1. IDEs in a New Device Space: An FDA View of Mitral John Laschinger, MD CDRH, ODE, DCD, SHDB Predictable And SuStainable Implementation Of National Registries For Cardiovascular Devices

2. Key Issues to Consider Registry Use in MV IDE Trials Applying Lessons learned from TAVR US Regulatory realities – Pre-Market – Post-Market US Regulatory realities – Pre-Market – Post-Market Sustainable model for success utilizing Registries

3. Clinical Considerations What Currently Works Well – Lessons form TAVR 3 FLEXABILITY – Tailor Trials New Device for New Use (TMVR) Strategy trial vs. established SOC New Device for Established Use New Device Approval Iteration of Approved Device Iterative Device Approval Old Device for New Use Label Expansion – Anchors, Access & populations FLEXABILITY – Tailor Trials New Device for New Use (TMVR) Strategy trial vs. established SOC New Device for Established Use New Device Approval Iteration of Approved Device Iterative Device Approval Old Device for New Use Label Expansion – Anchors, Access & populations Staged Pre-Clinical Testing Standardized Outcome Measures 30 day Safety Composites Time-Insensitive Effectiveness Composites Benchmark Outcomes – Early PG Staged Pre-Clinical Testing Standardized Outcome Measures 30 day Safety Composites Time-Insensitive Effectiveness Composites Benchmark Outcomes – Early PG

4. 4 What Currently Doesn’t Work Well – US Device Lag

5. 5 Changing the Pre – Post Market Balance CDRH Initiatives Pre-post Market Balance Expedited Access PMA CDRH Initiatives Pre-post Market Balance Expedited Access PMA Post-Market Surveillance Short Term Goals: Optimizing Pre-Market Data

6. 6 Long Term Goals – Attracting Sponsors to the US Enhanced Post-Market Surveillance Surveillance Steps: Early Entry: FIH and EFS Rapid Transitions Tailored Data Requirements Standardized Outcomes Measures “Staged” Trial Design Steps: Early Entry: FIH and EFS Rapid Transitions Tailored Data Requirements Standardized Outcomes Measures “Staged” Trial Design FIMPivotal FIM EFS (30 d) Pivotal JIT Pre-Clinical Testing Standardized Outcomes Performance Goals Tailored Trials Pre-Post Market Balance JIT Pre-Clinical Testing Standardized Outcomes Performance Goals Tailored Trials Pre-Post Market Balance Early Device Approval U.S. EFS (30d S & E) EFS Optimizing Data and Time

7. Tiered Certification – Device Development Enhancing the Value of Registries - SUSTAINABILITY *Research Infrastructure /expertise for Pivotal Trials Full dataset capabilities: 0- 30-day to 1-5 year 7 Premarket uses – Essential for sustainability and industry support Assurance of high quality reliable data Recognition that capabilities of participants vary Premarket uses – Essential for sustainability and industry support Assurance of high quality reliable data Recognition that capabilities of participants vary

8. Thank You! John Laschinger, MD Medical Officer, SHDB 301.796.1210 john.laschinger@fda.hhs.gov 8

9. 9

10. 10 Striking the Right Balance – Essential Role of Registries Closing the Gap - Minimizing Pre-Market Data

11.  Robust  Accurate - real-world performance  Timely  Quickly identifies poorly performing devices need for new or improved devices  Transparent  Patients and Physicians  Payors  Regulators  Industry  Facilitate device approval or clearance  Reliable and Sustainable Registries 11 Requirements For an Effective Post-Market Registry Information needed to make well-informed decisions Closing the Gap - Minimizing Pre-Market Data

12. 12 Acute Device Safety Performance Goals - Future: Risk population based Individual or Composite 30 day MAE rates for: – Mortality – Stroke – Paravalvular leak > 1+ – Major Vascular Injury – Life Threatening Bleeding – AKI Grade 3 – New Pacemaker/LBBB – Coronary Occlusion/MI – Urgent/Emergent OR Acute Device Safety Performance Goals - Future: Risk population based Individual or Composite 30 day MAE rates for: – Mortality – Stroke – Paravalvular leak > 1+ – Major Vascular Injury – Life Threatening Bleeding – AKI Grade 3 – New Pacemaker/LBBB – Coronary Occlusion/MI – Urgent/Emergent OR Safety: Timing and Performance Goals First Steps - We have developed Standard Outcomes for 30 day Safety! Standardized 30 day Safety Composite: Non-hierarchical composite Includes: all-cause mortality, disabling stroke, life threatening bleeding, acute kidney injury requiring dialysis major vascular complications Standardized 30 day Safety Composite: Non-hierarchical composite Includes: all-cause mortality, disabling stroke, life threatening bleeding, acute kidney injury requiring dialysis major vascular complications Minimizing Pre-Market Data - Outcome Standardization

13. Effectiveness: Timing and Performance Goals Device Success: Disabling Stroke free survival Original/Intended device in place No Additional valve/access related procedures No paravalvular Complications (e.g. PPM, Coronary occlusion, PVL > mild) Intended performance of valve ‒Gradient 1.5cm 2 ‒MR < 2+ ‒No hemolysis, fracture, migration, endocarditis or thrombosis Device Success: Disabling Stroke free survival Original/Intended device in place No Additional valve/access related procedures No paravalvular Complications (e.g. PPM, Coronary occlusion, PVL > mild) Intended performance of valve ‒Gradient 1.5cm 2 ‒MR < 2+ ‒No hemolysis, fracture, migration, endocarditis or thrombosis We have developed clinically meaningful composite measures of effectiveness that are time insensitive * * Can be determined at any time point post procedure – followed post-market over time 13 Individual Patient Success: Device success AND No re-hospitalizations for HF or treated valve related causes NYHA class ≤ 2, or improvement in NYHA class by at least 1 level from baseline 6MWT >50 meter increase vs. baseline KCCQ improvement by > 10 vs. baseline Individual Patient Success: Device success AND No re-hospitalizations for HF or treated valve related causes NYHA class ≤ 2, or improvement in NYHA class by at least 1 level from baseline 6MWT >50 meter increase vs. baseline KCCQ improvement by > 10 vs. baseline Minimizing Pre-Market Data - Outcome Standardization

14. 14 Closing the Gap: Time to Approval No Control Over Quality/Quantity of Early Data Out of Our Control! CE Mark IDE Approval IDE Approval FIM and EFS OUS DATA Safety and Performance ≈ Sufficient Safety to initiate a clinical trial Safety and Performance ≈ Sufficient Safety to initiate a clinical trial Current Reality TIME PMA Approval Safety and Effectiveness PMA Approval Safety and Effectiveness

15. CE Mark IDE Approval IDE Approval FIM and EFS OUS DATA Safety and Performance ≈ Sufficient Safety to initiate a clinical trial Safety and Performance ≈ Sufficient Safety to initiate a clinical trial Current Regulatory Reality TIME PMA Approval Safety and Effectiveness PMA Approval Safety and Effectiveness 15 No Control Over Quality/Quantity of Early Data Out of Our Control! Time to Device Approval: US vs. EU

16. 16 Getting better Data Earlier CE Mark PMA Approval PMA Approval US FIM /EFS PIVOTAL DATA Safety and Performance Getting Control: More Data Better Data Earlier Safety and Effectiveness Closing the Gap: Time to Approval Changing Reality

17. Discussion 17