Part A: QTc Exposure-Response Modeling Workshop: What is Required? Part B: Endpoints When Treating VT/VF in Patients with ICDs

7:45am-8:00am Breakfast

Part A
8:05am-8:20am Session I: Historical overview of the ICH E14 guidelines and the evolution to including C-QTc modeling Christine Garnett, PharmD (FDA)(15min)

8:20am-9:00am- Session II: The non-modelers version of expectations around the statistical analysis plan, report, and model(s) Steve Riley, PharmD, PhD (Pfizer)(40min)

9:00am- 9:30am Session III: Regulatory perspective for using C-QTc as the primary analysis: trial design, ECG quality evaluation, evaluation of modeling/simulation results, and decision making Dhananjay Marathe, PhD (FDA)(30min)

9:30am-10:30am Session IV: Clinical parameters of interest for concentration-QTc analysis of small studies Borje Darpo, MD (iCardiac Technologies)(15min)

 Discussion (45min)


Panelist: All speakers and
Lars Johannesen, PhD (FDA)
Georg Ferber, PhD (Independent Statistician)

 Break: 10:30-10:45


Part B
Objective: Reach consensus on regulatory- acceptable endpoints for clinical trials in ICD patients with ventricular arrhythmias.   Definitions?  Sources of Data? Analytical approaches?

CSRC Welcome & Introduction: Jonathan Seltzer, MD (ACI Clinical)

10:45am-12:45pm Session I: Background/Overview of Previous Endpoints
Moderator: Jonathan Seltzer, MD (ACI Clinical)

  • VT/VF Endpoints used in previous ICD trials (please specify and where possible comment on strengths and weaknesses) and natural history of VT/VF variability. What are the pros and cons of different endpoints? Wojciech Zareba, MD, PhD (University of Rochester Medical Center)(10min)

Endpoint Types: Strengths, limitations of specific endpoints or combinations of prospective endpoints

  • Device Endpoints: eg Shocks, Shocks meeting certain criteria, ATP (is there a role?), discuss how to account for ICD programming- standardized in some manner? Mintu Turakhia, MD (Stanford University)(10min)
  • Clinical Endpoints: eg  Death, arrhythmia, storm, VT ablation, and additional morbidities Preston Dunnmon, MD (FDA)(10min)
  • Patient Reported Endpoints:  eg Q0L, Anxiety Scale, activity (?accelerometer) Samuel Sears, PhD (East Carolina University)(10min)
  • Economic/Utilization Endpoints: eg Hospitalization, ER visits Peter Kowey, MD (Lankenau Medical Center)(10min)
  • Potential effects of drugs on ICD function (e.g., lack VT recognition, threshold/impedance changes) and potential safety endpoints James Reiffel, MD (Columbia)(10min)

Discussion (60min)

Lead Discussant: Peter Kowey, MD (Lankenau Medical Center)

Lunch 12:45pm-1:15pm

Potential endpoints that are most appropriate, relative strength and weaknesses.  How should ablation be considered?  Role and control of complementary therapies?  How do you account for natural variability in arrhythmia? How do your account for ICD programming?  How does length of trial effect evaluation? How do we deal with strength of evidence?  What outcomes might need adjudication?

1:15pm-2:15pm Session II: Prioritization of Endpoints for VT/ VF Approval
Moderator: Philip Sager, MD (Stanford University)

  • Endpoint analysis- secondary endpoints and alpha spending; potential use of ranked outcome measures James Hung, PhD (FDA)(10min)
  • Key Role of Secondary Endpoints- support a claim vs supporting the primary endpoint(s). What is required for a claim Norman Stockbridge, MD, PhD (FDA)(10min)

Discussion: Which endpoints are strong enough to stand alone to recommend approval? What are the design factors necessary for single and or composite endpoints to recommend approval? When should composite endpoints be used?   What are methods for assessment of composite endpoints?  Should components of composite endpoints be rank-ordered?  What is proper safety –efficacy balance?

Discussion (40min)

Lead Discussant James Reiffel, MD (Columbia)

2:15pm-3:15pm Session III: Primary Endpoints used for approval and consensus recommendations Jonathan Seltzer, MD (ACI Clinical)(10min)

Critical Discussion- Future of the Assessment of Drug-Induced Arrhythmias and the Comprehensive in Vitro Proarrhythmia Assay (CiPA)

7:45am-8:00am Breakfast

8:00am- 8:05am Welcome and Introduction- Philip Sager, MD (Stanford University)

8:05am-9:50 Session I: CiPA Overview and Scientific Underpinnings
Moderator: Philip Sager

  • The need for a new approach to assessing the proarrhythmic potential of drugs and Overview of CiPA- Philip Sager, MD (Stanford University)(15min)
  • Talk on TdP mechanisms and theoretical justification for CiPA- Craig January, MD (University of Wisconsin)(15min)
  • The impact of CIPA on drug discovery and development, implications, timelines- Norman Stockbridge, MD, PhD (FDA)(15min)


Discussion (60min)

Panelist: All Speakers and
Peter Kowey, MD (Lankenau Medical Center)

9:50am-11:30am Session II: In Silico Modeling and Ion Channel Approaches.
Moderator: David Strauss, MD, PhD (FDA)

  • Overview, scientific approach, planned outputs, and how data will be used Tom Colatsky, PhD (15min)
  • Overview of ion channel testing strategy (channel and protocol selection), and summary of HT studies Bernard Fermini, PhD (Coyne Scientific)(15min)
  • Summary of manual ion channel results and next steps- Wendy Wu, PhD (FDA)(15min)
  • In silico strategy: development, validation, proarrhythmic metrics, modelling output, key issues, and next steps- Zhihua Li, PhD (FDA)(15min)


Discussion (40min)

Panelist:  All Speakers and
Gary Mirams, PhD (University of Nottingham, UK)
Alfonso Bueno-Orovio PhD (University of Oxford)
Najah Abi-Gerges, PhD (Anabios)

 Lunch 11:30am-12:30pm


12:30pm-1:55pm Session III: Myocyte Efforts
Moderator: Gary Gintant, PhD (AbbVie)


Panelist: All Speakers and
Udo Kraushaar, PhD (Natural and Medical Sciences Institute)
Ksenia Blinova, PhD (FDA)

Discussion (40min)


1:55pm- 3:30pm Session IV: Phase 1 ECG assessment Under CiPA
Moderator: Robert Kleiman, MD (ERT)

David Strauss, MD, PhD (FDA)(15min)
Panelist:  All Speakers and
Corina Dota, MD (Astrazeneca)
Lars Johannesen, PhD (FDA)
Joel Xue, PhD (GE Healthcare)

Discussion (50min)

3:30pm-3:40pm Break


3:40pm-5:00pm Session V: CIPA Regulatory Acceptance and Implementation
Moderators: Norman Stockbridge and Philip Sager

  • CiPA Package, regulatory approaches, and implementation Philip Sager, MD (Stanford University)(15min)

What is the data package required for CIPA regulatory acceptance

Panelist: All Speakers, David Strauss, MD, PhD (FDA), and
Dan Bloomfield, M D  ( Merck)(5min)
Kaori Shinagawa, MD (PDMA)(5min)
Krishna Prasad, MD (MHRA)(5min)
Colette Strnadova, PhD (Health Canada)(5min)
Derek Leishman, PhD (Eli Lilly)(5min)
Doug Throckmorton, MD (FDA)(5 min)

Discussion (30min)

5:00pm-5:15pm Summary & Next Steps

CSRC Think Tank: Real World Data to Assess Cardiovascular Safety- Can We Improve Efficiencies in Phase 3 Development?

Objectives: Evaluate the use of “real-world” data sources to provide sufficient and acceptable evidence to make informed decisions regarding CV safety risks of drugs.  What are the data? Methodologies? MACE definitions? Sources of bias? Analytical approaches? How can limitations be overcome?

7:30-8:00 Continental Breakfast

8:00am- 8:15am CSRC Welcome & Introduction- Mary Jane Geiger, MD (Regeneron)

8:15am-8:45 Session I: Background/Overview of Key Issues

  • How well can studies using real-world (“big”) data provide valid and reliable information regarding CV safety risks? – Robert Temple, MD (FDA) (20 min)

8:45am-10:30am Session II: Data Types – Quality, Event Ascertainment, Limitations- Strengths, limitations, MACE (CV death, heart failure, non-fatal MI and stroke events) ascertainment /issues. Provide example(s) where data type has been used to identify a CV event.

Moderator: Philip Sager, MD (Stanford University)

  • Prospective Cohort Studies/Observational registries
  • Clinician reported data – Sebastian Schneeweiss, SD, MD (Harvard Medical School )(10 min)
  • Healthcare databases
  • Electronic health records (EHR) – Christina Mack, PhD (QuintilesIMS)(10 min)
  • Claims databases– Sharon-Lise Normand, PhD (Harvard Medical School)(10 min)
  • Linked databases: EHR/observational registries/claims databases Nancy Dreyer, PhD (QuintilesIMS)(10 min)
  • How are data from different sources or within a data set with multiple entries linked? How might linkage introduce bias? What advantages do hybrid databases offer?

Discussion (55min)

What is the best source of evidence? Does an optimal data type exist? If not, what would this look like?

10:30am-10:45am: Break

10:45am-11:00am Session III: Casualty

  • How is causality determined? Challenges to interpretation? Impact of confounders? How much could bias explain observations? – Timothy Lash, DSc (Emory University)(15 min)

11:00am-12:50am Session IV: Study Design/Analytic Methods, MACE Definitions/Identification & Exposure.

Moderator: Jonathan Seltzer, MD (ACI Clinical)

  • Optimal methods approaches in Existing Data– Patrick Ryan, PhD (Johnson &Johnson)(10 min)
  • Pragmatic Trial Designs – capturing endpoints and integrating data from non-linked sources – Matthew Roe, MD (Duke University Medical Center)(10 min)
  • The Salford Lung Study: an example of an executed pragmatic trial – what can we learn? – Frank Rockhold, PhD (Duke Clinical Research Institute) (10 min)
  • CV Event Definitions – What endpoints can be assessed? What definitions are / should be used? Can they be applied uniformly across data types (eg, EMR vs claims)? What are potential confounders and how can these be managed? Does adjudication add merit?– Brad Hammill, DrPH (Duke Medical Center)(10 min)
  • Reliability of Data Sources to Ascertain Drug Use, Compliance, & Exposure – Alan Brookhart, PhD (University of NC)(10 min)

Discussion (60 min)

Jonathan Seltzer, MD (ACI Clinical)

What is an optimal study design/analytic method to minimize bias? Can/should MACE event definitions be the same in observational trials vs RCT?  What level of uncertainty is acceptable? Is consistency or uniformity of observational study results necessary or something other than trials?

12:50pm-1:30pm Lunch

1:30pm-3:15pm Session V: Methodologies to Reduce Bias and Estimate Effect Size.

Moderators: Mary Jane Geiger, MD, PhD (Regeneron)

  • Provide case examples for illustration. Bias: Sources of and methods to reduce bias. Does lack of randomization introduce bias? Brian Bradbury, DSc (Amgen)(15Min)
  • Analytical approaches for estimating effect size and interpreting results – Marc Suchard, MD, PhD (UCLA)(20 min)
    • Novel approaches
    • Reproducibility of results across multiple databases
  • Limitations of Big data & Relationship between Elements of Data –- Anita Pramoda (Owned Outcomes) (10 min)

 Discussion (60min)

What level of evidence is needed to inform decision-making- regulatory, clinical practice? What is an acceptable odds ratio?

3:15pm-3:45pm Session VI: Key Points of Consensus & Recommendations.

Based on what is known about the current data, definitions, and methods, what are the minimum factors/considerations that would allow us to draw meaningful conclusions and believe them? What CV event definitions should be used?

Moderators:  Mary Jane Geiger, MD, PhD (Regeneron) Jonathan Seltzer, MD (ACI Clinical), Philip Sager, MD (Stanford University)


3:45pm- 4:00pm Wrap-up & Next Steps


CSRC Annual Meeting: 10 Years of Excellence

7:30am-8:00am Breakfast

8:00am- 8:05am Welcome and Introduction- Philip Sager, MD (Stanford University)

8:05am-8:45am Plenary Session I: The future of drug and device development: balancing benefit and risk – Janet Woodcock, MD (FDA) (20min)

Moderators: Mitchell Krucoff, MD (Duke University Medical Center), Norman Stockbridge MD, PhD (FDA)

Discussion (20min)

8:45am-11:20am Session II: Role of publicprivate partnerships

Moderators- Ignacio Rodriguez, MD (Roche), Rick Turner, PhD, DSc (QuintilesIMS)

  • CSRC- What has been contributed over the last 10 years
    • Brief history of the CSRC and Overview of accomplishments and areas of impact – Mitchell Krucoff, MD (Duke University Medical Center)(20min)
      • Regulatory impact- QT and CIPA, anticoagulants for NOAC’s, CRF forms, Outcome Studies, White Papers
      • Relationships with other organizations (include DIA relationship, Cardio-Oncology, Pediatric CV Safety) and regions
    • Impact of public-private partnerships in cardiology- Norman Stockbridge, MD, PhD (FDA)(15min)
    • MDEpiNet: lessons learned- Jesse Berlin, ScD (Johnson & Johnson)(15min)
    • CTTI (Clinical Trials Transformation Initiative): lessons learned- Annemarie Forrest, RN, MS, MPH (Duke University Medical Center)(15min)
    • How can working together be enhanced?

Discussion (60min)

Lunch 11:20pm-12:30pm

12:30pm-2:00pm Session III: Updates on Think Tanks- Impact and what has occurred since

Moderators- Jonathan Seltzer, MD, MBA (ACI Clinical), Thomas Todaro, MD, (MedPace)

  • CV Outcomes Think Tank
    • CV Outcomes Think Thank and current status DM outcome trials White Paper- Rick Turner, PhD, DSc (QuintilesIMS)(15 min)
    • Mu-opioid receptor Advisory Committee Meeting- Peter Kowey, MD (Lankenau Medical Center)(15min)
    • Reversal agents for NOAC’s- Paul Reilly, PhD (Boehringer Ingelheim)(15min)

Discussion (45min)

Break: 2:00pm-2:10pm

 2:10pm-3:15pm Session IV: Updates on Think Tanks Moderators: Philip Sager, MD (Stanford), Peter Kowey, MD (Lankenau Medical Center)

  • Prevention of Sudden Cardiac Death in the Young Salim F. Idriss, MD, PhD (Duke University Medical Center)(15min)
  • Phase 1 ECG assessment – focus on Think Tank to a collaborative research study to ICH revision- Borje Darpo, MD, PhD (iCardiac Technologies)(10min)
  • CiPA Effort- Gary Gintant, PhD (Abbvie)(10min)

Discussion (30min)

 3:15pm-4:15pm Discussion of potential future CSRC areas of focus and opportunities

Moderators- Theressa Wright, MD (Eli Lily), Mary Jane Geiger, MD (Regeneron)

  • Survey Results.

Panel Discussion


  • Mitchell Krucoff, MD (Duke University Medical Center)
  • Norman Stockbridge, MD, PhD (FDA)
  • Kaori Shinagawa, MD (PMDA)
  • Peter Kowey, MD (Lankenau Medical Center)
  • Philip Sager, MD (Stanford University)


NOAC monitoring, reversal agents, and post-approval safety and effectiveness evaluation: A Cardiac Safety Research Consortium think tank

Read the paper here: NOAC monitoring, reversal agents, and post-approval safety and effectiveness evaluation: A Cardiac Safety Research Consortium think tank

Reiffel JA, et al. NOAC monitoring, reversal agents, and post-approval safety and effectiveness evaluation: A cardiac safety research consortium think tank. Am Heart J. 2016; 177: 74-86

CSRC/DIA Think Tank: Enabling Social Listening for Cardiac Safety

Meeting Minutes

Overview: Postmarketing safety surveillance primarily relies on data from spontaneous adverse event reports, medical literature, and observational databases. Potential limitations of these data sources include potential underreporting, lack of geographic diversity, potential of patients’ perspectives being filtered through health care professionals and regulatory agencies, and time lag between event occurrence and discovery.

There is growing interest by safety stakeholders in exploring the use of social media (“social listening”) to supplement established approaches for pharmacovigilance. Health information posted online by patients is often publicly available, and thus represents an untapped source of postmarketing safety data that could supplement data from existing sources of cardiac safety information. The purpose of this think tank is to explore current methods of collecting and evaluating social listening data. Representatives from industry, academia, and the FDA will share their perspectives on the topic of social listening and discuss its potential implications in the field of cardiac safety.

8:30 am -9:00 am:      Welcome and Introductions

CSRC Introduction- John Finkle, GSK                                                DIA Introduction- Raleigh Malik, DIA                                                          Overview of key concepts- Greg Powell, GSK


9:00 am – 10:25 am:              Session 1

 Review of current safety surveillance methods and overview of social listening

Session chairs:  Greg Powell, GSK, Harry Seifert, GSK

                               Review current safety surveillance methods (Oanh Dang, FDA)

                               Overview of social listening methods (Carrie Pierce, Epidemico)

                               Practical examples of social listening for safety (Lorrie Schifano, GSK)

                               Social listening for cardiac safety research (Bruce Donzanti, Genentech)

                               Panel Discussion


10:25 am – 10:35 am:                        Break

10:35 am – 12:00 pm:                       Session 2


                             Practical considerations of social listening for cardiac safety – why this is valuable

                              Session chair:   Melissa Truffa, Abbvie

                            Patient perspective (Sally Okun- PatientsLikeMe)

                            Regulatory perspective MHRA (Phil Tregunno, MHRA)

                            Regulatory perspective FDA (Sara Eggers, FDA)

                           Pharma perspective (Mondira Bhattacharya- AbbVie)

                           Panel Discussion



12:00 pm- 12:45 pm              Lunch

12:45 pm – 2:10 pm:            Session 3


                         What evidence is needed to inform use of social listening for cardiac safety

                           Session chair:  John van Stekelenborg, Janssen

                         Social Media-people sharing CV experiences (Jeff Terkowitz, Inspire)

                         Academia point of view (Mitchell Krucoff, Duke Clinical Research Institute)

                         Cardiac risk factors (Kevin Campbell, UNC)

                         Industry point of view (John van Stekelenborg, Janssen)

                         Panel Discussion


 2:10 pm – 2:30 pm:              Closing remarks- Harry Seifert, GSK

This think tank is hosted by the Cardiac Safety Education Collaborative (CSEC)—a partnership between DIA and the Cardiac Safety Research Consortium (CSRC), an FDA and Duke University public-private partnership. The objective of the CSEC is to advance open dialogue of issues related to cardiac safety that represent barriers to medical product development, or issues that constitute limitations in current regulatory science. This think tank is part of the CSEC Signature Program that will span the course of a year and includes a webinar and various publications.

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 MD, PhD (FDA)(5min)

  • Using moxifloxacin to establish assay sensitivity in early phase clinical studies. Robert 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 meal. Jorg 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 control. Borje 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 logisticsPhilip 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)

  • Practical approaches to evaluating ECG biomarker results and regulatory perspective – David Strauss, MD, PhD (FDA)(15 min)
  • How sponsors could implement new ECG biomarker approaches – Jonas Pettersson, MD, PhD (Novo Nordisk) (10 min)
  • How core labs could implement new ECG biomarker approaches – Robert Kleiman MD (ERT) (10 min)

 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)

CSRC and MDEpiNet Think Tank Meeting: “The Role of Endpoint Adjudication in Medical Device Clinical Trials”

8:00am-9:50am Session I: Tailoring best practices for the evaluation of endpoints in clinical device trials.

  • Introductory Remarks:

William Maisel, MD, MPH (FDA) (10min)

Danica Marinac-Dabic MD, PhD (FDA) (10min)

  • Introduction: Current State of Endpoint Adjudication in Device Trials
    1. What are rationales for clinical trial adjudication; i.e. why and when is it appropriate or desired to adjudicate an endpoint.
      1. Regulatory View- Andrew Farb, MD (FDA) (10min)
      2. Industry View Thomas Christen, MD (Boston Scientific) (10min)
      3. Academic View- Donald Cutlip, MD (Harvard University) (10min)
  • What are the key components of the adjudication process including study endpoints and CEC elements (committee membership, charter, voting, QA, interactions with other clinical study committees, and independence from study sponsors/funders) Jonathan Seltzer, MD, MBA (ACI Clinical) (10min)
  • How do the following study elements add bias or variability to the adjudication of endpoints in device clinical trials? What types of trial designs and clinical study operational factors help to minimize bias/variation?  Are there other aspects of device trials which might contribute to or reduce endpoint variability? George Dangas , MD (Mt Sanai Medical Center)(10min)
    1. Study Blinding Challenges
    2. Variability in Operator Expertise and Operator Learning Curve Issues.
    3. Gathering the Necessary Data for Adjudication
    4. Role of Core Labs
    5. Sham/Mock Intervention

Standardized Endpoint Definitions. Karen Hicks, MD (FDA) (10min)

Panel Discussion: All Speakers

Lead Discussant: Pascal Vranckx, MD (Cardialysis)

What features of device trials would assist in the adjudication of endpoints?  When do we need adjudication to determine if an event occurred?  When do we need adjudication to ascertain device-related causality?  Is adjudication helpful in determining the impact the operator expertise or technique on outcomes?


10:00am-12:10 pm Session II- Practical Issues in the adjudication of events in device trials: Case studies which highlight the issues involved with adjudicating event occurrence, causality, blinding, operator variability, committee composition, endpoint definitions, gathering endpoint data, and clinical study operational issues. 

  1. Therapeutic Device Trials (e.g., Companion CHF) Peter Carson, MD (Washington, D.C. VA Medical Center)(10min)
  2. Implantable Diagnostic Device (e.g., Chronicle, CardioMems)- Alan Miller, MD (Health Science Center) (10min)
  3. Diagnostic Devices (e.g. Troponin, other biomarkers) Jim Januzzi, MD (Massachusetts General Hospital)(10min)
  4. Drug-Device Combination Products (e.g., Bio absorbable Drug-Eluting Stents) – Ted Heise, PhD, RAC (Cook Medical)(10min)
  5. FDA Perspective Bram Zuckerman, MD (FDA)(10min)

Panel Discussion: All Speakers & Rochelle Fink, MD, JD (FDA)

Lead Discussant: Wojciech Zareba, MD, PhD (University of Rochester Medical Center)


What practical issues should influence our thinking about adjudication?  Are there critical clinical study issues in which adjudication is required?  Are there issues in which adjudication is practically impossible?  Do these issues differ among clinical studies of stents, valves, diagnostics, pacers, and non-implantable devices used for procedures (e.g. ablation)?


Working Lunch 12:10pm-12:40pm


12:40pm- 3:00 pm Session III:    The Role of Adjudication in Efforts to Streamline the Process of Making Beneficial Devices Available to the Public: Regulatory and Reimbursement Issues

Post Market approval:  Safety/Efficacy Data collection to support development and expanded labelling:  The role of Big-Data in assessing post-marketing safety and effectiveness outcomes: What types of post-market data is susceptible to bias in reporting?  Is it likely that adjudication would reduce this bias?  How reliable are claims data or other large patient care databases to determine event rates without independent adjudication?

  1. Claims based data Matthew Brennan, MD,MPH (Duke University) (10min)
  2. Registry (e.g. TAVR) Mitchell Krucoff, MD (Duke University) (10min)
  3. Big-Data (e.g. EMR data, data consolidators) Jo Carol Hiatt, MD, MBA (Kaiser Permanente) (10min)
  4. Industry Perspective/Emerging data sources (e.g. PCORI, patient reported outcomes data) Richard Kuntz, MD (Medtronic)(10min)

Panel Discussion: All Speakers

Lead Discussant: Mitch Krucoff, MD (Duke University)

What types of post marketing events require adjudication?  What are the characteristics of types of devices that might require adjudication?  What are the key factors that provide for practical endpoint adjudication in the post-market setting?  Does the statistical power of databases obviate the need for adjudication?  If not, what are potential strategies for adjudication?  Can databases be used to identify potential events (reducing the burdens and costs associated with on-site study monitoring), which can then be independently adjudicated by a CEC?  Can database strategies replace registries?


  • Efficient use of premarket data sets to meet both FDA-CMS requirements:
    1. Engagement with CMS and FDA: What is it and what is its current status in device trials?  When can we use clinical study data to support both CMS and FDA requirements?  When would endpoint adjudication be helpful?
      1. Industry View Bradley Horst (Boston Scientific)(10min)
      2. Regulatory View- Murray Sheldon, MD (FDA)(10min)

CDRH’s Expedited Access PMA (EAP) Program. What is it?  Since the focus is to speed approval of devices meeting unmet medical need with less pre-market data than typically required for a PMA but with enriched post-market data collection, what is the role of adjudication in these situations to satisfy FDA data requirements post-market?  What is the role of adjudication in these situations to satisfy coverage with evidence development (CED) for CMS?  Is there a difference in adjudicating safety vs. effectiveness?  In what cases could the additional effort needed for endpoint adjudication reduce the length or breadth of post-market follow-up?

  1. CMS View- Daniel Canos (10min)
  2. Industry View—Wendel Smith, MD (Edwards Life Science) (10min)

CEC Summary Slides

3:00pm-3:30pm Summary and Next Steps