New Advances in the Assessment of Drug-Induced Arrhythmias and the Comprehensive In Vitro Proarrhythmia Assay (CiPA)

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)

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)

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)

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)

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)

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