E14 Questions and Answers (R3): The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs
June 10, 2016
Notice
Our file number: 16-106604-599
Adoption of International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) Guidance: E14 Questions & Answers (R3): The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs
Health Canada is pleased to announce the adoption of the ICH guidance E14 Q&A (R3): The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.
This guidance has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. The ICH Steering Committee has endorsed the final draft and recommended its adoption by the regulatory bodies of the European Union, Japan and USA.
In adopting this ICH guidance, Health Canada endorses the principles and practices described therein. This document should be read in conjunction with this accompanying notice and with the relevant sections of other applicable Health Canada guidances.
It is recognized that the scope and subject matter of current Health Canada guidances may not be entirely consistent with those of the ICH guidances that are being introduced as part of our commitment to international harmonization and the ICH Process. In such circumstances, Health Canada adopted ICH guidances take precedence.
Health Canada is committed to eliminating such discrepancies through the implementation of a phased-in work plan that will examine the impact associated with the adoption of ICH guidances. This will result in the amendment or, depending on the extent of revisions required, withdrawal of some Health Canada guidances.
This and other Guidance documents are available on the Health Canada website (http://www.hc-sc.gc.ca/index-eng.php).
Should you have any questions or comments regarding the content of the guidance, please contact:
Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS)
E-mail: bmors_enquiries@hc-sc.gc.ca
Telephone: 613-941-3171
Fax: 613-941-1365
Date Adopted: 2016/06/10
Effective Date: 2016/06/10
Foreword
In order to facilitate the implementation of the E14 Guideline, the International Conference on Harmonisation (ICH) Experts have developed a series of Questions and Answers.
Code | History | Date |
---|---|---|
E14 Q&As | Approval by the ICH Steering Committee under Step 4 | 4 June 2008 |
E14 Q&As (R1) |
Approval by the ICH Steering Committee under Step 4 of four newly added Questions on: Sex Differences; Incorporating New Technologies; Late Stage Monitoring; and Heart Rate Correction. | 5 April 2012 |
E14 Q&As (R2) |
Approval by the ICH Steering Committee under Step 4 of four newly added Questions on: Concentration-Response Relationships; Combination Products; Large Targeted Proteins and Monoclonal Antibodies; and Special Cases. | 21 March 2014 |
E14 Q&As (R3) |
Approval by the ICH Assembly under Step 4 of the revision of the Question #5.1 on: Use of Concentration Response Modeling of QTc Data. | 10 December 2015 |
ICH E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs (May 2005)
(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/
Step4/E14_Guideline.pdf)
Table of Contents
No. | Date of Approval | Questions | Answers |
---|---|---|---|
1.1 |
June 2008 |
Please discuss who should read electrocardiograms (ECGs), including the number and training of readers and the need for readers to be blinded. |
The document recommends that the reader should be skilled but does not identify specific training that is needed. A technician reading with cardiologist over-read would certainly be consistent with the guidance. The attempt of the guidance to limit the number of readers represented an attempt to increase consistency. The guidance asks for assessment of intra- and inter-reader variability and suggests "a few skilled readers" (not necessarily a single reader) to analyse a whole thorough QT study, since many readers may increase variability. Training would be another way to improve consistency. It is recommended for the thorough QT Study that core ECG laboratories blind subject, time and treatment in order to reduce potential bias. The T wave analysis, which calls for all 12 leads, can be performed after the QT analyses, and requires comparison to the baseline ECG; it can, however, be blinded as to treatment. |
1.2 |
June 2008 |
What is the position of ICH regarding the role of the following reading methods in the thorough QT/QTc study and other clinical trials?
|
The techniques currently in use for the measurement of ECG intervals can be classified into three broad categories: fully manual, fully automated, and manual adjudication. Within each of these general categories, many different methodologies are subsumed that differ in terms of lead selection, the conventions used for defining T wave offset, and the criteria for the inclusion and exclusion of U waves. ECG readings can be performed on the following waveform presentations:
Fully Manual Fully Automated Manual Adjudication (Manual Over-Read/Computer-Assisted/Semi-Automated) The ICH E14 Guideline currently recommends either fully manual or manual adjudication approaches for clinical trials in which the assessment of ECG safety is an important objective, such as the thorough QT/QTc study. When the thorough QT study is positive, fully manual or manual adjudication methods are currently recommended for an adequate sample of patients in late phase studies (see Section 2.3 in E14 document). When the thorough QT/QTc study is negative, routine ECG safety assessments in late phase clinical trials using fully automated reading methods would be adequate. |
1.3 |
June 2008 |
The ICH E14 Guideline contains the following statement: "If well-characterized data validating the use of fully automated technologies become available, the recommendations in the guidance for the measurement of ECG intervals could be modified." What would be expected of a sponsor that wished to validate and apply an automated reading method for regulatory submissions? |
Efforts to develop more sophisticated and reliable methods for automated ECG readings for both QT interval and T wave morphology assessment are encouraged. There are at present no large scale studies to validate the use of fully automated reading methods in patients; however, there are examples of thorough QT/QTc studies in healthy volunteers in which automated methods have been used and validated for QT interval measurements against manual methods. QT Interval measurement T wave morphology assessment Because changes in morphology can affect interval measurement, fully manual or manual adjudication (as defined in Question 1.2) techniques should be performed if treatment-emergent changes in morphology are observed. If, on the other hand, no morphology changes are observed, this would support the use of automated methodologies, provided they have been validated. |
1.4 |
April 2012 |
How does a sponsor incorporate new technology or validate new methodology into the measurement and/or analysis of the QT interval? |
The ICH process is better suited to the determination of regulatory policy once the science in a particular area has become more or less clear. In general, it is not well-suited to the qualification or validation of new technology. Sections 2.5.1 and 2.5.2 of the ICH E14 Guideline are rather discouraging about methodology outside conventional carts and human-determined measurements. Since ICH E14 was issued, 12-lead continuous recording devices have largely supplanted cart recorders in thorough QT studies without a formal validation process because of their performance in the context of a positive control. The impact of other innovative technologies can be assessed in studies incorporating a positive control. While some technologies could be assessed using other techniques in the absence of a positive control, this is more complex and beyond the scope of this Q&A. 12-lead continuous recording devices and other new technologies can be used in late phase clinical trials. Even though a positive control is not used in late stage studies, the new technology could be validated in other studies (such as the thorough QT study). In cases where a thorough QT study is not done, a sponsor can provide alternative methods for validating the technology. |
1.5 |
April 2012 |
The ICH E14 Guideline states that QT interval corrected by Fridericia's and Bazett's correction should be submitted in all applications; is this still necessary? Is there a recommended approach to QT correction that is different than that specified in ICH E14? |
Changes in heart rate could variably influence a drug's effect on repolarisation (i.e., QT interval) and correction methods with different characteristics are often applied. The principles set below would be applicable in all clinical studies (thorough QT or other studies). In adults, Bazett's correction has been clearly shown to be an inferior method of correcting for differences in heart rate among and within subjects. Therefore, QT interval data corrected using Bazett's corrections is no longer warranted in all applications unless there is a compelling reason for a comparison to historical Bazett's corrected QT data. Presentation of data with a Fridericia's correction is likely to be appropriate in most situations but other methods could be more appropriate. There is no single recommended alternative (see Q&A 1.4 on Incorporating New Technologies), but the following are some considerations.
|
No. | Date of Approval | Questions | Answers |
---|---|---|---|
2.1 |
June 2008 |
There are recognized differences in the baseline QTc between men and women. These were noted in early versions of the guidance. In E14, however, it is recommended that outliers be categorized as >450, >480 and >500 ms, regardless of gender. Can you say why there is no gender difference in the recommendation? |
The 450, 480, and 500 ms categories refer to the values the E14 document suggests sponsors might use in characterizing outliers. The numbers previously specified for males and females referred to "normal" QTc values, which may differ for men and women. This section was not included in the final document, however, and such considerations would be largely irrelevant to larger durations (e.g., 480, 500 ms). As the thorough QT/QTc study is designed to examine the propensity of a drug to prolong the QTc interval, it is appropriate to perform the study in male or female healthy volunteers. |
2.2 |
April 2012 |
Should we enroll both sexes in a thorough QT study, and does the study need to be powered for independent conclusions about each sex? |
Post-pubertal males have lower heart-rate corrected QT intervals than do pre-pubertal males or females generally. Women are generally smaller than men, so their exposure to a given fixed dose of a drug will generally be higher, and, if a drug prolongs QT, it can be expected to prolong it more in women because of the higher exposure. It is not settled whether and how often there are sex differences in response to QT-prolonging drugs not explained by exposure alone. The thorough QT study is primarily intended to act as a clinical pharmacology study in a healthy population using a conservative primary objective defining the drug's effect on QT. It is unlikely that any of a variety of baseline demographic parameters would introduce a large difference in QT response to a drug in subpopulations defined by factors such as age, co-morbidity, and gender that is not explained by exposure. It is encouraged, but not mandatory, to include both men and women in the thorough QT study. Analyses of Concentration-Response Relationship (CRR) by sex can be helpful for studying the effect of the drug on QT/QTc interval in cases where there is evidence or mechanistic theory for a gender difference. However, the primary analysis of a thorough QT study should be powered and conducted on the pooled population. If the primary analysis is negative and if there is no other evidence suggesting gender differences, subgroup analysis by sex is not expected. |
No. | Date of Approval | Questions | Answers |
---|---|---|---|
3.1 |
June 2008 |
The ICH E14 Guideline emphasizes the importance of assay sensitivity and recommends the use of a positive control. In order to accept a negative thorough QT/QTc study, assay sensitivity should be established in the study by use of a positive control with a known QT-prolonging effect. Please clarify how to assess the adequacy of the positive control in the thorough QT study. |
The positive control in a study is used to test the study's ability (its "assay sensitivity") to detect the study endpoint of interest, in this case QT prolongation by about 5 ms. If the study is able to detect such QT prolongation by the control, then a finding of no QT effect of that size for the test drug will constitute evidence that the test drug does not in fact prolong the QT interval by the amount of regulatory concern. There are two conditions required for ensuring such assay sensitivity:
Importantly, whatever approach is used, the effect of the positive control (magnitude of peak and time course) should be reasonably similar to its usual effect. Data suggesting an underestimation of QTc might question the assay sensitivity, thus jeopardizing the interpretability of the thorough QT study results. |
3.2 |
June 2008 |
Please clarify the need for blinding the positive control in the thorough QT study. |
The use of a double-blinded positive control does not appear to be essential, provided that the reading of ECGs is performed in a blinded manner as described in Question 1.2 and the study is carefully designed to ensure that specified study procedures are followed uniformly. This means that the same protocol for administering the test drug and placebo, taking blood samples and collecting the ECG data should also be used when giving the positive control. This does not mean that other aspects of the study, such as the duration of treatment with the positive control and the other treatment groups, would be identical. If blinding of the positive control is performed, common methods include the use of double-dummy techniques and over-encapsulation. |
No. | Date of Approval | Questions | Answers |
---|---|---|---|
4.1 |
June 2008 |
In ICH E14, the recommended metric to analyse for a cross-over study is the largest time-matched mean difference between the drug and placebo (baseline-adjusted) over the collection period. Please discuss the most appropriate metric to assess a drug's effect on QT/QTc interval when the data are collected in a placebo-controlled parallel design study (i.e., when there is no corresponding placebo value for each patient). |
Regardless of the study design, "the largest time-matched mean difference between drug and placebo (baseline-adjusted)" is determined as follows: The mean QTc for the drug (i.e., averaged across the study population) is compared to the mean QTc for placebo (averaged across the study population) at each time point. The "largest time-matched mean difference between drug and placebo" is the largest of these differences at any time point. The term "baseline-adjusted" in ICH E14 implies that the baseline data are taken into account in the statistical analysis. Differences in baseline assessment between cross-over and parallel design studies are discussed in Question 4.2. |
4.2 |
June 2008 |
Please discuss the need for baseline measurements, and when needed, how they should be collected, for cross-over and parallel design thorough QT studies. |
Adjustment for baseline measurements is potentially useful for several purposes, including detection of carry-over effects, reducing the influence of inter-subject differences and accounting for diurnal effects such as those due to food. There is no single best approach for baseline adjustment, but all planned baseline computations should be prospectively defined in the clinical trial protocol. Two kinds of baseline are commonly used: "time-matched" baseline (taken at exactly the same time-points on the day prior to the beginning of treatment as on the treatment day) and "pre-dose" baseline (taken shortly prior to dosing). The "pre-dose" baseline is used for adjustment for inter-subject differences but not for diurnal effects. The choice of baseline is influenced by whether the study is parallel or cross-over. For a parallel-group study a time-matched baseline allows the detection of differences in diurnal patterns between subjects that would not be detected by a predose baseline. In a parallel study a "time-matched" baseline day, if performed, would ideally occur on the day before the start of the study. In contrast, in a cross-over study a time-matched baseline is usually not necessary because adjustments for subject- and study-specific diurnal variation are implicit by design in the assessment of time-matched drug-placebo differences in QT/QTc effect. The "pre-dose" baseline is therefore usually adequate for cross-over studies. Obtaining replicate ECG measurements (for example, the average of the parameters from about 3 ECGs) within several minutes of each nominal time point at baseline and at subsequent times will increase the precision of the estimated changes in QT/QTc effect. |
No. | Date of Approval | Questions | Answers |
---|---|---|---|
5.1 |
December |
The ICH E14 Guideline states (in Section 3, page 12) that analysis of the relationship between drug concentration and QT/QTc interval changes is under active investigation. Has this investigation yielded a reasonable approach to concentration-response modeling during drug development? How can assessment of the concentration-response relationship guide the interpretation of QTc data? |
Concentration-response analysis, in which all available data across all doses are used to characterize the potential for a drug to influence QTc, can serve as an alternative to the by-time-point analysis or intersection-union test as the primary basis for decisions to classify the risk of a drug. In either case this result is an important component of the totality of evidence assessment of the risk of QT prolongation. The overall assessment of risk of QT prolongation includes nonclinical data, the time course of QT prolongation, the magnitude of QT prolongation, categorical analyses of outliers, and certain adverse events in patients that can signal potential proarrhythmic effects. There are many different types of models for the analysis of concentration-response data, including descriptive pharmacodynamic (PD) models (e.g., linear or Emax models), or empirical models that link pharmacokinetic (PK) models (dose-concentration-response) with PD models. It is recognized that concentration-response analyses of the same data using models with different underlying assumptions can generate discordant results. Therefore, it is important that the modeling methods and assumptions, criteria for model selection, rationale for model components, and potential for pooling of data across studies be specified prior to analysis to limit bias. Prospective specification of model characteristics (e.g., structural model, objective criteria, goodness of fit) based on knowledge of the pharmacology is recommended whenever possible. On occasion, the QT effect is not a direct function of plasma concentration. For example, drugs that cause QT prolongation as a result of changes in protein synthesis or trafficking or drugs with accumulation into myocardial tissues might demonstrate hysteresis. Testing for model assumptions, hysteresis (a plot of data by-time point and a hysteresis loop plot), and goodness of fit should be documented. Concentration-response analysis can be challenging when more than one molecular entity-multiple drugs or parent plus metabolites-contributes to the QTc effect. Important considerations
Decision-making When using a concentration-response analysis as the primary basis for decisions to classify the risk of a drug, the upper bound of the two-sided 90% confidence interval for the QTc effect of a drug treatment as estimated by exposure-response analysis should be <10 ms at the highest clinically relevant exposure to conclude that an expanded ECG safety evaluation during later stages of drug development is not needed. (See E14, Section 2.2.4 and Q&A #7). Other uses Providing insight into regimens not studied directly Predicting QTc effects of intrinsic and extrinsic factors that affect PK |
No. | Date of Approval | Questions | Answers |
---|---|---|---|
6.1 |
March 2014 |
The ICH E14 Guideline states that in certain cases a conventional thorough QT study might not be feasible. In such cases what other methods should be used for evaluation of QT/QTc and proarrhythmic potential? |
In certain cases the conventional "thorough QT/QTc" study design (a crossover study in healthy volunteers with short-term administration of the usual maximum dose and one higher dose with placebo and positive control) might need to be modified for a drug or active metabolite with a long half-life or delayed QT effect, or because of safety, tolerability or practical issues that preclude use in healthy subjects. In most cases alternative designs can be used that may affect power considerations, but do not compromise study interpretation. For example, multiple doses can be studied in a parallel design trial or can use patients with the disease for which the drug is intended rather than healthy volunteers. Where a placebo-controlled comparison using appropriate doses is not possible, alternative study designs should incorporate as many of the usual "thorough QT/QTc" design features as possible, and the quality and extent of the pre-clinical evaluation (ICH S7B Guideline) is particularly critical. Other useful supplementary data might include intensive ECG data acquisition in early phase single or multiple ascending dose studies, utilisation of concentration-response analysis, and evaluation of exposures that are greater than are anticipated with the intended marketed dose. A single dose of a positive control is generally sufficient, even if it precedes the investigational drug treatment. In the absence of a positive control, there is reluctance to draw conclusions of lack of an effect; however, if the upper bound of the two-sided 90% confidence interval around the estimated maximal effect on QTc is less than 10 ms, it is unlikely to have an actual mean effect as large as 20 ms. When a thorough QTc study of usual or modified design is not feasible, the intensity of late phase ECG monitoring will be dependent upon the quality and extent of the non-clinical and clinical evaluation. In situations where it is not possible to study higher exposures than are anticipated with the intended marketed dose, more intensive ECG monitoring might be necessary during Phase 3 trials. When the non-clinical and early clinical data do not suggest clinically relevant QTc prolongation, intensive late stage monitoring might not be necessary. Otherwise, monitoring could be conducted as if a thorough QT study had been positive to protect patients in later trials and to obtain information on the frequency of marked QTc prolongation in the patient population. (See Q&As 7.1). |
6.2 |
March 2014 |
The ICH E14 Guideline does not address the approach to QT measurement during drug development in the case of combination drug products. Is it recommended that measurement of QT prolongation be performed on drug combinations? |
In general, combinations of two or more drugs are unlikely to need a thorough QT/QTc study or intensive late stage monitoring, if the component drugs have been demonstrated to lack relevant effects in thorough QT/QTc studies as described in ICH E14. If one or more of the component drugs have not been individually characterised for effects on the QT/QTc interval, they may be evaluated in combination or independently. |
6.3 |
March 2014 |
Are sponsors expected to conduct thorough QT studies as part of the development of large proteins and monoclonal antibodies? |
Large targeted proteins and monoclonal antibodies have a low likelihood of direct ion channel interactions and a thorough QT/QTc study is not necessary, unless the potential for proarrhythmic risk is suggested by mechanistic considerations or data from clinical or non-clinical studies. |
No. | Date of Approval | Questions | Answers |
---|---|---|---|
7.1 |
April 2012 |
The ICH E14 Guideline describes in Section 2.3 (Clinical Trial Evaluation After the "Thorough QT/QTc Study") that "adequate ECG assessment to accomplish this [monitoring] is not fully established." Is there now a reasonable approach to evaluating QTc in late stage clinical development in the case of a finding of QT prolongation prior to late phase studies? |
Clarification of Approach to Evaluating QTc in Late Stage Clinical Development The recommended intensity of the monitoring and assessment in late-stage trials will depend on:
The following examples delineate the scope of recommended ECG investigations based on outcome of the thorough QT study or early clinical studies. These could be modified by other factors such as A-F above. Examples of ECG Monitoring in Late Stage:
The sponsor is encouraged to discuss these approaches with the relevant regulatory agency(ies) prior to initiation of the Phase 3 program. *A negative study as defined by the ICH E14 criteria is an upper one-sided 95% CI of QTc prolongation effect <10 ms. |
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