1. University of Pennsylvania
Success in “High-Risk / Inoperable” Patients is Enough for Submission to the FDA
Howard C. Herrmann, MD
University of Pennsylvania
Philadelphia
Disclosures
Research Funding: Edwards Lifesciences Inc
Discussion will include unapproved and off-label devices, procedures, and indications

2. FDA Requirements (www.fda.gov)
Class III medical device (poses significant risk of illness or injury)
Requires pre-market application (PMA) for approval
Most stringent type of device marketing application
The PMA must demonstrate:
“sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s)”

3. PARTNER Trial 2.0: One Valve, Two delivery systems, TF & TA
Eligibility Met For High Risk
Symptomatic, Critical Calcific Aortic Stenosis
Surgical (Cohort A); N=690
Medical Mgmt (Cohort B); N=350
Operable Assessment
Yes No
Femoral Access
Evaluation
Y/N
Femoral Access
Evaluation
Y/N No
Yes No
Out of study
Yes
1:1 Randomization
1:1 Randomization
1:1 Randomization
Medical
Mgmt
Control
AVR
Control
AVR
Control
Transfemoral TF vs
Transapical TA vs
Transfemoral TF vs
Sub-group analyses:
TA vs. control
TF vs. control
TF and TA vs. control (combined)

4. Questions That May Arise at Advisory Panel
Will success in high-risk / inoperable patients be enough for submission to the FDA?
Will safety and efficacy endpoints be met?
Is high-risk and “inoperable” adequately defined in the trial?
Is the goal worthwhile for patients?
Are there concerns about indication creep to younger patients/low risk if approved?
How will cost and reimbursement concerns enter into this equation?
Will physicians accept this new therapy for patients if results are similar to surgery?

5. Smith CR,

6. Smith CR,

7. Smith CR,

8. Smith CR,

9. Smith CR,

10. 362 patients with severe aortic stenosis not eligible for TAVI
Results:
362 patients with severe aortic stenosis not eligible for TAVI
274 (75.7%) Medical /BAV arm
88 (24.3%)
Surgical arm
Ben Dor et al, CRT website, manuscript submitted

11. Baseline characteristics and clinical profile and operative risk
Medical/BAV arm
N=274
Surgical AVR
N=88 P
Age (years)
81.4±9.1
79.9±8.7
0.16
Female (%)
154(56.2)
40 (45.4)
0.11
STS score (%)
12.8±7.0
8.5±5.1
<0.001
Standard Euroscore
13.3±3.4
10.5±3.0
Logistic Euroscore
42.4±22.8
24.4±18.1
NYHA Class IV %
138(50.4)
18(20.4)
Diabetes (%)
93(33.9)
32(36.3)
0.76
Hypertension (%)
222(81.1)
75(85.2)
0.37
CAD (%)
182(66.4)
56(63.6)
0.71
COPD (%)
86 (31.3)
16(18.1)
0.01
Renal failure (%)
118 (43.1)
26(29.5)
0.02
Prior CVA/TIA (%)
44 (16.0)
6(6.8)
Arrhythmia (%)
109(39.7)
20(22.7)
0.003
PVD (%)
25(28.4)
0.38
Prior CABG (%)
96(35.0)
27(30.6)
0.45
Ben Dor et al, CRT website, manuscript submitted

12. Death (%) 102(37.2%) 19(21.5%) 0.001 Medical /BAV arm N=274
Surgical AVR
N=88 P
Death (%)
102(37.2%)
19(21.5%)
0.001
Duration of follow up (days)
377.5 [ ]
386 [ ]
0.01
Ben Dor et al, CRT website, manuscript submitted

13. 1-year mortality 20-25% REVIVE and REVIVAL Pooled N=196
80.3%
[74.0, 86.5]
73.8%
[66.6, 81]
62.2%
[48.6, 75.8]
95% confidence limits
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9 1 6 12 18 24
Months past Procedure
Freedom from Death
Total at
risk (n)
108 66 13 8
161
88.8%
[83.9, 93.7]
REVIVE and REVIVAL Pooled
N=196
SOURCE COHORT I
N=463
1-year mortality 20-25%

14. Questions That May Arise at Advisory Panel
Will safety and efficacy endpoints be met?
I believe that they will be in both arms of Partner
Is high-risk and “inoperable” adequately defined in the trial?
Yes. Study well conducted with conference calls, strict STS criteria
Is the goal worthwhile for patients?
Yes. Large # of untreated, surgery refusals
Are there concerns about indication creep to younger patients/low risk if approved?
Absolutely. Will be a challenge for physicians and hospitals
How will cost and reimbursement concerns enter into this equation?
I anticipate some limits on use to approved indications, rationing, probably by physicians
Will physicians accept this new therapy for patients if results are similar to surgery?
Patients will drive the choice
Will success in high-risk / inoperable patients be enough for submission to the FDA? …Yes.