1. Summary of Proceedings: FDA Transmissible Spongiform Encephalopathies Advisory Committee 17 th Meeting 08 February 2005 FDA Blood Products Advisory Committee 82nd Meeting 17 March 2005 Gaithersburg MD David M. Asher, MD Laboratory of Bacterial, Parasitic and Unconventional Agents Division of Emerging & Transfusion-Transmitted Diseases Office of Blood Research & Review Center for Biologics Evaluation & Research US Food & Drug Administration

3.  Worldwide BSE update (Lisa Ferguson, APHIS, USDA )  UK notifications of recipients plasma derivatives re possible vCJD risk (Kate Soldan, Anna Molesworth, UK CJD Incidents Panel) [TSEs and surgical instrument decontamination (Lynn Sehulster, CDC) ] Developing a risk assessment model and initial risk estimates for exposure to agent of variant Creutzfeldt-Jakob disease (vCJD) via investigational use of UK factor XI in USA (Mark Weinstein, Dorothy Scott, Steven Anderson, FDA) Developing risk assessment models for exposure to vCJD agent via other coagulation factors (Steven Anderson, FDA)  vCJD in France (Jean-Philippe Brandel, EpidemioSurveillanceNetwork, Paris [presented in absentia and revised by Pedro Piccardo and Steven Anderson, FDA]) and UK (Sheila Bird, MRC Biostat Unit, Inst of Public Health, Cambridge) Possible deferral of blood and plasma donors with history of prior transfusion in European countries besides UK (Alan Williams, FDA  ---------------------------------------------------------------- = Decisional issues

5. Cases of BSE Registered in Great Britain through 1999 (DEFRA)

7. 23 Countries with BSE in Native Cattle [yr first reported & approx. total cases reported to OIE thro’ 28 Feb 2005] l UK 1986 (>183 000) [1202 ‘01; 1144 ’02; 612 ’03; 338 ’04] l Ireland 1989 (1489) l Switzerland 1990 (519) l France 1991 (945) l Portugal 1994 (950) l Belgium 1997 (129) l Netherlands 1997 (77) l Luxembourg 1997 (2) l Liechtenstein 1998 (2) l Denmark 2000 (13) l Germany 2000 (357) l Spain 2000 (519) l Italy 2000 (124) l Greece 2001 (1) l Czech Repub 2001 (15) l Slovakia 2001 (15) l Japan 2001 (15) l Slovenia 2001 (5) l Finland 2001 (1) l Austria 2001 (1) l Poland 2002 (22) l Israel 2002 (1) l Canada 2003 (1 ex UK+4)  [USA 2003 (1 ex Canada) ]

8. Total Reported UK Exports of MBM 1986 –1995 ( unconfirmed review by UK authorities of export records) No data 0 - < 5 5 - < 10 10 - < 20 20 - < 100 100 - < 1.000 1.000 - < 10.000 > 10.000 Legend: (in tonnes)

10. Unique Pathology of vCJD (Chazot G & al. Lancet 1996;347:1181. Will RG & al. Lancet 1996:347:921-5. Hill AF & al. Lancet 1999;353:183-9)

11. Variant CJD: Reasons for Greater FDA Concern about Potential Infectivity of Blood Lymphoid tissues of patients with vCJD contain much more protease-resistant prion protein than do those of patients with conventional forms of CJD. Infectivity of those tissues is not yet clear. (Note: Lymphoid tissues of some patients with conventional sporadic CJD [sCJD] have been infectious for non-human primates [ Brown P et al. Ann Neurol 1994;35:513 ].)  Implication: Blood, containing lymphoid cells, might be more infectious in vCJD than in classical forms of CJD. vCJD differs markedly from sCJD; distribution of infectivity in patients with sCJD might not be predictive for vCJD. vCJD is a new emerging disease not found in the USA except in one long-time UK resident. Actions of UK authorities implied lack of confidence in safety of blood of UK donors.  ----------------------------------------------------------------------------  Two cases of probable TT vCJD

12. Final Guidance for Industry: Revised Precautionary Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) & Variant Creutzfeldt- Jakob Disease (vCJD) by Blood and Blood Products Jan 9, 2002 www.fda.gov/cber/guidelines.htm Phase I (for implementation by May 31, 2002)  Indefinitely defer all donors who  have any form of CJD or are at increased risk of CJD  (no change from previous FDA guidance)  spent  3 mo in UK from Jan 1, 1980 to Dec 31, 1996  or who ever had blood transfusion in UK from 1980 to present  or who ever injected UK bovine insulin prepared in or after 1980  spent  5 yr in France from Jan 1, 1980 to the present  spent  6 mo on US military bases from Jan 1, 1980 to end of 1990 north of Alps or end of 1996 south of Alps

13. Final Guidance for Industry: Revised Precautionary Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) & Variant Creutzfeldt- Jakob Disease (vCJD) by Blood and Blood Products Jan 9, 2002 www.fda.gov/cber/guidelines.htm Phase II (for implementation by October 31, 2002)  Indefinitely defer all donors of Whole Blood but not donors of Source Plasma who spent  5 yr in Europe from Jan 1, 1980 to the present (including time in spent in UK 1980- 1996 and France 1980-present)  Exempt from deferral are  Donors of Source Plasma who spent any period of time in Europe except UK and France  Donors of plasma/serum to manufacture CBER- approved non-injectable products (specially labeled)

14. 170 Cases of vCJD Worldwide (end Feb 2005) UK154 France 9 Republic of Ireland 2 Italy 1 USA 1 Canada 1 Saudi Arabia 1 Japan 1 -------------------------------------------------------------  Six cases of vCJD in France (6) and 1 in Italy had no history of travel to UK. Nine others were current or former UK residents/visitors. Case from Japan spent <1 mo in UK (? 24 da) during BSE-high-risk period (1989).

15. Variant CJD in UK each Year since 1994 (from Will RG, unpublished Oct 2003) New Cases Deaths

16. Nine cases of vCJD in France 1994-2004 (Epidemiological data from J-P Brandel ) Onsets Deaths

17. 1 st Transfusion-Transmitted Case of vCJD (UK Parliament 17 Dec 2003; CA Llewelyn & al. Lancet 2004;363:417-421) March 1996 Clinically healthy young blood donor donated Whole Blood to the UK National Blood Service. RBC—not leukoreduced—transfused into 63 yr-old surgical patient. About March 1999 Three yr later, donor developed signs of variant CJD, died; vCJD was confirmed by autopsy. UK Transfusion Medicine Epidemiology Review (TMER) enrolled recipient (with 49 other recipients of vCJD-implicated labile blood components from 16 donors later Dx with vCJD—13 now living >5yr). December 2003 The recipient died age 69; post-mortem diagnosis was typical vCJD (PRNP-129-met/met homozygous). The recipient's age-adjusted food-borne risk of vCJD estimated by UK authorities to have been ~ 1:15,000 to 1:30,000.

18. 2 nd Transfusion-Transmitted Case of vCJD (Peden AH & al. Lancet 2004;264:527-529) 1999 Clinically healthy young blood donor donated Whole Blood to the UK National Blood Service. RBC—not leukoreduced—transfused into a surgical patient. 2000 Donor developed signs of variant CJD 18 mo later, died in 2001; vCJD confirmed by autopsy. UK Transfusion Medicine Epidemiology Review (TMER) enrolled recipient (with 49 other recipients of vCJD-implicated labile blood components from 16 donors later Dx with vCJD—13 now living >5yr). 2003 The recipient died of ruptured abdominal aortic aneurysm. No history of dementia and CNS, tonsils and appendix were normal. PrP sc was present in several areas of spleen, cervical lymph node. The recipient's age-adjusted food-borne risk of vCJD was estimated by UK authorities to have been ~ 1:15,000 to 1:30,000. Recipient’s genotype was PRNP 129-met/val heterozygous).

19. General Approaches to Assessing Risk FDA is committed to risk-based regulatory decision making. ----------------------------------------------------------- Recent Example: TSEAC Meeting 08 February 2005 ----------------------------------------------------------- TSE Risk Assessment for Plasma Derivatives Steven Anderson, PhD, MPP Office of Biostatistics & Epidemiology Center for Biologics Evaluation and Research U.S. Food and Drug Administration -----------------------------------------------------------

20. Risk of Product Contamination Source of raw materials Animal: low-risk origin, low-risk tissue  Certificate  Test for contaminant or Dx (better ones needed) Human: low-risk population  Donor or surrogate questionnaire  Donor screening test (needed) Manufacturing process Eliminate contaminating agent (validate method)  Inactivation  Removal Prevent cross contamination (“downstream” contamination)  Cleaning  Disinfection End use of product Route Dose (course, year, lifetime)

21.  Percentage pool used in production  Log 10 reduction ID 50 during processing  ivID 50 per unit FXI  ivID 50 per vial  Scenarios: include a pre- and post-surgery dose 20 – 50 u/kg SOURCE vCJD ID 50 plasma pool PROCESS Reduction by manufacture USE Dose per surgery InputModuleOutput  ID 50 in FXI post- processing  Yield FXI plasma pool  Total ID 50 per vial  Exposure estimate vCJD iv ID 50  Exposure estimates 3 scenarios Total i.c. ID 50 per vCJD donation  Total i.v. ID 50 per plasma pool of 20,000 donations  Probability vCJD in UK  Number vCJD donations per pool  ID 50 per ml plasma Factor XI Risk Assessment Exposure Assessment Overview

22. UK vCJD prevalence affects the number of possible vCJD donations per plasma pool to manufacture Factor XI. Prevalence of vCJD in UK Population Cases per million (epidemiological survey, ? worst-case data) Mean95% confidence interval 23749 to 692 Triangular distribution Parameters Mean Range UK Plasma pool Number of vCJD donations per 20,000 donations ~ 5 Most likely = 2 0 to 14 Prevalence x 2x10 4 10 6 1 50

23. UK FXI vCJD Exposure Assessment: Possible vCJD infectivity in UK plasma pool Quantity of vCJD ID 50 present per ml plasma  Intracerebral (ic) ID 50 per ml blood (animal ID 50 ) – Minimum 0.1 – Most likely 10 – Maximum 1,000  Assume 58% associated with plasma (Gregori, et al. 2004)  Adjust down 5-fold to 10-fold for reduced efficiency of intravenous (iv) vs ic route of exposure

24. FXI vCJD Exposure Assessment Reduction during manufacturing PROCESS AssumptionMinimumMost Likely Maximum Log 10 reduction vCJD agent infectivity 02.04.0 Log 10 reduction ID 50 during plasma processing Reduction based on processing steps Variability in processing and reductions achieved

25. Results of FXI Risk Assessment Model: Exposure to vCJD iv ID 50 (no conclusion about relationship between exposure and infection) Scenario Quantity of factor XI utilized Mean vCJD iv ID 50 5 th percentile 95 th percentile A single unit FXI 1 u2 x 10 -5 6.8 x 10 -7 7.0 x 10 -5 One vial FXI 1,000 u 2 x 10 -2 6.8 x 10 -4 7.0 x 10 -2 Scenario 1: 1 treatment 60 kg person 3,000 u 6 x 10 -2 2.1 x 10 -3 0.21 Scenario 2: 3 treatments 60 kg person 9,000 u 0.176.2 x 10 -3 0.6 Scenario 3: >3 treatments 60 kg person 15,000 u 0.28 1.0 x 10 -2 1.0

26. Exposure Risks Advantages of quantitative models 1.Transparent: assumptions articulated and available for modification 2.Data gaps: identified 3.Sensitivity Analysis (Importance Analysis): Most important elements “driving” overall risk identified, even without agreement on assumptions

27. vCJD DATA GAP: PREVALENCE Epidemiological Models Predicting the Size of the UK vCJD Epidemic (from R Will, thro Oct 2003) (Cousens)(Ghani) (d’Aignaux)(Valleron)(Boelle) (75) (80,000) (29) (13.7 million) (52) (6.1 million) (63) (136,000) (200) (3,000) (205)(183) (416)

28. PrP sc in Appendix, Tonsils: Association with vCJD (Hilton DA et al. Brit Med J 2002; 325: 633-634, J Pathol 2004;203:733-739) Estimated UK prevalence of abnormal PrP in lymphoid tissues 1 st survey: ~120/million (95% CI 0.5 – 900/million) 2 nd survey: ~237/million (95% CI 49-692/million) *1 yr, 2 yr,10 yr (neg) before onset of symptoms; 3 yr, 4 yr, 11 yr (neg) before death Postmortem vCJD19/20 Preclinical vCJD2/3 1 st Surgical Survey1/8318 2 nd Surgical Survey3/12,674

29. vCJD Data Gaps: Incubation periods, duration of blood infectivity, amounts infectivity in blood, human ivID50) Incubation  Food-borne cases US 9-21 yr Canada 11-19 yr Japan 12 yr [Ireland 5-10 yr]  Blood-borne cases First case 6 yr Second case > 5 yr  Blood infectivity before clinical vCJD:  3 yr

30. Sensitivity Analysis: Risk Drivers Estimates of FXI vCJD Exposure Risk Two major factors influenced FXI vCJD risk: 1.Number of vCJD donations per plasma pool  Risk reduction measure=donor deferrals 2.Reduction of vCJD agent during manufacture  Robustness (inactivation>removal)  Orthogonality (≥two processes preferred)  Additivity of process steps (must justify)  Validity (and relevance) of experimental data

31. Recipients surviving >5 yrs post transfusion of blood components from vCJD/CJD Donors (data from UK TMER and US ARC look-back studies [R Dodd], presented by S. Anderson, FDA TSEAC 14 Oct 2004) Fisher's Exact Test comparing rates of infection after transfusions from vCJD and CJD donors suggests a statistically significant difference between the two groups (  1.2% likelihood of difference by chance). Conclusion: Risk of TT CJD is less than TT vCJD. Infection No Infection vCJD 213 CJD 0116

32. Policies to Reduce Risk of Transmitting vCJD by Blood Products by Donor Selection: General Approaches Reduce risk that donor was exposed to BSE agent  Dietary exposure: Lived in BSE country (or military base importing beef from UK) =“geographic” deferrals  Other exposure: Use of UK bovine insulin Reduce risk that donor was exposed to vCJD agent of human origin  Transfusion, UK after 1980  [Transfusion, other BSE country—especially France]  [Surgery in BSE country after 1980: suggested by TSEAC member (not addressed by FDA or TSEAC)]

33. Estimated vCJD Blood Risk Reduction and Donor Loss from Possible Enhanced Deferral Policies (from A Williams, FDA, TSEAC 14 Oct 2004) Reduced Risk (in add’n to current 91%) Donor Loss (in add’n to current 6.4%) UK 3 mo (’80-96)  to 1 mo 4%3% Transfusion in France (’80-now) Uncertain but very small 1.4/10,000 Transfusion in Non-UK W Eu (’80-now) Uncertain but very small (Problem: EuroBlood) 3/10,000

34. TSEAC Advice to FDA 14 October 2004 1.Are measures currently recommended by FDA to reduce the risk of transmitting CJD and vCJD by blood products still justified?  Yes 14, No 0 2.Do recent scientific data on vCJD warrant consideration by FDA of any additional potentially risk-reducing measures for blood and blood products?  Yes 1, No 13 3.If so, please comment on the additional risk-reducing measures that FDA should consider at this time. [Investigate vCJD cases outside UK for ? exposure to blood. Consider deferral of donors transfused in non-UK BSE countries.]

35. TSEAC Advice to FDA 08 February 2005 1.Should FDA recommend deferral of Whole Blood donors transfused after the beginning of 1980? In France Yes 12, No 3, Abstain 1 Other W EuropeYes 0, No 15, Abstain 1 2.Should FDA recommend deferral of Source Plasma donors transfused in/after 1980? In France Yes 5, No 7, Abstain 4 Other W EuropeYes 0, No 16, Abstain 0

36. Limitation of deferral-based approaches to reduce the risk of blood-borne vCJD Problem  Many (? most) deferred donors are probably not infected with a TSE agent (needlessly deferred and alarmed). Possible solutions  Develop validated and reliable screening tests to detect infected donors and re-enter/reassure uninfected donors.  Develop validated and reliable methods to remove (inactivate or separate) infectious TSE agents from products. Current status  No FDA-licensed/approved TSE test (for diagnosis or donor screening)  No FDA-licensed method validated to remove TSE infectivity from red cells, platelets and plasma