1. Minimizing the Risks of TSE Agents in Human Tissues Melissa A. Greenwald, M.D. Division of Human Tissues Office of Cellular, Tissue and Gene Therapies; CBER TSEAC 12-13 February 2004

2. Introduction Human tissue safety will be discussed in the context of three general approaches to reduce the risk of TSE transmission: Human tissue safety will be discussed in the context of three general approaches to reduce the risk of TSE transmission:  Careful screening of donor for TSE and risk factors of TSE (testing if and when validated)  Control of recovery and processing to prevent contamination/cross-contamination  Use of steps during manufacturing to remove or inactivate (clear) TSE agents (currently, no known validated methods for Human Tissues)

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(Rules)  Current Recommendations (Guidance)  Proposed Regulations (Draft Rules)  Proposed Recommendations (Draft Guidance)

4. Current Regulations 21 CFR part 1270—Human Tissues Intended for Transplantation (1997) 21 CFR part 1270—Human Tissues Intended for Transplantation (1997)  Screening and testing of potential donors for HIV, HBV, and HCV (TSE not included)  Written procedures and recordkeeping  Inspection and enforcement provisions  Validated procedures to prevent infectious disease contamination or cross-contamination by tissue during processing – 1270.31(d)

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

6. Current Recommendations, cont. (2) Guidance for Industry: Validation of Procedures for Processing of Human Tissues Intended for Transplantation (3/2002)—clarifies 1270.31 (2) Guidance for Industry: Validation of Procedures for Processing of Human Tissues Intended for Transplantation (3/2002)—clarifies 1270.31  Infectious disease contamination includes viral, bacterial, fungal and TSE agents  Validated methods available to prevent contamination by viruses, bacteria and fungi  Currently there are no validated methods to prevent contamination by TSE agents

7. Current Recommendations, cont. (3) Guidance for Industry and FDA Staff—Class II Special Controls Guidance Document: Human Dura Mater (12/2003) – Center for Devices and Radiological Health (CDRH) (3) Guidance for Industry and FDA Staff—Class II Special Controls Guidance Document: Human Dura Mater (12/2003) – Center for Devices and Radiological Health (CDRH)  Discusses additional deferral criteria beyond those for CJD/vCJD  States that donor screening for CJD and vCJD should follow published blood donor criteria (includes travel history questions)

8. Current Recommendations, cont. Dura Mater Special Controls Guidance (CDRH), cont. Dura Mater Special Controls Guidance (CDRH), cont.  Defer potential donors who have:  Classic CJD risk factors (listed in document)  Degenerative/demyelinating diseases or other neurologic diseases (e.g., senile dementia, Alzheimer’s disease)  Died in neurological/psychiatric hospital

9. Proposed Regulations (1) Suitability Determination for Donors of Human Cellular and Tissue-Based Products; Proposed Rule (9/30/99) (1) Suitability Determination for Donors of Human Cellular and Tissue-Based Products; Proposed Rule (9/30/99)  Screening (including medical history interview) for risk factors for and clinical evidence of relevant communicable diseases, including HIV, HBV, HCV, TSEs  Testing for relevant communicable diseases, including HIV, HBV, HCV, syphilis

10. Proposed Regulations, cont. (2) Current Good Tissue Practice for Manufacturers of HCT/Ps; Inspection and Enforcement; Proposed Rule (1/2001) (2) Current Good Tissue Practice for Manufacturers of HCT/Ps; Inspection and Enforcement; Proposed Rule (1/2001)  Includes requirements for controls over facilities, personnel, equipment, environment, incoming materials, labeling, storage, process controls, process validation, record keeping, adverse reaction and product deviation reporting, tracking

11. Proposed CBER Regulations, cont. (2) Proposed GTPs (cont.) (2) Proposed GTPs (cont.)  Inspection and enforcement  Requirement to archive appropriate specimens from each donor of dura mater  Specific requirement for dura mater to be processed using validated method to reduce TSEs  Prohibition of pooling (placing in physical contact or mixed in a single receptacle)  Exemption or alternative from any GTP requirement—submit with valid data

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

13. CJD/vCJD Draft Guidance, cont. Donor screening recommendations for vCJD are based on the “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products” (1/2002) Donor screening recommendations for vCJD are based on the “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products” (1/2002) Recommended donor screening criteria for Human Tissues are the same as those listed in the blood guidance document Recommended donor screening criteria for Human Tissues are the same as those listed in the blood guidance document

14. Recommended vCJD Screening Criteria for Human Tissues Determine ineligible any donor who: Determine ineligible any donor who:  Diagnosed with vCJD  Diagnosed with dementia or other similar CNS diseases of unknown etiology  Has spent >/= 3 months in UK  US military/employees spending >/= 6 months at military base in Europe  Lived >/= 5 years in Europe  Received blood/products from UK  Injected bovine insulin

15. Anticipated Proposed Recommendations Donor Eligibility Draft Guidance Document to accompany the Donor Eligibility Rule Donor Eligibility Draft Guidance Document to accompany the Donor Eligibility Rule  Anticipate publication as a draft guidance in the general timeframe as the DE Final Rule  Plan to finalize the DE Guidance as one document to include CJD and vCJD measures described in 2002 draft guidance document  Until the DE Final Rule publishes, there are no requirements for vCJD screening

16. Interim Final Rule Human Cells, Tissues, and Cellular and Tissue- Based Products; Establishment Registration and Listing (1/27/2004) Human Cells, Tissues, and Cellular and Tissue- Based Products; Establishment Registration and Listing (1/27/2004)  Requires all establishments that manufacture HCT/Ps to register and list  Excludes manufacturers of human dura mater and heart valves, which will continue to be regulated as medical devices  Plan to revoke the interim rule when the Donor Eligibility and Good Tissue Practice Final Rules are published, when both products will be regulated as HCT/Ps

17. Any Questions from the Committee?

18. References Available in order of publication date at http://www.fda.gov/cber/tissue/docs.htm unless otherwise noted Available in order of publication date at http://www.fda.gov/cber/tissue/docs.htm unless otherwise noted http://www.fda.gov/cber/tissue/docs.htm Draft Guidance for Industry: Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)- 6/14/2002 Draft Guidance for Industry: Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)- 6/14/2002 Guidance for Industry: Validation of Procedures for Processing of Human Tissues Intended for Transplantation - 3/8/2002 Guidance for Industry: Validation of Procedures for Processing of Human Tissues Intended for Transplantation - 3/8/2002

19. References, cont. FEDERAL REGISTER Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue-Based Products; Inspection and Enforcement; Proposed Rule - 1/8/2001 FEDERAL REGISTER Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue-Based Products; Inspection and Enforcement; Proposed Rule - 1/8/2001 FEDERAL REGISTER Suitability Determination for Donors of Human Cellular and Tissue-Based Products; Proposed Rule - 9/30/1999 FEDERAL REGISTER Suitability Determination for Donors of Human Cellular and Tissue-Based Products; Proposed Rule - 9/30/1999 Guidance for Industry - Screening and Testing of Donors of Human Tissue Intended for Transplantation - 7/29/1997 Guidance for Industry - Screening and Testing of Donors of Human Tissue Intended for Transplantation - 7/29/1997

20. References, cont. FEDERAL REGISTER Human Tissue Intended for Transplantation; Final Rule - 7/29/1997 FEDERAL REGISTER Human Tissue Intended for Transplantation; Final Rule - 7/29/1997 Class II Special Controls Guidance Document: Human Dura Mater; Guidance for Industry and FDA 12/18/2003 http://www.fda.gov/cdrh/ode/guidance/054.html Class II Special Controls Guidance Document: Human Dura Mater; Guidance for Industry and FDA 12/18/2003 http://www.fda.gov/cdrh/ode/guidance/054.html http://www.fda.gov/cdrh/ode/guidance/054.html FEDERAL REGISTER Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing; Interim Final Rule; Opportunity for Public Comment - 1/23/2004 FEDERAL REGISTER Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing; Interim Final Rule; Opportunity for Public Comment - 1/23/2004

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