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CIPA Compound Selection Overview

CIPA Compound Selection Overview. Thomas J Colatsky Director, Division of Applied Regulatory Science OCP/OTS/CDER US Food and Drug Administration. Drug Sets Needed. Training set Validation set Test set.

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CIPA Compound Selection Overview

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  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 • Training set • Validation set • Test set http://www.freevector.com/site_media/preview_images/FreeVector-Beating-Heart-Graphics.jpg

  3. Training Set: Purpose http://www.freevector.com/site_media/preview_images/FreeVector-Beating-Heart-Graphics.jpg • 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

  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 http://www.freevector.com/site_media/preview_images/FreeVector-Beating-Heart-Graphics.jpg • 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

  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 http://www.freevector.com/site_media/preview_images/FreeVector-Beating-Heart-Graphics.jpg • 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

  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.

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