Samuel B. Barone, MD Division of Human Tissues “361” Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Samuel B. Barone, MD Division of Human Tissues

Overview What are HCT/Ps? History of Tissue Regulation “361” HCT/Ps Tissue Rules/21 CFR 1271 Registration Donor Eligibility Current Good Tissue Practice

What are HCT/Ps? Regulatory definition: Articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient Encompass a wide variety of products 21 CFR 1271.3(d)

Examples of HCT/Ps From deceased (cadaveric) donors: Musculoskeletal tissues Skin Dura mater Cardiovascular tissues Ocular tissues Tissue/device and other combined products From living donors: Hematopoietic stem/progenitor cells from peripheral and cord blood Other cell therapy products (e.g. pancreatic islets, mesenchymal stem/stromal cells, fibroblasts) Reproductive cells and tissues 21 CFR 1271.3(d)

Not HCT/Ps Vascularized organs Minimally manipulated bone marrow Tissues intended for educational or non-clinical research use (not intended for transplantation) Xenografts Blood products Secreted or extracted products; e.g., human milk, collagen, cell factors Ancillary products used in manufacture In vitro diagnostic products Blood vessels recovered with an organ 21 CFR 1271.3(d)

HISTORY OF TISSUE REGULATION

History of HCT/P Regulation 1993: interim final rule for immediate implementation in response to infectious disease concerns with imported tissues 1997: final rule Musculoskeletal, skin and ocular only (deceased donors) Legal authority: Section 361 of the Public Health Service (PHS) Act – prevent the introduction, transmission, or spread of communicable diseases

Proposed Approach 1997: FDA announced a proposed approach to all human cells, tissues, or cellular or tissue-based products (HCT/Ps) Tiered, risk-based approach Broader scope, included previously unregulated cells and tissues Issued through rulemaking in 3 parts Entire 21 CFR Part 1271 became effective on May 25, 2005

Goals HCT/Ps carry a potential risk of communicable disease transmission from the donor to the recipient Prevent the introduction, transmission, and spread of communicable diseases by HCT/Ps

21 CFR Part 1271 Applicability For some HCT/Ps (“361” HCT/Ps) it is the sole regulatory requirement Authority from section 361 of the PHS Act Prevent the introduction, transmission, or spread of communicable disease No pre-market review

“361” HCT/Ps Minimal manipulation Advertised/labeled for homologous use only Not combined with another article Does not have a systemic effect (except for autologous, family-related or reproductive use) 21 CFR 1271.10(a)

Other Cells and Tissues If the cells or tissues do not meet the requirements to be regulated solely under 361 of the PHS act, are also regulated as drugs, devices, and/or biological products pre-market approval required demonstrate safety and efficacy For these HCT/Ps, Part 1271 applies, but supplements other existing requirements

Tissue Reference Group Provides a single reference point for product specific questions concerning jurisdiction and applicable regulation of HCT/Ps http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ucm152857.htm  

21 Code of Federal Regulations Part 1271

21 CFR Part 1271 Regulation Issues Addressed Establishment Registration and Listing Applicability: types and uses of products that will be regulated by these rules, requirements for registering and listing products Donor Eligibility Requirements for donor screening and testing for “relevant communicable disease agents and diseases” Current Good Tissue Practice (CGTP) Manufacturing to ensure that HCT/Ps do not contain communicable disease agents, are not contaminated, and do not become contaminated

Registration and Listing

General Provisions Purpose; Scope Definitions Criteria for regulation solely under section 361 of PHS Act Exceptions from the requirements

Definition: Manufacture Manufacture means any or all steps in the recovery, processing, storage, labeling, or distribution of any human cell or tissue, and the screening or testing of the cell or tissue donor 21 CFR 1271.3(e)

Registration and Listing Any establishment that manufactures HCT/Ps must Register and submit a list of every HCT/P it manufactures within 5 days after beginning operation Re-register annually Update if change in location or ownership All foreign establishments importing HCT/Ps to the US must register and list each HCT/P 21 CFR 1271.21, 1271.10(b)

Registration and Listing cont. Establishment registration is not a pre-market review program An establishment may begin to market its product once it registers (361 HCT/Ps) There are periodic inspections, but distribution may begin before the establishment is inspected 21 CFR 1271.21, 1271.37

DONOR ELIGIBILITY

Donor Eligibility A donor-eligibility determination, based on donor screening and testing for relevant communicable disease agents and diseases (RCDADs), is required for all donors of HCT/Ps, with some exceptions HCT/P must not be administered until the donor has been determined to be eligible, with some exceptions 21 CFR 1271.45(b,c)

Donor Screening and Testing Screening for risk factors and clinical evidence of disease Current donor medical history interview Current physical assessment/examination Medical records; coroner and autopsy reports, if available Testing FDA-licensed, cleared, or approved tests CLIA-certified laboratory (very few outside the US) 21 CFR 1271.65/.80

Viable, Leukocyte-Rich Requirements Agent Required for Screening Testing HIV-1 and -2 All X Hepatitis B Hepatitis C Syphilis TSE WNV Sepsis Vaccinia (recent smallpox vaccination) HTLV-I and –II Viable, Leukocyte-Rich CMV Chlamydia trachomatis Reproductive Neisseria gonorrhoeae Click to add notes 21 CFR 1271.3(r)/.75/.85

Donor Screening and Testing FDA Guidance for Industry: Eligibility Determination for Donors (8/27/07) Provides FDA’s current thinking Assists manufacturers in complying with the requirements http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/ucm073964.htm

CURRENT GOOD TISSUE PRACTICE

Subpart D – Current Good Tissue Practice Methods, facilities, and controls for manufacturing to prevent communicable disease transmission Broad goals applicable to the wide range of HCT/Ps Establishments have the flexibility to determine how to meet goals through SOPs Narrower in scope than GMP Requires a quality program to prevent, detect, and correct deficiencies that could increase communicable disease risk 21 CFR 1271.150

Requirements Donor eligibility determinations Exemptions and Alternatives Quality Program Personnel Procedures Facilities Environmental Control and Monitoring Equipment Supplies and Reagents Recovery Processing and Process Controls Process Changes Process Validation Labeling Controls Storage Receipt, Pre-distribution Shipment, and Distribution Records Tracking Complaint File 21 CFR 1271.150-320

Procedures Establish and maintain procedures for all steps that are performed during manufacture of the HCT/P Designed to prevent circumstances that increase the risk of introduction, transmission, or spread of communicable disease Reviewed, approved and followed Available to personnel Can adopt standard procedures from another organization 21 CFR 1271.180

Adverse Reaction Reporting Adverse reaction: A noxious and unintended response to any HCT/P for which there is a reasonable possibility that the HCT/P caused the response Investigate any adverse reaction involving a communicable disease from an HCT/P that the establishment made available for distribution Report those that are fatal, life-threatening, result in permanent impairment or permanent damage, or necessitate medical or surgical intervention 21 CFR 1271.350(a)

HCT/P Deviation Reporting HCT/P deviation: A deviation from applicable regulations, standards, or established specifications, or an unexpected event that relates/may relate to communicable disease transmission or HCT/P contamination Investigate all deviations related to a distributed HCT/P That occurred in your facility or A facility under contract, agreement, or other arrangement to you Report certain deviations 21 CFR 1271.350(b)

Inspection and Enforcement Inspections Usually unannounced Frequency is at the Agency’s discretion Inspections include foreign establishments Donor confidentiality observed Orders of retention, recall, destruction, and cessation of manufacturing Address actions FDA can take if manufacture of HCT/Ps is in violation of the regulations 21 CFR 1271.400

Summary What are HCT/Ps? History of Tissue Regulation “361” HCT/Ps Tissue Rules/21 CFR 1271 Registration Donor Eligibility Current Good Tissue Practice

Additional Information 21 CFR 1271 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1271 Establishment Registration http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/EstablishmentRegistration/TissueEstablishmentRegistration/default.htm

Additional Information Adverse Reactions Reporting http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/ucm152576.htm Biological Product Deviations http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/BiologicalProductDeviations/default.htm

Information and Contacts Contact CBER: Consumer questions: email ocod@fda.hhs.gov Manufacturer questions: email matt@fda.hhs.gov Phone: 800-835-4709 or 301-827-1800 http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm106001.htm CBER Tissue Web-page for Copies of regulations, guidance and other documents Registration and listing information http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/default.htm