Regulation of Blood & Blood Products and
Cell, Tissue & Gene Therapies
Elizabeth Read, MDEpi 260UCSF
May 9, 2012
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
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
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
US Blood Supply
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
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
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 contamination 1 in 3,000• Acute lung injury (TRALI) 1 in 50,000• Cardiovascular overload (TACO) 1 in 5,000• Anaphylaxis 1 in 50,000
Paid Donors & Donor Screening/Testing Effects on Post Transfusion Hepatitis
(Alter et al)
Donor Self-Deferral & Screening/Testing Effects on Risk of HIV in Blood
(Busch & Perkins)
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!
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
Cell & Tissue-Based Therapies
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”
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
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
FDA Proposed Approach
• 1997 – FDA published “Proposed Approach to Regulation of Cellular and Tissue-Based Products”– Risk-based– Led to formal regulations and guidance
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”
HCT/Ps include
Musculoskeletal tissue and skinOcular tissueCellular therapiesHematopoietic stem/progenitor cellsTherapeutic cells (DLI)Somatic cells (including those derived from
adult and embryonic stem cells)Reproductive tissueCombination tissue/device, tissue/drugHuman heart valve allograftsHuman dura mater
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
Risk Criteria for HCT/Ps
Lower risk – regulated under section 361 of PHS ActAutologous or family related donors and minimally
manipulated and homologous useMinimally manipulated tissuesReproductive tissues
Higher risk – regulated under section 351 of PHS ActAllogeneic unrelated donors and/orMore than minimally manipulated and/orNon-homologous use
Risk-Based Regulatory Framework for HCT/PsLower risk
361 HCT/Ps
Higher risk
351 HCT/Ps
Establishment registration rule21 CFR 1271 subpart B
√ √
Donor eligibility rule21 CFR 1271 subpart C
√ √
cGTP manufacturing regulations21 CFR 1271 subpart D
√ √
cGMP regulations21 CFR 210 & 211
√
IND / IDE regulations21 CFR 312 & 812
√
Premarket approval (BLA)21 CFR 601
√
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
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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