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