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
Restricted accessOtherFirst published online July, 2005
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
The dangers inherent to the public via the use of drugs known to prolong the QT and QTc interval such as terfenadine and cisapride call for a careful evaluation of this potential in drug development. Methods in development for this assessment in preclinical and clinical development are reviewed, and statistical issues in the design and analysis of clinical trials used to assess this potential are described. Methods, measurement, and analysis are illustrated using data from clinical trials, and issues in the analysis and interpretation of data are developed. It is recommended that the statistical rigor of the International Conference on Harmonisation guidance currently in development for clinical assessment be enhanced and that further research be conducted in the choice of endpoints, testing of hypotheses, and interpretation of QT and QTc data.
PrioriSGRisk stratification in long QT syndrome. New Engl J Med.2003;348:1866–1874.
2.
MorganrothJVariability of the QT interval in healthy men. Am J Cardiology.1991;67:774–776.
3.
MossAJMeasurement of the QT Interval and the risk associated with QT interval prolongation. Am J Cardiology.1993;72:23B–25B.
4.
MolnarJDiurnal pattern of QT interval: How long is prolonged?J Am Coll Cardiology.1996;21:76–83.
5.
MalikMCammAJEvaluation of drug-induced QT interval prolongation. Drug Safety.2001;24: 323–351.
6.
MossAJDrugs that prolong the QT interval: Regulatory and QT-measurement issues from the USA and European perspectives. Ann Non-Invasive Electrocardiology.2003 (In press).
7.
Al-KhatibSMWhat clinicians should know about the QT interval. JAMA.2003;289: 2120–2127.
8.
PrattCMDose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: Distinguishing drug effect from spontaneous variability. Am Heart J.1996;131:472–480.
9.
PrattCMRisk of developing life-threatening ventricular arrhythmia associated with terfenadine in comparison with other over the counter antihistamines. Am J Cardiology.1994;73: 346–352.
10.
HonigPKChanges in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther.1992;52: 231–238.
11.
WysowskiDKPostmarketing reports of QT prolongation and ventricular arrhythmia in association with Cisapride and FDA Regulatory Actions. Am J Gastroenterology.2001;96: 1698–1703.
12.
TempleB.Overview of the concept paper: History of the QT/TdP concern. Paper presented at: DIA/FDA Workshop on QTc Prolongation; January 13, 2003; Rockville, MD.
13.
De PontiFOrganising evidence on QT prolongation and occurrence of Torsades de Pointes with non-arrythmic drugs. European J Clin Pharmacol.2001;57:185–209.
14.
DmitrienkoASmithBPAnalysis of the QT interval in clinical trials. Drug Inf J.2002;36: 269–279.
15.
U.S. Food and Drug Administration. TPD Preliminary concept paper. The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrythmic Potential for Non-arrythmic Drug Products.Rockville, MD: U.S. Food and Drug Administration; Released on November 15, 2002, revised on February 6, 2003.
16.
Committee for Proprietary Medicinal Products.Points to Consider: The Assessment of the Potential for QT Interval Prolongation by Non-cardiovascular Products.Committee for Proprietary Medicinal Products; 1997. http://www.emed.eu.int/index/indexhl.htm.
17.
International Conference for Harmonisation.(ICH) S7B Guidance. Guideline on Safety Pharmacology Studies for Assessing the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals.Geneva, Switzerland: International Conference for Harmonisation; 2003.
18.
SennS.Cross-over Trials in Clinical Research.2nd edition. New York: Wiley; 2002.
19.
JonesBKenwardMGDesign and Analysis of Cross-over Trials.2nd edition.London: Chapman and Hall; 2003.
20.
AginMKazieradDAbelRAnzianoRBillingWLaytonGMancusoJStrieterDXuWBlumRJorkaskyD.Assessing QT Variability in Healthy Volunteers. Pfizer Global Research and Development, Groton, CT, Ann Arbor, Ml, Sandwich, UK, Buffalo Clinical Research Center, Buffalo, NY. ACCP Meeting, September 2003.
21.
HinkelmannKKempthorneO.Design and Analysis of Experiments, Volume 1: Introduction to Experimental Design.New York: John Wiley and Sons; 1994.
22.
FrisonLPocockSJRepeated measures in clinical trials: Analysis using mean summary statistics and its implications for design. Stat Med.1992;11:1685–1704.
23.
WebberDMMeta-analysis of QTc interval—pooling data from heterogeneous trials. Pharma Stat.2002;1:17–23.
24.
BauerPRohmelJMaurerWHothornL.Testing strategies in multiple dose experiments using active control. Stat Med.1998;17:2133–2146.
25.
HauschkeDHothornL.Safety Assessment in toxicology studies: Proof of safety versus proof of hazard. In ChowSLiuJ, eds. Design and Analysis of Animal Studies in Pharmaceutical Development.New York: Marcel Dekker; 1998:197–226.
26.
HothornLHauschkeD.Identifying the maximum safe dose: A multiple testing approach. J Biopharma Stat.2000;20:15–30.
27.
DmitrienkoAWalterWWestfallP.Gatekeeping strategies for clinical trials that do not require all primary effects to be significant. Stat Med.2003;22:2387–2400.
28.
BretzFHothornLHsuJ.Identifying effective and/or safe doses by stepwise confidence intervals for ratios. Stat Med.2003;22:847–858.
29.
DmitrienkoASmithB.Repeated-measures models for the analysis of QT interval. Pharma Stat.2003;2:175–190.
30.
BazettHCAn analysis of time relations of electrocardiograms. Heart.1920;7:353–367.
31.
FridericiaLSDie Systolendauer im Elecktrokar-diogramm bei normalen Menschen und bei Herzkranken. Acta Medica Scandinavia.1920;53: 469–486.
32.
MolnarJWeissJSRosenthalJEThe missing second: What is the correct unit for the Bazett corrected QT interval?Am J Cardiology.1995;75: 537–538.
33.
SagieALarsonMGGoldbergRJBengtsonJRLevyD.An improved method for adjusting the QT interval for heart rate (the Framingham Heart Study). Am J Cardiology.1992;70:797–801.
34.
MalikM.Problems of heart rate correction in the assessment of drug-induced QT interval prolongation. J Cardiovascular Electrophysiol.2001;12: 411–420.
35.
FDA Advisory Committee Meeting, May 2003.
36.
Chuang-SteinC.Safety analysis in controlled clinical trials. Drug Inf J.1998;32:1363S–1372S.
37.
Funck-BrentanoCJaillonP.Rate-corrected QT iterval: Techniques and limitations. Am J Cardiology.1993;72:17B–22B.
38.
International Conference on Harmonisation. (ICH) E9. Guidance for Industry, E9 Statistical Principles for Clinical Trials.1998. www.fda.gov/cder/guidance/.
