E14 Clinical Evaluation of QT/QTc 
Interval Prolongation and  
Proarrhythmic Potential for  
Non-Antiarrhythmic Drugs   
Questions and Answers (R3) 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
June 2017 
ICH 
 
Revision 2
 
   
E14 Clinical Evaluation of QT/QTc 
Interval Prolongation and  
Proarrhythmic Potential for  
Non-Antiarrhythmic Drugs   
Questions and Answers (R3) 
 
Guidance for Industry 
 
 
 
[shorten addresses if necessary] 
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http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm    
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
  
June 2017 
ICH 
 
Revision 2 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
INTRODUCTION......................................................................................................................... 1 
I.  ELECTROCARDIOGRAMS METHODOLOGY (1) .................................................. 2 
II.  GENDER (2) ...................................................................................................................... 6 
III.  POSITIVE CONTROL (3) .............................................................................................. 7 
IV.  STUDY DESIGN (4) ......................................................................................................... 8 
V.  USE OF CONCENTRATION RESPONSE MODELING OF QTC DATA (5) ......... 9 
VI.  SPECIAL CASES (6) ...................................................................................................... 11 
VII.  ELECTROCARDIOGRAMS MONITORING IN LATE STAGE CLINICAL 
TRIALS (7) ...................................................................................................................... 13 
 
  Contains Nonbinding Recommendations 
 
E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs  
Questions and Answers (R3) 
1
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
INTRODUCTION 
 
Since the ICH E14 guidance was finalized in 2005, experiences implementing the guidance in 
the ICH regions have given rise to requests for clarification.  This question and answer (Q&A) 
document is intended to facilitate implementing the E14 guidance by clarifying key issues. 
 
This guidance is a revision of the ICH guidance titled E14 Clinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs  Questions 
and Answers (November 2008). This Q&A document has been revised as follows: 
 
  In April 2012, added questions on Sex Differences, Incorporating New Technologies, 
Late Stage Monitoring, and Heart Rate Correction 
  
  In March 2014, added questions on Concentration-Response Relationships, Combination 
Products, Large Targeted Proteins and Monoclonal Antibodies, and Special Cases 
 
  In December 2015, revised the question on Use of Concentration Response Modeling of 
QTC Data, to harmonize guidance on how concentration response modeling could be 
used for regulatory decision-making 
 
This revised guidance incorporates the March 2014 and December 2015 changes.  
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
                                                 
1 This guidance was developed within the Expert Working Group (Efficacy) of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (formerly the International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) and 
has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has 
been endorsed by the ICH Steering Committee at Step 4 of the ICH process, December 2015. At Step 4 of the 
process, the final draft is recommended for adoption to the regulatory authorities represented at ICH. 
  1  Contains Nonbinding Recommendations 
 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
 
 
QUESTIONS AND ANSWERS 
 
I.  ELECTROCARDIOGRAMS METHODOLOGY (1) 
 
Q1.  Please discuss who should read electrocardiograms (ECGs), including information 
on the number and training of readers and the need for readers to be blinded. (1.1) 
 
The document recommends that the reader should be skilled, but it does not identify specific 
training that is needed.  A technician reading with a cardiologist over-reading the document 
would certainly be consistent with the guidance.  The attempt of the guidance to limit the number 
of readers represents 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 analyze 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. 
 
Q2.  What is the position of ICH regarding the role of the following reading methods in 
the thorough QT/QTc study and other clinical trials? (1.2) 
 
  Fully manual 
  Fully automated 
  Manual adjudication (manual over-read, computer-assisted, semi-automated)?  
 
The techniques currently in use for the measurement of ECG intervals can be classified into three 
broad categories:  (1) fully manual, (2) fully automated, and (3) 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: 
 
  Raw waveforms:  ECG waveforms recorded from a single lead 
 
  2  Contains Nonbinding Recommendations 
 
  Representative waveforms (median beats, reference cycles):  Compositional waveforms 
constructed by a computer-based averaging process that involves aligning and combining 
data from all dominant, normally conducted raw ECG waveforms from a single lead 
 
  Global waveforms:  Composite representation of cardiac electrical activity constructed by 
superimposing representative waveforms from all or several simultaneously recorded 
leads to form a spatial-vector complex, by weighted averaging of individual 
representative complexes with low noise and long duration, or by other methods 
 
Fully manual 
 
When using a fully manual reading technique, a human reader is responsible for examining the 
ECG waveform and placing the fiducial points to mark the beginning and the end of the 
intervals, without the assistance of a computer algorithm.  Fully manual methods of fiducial 
point placement can be applied to raw, representative, and global waveforms.  When fully 
manual measurements are made from the raw ECG waveforms in a single lead, three or more 
cycles should be averaged, where available, to produce the final determination of interval 
duration.  An advantage of this approach is that the reader will not be influenced by prior 
computer placement of the fiducial points, but a weakness can be inter- and intra-reader 
variability, especially when measurements are performed over an extended time period (e.g., 
several months).  Laboratories using manual reading techniques should observe standard 
operating procedures based on prospectively defined criteria for determining where the fiducial 
points should be placed.  All readers in the laboratory should be trained in the consistent 
application of these criteria. 
 
Fully automated 
 
Fully automated reading methods rely entirely upon a computer algorithm for the placement of 
the fiducial points and the measurement of the ECG intervals.  Automated ECG interval 
measurements can be performed on raw, representative, or global ECG waveforms.  Most digital 
electrocardiographs are equipped with algorithms that perform measurements on global 
waveforms.  Although automated methods have the advantage of being consistent and 
reproducible, they can yield misleading results in the presence of noise or when dealing with 
abnormal ECG rhythms, low amplitude P or T waves, or overlapping U waves.  The techniques 
used for construction and measurement of representative waveforms and global waveforms vary 
between different computerized algorithms and between different software versions within 
individual equipment manufacturers.  As a result, between-algorithm and within-manufacturer 
variability of fully automated measurements can confound serial comparisons when the 
equipment or algorithm is not constant.   
 
Manual adjudication (manual over-read/computer-assisted/semi-automated) 
  
The manual adjudication approach refers to reading methods in which a computer algorithm is 
responsible for the initial placement of the fiducial points on the ECG waveform.  A human 
reader subsequently reviews the algorithmic placement of the fiducial points, performing 
adjustments wherever the computerized measurements are considered to be inaccurate.  This 
  3  Contains Nonbinding Recommendations 
 
approach can have the advantage of greater consistency and reproducibility than fully manual 
readings, while providing an opportunity to correct any mistakes made by the algorithmic 
readings.  Laboratories using manual adjudication techniques should observe standard operating 
procedures based on prospectively defined criteria for determining when fiducial points should 
be corrected.  All readers in the laboratory should be trained in the consistent application of these 
criteria.  The adjudication procedure should normally be performed on all waveforms being used 
for interval determination.  If an alternative approach is used, such as adjudication limited to 
outlier intervals above and below a reference range, this methodology should be validated as 
described in Question Q3 (1.3).  
 
The ICH E14 guidance 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 II.C (2.3) in the E14 guidance).  When the thorough QT/QTc 
study is negative, routine ECG safety assessments in late phase clinical trials using fully 
automated reading methods will be adequate. 
 
Q3.  The ICH E14 guidance 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? (1.3) 
 
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 
 
There are at present no clear and widely accepted criteria for validation of new semi-automated 
or automated methods, but it is expected that each would be validated independently for its 
ability to detect the QT/QTc prolongation effects of drugs that are near the threshold of 
regulatory concern.  Data supporting the validation of a new method should be submitted and 
could include descriptive statistics, Bland-Altman plots of agreement, superimposed plots of the 
baseline- and placebo-adjusted QTc and the RR as a function of time, together with data from 
any trials that have employed the method. 
 
T wave morphology assessment 
 
The suitability of automated ECG reading techniques for the assessment of morphological 
abnormalities has not yet been demonstrated.  If a sponsor intends to develop a fully automated 
approach, without visual assessment for morphological changes, validation studies should 
include a demonstration that the automated method is capable of reading and interpreting a test 
  4  Contains Nonbinding Recommendations 
 
set of abnormal ECGs correctly (e.g., abnormalities of T wave morphology, overlapping U 
waves).  As with methods for QT interval determination, there are at present no clear and widely 
accepted criteria for validation of novel methods. 
 
Because changes in morphology can affect interval measurement, fully manual or manual 
adjudication (as defined in Question Q2 (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. 
 
Q4.  How does a sponsor incorporate new technology or validate new methodology into 
the measurement and/or analysis of the QT interval? (1.4) 
 
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 II.E.1 (2.5.1) and II.E.2 (2.5.2) of the ICH E14 guidance 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.  Although some technologies could be assessed using 
other techniques in the absence of a positive control, this topic is more complex and beyond the 
scope of this question and answer.   
 
Twelve-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. 
 
Q5.  The ICH E14 guidance states that QT interval corrected by Fridericias and 
Bazetts correction should be submitted in all applications; is this still necessary?  Is 
there a recommended approach to QT correction that is different from that 
specified in ICH E14? (1.5) 
 
Changes in heart rate could variably influence a drugs effect on repolarization (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, Bazetts 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 
Bazetts corrections is no longer warranted in all applications unless there is a compelling reason 
for a comparison to historical Bazetts corrected QT data.  Presentation of data with a 
Fridericias correction is likely to be appropriate in most situations, but other methods could be 
  5  Contains Nonbinding Recommendations 
 
more appropriate.  There is no single recommended alternative (see Question Q4 (1.4) on 
Incorporating New Technologies), but the following are some considerations:  
 
1.  Analyses of the same data using different models for correcting QT can generate 
discordant results.  Therefore, it is important that the method(s) of correction, criteria for 
the selection of the method of correction, and rationale for the components of the method 
of correction be specified prior to analysis to limit bias.  Model selection should be based 
on objective criteria and should consider the uncertainty in parameter estimates.  
Alternative methods of correction should be used only if the primary method fails the 
pre-specified criteria for selection of the method of correction. 
 
2.  Corrections that are individualized to a subjects unique heart rate QT dynamic are not 
likely to work well when the data are sparse or when the baseline data upon which the 
correction is based do not cover at least the heart rate range observed in patients on the 
study drug. 
 
 
II.  GENDER (2) 
 
Q6.  There are recognized differences in the baseline QTc between men and women.  
These were noted in early versions of the guidance.  In the E14 guidance, however, it 
is recommended that outliers be categorized as > 450, > 480, and > 500 milliseconds 
(ms), regardless of gender.  Can you say why there is no gender difference in the 
recommendation? (2.1) 
 
The 450, 480, and 500 ms categories refer to the values the E14 guidance suggests sponsors 
might use in characterizing outliers.  The numbers that were specified previously for males and 
females referred to normal QTc values, which may differ for men and women.  This section 
was not included in the final guidance, however, and such considerations would be largely 
irrelevant to larger durations (e.g., 480 and 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 healthy male or female volunteers. 
 
Q7.  Should we enroll both sexes in a thorough QT study, and does the study need to be 
powered for independent conclusions about each sex? (2.2) 
 
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 that are 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 drugs effect on QT.  It is 
unlikely that any of a variety of baseline demographic parameters would introduce a large 
  6  Contains Nonbinding Recommendations 
 
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 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. 
 
 
III.  POSITIVE CONTROL (3) 
 
Q8.  The ICH E14 guidance 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. (3.1) 
 
The positive control in a study is used to test the studys 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: 
 
1.  The positive control should show a significant increase in QTc, i.e., the lower bound of 
the one-sided 95% confidence interval (CI) must be above 0 ms.  This shows that the trial 
is capable of detecting an increase in QTc, a conclusion that is essential to concluding 
that a negative finding for the test drug is meaningful. 
 
2.  The study should be able to detect an effect of about 5 ms (the QTc threshold of 
regulatory concern) if it is present.  Therefore, the size of the effect of the positive control 
is of particular relevance.  With this aim, there are at least two approaches: 
 
a.  To use a positive control showing an effect of greater than 5 ms (i.e., lower bound 
of a one-sided 95% CI > 5 ms).  This approach has proven to be useful in many 
regulatory cases.  However, if the positive control has too large an effect, the 
studys ability to detect a 5 ms QTc prolongation might be questioned.  In this 
situation, the effect of the positive control could be examined at times other than 
the peak effect to determine whether an effect close to the threshold of regulatory 
concern can be detected. 
 
b.  To use a positive control with an effect close to 5 ms (point estimate of the 
maximum mean difference with placebo close to 5 ms, with a one-sided 95% CI 
  7  Contains Nonbinding Recommendations 
 
lower bound > 0).  In using positive controls with smaller effects, it would be very 
important to have a reasonably precise estimate of the drugs usual effect. 
 
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. 
 
Q9.  Please clarify the need for blinding the positive control in the thorough QT study. 
(3.2) 
 
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 Q2 (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. 
 
 
IV.  STUDY DESIGN (4) 
 
Q10.  In the ICH E14 guidance, the recommended metric to analyze for a crossover 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 drugs 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). (4.1) 
 
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 the ICH E14 guidance implies that the baseline data are taken 
into account in the statistical analysis. 
 
Differences in baseline assessment between crossover and parallel design studies are discussed in 
Question Q11 (4.2). 
 
Q11.  Please discuss the need for baseline measurements, and when needed, how they 
should be collected, for cross-over and parallel design thorough QT studies. (4.2) 
 
  8  Contains Nonbinding Recommendations 
 
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 predose baseline (taken shortly prior to dosing).  The predose 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 crossover. 
 
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 crossover 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 predose baseline, 
therefore, is usually adequate for crossover 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. 
 
 
V.  USE OF CONCENTRATION RESPONSE MODELING OF QTC DATA (5) 
 
Q12.  The ICH E14 guidance states (in section III (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? 
(5.1) 
 
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 E  models), or empirical 
max
models that link pharmacokinetic (PK) models (dose-concentration-response) with PD models. It 
  9  Contains Nonbinding Recommendations 
 
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 metabolitescontributes to the QTc effect. 
 
Important considerations 
 
Concentration-response data would not necessarily come from a dedicated QT study, nor would 
it necessarily come from a single study.  However, there are several new and important 
considerations that are described below.  
 
1.  Data can be acquired from first-in human studies, multiple-ascending dose studies, or 
other studies. Additional data would be useful to ensure information on exposure well 
above the exposure at the maximum therapeutic dose, to cover the impact of 
accumulation with repeated dosing, drug-drug and drug-food interactions, organ 
dysfunction, or genetically impaired metabolism. It is anticipated that one would collect 
new data to add to previous data, if appropriate, rather than use new data for independent 
analyses. 
 
2.  Efficient concentration-response analysis using data acquired in studies with other 
purposes requires as much quality control as is needed for a dedicated study. This 
includes robust, high-quality ECG recording and analysis sufficient to support a valid 
assay for ECG intervals (see the E14 guidance and Question Q1 (1.1)). 
 
3.  If there is an intention to pool data from multiple studies, it is important to test for 
heterogeneity. 
 
4.  If there are data characterizing the response at a sufficiently high multiple of the 
clinically relevant exposure (see the E14 guidance, section II.B.2 (2.2.2)), a separate 
positive control would not be necessary. 
 
Decision-making 
 
Both the intersection-union test and the concentration-response analysis can estimate the 
maximum effect of a drug treatment on the QTc interval, but they are not used to test the same 
hypothesis.  As mentioned above, inspection of the time course of QT prolongation is important.  
  10  Contains Nonbinding Recommendations 
 
However, hypothesis testing based on a by-time point analysis (intersection-union test or point 
estimate and confidence intervals) is inappropriate in studies designed for a concentration-
response analysis, if not powered to assess the magnitude of QT prolongation for each time 
point.      
 
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 the E14 guidance, section II.B.4 (2.2.4), and 
Question Q16 (7.1)).  
 
Other uses 
 
In addition to serving as the basis for regulatory decision-making, concentration-response 
analysis has established its utility in several settings enumerated below. 
 
Providing insight into regimens not studied directly  
   
An understanding of the concentration-response relationship can help predict the QT effects of 
doses, dosing regimens, routes of administration, or formulations that were not studied directly. 
Interpolation within the range of concentrations studied is more reliable than extrapolation above 
the range. 
 
Predicting QTc effects of intrinsic and extrinsic factors that affect pharmacokinetics  
 
Understanding the concentration-response relationship can help predict the effects of intrinsic 
(e.g., cytochrome P450 isoenzyme status) or extrinsic (e.g., drug-drug PK interactions) factors, 
possibly affecting inclusion criteria or dosing adjustments in later phase studies. 
 
 
VI.  SPECIAL CASES (6) 
 
Q13.  The ICH E14 guidance 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? (6.1) 
 
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.   
 
  11  Contains Nonbinding Recommendations 
 
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 preclinical evaluation (ICH S7B guidance) is particularly 
critical.  Other useful supplementary data might include intensive ECG data acquisition in early 
phase single or multiple ascending dose studies, utilization of concentration-response analysis, 
and evaluation of exposures that are greater than those 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 on 
the 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 nonclinical 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 nonclinical 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 Question Q16 (7.1)). 
 
Q14.  The ICH E14 guidance 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? (6.2) 
 
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 the ICH E14 guidance.   
 
If one or more of the component drugs have not been individually characterized for effects on the 
QT/QTc interval, they may be evaluated in combination or independently. 
 
Q15.  Are sponsors expected to conduct thorough QT studies as part of the development 
of large proteins and monoclonal antibodies? (6.3) 
 
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 
nonclinical studies. 
 
 
  12  Contains Nonbinding Recommendations 
 
VII.  ELECTROCARDIOGRAMS MONITORING IN LATE STAGE CLINICAL 
TRIALS (7) 
 
Q16.  The ICH E14 guidance describes in section II.C (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? (7.1) 
 
Clarification of approach to evaluating QTc in late stage clinical development 
 
The purpose of a thorough QT study is to characterize the effect of the drug on ventricular 
repolarization (QT interval).  It is not the purpose of the thorough QT study to assess the risk of 
torsade de pointes (TdP) in the target population, but rather to determine whether further data are 
warranted to assess risk.  A finding of QT prolongation above the regulatory threshold of interest 
(a positive thorough QT study) might call for further electrocardiographic follow-up in late phase 
studies.  The extent of the follow-up would be affected by the magnitude of the estimated 
prolongation at doses and concentrations at which this occurs.  If prolongation is substantial at 
concentrations expected to occur in clinical studies, it is important to protect patients in later 
trials and to obtain further information on the frequency of marked QT prolongation.  In some 
cases in which there is a large margin of safety between therapeutic exposures and the exposures 
that result in significant ECG interval changes, an intensive ECG follow-up strategy might not be 
warranted. 
 
The recommended intensity of the monitoring and assessment in late-stage trials will depend on: 
 
A.  The magnitude of QTc prolongation seen in the thorough QT study or early clinical 
studies 
 
B.  The circumstances in which substantial QT prolongation might occur (i.e., in ordinary 
use or only when drug concentrations are markedly increased (e.g., by renal or 
hepatic impairment, concomitant medications)) 
  
C.  PK properties of the drug (e.g., high inter-individual variability in plasma 
concentrations, metabolites) 
 
D.  Characteristics of the target patient population that would increase the proarrhythmic 
risk (e.g., structural heart disease) 
 
E.  The presence of adverse effects that can increase proarrhythmic risk (e.g., 
hypokalemia, bradycardia, heart block) 
 
F.  Other characteristics of the drug (e.g., pharmacodynamics, safety pharmacology, 
toxicology, drug class, hysteresis) 
 
  13  Contains Nonbinding Recommendations 
 
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 through F above.   
 
Examples of ECG monitoring in late stage: 
 
1.  The thorough QT study results in a negative finding, as defined by the E14 criteria,2 at 
the therapeutic dose, but the supratherapeutic dose (relative to phase 3 dose) shows mean 
QTc effects between 10 and 20 ms.  If there is reasonable assurance that the higher dose 
represents drug exposures that are unlikely to be seen in the patient population, only 
routine ECG monitoring is recommended in late phase trials.  This approach provides 
reassurance for safety because patients are unlikely to experience a clinically significant 
QTc effect.  
 
2.  The thorough QT study results in a positive finding, as defined by the E14 criteria,3 at the 
therapeutic dose, with a mean prolongation < 20 ms.  For drugs with this magnitude of 
effect on the QTc interval, intensive monitoring of phase 3 patients is called for.   
 
Intensive ECG monitoring in clinical trials has two main objectives.  One objective is to 
provide protection to patients who might have large worrisome QT intervals > 500 ms.  A 
second objective is identifying the frequency of marked QT increases (e.g., prolonged QT 
> 500 ms or increases in QTc > 60 ms). 
 
Given the limitations of collecting ECGs in late stage trials, the focus of the analysis is on 
outliers, not on central tendency.  Other than descriptive statistics, detailed statistical 
analysis is not expected.  This monitoring is intended to be performed locally, without the 
involvement of a central core laboratory. 
 
The timing of ECG collection should be based on the known properties of the drug.  All 
patients should receive baseline, steady-state, and periodic ECGs during the trial.  In 
addition, ECGs should be collected around T  at the first dose and/or around steady 
max
state in a subgroup of patients or in dedicated studies.  ECG collection at around T  is 
max
not important for drugs with low fluctuations between peak and trough concentrations.  If 
the drug shows a delayed effect in QT prolongation, then the timing of ECG collection 
should reflect this delay. 
 
3.  The thorough QT study results in a negative finding, as defined by the E14 criteria,4 at 
the therapeutic dose, but the supratherapeutic dose shows a mean effect between 10 and 
20 ms.  If supratherapeutic exposure is anticipated at the clinical dose only in a well-
characterized subgroup, intensive monitoring as described in Example 2 above could be 
                                                 
2 A negative study, as defined by the ICH E14 criteria, is an upper one-sided 95% CI of QTc prolongation effect < 
10 ms. 
3 A positive study is any result that does not meet the definition of a negative study. 
4 A negative study, as defined by the ICH E14 criteria, is an upper one-sided 95% CI of QTc prolongation effect < 
10 ms. 
 
  14  Contains Nonbinding Recommendations 
 
carried out in this subset of the phase 3 population.  In this case, there should be 
reasonable assurance that the higher exposure is unlikely to be seen in the general patient 
population.  In contrast, if people in the general patient population (who cannot be readily 
identified in advance) will in some cases achieve this higher exposure, intensive ECG 
monitoring in the phase 3 population is expected, as in Example 2.   
 
4.  The therapeutic dose results in a mean QTc prolongation of > 20 ms.  For drugs with 
large QTc prolongation effects, intensive ECG assessment would be appropriate in all 
patients in phase 2/3.  Because of the risk of TdP, another important use of ECG 
monitoring in late phase trials would be to assess any risk mitigation strategies (e.g., 
electrolyte monitoring, dose reduction strategies).  Additional ECG assessment over and 
above what is recommended earlier in this question and answer might also be called for 
(e.g., 24-hour ECG recording, telemetry, multiple trough ECGs through steady state).  
 
The sponsor is encouraged to discuss these approaches with the relevant regulatory agency or 
agencies prior to initiation of the phase 3 program. 
 
 
  15