1. FDA Blood Products Advisory Committee 95 th Meeting 21 July 2009 Update: 21 st Meeting FDA Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC) 12 June 2009 Recent Events Related to TSEs: Implications for Safety of Human Blood, Blood Components and Plasma Derivatives David M. Asher, MD Laboratory of Bacterial, Parasitic & Unconventional Agents Division of Emerging & Transfusion-Transmitted Diseases Office of Blood Research & Review Center for Biologics Evaluation & Research US Food & Drug Administration

2. 2 vCJD abnormal prion protein found in a patient with haemophilia at post mortem News vCJD abnormal prion protein found in a patient with haemophilia at post mortem 17 February 2009 Evidence of infection with the agent (abnormal prion protein) that causes variant Creutzfeldt-Jakob Disease (vCJD) has been found at post mortem in the spleen of a person with haemophilia. The patient, who was over 70 years old, died of a condition unrelated to vCJD and had shown no symptoms of vCJD or any other neurological condition prior to his death. The vCJD abnormal prion protein was only identified during post mortem research tests. UK Health Protection Agency 17 February 2009 http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1234859690542?p=1231252394302 see also HPA publication 09 June 2009 http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_100357 www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1234859690542?p=1231252394302www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_100357  CJD abnormal protein found in a patient with haemophilia at post mortem  “Evidence of infection with the agent (abnormal prion protein) that causes variant Creutzfeldt-Jakob disease (vCJD) has been found at post mortem in the spleen of a person with haemophilia [treated 11 yr earlier with UK “vCJD-implicated” pdFVIII].  The patient, who was over 70 years old, died of a condition unrelated to vCJD and had shown no symptoms of vCJD or any other neurological condition prior to his death. The vCJD abnormal protein was only identified during post mortem research tests. …  What was until now a theoretical risk may be an actual risk to certain individuals …”

3. 3 Bovine spongiform encephalopathy (BSE) ─ Accepted as source of food-borne vCJD ─ Recent worldwide trends show decline in reported cases ─ Uncertainties (some at-risk countries did not report cases) vCJD ─Recent trends  Declining cases in UK (PRNP-codon-129 MM clinical cases)  Possible “second wave” (PRNP-codon-129 VV, MV: ?1 st case)  Marked discrepancy in UK prevalence estimates from  lymphoid tissue survey of abnormal prion protein (PrP TSE ) vs  case-based projections ─Transfusion transmission (TT) of vCJD by RBC in UK  4 TT vCJD infections attributed to non-leukoreduced RBC  No new report of TT vCJD since 2007  Presumptive transmission of vCJD by UK plasma derivative: reason for TSEAC meeting

4. 4  TSEAC Meeting Agenda  Transmission by plasma derivative: implications for safety of US plasma derived factor VIII and von Willebrand factor. Review of modified FDA Risk Assessment (decisional issue) BSE worldwide: US, Canadian and European regulatory responses (informational) 3 research topics related to TSEs and blood safety (informational): ─Monkey model for BSE and vCJD infectivity in blood ─Efforts to develop antemortem tests for identifying subjects during TSE incubation period ─Problems in correlating abnormal prion protein and TSE agent infectivity

5. 5 FDA TSEAC 21 st Meeting Agenda 12 June 2009 Decisional Issue: Modified FDA Risk Assessment for Potential Exposure to vCJD Agent in US-licensed pdFVIII and vW factor 1. vCJD in UK, TMER. RG Will, UK CJD Surveillance Unit, Edinburgh 2. FDA vCJD geographic deferral guidance. A Williams, FDA CBER OBRR 3. Plasma derivatives, TSE agents and their clearance. D Scott, FDA CBER OBRR 4. Studies of TSE agent clearance by steps in the manufacture of plasma derivatives. A Gröner, (CSL Behring) PPTA 5. Modified FDA Risk Assessment for pdFVIII and von Willebrand factor. S Anderson, FDA CBER OBE Open public hearing TSEAC discussions Vote on questions

6. 6 FDA TSEAC 21 st Meeting Agenda 12 June 2009 Informational Presentations 1. US BSE surveillance, USDA and beef safety, OIE and BSE. JA Hughes, USDA APHIS 2. BSE in Europe. M Plantady, European Commission, Brussels 3. BSE in Canada. N Murray, Canadian Food Safety Inspection Agency, Ottawa 4. FDA BSE enhanced animal feed safety rule. B Pritchett, FDA CVM 5. FDA interim final food safety rule. A McGoig FDA CFSAN 6. FDA proposed BSE medical products rule. T Finn, FDA CBER OVRR 7. Primate model of BSE and vCJD infectivity in blood. E Comoy, Commissariat à l’Énergie Atomique, France 8. Progress in developing antemortem TSE detection tests. L Gregori, FDA CBER OBRR 9. PrP TSE and TSE infectivity. P Piccardo, FDA CBER OBRR Discussion, open public hearing

7. 7 Questions for TSEAC  Based on an updated risk assessment, FDA continues to believe that the risk of variant Creutzfeldt-Jakob disease (vCJD) to patients who receive US-licensed plasma-derived coagulation factor VIII (pdFVIII) products is likely to be extremely small, although we do not know the risk with certainty. 1.Does the Committee agree with the updated and new inputs to the FDA risk assessment model for US-licensed plasma-derived pdFVIII ?  Updated inputs a.Estimated prevalence of UK vCJD infections b.Age at time of infection c.Time during incubation period when infectivity is present in blood  New inputs d.Genotype at PRNP codon 129: genetic susceptibility to vCJD infection and genotype proportions in US population e.Distributions of vCJD incubation periods for persons of different PRNP-129 genotypes f.Age distribution of persons with asymptomatic vCJD infections

8. 8 Questions for TSEAC (continued) 2.Original question:  Despite the finding of minimal additional risk in FDA’s modified risk assessment, should the recent report from the UK Health Protection Agency, attributing a case of vCJD infection to treatment 11 years earlier with a “vCJD- implicated” pdFVIII, alter FDA’s interpretation of the risk for US-licensed preparations of pdFVIII?  Question modified during meeting: (responding to recent analysis concluding vCJD infection was much less likely from exposures to food, red blood cell transfusions or endoscopy but—considering probable prevalence of pre-clinical vCJD in UK plasma donors—at least as likely to have resulted from treatments with non-vCJD-implicated pdFVIII):  Despite the finding of minimal additional risk in FDA’s modified risk assessment, should the recent report from the UK Health Protection Agency, attributing a case of vCJD infection to treatment with UK-sourced pdFVIII, alter FDA’s interpretation of the risk for US-licensed preparations of pdFVIII?

9. 9 Questions for TSEAC (continued) 3.Based on the available information, should FDA consider: a.Recommending additional risk-reducing steps for manufacture of plasma derivatives (e.g., modifications to current donor deferral policies)? b.Recommending revised warning labels for plasma derivatives? c.Recommending modifications to FDA’s public communications (e.g., to Web postings) regarding the risk of vCJD associated with the use of FDA-licensed plasma derivatives?

10. 10 vCJD: 211 cases worldwide UK = 168 cases; non-UK = 43 cases (8 ? ex UK) modified from CJD Surveillance Unit, Edinburgh Feb 2009 UK168 France23 (1? ex UK) Spain5 Ireland4 (2 ? ex UK) Netherlands3 Italy1 Portugal2 USA3 (2 ex UK; 1 ex Saudi Arabia) Canada1 (ex UK) Japan1 (ex UK) Saudi Arabia1 (origin uncertain)

11. 11 BSE and vCJD deaths in UK Feed ban 4 transfusion infections reported pdFVIII case 12/037/042/061/072/09

12. Recipients surviving > 5 yr post transfusion of labile blood components from vCJD/CJD donors compared ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- All transfusion-transmitted vCJD infections reported to date were in UK recipients of non-leukoreduced RBC (data from UK TMER and US ARC look-back studies [S Anderson, FDA TSEAC presentations; Dorsey et al. Transfusion 2009;49:977-84]) 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% likelihood that the difference occurred by chance). Conclusion: Risk of TT CJD is much less than TT vCJD. Question: Is blood of persons with other CJD ever infectious? * 20 still alive (6 died > 5 yr post transfusion; not tested); § 68 recipients  5 yr pre-CJD-onset of donor Infection No Infection vCJD426 * CJD0144 §

13. 13 Possible or probable incubation periods of v CJD (from R Will’s prior estimates of time resident left UK or received vCJD- implicated component transfusion or plasma derivative) Food-borne cases – US 9-21 yr – Canada11-19 yr – Japan 12 yr  (? UK point exposure) – Ireland5-10 yr Transfusion-transmitted cases – 1st case6.3 yr – 2nd case>5 yr (PrPTSE-pos lymphoid tissues, ? vCJD) – 3rd case7.8 yr – 4th case8.5 yr (same donor as 3rd case) Plasma-derivative associated case 11 yr

14. 14 How long before onset of clinical vCJD is blood infectious?  Intervals between blood donations and onset of vCJD case or infection in 3 implicated UK donors (to 4 infected recipients of non-leukoreduced packed RBC):  3.5, 1.5, 1.7, 1.4 years Significance: During last 3.5 years of incubation period, blood of [some] clinically healthy PRNP-codon-129-MM donors who later developed vCJD already infectious Open questions: How much longer than 3.5 yr might blood of PRNP-codon-129-MM donors incubating vCJD be infectious? How much TSE infectivity present in blood at different stages of infection? Is blood of vCJD-infected donors with other PRNP-129 genotypes also infectious during pre-clinical illness? How long? How much infectivity? What is the prevalence of latent vCJD infection in UK, other countries?

15. 15 Risk Characterization: Importance Analysis (S. Anderson FDA 2006) Importance (“sensitivity”) analysis ranked factors influencing vCJD exposure for prevalences of 0.7 to 700 cases per million.

16. 16 PrP TSE in vCJD tonsils (Hill AF et al. Lancet 1999;353:183-189)  IHC PrP TSE IHC CD35 (follicular dendritic cells) PrP TSE detected (by IHC, WB) in all tonsils, spleens and lymph nodes tested from autopsies of vCJD but not in same tissues from other types of CJD or other diseases. (See also Clewly JP et al. BMJ 2009;338:b1442: 0/63,007 frozen tonsils confirmed PrP TSE -positive)

17. 17 PrP TSE in vCJD tonsils (Hill AF et al. Lancet 1999;353:183-189) PrPTSE detected (by IHC, WB) in all tonsils, spleens and lymph nodes tested from autopsies of vCJD but not in same tissues from other types of CJD or other diseases. (See also Clewly JP et al. BMJ 2009;338:b1442: 0/63,007 frozen tonsils confirmed PrPTSE-positive)

18. 18 PrP TSE in UK appendices: implications for prevalence of subclinical or preclinical vCJD infections UK survey, normal vCJD, 2 yr pre-onset PrP TSE in appendices of most vCJD cases at autopsy (Hilton DA & al. BMJ 2002;325:633-4) PrP TSE in appendices of 2 vCJD cases 8 mo, 2 yr (but not a case 10 yr) before onset ( Hilton DA & al. Lancet 1998;352:703-4 and BMJ 2002;325:633-4) PrP TSE in 3/12,674 appendices from persons without overt vCJD in UK (Hilton DA & al. J Pathol 2004;203:733-9) 2/2 PrP TSE -positive samples genotyped PRNP-129-VV  (Ironside JW & al. BMJ 2006;332:1186-8) PRNP-129-VV genotype not reported in UK vCJD case summaries

19. 19 PPTA: Prion Reduction Capacity pdFVIII - TSEAC 120609 19 Prion Reduction Factors of FVIII Products (modified from A. Gröner representing PPTA) Product Overall Reduction [log 10 ] (further steps currently not studied, may contribute to the overall reduction factor) Bioassay Immunochemical assay (PrP TSE ) A 8.1 B ≥ 9.1 C 5.5 D 5.96.4 E ongoing4.0 F 6.5

20. 20 Summary (modified from A. Gröner representing PPTA) Manufacturing processes of plasma-derived FVIII products remove prions  reduction factors of at least 4 log10 were demonstrated [for all US-licensed products] PPTA members are not using UK [or other European] plasma [for manufacturing US- licensed plasma-derivative products]  Appropriate donor deferral procedures in place PPTA: Prion Reduction Capacity pdFVIII - TSEAC 120609

21. 21 PPTA Conclusion (modified from A. Gröner representing PPTA) Recent report from UK Health Protection Agency regarding patient with haemophilia has no bearing on the safety profile of products manufactured by PPTA members. The implicated product 8Y sourced from UK plasma Public statement on low prion clearance capacity of 8Y product (UK “vCJD-implicated product [assessment by Det Norske Veritas 2003]) Industry continues to be committed to research. PPTA: Prion Reduction Capacity pdFVIII - TSEAC 120609

22. 22 FDA Assessment of Possible Risks for Plasma-derived Products in the US 12 June 2009 21st TSEAC Meeting Gaithersburg, MD Steve Anderson, PhD, MPP with Hong Yang, PhD Richard Forshee, PhD Mark Walderhaug, PhD Office of Biostatistics and Epidemiology FDA Center for Biologics Evaluation & Research

23. 23 Model of vCJD US Plasma Exposure Assessment INPUTMODULEOUTPUT Epidemiological modeling based on UK vCJD cases UK surveillance data Module 1 vCJD Prevalence UK LOWER estimate of UK vCJD case prevalence HIGHER estimate of UK vCJD infection prevalence Donor travel history UK, FR, other Europe Adjustments for duration & year traveled, donor age Screening questionnaire Module 2 vCJD Prevalence US Donors Number US vCJD donors Number vCJD donors post- screening Total number vCJD donations Plasma pool size Quantity vCJD agent in pool Reduction of vCJD agent during manufacture Module 3 FVIII Processing Percentage plasma pools / vials with vCJD agent Quantity vCJD agent per FVIII vial Annual dose Factor VIII Severity of disease & treatment regimen Module 4 Utilization FVIII  Annual exposure (DOSE) FVIII recipients to vCJD agent

24. 24 FDA has updated the pdFVIII-vCJD Risk Assessment from 2006 pdFVIII-vCJD Risk Assessment in 2009 incorporates new data suggesting susceptibility of entire population to vCJD infection and includes: Three UPDATED inputs (added to Modules 1 and 2 of model) 1. Estimation of UK vCJD prevalence (1) 2. UK vCJD ages at time of infection (1) 3. Time during incubation period when infectivity present in blood (2)  75% Three NEW inputs (added to Module 2 of model) 4. Genotype susceptibility and genotype proportion in population 5. Distribution of incubation periods 6. Age distribution of asymptomatic infections

25. 25 FDA vCJD Plasma-Derivative Risk Assessment: Scope and type of assessment Scope of FDA pdFVIII Risk Assessment Estimates potential vCJD risk for US pdFVIII recipients – Severe Hemophilia A – Severe von Willebrand disease (Type 3) Potential vCJD risk estimated for 1 yr treatment (2002) Analytic Approach Quantitative risk assessment (QRA) Input data usually statistical distributions Probabilistic computer-based model Monte Carlo methods

26. 26 Monte Carlo Analysis Example: estimate i.v. ID 50 per ml plasma Adjustment i.c. to i.v. Distribution i.v. ID 50 per ml plasma Percent ID 50 in plasma Mean = 5.2 i.v. ID 50 2 10 30 0.1 1.0 58% i.c. ID 50 per ml blood x x Perform Multiplication 10,000 times Result of 10,000 iterations (5 th ) (95 th )

27. 27 Exposure Assessment: Module 1 Prevalence of vCJD in United Kingdom A. Epidemiological modeling vCJD cases (LOWER estimate) from Clarke and Ghani 2005 FDA modeling estimated a vCJD prevalence of: ~1.8 per million UK population (2006) ~4.5 per million UK population (2009) B. Tonsil/appendix tissue surveillance in UK patients (HIGHER estimate) Hilton et al. 2004 3 PrP TSE -positive samples in UK 12,674 samples tested by immunohistochemistry Mean of 1 positive in 4,225 individuals, or 237 per million GOAL: Estimate UK prevalence; use to estimate vCJD prevalence for France, other W Europe, US military bases in Europe  plasma donors in US

28. 28 Updated FDA vCJD-pdFVIII Risk Assessment of 2009: UPDATED model inputs Estimation of UK vCJD prevalence FDA Model: December 2006FDA Updated Model: June 2009 1) LOWER Case Prevalence estimate ~1.8 per million* * Based on Clarke and Ghani (2005) 1) LOWER Case Prevalence estimate ~4.5 per million* * Based on Clarke and Ghani (2005) 2) HIGHER Infection Prevalence estimate ~ 1 in 4,225* * Based on Hilton et al (2004) 2) HIGHER Infection Prevalence estimate ~ 1 in 4,225* * Based on Hilton et al (2004)

29. 29 Exposure Assessment: Module 2 vCJD prevalence in US plasma donors (cont.) Model considers effectiveness of US donor deferral policy (risk reduction measure) Model assumes mean elimination of 92% vCJD risk (range: 85-99%) for US donors by current donor deferral policy for travel: UK: 1980-1996, > 3 mos France: since 1980, > 5 years Other Europe: since 1980, > 5 years (recovered plasma donors only) US military bases in Europe: 1980-1996

30. 30 Distribution of vCJD incubation periods for PRNP-codon-129 MM and MV/VV populations

31. 31 Exposure Assessment: Module 3 Factor VIII Processing Modeling Approach for Module 3 Estimate probability plasma pool contains vCJD donation(s) Estimate quantity vCJD ID 50 per ml plasma, per pool Estimate log 10 reduction in quantity of i.v. ID 50 resulting from manufacturing process Adjust for “efficiency” of exposure by i.v. vs i.c. route GOAL Estimate: Percentage of pdFVIII vials containing vCJD agent Quantity vCJD agent per vial

32. 32 Infectivity clearance from product plasma pools: problems Each product has different purification steps  clearance Product-specific data: not available for all products Published data: not available for all purification steps;  studies vary FDA believes most (probably all) US-licensed pdFVIII is  manufactured by processes   4 log 10 clearance. FDA model stratified by 2 estimated clearance levels: 7-9 log 10 and 4-6 log 10 Exposure Assessment: Module 3 Factor VIII Processing (cont.)

33. 33 Exposure Assessment: Module 4 Utilization of Factor VIII Inputs Percentage vials with vCJD agent Quantity vCJD agent per vial Annual utilization / doses of Factor VIII per patient GOALS Predict: Annual potential dose vCJD ID 50 per patient Risk of vCJD infection based on animal dose-response information

34. 34 Exposure Assessment: Module 4 Utilization of FVIII Factors considered for utilization ─Type of disease:  Severe Hemophilia A,  Severe von Willebrand disease (vWD) (Type 3) ─Treatment regimens: Prophylaxis or Episodic Treatment ─Presence of FVIII inhibitor and immune tolerance Data ─CDC estimated size of HA and vWD populations ─CDC sponsored a 6-state hemophilia surveillance study, 1993- 1998 (total records: 17,848) estimating product usage

35. 35 Estimated vCJD risk from FDA model: severe Hemophilia A 7 - 9 Log 10 Reduction 4 – 6 Log 10 Reduction LOWER vCJD Case Prevalence HIGHER vCJD Infection Prevalence LOWER vCJD Case Prevalence HIGHER vCJD Infection Prevalence Treatment Regimen Inhibitor Status Year Risk Assessment Conducted Mean potential vCJD risk per person per year Mean potential vCJD risk per person per year Mean potential vCJD risk per person per yr Mean potential vCJD risk per person per year Prophylaxis No Inhibitor 2009 1 in 786 mill 1 in 44 mill1 in 767,0001 in 44,000 2006 1 in 4.1 bill 1 in 50 mill1 in 4 mill1 in 54,000 With Inhibitor – No Immune Tolerance 20091 in 356 mill1 in 37 mill1 in 340,0001 in 37,000 20061 in 3.5 bill1 in 40 mill1 in 4.8 mill1 in 41,000 With Inhibitor – With Immune Tolerance 20091 in 35 mill1 in 12 mill1 in 35,000 1 in 12,000 20061 in 551 mill1 in 15 mill1 in 638,000 1 in 15,000

36. 36 vCJD risk for estimated lower UK prevalence; Product having 4 – 6 log 10 reduction; prophylactic treatment vCJD risk for estimated lower UK prevalence; Product having 4 – 6 log 10 reduction; prophylactic treatment Treatment Regimen Inhibitor Status Year Risk Assessment Conducted Mean potential vCJD risk per person per yr Difference between 2009 and 2006 model results Prophylaxis No Inhibitor 20091 in 767,000 ~5 X higher 20061 in 4 mill With Inhibitor – No Immune Tolerance 20091 in 340,000 ~14 X higher 20061 in 4.8 mill With Inhibitor – With Immune Tolerance 20091 in 35,000 ~18 X higher 20061 in 638,000

37. 37 Conclusions (interim: work in progress) Updates to FDA 2009 model accounting for susceptibility of entire population have not caused important changes between the vCJD risk estimates for 2006 and 2009. Results from the model indicate estimates of potential vCJD risk for 2009: ─Increased using a LOWER vCJD prevalence estimate by approximately 5-fold to 18-fold ─However, results using a HIGHER vCJD prevalence were similar to estimates from 2006 Does not substantially change FDA’s interpretation of risk since the 2006 estimate was based on the HIGHER vCJD prevalence Accordingly, as in 2006, FDA assumes current vCJD risk from use of US-licensed pdFVIII may not be zero but is most likely extremely small.

38. 38 Questions for TSEAC  Based on an updated risk assessment, FDA continues to believe that the risk of variant Creutzfeldt-Jakob disease (vCJD) to patients who receive US-licensed plasma-derived coagulation factor VIII (pdFVIII) products is likely to be extremely small, although we do not know the risk with certainty. 1.Does the Committee agree with the updated and new inputs to the FDA risk assessment model for US-licensed plasma-derived pdFVIII?  Discussion: No disagreement (other improvements to model suggested). 2.Despite finding minimal additional risk in FDA’s modified assessment, should the recent report from the UK HPA, attributing a case of vCJD infection to treatment with UK-sourced pdFVIII, alter FDA’s interpretation of the risk for US-licensed preparations of pdFVIII?  Vote: Unanimous No (15 votes)—i.e., no changes suggested 3.Based on the available information, should FDA consider recommending: a.Additional risk-reducing steps for manufacture of plasma derivatives?  Discussion: Encourage processes that clear more spiked TSE agent. b.Revised warning labels for plasma derivatives?  Discussion: Yes (vCJD no longer just “theoretical” risk for pdFVIII) c.Modifications to FDA’s public communications about risk of vCJD for FDA-licensed plasma derivatives?  Discussion: Yes (include reference to case reported in UK)

39. 39 Transmissible spongiform encephalopathies normal brain spongiform degenerationstatus spongiosus