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Malcolm Moos Jr., M.D., Ph.D. Medical Officer CBER/OCTGT/DCGT moos@cber.fda

Cellular Therapies for Repair and Regeneration of Joint Surfaces—Product Characterization and Testing. Malcolm Moos Jr., M.D., Ph.D. Medical Officer CBER/OCTGT/DCGT moos@cber.fda.gov. Source. Process. Product Testing. Release Testing. Process control. “Device”. “Biologic”.

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Malcolm Moos Jr., M.D., Ph.D. Medical Officer CBER/OCTGT/DCGT moos@cber.fda

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  1. Cellular Therapies for Repair and Regeneration of Joint Surfaces—Product Characterization and Testing Malcolm Moos Jr., M.D., Ph.D. Medical Officer CBER/OCTGT/DCGT moos@cber.fda.gov

  2. Source Process Product Testing

  3. Release Testing Process control “Device” “Biologic” • Well-characterized • Precisely defined materials • Precisely defined structure • Tests that measure critical product parameters reliably • Data defining these parameters • Poorly characterized • Heterogeneous • Complex molecular entities • Inadequate analytical procedures • Insufficient scientific basis correlating measurable properties with biological activity

  4. Release Testing Process control “Device” “Biologic” • Well-characterized • Precisely defined materials • Precisely defined structure • Tests that measure critical product parameters reliably • Data defining these parameters • Poorly characterized • Heterogeneous • Complex molecular entities • Inadequate analytical procedures • Insufficient scientific basis correlating measurable properties with biological activity

  5. Source Process Release Testing

  6. Strategic considerations • “Measure twice, cut once”: • Up-front investment in each area may prevent costly waste of time and resources on sub-optimal process or variable/ineffective product • Better characterization makes many things easier

  7. Source Control • Anatomic site • Pathologic involvement • Cellular homogeneity/inhomogeneity

  8. HACDC in regenerating muscle In vitro culture is not required Freshly Isolated Chondrocytes

  9. Product Testing • Is guided by detailed understanding of the product and the manufacturing process • Should ensure consistency of process and product • Should predict in vivo activity

  10. Product Testing • Terminal markers may not predict biological function • Characterization of functional chondroprogenitors • Qualification by meaningful biological responses —An example of new alternatives

  11. 100 80 60 Theoretical correlation OCR/DNA (%) 40 20 0 Islet cell transplantation in diabetic mice Oxygen Consumption Rate and dye exclusion are uncorrelated 100 0 20 40 60 80 (K. Papas, University of Minnesota Department of Surgery, in preparation) Live/dead Staining (%)

  12. Response to Rat Islet Transplants in Diabetic Balb/C Mice (Anti-CD4) 800 700 600 500 400 300 200 100 0 0 50 100 150 200 250 300 350 400 450 Fractional Viability (%) 0 10 20 30 40 50 60 70 80 90 100 6 all cure 2/0/0 2/0/0 1/0/0 mixed 5 all fail 4 Oxygen Consumption Rate, OCR (nmol/min) 3 Viable Islet Equivalents, VIEQ 3/0/0 0/0/2 1/0/1 6/0/0 2/0/0 2 2/0/0 4/0/0 2/0/0 0/0/6 3/0/0 0/1/1 1/0/0 3/0/0 1 1/0/1 2/0/0 1/0/0 1/0/0 3/0/0 3/0/0 0/0/4 0/1/2 0/0/3 1/0/2 0/1/0 0/0/3 0/0/2 0 Normalized Oxygen Consumption Rate, OCR/DNA (nmol/min•mgDNA)

  13. ATP < 110 pmol/µg DNA ATP > 110 pmol/µg DNA Cure rates and days to cure in mice receiving 1,000 human IE according to ATP/DNA 100 P=0.008 80 60 Cure rate (%) 40 (B. Hering, University of Minnesota Department of Surgery, with permission) 20 0 0 10 20 30 40 Days after transplant

  14. The nude mouse model Dell’Accio et al, A&R, 2001

  15. The Shmoo —Al Capp, ca. 1948

  16. Instructions go both ways Recipient Donor

  17. Donor-Host Interactions? Cell product Synovial Joint Fluid Cover Articular surface Subchondral bone Remnants of calcified cartilage

  18. P gene expression Biological Response Competence Factors

  19. FGFR-3 Col2a1 BMP-2 ALK-1 Molecular profile of the stable chondrocyte FI 2 4 10 12 Population doublings β-actin Safranin O

  20. Relation of Gene score to Stable Cartilage Formation 3 Stable cartilage 2 Histology score 1 0 -5 -3 -1 1 3 5 Gene score

  21. Space—the final frontier? Thomas and Moos, 2004 (unpublished)

  22. Molecular Boundaries in Tissue Formation 400x Thomas and Moos, 2005 (submitted) Joint-specific growth factor Enzyme Overlap growth factor activation joint surface specification

  23. Thought Questions • Acceptance, selection, or instruction of starting material • Consider competence factors sufficient to define chondroprogenitors (rather than characteristics of terminal differentiation) • Distribution of characteristics in 3D may be critical • Qualification of potential tests against appropriate biological responses in vivo

  24. Questions for Discussion • Criteria for obtaining starting tissue • Characteristics of functional chondroprogenitor cells • Analytical methods to determine these characteristics • Qualification of these tests in preclinical models • Potency assays • Special issues for cells contained in natural or artificial matrices

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