Transcript Circulatory Support Devices Panel CoSeal® Surgical Sealant P010022

Circulatory Support
Devices Panel
Tuesday, September 11, 2001
CoSeal® Surgical Sealant
P010022
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DHHS / FDA / CDRH
FDA Review Team
• Paul Chandeysson, M.D. - clinical
• Srilekha Das, Ph.D. - chemistry
• Rosalie Elespuru, Ph.D. - genotoxicology
• Jennifer Goode, B.S. - preclinical
• John Langone, Ph.D. - sensitization
• Susan Zhou, Ph.D. - statistics
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DHHS / FDA / CDRH
Device Description
• In situ polymerized Polyethylene
Glycol (PEG) sealant
• Double syringe delivery system
• Seals within seconds of application
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DHHS / FDA / CDRH
Preclinical Concerns
• Sealant Characteristics
• Biocompatibility
• Sterility
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DHHS / FDA / CDRH
Sealant Characteristics
• Set Time
• Gel Strength & Adherence
• Delivery System Function
• Degradation
• In Vivo Performance
• Shelf Life
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DHHS / FDA / CDRH
Biocompatibility
• Blood/tissue contact
• Short term (24hr - 30d)
• ISO 10993
Outstanding Issue:
• Sensitization
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DHHS / FDA / CDRH
Sensitization Testing
• Guinea pig sensitization studies
• Mild to moderate levels of erythema in CoSeal
group at 24hr
• Response resolved by 48hr
• Labeling statement:
Material causes a mild sensitization response
in animals, effect on humans unknown.
• In situ polymerized material
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DHHS / FDA / CDRH
Sterility
• Electron Beam Radiation
• Validated according to ISO 11137
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DHHS / FDA / CDRH
Preclinical Summary
• Appropriate preclinical testing
performed
• Outstanding items:
- Sensitization
- Minor issues being addressed with
sponsor
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DHHS / FDA / CDRH
Clinical Studies
• US Randomized Multi-center Study
• European Non-randomized Multi-center Study
• European Feasibility Study
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DHHS / FDA / CDRH
US Multi-Center
• Randomized to Gelfoam/Thrombin
• Equivalence Hypothesis
• PRIMARY ENDPOINT: Hemostasis w/in 10 min.
• SECONDARY ENDPOINT: Immediate Hemostasis
• Follow-Up: 4 to 5 wks post discharge
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DHHS / FDA / CDRH
US Study Population
• Anastomoses of ePTFE grafts following
peripheral vascular surgery (arterial
bypass, dialysis access)
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DHHS / FDA / CDRH
US Demographics
# of Patients
Mean Age (Years)
Men
Hypertension
Diabetes
Coagulopathy
Thromboembolic Events
Arterial Bypass Graft
Vascular Access Graft
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CoSeal
74
63
41 (55%)
58 (78%)
39 (53%)
1 (1%)
26 (35%)
20 (39%)
43 (58%)
Control
74
61
37 (50%)
66 (89%)
39 (53%)
6 (8%)
27 (36%)
27 (36%)
44 (59%)
p-value
0.5419
0.5102
0.0744
1.0000
0.0528
0.8639
0.2165
0.8674
DHHS / FDA / CDRH
US Success Data
PRIMARY ENDPOINT: Hemostasis w/in 10 minutes
All Sites
Bypass Grafts
Access Grafts
Patch Grafts
Brisk Bleeding
Oozing
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CoSeal
Control
p-value
117/136
(86%)
40/53
(76%)
76/80
(95%)
1/3
(33%)
29/39
(74%)
88/97
(91%)
108/128
(84%)
34/45
(76%)
71/79
(90%)
3/4
(75%)
25/34
(74%)
83/94
(88%)
0.763
0.958
0.196
0.478
0.583
0.467
DHHS / FDA / CDRH
US Success Data
SECONDARY ENDPOINT: Immediate Hemostasis
All Sites
Bypass Grafts
Access Grafts
Patch Grafts
Brisk Bleeding
Oozing
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CoSeal
Control
p-value
64/136
(47%)
22/53
(42%)
42/80
(52%)
0/3
(0%)
16/39
(41%)
48/97
(50%)
25/128
(25%)
5/45
(11%)
18/79
(23%)
2/4
(50%)
1/34
(3%)
24/94
(26%)
<0.001
<0.001
<0.001
<0.001
<0.001
DHHS / FDA / CDRH
US Safety Data
• COSEAL: 188 AE’s in 56 patients
(e.g., edema, fever, erythema, infection,
thrombosis, occlusion, hematoma, etc)
- None related to CoSeal treatment
• CONTROL: 147 AE’s in 49 patients
- 2 AE’s in one patient may have been
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related to Control treatment (infection)
DHHS / FDA / CDRH
European Multi-Center
• n=131
• Anastomoses of ePTFE, Dacron & autologous
grafts following peripheral vascular surgery
(arterial bypass, dialysis access, femoral
arteriotomy)
• PRIMARY ENDPOINT: Hemostasis within 10
minutes
• Follow-Up: 4 to 5 wks post discharge
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DHHS / FDA / CDRH
EU Success Data
Number of sites treated
Success by Material Type
EPTFE Graft
Dacron Graft
Autologous Tissue
Overall Success
ITT
EVAL
219
202
97/119
(82%)
35/37
(95%)
61/63
(97%)
193/219
(88%)
97/106
(92%)
35/35
(100%)
61/61
(100%)
193/202
(96%)
p-value
0.0299
0.4933
0.4961
0.0059
NOTE: 17 technical errors in applying CoSeal
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DHHS / FDA / CDRH
European Feasibility
• n=15
• Anastomoses of ePTFE grafts following arterial
reconstruction in the lower extremities
• Follow-Up: post-op day 1; hospital discharge;
4 to 6 wks later
• 0 of 11 serious AEs related to CoSeal
(occlusions, hematoma, inflammation/fever,
progression of renal insufficiency requiring
dialysis)
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DHHS / FDA / CDRH
Fevers
• Prior to panel pack shipment, FDA had no
opportunity to review the information on fevers
included in Part 5.a.iv. of your panel pack
• Upon review of this data, FDA no longer has
any questions regarding fevers seen in the US
clinical study
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DHHS / FDA / CDRH
Questions for Panel
(Panel pack, Part 1)
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DHHS / FDA / CDRH
Question 1
The preclinical sensitization testing demonstrated that
this material causes a sensitization response in guinea
pigs.
The sponsor has agreed to address this issue in a
labeling statement regarding the potential for
sensitization in animal testing. Please discuss
whether a labeling statement is adequate, or if
additional testing is necessary to evaluate the
sensitization potential of this material in humans.
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DHHS / FDA / CDRH
Question 2
All of the adverse events seen in the US clinical
study were expected for this type of procedure
(e.g., edema, fever, erythema, infection,
thrombosis, occlusion, hematoma, etc.) and none
were attributed by the clinical investigators to
CoSeal Surgical Sealant. However, the total
number of adverse events in the treatment group
(n=188 events, occurring in 56/74 patients) was
higher than the control group (n=147 events
including 2 deaths, occurring in 49/74 patients).
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DHHS / FDA / CDRH
Question 2(cont.)
Please discuss the clinical importance of the
overall adverse events and complications
observed in these patients.
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DHHS / FDA / CDRH
Question 3
One aspect of the pre-market evaluation of a
new product is the review of its labeling. The
labeling must indicate which patients are
appropriate for treatment, identify potential
adverse events with the use of the device,
and explain how the product should be used
to maximize benefits and minimize adverse
effects. Please address the following
questions regarding the product labeling
(Panel pack, Part 2):
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DHHS / FDA / CDRH
Question 3(a)
The proposed labeling states that the sealant is indicated
for use in “sealing arterial and/or venous reconstructions”.
The US clinical study investigated use of CoSeal Surgical
Sealant in peripheral arterial bypass patching or grafting,
and AV shunting for dialysis access. The European clinical
study investigated use of the sealant in peripheral arterial
bypass patching or grafting, AV shunting for dialysis
access, and sealing of femoral arteriotomy sites.
Please discuss whether the clinical data provide
adequate information to determine the safety and
effectiveness of CoSeal Surgical Sealant for the
proposed indication.
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DHHS / FDA / CDRH
Question 3(b)
Please comment on the DIRECTIONS FOR USE
section as to whether it adequately describes how
the device should be used to maximize benefits and
minimize adverse events.
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DHHS / FDA / CDRH
Question 3(c)
Do you have any other recommendations regarding
the labeling of this device?
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DHHS / FDA / CDRH