Replacing the thorough QT study: reflections of a baby in the bath water

Since its implementation in 2005, the E14 guidance ‘Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs’ 1 promulgated by the International Conference on Harmonization (ICH) has elicited considerable dissatisfaction from many stakeholders at all levels. The ICH E14 guideline sets out our current paradigm for regulatory assessment of potential pro-arrhythmic risk of drugs during their clinical development. It evolved from two earlier regulatory strategies, one from the European Medicines Agency (EMA) in 1997 2 and the other (in a draft form) from Health Canada in 2001 3, neither of which mandated a specific clinical trial dedicated to evaluating a drug effect on QT interval. The E14 guidance went much further and described a new type of clinical trial, which has come to be known as the ‘Thorough QT Trial’ (TQT), but more accurately described as the ‘Thorough ECG Trial’ (TET) since the trial evaluates parameters other than just the QT interval on the surface electrocardiogram (ECG). The TET is an unusual trial. It fits very awkwardly into our usual schema of drug development as it is in effect a phase I type trial that is usually performed well after other phase I trials have been completed, and sometimes as late as phase III or not infrequently, as part of a post-marketing commitment. Before considering whether TET has proved to be an effective tool for early detection of an important safety signal during drug development, it is helpful to retrace the events that led to the ICH E14 guidance, and the birth of the TET. There are a number of reviews which already address this issue 4-6, but a brief summary is still in order. In essence, the TET was the ultimate outcome of proliferation during the 1980s and 1990s of drugs which were unexpectedly associated with sudden deaths during their post-marketing use. Most of these drugs were medications intended for relatively benign non-cardiac indications and were therefore removed from the market. Research quickly established that these episodes of sudden death were precipitated by an unusual form of ventricular tachycardia known as torsade de pointes (TdP), an arrhythmia that is typically preceded by prolongation of the QT interval as measured on the ECG. It was also soon determined that QT interval prolongation and TdP resulted from the ability of these drugs to block or inhibit the IKr channel, which is primarily responsible for conducting the major fraction of ventricular repolarizing outward current. Drug-induced QT prolongation is a pharmacological effect which one can readily measure by carefully recording and assessing ECGs. Not surprisingly, evidence of drug-induced QT prolongation came to be recognized as a valuable biomarker by which to identify new drugs that might be torsadogenic, leading to the use of QT interval in the TET as the key surrogate marker for identifying drugs with heightened clinical risk for TdP. Since its adoption in 2005 by the US Food and Drug Administration (FDA), EMA and Health Canada (Japan followed much later), the TET-based strategy outlined in ICH E14 (as well as the corresponding preclinical strategy recommended in the ICH S7B guideline 7) has become the standard for investigating new chemical entities for their propensity to induce QT interval prolongation, and by inference TdP. Well over 250 such studies have been conducted to date 6. The ICH E14 strategy, as it has developed over the past 8 years, has identified a number of drugs with clinically relevant QT-prolonging effect before their approval. A review of 163 TET studies, conducted in compliance with ICH E14 during 2005–2012, revealed 33 (20%) of them to be positive 8. Many of these drugs have been approved, albeit some with very restricted labelling and even black box warnings, with instructions for prescribing physicians concerning appropriate patient selection and appropriate patient monitoring when utilizing these medications 1, 8-11. It is perhaps too early to determine whether the E14 strategy constitutes a success in terms of reducing the clinical risk that really matters, the induction of TdP. This uncertainty is a natural corollary of the limitation of QT prolongation as an effective surrogate of the clinical risk of TdP. QT prolongation in and of itself has no adverse clinical consequences. Indeed, when adequately controlled, it may even be anti-arrhythmic and, therefore, beneficial. It is simply a surface manifestation of the underlying complex mechanisms which may ultimately lead to TdP. However, the relationship between prolongation of QT and induction of TdP is modulated by a wide variety of factors, both intrinsic (related to the drug itself) 12 and extrinsic (related to the patient) 13. Not surprisingly, there are drugs which significantly lengthen the QT interval, but which do not induce TdP 14. An example is ranolazine which blocks the IKr channel and therefore lengthens the QT interval 15, but which has not been reported to induce TdP. Ranolazine also blocks the late sodium current 16, and it is believed that this mitigates the proarrhythmic consequences of a prolonged QT interval that results from IKr channel blockade. Thus, while all drugs which induce TdP lengthen the QT interval, not all drugs which lengthen the QT interval induce TdP 17. In view of the foregoing, it is not surprising that since the release of the ICH E14 guidance, the TET has been the target of criticism. First and the foremost is the concern that the ICH E14 guidance and the TET have made pharmaceutical companies and regulators too fixated on QT prolongation, a fixation which has led pharmaceutical companies to abandon the development of many drugs which block IKr only modestly during preclinical studies or which have demonstrated only a small increase in QT interval in early clinical trials 9, 18. Medicinal chemists have also been busy designing candidate molecules which lack the off-target drug interaction with the hERG (human ether-a-go-go gene) channel, which is the alpha subunit of the IKr channel 18, 19 while, at the same time, attempting to find molecules with increasing efficacy through improved target specificity and selectivity. These two aims may often be mutually exclusive. Thus many new drugs are abandoned early in preclinical or phase I testing and do not reach phase III clinical trials. These drugs have never had the opportunity to demonstrate what might have been their clinically desirable effectiveness. Some of the drugs whose development has been halted early on due to QT concerns may have been breakthrough medications that are truly needed. Simply put, not enough right drugs, or perhaps some wrong drugs, are reaching the end of phase II and are undergoing a TET. Furthermore, in view of binary outcome from the Intersection Union Test as recommended in ICH E14, the TET has come to be viewed as having ‘pass or fail’ categorization. It is common to hear of the fears generated by a drug's ‘positive TET’ and of serious questions being raised by the sponsor as to the viability or wisdom of continuing the development of the compound. However, we have only limited understanding of the relationship between the magnitude of a drug's QTc effect and the actual clinical risk of TdP, and hardly any data on the reproducibility of the results of a TET. At the very outset, it was recognized by the E14 drafting group that a QT effect of 5–10 ms, as detected by a TET, was generally not a sign of the drug being potentially proarrhythmic. Instead, a breach of this threshold was intended to trigger further detailed scrutiny of its ECG effects during phase III trials, when the drug would be administered to larger group of patients with a range of co-morbidities and in receipt of co-medications 1. Thus, the TET was presumed to provide a precise assessment of a drug's effect on the QT interval, which would then guide the ECG monitoring strategy during phase III clinical trials and after approval for marketing. Another concern, which is not a trivial one for many small to medium sized companies, is the cost of running a TET, which typically is in the neighbourhood of 2–3 million dollars. Thus, this expensive trial is performed when all other healthy volunteer trials have been completed, and it yields only ECG safety data (in healthy volunteers). A TET may cost more than many of the other phase I trials combined and is typically conducted towards the end of phase II, when the tolerability, pharmacokinetics and the therapeutic dose for clinical use have been defined, a point at which the total expenditure on a new drug is still relatively modest compared with that of phase III trials. There are pharmacoeconomic simulations which suggest that a TET is not cost-effective in terms of the (clinical) return it produces 20. Thus, from the point of view of a pharmaceutical company, a TET is expensive and a very inefficient use of scarce resources. In response to the above well-argued concerns and dissatisfaction with TET, two broad strategies have recently been proposed for replacing it. The first proposal is to replace the TET by incorporating robust ECG monitoring during phase I single and multiple ascending dose (SAD/MAD) studies whereas the second proposal is to replace the TET with a series of more extensive preclinical in vitro studies and computer modelling of the results from these studies. Replacing a TET with an ECG-oriented SAD/MAD study would simply ‘bolt on’ additional intense ECG collection to the already pre-planned studies 21, 22. Intuitively, this strategy ought to be much less expensive than performing a TET. These SAD/MAD studies offer an otherwise unparalleled opportunity to study the concentration–effect relationship for QT changes at a wide range of dosages. It is now widely acknowledged that understanding of the concentration–QT effect relationship provides a more effective approach to managing the risk (and risk/benefit) than the Intersection Union Test recommended by ICH E14 22, 23. Currently, most drug development programmes include hERG channel assays performed in heterologous expression systems or human derived myocytes and an in vivo study, typically in dogs. Purkinje fibre studies or papillary muscle assays and perfused wedge preparation studies are also performed 24. The second proposal for replacing the TET, initiated by the FDA among others and referred to as the Comprehensive In vitro Pro-arrhythmia Assay (CIPA), calls for the use of in vitro ion channel studies followed by computer modelling of their results to predict a new drug's pro-arrhythmic potential. This proposal is based on mechanistic understanding of ventricular arrhythmias gained through investigations on over-expressed human cardiac ion channels, computer models of ventricular myocyte electrophysiology and isolated induced pluripotent stem cell-derived cardiomyocytes. The multiple ionic currents that influence the human ECG potentially include ICaL, IKr, IKs, IK1, INa(fast), and INa(late). In silico modelling, focusing on the propensity to manifest early after-depolarizations and increased proclivity of depolarization during phase 3 of repolarization, along with a complementary cell-based arm of CIPA, was proposed as a means to integrate the in vitro data into a prediction relevant to drug effects on human ventricular myocytes. There is a large literature-based dataset on the sensitivity and specificity of preclinical testing 25. It is evident that depending on test conditions, the predictability of these tests can vary substantially. We have computed that in broad terms, sensitivity and specificity, respectively, average 50% and 85% for hERG studies, 30% and 93% for action potential duration (APD) studies and 68% and 85% for in vivo studies evaluating QT interval prolongation as the endpoint. For torsadogenesis as the endpoint, sensitivity and specificity, respectively, average 95% and 84% for hERG studies, 65% and 91% for APD studies and 100% and 100% for in vivo studies. In view of this, the bold CIPA proposal is somewhat surprising since hitherto, the ICH S7B guidance advocating essentially the same preclinical investigations of QT liability as CIPA has not received the recognition it should have. Concerns have been expressed that typical phase I studies have too few subjects receiving placebo, and that phase I studies generally do not employ a positive control with a known effect on QT interval in order to establish assay sensitivity. These concerns, however, can be readily overcome by relatively minor enhancement of the protocols 21. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is a technically-focused organization of pharmaceutical and biotechnology companies with a mission of advancing science-based and scientifically-driven standards and regulations for pharmaceutical and biotechnology products worldwide. The IQ QTc Working Group aims to explore innovative approaches to evaluating QTc liability and risk assessment in early clinical drug development 26. In collaboration with the Interdisciplinary QT Review Team of the FDA and the Cardiac Safety Research Consortium (CSRC), the IQ QTc Working Group is developing a protocol for a phase I clinical research study designed to mimic the standard SAD/MAD studies in early clinical development that would test the positive and negative predictability of the concentration–QTc response modelling in phase I for the outcome of the TET study. The study will include multiple currently marketed drugs from the FDA database of agents that have had a positive TET study. A protocol synopsis and approach to statistical are reported to be The protocol synopsis and statistical approach will be with the FDA and the study is to in the first of 26. However, since there is no on and is the of a TET study, there will be a as to which should be more and in the that the from the TET and the SAD/MAD studies of a drug effect in a TET can be from the reproducibility of the effect of a single dose of widely as a positive control in TET studies. 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However, of the results of prediction of QTc prolongation with the TET results and of models suggest that phase studies are of assessing a new drug's QT liability 22, It is not our to more on which strategy is the most appropriate to identify the clinical risk of However, that the clinical use of a drug that cardiac typically on and monitoring of a QT interval, it that a assessment of its potential to the QT interval will still be during its development. A strategy that further is a of utilizing the from preclinical studies and QT interval and concentration–effect assessment in early phase clinical studies to molecules for which TET studies may not be In to the current of evidence from early phase clinical studies only the drug is to the QT interval, evidence from these studies should also be when the drug is to lack an effect on QT interval, the for a TET study. 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