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Regulation of Blood & Blood Products and Cell, Tissue & Gene Therapies

Regulation of Blood & Blood Products and Cell, Tissue & Gene Therapies. Elizabeth Read, MD Epi 260 UCSF May 9, 2012. Biologics Review at FDA. C D ER Monoclonal antibodies Therapeutic proteins (cytokines, enzymes, etc.) Immunomodulators

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Regulation of Blood & Blood Products and Cell, Tissue & Gene Therapies

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  1. Regulation of Blood & Blood Products andCell, Tissue & Gene Therapies Elizabeth Read, MD Epi 260 UCSF May 9, 2012

  2. Biologics Review at FDA CDER • Monoclonal antibodies • Therapeutic proteins (cytokines, enzymes, etc.) • Immunomodulators • Growth factors, cytokines, etc. intended to mobilize, stimulate, decrease, or alter in vivo hematopoeitic cell production CBER • Vaccines • Allergenics • Antitoxins/antivenins/venoms • Blood & blood products • HCT/Ps • Gene therapies • Xenotransplant products • Related devices/IVDs • Some combination products

  3. Blood & Blood Products • Bernard Fantus MD, Professor of Pharmacology and Therapeutics at the University of Illinois, founded the first US hospital blood bank at Cook County Hospital in 1937

  4. Blood & Blood Products In US (2006) • 16 million units of whole blood drawn from 9.5 million volunteer donors • 30 million blood components (RBCs, plasma, platelets) transfused per year to 5 million patients • Some of plasma from WB, plus separately collected 12 million units of source plasma, are processed into plasma derivatives

  5. US Blood Supply

  6. Blood Regulations & Standards • FDA • Blood cGMPs & Standards • BLAs - clinical trials not required • Drug cGMPs also apply • Guidances - donor screening/testing, etc. • AABB standards • voluntary, but in California are codified into law

  7. Blood Industry Culture & Consent Decrees • 1990s: Culture shift • From charitable community organizations to regulated biologics manufacturers • FDA consent decrees • Consent decrees issued to several blood centers for CGMP & other violations • ARC operating under consent decree since 1993, has paid fines of > $37 million to FDA

  8. Estimated Risk Per Unit of Blood Transfused in US (2009) • Fever or allergic reaction 1 in 200 • Hemolytic transfusion reaction 1 in 6,000 • Fatal hemolytic reaction 1 in 1,000,000 • HIV infection 1 in 1,900,000 • HBV infection 1 in 180,000 • HCV infection 1 in 1,600,000 • Bacterial contamination1 in 3,000 • Acute lung injury (TRALI) 1 in 50,000 • Cardiovascular overload (TACO) 1 in 5,000 • Anaphylaxis 1 in 50,000

  9. Paid Donors & Donor Screening/Testing Effects on Post Transfusion Hepatitis(Alter et al)

  10. Donor Self-Deferral & Screening/Testing Effects on Risk of HIV in Blood(Busch & Perkins)

  11. US Blood Donor Testing Requirements 2012 • Hepatitis B anti-HBsAg, anti-HBc • Hepatitis C anti-HCV, NAT • HIV-1,2 anti-HCV-1 & 2, NAT • HTLV I/II anti-HTLV I/II • Syphilis STS • West Nile Virus NAT • T. cruzi anti-T. cruzi – once • No screening tests are available, but donor questionnaire addresses risk, for malaria and vCJD • Emerging infectious diseases are always a risk!

  12. Plasma Protein Therapeutics • Fractionation products • Regulated as biological drugs + voluntary PPTA standards • Pools of source (apheresis) + recovered (from WB) plasma • Donors paid, but well-screened/tested • Fractionation process, specific viral inactivation steps, and B19 parvovirus NAT testing of pools, reduce virus in fractions • Persistent quality & safety concerns • Recombinant analog products • Regulated as biological drugs

  13. Cell & Tissue-Based Therapies

  14. Cell-based therapies originated with hematopoietic transplantation in 1970s • Sibling donor bone marrow harvested, filtered, and transferred to blood bags in operating room • BM product carried directly to patient unit for infusion • Minimal donor & product testing, graft manipulation, quality systems • FDA still considers conventional autologous and allogeneic related BMT as “Practice of Medicine”

  15. Tissue Transplantation • 1800s – early 1900s: early efforts in tissue transplantation (skin, bone, blood vessels) • 1949: US Navy tissue bank established • 1950s -1980s: heart valve, vein, skin allografting & banking • 1993: FDA interim final rule explicitly required screening and testing of tissue donors

  16. Novel Cell-Based Therapies1980s – 2000s • Development of many novel cell-based therapies • Hematopoietic transplants with “engineered” grafts • Cord blood as alternative HSC source • Immunotherapies • T cells & subpopulations, NK cells • Dendritic cell tumor vaccines • Cellular gene therapies • Cells isolated from organs/tissues (pancreatic islets) • Adult and embryonic stem cell-derived therapies • Engineered tissues

  17. FDA Proposed Approach • 1997 – FDA published “Proposed Approach to Regulation of Cellular and Tissue-Based Products” • Risk-based • Led to formal regulations and guidance

  18. FDA definitionHuman cells, tissues, and cellular and tissue-based products • HCT/Ps are “articles containing human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient”

  19. HCT/Ps include • Musculoskeletal tissue and skin • Ocular tissue • Cellular therapies • Hematopoietic stem/progenitor cells • Therapeutic cells (DLI) • Somatic cells (including those derived from adult and embryonic stem cells) • Reproductive tissue • Combination tissue/device, tissue/drug • Human heart valve allografts • Human dura mater

  20. HCT/Ps do not include

  21. Risk Criteria for HCT/Ps • Lower risk – regulated under section 361 of PHS Act • Autologous or family related donors and minimally manipulated and homologous use • Minimally manipulated tissues • Reproductive tissues • Higher risk – regulated under section 351 of PHS Act • Allogeneic unrelated donors and/or • More than minimally manipulated and/or • Non-homologous use

  22. Risk-Based Regulatory Framework for HCT/Ps

  23. Public Cord Blood Banking • FDA decided against standards-based regulatory approach like Blood • As 351 HCT/Ps, need clinical efficacy data for licensure • Banks don’t conduct trials • Clinical data from registry (NMDP/CIBMTR) • NY Blood Center: First cord blood BLA reviewed by CBER Sept 2011

  24. Summary of Challenges Common to Blood/Blood Products and HCT/Ps • Living cells • Special liquid or cryopreservation methods to ensure stability during hold/storage/transport • No terminal sterilization • Stringent donor screening/testing requirements + aseptic processing • Persistent concerns about infectious disease transmission • Immunogenicity - alloantigens (RBC, HLA, platelet) • Defined algorithms for compatibility testing and matching for “patient-specific” products

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