1. Global Experience with Peripheral DCBs/Stent Studies: C.R. Bard
George Papandreou, Ph.D.
Vice President of Quality and Regulatory Affairs
Lutonix / C.R. Bard Inc.

2. <George Papandreou, Ph.D.>
 Disclosure:
I am an employee of C.R. Bard, Inc.
Bard and Advancing Lives and the Delivery of Health Care are trademarks and/or registered trademarks of C. R. Bard, Inc. or an affiliate. All other trademarks are the property of their respective owners. Copyright © 2017 C. R. Bard, Inc. All rights reserved.

3. Treatment of the PAD Patient
Drug Coated Balloons
Wires
Sheaths
Stents
PTA Catheters

4. Clinical Studies to Support PMA Products
Feasibility Studies-
Probe of safety and effectiveness
Pivotal Studies
Randomized against standard of care
Labeling Expansion Studies
Extend device indication
Continued safety assurance
Post Market Studies

5. Clinical Trial Evolution
Late Lumen Loss
Primary Patency
TLR
Endpoints
Patients
Stringent inclusion/exclusion
Real world

6. Patients in RCTs vs. Real-World Studies
REACH1
LEVANT 22
LTX Global3
Resilient4
Age 69
67.8
68.2 68
Male
63.7%
61.1%
67.9%
70.9%
BMI >30%
29.8%
34.8%
24.7% -
Diabetes
43.9%
43.4%
39.5%
38.1%
Hypertension
81.7%
83.2%
84.9%
83.6%
Hyperlipidemia
72.1%
70.0%
79.9%
Previous CAD
53.4%
43.7%
35.6%
56.0%
Previous MI
31.7%
19.9%
20.1%
Renal Failure
3.3%
13.3%
Rutherford Class 1
3.0% 2
29.4%
20.6%
35.8% 3
62.7%
66.9%
61.2% 4
7.3%
7.4% 5
1.6%
1-Steg et al., JAMA 2007, 297(11), Rosenfield et al. N. Engl J Med 2015, 373(2), Thieme, TCT Laird et al., Circ. Cardiovasc. Interv. 2010, 3,

7. Patients in RCTs vs. Real-World Studies
LEVANT 21
LTX Global 2
Resilient3
ETAP4
Lesion Length (cm)
Lesion Location
SFA
Popliteal
Total Occlusions
20.6%
31.2%
17.0%
32.8%
Calcification
59.2%
50.2%
35.3% -
Real-world studies include a broader patient population than RCTs
1-Rosenfield et al. N. Engl J Med 2015, 373(2), Thieme, TCT Laird et al., Circ. Cardiovasc. Interv. 2010, 3, Rastan, et al. Circulation 2013, 127, 2535.

8. Lutonix® 035 DCB Indications and Clinical Trials
Indicated for percutaneous transluminal angioplasty, after appropriate vessel preparation, of de novo, restenotic, or in-stent restenotic lesions up to 300mm in length in native superficial femoral or popliteal arteries with reference vessel diameters of 4-7mm.
Balloon length
40-150mm
Balloon diameter
4.0 – 7.0mm
Lesion length
Less than 15cm
Less than 30 cm
Studies
Levant 2
Global Registry
ISR US Study
Long Lesion EU Study
“Please consult product labels and inserts for any indications, contraindications, hazards, warnings, precautions, and directions for use.”

9. Lutonix ® 035 Feasibility Studies
LEVANT 1 feasibility study was performed to confirm safety and drug effect of the Lutonix DCB.
Randomized study results supported CE Mark (2011).
Study Name
Treatment
Study Type
Subjects
Primary Endpoint
LEVANT 1
SFA
Randomized, Europe
101 total
49 – DCB
52 - POBA
Primary endpoint: Angiographic late lumen loss at 6 months.

10. Lutonix ® 035 Pivotal and Label Expansion Studies
Randomized IDE study with superior effectiveness and non-inferior safety was required for FDA approval.
Japan requires additional in-country study to confirm the pivotal study results.
Registry designs generally acceptable for label expansion:
Randomized study design in post-approval environment may not be enrollable.
Study Name
Treatment
Study Type
Subjects
Primary Endpoint
Pivotal IDE Studies
LEVANT 2
SFA
Randomized, US & Europe
476 total
316 – DCB
160 – POBA
Effectiveness: Primary Patency at 12 months.
Safety: Composite safety at 12 months.
Label Expansion Studies
Lutonix Long Lesion Study (≥ 14 cm)
Registry, Europe
118 - DCB
SFA ISR Study
Randomized → Registry, US
Ongoing (127 planned)
LEVANT Japan
Randomized, Japan
109 Total
71 – DCB
39 – POBA
Effectiveness: Primary Patency at 6 months.
Safety: Composite safety at 6 months.

11. Lutonix ® 035 Post Market Studies
Post-market study types:
Mandated post-approval studies
Company initiated ‘real-world’ registry studies.
Post approval studies show continued safety and effectiveness over a larger population/longer time points.
‘Real-world’ studies provide additional supportive information for safety and effectiveness with ‘standard of care’ follow-ups.
Study Name
Treatment
Study Type
Subjects
Primary Endpoint
LEVANT 2 Safety Registry
SFA
Registry, US & Europe
657 - DCB
Primary endpoint: Rate of unanticipated device- or drug- related adverse events over long-term.
Global SFA Real-World Registry
Registry, Europe
691 - DCB
Effectiveness: Freedom from TLR at 6 months.
Safety: Freedom at 30 days from VIVA safety endpoint.
BARD LifeStent & Lutonix DCB for Treatment of Long Lesions
SFA – Pre, Post-Dilatation of BMS
149 - DCB
Effectiveness: Primary Patency at 12 months.
SAFE DCB US Real-World Registry
Registry, US
DCB
Effectiveness: Freedom from TLR at 12 months.
Safety: Composite safety at 12 months.

12. LifeStent Indications and Clinical Trials
Intended to improve luminal diameter in the treatment of symptomatic de novo or restenotic lesions up to 240mm in length in the native SFA and popliteal artery with RVD mm
Stent length
20-160mm
20-200mm
Stent diameter
6-7mm
5-7mm
Studies
Resilient- SFA
SOLO (200mm)
ETAP- Popliteal
Reality (5mm)
Retrospective review in the treatment of long lesions
“Please consult product labels and inserts for any indications, contraindications, hazards, warnings, precautions, and directions for use.”

13. LifeStent Feasibility and Randomized Studies
RESILIENT 1 feasibility study was performed to assess peri-procedural safety and 6 month effectiveness.
Randomized clinical trials supported indications in the SFA and popliteal arteries
Study Name
Treatment
Study Type
Subjects
Primary Endpoint
RESILIENT 1
SFA
Registry, EU
20 – stent
Safety: Adverse Events (death, stroke, MI, dsital embolization, surgical revascularization, thrombosis, transfusion or renal failure) at 30 days
Effeciveness: primary patency at 6 months
Study Name
Treatment
Study Type
Subjects
Primary Endpoint
RESILIENT 2
SFA
Randomized, US (22 centers) & Europe (2 centers)
206 total
134 – stent
72 – POBA
Effectiveness: Freedom from TLR at 6 months.
Safety: 30 day mortality
ETAP
Popliteal
Randomized EU (9 centers)
246-total
119-stent
127-POBA
Effectiveness: Primary patency at 12 months

14. LifeStent Label Expansion Studies
LifeStent label expansion studies extended stent diameter (5mm) and length (200mm), as well as lesion length treatment (240mm)
LifeStent safety and effectiveness had to be confirmed in Japan
Study Name
Treatment
Study Type
Subjects
Primary Endpoint
Retrospective analysis of patients from RESILIENT and observational studies
SFA -240mm lesion length
Retrospective analysis
285-Stent
Acute safety: 30d safety vs VIVA OPG
Long-term safety: Freedom from death and amputation at 12 months
Effectiveness: Primary patency at 12 months for lesions at 50mm, 100mm, 160mm and 240mm.
REALITY
SFA- 5mm stent
Registry, Europe (1 center)
3--Stent
Effectiveness: successful deployment
Safety: Freedom at 30 days from death, amputation TVR and/or TLR.
LifeStent Solo 200mm
SFA – 200mm stent
Registry, Europe (7 centers)
76-Stent
Acute safety: Freedom from death, amputation, TLR and/or TVR at 30 days
Long-term safety: Freedom from TLR at 30 days and 12 months
Acute Effectiveness: Primary patency at 12 months.
Long-term effectiveness: Primary patency at 12 months
RELIABLE
SFA and prox. popliteal
Registry, Japan,
77- Stent
Target limb failure (device and/or procedure related death, amputation, TVR and TLR) at 12 months

15. LifeStent Post Market Studies
LifeStent post-approval study was part of the VQI PVI Registry
Study Name
Treatment
Study Type
Subjects
Primary Endpoint
LifeStent post-approval study
SFA and popliteal
Registry, US
74- Stent
Primary endpoint: freedom from MAE, TLR, TVR, acute lesion success, primary patency, primary assisted patency, secondary patency, sustained clinical success, sustained hemodynamic success, limb ischemia, ABI, stent fracture through 2 years

16. Conclusions
Pivotal, label expansion and post-approval studies were necessary for FDA approval of Bard DCBs and stents.
In-country studies were required for Japan approvals
Indication expansion can be supported by registry studies with appropriate clinical endpoints.

17. BARD® LIFESTENT® Vascular Stent System
LUTONIX® 035
INDICATIONS FOR USE
The Lutonix 035 Drug Coated Balloon PTA catheter is indicated for percutaneous transluminal angioplasty, after pre-dilatation, of de novo or restenotic lesions up to 300 mm in length in native superficial femoral or popliteal arteries with reference vessel diameters of 4-7mm.
BARD® LIFESTENT® Vascular Stent System
The LIFESTENT® Vascular Stent System is intended to improve luminal diameter in the treatment of symptomatic de novo or restenotic lesions up to 240 mm in length in the native superficial femoral artery (SFA) and popliteal artery with reference vessel diameters ranging from mm.