Minimizing the Risks of TSE Agents in Human Tissues

Melissa A. Greenwald, M.D.Melissa A. Greenwald, M.D.

Division of Human TissuesDivision of Human Tissues

Office of Cellular, Tissue and Gene Office of Cellular, Tissue and Gene Therapies; CBERTherapies; CBER

TSEAC 12-13 February 2004TSEAC 12-13 February 2004

Introduction

Human tissue safety will be discussed in the Human tissue safety will be discussed in the context of three general approaches to reduce the context of three general approaches to reduce the risk of TSE transmission:risk of TSE transmission: Careful screening of donor for TSE and risk Careful screening of donor for TSE and risk

factors of TSE (testing if and when validated)factors of TSE (testing if and when validated) Control of recovery and processing to prevent Control of recovery and processing to prevent

contamination/cross-contaminationcontamination/cross-contamination Use of steps during manufacturing to remove or Use of steps during manufacturing to remove or

inactivate (clear) TSE agents (currently, no inactivate (clear) TSE agents (currently, no known validated methods for Human Tissues)known validated methods for Human Tissues)

Introduction

FDA’s Regulatory Approach to TSE FDA’s Regulatory Approach to TSE Transmission (actual and potential) by Transmission (actual and potential) by Human TissuesHuman Tissues Current Regulations (Rules)Current Regulations (Rules) Current Recommendations (Guidance)Current Recommendations (Guidance) Proposed Regulations (Draft Rules)Proposed Regulations (Draft Rules) Proposed Recommendations (Draft Proposed Recommendations (Draft

Guidance)Guidance)

Current Regulations

21 CFR part 1270—Human Tissues Intended for 21 CFR part 1270—Human Tissues Intended for Transplantation (1997)Transplantation (1997) Screening and testing of potential donors for Screening and testing of potential donors for

HIV, HBV, and HCV (TSE not included)HIV, HBV, and HCV (TSE not included) Written procedures and recordkeepingWritten procedures and recordkeeping Inspection and enforcement provisionsInspection and enforcement provisions Validated procedures to prevent infectious Validated procedures to prevent infectious

disease contamination or cross-contamination disease contamination or cross-contamination by tissue during processing – 1270.31(d)by tissue during processing – 1270.31(d)

Current Recommendations

(1) Guidance for Industry: Screening and (1) Guidance for Industry: Screening and Testing of Donors of Human Tissue Testing of Donors of Human Tissue Intended for Transplantation (1997)—defer Intended for Transplantation (1997)—defer donors with:donors with: Risk factors for CJDRisk factors for CJD Does not include vCJD risk factorsDoes not include vCJD risk factors

Current Recommendations, cont. (2) Guidance for Industry: Validation of (2) Guidance for Industry: Validation of

Procedures for Processing of Human Procedures for Processing of Human Tissues Intended for Transplantation Tissues Intended for Transplantation (3/2002)—clarifies 1270.31(3/2002)—clarifies 1270.31 Infectious disease contamination includes Infectious disease contamination includes

viral, bacterial, fungal and TSE agentsviral, bacterial, fungal and TSE agents Validated methods available to prevent Validated methods available to prevent

contamination by viruses, bacteria and contamination by viruses, bacteria and fungifungi

Currently there are no validated methods Currently there are no validated methods to prevent contamination by TSE agentsto prevent contamination by TSE agents

Current Recommendations, cont.

(3) Guidance for Industry and FDA Staff—Class (3) Guidance for Industry and FDA Staff—Class II Special Controls Guidance Document: Human II Special Controls Guidance Document: Human Dura Mater (12/2003) – Center for Devices and Dura Mater (12/2003) – Center for Devices and Radiological Health Radiological Health (CDRH)(CDRH) Discusses additional deferral criteria beyond Discusses additional deferral criteria beyond

those for CJD/vCJDthose for CJD/vCJD States that donor screening for CJD and vCJD States that donor screening for CJD and vCJD

should follow published blood donor criteria should follow published blood donor criteria (includes travel history questions)(includes travel history questions)

Current Recommendations, cont.

Dura Mater Special Controls Guidance (Dura Mater Special Controls Guidance (CDRHCDRH), ), cont.cont. Defer potential donors who have:Defer potential donors who have:

Classic CJD risk factors (listed in document)Classic CJD risk factors (listed in document)Degenerative/demyelinating diseases or Degenerative/demyelinating diseases or

other neurologic diseases (e.g., senile other neurologic diseases (e.g., senile dementia, Alzheimer’s disease)dementia, Alzheimer’s disease)

Died in neurological/psychiatric hospitalDied in neurological/psychiatric hospital

Proposed Regulations

(1) Suitability Determination for Donors of (1) Suitability Determination for Donors of Human Cellular and Tissue-Based Products; Human Cellular and Tissue-Based Products; Proposed Rule (9/30/99)Proposed Rule (9/30/99) Screening (including medical history interview) Screening (including medical history interview)

for risk factors for and clinical evidence of for risk factors for and clinical evidence of relevant communicable diseases, including relevant communicable diseases, including HIV, HBV, HCV, TSEsHIV, HBV, HCV, TSEs

Testing for relevant communicable diseases, Testing for relevant communicable diseases, including HIV, HBV, HCV, syphilisincluding HIV, HBV, HCV, syphilis

Proposed Regulations, cont.

(2) Current Good Tissue Practice for (2) Current Good Tissue Practice for Manufacturers of HCT/Ps; Inspection and Manufacturers of HCT/Ps; Inspection and Enforcement; Proposed Rule (1/2001)Enforcement; Proposed Rule (1/2001) Includes requirements for controls over Includes requirements for controls over

facilities, personnel, equipment, environment, facilities, personnel, equipment, environment, incoming materials, labeling, storage, process incoming materials, labeling, storage, process controls, process validation, record keeping, controls, process validation, record keeping, adverse reaction and product deviation adverse reaction and product deviation reporting, trackingreporting, tracking

Proposed CBER Regulations, cont. (2) Proposed GTPs (cont.)(2) Proposed GTPs (cont.)

Inspection and enforcementInspection and enforcement Requirement to archive appropriate specimens Requirement to archive appropriate specimens

from each donor of dura mater from each donor of dura mater Specific requirement for dura mater to be Specific requirement for dura mater to be

processed using validated method to reduce processed using validated method to reduce TSEsTSEs

Prohibition of pooling (placing in physical Prohibition of pooling (placing in physical contact or mixed in a single receptacle)contact or mixed in a single receptacle)

Exemption or alternative from any GTP Exemption or alternative from any GTP requirement—submit with valid datarequirement—submit with valid data

Proposed Recommendations

Draft Guidance for Industry: Preventive Draft Guidance for Industry: Preventive Measures to Reduce the Possible Risk of Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Human Cells, Tissues, Disease (vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based Products and Cellular and Tissue-Based Products (HCT/Ps)—June 2002(HCT/Ps)—June 2002 Presented to TSEAC 26 June 2002Presented to TSEAC 26 June 2002

CJD/vCJD Draft Guidance, cont.

Donor screening recommendations for vCJD are Donor screening recommendations for vCJD are based on the “Guidance for Industry: Revised based on the “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products” (1/2002)(vCJD) by Blood and Blood Products” (1/2002)

Recommended donor screening criteria for Human Recommended donor screening criteria for Human Tissues are the same as those listed in the blood Tissues are the same as those listed in the blood guidance documentguidance document

Recommended vCJD Screening Criteria for Human Tissues Determine ineligible any donor who:Determine ineligible any donor who:

Diagnosed with vCJD Diagnosed with vCJD Diagnosed with dementia or other similar CNS Diagnosed with dementia or other similar CNS

diseases of unknown etiologydiseases of unknown etiology Has spent >/= 3 months in UKHas spent >/= 3 months in UK US military/employees spending >/= 6 months US military/employees spending >/= 6 months

at military base in Europeat military base in Europe Lived >/= 5 years in EuropeLived >/= 5 years in Europe Received blood/products from UKReceived blood/products from UK Injected bovine insulinInjected bovine insulin

Anticipated Proposed Recommendations Donor Eligibility Draft Guidance Document to Donor Eligibility Draft Guidance Document to

accompany the Donor Eligibility Ruleaccompany the Donor Eligibility Rule Anticipate publication as a draft guidance in the Anticipate publication as a draft guidance in the

general timeframe as the DE Final Rulegeneral timeframe as the DE Final Rule Plan to finalize the DE Guidance as one Plan to finalize the DE Guidance as one

document to include CJD and vCJD measures document to include CJD and vCJD measures described in 2002 draft guidance documentdescribed in 2002 draft guidance document

Until the DE Final Rule publishes, there are no Until the DE Final Rule publishes, there are no requirements for vCJD screening requirements for vCJD screening

Interim Final Rule Human Cells, Tissues, and Cellular and Tissue-Human Cells, Tissues, and Cellular and Tissue-

Based Products; Establishment Registration and Based Products; Establishment Registration and Listing (1/27/2004)Listing (1/27/2004) Requires all establishments that manufacture Requires all establishments that manufacture

HCT/Ps to register and listHCT/Ps to register and list Excludes manufacturers of human dura mater Excludes manufacturers of human dura mater

and heart valves, which will continue to be and heart valves, which will continue to be regulated as medical devices regulated as medical devices

Plan to revoke the interim rule when the Donor Plan to revoke the interim rule when the Donor Eligibility and Good Tissue Practice Final Eligibility and Good Tissue Practice Final Rules are published, when both products will Rules are published, when both products will be regulated as HCT/Psbe regulated as HCT/Ps

Any Questions from the Committee?

References Available in order of publication date at Available in order of publication date at

http://www.fda.gov/cber/tissue/docs.http://www.fda.gov/cber/tissue/docs.htmhtm unless unless otherwise notedotherwise noted

Draft Guidance for Industry: Preventive Measures Draft Guidance for Industry: Preventive Measures to Reduce the Possible Risk of Transmission of to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Human Creutzfeldt-Jakob Disease (vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)- 6/14/2002 Products (HCT/Ps)- 6/14/2002

Guidance for Industry: Validation of Procedures Guidance for Industry: Validation of Procedures for Processing of Human Tissues Intended for for Processing of Human Tissues Intended for Transplantation - 3/8/2002Transplantation - 3/8/2002

References, cont.

FEDERAL REGISTER Current Good Tissue FEDERAL REGISTER Current Good Tissue Practice for Manufacturers of Human Cellular and Practice for Manufacturers of Human Cellular and Tissue-Based Products; Inspection and Tissue-Based Products; Inspection and Enforcement; Proposed Rule - 1/8/2001Enforcement; Proposed Rule - 1/8/2001

FEDERAL REGISTER Suitability Determination FEDERAL REGISTER Suitability Determination for Donors of Human Cellular and Tissue-Based for Donors of Human Cellular and Tissue-Based Products; Proposed Rule - 9/30/1999Products; Proposed Rule - 9/30/1999

Guidance for Industry - Screening and Testing of Guidance for Industry - Screening and Testing of Donors of Human Tissue Intended for Donors of Human Tissue Intended for Transplantation - 7/29/1997Transplantation - 7/29/1997

References, cont. FEDERAL REGISTER Human Tissue Intended FEDERAL REGISTER Human Tissue Intended

for Transplantation; Final Rule - 7/29/1997for Transplantation; Final Rule - 7/29/1997 Class II Special Controls Guidance Document: Class II Special Controls Guidance Document:

Human Dura Mater; Guidance for Industry and Human Dura Mater; Guidance for Industry and FDA 12/18/2003 FDA 12/18/2003 http://www.fda.gov/cdrh/ode/guidance/054.htmlhttp://www.fda.gov/cdrh/ode/guidance/054.html

FEDERAL REGISTER Human Cells, Tissues, FEDERAL REGISTER Human Cells, Tissues, and Cellular and Tissue-Based Products; and Cellular and Tissue-Based Products; Establishment Registration and Listing; Interim Establishment Registration and Listing; Interim Final Rule; Opportunity for Public Comment - Final Rule; Opportunity for Public Comment - 1/23/2004 1/23/2004

Melissa A. Greenwald, MD(greenwald@cber.fda.gov)melissa.greenwald@fda.hhs.gov