Skip to main content
SpringerLink
Log in

Dealing with Global Safety Issues

Was the Response to QT-Liability of Non-Cardiac Drugs Well Coordinated?

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Drug-induced torsade de pointes (TdP) is a potentially fatal iatrogenic entity. Its reporting rate in association with non-cardiac drugs increased exponentially from the early 1990s and was associated with an increasing number of new non-cardiac drugs whose proarrhythmic liability was not appreciated pre-marketing. This epidemic provoked a comprehensive global response from drug regulators, drug developers and academia, which resulted in stabilization of the reporting rate of TdP. This commentary reviews the chronology and nature of, and the reasons for, this response, examines its adequacy, and proposes future strategies for dealing with such iatrogenic epidemics more effectively. It is concluded that the response was piecemeal and lacked direction. No one entity was responsible, with the result that important contributions from regulators, industry and academia lacked coordination. While the process of dealing with QT crisis seemed to have worked reasonably well in this instance, it does not seem wise to expect the next crisis in drug development to be managed as well. Future crises will need better management and the challenge is to implement a system set up to respond globally and efficiently to a perceived drug-related hazard. In this regard, we discuss the roles of new tools the legislation has provided to the regulators and the value of an integrated expert assessment of all pre-approval data that may signal a potential safety issue in the postmarketing period. We also discuss the roles of other bodies such as the WHO Collaborating Centre for International Drug Monitoring, CIOMS and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bellet S, Finkelstein D. Significance of QT prolongation in the electrocardiogram: based on the study of 168 cases. Am J Med Sci. 1951;222:263–78.

    Article  PubMed  CAS  Google Scholar 

  2. Shah RR. Cardiac repolarisation and drug regulation: assessing cardiac safety 10 years after the CPMP guidance. Drug Saf. 2007;30:1093–110.

    Article  PubMed  Google Scholar 

  3. Morganroth J. QT interval prolongation: is it beneficial or harmful? Am J Cardiol. 1993;72:1–59B.

    Article  Google Scholar 

  4. Lipicky RJ. A viewpoint on drugs that prolong the QT interval. Am J Cardiol. 1993;72:53–54B.

    Article  Google Scholar 

  5. Roden DM. Current status of class III antiarrhythmic drug therapy. Am J Cardiol. 1993;72:44–49B.

    Article  Google Scholar 

  6. Botstein P. Is QT interval prolongation harmful? A regulatory perspective. Am J Cardiol. 1993;72:50–52B.

    Article  Google Scholar 

  7. Waldo AL, Camm AJ. deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival with oral d-Sotalol. Lancet. 1996;348:7–12.

    Article  PubMed  CAS  Google Scholar 

  8. Fung MC. Hsiao-hui Wu H, Kwong K, et al. Evaluation of the profile of patients with QT prolongation in spontaneous adverse event reporting over the past three decades – 1969–98. Pharmacoepidemiol Drug Saf. 2000;9(Suppl. 1):S24–5.

    Google Scholar 

  9. Wysowski DK, Corken A, Gallo-Torres H, et al. Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisapride and Food and Drug Administration regulatory actions. Am J Gastroenterol. 2001;96:1698–703.

    Article  PubMed  CAS  Google Scholar 

  10. Yap YG, Camm AJ. Drug-induced QT prolongation and torsades de pointes. Heart. 2003;89:1363–72.

    Article  PubMed  CAS  Google Scholar 

  11. Bohets H, Lavrijsen K, Hendrickx J, et al. Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co-medication interactions. Br J Pharmacol. 2000;129:1655–67.

    Article  PubMed  CAS  Google Scholar 

  12. Shah RR. Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics. 2006;7:889–908.

    Article  PubMed  CAS  Google Scholar 

  13. Clarke A, Deeks JJ, Shakir SAW. An assessment of the publicly disseminated evidence of safety used in decisions to withdraw medicinal products from the UK and US markets. Drug Saf. 2006;29:175–81.

    Article  PubMed  Google Scholar 

  14. Olivier P, Montastruc J-L. The nature of the scientific evidence leading to drug withdrawals for pharmacovigilance reasons in France. Pharmacoepidemiol Drug Saf. 2006;15:808–12.

    Article  PubMed  Google Scholar 

  15. Therapeutic Goods Administration, Australia. Update on TGA decision to cancel prescription pain-killers. 21 Jun 2012. Available from URL: http://www.tga.gov.au/newsroom/media-2012-dextropropoxyphen-120621.htm. Accessed 20 Jul 2012.

  16. European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products (CPMP). Opinion following an article 31 referral (cisapride). EMEA/CPMP/24844/02. London, 7 Oct 2002. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Cisapride_31/WC500013943.pdf. Accessed 5 Apr 2012.

  17. European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products (CPMP). Points to consider: the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. CPMP/986/96. London, 17 Dec 1997. Available from URL: http://www.fda.gov/ohrms/dockets/ac/03/briefing/pubs/cpmp.pdf. Accessed 5 Apr 2012.

  18. Pratt CM, Ruberg S, Morganroth J, et al. Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability. Am Heart J. 1996;131:472–80.

    Article  PubMed  CAS  Google Scholar 

  19. Food and Drug Administration. Briefing document for NDA 20-644 (Serdolect) Psychopharmacologic Drugs Advisory Committee (PDAC) Meeting. 7 Apr 2009. Available from URL: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM161901.pdf. Accessed 20 Jul 2012.

  20. European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products (CPMP). Opinion of the Committee for Proprietary Medicinal Products pursuant to article 10 of Council Directive 75/319/EEC as amended. Mizollen (CPMP/1034/96-EN). London, 18 Dec 1996. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Mizollen_29/WC500011164.pdf. Accessed 5 Apr 2012.

  21. European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products (CPMP). Note for guidance on the investigation of drug interactions. CPMP/EWP/560l95. London, 17 Dec 1997. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002966.pdf. Accessed 5 Apr 2012.

  22. Lessons from cisapride [editorial]. CMAJ 2001; 164: 1269.

    Google Scholar 

  23. Fenichel RR. Development of drugs that alter ventricular repolarization. Am J Ther. 2002;9:127–39.

    Article  PubMed  Google Scholar 

  24. Specification for annotated electrocardiographic waveform data in electronic format: request for comments. Fed Register 2003; 68: 22719.

  25. Food and Drug Administration. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Preliminary concept paper for discussion purposes only (Nov 15, 2002). Available from URL: http://www.fda.gov/ohrms/dockets/ac/03/briefing/pubs%5Cprelim.pdf. Accessed 23 Jul 2012.

  26. International Conference on Harmonization. Organization of ICH: Global Cooperation Group. Available from URL: http://www.ich.org/about/organisation-of-ich/coopgroup.html. Accessed 20 Jul 2012.

  27. European Agency for the Evaluation of Medicinal Products, Committee for Medicinal Products for Human Use. ICH note for guidance on the nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals (ICH S7B). CHMP/ICH/423/02. London, Nov 2005. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002841.pdf. Accessed 5 Apr 2012.

  28. European Agency for the Evaluation of Medicinal Products, Committee for Medicinal Products for Human Use. ICH note for guidance on the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (ICH E14). CHMP/ICH/2/04). London, Nov 2005. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002879.pdf. Accessed 5 Apr 2012.

  29. European Medicines Agency, Committee for Medicinal Products for Human Use. ICH Topic E14. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs: questions and answers. EMEA/CHMP/ICH/310133/2008. London, Jun 2008. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002878.pdf. Accessed 5 Apr 2012.

  30. Garnett CE, Beasley N, Bhattaram VA, et al. Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol. 2008;48:13–8.

    Article  PubMed  CAS  Google Scholar 

  31. Zhang J. Testing for positive control activity in a thorough QTc study. J Biopharm Stat. 2008;18:517–28.

    Article  PubMed  Google Scholar 

  32. Yan LK, Zhang J, Ng MJ, et al. Statistical characteristics of moxifloxacin-induced QTc effect. J Biopharm Stat. 2010;20:497–507.

    Article  PubMed  Google Scholar 

  33. Florian JA, Tornøe CW, Brundage R, et al. Population pharmacokinetic and concentration – QTc models for moxifloxacin: pooled analysis of 20 thorough QT studies. J Clin Pharmacol. 2011;51:1152–62.

    Article  PubMed  CAS  Google Scholar 

  34. Tornøe CW, Garnett CE, Wang Y, et al. Creation of a knowledge management system for QT analyses. J Clin Pharmacol. 2011;51:1035–42.

    Article  PubMed  Google Scholar 

  35. Malik M, Zhang J, Johannesen L, et al. Assessing electrocardiographic data quality and possible replacement of pharmacologic positive control in thorough QTc studies by investigations of drug-free QTc stability. Heart Rhythm. 2011;8:1777–85.

    Article  PubMed  Google Scholar 

  36. Antzelevitch C, Sun ZQ, Zhang ZQ, et al. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol. 1996;28:1836–48.

    Article  PubMed  CAS  Google Scholar 

  37. Hondeghem LM, Carlsson L, Duker G. Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation. 2001;103:2004–13.

    Article  PubMed  CAS  Google Scholar 

  38. Weissenburger J, Davy JM, Chézalviel F. Experimental models of torsades de pointes. Fundam Clin Pharmacol. 1993;7:29–38.

    Article  PubMed  CAS  Google Scholar 

  39. Warmke JW, Ganetzky B. A family of potassium channel genes related to eag in drosophila and mammals. Proc Natl Acad Sci USA. 1994;91:3438–42.

    Article  PubMed  CAS  Google Scholar 

  40. Ahmed SR, Wolfe SM. Cisapride and torsades de pointes. Lancet. 1995;345:508.

    Article  Google Scholar 

  41. Hoover CA, Carmichael JK, Nolan PE Jr, et al. Cardiac arrest associated with combination cisapride and itraconazole therapy. J Cardiovasc Pharmacol Ther. 1996;1:255–8.

    PubMed  CAS  Google Scholar 

  42. Rampe D, Roy ML, Dennis A, et al. A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. FEBS Lett. 1997;417:28–32.

    Article  PubMed  CAS  Google Scholar 

  43. Priori SG. Exploring the hidden danger of noncardiac drugs. J Cardiovasc Electrophysiol. 1998;9:1114–6.

    Article  PubMed  CAS  Google Scholar 

  44. Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J. 2000;21:1216–31.

    Article  PubMed  CAS  Google Scholar 

  45. Sponer G. Prolongation of repolarization in pre-clinical investigations and phase I/II clinical trials: what should be done? Eur Heart J Supplements. 2001;3(Suppl. K):K101–4.

    Article  CAS  Google Scholar 

  46. Morganroth J. Focus on issues in measuring and interpreting changes in the QTc interval duration. Eur Heart J Supplements. 2001;3(Suppl. K):K105–11.

    Article  Google Scholar 

  47. Carlsson L. Drug-induced torsade de pointes: the perspectives of industry. Eur Heart J Supplements. 2001;3(Suppl. K):K114–20.

    Article  CAS  Google Scholar 

  48. Anderson MD, Al-Khatib SM, Roden DM, et al. Cardiac repolarization: current knowledge, critical gaps, and new approaches to drug development and patient management. Am Heart J. 2002;144:769–81.

    PubMed  CAS  Google Scholar 

  49. Serra DB, Affrime MB, Bedigian MP, et al. QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M3 selective receptor antagonist for the treatment of overactive bladder. J Clin Pharmacol. 2005;45:1038–47.

    Article  PubMed  CAS  Google Scholar 

  50. Morganroth J, Ilson BE, Shaddinger BC, et al. Evaluation of vardenafil and sildenafil on cardiac repolarization. Am J Cardiol. 2004;93:1378–83.

    Article  PubMed  CAS  Google Scholar 

  51. Extramiana F, Maison-Blanche P, Cabanis MJ, et al. Clinical assessment of drug-induced QT prolongation in association with heart rate changes. Clin Pharmacol Ther. 2005;77:247–58.

    Article  PubMed  CAS  Google Scholar 

  52. Honig PK, Wortham DC, Hull R, et al. Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics. J Clin Pharmacol. 1993;33:1201–6.

    Article  PubMed  CAS  Google Scholar 

  53. Sarapa N, Morganroth J, Couderc JP, et al. Electrocardiographic identification of drug-induced QT prolongation: assessment by different recording and measurement methods. Ann Noninvasive Electrocardiol. 2004;9:48–57.

    Article  PubMed  Google Scholar 

  54. Hanson LA, Bass AS, Gintant G, et al. ILSI-HESI cardiovascular safety subcommittee initiative: evaluation of three non-clinical models of QT prolongation. J Pharmacol Toxicol Methods. 2006;54:116–29.

    Article  PubMed  CAS  Google Scholar 

  55. Bass AS, Darpo B, Breidenbach A, et al. International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes. Br J Pharmacol. 2008;154:1491–501.

    Article  PubMed  CAS  Google Scholar 

  56. Food and Drug Administration. Cardiac Safety Research Consortium (CSRC). Available from URL: http://www.fda.gov/AboutFDA/PartnershipsCollaborations/PublicPrivatePartnershipProgram/ucm231121.htm. Accessed 5 Apr 2012.

  57. Rock EP, Finkle J, Fingert HJ, et al. Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am Heart J. 2009;157:827–36.

    Article  PubMed  CAS  Google Scholar 

  58. Min SS, Turner JR, Nada A, et al. Evaluation of ventricular arrhythmias in early clinical pharmacology trials and potential consequences for later development. Am Heart J. 2010;159:716–29.

    Article  PubMed  Google Scholar 

  59. Kligfield P, Green CL, Mortara J, et al. The Cardiac Safety Research Consortium electrocardiogram warehouse: thorough QT database specifications and principles of use for algorithm development and testing. Am Heart J. 2010;160:1023–8.

    Article  PubMed  Google Scholar 

  60. Rodriguez I, Erdman A, Padhi D, et al. Electrocardiographic assessment for therapeutic proteins: scientific discussion. Am Heart J. 2010;160:627–34.

    Article  PubMed  Google Scholar 

  61. FDA/PhRMA Task Force to assess QT risk by preclinical markers. Pink Sheet 1999; 61: 15.

    Google Scholar 

  62. Hammond TG, Carlsson L, Davis AS, et al. Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey. Cardiovasc Res. 2001;49:741–50.

    Article  PubMed  CAS  Google Scholar 

  63. Fenichel RR, Malik M, Antzelevitch C, et al. Drug-induced torsades de pointes and implications for drug development. J Cardiovasc Electrophysiol. 2004;15:475–95.

    Article  PubMed  Google Scholar 

  64. Redfern WS, Carlsson L, Davis AS, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res. 2003;58:32–45.

    Article  PubMed  CAS  Google Scholar 

  65. Hashimoto K. Torsades de pointes liability inter-model comparisons: the experience of the QT PRODACT initiative. Pharmacol Ther. 2008;119:195–8.

    Article  PubMed  CAS  Google Scholar 

  66. Dmitrienko A, Smith BP. Analysis of the QT interval in clinical trials. Drug Inf J. 2002;36:269–79.

    Google Scholar 

  67. Patterson SD, Agin M, Anziano R, et al. Investigating drug-induced QT and QTc prolongation in the clinic: a review of statistical design and analysis considerations. Report from the Pharmaceutical Research and Manufacturers of America QT Statistics Expert Team. Drug Inf J. 2005;39:243–66.

    Google Scholar 

  68. Antzelevitch C, Oliva A. Amplification of spatial dispersion of repolarization underlies sudden cardiac death associated with catecholaminergic polymorphic VT, long QT, short QT and Brugada syndromes. J Intern Med. 2006;259:48–58.

    Article  PubMed  CAS  Google Scholar 

  69. Jacobson I, Carlsson L, Duker G. Beat-by-beat QT interval variability, but not QT prolongation per se, predicts drug-induced torsades de pointes in the anaesthetised methoxamine-sensitized rabbit. J Pharmacol Toxicol Methods. 2011;63:40–6.

    Article  PubMed  CAS  Google Scholar 

  70. LaPointe NM, Kramer JM, Weinfurt KP, et al. Practitioner acceptance of the dofetilide risk-management program. Pharmacotherapy. 2002;22:1041–6.

    Article  PubMed  Google Scholar 

  71. LaPointe NM, Chen A, Hammill B, et al. Evaluation of the dofetilide risk-management program. Am Heart J. 2003;146:894–901.

    Article  Google Scholar 

  72. Shah RR. Drug-induced QT interval prolongation: regulatory perspectives and drug development. Ann Med. 2004;36(Suppl. 1):47–52.

    Article  PubMed  CAS  Google Scholar 

  73. De Bruin ML, Pettersson M, Meyboom RH, et al. Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death. Eur Heart J. 2005;26:590–7.

    Article  PubMed  Google Scholar 

  74. Oshiro C, Thorn CF, Roden DM, et al. KCNH2 pharmacogenomics summary. Pharmacogenet Genomics. 2010;20:775–7.

    Article  PubMed  CAS  Google Scholar 

  75. Gintant G. An evaluation of hERG current assay performance: translating preclinical safety studies to clinical QT prolongation. Pharmacol Ther. 2011;129:109–19.

    Article  PubMed  CAS  Google Scholar 

  76. CIOMS. Practical aspects of signal detection in pharmacovigilance. Report of CIOMS Working Group VIII. 2010. ISBN 92 9036 082 8. Available from URL: http://www.cioms.ch/publications/blurbs/WGVIIIblurbDRAFT.pdf. Accessed 25 Apr 2012.

  77. Health Level Seven International. Available from URL: www.hl7.org. Accessed 3 Jan 2013.

  78. Cardiac Safety Research Consortium. Available from URL: www.cardiac-safety.org. Accessed 3 Jan 2013.

  79. Hayashi S, Kii Y, Tabo M, et al. QT PRODACT: a multi-site study of in vitro action potential assays on 21 compounds in isolated guinea-pig papillary muscles. J Pharmacol Sci. 2005;99(5):423–541.

    Article  PubMed  CAS  Google Scholar 

  80. Metrics Champion Consortium. Available from URL: www.metricschampion.org. Accessed 3 Jan 2013.

  81. The WHO Uppsala Monitoring Centre. Available from URL: www.who-umc.org. Accessed 3 Jan 2013.

  82. CIOMS. Available from URL: www.cioms.ch. Accessed 3 Jan 2013.

  83. International Conference on Harmonization. Available from URL: www.ich.org. Accessed 3 Jan 2013.

Download references

Acknowledgments

The authors have not received any financial support for writing this commentary. Norman Stockbridge and Christine Garnett have no other affiliations or interests except at the FDA. Christine Garnett’s current affiliation is Certara, Cary, NC, USA. Joel Morganroth is the Chief Cardiac Consultant of eResearch Technology Inc. (ERT), Philadelphia, PA, USA, which provides cardiac safety services to the drug development community. Rashmi Shah was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency, London, UK, and the ICH E14 Topic Leader, representing the EU. Both Joel Morganroth and Rashmi Shah now provide expert consultancy services on the development of new drugs to a number of pharmaceutical companies.

Disclaimer

The views and opinions expressed in this review are those of the authors and do not necessarily represent the views or opinions of their affiliate organizations, any of the regulatory authorities or their advisory committees.

Author information

Authors and Affiliations

  1. Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA

    Norman Stockbridge

  2. eResearch Technology, 1818 Market Street #1000, Philadelphia, PA, 19103, USA

    Joel Morganroth

  3. Rashmi Shah Consultancy Ltd, Gerrards Cross, UK

    Rashmi R. Shah

  4. Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US FDA, Silver Spring, MD, USA

    Christine Garnett

Authors
  1. Norman Stockbridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joel Morganroth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rashmi R. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christine Garnett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joel Morganroth.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stockbridge, N., Morganroth, J., Shah, R.R. et al. Dealing with Global Safety Issues. Drug Saf 36, 167–182 (2013). https://doi.org/10.1007/s40264-013-0016-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-013-0016-z

Keywords

Search

Navigation