DHHS / FDA / CDRH 1 Circulatory Support Devices Panel Tuesday, September 11, 2001 CoSeal® Surgical Sealant P010022

DHHS / FDA / CDRH 2 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

DHHS / FDA / CDRH 3 Device Description In situ polymerized Polyethylene Glycol (PEG) sealant Double syringe delivery system Seals within seconds of application

DHHS / FDA / CDRH 4 Preclinical Concerns Sealant Characteristics Biocompatibility Sterility

DHHS / FDA / CDRH 5 Sealant Characteristics Set Time Gel Strength & Adherence Delivery System Function Degradation In Vivo Performance Shelf Life

DHHS / FDA / CDRH 6 Biocompatibility Blood/tissue contact Short term (24hr - 30d) ISO Outstanding Issue: Sensitization

DHHS / FDA / CDRH 7 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

DHHS / FDA / CDRH 8 Sterility Electron Beam Radiation Validated according to ISO 11137

DHHS / FDA / CDRH 9 Appropriate preclinical testing performed Outstanding items: - Sensitization - Minor issues being addressed with sponsor Preclinical Summary

DHHS / FDA / CDRH 10 Clinical Studies US Randomized Multi-center Study European Non-randomized Multi-center Study European Feasibility Study

DHHS / FDA / CDRH 11 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

DHHS / FDA / CDRH 12 Anastomoses of ePTFE grafts following peripheral vascular surgery (arterial bypass, dialysis access) US Study Population

DHHS / FDA / CDRH 13 US Demographics

DHHS / FDA / CDRH 14 PRIMARY ENDPOINT: Hemostasis w/in 10 minutes US Success Data

DHHS / FDA / CDRH 15 SECONDARY ENDPOINT: Immediate Hemostasis US Success Data

DHHS / FDA / CDRH 16 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 Data

DHHS / FDA / CDRH 17 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

DHHS / FDA / CDRH 18 EU Success Data NOTE: 17 technical errors in applying CoSeal

DHHS / FDA / CDRH 19 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)

DHHS / FDA / CDRH 20 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 Fevers

DHHS / FDA / CDRH 21 Questions for Panel (Panel pack, Part 1)

DHHS / FDA / CDRH 22 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.

DHHS / FDA / CDRH 23 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).

DHHS / FDA / CDRH 24 Question 2(cont.) Please discuss the clinical importance of the overall adverse events and complications observed in these patients.

DHHS / FDA / CDRH 25 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):

DHHS / FDA / CDRH 26 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 / CDRH 27 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 / CDRH 28 Question 3(c) Do you have any other recommendations regarding the labeling of this device?