further decrease variability in QT measurements by analyzing a larger number of beats.…”

Section: Drug Trials and Safety (Qt And Arrhythmia Evaluation)mentioning

confidence: 99%

2017 ISHNE-HRS expert consensus statement on ambulatory ECG and external cardiac monitoring/telemetry

Steinberg

Varma

Cygankiewicz

et al. 2017

Ann Noninvasive Electrocardiol

103

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Detection of QTc Effects in Small Studies—Implications for Replacing the Thorough QT Study

Abstract: For drugs with a QTc effect of around 12-14 ms, exposure response analysis applied to First-in-Man studies with careful ECG assessment can be used to replace the through QT study.

Cited by 53 publications

References 17 publications

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

A Comparison of Methods for Thorough QT Analysis for the Assessment of Cardiac Safety

2017 ISHNE-HRS expert consensus statement on ambulatory ECG and external cardiac monitoring/telemetry

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