International Conference On Harmonization E14 Research Articles

Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance.

Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during non-clinical drug development. The importance of QT liability detection has been reinforced by non-clinical [International Conference on Harmonization (ICH) S7B] and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a non-clinical in vivo QT assay in animals predicts the outcomes of a clinical QT evaluation in humans. The Health and Environmental Sciences Institute Pro-Arrhythmia Working Group performed a literature search (1960–2011) to identify both human and non-rodent animal studies that assessed QT signal concordance between species and identified drugs that prolonged or did not prolong the QT interval. The main finding was the excellent agreement between QT results in humans and non-rodent animals. Ninety-one percent (21 of 23) of drugs that prolonged the QT interval in humans also did so in animals, and 88% (15 of 17) of drugs that did not prolong the QT interval in humans had no effect on animals. This suggests that QT interval data derived from relevant non-rodent models has a 90% chance of predicting QT findings in humans. Disagreement can occur, but in the limited cases of QT discordance we identified, there appeared to be plausible explanations for the underlying disconnect between the human and non-rodent animal QT outcomes.

ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies.

The International Conference on Harmonization (ICH) guideline ICH E14, adopted in May 2005, sets out recommendations on the strategy for the clinical evaluation of the QT liability of a drug, whether it is new or an established drug (such as citalopram, ondansetron, saquinavir or dextropropoxyphene) with post-marketing reports of QTc prolongation and/or pro-arrhythmia. It focuses on the need during drug development to conduct a ‘thorough QT/QTc’ study, popularly referred to simply as a TQT study 1. This study is typically conducted in healthy volunteers and serves as the primary method for evaluating the potential effect of non-antiarrhythmic agents on cardiac repolarization. Since its adoption in May 2005, the ICH E14 Implementation Working Group (IWG), established by the ICH Steering Committee to update the guidance as necessary, has helpfully issued three sets Questions and Answers (Q&A) documents with the aim of clarifying some areas of uncertainty concerning the recommendations contained in ICH E14 or to take account of emerging science and technology. The first of these documents (Q&A(R)) was issued in June 2008 2 followed by another (Q&A(R1)) in April 2012 2 and the most recent one (Q&A(R2)) in March 2014 3. In the most recent Q&A document, all 16 questions dealt with by these three Q&A documents have now been consolidated into the following seven key groups of areas that required clarity and/or update: ECG recording methodology Gender Positive control Study design Concentration−response modelling of QTc data Special cases ECG monitoring in late stage clinical trials These efforts by the IWG to provide clarity and/or take account of emerging science are to be applauded and we have previously commented on the Q&A(R1) document issued in April 2012 4. In this current commentary, we begin by discussing four new additional questions answered by the IWG, one question on concentration−response modelling and three on special cases. For the sake of brevity and to avoid unnecessary repetition, we have summarized the IWG answers as best as we can. We then highlight some aspects of the IWG answers regarding ECG recording methodology that appear ambiguous, if not contradictory. We also provide our overall comments on the contents of the three Q&A documents as consolidated now and identify other areas that require attention in the future.

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

Replacing the thorough <scp>QT</scp> study: reflections of a baby in the bath water

ICH E14 Q & A (R1) document: perspectives on the updated recommendations on thorough QT studies.

The International Conference on Harmonization (ICH) guidance ICH E14 provides recommendations, focusing on a clinical 'thorough QT/QTc (TQT) study', to evaluate the QT liability of a drug during its development. An Implementation Working Group (IWG) was also established to assist the sponsors with any uncertainties and clarify any ambiguities. In April 2012, the IWG updated its June 2008 version of the Questions and Answers document to address additional issues. These include the gender of the study population, a reasonable approach to evaluating QTc changes in late stage clinical development and the recommended approach to correcting the measured QT interval. This commentary provides our observations and, when appropriate, recommendations, on these issues. We review briefly evidence that suggests that (i) the greater QT effect observed in females is not entirely related to differences in drug exposure and (ii) the Fridericia correction of measured QT interval is adequate for a majority of TQT studies. Until further evidence suggests otherwise, we recommend balanced gender representation in TQT studies, unless warranted otherwise, and for positive studies, subgroup analysis of key data by common demographic variables including the gender and ethnicity. We provide a general scheme for ECG monitoring in late phase clinical trials and consider that while intensive monitoring and centralized reading of ECGs in late phase clinical trials is the norm when a TQT study is positive, there are other circumstances that also call for high quality ECG reading. Therefore, locally read ECGs should only be acceptable as long as accurate high quality ECG data can be guaranteed.

Sugammadex is not associated with QT/QTc prolongation: methodology aspects of an intravenous moxifloxacin-controlled thorough QT study

Sugammadex is a novel γ-cyclodextrin and the first selective relaxant binding agent to be developed for the reversal of rocuronium and vecuroniuminduced neuromuscular blockade. According to International Conference on Harmonization (ICH) E14, a thorough QT/QTc study is required for most new compounds to assess the potential to cause QT prolongation, because a delay in cardiac repolarization may create an electrophysiological environment that favors the development of cardiac arrhythmias, most notably Torsade de Pointes. Therefore a thorough QTc study was conducted to evaluate the effect of sugammadex on the individually corrected QTc interval (QTcI). Following two baseline electrocardiogram (ECG) days (Day -2 and Day -1), in this randomized, double-blind, cross-over study, healthy volunteers received a sequence of four treatments comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control, open label), sugammadex 4 mg/kg and sugammadex 32 mg/kg. ECGs were recorded in triplicate at 12 time points up to ~ 24 h after study drug administration, and the QT intervals were evaluated manually under blinded conditions. The pre-specified primary endpoint was the largest time-matched mean QTcI difference compared with placebo across all time points. A total of 62 subjects received treatment, of which 58 completed the study. After intravenous moxifloxacin, QTcI prolongations compared with placebo exceeded the ICH E14 safety margin of 10 msec and the one-sided 95% lower confidence limit exceeded 5 msec, confirming assay sensitivity. For both sugammadex doses, the one-sided 95% upper confidence limits for the largest time-matched mean QTcI differences compared with placebo were ≤ 5.3 msec at each timepoint and thus considerably below the 10 msec safety margin. Unexpectedly, the two full-day baseline ECGs indicated systematically prolonged QTc values when comparing the first baseline with the second baseline day, reaching a maximum mean difference of 3.8 msec. Single therapeutic (4 mg/kg) and supra-therapeutic (32 mg/kg) intravenous doses of sugammadex are not associated with clinically important QTc prolongation.

The Cost-Effectiveness of Drug Regulation: The Example of Thorough QT/QTc Studies

We analyzed the cost-effectiveness of the International Conference on Harmonisation (ICH) E14 guideline that requires a thorough QT/QTc (TQT) study for all drugs under development. We compared two pharmacoeconomic scenarios: the health effects and costs resulting from implementing ICH E14 ("regulation" scenario) vs. not implementing ICH E14 ("no regulation" scenario). We used a dynamic population model to calculate the cost-effectiveness of ICH E14 for a prototype QT-prolonging antipsychotic drug entering the US and European markets. The incremental cost-effectiveness ratios of regulation vs. no regulation were ~€2.4 million per sudden cardiac death prevented and ~€187,000 per quality-adjusted life year (QALY) gained in users of antipsychotic drugs. The main driver of cost was the requirement for electrocardiogram (ECG) monitoring of users of QTc-prolonging drugs. Even when several of the assumptions in the model were varied, there were no results in favor of regulation. Our study shows that cost-effectiveness analysis of drug regulatory measures is feasible and should be considered before developing such measures.

Effects of Sugammadex Doses up to 32 mg/kg Alone or in Combination with Rocuronium or Vecuronium on QTc Prolongation

Sugammadex reverses the effects of rocuronium- and vecuronium-induced neuromuscular blockade, which are achieved by encapsulation. It is known that some non-antiarrhythmic drugs have the potential to delay cardiac repolarization and it is therefore recommended that the effects of all new drugs on the QT interval are assessed. This thorough corrected QT (QTc) study evaluated the effect of sugammadex alone and in combination with rocuronium or vecuronium on the individually corrected QTc interval (QTcI). This was a randomized, double-blind, six-period crossover, placebo-controlled study, with an open-label active-controlled component (moxifloxacin). The study was designed according to International Conference on Harmonization (ICH) E14 guidelines. The study was conducted in a clinical research unit from November 2006 to April 2007. Healthy male and female subjects (n = 84) were enrolled in the study. Subjects were randomized to six treatment sequences comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control), sugammadex 4 mg/kg, sugammadex 32 mg/kg, sugammadex 32 mg/kg with rocuronium 1.2 mg/kg and sugammadex 32 mg/kg with vecuronium 0.1 mg/kg. Triplicate ECGs were recorded at 13 timepoints up to 23.5 hours after study drug administration and QT intervals were evaluated manually under blinded conditions. The primary outcome was the largest time-matched mean difference in QTcI change from baseline compared with placebo across the 13 timepoints up to 23.5 hours after study drug administration. Blood samples were also collected for pharmacokinetic analysis. Of the 84 randomized healthy subjects, 80 completed the study. After moxifloxacin, QTcI prolongations were observed compared with placebo; the lower limit of the one-sided 95% confidence interval (CI) for the largest time-matched mean difference in QTcI change compared with placebo was 20.8 msec (90% CI 18.5, 23.1), thus exceeding the ICH E14 safety margin of 5 msec and demonstrating assay sensitivity. In contrast, the largest time-matched mean difference in QTcI (msec) from placebo with sugammadex treatments ranged from 2.1 (sugammadex 4 mg/kg alone) to 4.3 (sugammadex 32 mg/kg with vecuronium 0.1 mg/kg). For the largest time-matched mean difference in QTcI change compared with placebo the corresponding upper limit of the one-sided 95% CI was well below the 10 msec margin for both sugammadex doses. Telemetry results revealed that one subject experienced a non-sustained ventricular tachycardia 4 hours after sugammadex 32 mg/kg, which was self-terminating after 20 beats and considered unlikely to be drug related. Pharmacokinetic-QTc analysis showed a statistically significant (p < 0.01) relationship between sugammadex plasma concentration and QTcI; however, at mean maximum plasma concentrations of the therapeutic and supra-therapeutic sugammadex dose, the predicted one-sided upper 95% CI for the largest time-matched QTcI difference from placebo was below 10 msec. Rocuronium or vecuronium co-administration did not affect the relationship between sugammadex concentrations and QTc. Based on the results of this study of healthy subjects, it can be concluded that sugammadex alone or in combination with rocuronium or vecuronium is not associated with QTc prolongation.

Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies. Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations. Mean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin. Both levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies. This study has demonstrated the utility of levofloxacin on the assay in measuring mean QTc changes around 5 ms.

Performance Characteristics for Some Typical QT Study Designs Under the ICH E‐14 Guidance

The International Conference on Harmonization (ICH) guidance for clinical evaluation of QT prolongation (E14) affected drug development by advocating that a thorough QT study (TQT) be conducted during development to assess the QT prolongation liability of a compound. The ICH E14 Statistics Group shortly thereafter recommended that a noninferiority intersection-union test (IUT) be used to exclude a clinically worrisome QT prolongation. Recent analyses have indicated that the IUT might be overly conservative with respect to excluding QT prolongation. This report assesses the IUT false positive rate for 4 recently conducted TQT trials using simple simulation experiments. Positive TQT study rates ranged from negligible to nearly 60% depending on study design, sample size, and patient status, despite no drug effect. Addition of clinically nonmeaningful QT prolongations (up to 5 milliseconds) increased the positive study rate to 80% for 1 particular study design. Ultimately, these results reveal significant limitations of the IUT with respect to excluding an effect and study interpretation for certain trial designs.

Randomized, Double-Blind, Crossover Study to Investigate the Effect of Rivaroxaban on QT-Interval Prolongation

Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Unwanted pro-arrhythmic effects are a common reason for drugs failing to gain regulatory approval; these properties can be detected by assessing the effect of the drug on the QT interval. This study was performed, in accordance with International Conference on Harmonisation (ICH) E14 guidance, to assess whether rivaroxaban prolongs the QT interval. This was a prospective, randomized, double-blind, double-dummy, four-way crossover study. The study was conducted at a clinical pharmacology research unit. Healthy male and female subjects (n = 54) aged > or =50 years were enrolled and remained in the study unit for 3 days for each treatment. Of these, 50 patients were eligible for the QT analysis. Subjects received single oral doses of rivaroxaban 45 mg or 15 mg, moxifloxacin 400 mg (positive control), or placebo. Multiple ECGs were taken at frequent intervals after drug administration, and the QT interval was measured manually under blinded conditions at a central laboratory. The Fridericia correction formula (QTcF) was used to correct the QT interval for heart rate. The primary outcome was the effect of rivaroxaban or moxifloxacin on the placebo-subtracted QTcF 3 hours after administration. The frequency of outlying QTcF values and the tolerability of the treatments were also assessed. All treatments were well tolerated and had no effect on heart rate. Moxifloxacin established the required assay sensitivity; placebo-subtracted QTcF 3 hours after moxifloxacin administration was prolonged by 9.77 ms (95% CI 7.39, 12.15). Placebo-subtracted QTcF values 3 hours after rivaroxaban administration were -0.91 ms (95% CI -3.33, 1.52) and -1.83 ms (95% CI -4.19, 0.54) with rivaroxaban 45 mg and 15 mg, respectively. QTcF was not prolonged with rivaroxaban at any time, and the frequency of outlying results with rivaroxaban and placebo was similar. This thorough QT study, which was performed in accordance with ICH E14 guidelines, shows that rivaroxaban does not prolong the QTc interval. Therefore, the potential of rivaroxaban for the prevention and treatment of thromboembolic disorders, including chronic cardiovascular disorders, can be investigated in appropriate clinical studies without the need for intensive monitoring of the QTc interval.

The use of electrocardiograms in clinical trials: a public discussion of the proposed ICH E14 regulatory guidance

This meeting, jointly sponsored by the FDA, Drug Information Association and Heart Rhythm Society, examined crucial issues on nonclinical and clinical evaluation of the potential of new drugs to prolong the QT interval of an electrocardiogram (ECG). It gathered ∼ 350 attendees from pharmaceutical industry, academia, core ECG analysis laboratories, regulatory agencies (FDA, European Medicines Agency, Japanese Ministry of Health, Labour and Welfare, and Health Canada) and the International Conference on Harmonisation (ICH). Key issues discussed included the reliability of the S7B guideline strategy, design and usefulness of the ‘thorough QT/QTc study’ recommended by ICH E14 guideline, choice of 5 ms QTc prolongation as a threshold for regulatory concern, ECG reading, and statistical analysis. This report is restricted to the two main presentations dealing with the predictability of nonclinical tests for clinical outcomes – one defending the prognostic value of nonclinical tests and the other, from the FDA, which casts reservations on the predictive value of nonclinical studies. Commentary on the recent finalisation of ICH S7B and E14 guidelines are also provided.

Drugs, QT Interval Prolongation and ICH E14

Regulatory concerns on the ability of an ever-increasing number of non-cardiovascular drugs to prolong the corrected QT (QTc) interval and induce potentially fatal ventricular tachyarrhythmias have culminated in initiatives to harmonise internationally the regulatory guidance on strategies by which to evaluate new drugs for this liability. The International Conference on Harmonisation (ICH) has released consensus texts for clinical (ICH topic E14) and non-clinical (ICH topic S7B) strategies as regulatory drafts for wider consultation. Draft ICH E14 calls for a clinical 'thorough QT/QTc study' (typically in healthy volunteers) for new drugs with systemic bioavailability, regardless of the non-clinical data. This indifference to non-clinical data has sparked off a major debate, even among the regulators. The 'thorough QT/QTc study' is intended to determine whether a drug has a threshold pharmacological effect on cardiac repolarisation, as detected by QT/QTc prolongation, and proposes the use of a positive control to validate the study. The guideline recommends exploration of the effect of concentrations that are higher than those achieved following the anticipated therapeutic doses and, consequently, a negative 'thorough QT/QTc study', even in the presence of non-clinical data of concern, will almost always allow standard collection of on-therapy ECGs. The proposed threshold of a 5 ms increase in mean placebo-corrected QTc interval for designating a study as positive for an effect, with all its implications for subsequent development of the drug and its regulatory assessment and labelling, has also generated a controversy. This paper provides an overview commentary on some contentious or ambiguous aspects of draft ICH E14 with a view to stimulating a debate and inviting scientifically supported comments from stakeholders in order to ensure that the application of the ICH E14 strategy, when finalised and adopted, does not result in either restriction in the use (or even rejection) of a potentially beneficial drug or approval of an otherwise hazardous drug without the restrictions required to promote its safe use.

Drugs, QTc Interval Prolongation and Final ICH E14 Guideline

Regulatory concerns on the ability of an ever-increasing number of non-antiarrhythmic drugs to delay ventricular repolarisation, prolong the corrected QT (QTc) interval and induce potentially fatal ventricular tachyarrhythmias have culminated in the adoption of two, internationally harmonised, regulatory guidelines. On 12 May 2005, the International Conference on Harmonisation (ICH) reached an important milestone when it adopted the final texts for clinical (ICH topic E14) and non-clinical (ICH topic S7B) strategies by which drugs should be investigated for their potential to induce these effects during their development.ICH E14 provides recommendations to sponsors concerning the design, conduct, analysis and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarisation. Specifically, it calls for a clinical 'thorough QT/QTc study' (typically conducted in healthy volunteers), which is intended to determine whether a drug has a threshold pharmacological effect on cardiac repolarisation, as detected by QT/QTc interval prolongation. The E14 recommendations are generally applicable not only to new drugs that have systemic bioavailability but also to approved drugs when a new dose, route of administration or target population that may result in an increased risk is explored. The guideline provides for exceptions when this study may not be required.Recognising the fractious relationship between ICH E14 and ICH S7B, and the persistence of a number of issues that may require clarity and/or the emergence of other new scientific issues in the future, the ICH Steering Committee has formed an Implementation Working Group that is charged with providing clarity on aspects of the guideline that are ambiguous and responding to issues on which the sponsors are uncertain. This paper provides a commentary on some of the challenges that are likely to be faced by the sponsors of drugs during the next few years of application of these two guidelines. The adoption of these guidelines has left a number of questions unanswered and raised some new ones. When in doubt, the sponsor should seek formal regulatory clarity before making key decisions that may impact further development, assessment and approval of a new chemical entity. Although the goal of developing drugs with much lower torsadogenic potential and without inappropriate restriction in the use (or even rejection) of potentially beneficial drugs is within sight, it is questionable whether the risk of drug-induced pro-arrhythmia will be eliminated completely.