Download Patients in RCTs vs. Real-World Studies

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.
<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
Care are trademarks and/or registered trademarks of C. R. Bard, Inc. or an
C. R. Bard, Inc. or an affiliate. All other trademarks are the property of their
are the property of their respective owners. Copyright © 2017 C. R. Bard, Inc.
© 2017 C. R. Bard, Inc. All rights reserved.
Treatment of the PAD Patient
Wires
Drug Coated
Balloons
Sheaths
Stents
PTA Catheters

Clinical Studies to Support PMA
Products
Feasibility
Studies-
Pivotal
Studies
• Probe of
safety and
effectiveness
• Randomized
against
standard of
care
Labeling
Expansion
Studies
• Extend device
indication
Post Market
Studies
Continued
safety
assurance
Clinical Trial Evolution
Endpoints
Patients
Late Lumen
Loss
Primary
Patency
Stringent
inclusion/exclusion
TLR
Real world
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%
83.6%
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%
-
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%
Rutherford Class
1-Steg et al., JAMA 2007, 297(11), 1197 2-Rosenfield et al. N. Engl J Med 2015, 373(2), 145. 3-Thieme, TCT 2015 4- Laird et
al., Circ. Cardiovasc. Interv. 2010, 3, 267-276.
Patients in RCTs
vs. Real-World Studies
LEVANT
21
LTX
Global 2
Resilient3
ETAP4
6.27 +
4.14
10.12 +
8.42
7.05 +
4.43
4.13 +
3.10
SFA
SFA
SFA
Popliteal
Total
Occlusions
20.6%
31.2%
17.0%
32.8%
Calcification
59.2%
50.2%
35.3%
-
Lesion
Length (cm)
Lesion
Location
Real-world studies include a broader patient population than RCTs
1-Rosenfield et al. N. Engl J Med 2015, 373(2), 145. 2-Thieme, TCT 2015 3- Laird et al., Circ. Cardiovasc. Interv. 2010, 3, 267276. 4- Rastan, et al. Circulation 2013, 127, 2535.
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.”
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
LEVANT 1
Treatment
SFA
Study Type
Randomized,
Europe
Subjects
101 total
49 – DCB
52 - POBA
Primary Endpoint
Primary endpoint: Angiographic late
lumen loss at 6 months.
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
Pivotal IDE Studies
LEVANT 2
Treatment
Study Type
Subjects
SFA
Randomized, US &
Europe
476 total
316 – DCB
160 – POBA
Lutonix Long Lesion
Study (≥ 14 cm)
SFA ISR Study
SFA
Registry, Europe
118 - DCB
SFA
LEVANT Japan
SFA
Randomized → Registry,
US
Randomized, Japan
Primary Endpoint
Effectiveness: Primary Patency at 12 months.
Safety: Composite safety at 12 months.
Label Expansion Studies
Effectiveness: Primary Patency at 12 months.
Safety: Composite safety at 12 months.
Ongoing (127 planned) Effectiveness: Primary Patency at 12 months.
Safety: Composite safety at 12 months.
109 Total
Effectiveness: Primary Patency at 6 months.
71 – DCB
Safety: Composite safety at 6 months.
39 – POBA
Lutonix ® 035 Post Market Studies
• Post-market study types:
o Mandated post-approval studies
o 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
LEVANT 2 Safety
Registry
Global SFA Real-World
Registry
BARD LifeStent &
Lutonix DCB for
Treatment of Long
Lesions
SAFE DCB US RealWorld Registry
SFA
Treatment
Study Type
Registry, US & Europe
Subjects
657 - DCB
SFA
Registry, Europe
691 - DCB
SFA – Pre, PostDilatation of BMS
Registry, Europe
149 - DCB
SFA
Registry, US
1006 - DCB
Primary Endpoint
Primary endpoint: Rate of unanticipated device- or
drug- related adverse events over long-term.
Effectiveness: Freedom from TLR at 6 months.
Safety: Freedom at 30 days from VIVA safety
endpoint.
Effectiveness: Primary Patency at 12 months.
Safety: Freedom at 30 days from VIVA safety
endpoint.
Effectiveness: Freedom from TLR at 12 months.
Safety: Composite safety at 12 months.
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 4.0-6.5mm
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.”
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
RESILIENT 1
SFA
Treatment
Study Type
Registry, EU
Subjects
20 – stent
Primary Endpoint
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
RESILIENT 2
SFA
Treatment
Study Type
Randomized, US (22
centers) & Europe (2
centers)
Randomized EU (9
centers)
Subjects
206 total
134 – stent
72 – POBA
246-total
119-stent
127-POBA
Primary Endpoint
Effectiveness: Freedom from TLR at 6 months.
Safety: 30 day mortality
ETAP
Popliteal
Effectiveness: Primary patency at 12 months
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 SFA -240mm lesion Retrospective analysis
patients from
length
RESILIENT and
observational studies
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
LifeStent Solo 200mm
SFA – 200mm stent
Registry, Europe (7
centers)
76-Stent
RELIABLE
SFA and prox.
popliteal
Registry, Japan,
77- Stent
Effectiveness: successful deployment
Safety: Freedom at 30 days from death,
amputation TVR and/or TLR.
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
Target limb failure (device and/or procedure
related death, amputation, TVR and TLR) at 12
months
LifeStent Post Market Studies
• LifeStent post-approval study was part of the VQI PVI Registry
Study Name
LifeStent post-approval
study
Treatment
SFA and popliteal
Study Type
Registry, US
Subjects
74- Stent
Primary Endpoint
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
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.
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
INDICATIONS FOR USE
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 4.0 - 6.5
mm.