1. CIPA COMPOUND SELECTION OVERVIEW Thomas J Colatsky Director, Division of Applied Regulatory Science OCP/OTS/CDER US Food and Drug Administration

2. Drug Sets Needed 1) Training set 2) Validation set 3) Test set http://www.freevector.com/site_media/preview_images/FreeVector-Beating- Heart-Graphics.jpg

3. Training Set: Purpose Evaluate the performance of the consensus model (O’Hara-Rudy human ventricular myocyte) Identify any components that need to be improved or revised to reflect known activities Ion channels Cellular homeostasis Drug-channel interactions Other (e.g. adrenergic tone?) Use revised model to assess: Candidate risk metrics Simulation protocols needed to evaluate relative clinical proarrhythmia (TdP) risk http://www.freevector.com/site_media/preview_images/FreeVector-Beating- Heart-Graphics.jpg

4. Training Set Requirements Must be well characterized in both (a) clinical outcomes of TdP risk and (b) ion channel pharmacology Need both multi-channel and hERG specific drugs Range from no risk to high risk Scale TBD - use 5 Redfern categories as possible starting point? INaL, ICaL, IK1, IKr, IKs = currents of most interest Confirm (?) Need pharmacology data on each (mostly IC50s now) Kinetic information on channel block? Overlap with EJ Park’s protocol research? Consensus model(s) for drug-channel interaction? TARGET: 4-5 well-characterized drugs per risk category for a total of 20-25 drugs Training quality will reflect completeness of data sets – if incomplete, more data will be needed for a second round

5. Validation Set: Purpose Determine how well the fully trained model rank orders drugs with varying proarrhythmic (TdP) risk Confirm adequacy of candidate ion channels Identify whether model, metrics and/or simulation protocols need to be further improved or revised Finalize and make available: Consensus model (executable) Ion channels pharmacology requirements Risk definitions and scaling Risk metric performance characteristics http://www.freevector.com/site_media/preview_images/FreeVector-Beating- Heart-Graphics.jpg

6. Validation Set Requirements Must be well characterized in both (a) clinical outcomes of TdP risk and (b) ion channel pharmacology Need both multi-channel and hERG specific drugs Range from no risk to high risk Need pharmacology data on each of the required channels Are INaL, ICaL, IK1, IKr, IKs still the candidates of most interest? Standardized voltage clamp protocols TARGET: 4-5 well-characterized drugs per risk category for a total of 20-25 drugs (could be fewer)

7. Test Set: Purpose Try to “break” the model Use relatively unknown drugs for which outcome data (clinical/non-clinical) exist somewhere Individual companies can run the model and compare results CIPA In Silico group to be notified of “fails” and try to fix Intended to confirm the adequacy of the model, pharmacology, metric and risk scale Finalize and make available: Consensus model and its performance characteristics Ion channels pharmacology requirements Risk definitions and scaling Risk metric performance characteristics http://www.freevector.com/site_media/preview_images/FreeVector-Beating- Heart-Graphics.jpg

8. Test Set Requirements Must be well characterized in both clinical outcomes of TdP risk and ion channel pharmacology. Should include as many drugs as the pharmacology community needs to gain comfort and prove the concept.