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

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Donor eligibility rule21 CFR 1271 subpart C

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cGTP manufacturing regulations21 CFR 1271 subpart D

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cGMP regulations21 CFR 210 & 211

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IND / IDE regulations21 CFR 312 & 812

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Premarket approval (BLA)21 CFR 601

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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