CSRC Meeting & CSRC Think Tank: Detection, Assessment and Risk Mitigation of Cardiac Safety Signals in Oncology Drug Development

October 24, 2017

Day 1

1:15pm-2:30pm Session I: Update on CSRC Activities

Discussion: New ideas and suggestions for 2018

2:30pm-3:00pm Regulatory Science: FDA Paths Forward Mitchell Krucoff, MD (Duke Clinical Research Institute)

3:00pm-5:00pm Session II: Hot Topic- A new FDA Pilot Program for providing pre-market “real time” safety data: Implications for Monitoring CV safety in Oncology Trials in Real Time:

Moderator: Jonathan Seltzer, MD, MBA, MA (ACI Clinical)

  • Presentation of FDA Pilot for digital submission of expedited premarket safety Reports Norman Stockbridge, MD (FDA)
  • Risk: Benefit evaluation of cardiac toxicity in Oncology Drug approvals Bindu Kanapuru, MD (FDA)
  • Best practices for CV safety monitoring. Implications of real-time safety data in oncology clinical trials Susan Dent, MD (Ottawa University)

Discussion: Impact of availability of real time data on CV monitoring. What are the possibilities of pre-market ‘real time’ data for detection/mitigation of CV safety issues? What are limitations (e.g. potential false positives, false negatives)? What process/education changes need to be made to accommodate real time information? Should CSRC actively pursue developing best practices in this area?

  • What are the cardiovascular toxicities germane to oncology drug development? Javid Moslehi, MD (Vanderbilt University)(10mins)
  • What patient CV risk factors should be excluded from what types of oncologic agents Anthony Yu, MD (Memorial Sloan Kettering)(10mins)
  • Redefining Cardiac Eligibility Thresholds in Oncology Trials. Role of the Cardiovascular Core Lab Ana Barac MD, PhD (Georgetown University/Medstar Health)(10 mins)

Discussion: How can cardiologists improve evaluation of potential cardiac signals? Are there assumptions we should avoid that would retard our understanding of toxicities in the oncology population?

Lead Discussant: Anupam Agarwal, MD, MPH (Zogenix)

12:00pm-12:30pm Lunch

12:30pm-2:30pm Session III: Assessment of CV signals

What areas of study design for Phase 2 and Phase 3 oncology studies need to be addressed in order to ensure that CV signals are detected? Are there standard data fields/CRFs that should be completed for suspected CV signals? In what situation will suspected events require adjudication? Do they need to be characterized differently in the oncology population? What is needed for safety reporting?

Moderator: Boaz Mendzelevski, MD (Cardiac Safety Consultants)

  • Oncology Study design for assessment of CV safety endpoints
    • Design considerations for Cardio-oncology studies Boaz Mendzelevski, MD (Cardiac Safety Consultants)(12mins)
  • Utilization of biomarkers for CV safety assessments
    • Serial assessments of serum biomarkers and when they might be considered. Alan Jaffe, MD (Mayo Clinic)(10mins)
    • Cardiovascular imaging endpoints in oncology clinical trials Bonnie Ky, MD (University of Pennsylvania)(10min)
  • Practical considerations for CV safety monitoring
    • Strengths and weaknesses of standardized collection of cardiovascular risk data at baseline and MedDRA coding Anupam Agarwal, MD, MPH (Zogenix)(10mins)


October 25, 2017

Day 2

8:00am- 8:10am CSRC Welcome & Goals of the Think Tank- Jonathan Seltzer, MD, MBA, MA (ACI Clinical)

8:10am-9:40am Session I: Translational Medicine and Non-clinical signals of potential cardiac toxicity

What is the current state of non-clinical testing for CV safety? How does evaluation of oncology compounds in Phase 1/1st-in-human oncology studies differ from other compounds? How does mechanism of action and metabolic profile effect evaluation of nonclinical signals?

Moderator: Luana Pesco Koplowitz, MD, PhD (Ducks Flats Pharma)

  • An Overview of Translational Medicine in Cardio-Oncology Luana Pesco Koplowitz, MD, PhD (Ducks Flats Pharma)(10mins)
  • Cardiovascular Oncology: Do We Need Plumbers, Electricians, or Strength Trainers? Gary Gintant, PhD (Abbvie)(10mins)
  • Preclinical Assessment of Potential Small Molecule Kinase Inhibitor-Induced Cardiac Toxicity: Past, Present, and Future Baichun Yang, PhD (FDA)(10mins)
  • Induced Pluripotent stem Cells for Cardiac Safety Assessment and Precision Medicine: Regulatory Research at FDA Ksenia Blinova, PhD (FDA)(10mins)
  • Personalized Assessments of Drug-Induced Cardiac Toxicities Paul Burridge, PhD (Northwestern University)(10mins)
  • Discovery Phase Counterscreening for Functional Cardiotoxicity Mathew Brock, PhD (Genentech)(10mins)

Discussion: How can we characterize cardiac risk more precisely and earlier?

Lead Discussant: Gary Gintant, PhD (Abbvie)

9:40am-10:00am Break

10:00am-12:00pm Session II: Specific CV issues in Oncology Development

For specific areas such as HTN, LV dysfunction, pro-arrhythmia: What are the differences in the oncology population compared to a reference population? Why can’t we extrapolate from non-oncology population? What is the burden on cardiologists in evaluation of potential cardiac safety signals?

Moderator: Richard Steingart, MD (Memorial Sloan Kettering Cancer Center)

Discussion: What is the proper role of a cardiologist in oncology clinical trials? When is cardiac expertise needed at the site? When is cardiac expertise needed in evaluation of signals? Is there a need for a more precise characterization of cardiac events in the oncology population? Should suspected CV events be adjudicated?

Lead Discussant: Javid Moslehi, MD

2:30pm-3:10pm Session IV: Balancing CV risk vs benefit in Oncology Drug Development

Moderator: Jonathan Seltzer, MD, MBA, MA (ACI Clinical)

What are the patient and compound features that should be evaluated in determination of risk vs. benefit? What are the particular issues with respect to CV health/toxicity? How do we weigh these factors? Is there a common framework from which we can work to evaluate the value equation?

Panel Discussion: Regulatory, Industry, Patient, Academia, Payer

Lead Discussant: Jonathan Seltzer, MD, MBA, MA (ACI Clinical)

  • Laleh Amiri-Kordestani, MD (FDA)
  • Richard Steingart, MD (Memorial Sloan Kettering)
  • Jack Singer, MD (CTI Biopharma)

3:10pm- 3:30pm Wrap-up & 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