2019

 

2019 Meetings Slides and Agendas
Topic Date Title Slides and Agendas
NOACs; Pediatrics April 4, 2019 NOAC Use in the Pediatric Population: Defining the Path Forward Slides and Agenda

 

CSRC Think Tank: Defining the Clinical and Regulatory Landscape for Cardiogenic Shock

September 7, 2018

8:00am – 8:15am Introduction and Purpose of Think Tank Mitchell Krucoff, MD (Duke)

  • Introduction to CSRC
  • Anatomy of a Think Tank

8:15am – 8:45am Session I: Overview of shock

Session I Objectives:

8:45am – 9:00am BREAK

9:00am – 10:30am Session II: Defining unmet needs, clinical study barriers, and targets for drug and device therapy for shock: Part I Moderator: Joseph Rogers, MD (Duke)

Session II Objectives:

  • Define a population of intended use for drug and device therapies in cardiogenic shock.
  • Discuss and identify comparator cohorts for cardiogenic shock trials.
  • Discuss and identify primary and secondary outcomes for cardiogenic shock trials.

9:00am – 9:10am Cohorts to study: defining a “population of intended use”

9:10am – 9:20am Comparators for drug and device trials in shock patients

  • Clinical/best practice perspective Judith Hochman, MD (NYU Langone)

9:20am – 9:30am Outcome endpoints: mortality plus?

9:30am – 9:40am FDA Perspective Ileana Pina, MD
9:40am – 9:50am Health Canada Perspective Roy Masters, MD
9:50am – 10:30am Discussion

  • Lead Discussant: Ron Waksman, MD (Medstar Health)

10:30am – 10:45am BREAK

10:45am -12:15pm Session III: Defining unmet needs, clinical study barriers, and targets for drug and device therapy for shock: Part II | Moderator: David Morrow, MD MPH (Harvard)

Session III Objectives:

  • Discuss enrollment of patients who may not be capable of providing informed consent.
  • Discuss and identify novel evidence structures for future shock trials.
  • Discuss and identify novel statistical approaches for trials of shock therapies.

10:45am – 10:55am Informed consent

  • Clinical/best practice perspective Timothy Henry, MD (Cedars-Sinai)

10:55am – 11:05am Avenues for real world evidence, pragmatic trials, or novel infrastructure for shock trials

  • Clinical/best practice perspective Holger Thiele, MD (University of Leipzig)

11:05am – 11:15am Novel statistical approaches for shock studies

11:15am – 11:20am Improving Patient Outcomes in Cardiogenic Shock as a core mission of clinical development programs Seth Bilazarian, MD (Abiomed)

11:20am-11:30am FDA Perspective John Sapirstein, MD

11:30am – 12:10pm Discussion

  • Lead Discussant: Roseann White, MA (Duke)

12:10pm – 1:00pm LUNCH

1:00pm – 2:00pm Session IV: Future directions for device and drug development in shock. Moderator: Sunil Rao, MD (Duke)

Session IV Objectives:

  • Identify global collaborators for trials of shock therapies.
  • Discuss trial designs incorporating both drug and device therapies for patients with cardiogenic shock.
  • Discuss and define “-ARC” definitions of shock (SHARC).

1:00pm – 1:10pm Global collaboration: is it possible? Is it desirable? Clinical/best practice perspective William Abraham, MD (Ohio State)

1:10pm – 1:20pm Factorial device and drug study designs

  • Clinical/best practice perspective Roxana Mehran, MD (Mount Sinai)

1:20pm – 1:30pm Definitions: Shock-ARC (SHARC)

  • Clinical/best practice perspective George Dangas, MD (Mount Sinai)

1:30pm-1:40pm FDA Perspective Fortunato Senatore, MD, PhD
1:40pm – 2:30pm Discussion
2:30pm – Closing Remarks

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

2018

2018 Meetings Slides and Agendas
Topic Date Title Slides and Agendas
Cardiogenic Shock September 7, 2018 Defining the Clinical and Regulatory Landscape for Cardiogenic Shock Slides and Agenda
Arrhythmia, Proarrhythmia, CiPA May 21-22, 2018 New Advances in the Assessment of Drug-Induced Arrhythmias and the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Slides and Agenda

 

2017 Meetings

2017 Meetings Slides and Agendas
Topic Date Title Slides and Agendas
Sudden Cardiac Death February 10, 2017 CSRC Prevention of Sudden Cardiac Death in the Young: National Cardiac Screening Warehouse Pilot Study Slides & Agenda
Cardiovascular Regenerative Medicine September 15 -16, 2017 Co-sponsored Symposium with the Texas Heart Institute on Cardiovascular Regenerative Medicine Event Information
Oncology Drug Development October 24-25, 2017 CSRC Meeting and Detection, Assessment, and Risk Mitigation of Cardiac Safety Signals in Oncology Drug Development Think Tanks Slides & Agenda

 

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?

Break-9:50am-10:00am

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

2016 Meetings

2016 Meetings Slides and Agendas
Topic Date Title Slides and Agendas
Sudden Cardiac Death February 18, 2016 The 2nd Annual Think Tank on Prevention of Sudden Cardiac Death in the Young: Developing A Rational, Reliable and Sustainable National Health Care Resource Slides & Agenda
Endpoint Adjudication March 11, 2016 CSRC and MDEpiNet Thinktank Meeting: “The Role of Endpoint Adjudication in Medical Device Clinical Trials” Slides & Agenda
Proarrhythmia April 6, 2016 CSRC/FDA Workshop: The Proarrhythmic Assessment of New Chemical Entities Slides & Agenda
Social Listening June 3, 2016 CSRC/DIA Think Tank: Enabling Social Listening for Cardiac Safety Slides & Agenda
Annual Meeting October 18, 2016 CSRC 10th Annual Meeting Slides & Agenda
Efficiencies in Phase 3 Development October 19, 2016 CSRC Think Tank: Real World Data to Assess Cardiovascular Safety- Can We Improve Efficiencies in Phase 3 Development? Slides & Agenda

Think Tank Synopsis

Drug-induced Arrhythmia and CiPA December 6, 2016 Critical Discussion- Future of the Assessment of Drug-Induced Arrhythmias and the Comprehensive in Vitro Proarrhythmia Assay (CiPA)  Slides & Agenda
QTc ER Modeling and VT/VF December 7, 2016 Part A: QTc Exposure-Response Modeling Workshop: What is Required?

Part B: Endpoints When Treating VT/VF in Patients with ICDs

 Slides & Agenda

 

CSRC Roundtable Discussion: Cardiovascular Safety for Cell Therapies in Development for Cardiovascular Indications

Friday, October 23, 2015

Final agenda and links to presentation

8:30am-9:00am- Registration and continental breakfast

9:00am-9:10amIntroduction -Philip Sager, MD (Stanford University) (10min)

9:10am-10:35amSession I: Risk Profiling

Safety Considerations in Development of Cell Therapies for Cardiovascular Indications. Steve Winitsky, MD (FDA/CBER) (10min)
Risk as related to source of cells (autologous vs. allogeneic), manipulation, and harvesting procedures. Marc Penn, MD, PhD (Summa Cardiovascular Institute) (10min)
Proposals for approaching risk profiling based on preclinical and clinical data. Joseph Wu, MD, PhD (Stanford University) (10 min)
Device-therapeutic combination challenge. Amit Patel, MD (University of Utah) (10min)

Expert panel discussion (45min)

10:35am-11:50pmSession II: Dose Finding in Cell Therapies Development
Is demonstration of dose dependency required for establishing safety and bioactivity? Douglas Losordo, MD (Caladrius) (10min)
Role and unique challenges of potency assays in cardiovascular cell therapy. Andreas Zeiher, MD (University of Frankfurt) (10min)
Dose scaling based on non-human assays. Thomas Povsic, MD (Duke University) (10min)

Expert panel discussion (to include FDA representation) (45min)

11:50pm-12:00pm– Final remarks, and next steps

 

Is There a Role For Pharmacokinetic/Pharmacodynamics Guided Dosing For Novel Anticoagulants?

Thursday, December 3, 2015

Final agenda and links to presentations:

8:00am-8:10amIntroduction and goals of the Think Tank– Philip Sager, M.D. (Stanford University)

8:10am-10:40amSession I: What does the current information tell us about NOAC dosing? What evidence is there that there of the variable clinical responses to PK parameters? What conclusions can we draw from these data?
Moderator: Philip Sager, M.D. (Stanford University)
Lead Discussant: Norman Stockbridge, M.D., Ph.D. (FDA)

Setting the Stage: What is the problem we are trying to address regarding NOAC dosing? Christopher Granger, M.D. (Duke University) (20min)

Summary from the EMA/CHMP Workshop on the role of PK and PD in the use of direct oral anticoagulants – Jens Heisterberg, M.D. (CHMP) (10min)

For whom are the current dosages optimal? Who might benefit from alternative dosing strategies? Noel Chan, M.D. (Monash University/McMaster University) (10min)

What evidence is there that variable clinical responses to PK parameters exist for NOACs? What conclusions can we draw from these data?
(Which PK/PD factors associated with bleeding and thrombotic events? What patient factors are associated with stroke/thrombotic events? What is the extent of Intra-individual PK variability? Can PK/PD be used as a guide for dosing?)

Review of Data from

Dabigatran- Paul Reilly, Ph.D. (Boehringer Ingelheim Pharmaceuticals) (10min)
Rivaroxaban- Dagmar Kubitza, M.D. (Bayer) (10min)
Apixaban- Jack Lawrence, M.D. (Bristol-Myers Squibb) (10min)
Edoxaban- Michele Mercuri, M.D.,Ph.D (Daiichi Sankyo) (10min)

FDA Interpretation- Jeffry Florian, Ph.D. (FDA) (10min)

Discussion: What are the problems with the current NOAC dosing strategy? How big they; what groups or patients are most effected? If there are issues, what data will we need moving forward?

10:40-10:55:- Break

10:55am-1:00pmSession II: Is it possible that with better precision dosing we can do better in avoiding strokes and bleeds? What types of clinical evidence would be necessary to support PK/PD dosing? How do we ensure we are not hurting anyone?
Moderator: Jonathan Seltzer, M.D., M.B.A. (ACI Clinical)
Lead Discussant: Michele Mercuri, M.D., Ph.D. (Daiichi Sankyo)

Point/Counterpoint: PK-based dosing strategy should be recommended for certain patient populations to improve public health vs. PK based dosing strategy is impractical and may will not add value. Pro-Robert Temple, M.D. (FDA) (15min); Con-Scott Berkowitz, M.D. (Bayer Healthcare) (15min)

Initial PK measurement—should we do it?
Is there a rationale for monitoring?
Is it possible to measure and/or monitor?

What are the potential regulatory pathways for labeling PK based approaches? Since it is impractical to think that large trials would be undertaken to prove the benefit of PK driven dosing in already approved NOACS, what can or should be done? Do we need more evidence and what level of evidence? Is it necessary to do new clinical trial(s)? What outcomes or other endpoints would be necessary? What sort of evidence, if any, are needed to show that testing makes a difference?

Regulatory Speaker- Martin Rose, M.D. (FDA) (10min)
Academic/Industry Speaker- John Eikelboom, M.D., M.B.B.S. (McMaster University) (10min)

Discussion: What are reasonable goals to pursue for regulatory approval? What types of evidence are necessary for new labeling indications? What types of evidence will be required for new diagnostic tests? What are the pathways available? What are the obstacles?

1:00pm-2:00pm-Lunch

2:00pm-4:00pmSession III: Additional key issues impacting potential implementation
Moderator: Scott Berkowitz, M.D. (Bayer Healthcare);
Lead Discussant: Paul Reilly, Ph.D (Boehringer Ingelheim)

What is the pathway for approval of point of care test or companion diagnostic? What would the study look like? Lea Carrington, M.S., M.B.A. (FDA) (10min)

What is the pathway for approval of tests for measuring the specific anticoagulant activity of NOAC? Francois Depasse,PharmD (Stago)(10min)

Physician/Patient Issues

What are the current measurement technologies/assays? What might be needed? Which tests might be appropriate? Thomas Ortel, M.D., Ph.D. (Duke University) (10min)
How are doctors actually going to do this, i.e. adjust PK with patient bleeding risk – what are patient risk factor (biologic, cultural, con meds) What are the challenges and potential solutions to support PK/PD dosing? Peter Kowey, M.D. (Lankenau) (10min)

System Issues

Would payers (e.g. Medicare) be willing to support additional cost in order to enhance NOAC dosing? What type of evidence would be needed? James Rollins, M.D., Ph.D, (CMS) (10min)

Discussion

4:00pm-4:30pm-Wrap-Up, Next Steps