DHHS / FDA / CDRH 1 FDA Summary CryoLife BioGlue P010003 Lead FDA Reviewer Lisa Kennell.

DHHS / FDA / CDRHDHHS / FDA / CDRH1

FDA SummaryFDA Summary

CryoLife BioGlue

P010003Lead FDA Reviewer

Lisa Kennell

Introduction Introduction

• Regulatory history of BioGlue

• Clinical Summary

• Non-clinical testing to be discussed

• Panel Questions

FDA Review Team

Team Leader Lisa Kennell, B.S.

Clinical Reviewer Paul Chandeysson, M.D.

Immunology Katherine Merritt, Ph.D.

FDA SGE Henry Homburger, M.D.

Statistics T.C. Lu, M.S., M.A.

Chemistry Ellen Chen, Ph.D. and

Srilekha Das, Ph.D.

Regulatory History

IDE initially for adjunct to Type A (ascending) aortic dissection repair, submitted in 1998

Regulatory History

• Humanitarian Device Exemption (HDE) submitted June 1999, approved December 1999 for adjunct in repair of Type A and B aortic dissections

• HDE for treating diseases or patient populations with incidence rate of 4000 or less per year in U.S.

• no alternatives or alternatives are inadequate

• FDA reviews only safety and assesses probable benefit

• Type A and Type B dissections

Regulatory History

• After HDE approval, sponsor had protocol deviations in IDE study

• randomization breaches

• obtaining patient consent

• “off label” uses outside of the protocol patient entrance criteria and approved HDE indication

• began current cardiac/vascular study to address deviations

BioGlue Indication

The indication for use for the BioGlue is

“BioGlue Surgical Adhesive is indicated for use as an adjunct to standard methods of cardiac and vascular repair such as sutures (or staples) to provide hemostasis.”

Clinical SummaryClinical Summary

• BioGlue versus standard hemostasis

• Superiority Hypothesis

• 10% improvement in hemostasis with BioGlue

• 75 patients/treatment group

Entrance Criteria

• Include patients• needing cardiac or vascular repairs

• Exclude patients• with known hypersensitivity to albumin,

bovine products, glutaraldehyde

• needing intra-cerebral circulation repair

• needing repair of acute thoracic aortic dissections

Indication for SurgeryAnastomotic Location

Indication BioGlue Control InternationalAbd. aneur. 16 (21%) 19 (25%)

Arch aneur. 23 (30%) 19 (26%) 15

Other aneur. 16 (21%) 13 (18%)

Periph. vasc. 4 (5%) 7 (9%) 25

Root dilation 4 (5%) 3 (4%)

Carotid 10 (13%) 9 (12%) 6

Aortic valve 7 (9%) 14 (19%) 5

• Primary Endpoint

• Anastomotic hemostasis (no need for additional agents to control bleeding at any point)

Clinical SummaryClinical Summary•Secondary Endpoints• Exposure to donor blood products

• Additional hemostatic agents

• Re-operation for bleeding

• Major and Minor adverse events

• Mortality

Effectiveness ResultsPrimary Endpoint

Parameter BioGlue Control P value

Hemostasisper patient

61% (46/75) 39% (29/74) 0.014

Hemostasisper anast.

81% (164/202) 57% (105/184) <0.001

Effectiveness ResultsSecondary Endpoints

Parameter BioGlue Control P Value

RBC used 2.3 3.6 1.9 2.4 0.12

Platelets 5.1 10.1 6.2 10.0 0.07

Plasma 3.8 6.6 3.3 5.0 0.16

CryoPrecip 4.3 11.9 2.0 8.3 0.01

Pledgets 26% 36% 0.047

Effectiveness ResultsSecondary Endpoints

Parameter BioGlue Control P value

Make upstitches

82% (31/38) 81 (64/79) 1.00

Hemostaticagent

8% (3/38) 10% (8/79) 1.00

AdditionalBioGlue

55% (21/38) N/A N/A

Reop forBleed

0 1.4% (1/74)

Other 8% (3/38) 19% (15/79) 0.263

Major Safety Results

Complication BioGlue Control P value

Total Death 6.5% 6.8% 0.999

Early (<30 day) Death 3.9% (3/76) 2.7% (2/74) 0.323

Late (3 mo.) Death 1.3% (1/76) 4.1% (3/74) 0.363

Major Safety Results

Parameter BioGlue Control P Value

Hemorrhage 3.9% 4.1% 1.000

Infection 16.9% 13.5% 0.653

NeurologicalDeficit

6.5% 21.6% 0.009

Inflammatory orimmune allergicrxn.

2.6% 0 0.497

Preclinical Dataand Discussion Items

•Immunogenicity

Summary of Non-Clinical Testing

• Immunogenicity

•Buehler hypersensitivity test (no adjuvant)

•Kligman hypersensitivity test (with adjuvant)

•Antigenicity in guinea pigs (with ELISA Ag/Ab assay)

Summary of Non-Clinical Testing

• Immunogenicity•complement activation in vitro

•Bovine Serum Albumin (BSA) concentration after various polymerization times from 1.5 min to 24 hr via bicinchoninic acid (BCA) and Lowry assays

•Biodegradation in animals

Results of Non-Clinical Immunogenicity Testing

• Ag/Ab ELISA assays resulted in low titers of Ab to BioGlue and to BSA in sensitized groups

• Lowry assay showed unbound protein, but BCA assay did not

• Animal studies suggest BioGlue encapsulation or reaction limited to local inflammatory response in most, but some animals showed degradation

Independent ReviewHenry Homburger, M.D.

Section of Clinical Chemistry and Medical Labs, Mayo Clinic

What is the likelihood that a clinical immunologic response will occur?

• Data presented are not sufficient to reach a firm conclusion

• Animal studies show that antigen-specific T lymphocytes may persist, but this does not necessarily indicate an increased risk of a clinically significant immunologic reaction

What is the likelihood that a clinical immunologic response will occur?

• A transitory immune response is not likely to be clinically significant but may prime the immune system for subsequent exposures, which could be clinically significant

• Persistence of antigen at the surgical site has a theoretical risk of immune complex mediated disease

Recommendations:• It would be difficult to design further animal studies

to evaluate the human risk

• It is “prudent and advisable” to provide extensive product labeling

• Caution against the repeated use in the same person

• Recommend post-market testing for specific antibodies and for in vitro measurement of delayed hypersensitivity

Panel Questions

Panel Questions-Effectiveness

1. Please discuss the clinical implications of the primary and secondary endpoint data.

2. The sponsor states in the submission that “Our clinical investigators believe that the routine use of BioGlue in these patients will allow them to modify their blood management protocol and should minimize the potentially life-threatening complication of postoperative hemorrhage.” Please comment on whether there is adequate information to support the statement.

3. Based on the information provided in the premarket approval application, please discuss whether the information supports reasonable assurance of safety and effectiveness of the BioGlue.

Panel Questions-LabelingPanel Questions-Labeling

4a. Please discuss the findings of the immunogenicity testing, especially as they relate to BOTH the physician and/or any patient labeling. Should patients be advised of specific adverse events to be aware of that may suggest they are experiencing a sensitization reaction?

Panel Questions-Immunogenicity

4b. Please discuss the immunogenicity data. Are additional pre- or post-marketing studies needed to assess the immune potential of BioGlue?

Panel Questions-LabelingPanel Questions-Labeling

5. Please comment on the INDICATIONS FOR USE section as to whether it identifies the appropriate patient population for treatment with BioGlue?

“BioGlue Surgical Adhesive is indicated for use as an adjunct to standard methods of cardiac and vascular repair such as sutures (or staples) to provide hemostasis.”

Panel Questions-Labeling

6. Please comment on the DIRECTIONS FOR USE as to whether they adequately describe how the BioGlue should be used to maximize benefits and minimize adverse events?

Panel Questions-Labeling

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

DHHS / FDA / CDRH 1 FDA Summary CryoLife BioGlue P010003 Lead FDA Reviewer Lisa Kennell.

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FDA Review Team For P010003 CryoLife BioGlue®

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