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Step 1 Draft 2 (July 17,
2003) Draft 3 (November 12, 2003), Draft 4 (June 10, 2004)
THE CLINICAL EVALUATION OF QT/QTc INTERVAL PROLONGATION AND
PROARRHYTHMIC POTENTIAL FOR NON-ANTIARRHYTHMIC DRUGS
Preliminary Concept Paper
For Discussion Purposes Only
This draft guidance, when finalized, will
represent the Food and Drug Administration's (FDA's) current
thinking on this topic. It does not create or confer any rights
for or on any person and does not operate to bind FDA or the
public. You can use an alternative approach if it satisfies the
requirements of the applicable statutes and regulations. If you
want to discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
TABLE OF CONTENTS
INTRODUCTION
1.1 Background
1.2 Objectives
1.3 Scope
2.0 CLINICAL TRIALS
2.1 Design
Considerations
2.1.1 Subject Enrollment,
Safety Monitoring, and Discontinuation Criteria
2.1.2 'Thorough
QT/QTc Study': Dose-Effect and Time Course Relationships
2.1.3 Clinical Trial
Evaluation After the ‘Thorough QT/QTc Study
2.2 Collection,
Assessment and Submission of Electrocardiographic Data
2.2.1 Collection of
Standard 12-Lead Electrocardiograms (ECGs)
2.2.2 Assessment of
Standard 12-Lead ECGs
2.2.3 Ambulatory ECG
Monitoring
2.2.4 Submission of
Interval and Waveform Data
3.0 ANALYSIS OF ECG DATA
FROM CLINICAL TRIALS
3.1 QT Interval
Correction Formulae
3.1.1
Population-Derived Correction Formulae
3.1.2
Correction Formulae Derived from
Within-Subject Data
3.2 Analysis of QT/QTc
Interval Data
3.2.1 Analyses of
Central Tendency
3.2.2 Categorical
Analyses
3.2.3 QT/QTc
Interval Dispersion
3.3 Morphological
Analyses of ECG Waveforms
4.0 ADVERSE EVENTS
4.1 Clinical Trial
Adverse Event Reports
4.2 Premature
Discontinuations or Dosage Reductions
4.3 Pharmacogenetic
Considerations
4.4 Post-Marketing
Adverse Event Reports
5.0 REGULATORY
IMPLICATIONS, LABELLING, AND RISK MANAGEMENT STRATEGIES
5.1 Relevance of
QT/QTc Interval Prolonging Effects to the Approval Process
5.2
Labelling Issues for Drugs that Prolong the QT/QTc Interval
5.3 Post-Marketing
Risk Management for Drugs that Prolong the QT/QTc Interval
THE
CLINICAL EVALUATION OF QT/QTc INTERVAL PROLONGATION AND
PROARRHYTHMIC POTENTIAL FOR NON-ANTIARRHYTHMIC DRUGS
An undesirable
feature of some non-antiarrhythmic drugs is their ability to delay
cardiac repolarization, an effect that can be measured as
prolongation of the QT interval on the surface electrocardiogram (ECG).
The QT interval represents the duration of ventricular
depolarization and subsequent repolarization, beginning at the
initiation of the QRS complex and ending where the T wave returns to
isoelectric baseline. A delay in cardiac repolarization creates an
electrophysiological environment that favors the development of
cardiac arrhythmias, most clearly torsade de pointes, but possibly
other ventricular arrhythmias as well. Torsade de pointes (TdP) is
a polymorphic ventricular tachyarrhythmia that appears on the ECG as
continuous twisting of the vector of the QRS complex around the
isoelectric baseline. A feature of TdP is pronounced prolongation
of the QT interval in the supraventricular beat preceding the
arrhythmia. TdP can degenerate into ventricular fibrillation,
leading to sudden death.
While the degree of
QT prolongation is recognized as an imperfect biomarker for
proarrhythmic risk, there is a qualitative relationship between QT
prolongation and the risk of TdP, especially for drugs that cause
substantial prolongation of the QT/QTc interval.
Because of its
inverse relationship to heart rate, the QT interval is routinely
transformed (normalized) by means of various formulae into a heart
rate independent “corrected” value known as the QTc interval. The
QTc interval is intended to represent the QT interval at a
standardized heart rate of 60 bpm. For drugs that prolong the QT/QTc
interval, the mean degree of prolongation has been roughly
correlated with the observed risk of clinical proarrhythmic events.
It is not clear, however, whether arrhythmia development is more
closely related to an increase in the absolute QT interval or an
increase in the relative (“corrected”) QT interval (QTc). Most
drugs that have caused TdP clearly increase both the absolute QT and
the QTc (hereafter called QT/QTc). The combination of QT/QTc
interval prolongation and documented cases of TdP (fatal and
non-fatal) associated with the use of a drug has resulted in
regulatory actions, including withdrawal from the market, relegation
to second-line status or denial of marketing authorization. Because
prolongation of the QT/QTc interval is the ECG finding associated
with the increased susceptibility to these arrhythmias, an adequate
pre-marketing investigation of the safety of a new pharmaceutical
agent should include rigorous characterization of its effects on the
QT/QTc interval. The relevant non-clinical and clinical data will
be used to make an integrated assessment of proarrhythmic risk for
novel drug therapies.
1.2
Objectives
This document
provides recommendations to sponsors concerning the design, conduct,
analysis, and interpretation of clinical studies to assess the
potential of a drug to delay cardiac repolarization. This
assessment should include testing the effects of new agents on the
QT/QTc interval as well as the collection of cardiovascular adverse
events. The investigational approach used for a particular drug
should be individualized, depending on the pharmacodynamic,
pharmacokinetic, and safety characteristics of the product, as well
as on its proposed clinical use.
The assessment of
the effects of drugs on cardiac repolarization is the subject of
active investigation. When additional data (non-clinical and
clinical) are accumulated in the future, this document may be
reevaluated and revised.
1.3 Scope
The recommendations contained in this document
are generally applicable to new drugs having systemic
bioavailability. The focus is on agents being developed for
uses other than the control of arrhythmias, as antiarrhythmic drugs
can prolong the QT/QTc interval as a part of their mechanism of
clinical efficacy. While this document is
concerned primarily with the development of novel agents, the
recommendations might also be applicable to approved drugs when a
new dose or route of administration is being developed that results
in significantly higher Cmax or AUC values. Additional
ECG data might also be considered appropriate if a new indication or
patient population were being pursued. The evaluation of the effect
of a drug on the QT interval would also be considered important if
the drug or members of its chemical or pharmacological class have
been associated with QT/QTc interval
prolongation, TdP, or sudden cardiac death during post-marketing
surveillance.
2.1 Design Considerations
In general, drugs
should receive an electrocardiographic evaluation, beginning early
in clinical development, typically including a single trial
dedicated to evaluating their effect on cardiac repolarization
(‘thorough QT/QTc study’). The ability of a drug to prolong the QT/QTc
interval is linked to pharmacologic effects that can be investigated
in non-clinical models as well as clinically. At present, whether
non-clinical testing can exclude a clinical risk for QT/QTc
prolongation is controversial. Conduct of the ‘thorough QT/QTc
study’, as described in section 2.1.2, would be needed in almost all
cases for regions where non-clinical data are not considered able to
preclude risk of QT/QTc prolongation. For regions where
non-clinical data are considered informative enough about the risk
of QT/QTc prolongation in humans, the recommendations in this
guidance for the clinical evaluation of QT/QTc could be modified.
Additional factors that could influence the need for such a study
include duration of treatment, metabolic profile, pharmacodynamic
duration of action, and previous experience with other members of
the same chemical or pharmacological class.
As discussed
below, the results of the ‘thorough QT/QTc study’ will influence the
amount of information collected in later stages of development:
·
A negative ‘thorough QT/QTc study’, even in the
presence of non-clinical data of concern, will almost alwaysallow
the collection of on-therapy ECGs in accordance with the current
practices in each therapeutic area to constitute sufficient
evaluation during subsequent stages of drug development (see section
2.1.3);
·
A positive ‘thorough QT/QTc study’ will almost always
call for an expanded ECG safety evaluation during later stages of
drug development (see section 2.1.3).
Subject enrollment, discontinuation criteria
and safety monitoring for a given trial would be influenced by the
clinical and non-clinical information available on the effects of
the drug on cardiac repolarization.
Regarding subject
enrollment, until the effects of the drug on the QT/QTc interval
have been characterized, the following exclusion criteria are
suggested:
·
A marked baseline prolongation of QT/QTc interval (e.g.,
repeated demonstration of a QTc interval >450);
·
A history of additional risk factors for TdP (e.g.,
heart failure, hypokalemia, family history of Long QT Syndrome);
·
The use of concomitant medications that prolong the
QT/QTc interval;
If supported by the
QT/QTc interval safety data from the early studies, later
clinical trials could expand the eligibility criteria to include a
broader spectrum of patients who are likely to receive the drug once
approved.
Regarding safety
monitoring, the procedures to follow if a patient experiences an
adverse event suggestive of TdP should be specified in the clinical
trial protocol.
Discontinuation of
a subject from a clinical trial should be considered if there is a
marked prolongation of the QT/QTc interval during treatment with the
study drug, especially if the measurement is obtained from more than
one ECG. While increases in QT/QTc to >500 ms or of >60 ms over
baseline are commonly used as thresholds for potential
discontinuation, the exact criteria chosen for a given trial will
depend on the risk-tolerance level considered appropriate for the
indication and patient group in question.
2.1.2 The ‘Thorough QT/QTc Study’:
Dose-Effect and Time Course Relationships
An adequate drug
development programme should ensure that the dose-response and
generally the concentration-response relationship for QT/QTc
prolongation have been characterized, including exploration of
concentrations that are higher than those achieved following the
anticipated therapeutic doses. Data on the drug concentrations
around the time of ECG assessment would aid this assessment. If not
precluded by considerations of safety or tolerability due to adverse
effects, the drug should be tested at substantial multiples of the
anticipated maximum therapeutic exposure. Alternatively, if the
concentrations of a drug can be increased by drug-drug or drug-food
interactions involving metabolizing enzymes (e.g., CYP3A4,
CYP2D6) or transporters (e.g., P-glycoprotein), these studies
can be performed under conditions of maximum inhibition. This
approach calls for a detailed understanding of the absorption,
distribution, metabolism and excretion of the drug. In general, the
duration of dosing or dosing regimen should be sufficient to
characterize the effects of the drug and its active metabolites at
relevant concentrations.
The ‘thorough QT/QTc
study’ is intended to determine whether the drug has a threshold
pharmacologic effect on cardiac repolarization, as detected by QT/QTc
prolongation. The study is typically carried out in healthy
volunteers (as opposed to individuals at increased risk of
arrhythmias) and is used to determine whether or not the effect of a
drug on the QT/QTc interval in target patient populations need to be
studied intensively during later stages of drug development.
Although data are limited, it is expected that the results of the
‘thorough QT/QTc study’ would not be affected by ethnic factors.
The ‘thorough QT/QTc
study’ would typically be conducted early in clinical development to
provide maximum guidance for later trials, although the precise
timing will depend on the specifics of the drug under development.
It would usually not be the first study, as it is important to have
basic clinical data for its design and conduct, including
tolerability and pharmacokinetics. It would often be conducted in
healthy volunteers. Some drugs might not be suitable for study in
healthy volunteers because of issues related to tolerability (e.g.,
neuroleptic agents, chemotherapeutics).
The timing of the collection of ECGs and the study design (e.g.,
single or multiple dose, duration) of the ‘thorough QT/QTc study’
should be guided by the available information about the
pharmacokinetic profile of the drug. For drugs with short
half-lives and no metabolites, a single dose study might be
sufficient. Studies should characterize the effect of a drug on the
QT/QTc throughout the dosing interval. While the peak serum
concentration does not always correspond to the peak effect on QT/QTc
interval, care should be taken to perform ECG recordings at time
points around the Cmax. As one intent of a positive control is to
establish assay sensitivity, in multiple dose studies of new drugs a
positive control only needs to be used long enough to have its
expected effect.
The ‘thorough QT/QTc
study’ should be adequate and well-controlled, with mechanisms to
deal with potential bias, including use of randomization,
appropriate blinding, and concurrent placebo control group. As this
study has a critical role in determining the intensity of data
collection during later stages of drug development, it is important
to have a high degree of confidence in the ability of the study to
detect differences of clinical significance. The confidence in the
ability of the study to detect QT/QTc prolongation can be greatly
enhanced by the use of a concurrent
positive control group to establish assay sensitivity.
Absence of a positive control should be justified and alternative
methods to establish assay sensitivity provided. It is difficult to
determine whether there is an effect on the mean QT/QTc interval
that is so small as to be of no consequence. However, drugs that
prolong the mean QT/QTc interval by around 5 ms or less do not
appear to cause TdP. On that basis, the positive control (whether
pharmacological or non-pharmacological) should be well-characterized
and consistently produce an effect corresponding to the largest
change in the QT/QTc interval that is currently viewed as clinically
not important to detect (a mean change of around 5 ms or less).
Based on similar
considerations, a negative ‘thorough QT/QTc study’ is one where the
largest time-matched mean difference between the drug and placebo
(baseline-subtracted) for the QTc interval is around 5 ms or less,
with a one-sided 95% confidence interval that excludes an effect
>8.0 ms.
This upper bound was chosen to reflect the uncertainty related to
the variability of repeated measurements. As with other data, the
presence of outliers (see section 3.2.2) should also be explored.
If an
investigational drug belongs to a chemical or pharmacological class
that has been associated with QT/QTc prolongation, a positive
control selected from other members of the same class is recommended
to permit a comparison of effect sizes, preferably at equipotent
therapeutic doses.
Crossover or
parallel group study designs can be suitable for trials assessing
the potential of a drug to cause QT/QTc interval prolongation.
Crossover studies at least have two potential advantages:
·
They usually call for smaller numbers of subjects than
parallel group studies, as the subjects serve as their own controls
and hence reduce variability of differences related to diurnal
variations and inter-subject variability;
·
They might facilitate heart rate correction approaches
based on individual subject data.
Parallel group
studies might be preferred under certain circumstances:
·
For drugs with long elimination half-lives for which
lengthy time intervals would be required to achieve steady-state or
complete washout;
·
If carryover effects are prominent for other reasons,
such as irreversible receptor binding or long-lived active
metabolites;
·
If multiple doses or treatment groups are to be
compared.
A critical problem in the measurement of the QT/QTc interval is its
intrinsic variability. This variability results from many factors,
including activity level, postural changes, circadian patterns, and
food ingestion. It is considered essential to address intrinsic
variability in the conduct of the ‘thorough QT/QTc study’. This can
be accomplished in several ways, including the collection of
multiple ECGs at baseline and during the study.
2.1.3 Clinical Trial Evaluation After the
‘Thorough QT/QTc Study’
In the absence of
QT/QTc interval prolongation in the ‘thorough QT/QTc study’ (see
section 2.1.2), the collection of baseline and periodic on-therapy
ECGs in accordance with the current investigational practices in
each therapeutic field is, in general, considered appropriate.
If the ‘thorough QT/QTc study’ is positive, additional evaluation in
subsequent clinical studies should be performed. One objective of
this evaluation should be to fully characterize the dose-,
concentration-, and time- relationships of the drug on the QT/QTc
interval in the target patient population(s) at therapeutic and
supratherapeutic serum concentrations. The latter can be achieved
in two ways: through administration of high doses or use of
metabolic inhibitors (if applicable).
Another objective of
this evaluation should be to collect information on the adverse
events that occur in the trials following the positive ‘thorough QT/QTc
study’. This would include patients who develop marked QT/QTc
prolongation (e.g., >500 ms) or experience a serious
cardiovascular adverse event that suggests an arrhythmia (e.g.,
TdP). Such patients should be evaluated closely for risk factors
that might have contributed to this event (e.g., genotyping
for Long QT Syndromes, see section 4.3).
If the ‘thorough
QT/QTc study’ is positive, analyses of the ECG and adverse event
data from certain patient sub-groups are of particular interest,
such as:
·
Patients with electrolyte abnormalities (e.g.,
hypokalemia);
·
Patients with congestive heart failure;
·
Patients with impaired drug metabolizing capacity or
clearance (e.g., renal or hepatic impairment, drug
interactions);
·
Female patients;
·
Patients aged <16 and over 65 years.
Even if the
‘thorough QT/QTc study’ is negative, if other evidence of an effect
in a patient population from subsequent studies (e.g., marked
QT/QTc interval prolongation, TdP) were to emerge, then additional
investigation would be needed.
The recommendations
below are most relevant to the ‘thorough QT/QTc study’ and to any
studies investigating a drug with a known effect on cardiac
repolarization.
Until better ways
are established to assess proarrhythmic risk during drug
development, the measurement of the QT/QTc interval on the surface
ECG is central to the detection of that risk. The clinical ECG
database is typically derived from the collection of 12-lead surface
ECGs, although ambulatory ECG techniques show promise (see section
2.2.3).
2.2.2 Assessment of Standard 12-Lead ECGs
Several methods for
measuring ECG intervals have been used in clinical trials, and for a
given trial, the sponsor should describe the accuracy and precision
of QT/QTc interval measurements using the selected system. The
method chosen will depend on the level of precision needed for a
given trial. For example, the ‘thorough QT/QTc study’ would warrant
particularly careful attention to interval measurement. At present,
this would usually involve the measurement by a few skilled readers
operating from a centralized ECG laboratory, although other methods
(e.g., semi-automated ECG reading) can be acceptable when
appropriately supported. Readers of ECGs should be blinded to time,
treatment and subject identifier, and one reader should read all the
ECG recordings from a given subject. The degree of inter- and
intra-reader variability should be established by having the
assessors reread a subset of the data (both normal and abnormal)
under blinded conditions. Criteria for ECG diagnoses and for
identification of adverse events should be pre-defined by the
sponsor. 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. In the absence of a concern in the early clinical trial(s),
automated ECG readings have a role in the rapid assessment of ECGs
for safety.
The quality of the
ECG database can depend on the use of modern equipment with the
capacity for digital signal processing. Such equipment should be
recently serviced and calibrated. Machine calibration records and
performance data should be maintained on file. In the case of
multicentre trials, training sessions are encouraged to ensure
consistency of operator technique (e.g., skin preparation, lead
placement, patient position) and data acquisition practices.
While the most
appropriate lead(s) and methodology to measure the QT interval have
not been established, lead II is often used. A consistent approach
should be used for a given trial.
Morphological
changes in the T-U complex might occur. Information should be
provided on changes in T and U wave morphologies (see section 3.3).
Discrete U waves should be excluded from the QT/QTc interval
measurement
While ambulatory ECG
monitoring has historically not been sufficiently validated to be
considered as the primary assessment ECG for QT/QTc interval
effects, newer systems that allow for the collection of multiple
leads that more closely approximate a surface ECG have potential
value to collect interval data. The use of ambulatory ECG monitors
might additionally allow detection of extreme QT/QTc interval events
that occur infrequently during the day and asymptomatic
arrhythmias. Data on the QT/RR from ambulatory ECG monitoring can
also prove useful in the calculation of individualized QT
corrections. However, as QT/QTc intervals measured by this
methodology might not correspond quantitatively to those from
standard surface ECGs, data obtained from the two methodologies
might not be suitable for direct comparison, pooling, or
interpretation using the same thresholds of concern.
Regional guidance
should be sought for information on the submission of ECG interval
data and overall assessments.
Evaluation of the effects of a drug on the standard ECG intervals
and waveforms is considered a fundamental component of the safety
database of any new drug application.
Regardless of the outcome of the ‘thorough QT/QTc study’, ECG
changes recorded as adverse events should be pooled from all studies
for analysis. ECG interval data from the ‘thorough QT/QTc study’
should only be pooled with subsequent trials of similar rigor with
regard to ECG data collection and analysis, but should not be pooled
with trials using less rigorous ECG collection. Standardization of
ECG collection for similar studies within a clinical trial programme
will facilitate pooled analyses.
As the QT interval
has an inverse relationship to heart rate, the measured QT intervals
are generally corrected for heart rate in order to determine whether
they are prolonged relative to baseline. Various correction
formulae have been suggested, of which Bazett’s and Fridericia’s
corrections are the most widely used. In early trials evaluating
the effects of a new drug on the QT/QTc interval in healthy
volunteers, designed to detect relatively small effects (e.g.,
5 ms), it is important to apply the most accurate correction
available (e.g., methods using individually-derived
relationships between RR and QT intervals). For later trials, where
less ECG information is available, population-derived corrections,
including standard correction formulae, can provide useful
information.
Because the best
correction approach is a subject of controversy, uncorrected QT and
RR interval data, heart rate data, as well as QT interval data
corrected using Bazett’s and Fridericia’s corrections should be
submitted in all applications, in addition to QT interval data
corrected using any other formulae. The sponsor should pre-specify
the primary correction method. A concurrent positive control group
is strongly encouraged to support the use of newer correction
approaches (e.g., individual subject correction) in order to
demonstrate the ability of the correction method to allow detection
of relevant effects on the QT/QTc interval.
3.1.1
Population-Derived Correction Formulae
Examples of such
corrections include the following:
1) Bazett’s correction: QTc =QT/RR0.5
2) Fridericia’s
correction: QTc = QT/RR0.33
Bazett’s correction is frequently used in clinical practice and in
the medical literature. In general, however, Bazett’s correction
overcorrects at elevated heart rates and under corrects at heart
rates below 60 bpm and hence is not an ideal correction.
Fridericia’s correction is more accurate than Bazett’s correction in
subjects with such altered heart rates.
3) Corrections
based on linear regression techniques
Application of
linear regression techniques to plots of QT/RR data for the placebo
or baseline study population allows for the estimation of the slope
(b), which can be used for standardizing the data from both the drug
and control groups to a normalized heart rate of 60 beats per
minute, using the equation QT = a + b(RR). The Framingham
correction [QTc = QT + 0.154(1-RR)] is one example of a correction
derived by linear regression.
4) Corrections
using linear or non-linear regression modeling on pooled data from
large databases
3.1.2
Correction Formulae Derived from Within-Subject Data
Corrections for
heart rate using individual subject data have been developed,
applying regression analysis techniques to individual pre-therapy QT
and RR interval data over a range of heart rates, then applying this
correction to on-treatment QT values. These approaches are
considered most suitable for the ‘thorough QT/QTc study’ and early
clinical studies, where it is possible to obtain many QT interval
measurements for each study subject. As adaptation of the QT/QTc
interval to changes in heart rate is not instantaneous, care should
be taken to exclude ECG recordings collected during times of rapid
heart rate changes due to this QT/RR hysteresis effect.
Although increases from baseline in the QT/QTc interval constitute
signals of interest, interpretation of these differences is
complicated by the potential for changes not related to drug
therapy, including regression toward the mean and choice of extreme
values. Regression toward the mean refers to the tendency of
subjects with high baseline values to have lower values at later
time points, while subjects with low baseline values tend to
experience increases. The direction of regression depends on
initial selection criteria (for example, if subjects with high
baseline QT/QTc interval values are excluded from the trial, values
recorded during treatment will tend to rise relative to baseline
levels). The process of choosing the highest of multiple observed
values will also almost invariably cause an apparent change from any
single baseline value, a phenomenon found in both drug and
placebo-treated groups.
The QT/QTc interval data should be presented both as analyses of
central tendency (e.g., means, medians) and categorical
analyses. Both can provide relevant information on clinical risk
assessment.
The effect of an
investigational drug on the QT/QTc interval is most commonly
analyzed using the largest time-matched mean difference between the
drug and placebo (baseline-subtracted) over the collection period (e.g.,
hourly, weekly, monthly). Additional approaches to the assessment
of central tendency could include analysis of time-averaged QT/QTc
intervals or analysis of changes occurring at the Cmax for each
individual.
Categorical analyses of QT/QTc interval data are based on the number and
percentage of patients meeting or exceeding some predefined upper
limit value. Clinically noteworthy QT/QTc interval signals might be
defined in terms of absolute QT/QTc intervals or changes from
baseline. Absolute interval signals are QT/QTc interval readings in
excess of some specified threshold value. Separate analyses should
be provided for patients with normal and elevated baseline QT/QTc
intervals. As with all QT/QTc interval analyses, categorical
analyses are most informative when it is possible to compare the
rate of supra-threshold readings in the treatment and control
groups.
There is no consensus concerning the choice of upper limit values
for absolute interval signals and change from baseline signals.
While lower limits increase the false-positive rate, higher limits
increase the risk of failing to detect a signal. In clinical
trials, a prolongation of QTc > 500 ms during therapy has been a
threshold of particular concern. Multiple analyses using different
signal values are a reasonable approach to this uncertainty,
including:
·
Absolute QTc interval
prolongation:
·
QTc interval >
450
·
QTc interval >
480
·
QTc interval >
500
·
Change from baseline in QTc interval:
·
QTc interval increases from baseline
³30
·
QTc interval increases from baseline
³60
QT/QTc interval
dispersion, defined as the difference between the shortest and the
longest QT/QTc interval measured on the 12-lead ECG, has been
thought to reflect the regional heterogeneity of cardiac
repolarization. Normal values are typically in the range of 40-60
ms. Absolute values of ³100
ms and changes from baseline of >100% have been suggested as
clinically noteworthy signals for categorical analyses. The value
of assessment of QT/QTc interval dispersion as a measure of
proarrhythmic risk of a drug is, however, the subject of debate, and
the predictive value of this parameter has yet to be demonstrated.
Analyses of QT/QTc dispersion should therefore be used, if at all,
to supplement more standard analyses of QT/QTc interval duration.
While the predictive value of changes in ECG morphology, such as the
development of U waves, has not been established, morphological
abnormalities should be described and the data presented in terms of
the number and percentage of subjects in each treatment group having
changes from baseline that represent the appearance or worsening of
the morphological abnormality. Typically these data will be
obtained as a part of the ‘thorough QT/QTc study’.
4.0 ADVERSE Events
In addition to data on changes in ECG intervals, adverse event data
can be another source of information on proarrhythmic potential,
including:
-
Premature discontinuations and dosage adjustments during clinical
studies;
-
Post-marketing adverse event reports if available.
Although
drug-induced prolongation of the QT/QTc interval is usually
asymptomatic, an increased rate of certain adverse events in
patients taking an investigational agent can signal potential
proarrhythmic effects. The rates of the following clinical events
should be compared in the treated and control patients, particularly
when there is evidence of an effect on the QT/QTc interval:
·
Torsade de pointes;
·
Sudden death;
·
Ventricular tachycardia;
·
Ventricular fibrillation and
flutter;
·
Syncope;
·
Dizziness;
·
Seizures.
Torsade de pointes (TdP)
is infrequently captured in most clinical databases, even those for
drugs known to have significant proarrhythmic effects. Given this,
the failure to observe an episode of TdP in a drug application
database is not considered sufficient grounds for dismissing the
possible arrhythmogenic risks of a drug when these are suspected on
the basis of ECG and other clinical data. The other adverse events
listed above, while less specific for an effect on cardiac
repolarization, are more commonly captured in clinical trials, and
an imbalance in their frequency between study groups can signal a
potential proarrhythmic effect of the investigational agent.
Sub-group analyses should be conducted in terms of age, gender,
pre-existing cardiac disease, electrolyte disturbances, and
concomitant medications. Comparing cause-specific rates of death is
difficult, but a difference in the fraction of total deaths
qualifying as “sudden” has also been proposed as a marker for
proarrhythmic potential.
Detailed patient
narratives should be provided for all serious cardiac adverse
events, as would be the case for any serious event or events leading
to discontinuation. In assessing the possible causal relationship
of drug-induced QT/QTc interval prolongation to the event, attention
should be directed to considerations such as temporal relationship
and ECG results collected at the time of the event. As the QT/QTc
interval is subject to considerable fluctuation, a possible role for
QT/QTc interval prolongation should not be dismissed on the basis of
normal on-therapy ECG measurements performed prior to, or near the
time of the adverse event. In addition to an appropriate adverse
reaction report, patients with marked QT/QTc prolongation or an
episode of TdP might provide useful information on risk management.
When identified, they should therefore be examined closely for other
risk factors (e.g., genetic predisposition, see section
4.3). Rechallenge with the investigational drug under appropriately
monitored conditions can provide useful information on dose- and
concentration-response relationships.
In evaluating the
safety database of a new drug, consideration should be given to the
extent to which the inclusion and exclusion criteria for patient
eligibility might have influenced the study population with respect
to the risk of QT/QTc interval prolongation and associated adverse
events (e.g., exclusion of patients with cardiac
co-morbidities or renal/hepatic impairment, prohibition of diuretics
as concomitant medications). Ideally, the major clinical studies
should include an adequate representation of female and elderly
patients, as well as patients with co-morbidities and concomitant
medications typical of the expected user population.
If a subject
experiences symptoms or ECG findings suggestive of an arrhythmia
during a clinical trial, immediate evaluation by a cardiac
specialist is recommended, both for the purposes of treating the
patient and for discussions related to continuation/ re-institution
of the therapy.
Particular
attention should be directed to subjects or patients who are
discontinued from clinical trials due to QT/QTc interval
prolongation. Information should be provided on the basis for
premature discontinuation of the patient (e.g., a QT/QTc
interval value in excess of a protocol-defined upper limit,
occurrence of QT/QTc interval prolongation in association with
symptoms of arrhythmia), as well as the dose and duration of
treatment, plasma levels if available, demographic characteristics,
and the presence or absence of risk factors for
arrhythmia.
Dosage reductions
prompted by QT/QTc interval prolongation should also be documented.
Many forms of Long
QT Syndrome are now known to be linked to mutations in genes
encoding cardiac ion channel proteins. Because of incomplete
penetrance, not all carriers of mutated ion channel genes will
manifest QT/QTc interval prolongation in screening ECG evaluations.
Common polymorphisms can affect ion channels, leading to an
increased sensitivity to drugs that affect repolarization. When
possible, and following informed consent, patients who experience
marked prolongation of the QT/QTc or TdP while on drug therapy
should be genotyped.
Because documented cases of TdP are relatively rare, even for drugs
that prolong the QT/QTc, they are often not reported until large
populations of patients have received the agent in post-marketing
settings. The available post-marketing adverse event data should be
examined for evidence of QT/QTc interval prolongation and TdP and
for adverse events possibly related to QT/QTc interval prolongation,
such as cardiac arrest, sudden cardiac death and ventricular
arrhythmias (e.g., ventricular tachycardia and ventricular
fibrillation). A well-characterized episode of TdP has a high
probability of being related to drug use, whereas the other events
that are reported more commonly would be of particular concern if
reported in a population at low risk for them (e.g., young
men experiencing sudden death).
Substantial
prolongation of the QT/QTc interval, with or without documented
arrhythmias, could be the basis for non-approval of a drug or
discontinuation of its clinical development, particularly when the
drug has no clear advantage over available therapy and available
therapy appears to meet the needs of most patients. Failure to
perform an adequate non-clinical and clinical assessment of the
potential QT/QTc interval prolonging properties of a drug can
likewise be justification to delay or deny marketing authorization.
For non-antiarrhythmic drugs, the outcome of the risk benefit
assessment will generally be influenced by the size of the QT/QTc
interval prolongation effect, whether the effect occurs in most
patients or only in certain defined outliers, the overall benefit of
the drug, and the utility and feasibility of risk management
options. The inclusion of precautionary material in the prescribing
information will not necessarily be considered an adequate risk
management strategy, if implementation of the recommendations in a
clinical use setting is judged to be unlikely.
If QT/QTc interval
prolongation is a feature shared by other drugs of the therapeutic
class in question, evaluation of the new drug could usefully involve
a comparison of the magnitude and incidence of any QT/QTc interval
prolongation effects relative to those of other members of its class
in concurrent positive control groups.
It is difficult
to determine whether there is an effect on the mean QT/QTc interval
that is so small as to be inconsequential, but the risk of
arrhythmias appears to increase with the extent of QT/QTc
prolongation. Drugs that prolong the mean QT/QTc interval by around
5 ms or less do not appear to cause TdP. Whether this signifies
that no increased risk exists for these compounds or simply that the
increased risk has been too small to detect is not clear. The data
on drugs that prolong the mean QT/QTc interval by more than around 5
and less than 20 ms are inconclusive, but some of these compounds
have been associated with proarrhythmic risk. Drugs that prolong the
mean QT/QTc interval by >20 ms have a substantially increased
likelihood of being proarrhythmic, and might have clinical
arrhythmic events captured during drug development.
Regardless of the
degree to which a drug prolongs the QT/QTc interval, decisions about
its development and approval will depend upon the morbidity and
mortality associated with the untreated disease or disorder and the
demonstrated clinical benefits of the drug, especially as they
compare with available therapeutic modalities. Demonstrated
benefits of the drug in resistant populations or in patients who are
intolerant of, or have a labeled contraindication to, approved drugs
for the same disease represent additional relevant clinical
considerations that might justify approval of the drug, if the
indication were limited to use in such patients.
Some factors have
been proposed that can modify the risk of QT/QTc prolongation. For
instance, it has been suggested that some drugs might prolong the
QT/QTc interval up to a “plateau” value, above which there is no
dose-dependent increase, although this has not been demonstrated
adequately to date. It has also been suggested that proarrhythmic
risk might be influenced by other pharmacologic effects (e.g.,
other channel effects). In any case, it is important to identify
the “worst case scenario” for drugs that have demonstrated effects
on QT/QTc interval as a part of risk assessment (i.e., the
QT/QTc interval measured in the target patient population at the
time of peak effect and under conditions of the highest blood levels
that can be attained during therapy).
It is recognized that there will be regional differences in
labelling. However, it is recommended that the following be
considered:
·
A warning/precautionary statement
about the risk;
·
A description of the design and
results of the trials investigating the effect on the QT/QTc
interval, including the absence of demonstrated effect;
·
The dosage recommendations;
·
A list of conditions known to
increase the proarrhythmic risk (e.g., congestive heart
failure, Long QT Ssyndrome, hypokalemia);
·
A precautionary statement regarding
the concomitant use of two or more QT/QTc interval prolonging drugs
and other interactions increasing the risk.
·
Recommendations for patient
monitoring (ECG and electrolytes) and management of patients with
QT/QTc prolongation or symptoms suggestive of an arrhythmia.
The use of dosing
adjustments following institution of therapy appears to materially
decrease the risk of TdP in hospitalized patients receiving an
antiarrhythmic drug; no similar data are available for drugs of
other therapeutic classes. For approved drugs that prolong the QT/QTc
interval, risk-management strategies aimed at minimizing the
occurrence of arrhythmias associated with their use have focused on
education of the health-care providers and patients.
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Date created: October 21, 2004 |
