EDITORIAL

The Thorough QT Study: Is Its Demise on the Horizon?

Philip T. Sager, M.D., F.A.C.C., F.A.H.A.,∗ and Peter Kowey, M.D., F.A.C.C.,F.A.H.A.†From the ∗Stanford School of Medicine, Cardiac Safety Research Consortium, Palo Alto, CA, and †Division ofCardiovascular Disease, Lankenau Medical Center and Institute for Medical Research, Wynnewood, PA

Ann Noninvasive Electrocardiol 2014; 00(0):1–3

In response to concerns regarding the publichealth implications of drugs being approved thathave a proclivity to cause the potentially lethalventricular arrhythmia torsade de pointes (TdP),there was an international regulatory call to actionin 2001. This culminated in the 2005 InternationalCommittee on Harmonization (ICH) ICH E-14guidance “The Clinical Evaluation of QT/QTcInterval Prolongation and Proarrhythmic Potentialfor Non-Antiarrhythmic Drugs.”1,2 Since then,almost all new chemical entities with systemicexposure have undergone a dedicated study todetermine the potential of the compound toprolong the QTc interval. A “positive finding” inthis resource-intensive study can have a majorimpact on the remainder of a drug’s development(e.g., extensive ECG assessments during phase 3,potential approval delays, etc.) and, in some cases,has resulted in termination of the developmentprogram.

The article by Darpo and colleagues3 in thisJournal details a prospective study to test thehypothesis that using PK/QTc modeling in a singleascending dose design study, such as is typicallyperformed in the first-in-human study (FIM), willbe sufficiently sensitive to detect QTc effects, tobe acceptable in lieu of the thorough QT (TQT)study. Reasons to be optimistic that this importanteffort is likely to be successful include the factthat careful core-lab analyzed ECG assessmentsin phase 1 is an approach that is already being

Address for correspondence: Philip T. Sager, M.D., F.A.C.C., F.A.H.A., Stanford University School of Medicine, Scientific ProgramsCommittee, Cardiac Safety Research Consortium, Palo Alto, CA 94305, USA. Fax: 415-970-9593; E-mail: psager@stanford.edu

used by some pharmaceutical companies to makeearly determinations of the potential for QTc pro-longation (AstraZeneca personal communication),and that the science underlying exposure-responsemodeling is robust.4,5 More than 350 TQT studieshave demonstrated that QTc interval prolongation,when present, is almost uniformly closely tied toplasma concentrations. PK/QTc modeling utilizespaired QTc and PK assessments regardless of dose,providing far greater power to observe (or exclude)a QTc signal than would be possible with the time-matched methodology that is the primary analysisapproach used in TQT studies.

The potential of this effort to move the clinicaland regulatory assessment of the potential forQTc prolongation from phase 2 to early inphase 1 assessment could beneficially impactdrug development by identifying or excluding apotential cardiovascular (CV) safety issue earlier,thus saving resources expended on a stand-aloneTQT study. In addition, early signal detectionmight result in refocusing the drug toward patientswith greater potential benefit. However, as theauthors point out, <10% of drugs undergoing FIMstudies complete phase 3. Thus, companies willneed to make decisions about the strategy for anyindividual drug, integrating preclinical ion channel,animal QT data, and toxicology data along withother CV safety items related to the chemicaland drug class, to determine the adequacy ofearly QTc evaluation versus waiting to perform

C© 2014 Wiley Periodicals, Inc.DOI:10.1111/anec.12127

1

2 � A.N.E. � 2014 � Vol. 00, No. 0 � Sager, et al. � Demise of the Thorough QT Study

the TQT study later in development. Concernsabout a potential QT effect or bringing forward adrug in a class that has had safety signals, wouldlikely strongly favor the FIM PK/PD approach.The relative cost implications of the variousECG strategies, integrating different risk scenarios,would need to be considered. For example, somecompanies might choose to perform the FIM studyusing appropriately designed protocols that permitthe collection of high quality ECG data, but onlyanalyze the ECG data when it is clear that thedrug does not have significant noncardiac toxicityor adverse events that could derail development.

There are several other issues that need to befurther weighed. The PK/PD FIM approach ascurrently applied, does not assess assay sensitivity.It is not feasible to add an active control armto a FIM study, and while statistical approachescan potentially be utilized to address this issue,6 itremains to be seen if assay sensitivity is critical forthe PK/PD approach to be used in lieu of the TQTstudy.

The study described by Darpo et al.3 has moresubjects per dose group (nine receiving activedrug and six receiving placebo compared to sixand two, respectively). However, this is mitigatedby the fact that only two doses are studied andthat a typical FIM study typically has ∼5 dosegroups. However, the PK/PD FIM approach mayhave reduced applicability for FIM studies thatutilize smaller cohorts or fewer dose groups orthose that do not truly explore supra-therapeuticexposures. Drugs with long half-lives may requiremultiple doses to reach sufficient exposures andthis approach could be utilized in the multipleascending dose study.

Finally, the FDA has been involved in thedevelopment of this experimental approach. Inorder for positive results to meaningfully impactdrug development, it is critical that other regulatoryauthorities accept the new approach and that ICH-E14 be revised. Acceptance of the PK/PD approachin one region but not in another might not obviatethe need for a TQT study in an individual drugdevelopment program.

The major weakness of using QTc prolongationto assess risk of TdP is that it does not directlyaddress the most critical issue: is the drugactually proarrhythmic? A significant increase inthe QTc is sensitive, but not highly specific forthe development of TdP.7 For example, ranolazineand phenobarbital prolong the QTc but are

not associated with TdP. Amiodarone markedlyincreases the QTc (occasionally >550 ms), but it isonly very rarely associated with TdP. Additionally,verapamil potentially blocks the human ether-a-go-go-related gene (hERG)-related current, theionic effect most commonly associated with drug-induced proarrhythmia. However, verapamil doesnot prolong the QTc at therapeutic exposures.While all of these examples block hERG, theyalso modulate other cardiac ionic currents, whichappear to prevent the proarrhythmic effects ofhERG blockade and QTc prolongation. These andother examples illustrate that hERG block and QTcprolongation can be differentiated from TdP riskfor some drugs. Since ICH E14 has been put intoplace in 2005, many drugs have prolonged theQTc above the threshold of regulatory concern andreceived labeling warning regarding QTc prolonga-tion and the potential for cardiac proarrhythmia.How likely is it that many of these agents resultingin small QTc increases are actually proarrhythmic?

The current paradigm undoubtedly results inthe premature discontinuation of drugs becauseof QTc prolongation and concerns of a perceivedsafety risk despite the real possibility that thereis not a real proarrhythmic risk.8 The costs andcomplexity of developing a drug with a “QTcsignal” is burdensome with real concerns regardinglabeling with arrhythmia warnings. The net resultis that drugs that could have conceivably addressedunmet medical needs and had positive benefit: riskratios, are being prematurely terminated.

Given this issue, the Cardiac Safety ResearchConsortium (CSRC), in conjunction with the Healthand Environmental Sciences Institute (HESI) andthe FDA held a Think Tank on July 23, 2013 atthe FDA to critically discuss a new paradigm todirectly evaluate the potential for a drug to beproarrhythmic. The focus would be on nonclinicalproarrhythmic assays and the goal would be toreduce the premature termination of drugs thateffect hERG or increase the QTc but do not appearto be proarrhythmic. This would effectively movethe bulk of proarrhythmia signal detection to thediscovery phase, where the assays could potentiallyplay a role in candidate selection, and obviate theTQT.9 Collaborative work streams are now beingput into place to perform the necessary work.

Specific efforts are concentrated on assessing theeffect of a drug on a platform of ion channels usingin silico techniques10 to assess the proarrhythmicpotential. The proclivity to develop early after

A.N.E. � 2014 � Vol. 00, No. 0 � Sager, et al. � Demise of the Thorough QT Study � 3

depolarizations and enhanced susceptibility ofventricular depolarization during the repolarizationphase are being studied. Conceivably, the resultscould be confirmed in a human myocyte study,potentially using induced pluripotent stem cells.11

ECG assessment in phase 1 will still be important.It will be critical to determine whether thereare findings in humans that were not anticipatedbased on the nonclinical assays (and thus themechanism would need to be understood) aswell as the effects of a drug on other importantECG variables such as atrioventricular nodalconduction, ventricular conduction, heart rate, andpossibly T-wave morphology.

This is an exciting time. Initiatives such asFIM PK/PD assessments in lieu of the TQT andthe new preclinical paradigm could conceivablymove the bulk of proarrhythmia assessment tothe discovery phase. It has the potential to makedrug development more efficient and significantlyreduce the number of cases in which there is aneed for the TQT study. We anxiously await theresults of the study described by Darpo et al.3

and the efforts of the work-streams focused on thedeveloping a new approach to the assessment ofproarrhythmia risk.

REFERENCES1. ICH E14 Questions & Answers, April 2012. Available at

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R1_step4.pdf.Accessed November 2013.

2. ICH Harmonized Tripartite Guideline E14. Theclinical evaluation of QT/QTc interval prolongationand proarrhythmic potential for non-antiarrhythmicdrugs, May 2005. Available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R1_step4.pdf.Accessed November 2013.

3. Darpo B, Sarapa N, Garnett C, et al. The IQ-CSRC prospec-tive clinical phase 1 study: “Can early QT assessment usingexposure response analysis replace the thorough QT study?”Ann Noninv Electrocardiol 2014;00:00–00.

4. Darpo B, Garnett C. Early QT assessment—how can ourconfidence in the data be improved? Br J Clin Pharmacol2012;76:642–648.

5. Garnett CE, Beasley N, Bhattaram VA, et al. Concentration-QT relationships play a key role in the evaluationof proarrhythmic risk during regulatory review. J ClinPharmacol 2008;48:13–18.

6. Malik M, Zhang J, Johannesen L, et al. Assessingelectrocardiographic data quality and possible replacementof pharmacologic positive control in thorough QT/QTcstudies by investigations of drug-free QTc stability. HeartRhythm 2011;8:1777–1785.

7. Sager PT. Key clinical considerations for demonstratingthe utility of preclinical models to predict clinical drug-induced torsades de pointes. Br J Pharmacol 2008;154:1544–1549.

8. Stockbridge N, Morganroth J, Shah RR, et al. Dealingwith global safety issues: Was the response to QT-liabilityof non-cardiac drugs well coordinated? Drug Saf 2013;36:167–182.

9. Chi KR. Revolution dawning in cardiotoxicity testing. NatRev Drug Discov 2013;12:565–567.

10. Mirams GR, Cui Y, Sher A, et al. Simulation of multipleion channel block provides improved early predictionof compounds’ clinical torsadogenic risk. Cardiovasc Res2011;91:53–61.

11. Navarrete EG, Liang P, Lan F, et al. Screeningdrug-induced arrhythmia events using human inducedpluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays. Circulation 2013;128:S3–S13.