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DHHS / FDA / CDRHDHHS / FDA / CDRH1
Circulatory Support Devices Panel
Circulatory Support Devices Panel
Tuesday, September 11, 2001
CoSeal® Surgical Sealant
P010022
DHHS / FDA / CDRHDHHS / FDA / CDRH2
FDA Review TeamFDA 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
DHHS / FDA / CDRHDHHS / FDA / CDRH3
Device DescriptionDevice Description
• In situ polymerized Polyethylene Glycol (PEG) sealant
•Double syringe delivery system
•Seals within seconds of application
DHHS / FDA / CDRHDHHS / FDA / CDRH4
Preclinical ConcernsPreclinical Concerns
•Sealant Characteristics
•Biocompatibility
•Sterility
DHHS / FDA / CDRHDHHS / FDA / CDRH5
Sealant CharacteristicsSealant Characteristics•Set Time
•Gel Strength & Adherence
•Delivery System Function
•Degradation
• In Vivo Performance
•Shelf Life
DHHS / FDA / CDRHDHHS / FDA / CDRH6
BiocompatibilityBiocompatibility•Blood/tissue contact
•Short term (24hr - 30d)
• ISO 10993
Outstanding Issue:
•Sensitization
DHHS / FDA / CDRHDHHS / FDA / CDRH7
Sensitization TestingSensitization 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
DHHS / FDA / CDRHDHHS / FDA / CDRH8
SterilitySterility
•Electron Beam Radiation
•Validated according to ISO 11137
DHHS / FDA / CDRHDHHS / FDA / CDRH9
•Appropriate preclinical testing performed
•Outstanding items:
-Sensitization
-Minor issues being addressed with sponsor
Preclinical SummaryPreclinical Summary
DHHS / FDA / CDRHDHHS / FDA / CDRH10
Clinical StudiesClinical Studies
• US Randomized Multi-center Study
• European Non-randomized Multi-center Study
• European Feasibility Study
DHHS / FDA / CDRHDHHS / FDA / CDRH11
US Multi-CenterUS 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
DHHS / FDA / CDRHDHHS / FDA / CDRH12
• Anastomoses of ePTFE grafts following peripheral vascular surgery (arterial bypass, dialysis access)
US Study PopulationUS Study Population
DHHS / FDA / CDRHDHHS / FDA / CDRH13
US DemographicsUS Demographics
CoSeal Control p-value
# of Patients 74 74 -
Mean Age (Years) 63 61 0.5419
Men 41 (55%) 37 (50%) 0.5102
Hypertension 58 (78%) 66 (89%) 0.0744
Diabetes 39 (53%) 39 (53%) 1.0000
Coagulopathy 1 (1%) 6 (8%) 0.0528
Thromboembolic Events 26 (35%) 27 (36%) 0.8639
Arterial Bypass Graft 20 (39%) 27 (36%) 0.2165
Vascular Access Graft 43 (58%) 44 (59%) 0.8674
DHHS / FDA / CDRHDHHS / FDA / CDRH14
PRIMARY ENDPOINT: Hemostasis w/in 10 minutes
US Success DataUS Success Data
CoSeal Control p-value
All Sites 117/136(86%)
108/128(84%)
0.763
Bypass Grafts 40/53(76%)
34/45(76%)
0.958
Access Grafts 76/80(95%)
71/79(90%)
0.196
Patch Grafts 1/3(33%)
3/4(75%)
0.478
Brisk Bleeding 29/39(74%)
25/34(74%)
0.583
Oozing 88/97(91%)
83/94(88%)
0.467
DHHS / FDA / CDRHDHHS / FDA / CDRH15
SECONDARY ENDPOINT: Immediate Hemostasis
US Success DataUS Success Data
CoSeal Control p-value
All Sites 64/136(47%)
25/128(25%)
<0.001
Bypass Grafts 22/53(42%)
5/45(11%)
<0.001
Access Grafts 42/80(52%)
18/79(23%)
<0.001
Patch Grafts 0/3(0%)
2/4(50%)
-
Brisk Bleeding 16/39(41%)
1/34(3%)
<0.001
Oozing 48/97(50%)
24/94(26%)
<0.001
DHHS / FDA / CDRHDHHS / FDA / CDRH16
•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 related to Control treatment (infection)
US Safety DataUS Safety Data
DHHS / FDA / CDRHDHHS / FDA / CDRH17
European Multi-CenterEuropean 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
DHHS / FDA / CDRHDHHS / FDA / CDRH18
EU Success DataEU Success Data
NOTE: 17 technical errors in applying CoSeal
ITT EVAL p-value
Number of sites treated 219 202
Success by Material TypeEPTFE Graft 97/119
(82%)97/106(92%)
0.0299
Dacron Graft 35/37(95%)
35/35(100%)
0.4933
Autologous Tissue 61/63(97%)
61/61(100%)
0.4961
Overall Success 193/219(88%)
193/202(96%)
0.0059
DHHS / FDA / CDRHDHHS / FDA / CDRH19
European FeasibilityEuropean 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)
DHHS / FDA / CDRHDHHS / FDA / CDRH20
• 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
FeversFevers
DHHS / FDA / CDRHDHHS / FDA / CDRH21
Questions for PanelQuestions for Panel
(Panel pack, Part 1)
DHHS / FDA / CDRHDHHS / FDA / CDRH22
Question 1Question 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.
DHHS / FDA / CDRHDHHS / FDA / CDRH23
Question 2Question 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).
DHHS / FDA / CDRHDHHS / FDA / CDRH24
Question 2(cont.) Question 2(cont.)
Please discuss the clinical importance of the overall adverse events and complications observed in these patients.
DHHS / FDA / CDRHDHHS / FDA / CDRH25
Question 3Question 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):
DHHS / FDA / CDRHDHHS / FDA / CDRH26
Question 3(a)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.
DHHS / FDA / CDRHDHHS / FDA / CDRH27
Question 3(b)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.
DHHS / FDA / CDRHDHHS / FDA / CDRH28
Question 3(c) Question 3(c)
Do you have any other recommendations regarding the labeling of this device?