1. FDA Blood Products Advisory Committee Meeting 03 August 2011 Gaithersburg MD Summary of Transmissible Spongiform Advisory Committee Meeting 01 August 2011 Issue Donor Deferral/Ineligibility for Time Spent in Saudi Arabia to Reduce Risk of vCJD Transmitted by Blood and Blood Products and by Human Cells, Tissues and Cellular and Tissue-Based Products (HCT/Ps) David M. Asher Laboratory of Bacterial & TSE Agents Division of Emerging & Transfusion-Transmitted Diseases Office of Blood Research & Review Center for Biologics Evaluation & Research US Food & Drug Administration

2. 2 Acknowledgements CBER Steven Anderson OBE Bryan Emery OM Jay Epstein OBRR Joe Giglio OBRR Melissa Greenwald OCTGT Luisa Gregori OBRR Ginette Michaud OBRR Pedro Piccardo OBRR Martin Ruta OBRR Jennifer Scharpf OBRR Alan Williams OBRR Hong Yang OBE Judith Badoo OD Joan Blair OD Diane Maloney OD Other FDA Sousan Altae OC OIP Layla Batarseh OC OIP Burt Pritchett CVM TSEAC Frank Rentas DoD Mo Salmon CO State U Other Robert Will UK CJDSU Michael Coulthart HPA Canada Lawrence Schonberger CDC David Lincoln DoD Kingdom of Saudi Arabia  Food and Drug Authority

3. 3  FDA seeks advice from TSEAC on whether, based on three cases of vCJD in individuals likely to have been infected with the BSE agent in Saudi Arabia, to modify current vCJD-related safety recommendations deferring certain blood and plasma donors or finding certain donors of HCT/Ps ineligible to donate  for time spent in Saudi Arabia. Issue for TSEAC

4. 4 vCJD and blood safety Variant CJD: a human infection with BSE agent (= a “zoonosis”) Most vCJD infections food-borne Five vCJD infections in UK attributed to blood products Only one risk-reduction strategy available for blood components and HCT/Ps: reduce number of donors exposed to BSE agent = geographic donor deferral/ineligibility Donor testing not yet available Reliable infectivity removal techniques not yet available (except for plasma derivatives)

5. 5 vCJD and blood safety (2) Geographic donor deferrals reduce risk but non- specific, inefficient Donor deferral recommendations not fully effective, not completely consistent When persons in new countries are recognized to pose a potential vCJD risk, FDA believes it prudent to consider modifying FDA geographic BSE-related recommendations for suitability/eligibility.

6. 6 pdFVIII case Feed ban 4 transfusion infections 12/037/042/061/072/09 BSE vCJD BSE and vCJD deaths in UK

7. 7 Estimated incubation periods of vCJD Food-borne vCJD Estimated median of 12-13 yr for cases to date in persons with PRNP 129-MM genotype (~ 40% of normal UK population). Predicted median ?? 32 yr in persons with genotypes MV (~ 50% UK) and VV (~ 10% UK). Small numbers of cases predicted up to ? > 40 yr after exposure Transfusion-transmitted vCJD –1st case 6.3 yr –2nd case > 5 yr (PrPTSE-pos lymphoid tissues) –3rd case 7.8 yr –4th case 8.5 yr (same donor as 3rd case) Plasma-derivative associated case – ? 11 yr

8. Transfusion look-back studies: recipients surviving > 5 yr post transfusion of labile blood components from vCJD/sporadic CJD donors ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- All transfusion-transmitted vCJD infections reported to date were in UK recipients of non-leukoreduced RBC (cf. look-back studies: UK TMER; US ARC ) Conclusion: Transfusion-transmitted vCJD definite; transfusion-transmitted sporadic CJD not detected Disease (or infection) No Disease vCJD429 CJD0144 §

9. 9 How long before onset of clinical vCJD is blood infectious?  Intervals between blood donations and onset of vCJD case or infection for 3 implicated UK donors  to 4 infected recipients of non-leukoreduced packed RBC:  1.4, 1.5, 1.7, 3.5 years Conclusion: During the last 3.5 years of incubation period, blood of [some] clinically healthy PRNP-codon-129-MM donors who later developed vCJD is already infectious.

10. 10 vCJD attributed to infection in Saudi Arabia 3 vCJD cases in long-time residents of Saudi Arabia All had common vCJD PRNP-129 genotype (MM) No history of transfusion (2 had surgery) Presumably food-borne infection Dates of residence in Saudi Arabia for all 3 cases encompass plausible vCJD food-borne incubation periods. Other countries less likely places where infection might have acquired, though not impossible

11. 11 3 vCJD cases from the Kingdom of Saudi Arabia (KSA) Case 1Case 2Case 3 Birth yr, place (citizenship) 1970 KSA (KSA) 1983 KSA (Egypt) 1986 KSA (Bangladesh) Early years in KSA 271612 (1986-99) Other residencesUSA 1 yrUSADubai (UAE), Bangladesh, USA, Canada Travel UK, FranceUKUK, Europe Age at onset 3323 Residence at Dx KSAUSACanada Dxbrain bxadenoid/brain bxtonsil bx

12. 12 vCJD resembles other forms of CJD but is unique. normal brain sCJD cortical spongiform change vCJD florid plaquevCJD lymphoid PrP

13. 13 vCJD attributed to infection in Saudi Arabia (2) No vCJD case has been convincingly attributed to residence in any other country of the region. US (CDC) and Canadian (HPA/Health Canada ) authorities concluded that vCJD was most likely acquired in Saudi Arabia.  Before they became clinically ill, all 3 Saudi- associated vCJD cases would have been considered suitable/eligible to donate blood, plasma and HCT/Ps per current FDA recommendations. Three UK-associated cases in Dx in N America would have been deferred/ineligible.

14. 14 UK probably exported to Saudi Arabia products potentially contaminated with the BSE agent during the generally-accepted UK BSE-highest-risk period (1980-1996). ─Live cattle ─Beef products ─Meat-and-bone meal (MBM) Saudi Arabia has not recognized BSE in native cattle. BSE has been recognized rarely in two other countries in the Middle East. ─Oman: 2 bovines imported from UK in 1989 ─Israel: 1 native bovine in 2002 Estimating possible risk of dietary exposure to BSE agent in Saudi Arabia

15. 15 UK exports to other countries of the region 1980-1996 Exports to the region from other BSE countries Cross border trade in the region Risk that undetected indigenous BSE was established in bovines and (theoretically) in other ruminants in Saudi Arabia from Rendering practices and feeding of MBM to ruminants Estimating possible risk of dietary exposure to BSE agent in Saudi Arabia (2) _________________________________________________ Uncertain but possibly relevant BSE risks

16. 16 vCJD cases per estimated population 2011 Country vCJD cases a Estimated population 2011 b Crude rate c UK17562,688,0002.8 x 10 -6 Ireland24,671,0004.3 x 10 -7 France2465,103,0003.7 x 10 -7 Portugal210,760,0001.9 x 10 -7 Netherlands316,847,0001.8 x 10 -7 Spain546,755,0001.1 x 10 -7 Saudi Arabia326,132,0001.1 x 10 -7 Italy261,017,0003.3 x 10 -8 Japan1126,476,0007.9 x 10 -9 [a] Cases resident in UK  6 mo attributed to UK. [b] US Census Bureau estimates mid-2011 [c] Not corrected for population age distribution or efficiency of case recognition/reporting.

17. 17 UK Exports of Bovine Carcass Meat 1978 – 1998 (M. Ricketts/WHO Presentation to TSEAC 17 Jan 2002 http://www.fda.gov/OHRMS/DOCKETS/ac/02/slides/3834s1.htm) http://www.fda.gov/OHRMS/DOCKETS/ac/02/slides/3834s1.htm No data 0 - < 5 5 - < 10 10 - < 20 20 - < 100 100 - < 1.000 1.000 - < 10.000 > 10.000 Legend: (in tonnes)

18. 18 Total UK Exports of MBM 1988 – 1993 (M. Ricketts/WHO Presentation to TSEAC 17 Jan 2002 http://www.fda.gov/OHRMS/DOCKETS/ac/02/slides/3834s1.htm ) http://www.fda.gov/OHRMS/DOCKETS/ac/02/slides/3834s1.htm No data 0 - < 5 5 - < 10 10 - < 20 20 - < 100 100 - < 1.000 1.000 - < 10.000 > 10.000 Legend: (in tonnes)

19. 19 Estimating possible risk of dietary exposure to BSE agent in Saudi Arabia. _____________ Meat imports from the UK (1980–1996) Sanchez-Juan P et al. Source of variant Creutzfeldt-Jakob disease outside United Kingdom. Emerg Infect Dis 2007;13:1166-9 

20. 20 FDA Considerations Regarding Saudi vCJD Cases Crude rate of total vCJD cases for Saudi Arabia not greatly different from rates for several European countries Overall risk for dietary exposure to BSE agent by the Saudi Arabian population as a whole, based on public information, less than that in UK Since 1999, FDA used model to estimate risk of dietary exposure to BSE agent in various countries as % of risk in UK (risk in UK 1980-1996 taken to be 100%) FDA adjusts recommended geographic deferrals taking into consideration risk relative to UK risk. Caveat. Underlying information is highly uncertain.

21. 21 FDA previously recommended BSE-related deferral of certain blood donors based on estimated geographic risk relative to UK risk 1980-1996 Main BSE risk of concern: eating UK beef Donor dietary histories not reliable Proxy for history of beef consumption: time donor spent in BSE risk country Assumption: dietary risk is stochastic, directly related to time spent in BSE country of concern Relative to UK 1980-1996 = 1.00 ─France = 0.05 ─Switzerland = 0.015 ─Other Western European countries = Switzerland ─US military bases in Europe = 0.35

22. 22 Estimating risk of exposure to BSE agent in Saudi Arabia 1980-1996 What might be a reasonable BSE-exposure risk estimate relative to UK and period of concern for donors resident in Saudi Arabia? Saudi populations of concern 1980-1996 1.US military (very few US military dependents lived in Saudi Arabia) 2.US military contract workers and dependents 3.Non-military contract workers and dependents 4.Saudi nationals

23. 23 FDA current considerations regarding possible additional deferrals/ineligibility criteria for certain blood and HCT/P donors resident in Saudi Arabia 1990-1996. 1. US Military  US military in Saudi Arabia FDA assumes that the risk of dietary exposure to the BSE agent on Saudi bases was similar to the risk on US military bases in Europe South of the Alps = 35% UK risk 1980-1996.  DoD recently estimated that actual procurements of UK beef might have been somewhat less than on European bases.

24. 24 FDA current considerations regarding possible additional deferrals/ineligibility criteria for certain blood and HCT/P donors resident in Saudi Arabia 1990-1996. 1. US Military (2) US military in Saudi Arabia 1980-1996  FDA currently recommends deferral/ineligibility for donors of blood Source Plasma and HCT/Ps US military and dependents who spent  6 mo on bases South of the Alps 1980-1996. New FDA consideration  Recommend similar suitability criteria for donors who served as US military personnel resident on Saudi bases 1980-1996

25. 25 2. Other residents of Saudi Arabia. Military and Non-military Contractors and Saudi Nationals FDA assumes that BSE exposure risk of all contract workers is similar to that for the general Saudi population, because they all purchased food from local (non-US-military) establishments.  Caveat: Diets and medical care of contractors might not have been the same as that of the general Saudi population, possibly resulting in ─? Greater consumption of all beef and UK beef ─? Greater likelihood of diagnosing vCJD

26. 26 2. Other Residents of Saudi Arabia. Saudi Nationals (2)  Dietary risk of BSE exposure by Saudi nationals was probably much lower than the risk for the UK population 1980-1996: UK export/Saudi import records suggest only ~ 10% of Saudi beef imported from UK Average per-capita beef consumption in Saudi Arabia ~ 25% UK Total estimated Saudi dietary BSE exposure risk  ~ 2.5% UK risk

27. 27 2. Other Residents of Saudi Arabia (3) Military and Non-military Contractors and Saudi Nationals FDA assumes that risk of dietary exposure to UK beef by contract workers and Saudi nationals was similar to risk in non-UK Western European countries during years 1980-1996. Non-UK countries of Western Europe with highest vCJD risk: France (and Ireland). A prudent precautionary assumption is that the risk in Saudi Arabia is unlikely to exceed the risk in France. FDA assumes that BSE-exposure risk in Saudi Arabia, unlike France (which has had BSE in native bovines), is attributable almost entirely to imports of UK beef products, so that risk became negligible after the end of 1996.

28. 28 2. Other Residents of Saudi Arabia (4) FDA currently recommends deferral/ineligibility for all donors of blood, Source Plasma and HCT/Ps who spent  5 yr in France (as well as for donors with history of transfusion in France) from 1980 to the present time. New FDA consideration for non-US-military residents of Saudi Arabia  Recommend suitability/eligibility criteria for any donor of Whole Blood, Source Plasma or HCT/Ps who spent cumulative 5 years or longer in Saudi Arabia during the years 1980-1996 (similar to recommendations for residents of France but not extending to the present time and not including deferral for history of transfusion)

29. 29 Geographic vCJD-related Blood Donor Deferrals in US and Canada US FDA a Canadian Blood Services Héma-Québec UK  3 mo 1980-96  1 mo 1980-96 France  5 yr 1980-present  5 yr 1980-present  3 mo  1980-present Other Western Europe (WE)  5 yr 1980-present  28 countries  5 yr 1980-present 12 countries  6 mo 1980-present 12 countries Hx of transfusion UK, France 1980-present UK, France, WE 1980-present Saudi Arabia no deferral  6 mo 1980-96 a FDA recommends deferral of personnel resident on US military bases in Europe: North of Alps 1980-1990; South of Alps 1980-1996.

30. 30 Estimated Loss (under most likely scenario) of US Blood Donors/Donations Expected from Deferrals for Residence in Saudi Arabia 1980-96 (Hong Yang/Steven Anderson OBE CBER FDA) US Military US Military Contractor s US Non- military Contractor s Immigrants SA to USTotal Population deferrable 420,000045,90024,800490,000 Blood donors lost 21,00002,3001,200 24,000 a Blood units lost 35,70003,9102,040 41,700 a Estimated total US blood donors 2008  11 million. Most likely loss from deferrals for donors in Saudi Arabia  0.2%

31. 31 Conclusions Three cases of vCJD are attributed to dietary exposures to BSE agent in Saudi Arabia 1980-1996. Under current FDA recommendations, those donors would have been suitable/eligible donors of blood, plasma and HCT/Ps. Crude prevalence of vCJD cases in Saudi Arabia is not markedly less than those in several European countries. The most likely source of dietary exposure to the BSE agent in Saudi Arabia was imported UK beef.

32. 32 Conclusions (2) UK beef exports to Saudi Arabia ceased by the end of 1996. FDA acknowledges a theoretical possibility that Saudi Arabia might have imported BSE-contaminated products from other countries after 1996 or introduced BSE into its own cattle herds; those are less likely sources of exposure.

33. 33 Conclusions (3) The US military procured an unknown but possibly significant amount of beef from the UK in 1980-1996 for bases in Saudi Arabia. FDA considers a plausible worst-case assumption that the amount of UK beef consumed by US military in Saudi Arabia 1980-1996 might have been similar to that on European US military bases South of the Alps 1980-1996. FDA assigned a geographical BSE risk of 35% UK risk 1980-1996 to European US military bases South of the Alps during the same years.

34. 34 Conclusions (4) FDA currently recommends deferral/ineligibility for donors of blood, Source Plasma and HCT/Ps who served in the US military and for their dependents who spent  6 mo on bases South of the Alps 1980-1996. FDA is considering a recommendation to defer/consider ineligible donors who served as for  6 mo on US military bases in Saudi Arabia 1980-1996.

35. 35 Conclusions (5) At least 10% beef consumed by Saudi nationals living in Saudi Arabia 1980-1996 might have been imported from the UK. Estimated per-capita beef consumption in Saudi Arabia appears to be less than that in UK (~25%). FDA has tentatively assigned to Saudi Arabia a risk of dietary exposure to the BSE agent 1980- 1996 = 2.5% that in the UK. Contractors bought beef products in the same establishments as did Saudi nationals.

36. 36 Conclusions (6) FDA considers all contractors to have had the same potential risk of dietary exposure to BSE agent in Saudi Arabia 1980-1996 as did Saudi nationals. Considering current estimates of crude prevalence of vCJD in Saudi Arabia compared with European countries, FDA considers it prudent to assume, as a realistic worst case, that true prevalence of vCJD in Saudi Arabia is unlikely to exceed that in France. FDA believes that opportunities for dietary exposure to BSE agent in Saudi Arabia—unlike France— became negligible after the end of 1996.

37. 37 Conclusions (7) FDA currently recommends deferral/ineligibility for all donors of blood, Source Plasma and HCT/Ps who spent  5 yr in France 1980 to present FDA is considering a similar recommendation to defer/consider ineligible donors of Whole Blood, Source Plasma and HCT/Ps who spent a cumulative period of 5 yr or longer in Saudi Arabia 1980-1996. FDA estimates that the likely number of additional otherwise suitable blood donors who would be deferred under the new recommendations would be relatively small (perhaps 0.2% of current donors).

38. 38 TSEAC Voted 1. Do available data support consideration by FDA [because of analogy to risks in Western Europe ] to recommend deferring donors of blood and blood components, including Source Plasma, and to be ineligible donors of HCT/Ps who QuestionYesNoAbstain 1(a) spent  6 mo as US military on KSA bases 1980-96? or 1240 1(b) otherwise lived in KSA 1980-96? 1510

39. 39 TSEAC comments on Question 1 More donors of Source Plasma might be deferred than donors of blood—should be estimated. Since no cases of vCJD have been observed among more than 5 million former military who lived on bases in Europe and Saudi Arabia 1980-1996, the risk of BSE exposure has probably been overestimated. US military procurement carefully excluded “specified risk materials” from imported UK beef, probably lowering dietary risk.

40. 40 Questions for TSEAC (2) 2.Please discuss the likely contribution of those recommendations to the safety of the products involved and the possible impact on supplies of blood, blood components, plasma derivatives and HCT/Ps. Members commented: Most risk is from inapparent infections in donors with less susceptible genotypes (PRNP-129 MV and VV). Concern about lack of reliable data Concern about many other countries that probably imported BSE-contaminated products but have questionable surveillance for BSE, vCJD. Donors resident in those countries are considered suitable.

41. 41 Questions for TSEAC (3) 3.Please comment on additional information that might better inform FDA’s consideration of the proposed or any further safety measures. Members commented: There should now be sufficient empirical information (vCJD cases recognized in various risk groups) to revisit deferral/eligibility criteria and stop basing policy decisions on risk models where reliable observational data are available. Continued and improved TSE disease surveillance efforts are important. Risk-benefit of donor deferrals/eligibility criteria should be reevaluated. Rapid testing for PrP TSE in brain tissues from cadaveric cell/tissue donors should be encouraged.