Percutaneous Valve Trials Reality Check: Need for Rigorous Evaluation

1. Percutaneous Valve Trials Reality Check:Need for Rigorous Evaluation Julie Swain M.D. Cardiac Surgeon Consultant Division of Cardiovascular Devices, FDA AATS/ACC Chicago 2009 Heart Valve Summit

2. No Conflict of Interest For copies of these slides email: Julie.Swain@FDA.HHS.gov Swain

3. The Reality FDA approval is generally needed for a device to be “successful” worldwide The FDA requires rigorous scientific evidence demonstrating that the risk/benefit ratio is favorable (e.g. “reasonable assurance of safety and effectiveness”) Swain

4. Percutaneous valve technology qualifies as enough of a departure from current standard of care clinical practice that most devices of this nature will need to be evaluated through a randomized, controlledclinical trial. Swain

5. Risk/Benefit Ratio: The Reality • Percutaneous valves will be less effective, but will have less risks, than open operation • Percutaneous valves will be more effective, but have more risks, than medical therapy Swain

6. Sufficient safety evidence is needed to begin clinical studies in U.S. – most disapprovals based on inadequate bench and/or animal testing. This is especially important for devices with novel materials. • Early collaboration with FDA is a key to addressing and resolving issues (the “pre-IDE” process) Swain

7. Who are the Investigators in the Trial?The Reality: Cardiologist and Surgeon Expertise Must be Equivalent • Highly capable intracardiac interventional cardiologists are the investigators in the trials • The aortic valve surgeons should have expertise in high risk AVR patients • The mitral valve surgeons should have expertise in mitral valve repair Swain

8. The Control Arm “How would the patient be treated today in a center of excellence if the new device were not used?” Selection of Control group determines: • which patients enrolled (inclusion/exclusion criteria) • endpoints/time of endpoints • statistical design (superiority, non-inferiority) • risk/benefit determination • labeling/marketing/?CMS payment Selecting a control group is often the most difficult part of trial design – the group must be clinically reasonable and statistically evaluable Swain

9. Endpoints Clinical endpoints must be: - clearly defined - clinically relevant - easily interpretable (difficult with composites) - device-appropriate (different devices and populations require different types of analyses) Swain

10. Need for 1-2 year EP, 5-10 year follow-up • Unknown durability in humans • Unknown effect on heart failure progression/ventricular remodeling • Unknown long-term clinical effects of partial repair of regurgitation in mitrals • Unknown effect on the ability to do subsequent surgical valve repair for mitrals and open valve replacement for aortics Swain

11. Reality: Where are trials conducted? Need same: protocol, patients, treatment, followup Swain

12. Reality: Judging the Risk/Benefit Ratio • Risk/benefit is a qualitative clinical judgment (meeting endpoints does not assure approval) • Composite endpoints (such as for safety) are not hierarchically weighted so must be qualitatively judged • If “all comers” are included, then device approval will have to show benefit in the least sick group Swain

13. Aortic Valve Swain

14. Who Are the Patients for Percutaneous Aortic Valves in 2009? • “inoperable” – as decided by experienced surgeon/cardiologist team (remembering that percutaneous valve may require general anesthesia, retroperitoneal cutdown or thoracotomy, CPB, etc.) • “high risk” – final estimate by surgeon guided by STS risk prediction guidelines Swain

15. Justification of Need for Percutaneous Aortic Valves: Assumptions ALL AORTIC STENOSIS OPERATION BAV Medical Rx = TCV Swain

16. Large Unmet Need? • What is the evidence that patients with severe aortic stenosis who are seen by excellent cardiologists and surgeons at tertiary referral centers are not treated? • The issue may be education of referring physicians and patients • Cleveland Clinic experience 2004 Swain

17. Current Reality ALL AORTIC STENOSIS BAV +RAD Transcatheter Valves Medical Rx Operation Swain

18. Aortic Control Group Decision Tree Documented by validated Risk Score (STS) and clinical assess Cardiologist decides treatment is necessary RCT RCT RCT = randomized, controlled trial Swain

19. Special Aortic Valve Trial Consideration: Mode of Implantation • Direct into aorta (small chest incision) • Transapical (small thoracotomy) • Trans-iliac/retroperitoneal (open surgical access) • Transfemoral (percutaneous or open) “System” – includes all 4 of the above approaches Swain

20. Mitral Valve Swain

21. Unique Aspects of Mitral Devices(more challenging than aortics) • Different concepts • (CS, leaflets, transmyocardial, etc) • Unique engineering and preclinical concerns • Multiple etiologies of disease • Organic or degenerative (Barlow’s/MV prolapse, fibroelastic deficiency) • Functional (non-ischemic) • Functional (ischemic) (may be difficult to pool these etiologies) Swain

22. Mitral Control Group Decision Tree Documented by validated Risk Score (STS) and clinical assess Cardiologist decides treatment is necessary May require many patients for many years RCT RCT RCT RCT = randomized, controlled trial Swain

23. Endpoints: Mitral Valve Amount of MR as an endpoint may not be a clinically proven surrogate, especially in functional/ischemic MR • Mitral regurgitation repair devices: • repair to 0 or 1+ MR (in patients meeting ACC Guidelines for intervention) • May need co-primary endpoints or powered secondary endpoints with specific statistical plan for secondary endpoints defining “success” • Possible EP’s – survival, MR, echo dimensions, LV mass, function (VO2, 6MWT), QOL (consider placebo effect) Determining Risk/Benefit balance will be a challenge Swain

24. Deciding “which way is up” for percutaneous valve trial design is challenging! Swain

25. Reality Check Conclusion Development of clinical trial designs for percutaneous valves requires collaborative efforts from investigators, industry, and the FDA Swain