CSRC/FDA Workshop: The Proarrhythmic Assessment of New Chemical Entities

Description: The ICH E14 clinical guidance has been revised (December 2015) and now enables the use of exposure response (ER) analysis applied to early phase clinical data to provide definitive evidence of the lack of a QT effect of a drug in development. ER analysis has evolved as an increasingly important method to assess a drug’s ECG effects; most drugs that cause concerning QT prolongation do this in direct relation to increasing plasma concentrations. Since the power of ER analysis to exclude small ECG effects is greater than the ‘by timepoint’ analysis, it can be used in early clinical phase studies to provide ECG data with the same level of confidence as from the TQT study. A remaining concern with this approach may however be the lack of a positive control. In TQT studies, the positive control demonstrates that a small QT effect can be detected and thereby provides protection against a false negative result.

This session will discuss ER analysis applied to early phase clinical data with emphasis on whether a positive control is needed and alternative methods to establish the study’s sensitivity in lieu of a pharmacological positive control.

Questions to be addressed:

  • How can exposure response analysis of ECG data from early phase clinical studies be used to detect or exclude clinically relevant effects of a new chemical entity?
  • How can protection against false negative result be provided in lieu of a positive control?
  • Which data do regulators expect to grant a TQT study waiver?

7:45am-8:00am Breakfast

8:00am-8:05am: Welcome and introduction – Borje Darpo MD, PhD (iCardiac Technologies)(5min)

8:05am- 8:25am Session I: Exposure response analysis to evaluate a drug’s effect on ECG parameters. Christine Garnett PharmD (FDA) (20min)

  • Role in regulatory decision making
  • Proposed criteria for a negative QT assessment using ER analysis applied to early clinical study data
  • How should a clinician without in-depth insight into exposure response modeling evaluate whether the results from the analysis provides an acceptable estimate of the drug’s QT effect

8:25am-8:35am Q&A (10min)

8:35am-8:50am Session II: Which type of data does FDA’s Interdisciplinary Review Team expect to waive a TQT study? Jiang Liu MD(FDA)(15 min)

  • Points to consider when performing definitive QT assessment in early stage clinical studies
  • In which scenarios is it better to perform definitive QT assessment in a MAD study?
  • Key parameters impacting the power of small studies to exclude a QT effect using ER analysis

8:50am-8:55am Q&A (5min)

8:55am-10:20am Session III: Proposed Methods to Replace the Positive Control in QT Studies Introduction to the topic: What is the role of the positive control?

Norman Stockbridge MDPhD (FDA)(5min)

  • Using moxifloxacin to establish assay sensitivity in early phase clinical studiesRobert Kleiman MD (ERT)(15min)
    • How can moxifloxacin be incorporated in to a standard clinical pharmacology study?
    • Which criteria should be used to demonstrate assay sensitivity with moxifloxacin in small studies?

9:15am- 9:20am Q&A (5min)

  • The pharmacological positive control can be replaced by a mealJorg Taubel MD (Richmond Pharmacology)(15 min)
    • How to implement the food procedure into a standard SAD or MAD trial
    • Proposed criteria for assay sensitivity for the food effect

9:35am-9:40am Q&A (5min)

  • Quality metrics applied to ECG data as a replacement for the positive control. Marek Malik MD (slides not available for posting) (St. George’s University of London)(15 min)
    • Which quality metrics can be applied to data from early phase clinical studies?
    • How would quality assurance provide protection against false negative results?

9:55am-10:00am Q&A (5min)

  • Bias evaluation provides protection against false negative results and can replace the positive controlBorje Darpo MD, PhD (iCardiac Technologies)(15min)
    • Evaluation of reported QTc values vs. a fully automated background to detect insensitive methods
    • Proposed criteria for bias evaluation

10:15am-10:20am Q&A (5min)

10:20am-11:20am Session IV: Panel DiscussionAlternative ways of establishing assay sensitivity in lieu of a pharmacological positive control- study be more effective? Moderators: Christine Garnett- PharmD and Borje Darpo- MD,PhD

Discussion and Q&A (55min)


  • All Speakers
  • Krishna Prasad MD (EMA)
  • Kaori Shinagawa MD (PDMA)
  • Georg Ferber PhD (Independent Statistician)
  • ICH E14 Implementation Working Group members

11:15am-11:20am Q&A (5min)

11:20am-11:25am Summary and Proposed Steps. Christine Garnett PharmaD (FDA)(5min)

11:25am-12:30pm Lunch

Background – It is well established that drug-induced QT interval prolongation is not always proarrhythmic when multiple ion channels are affected.  The Comprehensive In Vitro Proarrhythmia Assay (CiPA) is being developed to use non-clinical cardiac safety evaluations to directly determine a drug’s proarrhythmic potential, irrespective of effects on the QT interval. As part of CiPA, it will be important to determine if a drug’s effects in humans is similar to what would be expected based on the preclinical ion channel data.

12:30pm- 12:35pm: Purpose of the meeting and logistics– Philip Sager-MD (Consultant, Stanford University)(5 min)

12:35pm- 12:50pm Overview of CiPA and the Role of Phase 1 ECG Assessment Under CIPA – Philip Sager MD (Stanford University)(15 min)

12:50am- 1:40pm Potential ECG biomarker approaches (50 min) Moderator David Strauss MD, PhD (FDA)

  • Novel ECG biomarkers – Joel Xue PhD (GE Healthcare) (10 min)
  • Theoretical underpinnings of the ECG and additional insights beyond the PR, QRS, and QTc- Fabio Badilini  (AMPS) (10 min)
  • Analysis comparing different approaches – Jose Vicente PhD, MS (FDA) (15 min)
  • J-Tpeak-Tend and Tpeak-Tend, including exposure response analysis, methodology and open source software – Lars Johannesen PhD (FDA)(15 min)

1:40pm- 2:25pm Panel Discussion: Science and choice of the biomarkers to best fit needs of CiPA (45 min)

Facilitator: David Strauss MD, PhD (FDA)

  • Joel Xue PhD (GE Healtchare)
  • Fabio Badilini PhD (AMPS)
  • Jean-Philippe Couderc- PhD, MBA (University of Rochester)
  • Jose Vicente PhD, MS (FDA)
  • Lars Johannesen PhD (FDA)
  • Philip Sager MD (Consultant, Stanford University)
  • Jeremy Ruskin MD (Massachusetts General Hospital)
  • Robert Kleiman MD (ERT)

2:25pm-2:45pm Break (20min)

2:45pm- 3:15pm Practical considerations around implementation (30 min) Moderator: Philip Sager (Stanford University)

3:15pm-4:15pm Panel Discussion: Practical considerations around implementation (60 min)

Facilitator: Philip Sager

  • Jonas Pettersson MD, PhD (Novo Nordisk)
  • Robert Kleiman MD (ERT)
  • David Strauss MD, PhD (FDA)
  • Norman Stockbridge MD, PhD (FDA)
  • Jay Mason MD (University of Utah),
  • Corina Dota MD (AstraZeneca)
  • Peter Kowey MD (The Lankanau Institute of Medical Research)
  • Borje Darpo MD PhD (iCardiac Technologies)

4:15pm-4:25pm Summary and proposed next steps (10min)

  • Philip Sager MD (Stanford University)
  • David Strauss MD. PhD (FDA)
  • Robert Kleiman MD (ERT)
  • Jose Vicente PhD, MS (FDA)