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CIPA Compound Selection Overview

This document outlines the objectives and requirements for the CIPA (Comprehensive In Silico Predictive Assessment) initiative, managed by Thomas J. Colatsky and the FDA's Division of Applied Regulatory Science. It details the preparation of training, validation, and test sets aimed at evaluating drug-induced proarrhythmia risk (Torsades de Pointes, TdP) through well-characterized drug models and ion channel interactions. Key focuses include consensus model performance, drug-channel pharmacology, and the rigorous validation of risk metrics to ensure safety in new drug assessments.

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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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