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FDA Summary. CryoLife BioGlue P010003 Lead FDA Reviewer Lisa Kennell. 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.
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FDA Summary CryoLife BioGlue P010003 Lead FDA Reviewer Lisa Kennell
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 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
Clinical Summary • Primary Endpoint • Anastomotic hemostasis (no need for additional agents to control bleeding at any point)
Clinical Summary • Secondary Endpoints • Exposure to donor blood products • Additional hemostatic agents • Re-operation for bleeding • Major and Minor adverse events • Mortality
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
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
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
Panel Questions-Effectiveness 1. Please discuss the clinical implications of the primary and secondary endpoint data.
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.
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.
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?
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-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?
