An FDA/CSRC/HESI-sponsored think tank meeting was convened in Washington, D.C., on May 21- 22, 2018, to discuss the latest data from the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative. This synopsis provides a very high level report of results presented.
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 of drug-induced effects on ionic currents focuses primarily on hERG, late sodium, and L‐type calcium (calcium) currents. In silico computer modeling integrates individual ion channel data to predict the clinical risk of Torsade. ECG biomarkers, e.g., the heart rate-corrected J-Tpeak interval (J-Tpeakc), are studied in Phase 1 clinical trials to check for unanticipated effects compared with nonclinical ion channel data and in silico modeling predictions. In vitro drug effects on human induced pluripotent stem cell-derived ventricular cardiomyocytes can be optionally examined for the same purposes.
Click here for the full meeting synopsis.
May 21, 2018 – Day 1
8:00am – Continental Breakfast
Welcome and Introduction
Philip Sager, MD (Stanford University) (15 min)
8:15am-9:45am Session I: Overview
Moderator: Gary Gintant, PhD (AbbVie)
- TdP mechanisms and insights- scientific rationale for CiPA: Gary Gintant, PhD (Abbvie) (15 min)
- The need for a new approach to assessing the proarrhythmic potential of drugs and overview of CiPA: Philip Sager, MD (Stanford University) (15 min)
- The potential role of CIPA on drug discovery, development, and regulatory pathways: David Strauss, MD, PhD (US FDA) (20 min)
Q&A / Panel Discussion (40 min) Speakers and
- Krishna Prasad, MD (EMA)
- Corina Dota, MD (AstraZeneca)
- Peter Kowey, MD (Lankenau Heart Institute)
9:45am-10:00am Break
10:00am-12:00pm 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) (15 min)
- Summary of In Silico model approach and validation study; In Silico Results: Zhihua Li, PhD (US FDA) (30 min)
- Ion Channel Assays and Data – lessons learned and data quality criteria: Wendy Wu, PhD (US FDA) (30 min)
Q&A / Panel Discussion (45 min) Speakers and
- Najah Abi Gerges, PhD (AnaBios)
- Jim Kramer, PhD (Charles River)
- Takashi Yoshinaga, PhD (Eisai)
12:00pm-12:30pm Working Lunch
12:30pm-2:30pm Session III: IPS-Stem Cells and Phase 1 ECG
Moderators: David Strauss, MD, PhD (US FDA)
- IPS-Stem Cells: Summary of approach, Detailed results and implications: Ksenia Blinova, PhD (US FDA) (30min)
- New ECG biomarkers and their potential role in CiPA; Results and implications: Jose Vicente Ruiz, PhD (US FDA)(30 min)
- Implementation of ECG biomarkers: Borje Darpo, MD, PhD (ERT) (10 min)
Q&A / Panel Discussion (50 min) Speakers and
- Gary Gintant, PhD (Abbvie)
- Yasunari Kanda, PhD (Japan NIHS)
- Charles Benson, MD, PhD (Eli Lilly)
2:30pm-2:45pm Break
2:45pm-4:50pm Session IV: Regulatory Evaluation and Potential Implementation
Moderator: Philip Sager, MD (Stanford University)
- Data summary overview: David Strauss, MD, PhD (US FDA) (15 min)
- How CiPA might impact pre-clinical safety testing and S7B: Derek Leishman, PhD (Eli Lilly) (20 min)
- How CiPA might be implemented in clinical development and regulatory decision making: Christine Garnett, PharmD (US FDA) (20 min)
- Regulatory considerations and next steps: Krishna Prasad, MD (MHRA) (10 min)
Q&A/Panel discussion (60 min) Speakers and
- Colette Strnadova, PhD (Health Canada)
- Kaori Shinagawa, MD, PhD (PMDA)
- Jean-Pierre Valentin, PhD (UCB, EFPIA)
- Maki Ito MD, PhD (JPMA, Merck)
5:00pm Adjourn
May 22, 2018 – Day 2
7:30am-8:00am Continental Breakfast
8:00am-8:10am General Instructions
8:10am–10:30am Work Stream Breakouts
Breakout 1 – In Silico
Leaders: Zhihua Li, PhD (US FDA); Gary Mirams, PhD (University of Nottingham); Takashi Yoshinaga, PhD (Eisai)
The In Silico Breakout Session discussion will focus the on:
- Considerations of implementing the proposed CiPA model and qNet metric
- General principles to qualify any new models and metrics to be used under the CiPA paradigm
Breakout 2 – Ion Channel
Leaders: Wendy Wu, PhD (US FDA); James Kramer, PhD (Charles River); Najah Abi-Gerges, PhD (AnaBios)
The Ion Channel Breakout Session discussion will focus the on:
- Data quality standards (for consideration of cell integrity and recording quality)
- Current run-up, run-down, steady state
- Unified experimental protocol for CiPA
- Temperature for hERG channel recording
- Agonist for late NaV1.5 current
- Charge carrier for CaV1.2 current
- Where and how drug effects are measured during the voltage protocols
Breakout 3 – Myocyte
Leaders: Gary Gintant, PhD (Abbvie); Ksenia Blinova, PhD (US FDA); Yasunari Kanda, PhD (Japan NIHS)
The Myocyte Breakout Session discussion will focus the on:
- Brief review of Validation Study results
- Findings of JiCSA study results
- Comparison of JiCSA and Validation study results (points of concordance, discordance, models)
- Comparison of sensitivity of different cell lines (noncore sites study)
- Setting best practices and calibration standards
- Roles of myocytes (internal decision-making vs. regulatory perspectives, flow chart examples, benefits vs. current regulatory paradigm)
Breakout 4 – Phase 1 ECG
Leaders: Jose Vicente Ruiz, PhD (US FDA); Christine Garnett, PharmD (US FDA)
The ECG Breakout Session will focus on:
- Summary of results supporting J-Tpeak use to inform multi-ion channel effects
- Heart rate dependency of J-Tpeak interval
- J-Tpeak/RR adaptation and hysteresis
- Population vs. subject-specific corrections
- Challenges in concentration-ECG-response models
- Identifying nonlinear relationships in small sized trials
- Impact on interpretation of results
- Role of ECG in a potential implementation of CiPA
- Integrated risk assessment, context of use and potential thresholds
- How to handle discrepancies
- Limitations
- Are we ready?
10:30am-11:00am Break
11:00am-12:00pm Reports from Work Stream Breakouts
12:00pm-12:30pm Working Lunch
12:30pm-2:30pm Advances in Clinical QTc Assessments and Updates from the FDA QT Interdisciplinary Review Team (IRT)
Moderator: Philip Sager, MD (Stanford University)
- Recent insights from the FDA QT IRT on ConcentrationQTc analysis and requirements for obtaining a ‘TQT study waiver:’ Dhananjay Marathe, PhD (US FDA) (15 min)
- Application of bias metrics during IRT review: Lars Johannesen, PhD (US FDA) (10 min)
- Issues with exposure-response analysis, how we can close the gap: Georg Ferber, PhD (Consultant) (20 min)
- QTc evaluation for drugs with a substantial heart rate effect: Marek Malik, MD, PhD (University of London) (15 min)
Q&A / Panel Discussion (60 min)
- Christine Garnett, PharmD (US FDA)
- Borje Darpo, MD, PhD (ERT)
- Dalong Huang, PhD (US FDA)
2:30 pm Adjourn