1. What Regulatory Challenges Do the Next Wave of TAVR Devices Face in the U.S.?
Keith Dawkins MD FRCP FACC FSCAI
Global Chief Medical Officer
Executive Vice President
Boston Scientific Corporation

2. Conflict of Interest
Boston Scientific Corporation
Employee
Stockholder

3. Global TAVR Sales & Annual Growth
37%
Sales ($B)
CAGR (%)
$1.5B 6%
Source: Bernstein Estimates & Analysis; Company reports (

4. Global TAVR vs. SAVR Procedures
2023
Procedures (n)
Source: Bernstein Estimates & Analysis; Company reports (

5. TAVR Penetration for Risk( WW)
95%
32% 0%
12%
Percentage (%)
Source: Bernstein Estimates & Analysis; Company reports (

6. TAVR: Access Route (EU)
←78%
←16%
←3%
Transapical
Procedures (%)
Transfemoral
Source: BIBA Med Tech (Q3 2014)

7. Eligible Patients for TAVI (%)
With increasing experience, long-term TAVR performance will be key driver to device adoption
Focus on safety &
acute performance
Focus on leaflet durability
& mechanical integrity
100 -
80 -
60 -
40 -
20 -
0 -
Eligible Patients for TAVI (%)
Surgically
Unsuitable
Surgically
High Risk
Surgically
Moderate Risk
Surgically
Normal Risk
Time

8. Structural Valve Deterioration following SAVR Carpentier-Edwards Stented Bioprosthesis (Bovine Pericardium)
Author
Year
Mean
Follow-Up (yrs)
Age (yrs)
Freedom
From SVD* (%)
Poirier
1998
4.8 NR
79.9
Neville
4.7 68 †
Banbury
2001
12.0 65 †
Dellgren
2002
5.0 71
86.0
Biglioli
2004
6.0 67
77.0
McClure
2010 74
82.3
*SVD: Structural Valve Deterioration †Varies with age
years after surgical aortic valve replacement, % of bioprostheses demonstrate structural deterioration
McClure RS: Ann Thorac Surg 2010;89:

9. Systematic Literature Review (December 2002 – March 2014) n=87
Transcatheter Heart Valve Failure
Systematic Literature Review (December 2002 – March 2014) n=87
Mylotte D: Eur Heart J 2014:doi: /eurheartj/ehu388

10. Changing Clinical Trial Paradigm
Randomized TAVR Device
vs.
OMT
Surgical AVR
TAVR Device
Randomized
OPC
The Role of World Wide Data?

11. The Lotus™ Valve Design Goals Therapy Goals
To provide physicians total control during the entire TAVR procedure
Adaptive™ Seal designed to promote annular sealing and prevent paravalvular
Fully repositionable & retrievable
Therapy Goals
Precise, predictable placement to help reduce the risk of coronary obstruction, valve embolization, malposition, and valve-in-valve
Reduction in paravalvular leakage is associated with improved outcomes

12. The Lotus™ Valve: Key Features
Braided Nitinol Frame
Designed for strength, flexibility. Ability to retrieve, reposition & redeploy
Locking Mechanism
Enables operator
control of implant
Bovine Pericardium
Proven long-term
material
Central Radiopaque Marker
Aids precise positioning
Adaptive™ Seal
Minimizes paravalvular leak by conforming to irregular anatomical surfaces

13. The Lotus™ Valve System
Annulus Diameter
20mm
23mm
25mm
27mm
23 mm Lotus Valve
25 mm Lotus Valve
27 mm Lotus Valve
Deployed Lotus Valve OD
23 mm
25 mm
27 mm
Deployed Valve Height
19 mm

14. The Lotus™ Valve: Adaptive Seal™
Competitor
Valve
Paravalve
Leak
Lotus
Valve
Adaptive™
Seal

15. Lotus™ Valve Clinical Program
REPRISE I
Feasibility Study; Acute Safety & Performance (Extreme/High Risk)
N=11; single arm; 23mm valve size
Primary Endpoint: Device success (VARC-1) without MACCE
2-year follow-up reported
REPRISE II
CE-Mark Study; Safety & Performance (Extreme/High Risk)
N=120; single arm; 23 & 27mm valve sizes
Primary Device Performance: Mean pressure gradient at 30d
1-year follow-up reported
REPRISE II
Extension
Safety & Performance Study (Extreme/High Risk)
N=130; single arm; 23 & 27mm valve sizes
Primary Safety Endpoint: All-cause mortality at 30d
30-day follow-up reported
RESPOND
Post Market Safety & Performance Study (Real World)
N=1000; single arm; 23, 25 & 27mm valve sizes
Primary Endpoint: All-cause mortality at 30d & 1y
Enrolling
REPRISE III
FDA Approval Study; Safety & Efficacy (Extreme/High Risk)
N~1000; Global RCT vs. CoreValve; 23, 25 & 27mm valve sizes
Primary Endpoint: All-cause mortality & disabling stroke at 12m
Enrolling

16. REPRISE II Aortic Regurgitation Over Time Core Lab Adjudicated Data
Central
Combined
Paravalvular
1.4
1.8
0.5
0.6
100% -
13.3%
11.9
13.6
15.5
16.7
None
Trace
Mild
Moderate
Severe
5.6
80% -
16.9
18.3
60% -
47.7
Percent of Evaluable Echocardiograms
65.8
64.0
80.2
40% -
16.5
20% -
22.5
0% -
Baseline (N=218)
Discharge (N=219)
30 Days (N=186)
30 Days (N=177)
Post-dilation was not allowed per protocol and was not performed in any case.

17. REPRISE III: Repositionable Percutaneous Replacement of Stenotic Aortic Valve through Implantation of Lotus™ Valve
Objective:
To evaluate the safety and effectiveness of the Lotus™ Valve System in symptomatic subjects with calcific, severe native aortic stenosis who are considered at extreme or high risk for surgical valve replacement
Study Design:
REPRISE III is a prospective, multicenter, 2:1 randomized (Lotus Valve System versus a commercially available CoreValve Transcatheter Aortic Valve Replacement System). Up to 60 centers in the United States, Canada, Western Europe, and Australia; 912 patients randomized
Endpoints:
Primary Safety Endpoint: Composite of all-cause mortality, stroke, life-threatening and major bleeding events, stage 2 or 3 acute kidney injury, or major vascular complications at 30 days
Primary Effectiveness Endpoint: Composite of all-cause mortality, disabling stroke, or moderate or greater paravalvular aortic regurgitation (based on core lab assessment) at 1 year
Secondary Endpoint: Moderate or greater paravalvular aortic regurgitation (based on core lab assessment) at 1 year

18. Inaugural Meeting of the ParavaIvular Leak
Academic Research Consortium
February 20, 2015

19. Regulatory Requirements for Second Generation TAVR Devices
Fulfill the Current Standards
Safety
Efficacy (including PVL)
Ease of Use
Durability
Set New Standards
Lower Risk & Younger Patients
Role of Cerebral Protection
Valve-in-Valve
Improved User Experience
Reduce Cost

20. Potential US Regulatory Challenges
Next generation devices face a potentially higher standard as these devices can now be compared against first generation devices in a randomized control study
FDA is often ‘under pressure’ to approve the first (make the technology available) and second (provide alternate) devices while the next wave of devices may be subject to a lengthier review process
Field issues arising from off-label use of early generation devices can lead to an increase in bench test requirements for next generation devices above what was originally required for first generation devices
FDA become familiar with test methods used by first generation devices and use these as reference points during review of next generation devices even though the technology may be significantly different
As users become more familiar with the technology, next generation devices may be used in more challenging clinical situations compared to first generation devices, potentially resulting in worse outcomes