Synopsis
An FDA/CSRC/HESI-sponsored think tank meeting was convened to discuss the latest data from the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative. The four components of CiPA collectively seek to characterize more clearly the torsadogenic risk of drugs by providing a more comprehensive assessment of a drug’s effect on multiple cardiac ionic currents rather than just hERG.
In vitro assessment focuses primarily on hERG, late sodium, and L‐type calcium currents. In silico computer modeling integrates individual ion channel data to predict clinical risk, while ECG biomarkers (e.g., J-Tpeakc) are studied in Phase 1 trials to verify unanticipated effects. In vitro effects on human induced pluripotent stem cell-derived ventricular cardiomyocytes (hiPSC-CMs) offer additional validation for these mechanistic predictions.
May 21, 2018 – Day 1 Agenda
Session I: Overview
Moderator: Gary Gintant, PhD (AbbVie)
- TdP mechanisms and insights: Gary Gintant, PhD (Abbvie)
- The need for a new approach to assessing proarrhythmic potential: Philip Sager, MD (Stanford University)
- Potential role of CiPA on drug discovery and regulatory pathways: David Strauss, MD, PhD (US FDA)
Session II: In Silico Modeling and Ion Channel Approaches
Moderator: Gary Mirams, PhD (University of Nottingham)
- In Silico modeling - state of the art: Gary Mirams, PhD (University of Nottingham)
- Summary of In Silico model approach and validation: Zhihua Li, PhD (US FDA)
- Ion Channel Assays and Data – lessons learned: Wendy Wu, PhD (US FDA)
Session III: IPS-Stem Cells and Phase 1 ECG
Moderator: David Strauss, MD, PhD (US FDA)
- IPS-Stem Cells: Summary of approach and implications: Ksenia Blinova, PhD (US FDA)
- New ECG biomarkers and their potential role in CiPA: Jose Vicente Ruiz, PhD (US FDA)
- Implementation of ECG biomarkers: Borje Darpo, MD, PhD (ERT)
May 22, 2018 – Day 2 Breakout Sessions
Breakout 1 – In Silico
Focus: Implementing the proposed CiPA model and qNet metric; principles to qualify new models and metrics under the CiPA paradigm.
Breakout 2 – Ion Channel
Focus: Data quality standards, unified experimental protocols for CiPA, and 측정(measurement) methods. Key technical discussions included temperature for hERG recording and the selection of an appropriate Agonist for late NaV1.5 current (such as Mexiletine HCl) to calibrate recording systems.
Breakout 3 – Myocyte
Focus: Comparison of JiCSA and Validation study results; setting best practices and calibration standards for stem-cell derived cardiomyocytes.
Breakout 4 – Phase 1 ECG
Focus: Summary of results supporting J-Tpeak use, heart rate dependency, and challenges in concentration-ECG-response models in small-sized trials.
Advances in Clinical QTc Assessments and Updates from the FDA IRT
The final session addressed recent insights from the FDA QT Interdisciplinary Review Team (IRT). Discussions included requirements for obtaining a TQT study waiver, the application of bias metrics during review, and exposure-response analysis to close the gap between pre-clinical and clinical findings.
