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Electrocardiographic Data Quality in Thorough QT/QTc Studies

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Abstract

Background

Most drugs with systemic bioavailability have to undergo a thorough QT (TQT) study, which includes a pharmacologic positive control. A set of QTc-quality tests was recently proposed with the possible aim of removing the need for a positive control.

Objective

We evaluated the influence of QT measurement and QTc computation methodology on the proposed QTc-quality tests.

Methods

The baseline ECG waveforms and fiducial points were retrieved from 34 crossover TQT studies that had full-day baseline ECGs prior to each study period. The QT measurement methodology and recorder type were retrieved from study reports. The influence of QTc computation methodology was investigated by applying the pattern-matching technique and/or using the 10-s average heart rate.

Results

There were no statistical differences in any QTc-quality test values between studies using continuous or 10-s bedside recordings and, in a subset of the quality test, an increase of data quality for semi-automatically read studies compared with those manually read (p < 0.01). There was a significant improvement (p < 0.01) in all the QTc-quality test values for QTc measurements obtained by using pattern matching with or without 10-s average heart rate in comparison to the original QTc measurements.

Conclusion

The findings suggest that QTc quality is mostly driven by the QTc measurement methodology rather than other study-related factors.

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References

  1. ICH. Guidance for Industry E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 2005.

  2. ICH. Guidance for industry E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Questions and answers; 2008.

  3. Malik M, Zhang J, Johannesen L, Hnatkova K, Garnett C. Assessing electrocardiographic data quality and possible replacement of pharmacological positive control in thorough QT/QTc studies by investigations of drug-free QTc stability. Heart Rhythm. 2011;8(11):1777–85.

    Article  PubMed  Google Scholar 

  4. Johannesen L, Garnett C, Malik M. Impact of electrocardiographic data quality on moxifloxacin response in thorough QT/QTc studies. Drug Saf. 2014. doi:10.1007/s40264-014-0142-2

  5. Hnatkova K, Smetana P, Toman O, Bauer A, Schmidt G, Malik M. Systematic comparisons of electrocardiographic morphology increase the precision of QT interval measurement. Pacing Clin Electrophysiol. 2009;32(1):119–30.

    Article  PubMed  Google Scholar 

  6. Fridericia LS. Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken. Acta Med Scand. 1920;54(1):170.

    Google Scholar 

  7. Badilini F, Vaglio M, Sarapa N. Automatic extraction of ECG strips from continuous 12-lead Holter recordings for QT analysis at prescheduled versus optimized time points. Ann Noninvasive Electrocardiol. 2009;14(Suppl 1):S22–9.

    Article  PubMed  Google Scholar 

  8. Meyer O, Ferber G, Greig G, Holzgrefe HH. Pattern recognition analysis of digital ECGs: decreased QT measurement error and improved precision compared to semi-automated methods. J Electrocardiol. 2013;46(2):118–25.

    Article  PubMed  Google Scholar 

  9. Malik M, Hnatkova K, Novotny T, Schmidt G. Subject-specific profiles of QT/RR hysteresis. Am J Physiol Heart Circ Physiol. 2008;295(6):H2356–63.

    Article  CAS  PubMed  Google Scholar 

  10. Natekar M, Hingorani P, Gupta P, Karnad DR, Kothari S, de Vries M, et al. Effect of number of replicate electrocardiograms recorded at each time point in a thorough QT study on sample size and study cost. J Clin Pharmacol. 2011;51(6):908–14.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The opinions presented here are those of the authors and no official support or endorsement by the FDA is intended or should be inferred. Marek Malik is an Honorary ORISE Research Fellow of the FDA. Lars Johannesen, Christine Garnett, and Marek Malik have no conflicts of interest directly related to this article.

The authors are grateful to Dr. Norman Stockbridge of the FDA for his substantial guidance on the topic and his help with preparing this manuscript. This project was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA.

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Authors and Affiliations

  1. Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA

    Lars Johannesen & Christine Garnett

  2. Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Lars Johannesen

  3. Certara, Cary, NC, USA

    Christine Garnett

  4. St. Paul’s Cardiac Electrophysiology, University of London, and Imperial College, London, UK

    Marek Malik

  5. US FDA, 10903 New Hampshire Avenue, Bldg 62, RM 2127E, Silver Spring, MD, 20993, USA

    Lars Johannesen

Authors
  1. Lars Johannesen
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  2. Christine Garnett
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  3. Marek Malik
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Corresponding author

Correspondence to Lars Johannesen.

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Johannesen, L., Garnett, C. & Malik, M. Electrocardiographic Data Quality in Thorough QT/QTc Studies. Drug Saf 37, 191–197 (2014). https://doi.org/10.1007/s40264-014-0140-4

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  • DOI: https://doi.org/10.1007/s40264-014-0140-4

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