1. Chair –Derek Leishman Rapportuers –Dianne Garnes and Jean-Pierre Valentin Session II – Dynamics of Periodicity

2. Other issues such as non-TdP type arrhythmias are involved. However, they are outside the scope of this workshop and should be addressed elsewhere. First step may be to understand the scope of the issue Gap of knowledge: –Between animal versus human physiology / pharmacology –Focus on identifying patient population (e.g., genetic predisposition) –Understanding the dynamics of the ECG associated with TdP Session II – Dynamics of Periodicity

3. Questions & issues –Descriptions of QT dynamics – determine succinct ways to summarize, quantify and describe the dynamics of QT –Contrast the QT dynamics under normal conditions, conditions of autonomic perturbation and under the conditions which precede pro-arrhythmia –Discuss the models and methods by which the dynamics of QT may be determined in animals and in man: choice of species, data collection methods, data analysis methods –Identify a limited series of studies which could be conducted to illustrate; (a) the dynamics of QT periodicity under normal conditions, (b) under conditions of altered periodicity not thought to be proarrhythmic e.g., some autonomic perturbations, (c) in the presence of a QT prolonging agent associated with TdP and (d) in the presence of an agent which prolongs QT but is not thought to be proarrhythmic.

4. Session II – Dynamics of Periodicity Descriptions of QT dynamics – determine succinct ways to summarize, quantify and describe the dynamics of QT –Not satisfied by current parameters QT/QTc 2 types of compounds of interest –Small increase in QT »Indirect effect on cardiac repolarisation (autonomic system) »Direct effect but safe ? –Large increase in QT »But safe (e.g. amiodarone) »How do you go forward –Alternatives which could be considered / validated QT / TQ or QT / RR relationship Beat to beat variability Morphology / shape of ECG waves (T & U)

5. Session II – Dynamics of Periodicity Discuss the models and methods by which the dynamics of QT may be determined in animals and in man: choice of species, data collection methods, data analysis methods –Consideration for model Must be predictive Species – gap beyond dog (e.g., Monkey) Susceptibility to TdP in animal models Single vs chronic exposure Dose response vs exposure Reproducibility / Intra-individual comparison Transferable to man

6. Session II – Dynamics of Periodicity Models &methods con’t.: –Test compounds In discussion with FDA, CHMP, PMDA Non-IKr QT prolongers Range of IKr blockers –(Categories as per Redfern et al. 2003; Webster et al., 2002) Non-“Big GUNS” ! –With “Thorough QT/QTc” study

7. Session II – Dynamics of Periodicity Identify a limited series of studies which could be conducted to illustrate; (a) the dynamics of QT periodicity under normal conditions, (b) under conditions of altered periodicity not thought to be proarrhythmic e.g., some autonomic perturbations, (c) in the presence of a QT prolonging agent associated with TdP and (d) in the presence of an agent which prolongs QT but is not thought to be proarrhythmic. –Comparison of different analysis of continuously recorded ECGs data across species Beat to beat variability of QT, QT-TQ; T / U waves morphology