1. UNCERTAINTY OF RISK: THE CASE OF THE TRICUSPID DEVICES
Bernard Vasseur, MD
Medical Officer, SHDB

2. Disclosures and Disclaimer
Bernard G Vasseur, M.D.
I am a full time employee of the FDA. I have no financial conflicts of interest to report.
The views expressed in this presentation are those of the presenter and do not represent the official policies of the FDA.

3. TRICUSPID as an AFTER THOUGHT
Smaller number than mitral patients
Often treated in concert with mitral disease
High mortality as standalone procedure
Approved TV devices (Class III):
No Surgical Valves
Surgical Valved Conduit (Tricuspid Atresia)
Cleared TV devices (Class II)
Surgical Annuloplasty Rings

4. 2014 AHA/ACC Guideline Valvular Heart Disease – Tricuspid Regurgitation Nishimura RA. J Am Coll Cardiol. 2014;63(22):
Surgical TV Annuloplasty targets

5. 2014 AHA/ACC Guideline Valvular Heart Disease – Tricuspid Regurgitation Nishimura RA. J Am Coll Cardiol. 2014;63(22): * *
Transcatheter TV Device targets
* > High surgical risk

6. Where are We Now - EFS Numerous TV devices now under development
Device targets
Dilated annulus
Central leaflet mal-apposition
Valve replacement (endocarditis)
Purpose:
Acquire safety data,
Finalize procedure and device design in preparation for pivotal trial
Develop appropriate outcome measures

7. Clinical Data Development Plan
Know Your Device and The Outcomes That Matter
What does your device do ?
Mechanism and performance over time
When should it be Applied?
Timing in the course of Natural History
Early vs. late
What are the safety risks to the patient vs. SOC?
Can the device be safely implanted?
Does the device wear out or fail?
Expected adverse events – procedure and device
What are they?
When are they expected to occur?
Are there effective mitigations?
What is the clinical need – are there effectiveness benefits for the patient?
What is the main clinical benefit?
Is the clinical benefit meaningful?
How soon can effectiveness be seen?
How long will effectiveness last?
Which or What proportion of patients will benefit?
How do we measure it and are there appropriate controls/comparators?
What alternatives treatments are available?
Does it address an unmet clinical need?
What statistical hypotheses should be tested?
Are there reliable biomarkers?
Begin with the end in mind!
Safety and Effectiveness
Benefits outweigh Risks
Pre vs. Post-market Data
Should reflect the time frame of expected benefits and risks

8. What is Safety Factors to Consider
Safety Profile Differences – Balanced Safety Endpoint Needed
Device vs. Comparator - Drug or Open Surgery
Procedural AE’s
Access
Anchor points
Tissue Disruption, Tamponade
Device Misplacement, Malfunction or Embolism
Coronary obstruction, pacemaker
Device/Comparator AE’s
Short and long term
Effects on other organ systems related to procedure/device
e.g. renal or hepatic failure, thromboembolism, hemolysis, etc

9. What is Effectiveness for TV Disease?
Nishimura RA. J Am Coll Cardiol. 2014;63(22):
Symptom endpoints
Right sided function endpoints

10. What is Effectiveness More Questions Than Answers
Alive with expected Device Performance for TR Therapy
Correction (< mild) vs. Reduction (> moderate)
Survival Advantage
Reduction in HF events
Hospitalization & equivalents
Improvements in:
Symptoms (e.g. NYHA Class, ascites)
Function (e.g. 6MWT)
Quality of life (e.g. KCCQ)
Supportive Secondary Endpoints
Prevention of deterioration in ventricular function or volume
Improvements in Atrial/Ventricular volume or function
Will any Rx affect these?
Confounding effects of residual left sided disease?
Is palliation the primary benefit expected?
Will reverse remodeling occur?
Differential effects of TR reduction vs. correction?

11. Patient Centered Outcomes Customized based on Device Intended Use*
% of Patients with…
Timing of Measurement
Relevant patient questions
Technical Success
Successful implant of the single intended device without additional unplanned emergency procedure/intervention
At exit from Procedure
(OR or Cath lab)
How successful is the procedure to implant the device?
Procedural Success
Technical/Device Success without major adverse events (MAE’s)
At discharge (D/C) from hospital or 30 days, whichever is later
What are my chances of having the device placed successfully and having no major complications?
Device
Success
Original implant in place performing structurally and functionally as intended, without device related complications or need for additional procedures
All post-procedure time intervals starting at D/C or 30 days
Once the device is in place, does it break or fail? Does it perform well or cause problems over time?
Individual Patient Success
Device Success with meaningful clinical improvement in Symptoms, Function, or Quality of Life (QoL)
All post-procedure intervals starting at 6 months
If my device is successful, will I be able to resume my normal life? Will it make me feel or function better? Will my QoL improve?
*Adapted from Stone GW et al. J Am Coll Cardiol 2015;66:308–321

12. Thank You! Bernard Vasseur, MD Medical Officer, SHDB 240-402-9852

14. Possible Pivotal Trial Designs – Primary TR TV Repair or Bioprosthetic Replacement Indicated
Do these exist ?
Patients Indicated (Class I) for Surgical TV Repair
Patients judged to be amenable to test and control Rx
TV Surgical Repair
Test Device TV Repair
Patients Indicated for Bioprosthetic Surgical TV Replacement
Patients judged to be amenable to test and control Rx
TV Surgical Replacement
Test Device TV Replacement
Central Screening Committee:
Indications
Suitability
Similar Risk Profile
Local Heart Team
Assessment
Local Heart Team
Assessment
Randomized
Randomized
Inoperable
Nested Registry DEVICE

15. Evaluation of New Devices Comparison to Current Standard of Care (SOC)
Safety
Effectiveness
Non-inferior
Superior
Know Your Goals
Potentially acceptable clinical alternatives to current SOC therapy
New SOC Therapy

16. CLASS I
1. Tricuspid valve surgery is recommended for patients with severe TR (stages C and D) undergoing left-sided valve surgery.
(Level of Evidence: C)