TSEAC June 26, 2002

1. Topic 1. Validation of Procedures to Prevent Contamination and Cross-Contamination with TSE Agents of Human Tissue Intended for Transplantation TSEAC June 26, 2002

2. Issue • FDA requests advice from TSEAC on • Measures for donor screening • Measures for tissue recovery and processing • Clearance of TSE agents (design of a study) • Appropriate to prevent contamination and cross-contamination of human cells, tissues, and cellular and tissue-based products (HCT/Ps) by TSE agents

3. Background • Three approaches to reduce risk of TSE transmission: • (1) careful screening of donor for TSE and risk factors of TSE (testing if and when validated) • (2) control of recovery and processing to prevent contamination/cross-contamination • (3) use of steps during manufacturing to remove or inactivate (clear) TSE agents

4. Iatrogenic transmission through HCT/Ps • Human dura mater transplantation • >100 cases worldwide (3 in U.S.) • Most from dura mater that had been commingled during processing • Human corneal transplantation • 1 definite case (U.S., 1974) • 1 probable case (Japan, 1994) • 1 possible case (Germany, 1997) • Potential cases (U.K., 1999) • Human pituitary-derived hormone administration—to be discussed

5. Potential Transmission of CJD/vCJD by Other HCT/Ps • Experimental evidence in animals • Brown P et al. Annals of Neurology 1994—300 cases of experimentally transmitted human spongiform encephalopathies

6. FDA’s Regulatory Approach to TSE Transmission (actual and potential) by HCT/Ps • Current regulations (rules) • Current recommendations (guidance) • Proposed regulations • Proposed recommendations

7. Current Regulations • 21 CFR part 1270—Human Tissue Intended for Transplantation--1997 • Screening and testing of potential donors for HIV, HBV, HCV (TSE not included); written procedures; records • Validated procedures to prevent infectious disease contamination or cross-contamination by tissue during processing-1270.31(d) • Inspection and enforcement provisions

8. Current Recommendations • (1) Guidance for Industry: Screening and Testing of Donors of Human Tissue Intended for Transplantation (’97)--defer donors with: • Diagnosis of CJD • Family history of CJD • History of receiving dura mater transplant • History of receiving human pituitary growth hormone

9. Current Recommendations, cont. • (2) Guidance for Industry: Validation of Procedures for Processing of Human Tissues Intended for Transplantation (3/’02)—clarifies 1270.31 • Infectious disease contamination includes viral, bacterial, fungal and TSE agents • Validated methods to prevent contamination by viruses, bacteria, fungi now • Validated methods to prevent contamination by TSE agents—if and when such methods are agreed upon by scientific experts; become available

10. Current Recommendations, cont. • (3) Guidance for the Preparation of a Premarket Notification Application for Processed Human Dura Mater (10/’99) • All of above donor suitability recommendations; any degenerative or demyelinating disease of CNS; death in a neurological/psychiatric hospital • Gross and histological exam of full brain • Disinfection by a method validated to reduce CJD infectivity • Prohibition of batch processing

11. Proposed Regulations • (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 and clinical evidence of HIV, HBV, HCV, TSEs; additional screening for particular HCT/Ps • Testing for HIV, HBV, HCV, syphilis; additional testing for particular HCT/Ps

12. Proposed Regulations, cont. • (2) Current Good Tissue Practice for Manufacturers of HCT/Ps; Inspection and Enforcement; Proposed Rule (1/8/01) • Controls over facilities, personnel, equipment, environment, incoming materials, labeling, storage, process controls, process validation, record keeping, adverse reaction and product deviation reporting, tracking • Inspection and enforcement

13. Proposed Regulations, cont. • (2) GTP • Prohibition of pooling (placing in physical contact or mixed in a single receptacle) • Exemption or alternative from any GTP requirement—submit request with valid data • Ex.-request for an exemption from pooling prohibition: FDA would weigh potential increased risk of contamination and cross-contamination with emerging infectious disease agents (e.g., TSE agents) against potential benefit of improved elimination of conventional infectious disease agents (virus, bacteria, fungi)

14. Proposed Recommendations • Draft guidance for comment about donor screening and deferral to reduce possible risk of CJD/vCJD transmission by HCT/Ps—risk factors for CJD and vCJD--deferrals for travel/residence in BSE-affected countries—similar to guidance for blood donors (1/’02)

15. Additional Donor Screening Measures • (1) Upper age limit for donors • Median age at death from CJD is 68 years • ?incubation period--?infectious during incubation period • Proposed for blood donors, but not implemented • May seriously reduce tissue supply (e.g., 50% of U.S. donors of ocular tissue are age 61 or older) • Not recommended by tissue bank or eye bank standards, except semen donors <40; oocyte donors <35; donors of cardiovascular tissue <61; at the discretion of individual medical director

16. Additional Donor Screening Measures, cont. • (2) Exclusion for head trauma • To avoid possible CNS contamination • Not addressed in industry standards • May reduce tissue supply (e.g., 13% of eye donors’ cause of death is trauma)

17. Additional Donor Screening Measures, cont. • (3) Negative brain autopsy • Delay in distributing time-sensitive HCT/Ps (e.g., cornea) • (4) Negative brain biopsy • Would need to be validated to show that is it predictive of autopsy diagnosis of TSE

18. Charge • Evaluate appropriateness of the measures and controls discussed (or other) to prevent TSE transmission to recipients of HCT/Ps • Additional donor screening criteria • Specified methods of recovery and processing specific methods of decontamination removal and/or inactivation of TSE agents

19. Charge, cont. • Should pooling (commingling) of HCT/Ps from different donors during manufacturing ever be permitted? If so, what controls should FDA require in assessing whether a request for an exemption from the proposed pooling prohibition should be granted?

20. Questions for the Committee • 1. Which of the following measures and controls is (are) appropriate to prevent TSE agent transmission to recipients of human cells and tissues?

21. Questions, cont. • 1. A. Recommend additional donor eligibility/exclusion criteria • Upper age limit • Head trauma exclusion • Negative brain autopsy or biopsy

22. Questions, cont. • 1. B. Recommend specified methods of HCT/P recovery and/or processing to prevent contamination and cross-contamination by TSE agents • Decontamination of instruments and surfaces • Methods for removal and/or inactivation of TSE agents during manufacturing • Single donor aseptic processing or permit pooled processing under certain circumstances (which ones?) with adequate controls (which ones?)

23. Questions, cont. • 1. C. Other appropriate measures and controls

24. Questions, cont. • 2. Please comment on the design of a satisfactory TSE agent clearance study for HCT/Ps, in terms of the following criteria: • A. Suitable TSE agent strain and animal model • B. Accept measurement of abnormal forms of prion protein alone, or require infectivity assays

25. Questions, cont. • 2. Design of a clearance study, cont. • C. Accept substantial reduction (how much?) or require complete elimination of detectable prion protein and/or infectivity • D. Accept a single validated method or require that more than one validated method for eliminating TSE agents be included in the study • E. Other