1. Regulation of Blood & Blood Products and Cell, 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/veno ms 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 reaction1 in 200 Hemolytic transfusion reaction1 in 6,000 Fatal hemolytic reaction1 in 1,000,000 HIV infection1 in 1,900,000 HBV infection1 in 180,000 HCV infection1 in 1,600,000 Bacterial contamination1 in 3,000 Acute lung injury (TRALI)1 in 50,000 Cardiovascular overload (TACO)1 in 5,000 Anaphylaxis1 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 Banti-HBsAg, anti-HBc Hepatitis Canti-HCV, NAT HIV-1,2anti-HCV-1 & 2, NAT HTLV I/IIanti-HTLV I/II SyphilisSTS West Nile VirusNAT T. cruzianti-T. cruzi – once No screening tests are available, but donor questionnaire addresses risk, for malaria and vCJD Emerging infectious diseases are always a risk!

13. 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

14. Cell & Tissue-Based Therapies

15. 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”

16. 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

17. Novel Cell-Based Therapies 1980s – 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

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

19. FDA definition Human 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”

20. 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

21. HCT/Ps do not include Vascularized whole organs HRSA regulates (separate public law) Bone marrow, minimally manipulated, homologous use - AUTO or FAMILY DONOR Practice of medicine (not regulated by FDA) Bone marrow, minimally manipulated, homologous use – UNRELATED DONOR HRSA regulates Xenografts FDA separate regs Blood & blood products FDA separate regs Secreted or extracted products (e.g., human milk, collagen, cell factors) FDA separate regs In vitro diagnostic products FDA separate regs

22. 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

23. Risk-Based Regulatory Framework for HCT/Ps Lower risk 361 HCT/Ps Higher risk 351 HCT/Ps Establishment registration rule 21 CFR 1271 subpart B √√ Donor eligibility rule 21 CFR 1271 subpart C √√ cGTP manufacturing regulations 21 CFR 1271 subpart D √√ cGMP regulations 21 CFR 210 & 211 √ IND / IDE regulations 21 CFR 312 & 812 √ Premarket approval (BLA) 21 CFR 601 √

24. 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

25. 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