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?


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)


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

CSRC Think Tank:
Prevention of Sudden Cardiac Death in the Young:
Developing A Rational, Reliable and Sustainable National Health Care Resource

White Oak Facility, FDA Headquarters • Silver Spring, Maryland• February, 20 2015

Meeting Agenda

Session Time Topics & Speakers
7:30am-8:00am Registration & Breakfast
8:00am-8:20am- Welcome & Introductions
Co-Chairs : Brief statements review of goals of the meeting and the agenda –Theressa Wright, M.D. (Eli Lilly)(10min)
Collaboration, Cardiac Safety & Children: The CSRC View
Who, What, & Why: The Mission of the CSRC – Mitchell Krucoff, M.D. (Duke University) (10min)
8:20am 8:50am Plenary Session: Sudden Cardiac Death in the Young
An issue of national and international public interest– Jonathan Kaltman, M.D. (NHLBI)(10min)
An issue of the family (personal prospective)- Sharon Bates (Anthony Bates Foundation)(10min)
An issue of public health and cardiac safety?- Norman Stockbridge, M.D., Ph.D (FDA) (10min)
8:50am-10:10am Pathophysiology and Detection How do we find who is at risk and what happens when we do?
Moderator: Theressa Wright, M.D. (Eli Lilly)
SCD in the young: How good are we at detection in the best circumstances?-Mitchell Cohen, M.D. (Phoenix Children’s Hospital) (10min)
False positives and negatives: What are our worst fears with screening?- Michael Ackerman, M.D., Ph.D (Mayo Clinic)(10min)
Panel Discussion-Benefits and drawbacks of screening (60mins)
FDA Perspective- Lynne Yao, M.D. (FDA)
Japan Perspective-Kaori Shinagawa, M.D., Ph.D (PMDA Japan Regulatory Agency)
Pharmaceutical perspective- Robert Kleiman, M.D. (ERT)
Parent/Foundation Perspective – Martha Lopez-Anderson (Parent Heart Watch)
Sport Organization Perspective-Brian Hainline, M.D. (NCAA)

10:10am-10:25-Break (15min)

10:25am-12:15pm Global Perspective on Screening for SCD in the Young
Moderator: John Finkle, M.D. (GSK)
International Perspective “Screening approaches for sudden death in Italy”- Antonio Pelliccia, M.D. (University of Rome/ L’Aquila)(10min)
International Perspective: “Screening approaches for sudden death in Japan”-Kaori Shinagawa, M.D. (PMDA Japan Regulatory Agency)(10min)
International Perspective: Screening approaches for sudden death in Israel”– Sami Viskin, M.D. (Tel Aviv Medical Center ) (10min)
The state of screening in the US: results of a national survey– Christine Lawless M.D., MBA (University of Nebraska) (15min)
Panel Discussion- What are the roadblocks to screening? (65min)
FDA Perspective- Lynne Yao, MD.
Academic Perspective (Psychological)- Irfan Asif, M.D. (Greenville Health System-Greenville, South Carolina)
Industry Perspective- Albert J Allen, M.D., Ph.D. (Eli Lilly)
Academic Perspective- Stuart Berger, M.D. (University of California- Davis)
Foundation Perspective- Lisa Salberg (Hypertrophic Cardiomyopathy Association)

12:15pm-1:00pm- Lunch (45min)

1:00pm- 2:30pm Can we develop a uniform standard for screening
Moderator: Salim Idriss, M.D., Ph.D. (Duke University)
Can we develop uniform approach to screening? -Kimberly Harmon, M.D. (University of Washington) (10min)
Can we develop uniform screening parameters for ECG? -Elizabeth Saarel, M.D. (Primary Children´s Hospital-Salt Lake City, UT) (10min)
What is role of echocardiography? -Nancy Goldman Cutler, M.D. (Beaumont Children’s Hospital- Royal Oak, MI ) (10min)
Panel Discussion- Discussion about development of a uniform screening approach, a screening ‘toolkit’ for programs to have uniform approach (60min)
Industry Perspective- Margaret Keehn, RN (GE Healthcare)
Foundation Perspective- Darren Sudman, JD (Simon’s Fund)
Sport Organization Perspective-Brian Hainline, M.D. (NCAA)

2:30pm-2:45pm-Break (15min)

2:45pm-4:45pm How do we develop and utilize a repository of data from screening?
Moderator: Mitchell Krucoff, M.D. (Duke University)
Developing a consensus on formats for digital ECGs: The background of the FDA ECG warehouse Justin Mortara, Ph.D (Mortara Instruments) (5min)
What are essential elements for a screening database? -Darren Sudman, JD (Simon’s Fund) (5min)
What are the nuts and bolts of image storage in a repository? Mark Kohls, MSc, MBA, Esq. (GE Healthcare)(5min)
What are the legal aspects of screening data collection and storage? Jeff Sopp, MBA (PRIVIT)(5min)
Panel Discussion What are the nuts and bolts of developing a large scale screening data repository? What screening data should be deposited? How should data be stored? Who should have access to these data? What are the legal considerations and needs for such a repository? Who is doing the work on the ground and how do we facilitate making data collection uniform, robust, legal, and lasting? Can data collection be automated? (100min)
Academic Perspective- Paul Kligfield, M.D. (New York-Presbyterian/Weill Cornell)
Industry Perspective- Fabio Badilini, M.D. (AMPS,LLC)
Academic Perspective- Sanjay Parikh, M.D. (Children’s Heart Center at St. Vincent)
4:45pm-5:45pm What are our next steps for action?
Moderator: John Finkle, M.D. (GSK)
Identification of gaps– Salim Idriss, M.D., Ph.D. (Duke University) (10min)
Discussion- How to close the gaps: Partnerships & Collaborations (50min)
5:45pm- 6:00pm-  Closing comments

Post #1419

CSRC Annual Meeting 2015

White Oak Facility, FDA Headquarters • Silver Spring, Maryland• February, 19 2015

Meeting Agenda

Session Time Topics & Speakers
8:00am-8:10am Introduction– Philip Sager, MD (Stanford University/Sager Consulting Experts) (10min)
8:10am-9:55am Plenary Session: The Landscape for Innovation in CV Safety
Moderators: Mitchell Krucoff, M.D.,
FDA Priorities and the CSRC – Robert M. Califf, M.D. (20min)
DIA Priorities and the CSRC– Barbara Lopez Kunz (20min)
Panel Discussion (65min)
Speakers and John Finkle, MD GSK
9:55am-10:10am-Break (15min)
10:10am-11:40am Mini- Think Tank 1: Replacing the Thorough QT Study-Is The Time Now?
Moderators: Philip Sager, M.D., Borje Darpo M.D., Ph.D.
CSRC/IQ- use of early human study QT date to replace the TQT
Results of the prospective study and implications- Borje Darpo M.D., Ph.D. (Consultant) (15min)
CIPA- replacing the TQT with non-clinical proarrhythmia testing? What is the need for a new paradigm and Current status, opportunities, and challenges- Hugo Vargas, Ph.D. (Amgen) (20min)
Panel Discussion (55mins)
Norman Stockbridge, M.D., Ph.D. (FDA), Christine Garnett, Pharm.D.(FDA), Corina Dota, M.D.(AstraZeneca)
11:40am-12:25pm CSRC Think Tank Updates
Moderators: John Finkle, M.D. (GSK), Jerrold Levy, M.D. (Duke University)
Key issues concerning the development of reversal agents for novel anticoagulants- Consensus pathway forward and how to evaluate post-marketing risk- Jeffrey Weitz, M.D. (McMaster University) (10min)
Use and feedback on the CV data collection forms- Mary Beth Sabol, M.D. (GSK) (10min)
Brief Panel Discussion (25min)
Speakers and Jonathan Seltzer, M.D., MBA (ACI Clinical)
12:25pm-12:55pm-Working Lunch (30min)
12:55pm-3:05pm Mini-Think Tank 2: CV Outcome Studies and Scientific Advances in Registries to Evaluate CV Safety
Moderators: Jeffrey Anderson, M.D. (Intermountain Heart Institute)
Thresholds for requiring Randomized CV outcome studies for safety assessment
Updates from the CSRC Outcome Study Thresholds Think tank and future directions- Philip Sager, M.D. (Sager Consulting Experts)(10min)
FDA Viewpoint- Thresholds for requiring CV Outcome studies for safety-Norman Stockbridge, M.D., Ph.D. (FDA)(10min)
How is benefit and risk appropriately balanced with respect to CV outcomes (to include a discussion of hazard ratio selections and number needed to harm boundaries)?- Sanjay Kaul, M.D., Ph.D (Cedar-Sinai Medical Center)(10min)
The roles for Adjudication of CV Events in drug development- Jonathan Seltzer, M.D., MBA (ACI Clinical)(10min)
Registries for CV Safety Assessment
Methodological issues in safety signal detection using heterogeneous data sources and the accuracy of diagnoses - Sharon- Lise Normand, Ph.D. (Harvard University)(10min)
The use and challenges of using electronic health care data for CV safety assessment David Graham, M.D., MPH(FDA) (10min)
Panel Discussion (60min)
3:05pm-3:35pm-Break (30min)
3:35pm-4:05pm Abstract presentations on potential new CSRC initiatives
Moderators: Catherine Ortemann-Renon, Pharm.D., Ph.D. (Sanofi)
Abstract Update: Drug-Induced Cardiac Abnormalities in Premature Infants and Neonates- Luana Koplowitz, M.D., Ph.D. (Duck Flats)(8mins)
Concentration-QTc analysis to obviate the need for a dedicated QTc study in cancer patients: ixazomib, an oral proteasome inhibitor, as a case study- Neeraj Gupta, Ph.D. (Takeda)(8min)
Arrhythmia Normal Limits in Healthy Clinical Research Volunteers- Polina Voloshko, M.D. (Cardiocore)(8min)
4:05pm-5:05pm Areas of future direction and impact for the CSRC
Moderators: Theresa Wright, M.D. (Eli Lilly), Mary Jane Geiger, M.D., Ph.D. (Regeneron)
Global Regulatory and Academic Partnerships- How Can The CSRC Increase Its Impact
Japan- Kaori Shinagawa, M.D., Ph.D. (PMDA)(5min)
Canada- Colette Strnadova, Ph.D. (Health Canada) (5min)
CDER- Norman Stockbridge, M.D. Ph.D. (FDA)(5min)
Jeffrey Anderson, M.D (Intermountain Heart Institute)(5min)
Sanjay Kaul, M.D., Ph.D. (Cedar-Sinai Medical Center)(5min)
Panel Discussion (60min)
Speakers and John Finkle, M.D. (GSK), Mitchell Krucoff, M.D. (Duke University), Philip Sager, M.D.,(Sager Consulting Experts)

NOAC Reversal Agent Think Tank Follow-up: Post Approval Safety and Effectiveness
White Oak Facility, FDA Headquarters • Silver Spring, Maryland• February, 3 2015
Meeting Agenda

Session Time Topics & Speakers
8:00am-8:15am- Introduction– Philip Sager, MD (Stanford University/Sager Consulting Experts)
8:15am-8:30am- Projecting to the future: Peter Kowey, MD (Lankenau) (15min)
Using PK/PD to inform NOAC reversal agent dosing: Should we consider pharmacometric-guided dosing of NOAC reversal agents to maximize the benefit: risk relationship?
– Post-marketing assessment of use in life-threatening bleeding situations will be critical for appropriate monitoring.
8:30am-10:15am Using Pharmacokinetic and pharmacodynamic parameters to inform NOAC dosing: Should we consider pharmacometric-guided dosing of NOAC agents to maximize the benefit: risk relationship?
Lead Discussant- Philip Sager, MD (Stanford University/Sager Consulting Experts)
– Regulatory Considerations-Robert Temple, MD, PhD (FDA, CDER) (15min)
Industry Considerations– Paul Reilly, PhD (Boehringer-Ingelheim)(15min)
– Clinical Perspective: What are the opportunities and challenges of using a pharmacometric approach? Jeffrey Weitz, MD (McMaster University) (15min)
Discussion (60min)

10:15-10:30am Break (15min)

10:30am-12:45pm Defining the Data Elements for Safety and Effectiveness Monitoring of the NOAC Reversal Agents: For each perspective: What are examples of post marketing data you think are most appropriate to these types of products? What indications should be tracked and what information is needed for these indications? How strong does the level of evidence have to be to support safety? How strong to rule out inappropriate use?
Lead Discussant- Mitchell Krucoff, MD (Duke University)
Clinical Considerations: Academic-James Reiffel, MD (Columbia University) (10min)
Clinical Considerations: Emergency Medicine- Charles Pollack, MD (University of Pennsylvania) (10min)
Regulatory Considerations– Victor Baum, MD (FDA Office of New Drugs/Biologics) (10min)
Regulatory Considerations– Peter Waldron, MD (FDA CDER Office of Surveillance and Epidemiology/ CBER Office Of Biostatistics and Epidemiology) (10min)
– Payer Consideration: Private Payers, Hospital Systems
Lewis Sandy, MD (United Health Group) (10min)
Brian Caveney, MD (Blue Cross Blue Shield) (10min)
Discussion (75min)

12:45pm- 1:15pm- Lunch Break (30min)

1:15pm- 2:45pm Potential Data sources for Surveillance: What are the advantages and disadvantages of each type of data? Can they provide what is required from earlier sessions? Implementing an Effective Post-Approval Active Surveillance Strategy: How can we best achieve the goals for safety and effectiveness monitoring? What types of data sources are out there? What are the strengths and weaknesses? What are acceptable methodologies for surveillance? What are the success cases/failures? What are limitations?
Lead Discussant- Troy Sarich, PhD (Janssen)
– Current Methodologies for Safety Surveillance
-AERS Reporting- Anne Tobenkin, PharmD (FDA)(10min)
Sentinel approach– Marsha Reichman, PhD (FDA) (10min)
-Direct-from-Patient Data Integrated with Electronic Medical Record Information- Kenneth Borow, MD (MediMergent) (10min)
Active PM surveillance and considerations for an active comparator – Paul Stang, PhD (Janssen)(10min)
Pharmacoepidemiology approaches and Big Data– Nancy Dreyer, PhD (Quintiles) (10min)
Discussion (40min)
2:45pm-3:30pm Summary- What should be our recommended Approach: Options for NOAC Reversal Agents: A Structured Roundtable Discussion
Moderator-Jonathan Seltzer, MD, MBA (ACI Clinic)


2015 Meetings Slides and Agendas
Topic Date Title Slides and Agendas
Novel Anticoagulants February 3, 2015 NOAC Reversal Agent Think Tank Follow-up: Post-Approval Safety and Effectiveness Slides & Agenda
Annual Meeting February 19, 2015 2015 Annual Meeting Slides & Agenda
Sudden Cardiac Death February 20, 2015 Prevention of Sudden Cardiac Death in the Young: Developing A Rational, Reliable and Sustainable National Health Care Resource Slides & Agenda
Cell Therapies for CV Indications October 23, 2015 CSRC Roundtable Discussion: Cardiovascular Safety for Cell Therapies in Development for Cardiovascular Indications Slides & Agenda
Social Listening November 4, 2015 CSRC/DIA: Social Listening and Safety Surveillance— Enabling Opportunities for Cardiac Safety Slides
Long-Term Electrocardiographic Monitoring December 2, 2015 Long Term Electrocardiographic Monitoring: Its Role in Clinical Drug Development and Population Screening Slides & Agenda
Novel Anticoagulants December 3, 2015 Is There a Role For Pharmacokinetic/Pharmacodynamics Guided Dosing For Novel Anticoagulants? Slides & Agenda