Guidance for Industry 
 
S7B Nonclinical Evaluation of  
the Potential for Delayed  
Ventricular Repolarization  
(QT Interval Prolongation)  
by Human Pharmaceuticals 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
October 2005 
ICH 
 
 
   
Guidance for Industry 
 
 
 
S7B Nonclinical Evaluation of  
the Potential for Delayed  
Ventricular Repolarization  
(QT Interval Prolongation)  
by Human Pharmaceuticals 
 
 
Additional copies are available from: 
 
Office of Training and Communication 
Division of Drug Information, HFD-240 
Center for Drug Evaluation and Research 
Food and Drug Administration 
5600 Fishers Lane 
Rockville, MD  20857 
(Tel) 301-827-4573 
 http://www.fda.gov/cder/guidance/index.htm 
 
Office of Communication, Training and  
Manufacturers Assistance, HFM-40  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
1401 Rockville Pike, Rockville, MD 20852-1448  
 http://www.fda.gov/cber/guidelines.htm.   
  
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
October 2005 
ICH 
   
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION (1, 1.1)................................................................................................1 
A.  Background (1.2)..................................................................................................................2 
B.  Scope of the Guidance (1.3)...................................................................................................3 
C.  General Principles (1.4) ........................................................................................................3 
II.  GUIDANCE (2).................................................................................................................3 
A.  Objectives of S7B Studies (2.1)..............................................................................................3 
B.  Considerations for Selection and Design of Studies (2.2).......................................................3 
C.  Nonclinical Testing Strategy (2.3).........................................................................................4 
1. In Vitro I  Assay  (2.3.1)........................................................................................................5 
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2. In Vivo QT Assay (2.3.2).........................................................................................................5 
3. Chemical/Pharmacological Class (2.3.3).................................................................................5 
4. Relevant Nonclinical and Clinica lnformation (2.3.4)................................................................5 
5. Follow-up Studies  (2.3.5).......................................................................................................5 
6. Integrated Risk Assessment (2.3.6)...........................................................................................6 
7. Evidence of Risk (2.3.7)..........................................................................................................7 
D.  Timing of S7B Nonclinical Studies and Integrated Risk Assessment in Relation to Clinical 
Development (2.4).........................................................................................................................7 
III.  TEST SYSTEMS (3).........................................................................................................7 
Considerations for Test Systems (3.1)...........................................................................................7 
A.  Use of Positive Control Substances and Reference Compounds (3.1.1).................................7 
B.  In Vitro Electrophysiology Studies (3.1.2).............................................................................7 
C.  In Vivo Electrophysiology Studies (3.1.3)..............................................................................9 
D.  Simulated Pathological Conditions and Arrhythmias (3.1.4)...............................................10 
  Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
 
S7B Nonclinical Evaluation of the Potential for Delayed Ventricular 
Repolarization (QT Interval Prolongation) by Human 
Pharmaceuticals 
 
 
 
 
 
This guidance represents 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 the approach 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.  
 
 
 
 
I.  INTRODUCTION (1, 1.1)2 
 
This guidance describes a nonclinical testing strategy for assessing the potential of a test 
substance to delay ventricular repolarization.  The guidance includes information concerning 
nonclinical assays and integrated risk assessments.  The assessment of the effects of 
pharmaceuticals on ventricular repolarization and proarrhythmic risk is the subject of active 
investigation.  When additional data (nonclinical and clinical) are accumulated in the future, they 
will be evaluated and this guidance might be revised. 
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
                                                 
1 This guidance was developed within the Expert Working Group (Safety) of 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 Steering Committee at Step 4 of the ICH process, May 2005.  At Step 4 of the process, the final 
draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. 
2 Arabic numbers reflect the organizational breakdown in the document endorsed by the  ICH  Steering Committee 
at Step 4 of the ICH process, May 2005.  
 
  1 Contains Nonbinding Recommendations 
 
A.  Background (1.2) 
 
The QT interval (time from the beginning of the QRS complex to the end of the T wave) of the 
electrocardiogram (ECG) is a measure of the duration of ventricular depolarization and 
repolarization.  QT interval prolongation can be congenital or acquired (e.g., pharmaceutical-
induced).  When ventricular repolarization is delayed and the QT interval is prolonged, there is 
an increased risk of ventricular tachyarrhythmia, including torsade de pointes, particularly when 
combined with other risk factors (e.g., hypokalemia, structural heart disease, bradycardia).  Thus, 
much emphasis has been placed on the potential proarrhythmic effects of pharmaceuticals that 
are associated with QT interval prolongation. 
 
Ventricular repolarization, determined by the duration of the cardiac action potential, is a 
complex physiological process.  It is the net result of the activities of many membrane ion 
channels and transporters.  Under physiological conditions, the functions of these ion channels 
and transporters are highly interdependent.  The activity of each ion channel or transporter is 
affected by multiple factors including, but not limited to, intracellular and extracellular ion 
concentrations, membrane potential, cell-to-cell electrical coupling, heart rate, and autonomic 
nervous system activity.  The metabolic state (e.g., acid-base balance) and location and type of 
cardiac cell are also important.  The human ventricular action potential consists of five sequential 
phases: 
 
  phase 0: The upstroke of the action potential is primarily a consequence of a rapid, transient 
influx of Na+ (I ) through Na+ channels. 
Na
  phase 1: The termination of the upstroke of the action potential and early repolarization 
phase result from the inactivation of Na+ channels and the transient efflux of K+ (I ) through 
to
K+ channels. 
  phase 2: The plateau of the action potential is a reflection of a balance between the influx of 
Ca2+ (I )  through L-type Ca2+ channels and outward repolarizing K+ currents. 
Ca
  phase 3: The sustained downward stroke of the action potential and the late repolarization 
phase result from the efflux of K+ (I  and I ) through delayed rectifier K+ channels. 
Kr Ks
  phase 4: The resting potential is maintained by the inward rectifier K+ current (I ). 
K1
Prolongation of the action potential can result from decreased inactivation of the inward Na+ or 
Ca2+ currents, increased activation of the Ca2+ current, or inhibition of one or more of the 
outward K+ currents.  The rapidly and slowly activating components of the delayed rectifier 
potassium current, I   and I , seem to have the most influential role in determining the duration 
Kr Ks
of the action potential and thus the QT interval.  The human ether-a-go-go-related gene (hERG) 
and KvLQT1 gene encode pore-forming proteins KCNH2 and KCNQ1 that are thought to 
represent the a -subunits of the human potassium channels responsible for I  and I , 
Kr Ks
respectively.  These a -subunit proteins can form hetero-oligomeric complexes with auxiliary b -
subunits (i.e. MiRP and MinK gene products), which have been speculated to modulate the 
gating properties of the channel proteins.  The most common mechanism of QT interval 
prolongation by pharmaceuticals is inhibition of the delayed rectifier potassium channel that is 
responsible for I . 
Kr
 
  2 Contains Nonbinding Recommendations 
 
B.  Scope of the Guidance (1.3) 
 
This guidance extends and complements the ICH guidance on S7A Safety Pharmacology Studies 
for Human Pharmaceuticals.  This guidance applies to new chemical entities for human use and 
marketed pharmaceuticals when appropriate (e.g., when adverse clinical events, a new patient 
population, or a new route of administration raises concerns not previously addressed).  
Conditions under which studies are not called for are described in ICH S7A. 
 
C.  General Principles (1.4) 
 
Principles and recommendations described in ICH S7A also apply to the studies conducted in 
accordance with the present guidance.  In vitro I  and in vivo QT assays described in sections 
Kr
II.C.1 and C.2 (2.3.1 and 2.3.2) when performed for regulatory submission should be conducted 
in compliance with good laboratory practice (GLP).  Follow-up studies described in section 
II.C.5 (2.3.5) should be conducted in compliance with GLP to the greatest extent feasible. 
 
In vitro and in vivo assays are complementary approaches; therefore, according to current 
understanding, both assay types should be conducted. 
 
The investigational approach and evidence of risk should be individualized for the test substance, 
depending on its pharmacodynamic, pharmacokinetic, and safety profiles. 
 
 
II.  GUIDANCE (2) 
 
A.  Objectives of S7B Studies (2.1) 
 
The objectives of studies are to: (1) identify the potential of a test substance and its metabolites 
to delay ventricular repolarization, and (2) relate the extent of delayed ventricular repolarization 
to the concentrations of a test substance and its metabolites.  The study results can be used to 
elucidate the mechanism of action and, when considered with other information, estimate risk for 
delayed ventricular repolarization and QT interval prolongation in humans. 
 
B.  Considerations for Selection and Design of Studies (2.2) 
 
Nonclinical methodologies can address the following: 
 
  Ionic currents measured in isolated animal or human cardiac myocytes, cultured cardiac cell 
lines, or heterologous expression systems for cloned human ion channels 
  Action potential parameters in isolated cardiac preparations or specific electrophysiology 
parameters indicative of action potential duration in anesthetized animals 
  ECG parameters measured in conscious or anesthetized animals 
  Proarrhythmic effects measured in isolated cardiac preparations or animals 
  3 Contains Nonbinding Recommendations 
 
As indicated above, these four functional levels can be investigated by in vitro and/or in vivo 
methods.  Findings from the functional levels listed above are considered useful and 
complementary. 
 
In vitro electrophysiology studies can explore potential cellular mechanisms that might not be 
evident from in vivo data.  Changes in other cardiovascular parameters or effects on multiple ion 
channels can complicate interpretation of data.  Complementary assessments in other systems 
can address this issue.  Although delay of repolarization can occur through modulation of several 
types of ion channels, inhibition of I  is the most common mechanism responsible for 
Kr
pharmaceutical-induced prolongation of QT interval in humans. 
 
In vivo models that possess the full complement of molecular, biochemical, and physiological 
systems can also be informative with regard to the response in humans to the test substance.  
Carefully designed and conducted in vivo studies allow evaluation of parent substance and 
metabolites and can enable estimation of safety margins.  In vivo ECG evaluations provide 
information on conduction properties and noncardiac influences (e.g., autonomic nervous system 
tone).  Studies of action potential parameters provide information on the integrated activity of 
multiple ion channels in the heart. 
 
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C.  Nonclinical Testing Strategy (2.3) 
 
The following sections describe a general nonclinical testing strategy for assessing risk for 
delayed ventricular repolarization and QT interval prolongation that is pragmatic and based on 
  4 Contains Nonbinding Recommendations 
 
currently available information.  The figure illustrates the component elements of the testing 
strategy, but not specific test systems or their designs. 
 
1.  In Vitro I  Assay  (2.3.1) 
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An in vitro I assay evaluates the effects on the ionic current through a native or expressed I  
Kr  Kr
channel protein, such as that encoded by hERG (see section III.B (3.1.2)). 
 
2.  In Vivo QT Assay (2.3.2) 
 
An in vivo QT assay measures indices of ventricular repolarization such as QT interval (see 
section III. C (3.1.3)).  This assay can be designed to meet the objective of both ICH S7A 
(cardiovascular core battery study) and S7B.  This will reduce the use of animals and other 
resources. 
 
3.  Chemical/Pharmacological Class (2.3.3) 
 
Consideration should be given to whether the test substance belongs to a 
chemical/pharmacological class in which some members have been shown to induce QT interval 
prolongation in humans (e.g., antipsychotics, histamine H-1 receptor antagonists, 
fluoroquinolones).  This factor should, where appropriate, influence the choice of reference 
compound(s) and be included in the integrated risk assessment. 
 
4.  Relevant Nonclinical and Clinica lnformation (2.3.4) 
 
Additional information for the integrated risk assessment can include results from: 
  Pharmacodynamic studies 
   Toxicology/safety studies  
  Pharmacokinetic studies, including plasma levels of parent substance and metabolites 
(including human data if available) 
  Drug interaction studies  
  Tissue distribution and accumulation studies 
  Postmarketing surveillance 
 
5.  Follow-up Studies  (2.3.5) 
 
Follow-up studies are intended to provide greater depth of understanding or additional 
knowledge regarding the potential of test substance for delayed ventricular repolarization and QT 
interval prolongation in humans.  Such studies can provide additional information concerning 
potency, mechanism of action, slope of the dose-response curve, or magnitude of the response.  
Follow-up studies are designed to address specific issues, and as a result, various in vivo or in 
vitro study designs can be applicable. 
 
  5 Contains Nonbinding Recommendations 
 
In circumstances where results among nonclinical studies are inconsistent and/or results of 
clinical studies differ from those for nonclinical studies, retrospective evaluation and follow-up 
nonclinical studies can be used to understand the basis for the discrepancies.  Results from 
follow-up studies can be a significant component of an integrated risk assessment. 
 
Relevant nonclinical and clinical information along with the following should be considered in 
the selection and design of follow-up studies: 
 
  Use of ventricular repolarization assays that measure action potential parameters in isolated 
cardiac preparations (see section III.B (3.1.2))  
  Use of specific electrophysiological parameters indicative of action potential duration in 
anesthetized animals (see section III.C (3.1.3))  
  Repeated administration of test substance 
  Selection of animal species and gender(s) 
  Use of metabolic inducers or inhibitors 
  Use of concurrent positive control substances and reference compounds (see section III.A 
(3.1.1)) 
  Inhibition of other channels not previously evaluated 
  Measurement of electrophysiological parameters at multiple time points  
  Confounding effects in conscious animals that limit the interpretation of data such as test 
substance-induced effects on heart rate or autonomic tone, or toxicities such as tremor, 
convulsion, or emesis 
6.  Integrated Risk Assessment (2.3.6) 
 
The integrated risk assessment is the evaluation of nonclinical study results including the results 
from follow-up studies and other relevant information.  The integrated risk assessment should be 
scientifically based and individualized for the test substance.  Such an assessment can contribute 
to the design of clinical investigations and interpretation of their results.  When available, the 
integrated risk assessment should be included in the Investigators Brochure and the Nonclinical 
Overview (ICH M4).  Depending on the stage of drug development, the integrated risk 
assessment should also consider:  
 
  Assay sensitivity and specificity  
  Potencies of test substance in S7B assays relative to reference compound(s)  
  Relationship between the exposures associated with an effect on repolarization and those 
eliciting the primary pharmacodynamic effect in the nonclinical test species or the proposed 
therapeutic effect in humans 
  Contribution of metabolites to QT interval prolongation as well as metabolic differences 
between humans and animals 
  6 Contains Nonbinding Recommendations 
 
7.  Evidence of Risk (2.3.7) 
 
Evidence of risk is the overall conclusion from the integrated risk assessment for a test substance 
to delay ventricular repolarization and prolong QT interval in humans. 
 
D.  Timing of S7B Nonclinical Studies and Integrated Risk Assessment in 
Relation to Clinical Development (2.4) 
 
Conduct of S7B nonclinical studies assessing the risk for delayed ventricular repolarization and 
QT interval prolongation prior to first administration in humans should be considered.  These 
results, as part of an integrated risk assessment, can support the planning and interpretation of 
subsequent clinical studies. 
 
III.  TEST SYSTEMS (3) 
Considerations for Test Systems (3.1) 
This section provides an overview of methodologies currently used to assess the potential for a 
test substance to delay ventricular repolarization and to prolong QT interval.  The following 
should be considered  in selecting the most appropriate test systems. 
 
  Assay methodology and experimental endpoints are scientifically valid and robust. 
  Assays and preparations are standardized. 
  Results are reproducible. 
  Endpoints/parameters of the assays are relevant for assessing human risk. 
 
A.  Use of Positive Control Substances and Reference Compounds (3.1.1) 
 
A sub-maximally effective concentration of a positive control substance should be used to 
demonstrate the responsiveness of in vitro preparations for ion channel and action potential 
duration assays and should be included in every study.  In the case of in vivo studies, positive 
control substances should be used to validate and define the sensitivity of the test system, but 
need not be included in every study. 
 
For test substances belonging to a chemical/pharmacological class that is associated with QT 
interval prolongation in humans, the use of concurrent reference compound(s) (member(s) of the 
same class) in in vitro and in vivo studies should be considered to facilitate ranking the potency 
of the test substance in relation to its comparators. 
 
B.  In Vitro Electrophysiology Studies (3.1.2) 
 
In vitro electrophysiology studies can provide valuable information concerning the effect of a 
test substance on action potential duration and/or cardiac ionic currents.  These assays have an 
important role in assessing the potential for QT interval prolongation and elucidating cellular 
mechanisms affecting repolarization.  In vitro electrophysiology studies employ either single cell 
  7 Contains Nonbinding Recommendations 
 
(e.g., heterologous expression systems, disaggregated cardiomyocytes) or multicellular (e.g., 
Purkinje fiber, papillary muscle, trabeculae, perfused myocardium, intact heart) preparations.  
Heterologous expression systems, where human ion channel protein(s) are expressed in 
noncardiac cell lines, are used to assess the effects of a test substance on a specific ion channel.  
Disaggregated myocytes are technically more challenging than the expression systems but have 
the advantage of being suitable for assessing effects on both action potential duration and ionic 
currents.  Although single cell preparations are more fragile, they minimize diffusional barriers 
to the site of action.  Multicellular preparations are stable test systems to study action potential 
duration.  The analysis of parameters for each phase of the action potential such as V  for 
max
phase 0 (I ), APD or APD  for phase 2 (I ) and triangulation for phase 3 (I ) can be useful 
Na 30  40 Ca K
to investigate the effects on specific channels responsible for these phases.  In addition, some 
parameters derived from the Langendorff preparation have been reported to provide information 
regarding proarrhythmic risk. 
 
Tissue and cell preparations for in vitro assays are obtained from different laboratory animal 
species including rabbit, ferret, guinea pig, dog, swine, and occasionally from humans.  The ionic 
mechanisms of repolarization in adult rats and mice differ from larger species, including humans 
(the primary ion currents controlling repolarization in adult rats and mice is I ); therefore, use of 
to
tissues from these species is not considered appropriate.  Species differences in terms of which 
cardiac ion channels contribute to cardiac repolarization and to the duration of the action 
potential should be considered in selecting a test system.  When native cardiac tissues or cells are 
used, the characteristics and source of the preparation should be considered because the 
distribution of ion channel types varies according to the region and type of cell. 
 
Test substance concentrations for in vitro studies should span a broad range, covering and 
exceeding the anticipated maximal therapeutic plasma concentration.  Ascending concentrations 
should be tested until a concentration-response curve has been characterized or physicochemical 
effects become concentration-limiting.  Ideally, the duration of exposure should be sufficient to 
obtain steady-state electrophysiological effects, unless precluded by the viability of the cell or 
tissue preparation.  The duration of exposure should be indicated.  Appropriate positive control 
substances should be used to establish the sensitivity of the in vitro assay system. 
 
Factors that can confound or limit the interpretation of in vitro electrophysiology studies include 
the following: 
 
  The testing of high concentrations of the test substance can be precluded by limited 
solubility in aqueous physiological salt solutions. 
  Adsorption to glass or plastic or nonspecific binding to the test matrix can reduce the 
concentration of the test substance in the incubation or perfusion medium. 
  Test substance concentrations can be limited by cytotoxic or physicochemical attributes of 
the test substance that disrupt cell membrane integrity so that electrophysiological endpoints 
cannot be obtained. 
  Cardiac cells and tissues have limited capacity for drug metabolism; therefore, in vitro 
studies using the parent substance do not provide information on the effects of metabolites.  
When in vivo nonclinical or clinical studies reveal QT interval prolongation that is not 
  8 Contains Nonbinding Recommendations 
 
consistent with data from in vitro studies using the parent substance, testing metabolites in 
the in vitro test systems should be considered. 
New technologies for potassium channel assays are being developed.  Novel ion channel activity 
assays can be useful in preliminary screening of test substances to identify lead candidates.  It is 
important to demonstrate concordance between conventional and new technologies before 
adopting new technologies for regulatory purposes. 
 
Competition binding protocols, in which test substances are studied for their ability to displace a 
radiolabeled hERG channel blocker from a cell line expressing hERG, are used.  However, 
competition for radioligand-binding sites provides no information on agonistic or antagonistic 
effects of the test substance on I .  Moreover, this assay will not identify test substances that 
Kr
bind to hERG at sites other than the radioligand binding sites.  Based upon these potential 
limitations, this assay is not considered a substitute for voltage clamp assays described above. 
 
C.  In Vivo Electrophysiology Studies (3.1.3) 
 
Intact animal models allow investigation of ventricular repolarization or associated arrhythmias 
where integrated effects on the full complement of ion channel and cell types are assessed.  Also, 
potential neuronal and hormonal influences on the pharmacodynamic effect of the 
pharmaceuticals are present in animals. 
 
The QT interval of the ECG is the most commonly used endpoint to gauge effects of a test 
substance on ventricular repolarization.  In specialized electrophysiology studies, information 
regarding the ventricular repolarization (e.g., monophasic action potential duration and effective 
refractory period) can also be obtained from in vivo models.  Additional safety parameters of 
interest, including blood pressure, heart rate, PR interval, QRS duration, and arrhythmias, can be 
assessed simultaneously. 
 
The QT interval and heart rate have an inverse, nonlinear relationship, which varies among 
species and between animals within a species.  Thus, a change in heart rate exerts an effect on 
QT interval, which can confound the assessment of the effect of the test substance on ventricular 
repolarization and the QT interval.  There are two important situations where there is variability 
in heart rate among animals: one is due to difference in autonomic tone, and the other is due to 
effects of test substances on heart rate.  Therefore, the interpretation of data from in vivo test 
systems should take into account the effect of coincident changes in heart rate.  Ideally, QT 
interval data obtained after administration of a test substance should be compared with control 
and baseline data at similar heart rates.  When the heart rate variability is not due to the test 
substance, it can be reduced by acclimatization, or the use of anesthetized animal models.  When 
the effects are due to a test substance, the most common approach is to correct the QT interval 
for heart rate (QTc) using formulae such as Bazett or Fridericia.  The choice of heart rate 
correction formula should be justified with data from the test system.  When differences in heart 
rate between treatment and control are large, the correction formulae may not be effective for 
assessing risk of QT interval prolongation.  An alternative approach is to maintain a constant 
heart rate using cardiac pacing.  An analysis of QT/RR relationship, including correction of the 
QT interval using formulae for individual animals, may be more appropriate. 
 
  9 Contains Nonbinding Recommendations 
 
Laboratory animal species used for in vivo electrophysiology studies include dog, monkey, 
swine, rabbit, ferret, and guinea pig.  The ionic mechanisms of repolarization in adult rats and 
mice differ from larger species, including humans (the primary ion currents controlling 
repolarization in adult rats and mice is I ); therefore, use of these species is not considered 
to
appropriate.  The most appropriate in vivo test systems and species should be selected and 
justified. 
 
The dose range should be in accord with that discussed in ICH S7A and, whenever feasible, 
should include and exceed the anticipated human exposure.  The dose range can be limited by 
animal intolerance to the test substance (e.g., emesis, tremor, or hyperactivity).  For studies 
designed to relate the extent of delayed ventricular repolarization to concentrations of the parent 
test substance and its metabolites, controlled exposure via constant intravenous infusion can be 
used.  Monitoring exposure to the test substance and metabolites (see ICH S3A) provides 
opportunities to interpret dose- and concentration-response data and to design follow-up studies, 
if appropriate. 
 
Factors that should be considered in conducting studies and interpreting the results include the 
following:  
  Data acquisition and analysis methods   
  Sensitivity and reproducibility of the test systems  
  Dosing period and measurement points  
  Heart rate and other effects that confound interpretation of QT interval data  
  Inter-species and gender differences (e.g., cardiac electrophysiology, hemodynamics, or 
metabolism of pharmaceuticals) 
  Pharmaceuticals that have effects on several ion channels, yielding complex dose-response 
relationships that could be difficult to interpret 
 
D.  Simulated Pathological Conditions and Arrhythmias (3.1.4) 
 
The precise relationship between test substance-induced delay of ventricular repolarization and 
risk of proarrhythmia is not known.  Directly assessing the proarrhythmic risk of pharmaceuticals 
that prolong the QT interval would be a logical undertaking.  Indices of proarrhythmic activity 
(e.g., electrical instability, temporal and/or spatial dispersion of refractoriness, reverse use-
dependency, changes in action potential configuration) and animal models might have utility in 
assessing proarrhythmia.  Interested parties are encouraged to develop these models and test their 
usefulness in predicting risk in humans. 
 
 
  
  10