FDA Summary

1
FDA Summary

• CryoLife BioGlue
• P010003
• Lead FDA Reviewer
• Lisa Kennell

2
Introduction

• Regulatory history of BioGlue
• Clinical Summary
• Non-clinical testing to be discussed
• Panel Questions

3
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.

4
Regulatory History

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

5
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

6
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

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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.

8
Clinical Summary
9
Clinical Summary

• BioGlue versus standard hemostasis
• Superiority Hypothesis
• 10 improvement in hemostasis with BioGlue
• 75 patients/treatment group

10
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

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Indication for SurgeryAnastomotic Location
12
Clinical Summary

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

13
Clinical Summary

• Secondary Endpoints
• Exposure to donor blood products
• Additional hemostatic agents
• Re-operation for bleeding
• Major and Minor adverse events
• Mortality

14
Effectiveness ResultsPrimary Endpoint
15
Effectiveness ResultsSecondary Endpoints
16
Effectiveness ResultsSecondary Endpoints
17
Major Safety Results
18
Major Safety Results
19
Preclinical Dataand Discussion Items

• Immunogenicity

20
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)

21
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

22
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

23
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

24
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?
• 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

25
Independent ReviewHenry Homburger, M.D.Section
of Clinical Chemistry and Medical Labs, Mayo
Clinic

• 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

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Panel Questions
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Panel Questions-Effectiveness
1. Please discuss the clinical implications of
the primary and secondary endpoint data.
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Panel Questions-Effectiveness
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.
29
Panel Questions-Effectiveness
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.
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Panel 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?
31
Panel Questions-Immunogenicity
4b. Please discuss the immunogenicity data. Are
additional pre- or post-marketing studies needed
to assess the immune potential of BioGlue?
32
Panel 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.
33
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?

34
Panel Questions-Labeling

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