Dorothy Scott, M.D. Office of Blood Research and Review FDA October 25, 2001

1. Topic 1: FDA Draft Guidance “Revised Preventive Measures to Reduce the Possible Risk of Transmission of CJD and vCJD by Blood and Blood Products” Dorothy Scott, M.D. Office of Blood Research and Review FDA October 25, 2001

2. Previous Guidance- Deferrals • vCJD, CJD • Risk factors for classical CJD (Family history, growth hormone injections, dura mater transplant • BSE exposure risk: travel/residence in U.K. > 6 months 1980-1996; injection bovine insulin (U.K. source)

3. Post 1999 Guidance • Increasing rate of vCJD epidemic in United Kingdom • Increased BSE epidemic detected in Europe (more countries, more cattle) • Sheep transfusion transmission BSE (Lancet 366:999-1000, 2000) • Continued scientific uncertainty - vCJD transmitted by blood ?

4. TSEAC 6/28/2001 • Considered increased donor deferral for vCJD risk (BSE exposure) • Weighed risk of shortage blood and need for precautionary measures • long incubation period limits epidemiological studies although if transmission possible, deferrals have current importance • experimental studies on infectivity of vCJD blood limited to date • blood shortage possible if large donor deferrals recommended

5. TSEAC 6/28/2001 Opinions and votes by TSEAC incorporated into FDA draft guidance 8/27/01 (http://www.fda.gov/cber/gdlns/cjdvcjd.htm) New donor deferrals decrease risk (based upon exposure to BSE) 91%; 5% donor loss anticipated (based on REDS survey data) - Phased implementation - Pilot studies for more stringent deferrals - Blood vs. Plasma (European donor deferral) - Blood supply monitoring

6. FDA Draft Guidance: Donor Deferrals Phase IImplementation 5/31/02 1. U.K. > 3 months, 1980- 1996 2. France > 5 years, 1980- present 3. U.S. military base, > 6 months 1980- 1990 N. of Alps; 1980- 1996 S. of Alps 4. Recipients of transfusion in U.K.

7. U.K. Donor Deferral 1980- 1996Food Chain Controls • U.K. implemented measures to prevent entry BSE into human food chain by 1996 • SRM ban (brain, spinal cord, intestines, etc.) • ban on mechanically recovered meat from vertebral columns • over-30-months scheme From “BSE in Great Britain: A Progress Report,” DEFRA June 2001 http://www.defra.gov.uk/animalh/bse/index.html

8. Cases of BSE by year of report - U.K. Through June 30, 2001 - The Declining Epidemic and Effectiveness U.K. Measures Year BSE cases (a) 442 (all cases prior to becoming notifiable) 1988 2469 1989 7137 1990 14,181 1991 25,032 1992 36,682 1993 34,370 1994 23,945 1995 14,302 1996 8,016 1997 4,312 1998 3,179 1999 2,274 2000 1354 2001* 311 Total 178,006 From “BSE in Great Britain: A Progress Report,” DEFRA June 2001 http://www.defra.gov.uk/animalh/bse/index.html

9. Non-European BSE First case documented September 2001in Japan - Confirmed in U.K. - USDA import ban announced 9/2001 MBM from U.K. shipped to many non-European countries, now also at risk for BSE - Need to assimilate current deferrals - Future consideration additional deferrals - Emphasizes importance food chain controls

10. FDA Draft Guidance: Donor Deferrals Phase IIImplementation 10/31/02 Deferral Blood donors who have lived in Europe > 5 years 1980 - present Donors of Source Plasma for plasma derivatives remain eligible

11. Source Plasma • Model TSE agents partitioned/removed during plasma fractionation • European risk of vCJD low (small BSE epidemic relative to U.K.) • Magnitude of risk reduction achieved by fractionation at a minimum, 2 logs greater than that achievable by donor deferral • Effects on nationwide/worldwide plasma supplies uncertain, but potentially severe

12. Source Plasma • Source vs. recovered plasma- differentiated to prevent potential errors in use of deferred non-plasma components • Recommendation will be reevaluated in light of additional epidemiologic evidence, transmission studies, and advances in validation of removal TSE agents by manufacturing

13. Effects of New Donor Deferrals Upon Supply of Blood/blood components • FDA- recommended deferrals: 5% of donors deferred (REDS study) • greater proportion in coastal cities • 35% of NYBC supply affected (Euroblood + U.S. deferrals) • Industry-proposed deferrals (3 months U.K.; 6 months Europe): 3% donors deferred (industry study); 9 % donors deferred (REDS study)

14. TSEAC Proposal Concerning Implementation of New Donor Deferrals, that “a national recruitment campaign and a system to monitor adequate blood supply,” be instituted

15. Current Efforts to Attenuate Effect of New Donor Deferrals on Blood Supply • Phased-in deferrals, particularly European deferral (least risk - least BSE exposure) • Recommending Pilot studies for more stringent deferrals • pilot program - donor recruitment, evaluation donor loss, endpoints for pilot • monitor recruitment efforts, fluctuations in hospital demand

16. Current Efforts to Attenuate Effect of New Donor Deferrals on Blood Supply • National monitoring of blood supply, demand in place • Encouragement of donor recruitment • Encouraged cooperation among blood providers to supply in case of regional shortages

17. Draft Guidance - Future • Collection and evaluation comments to the docket (period extended through October 28, 2001) • Issuance of final guidance, with revisions • Monitoring of blood supply as recommendations effected • Continued assessment blood and plasma risk/benefit of donor deferrals

18. TSEAC-Recommended Donor Deferrals – Risk Reduction Current Risk reduced 72 % (Total Risk Reduced 91%)