DHHS / FDA / CDRHDHHS / FDA / CDRH1

Circulatory Support Devices Panel

Circulatory Support Devices Panel

Tuesday, September 11, 2001

CoSeal® Surgical Sealant

P010022

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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

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Device DescriptionDevice Description

• In situ polymerized Polyethylene Glycol (PEG) sealant

•Double syringe delivery system

•Seals within seconds of application

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Preclinical ConcernsPreclinical Concerns

•Sealant Characteristics

•Biocompatibility

•Sterility

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Sealant CharacteristicsSealant Characteristics•Set Time

•Gel Strength & Adherence

•Delivery System Function

•Degradation

• In Vivo Performance

•Shelf Life

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BiocompatibilityBiocompatibility•Blood/tissue contact

•Short term (24hr - 30d)

• ISO 10993

Outstanding Issue:

•Sensitization

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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

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SterilitySterility

•Electron Beam Radiation

•Validated according to ISO 11137

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•Appropriate preclinical testing performed

•Outstanding items:

-Sensitization

-Minor issues being addressed with sponsor

Preclinical SummaryPreclinical Summary

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Clinical StudiesClinical Studies

• US Randomized Multi-center Study

• European Non-randomized Multi-center Study

• European Feasibility Study

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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

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• Anastomoses of ePTFE grafts following peripheral vascular surgery (arterial bypass, dialysis access)

US Study PopulationUS Study Population

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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

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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

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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

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•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

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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

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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

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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)

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• 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

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Questions for PanelQuestions for Panel

(Panel pack, Part 1)

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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.

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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).

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Question 2(cont.) Question 2(cont.)

Please discuss the clinical importance of the overall adverse events and complications observed in these patients.

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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):

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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.

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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.

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Question 3(c) Question 3(c)

Do you have any other recommendations regarding the labeling of this device?