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Peter L. Hudson, Ph.D. Biologist Division of General, Restorative, and Neurological Devices Office of Device Evaluation

Peter L. Hudson, Ph.D. Biologist Division of General, Restorative, and Neurological Devices Office of Device Evaluation Center for Devices and Radiological Health Food and Drug Administration. Preclinical Evaluations. Toxicology/Biocompatibility

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Peter L. Hudson, Ph.D. Biologist Division of General, Restorative, and Neurological Devices Office of Device Evaluation

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  1. Peter L. Hudson, Ph.D. Biologist Division of General, Restorative, and Neurological Devices Office of Device Evaluation Center for Devices and Radiological Health Food and Drug Administration

  2. Preclinical Evaluations • Toxicology/Biocompatibility • Experiments to demonstrate bone inductive properties • Remaining questions

  3. Preclinical EvaluationsToxicology/Biocompatibility • Acute single and multiple dose general toxicology expt.’s • Chronic toxicity • Intracutaneous toxicity • Delayed contact sensitization • Cytoxicity • Systemic toxicity • In vitro hemolysis • Implantation • Mutagenicity • Teratology and fertility studies

  4. Preclinical Evaluations/Induction of Bone • Induction of bone • critical-size defect repair models • fracture repair repair models • spinal fusion repair models

  5. FDA Questions • Potential to stimulate transformed cells • Potential for an immune response to rhBMP-2 to cause adverse effects

  6. FDA Questions • Potential to stimulate transformed cells

  7. Pharmacokinetics/Pharmacology • Rapid distribution • Rapid clearance via renal pathway

  8. Preclinical Evaluations/Carcinogenicity • Ames mutagenicity study • 1 year femoral onlay rat study • Inhibition of tumor growth in vitro with human tumor cell lines • Growth potential on primary tumor isolates in vitro (Soda, H. et al.)

  9. Planned Additional Studies • Tumor cell line BMP receptor expression • In vitro evaluation of effect of BMP-2 on cell proliferation/growth • In vivo (nude mouse) evaluation of the potential for BMP-2 to stimulate the proliferation of BMP-2 receptor expressing tumor cells

  10. FDA Questions • Potential for an immune response to rhBMP-2 to cause adverse effects

  11. Antibody experiments • ELISAs for anti-rhBMP-2 and collagen type I • Rats, dogs and rhesus monkey models

  12. Human antibody findings • 2/277 patients developed antibodies to rhBMP-2 • No adverse clinical effect was correlated with positive antibody formation

  13. FDA Questions • Potential for an immune response to rhBMP-2 to cause adverse effects • Embryogenesis • Maternal Immune Response

  14. BMP-2 Knockout Experiments • Embryonic lethality • Amnion/chorion and heart congenital abnormalities

  15. Defective Eyes in BMP-7 KO Defective Kidneys in BMP-7 KO Defective Development in BMP-2 KO wt -/- wt -/- BMP Knockout mice

  16. Hypothetical fetal expression/restimulation of maternal immune response Secondary Ab response Primary Ab response Fetal expression of BMPs boosts maternal Ab response Exogenous BMP used at site of fusion Potentially devastating effects of Abs on fetus

  17. Reproduction/Teratology • Additional animal evaluations to investigate the potential of anti-BMP-2 antibodies to cause teratogenic effects • Additional animal evaluations to investigate the potential for fetal BMP-2 expression to cause adverse immunologic effects in women • Registry for women of childbearing potential • Other suggestions?

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