1. David M. Asher, MD Division of Emerging & Transfusion-Transmitted Diseases Office of Blood Research & Review Center for Biologics Evaluation & Research Food and Drug Administration Joint Meeting Transmissible Spongiform Encephalopathies & Blood Products Advisory Committees January 17, 2001 Effectiveness of measures taken to protect humans from food-borne exposure to the BSE agent: Implications for risk of variant Creutzfeldt-Jakob disease and blood safety

2. Issue FDA seeks advice from the TSE Advisory and the Blood Products Advisory Committees on whether food chain controls to prevent human exposure to BSE as implemented in the UK since 1996 provide a sufficient basis to obviate the need to defer blood and plasma donors based on their subsequent travel or residence in a BSE risk country.

3. Approaches to Remote or Theoretical Risks of Contamination in Regulated Products l Accept risk with disclosure, or l Attempt to reduce risk while maintaining benefit -Limit sources of raw materials to the safest possible -Use manufacturing processes that reduce the risk -Restrict use of the product

4. History of FDA Guidances on Precautionary Measures to Reduce Possible Risk of Transmission of Creutzfeldt-Jakob Disease & Variant Creutzfeldt- Jakob Disease by Blood & Blood Products l Risk is theoretical only—no anecdotal or epidemiological evidence for human infection via blood; studies found TSE agents in animal blood. l 1987: FDA recommended precautionary deferral of recipients of human cadaveric pituitary growth hormone as blood donors. l 1996: FDA recommended precautionary withdrawal of blood, components, plasma derivatives from donors with CJD or at increased risk of getting CJD (iatrogenic or familial) and deferral of donors at increased risk.

5. History of FDA Guidances on CJD/vCJD regarding Blood and Blood Products l Sept 1998, Aug 1999: FDA no longer recommended withdrawal of plasma derivatives from donors at increased risk of most forms of CJD but retained that recommendation for variant CJD (vCJD).  Additional epidemiological evidence failed to implicate blood exposure as risk factor for sporadic CJD (sCJD).  CJD withdrawals had contributed to shortages of plasma derivatives.  But vCJD appeared to have different pathogenesis from sCJD, and experience with vCJD was limited.

6. History of FDA Guidances on CJD/vCJD regarding Blood and Blood Products l Nov 1999: FDA also recommended precautionary deferral of blood donors who had spent 6 months or more in the UK between 1980 (estimated start of the BSE epidemic) and the end of 1996 (when UK had fully implemented a variety of measures to control BSE and prevent human exposure to the BSE agent).  Estimated reduction in exposure (as blood donor days spent in UK) = 87%.  Estimated expected loss of blood donors = 2.2%

7. FDA Revised Guidance on CJD/vCJD & Blood Jan 2002: Estimated Reduction in Risk-adjusted Donor Days after Implementation (A. Williams, OBRR, CBER, FDA) Estimated total risk reduction 91% (72% of current risk) Estimated final donor loss 4.6-5.3% If ARC and other programs are more aggressive, then both overall donor loss and risk reduction will be higher.

8. 18 Countries with BSE in Native Cattle [yr first reported & approx. total cases through 2001 per OIE Dec 2001] l UK 1986 (>180 000) [1443 cases in 2000; >688 in 2001] l Ireland 1989 (721) l Switzerland 1990 (390) l France 1991 (410) l Portugal 1994 (581) l Belgium 1997 (44) l Netherlands 1997 (19) l Luxembourg 1997 (1) l Liechtenstein 1998 (2) l Denmark 2000 (5) l Germany 2000 (112) l Spain 2000 (66) l Italy 2000 (27) l Greece 2001 (1) l Czech Repub. 2001 (2) l Slovakia 2001 (1) l Japan 2001 (2,?3) l Slovenia 2001 (?1)

9. Measures thought to be effective in protecting humans from food-borne exposures to BSE agent l BSE control in ruminants l Age-based slaughter schemes l Separation of high-risk materials from edible meat - Removal of “specified risk materials” (SRM) - Prohibition of recovery systems that contaminate meat products with SRM - Prevention of brain emboli at slaughter l Application of the same controls to imported and domestic meat products

10. Measures thought to be effective in protecting humans from food-borne exposures to BSE agent l Effective control of BSE in cattle and small ruminants (sheep and goats) -OIE-compliant national surveillance programs (extensive testing of brain tissues from animals at increased risk of BSE) -Prohibitions on feeding of most mammalian proteins to ruminants (“feed bans”) with steps to reduce chances of accidentally feeding such proteins -Immediate condemnation and prompt destruction of animals showing signs of BSE -Preventive culling of animals at increased risk

11. Measures thought to be effective in protecting humans from food-borne exposures to BSE agent l Age-based slaughter schemes Intended to reduce risk by prohibiting consumption of meat products from ruminants slaughtered after an age when substantial amounts of BSE agent are likely to be present in tissues, generally taken to be no later than 30 months for cattle Example: UK Over Thirty-Month Scheme

12. Measures thought to be effective in protecting humans from food-borne exposures to the BSE agent l Separation of high-risk materials from edible meat products -Prohibition of slaughter methods that may embolize brain tissue, e.g. intracranial air injection and “pithing” -Removal of “specified risk materials” (SRM=CNS, lymphoid, intestinal tissues) from ruminant carcasses at the time of slaughter and effective segregation of SRM from edible materials -Prohibition of “advanced” or “mechanical” meat recovery systems

13. Measures thought to be effective in protecting humans from food-borne exposures to the BSE agent l Application of same measures to protect the human food chain to imported food and domestically produced food

14. Charge Please evaluate the probable effectiveness of those measures taken by the UK to protect humans from food-borne exposure to the BSE agent and their value in mitigating risk otherwise addressed through donor deferral.

15. Question 1 Do members of the committee agree that the combination of measures implemented in the UK by the end of 1996 to protect the human food chain from BSE contamination are sufficient to obviate the need for donor deferrals based on subsequent travel or residence in the UK?

16. Question 2 If the answer to Question 1 is “yes,” which measures should the FDA consider to be of greatest importance when it considers future revisions in recommendations for determining the suitability of donors who spent time in other BSE countries?

17. Question 3 If the answer to Question 1 is “no,” what other measures, if any, would committee members consider sufficient to obviate the need for donor deferrals based on subsequent travel or residence in a BSE- endemic country?