E14 and S7B Clinical and Nonclinical 
Evaluation of QT/QTc Interval 
Prolongation and  
Proarrhythmic Potential  
Questions and Answers  
 
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) 
 
August 2022 
ICH
 
   
 
 
E14 and S7B Clinical and Nonclinical 
Evaluation of QT/QTc Interval 
Prolongation and 
Proarrhythmic Potential  
Questions and Answers  
 
Guidance for Industry 
 
 
 
 
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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) 
  
August 2022 
ICH
 
  Contains Nonbinding Recommendations 
 
FOREWORD 
  
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, and high-quality medicines are developed, registered, and maintained 
in the most resource-efficient manner.  By harmonizing the regulatory expectations in regions 
around the world, ICH guidelines have substantially reduced duplicative clinical studies, 
prevented unnecessary animal studies, standardized safety reporting and marketing application 
submissions, and contributed to many other improvements in the quality of global drug 
development and manufacturing and the products available to patients.   
  
ICH is a consensus-driven process that involves technical experts from regulatory authorities and 
industry parties in detailed technical and science-based harmonization work that results in the 
development of ICH guidelines.  The commitment to consistent adoption of these consensus-
based guidelines by regulators around the globe is critical to realizing the benefits of safe, 
effective, and high-quality medicines for patients as well as for industry.  As a Founding 
Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a major role in the 
development of each of the ICH guidelines, which FDA then adopts and issues as guidance to 
industry.   
 
 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
INTRODUCTION......................................................................................................................... 1 
E14 QUESTIONS AND ANSWERS ........................................................................................... 2 
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) ...................................................................................................... 12 
VII.  ELECTROCARDIOGRAMS MONITORING IN LATE-STAGE CLINICAL 
TRIALS (7) .................................................................................................................................. 14 
S7B QUESTIONS AND ANSWERS ......................................................................................... 16 
I.  INTEGRATED RISK ASSESSMENT (1) .................................................................... 16 
II.  BEST PRACTICE CONSIDERATIONS FOR IN VITRO STUDIES (2) ................ 19 
III.  BEST PRACTICE CONSIDERATIONS FOR THE IN VIVO QT STUDIES (3) ... 24 
IV.  PRINCIPLES FOR PROARRHYTHMIA MODELS (4) ........................................... 26 
 
 
 
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
E14 and S7B Clinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential  
Questions and Answers  
Guidance for Industry1 
 
 
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 
 
This question-and-answer (Q&A) document is intended to clarify key issues to facilitate 
implementing the ICH guidances for industry E14 Clinical Evaluation of the QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs (October 2005) and 
S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval 
Prolongation) by Human Pharmaceuticals (October 2005).2  This guidance revises ICH E14 
Q&As Q12 (5.1) and Q13 (6.1), and adds new ICH S7B Q&As Q17 (1.1) to Q30 (4.2).  This 
guidance finalizes the draft guidance issued in September 2020. 
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA 
guidance documents, including this guidance, should be viewed only as recommendations, unless 
specific regulatory or statutory requirements are cited.  The use of the word should in Agency 
guidance means that something is suggested or recommended, but not required. 
 
 
 
1 This guidance was developed within the Expert Working Groups (Efficacy and Safety) 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 (ICH) 
and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document 
has been endorsed by the ICH Assembly at Step 4 of the ICH process, February 2022. At Step 4 of the process, the 
final draft is recommended for adoption to the regulatory bodies of the ICH regions. 
2 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
  1  Contains Nonbinding Recommendations 
 
E14 QUESTIONS AND ANSWERS 
 
I.  ELECTROCARDIOGRAMS METHODOLOGY (1)3 
 
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 
 
  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 
 
3 The numbers in parentheses reflect the organizational breakdown of the document endorsed by the ICH Assembly 
at Step 4 of the ICH process, February 2022. 
  2  Contains Nonbinding Recommendations 
 
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 
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 
  3  Contains Nonbinding Recommendations 
 
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 E14 Q&A 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 
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-
  4  Contains Nonbinding Recommendations 
 
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 the ICH 
E14 guidance 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 the ICH E14 guidance? (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 
more appropriate.  There is no single recommended alternative (see E14 Q&A 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 
  5  Contains Nonbinding Recommendations 
 
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 
prespecified 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 
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 
  6  Contains Nonbinding Recommendations 
 
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 
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. 
 
  7  Contains Nonbinding Recommendations 
 
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 E14 Q&A 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 
E14 Q&A Q11 (4.2). 
 
Q11.  Please discuss the need for baseline measurements, and when needed, how they 
should be collected, for crossover and parallel design thorough QT studies. (4.2) 
 
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 
  8  Contains Nonbinding Recommendations 
 
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 
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 
  9  Contains Nonbinding Recommendations 
 
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. 
 
Dose and exposure definitions 
 
  Therapeutic dose:  dose evaluated in phase 3 trial or recommended in 
product labeling 
 
  Clinical exposure:  mean steady-state maximum concentration (Cmax,ss) associated 
with the maximum therapeutic dose 
 
  High clinical exposure:  exposure (Cmax,ss) achieved when the maximum therapeutic 
dose is administered in the presence of the intrinsic or extrinsic factor (e.g., organ 
impairment, drug-drug interaction, food effect) that has the largest effect on 
increasing Cmax,ss 
 
  Supratherapeutic dose:  dose that provides exposures (mean C ) exceeding the high 
max
clinical scenario 
 
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, provided that the concentrations that can be safely achieved are well above 
the exposure at the maximum therapeutic dose at steady-state and reflect high clinical 
exposure scenario situations such as drug-drug and drug-food interactions, organ 
dysfunction, and/or genetically impaired metabolism. Whenever possible, sponsors are 
encouraged to explore a wide dose range in early-phase studies to enable characterization 
of effects at high concentrations. 
 
2.  Efficient concentration-response analysis using data acquired in studies with other 
purposes should have 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 E14 Q&A Q1 (1.1)). 
 
  10  Contains Nonbinding Recommendations 
 
3.  If there is an intention to pool ECG interval data from multiple studies, it is important to 
test for heterogeneity.  Pooling of studies that were not planned for this purpose can 
produce bias.  This potential should be critically discussed in the analysis plan. 
 
4.  A separate positive control would not be necessary if either of the following conditions is 
met: 
 
a.  There are data characterizing the response at a sufficient multiple (commonly 2x) 
of the high clinical exposure (see ICH E14 guidance, section II.B.2 (2.2.2)). 
 
b.  If the high clinical exposure has been achieved in the clinical ECG assessment but 
a sufficient multiple has not been obtained (e.g., for reasons of safety or 
tolerability, saturating absorption), then a nonclinical integrated risk assessment 
can be used as supplementary evidence.  The reason higher doses were not tested 
should be adequately justified.  See ICH S7B Q&A Q17 (1.1) for details; in 
summary, the nonclinical studies should include: (1) a hERG assay, following 
best practice considerations (see ICH S7B Q&As, section II (2)), that shows low 
risk as defined in ICH S7B Q&As Q17 (1.1) and Q18 (1.2) and (2) no evidence of 
QTc prolongation in an in vivo assay conducted according to ICH S7B at 
exposures that cover high clinical exposures (see ICH S7B Q&As, Q17 (1.1) and 
section III (3); note that some recommendations only apply to decision-making 
under ICH E14 Q&A Q13 (6.1)). 
 
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.  
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 E14 
Q&A 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. 
 
  11  Contains Nonbinding Recommendations 
 
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) 
 
An integrated nonclinical and clinical QT/QTc risk assessment can be particularly valuable when 
a thorough QT study or concentration-QTc analysis meeting similar quality control as needed for 
a dedicated study as described in E14 Q&A Q12 (5.1) is not feasible.  This situation can arise 
under scenarios where a placebo-controlled comparison is not possible; safety considerations 
preclude administering supratherapeutic doses to obtain high clinical exposures and/or safety or 
tolerability prohibit the use of the product in healthy participants.  The design elements that 
include placebo and healthy participant dosing assist in decreasing variability, but their absence 
does not preclude interpretation. 
 
The integrated nonclinical and clinical QT/QTc risk assessment should include: 
 
1.  The hERG assay, an in vivo QT assay, and any follow-up nonclinical studies, especially 
those selected to overcome the challenges encountered in the clinical studies (see ICH 
S7B Q&As Q17 (1.1) and Q18 (1.2) 
 
2.  Alternative QT clinical study designs incorporating ECG assessments with as many of 
the usual thorough QT/QTc design features as possible (see ICH E14 guidance, section 
II.B (2.2), and E14 Q&A Q12 (5.1)) 
 
In situations where it is not possible to evaluate the QT/QTc effects at high clinical exposure, it 
is particularly important that the nonclinical in vivo studies are conducted at exposures covering 
the high clinical exposure (see ICH E14 Q&A Q12 (5.1) for definition of high clinical exposure). 
 
An integrated QT/QTc risk assessment can also be particularly valuable for drugs with 
confounding heart rate effects that could impact accurate determination of the QTc.  Advanced 
methodologies for controlling (e.g., pacing) or correcting for heart rate changes in the nonclinical 
  12  Contains Nonbinding Recommendations 
 
in vivo studies and/or conducting QTc assessments in the intended patient population might be 
informative in this situation.  If tolerance to the chronotropic effect develops with repeat dosing, 
upward titration regimens can sometimes be employed to avoid or minimize the confounding 
effects of drug-induced heart rate changes on the QTc assessment. 
 
Decision-Making 
 
A totality of evidence argument based on the results of an integrated nonclinical and clinical 
QT/QTc assessment could be made at the time of marketing application. 
 
A drug that meets the following criteria would be considered to have a low likelihood of 
proarrhythmic effects due to delayed repolarization: 
 
1.  The nonclinical studies, following best practice considerations for in vitro studies (see 
ICH S7B Q&As, section II (2)) and in vivo studies (see ICH S7B Q&As, section III (3)), 
show low risk as defined in ICH S7B Q&A Q17 (1.1). 
 
2.  The high-quality ECG data (see ICH E14 guidance and E14 Q&As, section I (1)) 
collected in the alternative QT clinical assessment do not suggest QT prolongation, 
generally defined under this Q&A as an upper bound of the two-sided 90% confidence 
interval around the estimated maximal effect on QTc less than 10 ms, as computed by the 
concentration-response analysis or the intersection-union test.  If applicable, there should 
be no notable imbalances between treatment/dose arms in the proportion of subjects 
exceeding outlier thresholds. 
 
3.  A cardiovascular safety database that does not suggest increased rate of adverse events 
that signal potential for proarrhythmic effects (ICH E14 guidance, section IV (4)). 
 
When justified, a totality of evidence argument for a drug to have a low likelihood of 
proarrhythmic effects due to delayed repolarization could still be made for a drug that has an  
upper bound of the two-sided 90% confidence interval around the estimated maximal effect on 
QTc of 10 ms or more.  The determination will depend on the quality and details of the clinical 
data (e.g., estimated QTc mean and upper bound values, slope of any concentration-QTc 
relationship) and nonclinical data (e.g., difference between the hERG safety margin for the 
investigational drug and the threshold for defining low risk). 
 
If nonclinical studies do not show low risk (or are not performed), there is reluctance to conclude 
a lack of an effect in an absence of a positive control; however, if the upper bound of the two-
sided 90% confidence interval around the estimated maximal effect on QTc is less than 10 ms, 
the treatment is unlikely to have an actual mean effect as large as 20 ms. 
 
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) 
 
  13  Contains Nonbinding Recommendations 
 
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. 
 
 
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 
 
  14  Contains Nonbinding Recommendations 
 
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) 
 
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,4 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,5 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. 
 
4 A negative study, as defined by the ICH E14 guidance criteria, is an upper one-sided 95% CI of QTc prolongation 
effect < 10 ms. 
5 Ibid. 
  15  Contains Nonbinding Recommendations 
 
 
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,6 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 
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. 
 
 
S7B QUESTIONS AND ANSWERS 
 
I.  INTEGRATED RISK ASSESSMENT (1) 
 
Q17.  What is the general strategy for use of nonclinical information as part of an 
integrated risk assessment for delayed ventricular repolarization and torsade de 
pointes that can inform the design of clinical investigations and interpretation of 
their results? (1.1) 
 
The ICH S7B guidance describes a nonclinical strategy for assessing risk of delayed ventricular 
repolarization and QT interval prolongation (section II.C (2.3)).  A mechanistic understanding of 
the development of torsade de pointes (TdP) and the emergence of new types of assays have 
made it possible to obtain more information to assess TdP risk from nonclinical assays. 
 
6 Ibid. 
 
  16  Contains Nonbinding Recommendations 
 
 
The in vitro IKr/hERG assay and in vivo QT assay as well as optional follow-up studies, as 
described in the ICH S7B guidance, are conducted for hazard identification and risk assessment 
relevant to delayed ventricular repolarization.  It is generally accepted that drugs (note that the 
word drug(s) in the S7B Q&As is used interchangeably with word pharmaceutical(s) in the 
ICH S7B guidance) that delay ventricular repolarization may have increased risk of TdP. 
 
In addition to supporting the planning and interpretation of First-in-Human clinical studies, 
nonclinical investigations can also contribute to an integrated risk assessment for TdP in later 
stages of development when clinical data are available.  The following are points to consider 
when using in vitro IKr/hERG data and in vivo QT data in combination with clinical QT data as 
part of an integrated risk assessment for situations described in ICH E14 Q&As Q12 (5.1) and 
Q13 (6.1). 
 
1.  To predict whether or not the hERG block poses a risk of interfering with ventricular 
repolarization or TdP, evaluation of the hERG safety margin based on results of a best 
practice assay (see S7B Q&As Q18 (1.2) and Q19 (2.1)) is recommended.  ICH S7A 
guidance, section II.F (2.6) describes considerations for when human metabolite(s) 
should be assessed with in vitro systems. In these cases, the metabolites hERG safety 
margin should also be evaluated. 
 
2.  In the in vivo study, the effects on the QTc interval should be assessed at exposures that 
cover the anticipated high clinical exposure scenario.  The adequacy of exposure to any 
major human metabolites should be determined (see ICH S7A guidance, sections II.C.3.b 
(2.3.3.2) and II.F (2.6), and S7B Q&A Q28 (3.5)).  In addition, if the assay is to be used 
as part of an integrated clinical and nonclinical risk assessment for situations where a 
conventional thorough QT study is not feasible as described in ICH E14 Q&A Q13 (6.1), 
the in vivo study should have sufficient sensitivity to detect a QTc prolongation effect of 
a magnitude similar to dedicated clinical QT studies (see ICH S7B Q&A Q27 (3.4)). This 
additional consideration (sensitivity similar to dedicated clinical QT studies) does not 
apply to decision-making prior to First-in-Human studies or under ICH E14 Q&A Q12 
(5.1). 
 
A drug with low TdP risk would be expected to have (1) a hERG safety margin higher than a 
threshold defined based on the safety margins computed under the same experimental protocol 
for a series of drugs known to cause TdP (see ICH S7B Q&A Q18 (1.2) for additional details); 
and (2) no QTc prolongation in an in vivo assay of sufficient sensitivity conducted at exposures 
of parent compound and major human metabolites that exceed clinical exposures.  See ICH S7A 
guidance, section II.F (2.6) for considerations of human metabolite(s) in the in vitro or in vivo 
nonclinical assays.  If these results are used to support an integrated clinical and nonclinical risk 
assessment strategy as described in ICH E14 Q&As Q12 (5.1) and Q13 (6.1), no additional 
nonclinical studies are needed.  When there are factors that can confound or limit the 
interpretation of the nonclinical studies, such as metabolites and heart rate changes, follow-up 
studies as described in the ICH S7B guidance (section II.C.5 (2.3.5)) can be performed to 
address these specific issues. 
 
  17  Contains Nonbinding Recommendations 
 
If the hERG assay and/or the in vivo QT study suggest an effect at clinical exposures, the drug 
has a risk of interfering with ventricular repolarization. Under this scenario, the drugs TdP risk 
could be affected by various other factors, such as blocking of additional repolarization currents 
(e.g., slow delayed rectifier potassium current [Iks]), blocking of inward currents (e.g., sodium 
and L-type calcium currents), effects on the trafficking of ion channel proteins from cytoplasmic 
sites to the surface membrane, metabolites with ion channel activities, and non-ion channel 
mediated QT prolongation.  Follow-up studies (ICH S7B guidance, section II.C.5 (2.3.5)) could 
be performed to further explore the mechanisms and assess the TdP risk.  If applicable, best 
practice considerations should be followed for assessment of additional ion channel currents 
(S7B Q&A Q19 (2.1)), in vitro cardiomyocyte assays (S7B Q&As Q20 (2.2) to Q23 (2.5)), or in 
vivo studies (S7B Q&As Q24 (3.1) to Q28 (3.5)).  An appropriately qualified proarrhythmia risk 
prediction model (see S7B Q&As Q29 (4.1)  to Q30 (4.2)) could be used according to its context 
of use to assess the possibility of TdP in humans.  Use of in vitro and in silico models can reduce 
animal use in follow-up studies in accordance with the 3R (reduce/refine/replace) principles.  
The assessment of TdP risk using these follow-up studies, although optional, can be used 
together with other relevant nonclinical and clinical information to contribute to the design of 
subsequent clinical investigations and interpretation of their results. 
 
Q18.  What is the recommended method to compute the hERG safety margin? (1.2) 
 
A drugs potency for hERG block, usually calculated as half-inhibitory concentration (IC50), can 
be normalized to the drugs estimated clinically relevant exposures in patients to calculate the 
safety margin.  As more information is obtained during the clinical development, the estimated 
values of clinical exposures can be refined.  When estimating hERG block potency, it is 
recommended to use standardized procedures and to consider the principles described in S7B 
Q&A Q19 (2.1). 
 
The free drug exposure is computed based on the drugs total plasma concentration and the 
fraction of protein binding. Because of uncertainties in the protein binding measurements, the 
unbound (free) fraction in plasma should be set to 1% if experimentally determined to be < 1%. 
This approach has been used in the regulatory assessment for the risk of drug- drug interactions. 
If protein binding values cannot be accurately assessed (e.g., questionable validation of the 
bioanalytical method, deviations from best practices), safety margins should be calculated for 
both steady-state free and total C . 
max
 
In terms of the exposure to use in the denominator of the safety margin calculation for supporting 
decision-making under ICH E14 Q&As Q12 (5.1) or Q13 (6.1), it is generally recommended that 
the high clinical exposure be used as defined in ICH E14 Q&A Q12 (5.1) (i.e., mean steady-state 
maximum concentration (C ,  when the maximum therapeutic dose is administered in the 
max ss)
presence of the intrinsic or extrinsic factor that has the largest effect on increasing C ). 
max,ss
 
To assess whether the hERG block poses a risk of delaying ventricular repolarization or TdP, the 
resulting safety margin should be compared to the range of safety margins computed under the 
same experimental protocol for a series of reference drugs that have known clinical TdP risk and 
cover diverse electrophysiological properties.  Additional pharmacological principles or 
modeling can be used to justify the use of a certain safety margin threshold (e.g., relationship 
  18  Contains Nonbinding Recommendations 
 
between hERG block and QTc prolongation from semi-mechanistic 
pharmacokinetic/pharmacodynamic models or systems pharmacology models; see Leishman et 
al. 2020,7 for examples).  This should be supported by experimental data based on the principles 
in these S7B Q&As (e.g., same experimental protocol applied to a series of drugs with known 
clinical TdP risk). 
 
Data supporting the safety margin threshold to define a drug as having low TdP risk should be 
supplied in or appended to the submitted study report.  If a recommended hERG margin 
threshold is published based on principles in these S7B Q&As, a sponsor (or a contract 
laboratory) seeking to use the same threshold should demonstrate that the inter-laboratory 
variability of IC50s from a set of calibration drugs under the same experimental protocol does 
not significantly decrease the sensitivity of the safety margin threshold for detecting drugs that 
are not low risk for TdP.  Appropriate statistical methods should be applied to quantify 
experimental IC50 variability and calculate uncertainty of the safety margin as 
confidence/credible intervals. 
 
 
II.  BEST PRACTICE CONSIDERATIONS FOR IN VITRO STUDIES (2) 
 
Q19.  What are some best practice considerations when evaluating drug potency on 
affecting cardiac ionic currents using patch clamp method and overexpression cell 
lines? (2.1) 
 
As outlined in the ICH S7B guidance, the in vitro IKr/hERG assay plays a critical role in 
assessing the risk for delayed repolarization and QT interval prolongation prior to first 
administration in humans.  Nonclinical investigations can also contribute to an integrated risk 
assessment in later stages of development when clinical QT data are available.  The following 
best practice aspects should be considered when sponsors are using IKr/hERG data to support 
interpretation of clinical QT data in specific scenarios as described in S7B Q&As Q17 (1.1) and 
Q18 (1.2) and ICH E14 Q&As Q12 (5.1) and Q13 (6.1), and when using calcium (i.e., CaV1.2) 
and sodium (i.e., NaV1.5) data to support a proarrhythmia assessment (ICH S7B Q&A Q17 
(1.1)).  It is not the intent of these S7B Q&As to make specific recommendations for a sponsors 
screening activities or for all IKr/hERG assays to support first administration in humans. 
 
Several experimental factors are known to influence the potency of drug effects on cardiac ionic 
currents.  These include the voltage protocols used to evoke specific ionic currents; experimental 
conditions (such as recording temperature, composition of solutions, manual versus automated 
assay systems); data acceptance criteria; and data analysis methods employed.  Some 
recommended best practices are therefore provided to enhance reproducibility of in vitro results 
and the translation to clinical findings. These recommendations are generalizable to voltage 
clamp experiments characterizing potency of drug inhibition (or potentiation) of cardiac currents. 
 
 
7 DJ Leishman, MM Abernathy, and EB Wang, 2020, Revisiting the HERG Safety Margin After 20 Years of 
Routine hERG Scrrening, Journal of Pharmacological and Toxicological Methods, 105:106900 
(https://doi.org/10.1016/j.vascn.2020.106900).  
  19  Contains Nonbinding Recommendations 
 
1.  Recording temperature:  The effects of some drugs are temperature-sensitive, and there is 
currently no method to predict which molecules exhibit temperature-dependent effects or 
the magnitude of these effects.  Thus, patch clamp experiments on cells overexpressing 
cardiac ion channels, including hERG, CaV1.2, and NaV1.5, should be performed at near 
physiological temperature (3537 C). 
 
2.  Voltage protocol:  The voltage protocols used to evoke ionic currents should approximate 
the appropriate elements of a ventricular action potential and be repeated at frequencies 
that are sufficient to minimize the possibility of missing the effects of a test drug at 
physiologically relevant heart rates.  For hERG, a stimulation frequency of 0.2  1 Hertz 
is recommended.  For CaV1.2 and NaV1.5 currents, a stimulation frequency of 0.2 Hertz 
is recommended.  The voltage protocol should include steps that enable monitoring of 
cell health and consistent electrophysiological recordings throughout the experiment (i.e., 
estimation of input and series resistance across time).  If high seal resistance is achieved, 
holding current and input resistance (i.e., measures of passive membrane properties at 
rest) can be used as indicators of cell health and experimental stability. After application 
of the test drug and if recording quality remains acceptable, a saturating concentration of 
a selective blocker should be applied to cells to determine residual background current in 
individual cells.  If prominent, background current should be factored into potency 
determinations. 
 
3.  Recording quality:  Seal resistance should be high enough so that the leak conductance at 
all voltages specified by the voltage protocol and series resistance do not compromise 
voltage control.  The extent of series resistance compensation applied to optimize voltage 
control should be noted.  Stability of the ionic current should be demonstrated with 
baseline recordings (prior to drug application) of sufficient duration to characterize drug-
independent changes (such as current run-down).  The time course of drug effects should 
be monitored until steady-state effect is obtained, and each cell can be exposed to one or 
more drug concentrations as long as cell health and recording quality remain stable. 
 
4.  Primary endpoint measures:  The primary derived endpoints are inhibitory concentration 
such as the IC50 value (reported in both micromolar and nanogram/milliliter units) and 
Hill coefficient.  If 50% current inhibition could not be achieved, a justification of the 
highest concentration tested should be provided together with the relation of this 
concentration to therapeutic free and total drug levels.  Where necessary, to isolate the 
current-of-interest, the background current remaining after a high concentration of 
selective blocker application should be subtracted.  If current inhibition with a selective 
blocker could not be achieved, leak current can be calculated and subtracted from the 
current traces.  This approach assumes that only the current-of-interest is voltage-
dependent, hence evidence and justification should be provided on why it was used. 
 
5.  Data summary:  Inhibition at each drug concentration for each cell should be provided, 
along with the mean values of IC50 and Hill coefficient (and appropriate measures of 
data variability).  To demonstrate recording quality, the study report should also contain 
time-course plots of current amplitude, input resistance, holding current for individual 
cells in control condition followed by drug application, and drug equilibration.  If time-
  20  Contains Nonbinding Recommendations 
 
dependent changes such as current run-up or run-down in baseline condition were 
corrected for drug inhibition estimation, the correction method applied should be 
described. 
 
6.  Concentration verification:  The concentration of test compound to which the cells were 
exposed should be verified by applying a validated analytical method to the solution 
collected from the cell chamber.  Both nominal and measured concentrations should be 
reported.  If the nominal and measured concentrations differ significantly from each 
other, measured concentrations should be used to construct the concentration-response 
relationship to estimate IC50 and Hill coefficient. 
 
7.  Positive and negative controls:  The positive control drug should be one of the reference 
drugs referred to in S7B Q&A Q18 (1.2).  The positive control drug should be tested 
using sufficient replicates and two or more concentrations achieving 20-80% block, to 
demonstrate consistency and reproducibility with the reference drug data.  If positive 
control data fall outside the range of expected values, then the study is inconclusive, and 
it is not recommended that the data be used to support the purposes outlined in ICH E14 
Q&As Q12 (5.1) and Q13 (6.1).  Vehicle (negative) controls should be included in the 
experiments.  The vehicle should include all non-compound materials in the test article 
solution, such as solubilizing agents and preservatives. 
 
Q20.  What are the relevant endpoints of an informative in vitro human cardiomyocyte 
repolarization follow-up study? (2.2) 
 
As outlined in the ICH S7B guidance, follow-up studies (section II.C.5 (2.3.5)) can include in 
vitro ventricular repolarization assays.  Follow-up studies are not performed for all submissions 
and are often designed to address specific issues.  Since implementation of the ICH S7B 
guidance, new technologies have become available, including assays with human-induced 
pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).  S7B Q&As Q20 (2.2) to Q23 (2.5) 
outline best practice considerations when in vitro cardiomyocyte assays are performed as follow-
up studies. 
 
Drug-induced changes in the intracellular or extracellular action potential waveforms recorded 
from hiPSC-CM preparations and acutely isolated adult human ventricular myocytes reflect the 
integrated effect on multiple ionic currents, exchangers, and carriers. Changes in cellular 
repolarization recognized as markers of ventricular proarrhythmia include delayed and abnormal 
repolarization (manifest as early afterdepolarizations, triggered activity or irregular beating) and 
should be noted. 
 
Drug-induced effects on cardiomyocyte calcium handling (calcium transients, contractility, or 
calcium homeostasis) could affect electrophysiological activity.  These effects may manifest as 
abnormal mechanical activity associated with proarrhythmic mechanisms (e.g., prolonged 
contractions, single or multiple premature contractions linked to triggered electrical activity such 
as early afterdepolarizations).  The assessment of changes in calcium handling is useful for 
describing the presence or absence of potential proarrhythmic activity.  However, such measures 
are inadequate to fully characterize the electrophysiological effects of a drug on repolarization. 
  21  Contains Nonbinding Recommendations 
 
 
Q21.  What elements of the test system should be considered for an in vitro human 
cardiomyocyte repolarization assay? (2.3) 
 
It is important to describe the biological preparation and technology platform that define baseline 
electrophysiological characteristics and drug responses. 
 
  Biological preparation:  The origins of cells studied, and human donor characteristics 
should be specified.  If complex preparations containing hiPSC-CMs are used (e.g., co-
cultures, organoids, engineered heart tissues), descriptions of the protocols used in 
creating these preparations should be provided.  For primary human cardiomyocyte 
preparations, the tissue sources, harvesting, isolation, and enrichment procedures 
followed should be described.  Acceptable morphological and functional inclusion 
criteria for the preparations as well as electrophysiologic characteristics (including 
baseline action potential/field potential durations, spontaneous beat frequency and 
variability (if applicable), resting membrane potential, upstroke characteristics, 
conduction patterns and/or velocity) should be clearly defined.  Estimates of the 
proportion of preparations fulfilling criteria should be included. 
 
  Technology platform:  The methodologies used (e.g., transmembrane potential recordings 
(whole cell patch clamp, sharp electrode, or voltage-sensing dye approaches), 
extracellular recordings using field potentials, visual or impedance-based motion 
approaches, or calcium-sensing dyes) should be clearly described.  The analysis package 
used for marking and interpreting waveforms should be described, with representative 
recordings (along with pertinent waveform markings) provided.  A description of the 
plates or chambers used (including presence or absence of flow, substrate composition, 
recording electrode characteristics) should be provided. 
 
Q22.  What are important considerations when designing and implementing experimental 
protocols for in vitro cardiomyocyte repolarization studies? (2.4) 
 
Protocols should be designed to address a specific question (e.g., concentration-dependent effects 
on repolarization).  The rationale of choosing a single- or sequential-dose protocol should be 
provided.  Bath temperature should be stable at physiologic (3537 oC) temperature.  The 
sampling window for data collection should be clearly defined.  Deviations from protocols 
should be clearly described, along with expected consequences. 
 
  For spontaneously beating preparations, changes in beating rate influence repolarization 
independent of direct drug effects on repolarizing currents.  Spontaneous beat rates in the 
absence and presence of drugs should be clearly indicated along with the extent of drug-
induced rate changes.  The choice and justification of correction formula used when 
assessing repolarization effects in such preparations should be provided.  Due to 
limitations of rate correction in spontaneously beating hiPSC-CMs, interpretation of 
potential repolarization changes may not be possible when a drug causes a rate change. 
 
  22  Contains Nonbinding Recommendations 
 
  For paced preparations, the pacing protocol (pattern and duration) should be described 
and performed in the presence and absence of test compound. 
 
  To demonstrate recording quality, the study report should contain time-course plots of 
primary endpoints (demonstrating drug equilibration) and other parameters that can be 
used to infer stability of the preparations and signal recordings. 
 
  Concentration-dependent repolarization effects can be derived based on vehicle-
corrected and/or baseline subtracted comparisons of drug versus vehicle treated 
preparations.  For higher throughput multi-well platforms, it is preferable to conduct 
vehicle and test drug studies on the same plate.  The number of replicates (useful for 
evaluating reproducibility but not inferential statistical testing) should be reported.  
Power calculations are helpful to establish statistical sensitivity to repolarization 
endpoints. 
 
  It is important to characterize drug exposures during in vitro cardiomyocyte 
repolarization studies.  For well-based studies, drug exposures could be verified using 
media sampled from test wells or from satellite studies (parallel studies using identical 
protocols and study conditions conducted without measuring electrophysiologic 
measurements).  With continuous flow systems, the sampling of effluent from test 
chambers is valuable for assessing drug exposures.  Exposures should be presented as 
total drug concentration and free drug concentrations (if plasma protein binding 
characteristics in the media used is known). 
 
Q23.  How does one define biological sensitivity of a cardiomyocyte in vitro repolarization 
assay? (2.5) 
 
The electrophysiologic sensitivity of cardiomyocyte preparations should be calibrated with 
established positive controls to confirm their fit for purpose role in defining pharmacological 
block of cardiac ion channel(s).  This is readily accomplished by constructing concentration- 
response curves with recognized and specific ion current blocking agents. 
 
  At minimum, it is important to characterize sensitivity to block of the prominent outward 
repolarizing current IKr/hERG with specific blocking agents (e.g., E-4031 or dofetilide) 
over relevant concentration ranges. 
 
  Block of the inward L-type calcium current (ICaL) and late sodium current (INaL) may 
mitigate delayed repolarization.  Demonstrating sensitivity to specific ICaL (e.g., 
nifedipine or nisoldipine) and INaL (e.g., mexiletine or lidocaine) blocking agents is 
helpful for clarifying integrated cellular electrophysiological responses of multi-channel 
blocking drugs. 
 
 
  23  Contains Nonbinding Recommendations 
 
III.  BEST PRACTICE CONSIDERATIONS FOR THE IN VIVO QT STUDIES (3) 
 
Q24.  What are best practice considerations for species selection and general design of the 
(standard) in vivo QT study? (3.1) 
 
The most appropriate species should be selected and justified (ICH S7B guidance, section II.C 
(3.1.3)).  It is preferable to use the same animal species in the safety pharmacology and non-
rodent toxicity studies to facilitate understanding of the possible relationship between adverse 
cardiovascular pharmacodynamic effects and structural effects on the heart, and to obtain 
complementary information on systemic exposure level (toxicokinetics). 
 
Although it is customary to use conscious freely moving telemeterized animals for the in vivo 
QT studies, the choice of alternative model approaches (e.g., anesthetized or paced animals) 
might be justified in certain circumstances to achieve adequate exposures or to overcome 
specific compound-related challenges (e.g., changes in heart rate, tolerability, or bioavailability 
limitations in conscious animals). 
 
Q25.  What should be considered for exposure assessment during the in vivo QT study? 
(3.2) 
 
The ICH S7B guidance states that drug exposures should include and exceed anticipated 
therapeutic concentrations.  If the in vivo QT data are to be used as part of an integrated risk 
assessment for situations described in ICH E14 Q&As Q12 (5.1) and Q13 (6.1), the exposure 
should cover the anticipated high clinical exposure scenario (see S7B Q&A Q17 (1.1)).  An 
assessment of exposure in the same animals used for the pharmacodynamic assessment is 
encouraged.  Sampling should take place at relevant timepoints and in a manner that limits 
interference with the pharmacodynamic effects.  This could be done by sampling complete 
pharmacokinetic profiles in the same animals on a separate day after an adequate washout or 
different animals.  At least one pharmacokinetic sample should be obtained during the 
pharmacodynamic assessment day to demonstrate consistency with the full pharmacokinetic 
profiles.  In certain cases, the analysis of QTc interval together with adequate pharmacokinetic 
sampling makes it possible to perform dedicated exposure-response modeling similar to 
concentration-QT analysis for clinical QT studies.  This can be helpful when the study should be 
powered to detect an effect similar to dedicated QT studies in humans (e.g., when using in vivo 
QT data as part of an integrated nonclinical and clinical risk assessment as described in ICH E14 
Q&A Q13 (6.1)) because it can reduce the number of animals in accordance with the 3R 
(reduce/refine/replace) principles.  In addition, exposure-response modeling may be helpful in 
other circumstances when QT prolongation is observed or anticipated based on hERG assay 
results. 
 
Q26.  What information is needed to support the choice of heart rate correction method in 
an in vivo QT assay? (3.3) 
 
Optimally, the sponsor should demonstrate the independence of QTc to RR (RR is the time 
between heart beats, measured as R waves on the ECG) intervals observed in the study through 
QTc versus RR plots accompanied by additional information (e.g., number of matched QTc-RR 
  24  Contains Nonbinding Recommendations 
 
pairs, correlation metric, 95% confidence intervals, p-values). QT-RR interval relationship is 
also important.  Justification of correction factors used for QT measures should be provided 
when test drugs affect heart rate.  In certain cases, individual QT correction based on QT-RR 
relationship is a preferred method because it is more accurate and sensitive than the general 
methods such as Bazett, Fridericia, or Van de Water when the test drugs affect heart rate.  The 
main reason for not using correction formulae based on historical data is the fixed-rate correction 
coefficients.  Non-rodent species show species-specific and individual differences in their QT-
RR relationships. 
 
Q27.  How should the sensitivity of the assay be evaluated? (3.4) 
 
The test system used for an in vivo QT assay should provide a robust response.  Assay sensitivity 
of relevant functional endpoints should be evaluated and reported to enable data interpretation 
(in supporting initiating first-in-human studies and/or an integrated nonclinical and clinical 
integrated risk assessment to be applied under the scenarios in ICH E14 Q&A Q12 (5.1) or Q13 
(6.1) and contextualization.  Demonstration of assay sensitivity can be achieved by defining 
minimum detectable differences and testing the effects of positive controls.  Statistical power 
calculations could also be provided from historical data from the same laboratory using the 
identical protocol.  If historical positive control data are used to justify assay sensitivity or 
statistical power is calculated from historical control data, then the variance of the present data 
should be consistent with that seen historically. 
 
If study results are to be used to support an integrated nonclinical and clinical risk assessment 
described in ICH E14 Q&A Q13 (6.1), then the study should have sensitivity to detect a QTc 
prolongation effect of a magnitude similar to dedicated clinical QT studies, taking into 
consideration inter-species differences in the normal range of values for the QTc interval.  The 
overall sensitivity of the nonclinical assay in comparison to clinical QT studies depends on both 
the electrocardiographic assessment and the exposure achieved in the in vivo assay relative to 
high clinical exposure.  This can help reduce the numbers of animals used in accordance with the 
3R (reduce/refine/replace) principles.  The following hypothetical example is offered for 
consideration with recognition that the QTc threshold and exposure multiples selected for a 
particular study should be justified by data obtained in the specific species tested, using 
recognized reference compounds under conditions consistent with the best practice 
recommendations set forth in these S7B Q&As. 
 
  Hypothetical Example:  The minimal detectable difference might be 5 milliseconds if 
drug exposure in the animal study only covers the high clinical exposure, but might be 
higher if a larger multiple of high clinical exposure is achieved (e.g., 10 milliseconds if 
3X high clinical exposure is achieved, or a higher QTc threshold if an even larger 
multiple is achieved). 
 
Q28.  What are the recommended conventions for presenting the pharmacodynamic
  and pharmacokinetic results of an in vivo QT assay? (3.5) 
 
  25  Contains Nonbinding Recommendations 
 
Pharmacodynamic Content 
 
  Summary tables and figures showing absolute mean values, mean percentage change 
from baseline, confidence intervals, and p-values for changes from baseline and vehicle 
control should be included. 
 
  If study results are being used to support ICH E14 Q&A Q13 (6.1), then data from 
positive controls should be included or appended.  If historical positive controls are used, 
then the variance of the present data should be consistent with that seen historically, 
which can be demonstrated by reporting minimal detectable differences with by time 
analysis.  A statement should be provided that the data for the new drug and the historical 
data were collected according to the same protocol and statistical analysis plan.  If 
deviations are present, they should be clearly justified.  If concentration-QTc modeling is 
performed, reporting should follow similar principles as for human concentration-QTc 
modeling (see ICH E14 Q&A Q12 (5.1)). 
 
Pharmacokinetic Content 
 
  Tabulations of summary statistics for C , AUC, and T  for the parent drug and 
max max
metabolites along with plasma concentration versus time plots (if sufficient samples have 
been collected to support their calculation) should be provided. 
 
Individual animal data should be provided. 
 
 
IV.  PRINCIPLES FOR PROARRHYTHMIA MODELS (4) 
 
Q29.  The ICH S7B guidance (section III.D (3.1.4)) states that directly assessing the 
proarrhythmic risk of pharmaceuticals that prolong the QT interval would be a 
logical undertaking and interested parties are encouraged to develop these models 
and test their usefulness in predicting risk in humans.  What are general principles 
to evaluate whether a proarrhythmic risk prediction model could be used as part of 
an integrated risk assessment strategy? (4.1) 
 
Different models, including in silico, in vitro, ex vivo and in vivo models, have the potential to 
be used as part of an integrated risk assessment strategy to evaluate the proarrhythmic risk of 
QT-prolonging pharmaceuticals in humans. Using in vitro and in silico models can also reduce 
animal use in accordance with the 3R (reduce/refine/replace) principles. Because these models 
have a common feature of using nonclinical experimental data as input and generating human 
proarrhythmia risk prediction as output, they can generally be referred to as proarrhythmia risk 
prediction models.  The model input can vary among different models, for example, ion channel 
pharmacology data as input to in silico models, drug-induced changes in cellular repolarization 
and/or arrhythmia events as input to hiPSC-CM models, and drug- induced electrocardiographic 
changes as input to ex vivo/in vivo models.  However, the model output (either discrete risk 
categories or continuous risk scores) is similar among different models.  Such a feature makes it 
possible to develop generic principles for evaluating the predictivity of proarrhythmia risk 
  26  Contains Nonbinding Recommendations 
 
prediction models without specifying the type of underlying experimental data used as model 
input.  The following general principles should be applied to all proarrhythmia risk prediction 
models intended to be used as part of an integrated risk assessment for regulatory purposes.  
Although the main focus of these principles is to evaluate a models predictivity of TdP risk, 
they are general enough to guide the development of models predicting different types of 
proarrhythmia. 
 
1.  A defined endpoint consistent with the context of use of the model.  Examples of model 
endpoints (e.g., TdP risk versus QT prolongation risk) can be found in Li et al. 2020.8 
 
2.  A fully disclosed algorithm to translate experimental measurements (model input) to 
proarrhythmia risk (model output), allowing independent reproduction of the model 
development process using the associated training and validation datasets to evaluate the 
model performance. 
 
3.  A defined domain of applicability/scope and limitations of the model.  This includes the 
experimental protocols to generate model input (experimental data capturing 
pharmacological effects of drug), and the compounds tested should have the same 
arrhythmic mechanisms covered by the model. 
 
4.  A prespecified analysis plan and criteria to assess model predictivity.  The analysis plan 
should include methods to separate the training and validation steps.  In the training step, 
a series of reference compounds is used to adjust the model.  In the validation step, 
another series of reference compounds is used to evaluate the performance of the 
prespecified model.  The reference compounds used for the training and validation steps 
should not overlap. 
 
5.  A mechanistic interpretation of the model, which describes the relationship between the 
model inputs and mechanism for the arrhythmia. 
 
6.  The uncertainty in the model inputs should be captured and propagated to the model 
predictions.  The experimental variability associated with model input should be 
quantified using appropriate statistical methods and then translated into probabilities of 
the predicted risk. 
 
After a proarrhythmia risk prediction model has been developed, a process should be followed to 
evaluate whether the model development complied with these principles. Such a process would 
support that the model is qualified for the intended context of use as part of an integrated risk 
assessment for regulatory purposes.  Some health authorities have procedures for the formal 
qualification of models that allow for a model to be used within the qualified context of use 
without the regulatory authority needing to reconsider and reconfirm its suitability.  Model 
developers are encouraged to contact a regulatory agency about its specific model qualification 
procedures.  After a model has been qualified, the use of such a model is not limited to the 
 
8 Z Li, GR Mirams, T Yoshinaga et al., 2020, General Principles for the Validation of Proarrhythmia Risk Prediction 
Models:  An Extension of the CiPA In Silico Strategy, Clinical Pharmacology & Therapeutics, 107(1): 102-111 
(https://doi.org/10.1002/cpt.1647).  
  27  Contains Nonbinding Recommendations 
 
specific facility that submitted the qualification package.  However, if another facility intends to 
use the qualified model, that facility should perform laboratory-specific calibration and 
validation of the model using a subset of the reference compounds that were originally used to 
develop the model.  An illustrative process of performing laboratory-specific calibration and 
validation is given in Han et al. 2020.9 
 
Q30.  How can a sponsor use a model for regulatory submission and what are the 
limitations? (4.2) 
 
Sponsors can use results from a qualified proarrhythmia model as one component in the totality 
of evidence approach to risk assessment under the context of use for which the model was 
developed and qualified.  When a facility intends to use the model to produce data for regulatory 
submission, a set of control compound(s) should be tested to assess the consistency between the 
new data and the historical laboratory-specific validation data. The number and type of 
laboratory-specific calibration and control compounds should be justified. 
 
If a proarrhythmia model is included in a regulatory submission, proof of qualification of the 
model under the guidance of the general principles in this Q&A should be provided in an 
appendix to the study report.  Supportive documentation could include published papers, if the 
included validation dataset is described in sufficient detail to allow an independent assessment.  
Importantly, the general principles for model qualification set forth in this Q&A only support the 
use of a proarrhythmia risk prediction model as part of an integrated risk assessment that 
incorporates all relevant nonclinical and clinical information. 
 
 
 
9 X Han, M Samieegohar, BJ Ridder et al., 2020, A General Procedure to Select Calibration Drugs for Lab-Specific 
Validation and Calibration of Proarrhythmia Risk Prediction Models:  An Illustrative Example Using the CiPA 
Model, Journal of Pharmacological and Toxicological Methods, 105:106890 
(https://doi.org/10.1016/j.vascn.2020.106890).  
  28