1. Possible Approval Pathways for Mitral Valve Device Therapies FDA View
John Laschinger, M.D.
Medical Officer
Structural Heart Device Branch
DCD/ODE/CDRH

2. Disclosures and Disclaimer
John C. Laschinger, 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. Mitral Regurgitation (MR) Simple Problem (valve leaks), Complex Disease
Primary (Degenerative) MR
Valve complex is the Disease
Annulus, Leaflet and/or Chordae Pathology
e.g. Barlow’s, Marfan, Fibroelastic deficiency
Surgery is gold standard
Early restoration of MV competence is “curative”
Device Repair/Replacement requires RCT proof of clinical equivalence
MV Repair is Comparator
Patients with Class I Indication
Individual Surgeon skill/experience a factor
Underutilized
Optimal repair (MR < mild) essential
Secondary(Functional) MR
Primarily a disease of the ventricle
Valve leaflets typically normal
LV enlarged and Papillary muscle(s) displaced restricted leaflet motion
Annular dilatation
No Gold Standard Therapy
Progressive LV Dysfunction - Is MR Cause or Effect?
MR Correction - not curative - palliative??
Is MR reduction palliative, does it halt progression?
Optimal comparator therapy – Uncertain
Medical Therapy (GDMT)
Titration and adherence
MR reduction - devices
MR correction
Surgical Repair - Prone to recurrence
Surgery and Device Replacement – higher initial risks

4. Clinical Evidence Acquisition Plan Enrollment and Data Quality Assurance
Identification of Appropriate Study Sites
Patient mix*
Facility resources*
Track record of performance in clinical research studies (personnel, enrollment, protocol adherence, complete and accurate data, etc)
Identification of appropriate patients
Central Steering Committee
Assurance of Appropriate Personnel
Heart Team – minimum composition
Skilled* Interventionalist
Skilled* Surgeon
Heart Failure Physician
Skilled* Echocardiographer available in Cath lab/OR
Adjudication of Critical Data
Primary Endpoint Outcomes, Major Adverse Events
Imaging Endpoints
*based on disease/therapies

5. What is Control Therapy Choice of Comparator for MR trials
Dictated by Indication for Use
Disease (intended use)
Availability of standard of care (SOC) therapy
Unmet clinical need
Population of Use (conditions of use)
Cause of valvular dysfunction - Primary vs. Secondary MR (ischemic or non-ischemic)
Operative risk status
Timing in Disease Course
Severity of resulting or underlying ventricular remodeling and dysfunction
Severity of symptoms
Importance of Heart Failure Team
Assurance of uniform treatment application & compliance
Control Rx - adequacy and adherence
Test Rx – Operator/interventionalist skills
Appropriate utilization of GDMT (+ CRT and/or CAD-Rx) in all patients

6. What is Safety Factors to Consider
Safety Profile Differences - Balanced Primary Safety Endpoints
Timing of Outcome determinations
Short Term
Long term
Account for variable risks by therapy
Drug
Transcatheter Device
Open Surgery
Procedural AE’s
Mortality - Neurological Events
Bleeding - Acute Kidney Injury
Cardiovascular (MI, Arrhythmias) - Access Injury/Tamponade
Specific device-related technical failure issues and complications
Adjudicated for Device relatedness
Access – Vascular, apical, septal, open surgical
Anchor points - Tissue Disruption; Device Misplacement, Malfunction, Embolism
Durability – Fracture, thrombosis
Damage or interaction with surrounding tissues (e.g. mitral apparatus, coronary compression)
Infection
Paravalvular leak
Hemolysis
Unplanned additional devices
Need for emergent unplanned intervention or surgery

7. (MR increase > 1 Grade)
Judging Effectiveness Depends on Disease, Device, Available Rx and Timing
Required:
Alive , with
Expected device/surgery performance for MR therapy:
Correction (MR < mild)
Reduction (MR decrease > 1 grade)
Clinically meaningful benefit:
Prevention or delay in the clinical progression of the effects of the disease:
Survival Advantage
Fewer Morbid Events
Reduction in HF events (Hospitalization & equivalents)
Reduced need for chronic medications
Clinical improvement(s) of value to the patient:
Symptoms (e.g. NYHA Class)
Function (e.g. 6MWT)
Quality of life (e.g. KCCQ)
Helpful:
Supportive Secondary Endpoints
Favorable trends in biomarkers
Improvements in Ventricular volume or function
Prevention of deterioration in ventricular function or volume
Durable over time
Low/no MR recurrence
(MR increase > 1 Grade)
Hemodynamic Success

8. Secondary Mechanistic
Transcatheter Valve Repair and Replacement Traditional Hierarchy of Importance for Effectiveness Measures
Lowest
Highest
Secondary Mechanistic
Increased survival
Prevention or delay of the clinical effects of the disease – HF hospitalization
Significant improvements
Symptoms
Daily function
Quality of life
Longitudinal Hemodynamic success
Prevention or Delay in the progression
of the anatomic effects of the disease

9. Secondary Mechanistic
Transcatheter Valve Repair and Replacement What’s important to the Patient?
“Years of Life” vs. “Life in Years”
Increased survival
Prevention or delay of the clinical effects of the disease – HF hospitalization
Longitudinal Hemodynamic success
Significant improvements
Symptoms
Daily function
Quality of life
Prevention or Delay in the progression
of the anatomic effects of the disease
Lowest
Highest
Secondary Mechanistic
Lowest
Minimally Symptomatic Patient, “Curable” Patient
Severe Symptoms, Failed Medical Rx Patient
Highest

10. Patient Centered Outcomes Customized based on Device Indications for Use*
% of Patients Alive 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 and no 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 without major complications?
Device
Success
… the 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? Can it cause problems over time? How long does it last?
Individual Patient Success
…device Success and return to pre-procedure environment and meaningful clinical improvement in Symptoms, Function, or Quality of Life (QoL)
All post-procedure intervals starting at 6 months
If my device works, will I be able to resume my normal life and stay out of the hospital? Will this improve how I feel and function and my QoL? For how Long?
*Adapted from Stone GW et al. J Am Coll Cardiol 2015;66:308–321

11. Curative or Palliative
Valve Repair and Replacement Effectiveness Measures for Symptomatic Valve Disease
For Diseases where Device Therapy is proven to be clinically effective vs. the natural history of underlying disease, one or more of the following clinically meaningful changes is observed:
“Traditional” Outcomes Patient Centered Outcomes
Hemodynamic success
Significant improvements
Symptoms
Daily function
Quality of life
Prevention or decreased incidence of
the clinical effects of the disease
Prevention or Delay in the anatomic
progression of the effects of the disease
Increased survival
Early
(OR to 30 days)
Expected
Observation
Time
Late
(1 year to Years)
Mid
(6mo – 1 year)
Technical Success (OR exit)
Procedural Success (30 day)
Device Success
(all time intervals > 30 days)
Durability of device
Individual Patient Success
(all intervals > 6 months)
Durability of benefit
Stability over time
Curative or Palliative

12. Valve Approval Remaining Relevant Questions (2017)
Is there anything about the valve that makes it more difficult or less safe to insert
Procedural Success at 30 days
Is the valve structure and performance durable over time
Device Success days and yearly
Does correction of the underlying valve disorder result in meaningful and durable clinical benefits to the patient
Individual Patient Success 6months and yearly

13. PMA Approval - Clinical Decision Accounting for Unmet Need and Patient Preference
Benefit-Risk Determination

14. Thank You! John Laschinger, MD Medical Officer, SHDB 301.796.1210

16. Hemodynamic Performance Effectiveness
Hemodynamic Success (Valve Dependent)
Mean gradient
30 day
1 year
Indexed Effective Orifice Area – change over time
Central Insufficiency – change over time
30 day and 1 year Device Success: Aortic < 20mmHG
Mitral < 5mmHg
Device Failure (both): Increase > 25% increase over post-procedure baseline
30 day and 1 year Device Success:
Stenosis: Increase in EOAI > 50% over pre-procedure baseline
Regurgitation: EOAI in normal range post-procedure
Device Failure (both) = decrease > 10% of post-procedure baseline
Device Success: Central Regurgitation < Mild
PVL < mild
Total Regurgitation < Mild
Device Failure: Central Regurgitation > Mild
PVL > mild
Total Regurgitation > Mild

17. Imaging Durability Evidence of Bioprosthetic Valve Disease
Hemodynamic deterioration (mild, moderate, severe; + Symptoms)
Thrombotic leaflet thickening responding to anticoagulation - HALT or HAM; + HD, + Symptoms
Imaging evidence of persistent Structural Valve Deterioration (e.g. Loss of leaflet or frame structure, integrity or function; + HD – stenosis and/or insufficiency; + Symptoms)
Prosthetic Valve Failure (referral for Explant, valve related death or SVD discovered at autopsy; Cause – a or c above)