CIPA COMPOUND SELECTION OVERVIEW

Thomas J ColatskyDirector, Division of Applied Regulatory Science OCP/OTS/CDER

US Food and Drug Administration

Drug Sets Needed

1) Training set

2) Validation set

3) Test sethttp://www.freevector.com/site_media/preview_images/FreeVector-Beating-Heart-Graphics.jpg

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

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

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

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)

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

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.