DHHS / FDA / CDRH 1 FDA Summary CryoLife BioGlue P010003 Lead FDA Reviewer Lisa Kennell.
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Transcript of 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
DHHS / FDA / CDRHDHHS / FDA / CDRH2
Introduction Introduction
• Regulatory history of BioGlue
• Clinical Summary
• Non-clinical testing to be discussed
• Panel Questions
DHHS / FDA / CDRHDHHS / FDA / CDRH3
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.
DHHS / FDA / CDRHDHHS / FDA / CDRH4
Regulatory History
IDE initially for adjunct to Type A (ascending) aortic dissection repair, submitted in 1998
DHHS / FDA / CDRHDHHS / FDA / CDRH5
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
DHHS / FDA / CDRHDHHS / FDA / CDRH6
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
DHHS / FDA / CDRHDHHS / FDA / CDRH7
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.”
DHHS / FDA / CDRHDHHS / FDA / CDRH8
Clinical SummaryClinical Summary
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Clinical SummaryClinical Summary
• BioGlue versus standard hemostasis
• Superiority Hypothesis
• 10% improvement in hemostasis with BioGlue
• 75 patients/treatment group
DHHS / FDA / CDRHDHHS / FDA / CDRH10
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
DHHS / FDA / CDRHDHHS / FDA / CDRH11
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
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Clinical SummaryClinical Summary
• Primary Endpoint
• Anastomotic hemostasis (no need for additional agents to control bleeding at any point)
DHHS / FDA / CDRHDHHS / FDA / CDRH13
Clinical SummaryClinical Summary•Secondary Endpoints• Exposure to donor blood products
• Additional hemostatic agents
• Re-operation for bleeding
• Major and Minor adverse events
• Mortality
DHHS / FDA / CDRHDHHS / FDA / CDRH14
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
DHHS / FDA / CDRHDHHS / FDA / CDRH15
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
DHHS / FDA / CDRHDHHS / FDA / CDRH16
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
DHHS / FDA / CDRHDHHS / FDA / CDRH17
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
DHHS / FDA / CDRHDHHS / FDA / CDRH18
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
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Preclinical Dataand Discussion Items
•Immunogenicity
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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)
DHHS / FDA / CDRHDHHS / FDA / CDRH21
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
DHHS / FDA / CDRHDHHS / FDA / CDRH22
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
DHHS / FDA / CDRHDHHS / FDA / CDRH23
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
DHHS / FDA / CDRHDHHS / FDA / CDRH24
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
DHHS / FDA / CDRHDHHS / FDA / CDRH25
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
DHHS / FDA / CDRHDHHS / FDA / CDRH26
Panel Questions
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Panel Questions-Effectiveness
Panel Questions-Effectiveness
1. Please discuss the clinical implications of the primary and secondary endpoint data.
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Panel Questions-Effectiveness
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.
DHHS / FDA / CDRHDHHS / FDA / CDRH29
Panel Questions-Effectiveness
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.
DHHS / FDA / CDRHDHHS / FDA / CDRH30
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?
DHHS / FDA / CDRHDHHS / FDA / CDRH31
Panel Questions-Immunogenicity
Panel Questions-Immunogenicity
4b. Please discuss the immunogenicity data. Are additional pre- or post-marketing studies needed to assess the immune potential of BioGlue?
DHHS / FDA / CDRHDHHS / FDA / CDRH32
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.”
DHHS / FDA / CDRHDHHS / FDA / CDRH33
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?
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Panel Questions-Labeling
7. Do you have any other recommendations regarding the labeling of this device?