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ICH E14 Step 2: The Clinical Evaluation of QT/QTc Interval Prolongation and
Proarrhythmic Potential For Non-Antiarrhythmic Drugs

EMEA Explanatory Notes: The EMEA explanatory notes released as part of the Step 2
draft guidance succinctly summarizes the most pressing issues facing the clinical
evaluation QT. The notes invite scientific input supported by current experimental or
published evidence if possible, on six different aspects of the guidance:
1. The extent to which negative non-clinical studies (see ICH S7B guidance) can exclude
a clinical risk beyond a reasonable doubt.
2. Categories for drugs for which there would be no need for a clinical ‘thorough QT/QTc
study’
3. Categorization of clinical risk for drugs that prolong the mean QT/QTc interval by
around 5 msec of less, 6 to 10 msec, 11 to 15 msec, 16 to 20 msec and those that prolong
the mean QT/QTc interval by more than 21 msec.
4. Definition of a negative ‘thorough QT/QTc study’ as one where the largest timematched
mean differenced between the drug and placebo (baseline subtracted) for the
QTc interval is a round 5 msec or less, with a one-sided confidence interval that excludes
an effect >8.0 msec, this upper bound was chosen to reflect the uncertainty related to the
variability of repeated measurements.
5. Relative emphasis on population mean values versus individual outlier analysis in
determining the outcome of the ‘thorough QT/QTc study’ as either positive or negative.
6. The extent to which results of a negative clinical ‘thorough QT/QTc study’ can be
extrapolated to exclude a risk in patients, especially in the context of patients with
increased risk (e.g., extending the indication of an antihypertenisve drug to include
subsequently those with chronic heart failure).
It is our understanding that ICH is planning a public meeting for the spring of 2005 to
discuss both the E14 and S7B Step 2 guidance documents. The EMEA explanatory notes
constitute a ready-made agenda for this public meeting. Pfizer fully supports the
proposed public meeting, and offers our active participation at the meeting.
General Comments:
With E14 now at Step 2, FDA needs to consider developing internal guidance on the
assessment of the effect of drugs on cardiac repolarization. Looking at recent examples
of labeling and approval packages, review Divisions are often working to different
standards when considering QT issues. Guidance in the form of a MaPP would serve to
clarify assessment standards for both review Divisions and Sponsors, especially
V:08-Dec-04 [Docket 2004D-0377] Page 2
regarding points where ICH regional differences in the evaluation of QT prolongation are
now emerging.
1.2 Objectives
The document comments that 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 re-evaluated and
revised”. The questions posed in the EMEA explanatory notes need to be pursued
cooperatively by Regulatory Agencies and the Pharmaceutical Industry as a process for
updating the guidance.
In cases where drugs are in development for the treatment of serious and life threatening
conditions (e.g., oncology products), it may not be feasible or appropriate to perform a
‘thorough QT” study in a healthy volunteer patient population. The guidance should
consider expanding on cases where a ‘thorough QT’ study might not be appropriate and
provide some discussion on what types of QT analysis could be performed on the clinical
trials data (comparing patient ECG data from baseline and while on treatment; broader
use of categorical analysis for looking at QT data).
2.1 Design Consideration
As noted in the Step 1 ICH E14 Clinical QT guidance, the QT/QTc interval is subject to
significant intrinsic variability resulting from many factors (e.g. activity level, postural
changes, circadian patterns, and food ingestion). These factors all relate to autonomic
tone and there is extensive literature demonstrating that changes in autonomic tone affect
QT/QTc. This is consistent with the observation that vasodilators such as alfuzosin and
vardenafil can prolong QTc by 5-10 msec despite no known effect on ion channels. It is
becoming clear that when designing future “thorough QT” studies both drug and nondrugs
related effects on autonomic tone must be considered.
Under what circumstances would additional information from the collection of ECGs be
"necessary" as opposed to "allowed" from the regulatory perspective? Would particular
"special populations" be required as part of this "collection"? What would constitute
satisfactory data if this "collection" were "allowed?"
2.1.1. Subject Enrollment, Safety Monitoring, and Discontinuation Criteria
The section avoids mention of large populations known

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