1. Transmissible Spongiform Encephalopathies Advisory Committee 23 rd Meeting Gaithersburg, MD – August 1, 2011 CJD and vCJD Donor Policies: Blood and Blood Components Luisa Gregori Division of Emerging and Transfusion-Transmitted Diseases OBRR/CBER/FDA 1|Gregori|TSEAC, August 1, 2011

2. Overview of FDA Policies Regarding Deferral of Blood Donors at Increased Risk for CJD and vCJD Rationale for blood donor deferrals History of FDA policies Current Guidance 2|Gregori|TSEAC, August 1, 2011

3. Rationale for Blood Deferrals Fatal No cure or therapy No test to identify asymptomatic CJD or vCJD blood donors No infectivity removal technology for all cellular components RBC filters are under development Limited clearance studies with TSE agents for plasma products (FDA allowed claims) 3|Gregori|TSEAC, August 1, 2011

4. Endogenous Infectivity in Blood TSE infectivity was transmitted by blood transfusion in animal studies Sheep with scrapie or BSE Deer with CWD Four cases of transfusion-transmitted vCJD One case of transmission by UK plasma-derived Factor VIII No cases of transmission with CJD Is CJD infectivity transmissible by blood transfusion? 4|Gregori|TSEAC, August 1, 2011

5. Transmissibility by Blood Transfusion of vCJD versus CJD 5|Gregori|TSEAC, August 1, 2011 Disease (or infection) No Disease vCJD429 CJD*0144 * Dorsey et al, Transfusion 2009 Recipients surviving > 5 yr post transfusion

6. Look-back studies suggest no evidence of transmission of CJD by blood transfusion Relatively small number of patients High rate of lost-to-follow up Limited medical records No autopsies to rule out preclinical CJD infection 6|Gregori|TSEAC, August 1, 2011 CJD Infected Blood Poses a Theoretical Risk (1) Hewitt et al, Vox Sang 2006; Dorsey et al, Transfusion 2009

7. One recent case-study suggests a possible association with history of blood transfusion but only in cases with 10-year lag (Puopolo et al, Transfusion 2011) Prone to biases Difficult to select control cases A UK study shows no evidence of association (in press) Theoretical risk of transfusion transmission for CJD versus demonstrated risk for vCJD 7|Gregori|TSEAC, August 1, 2011 CJD Infected Blood Poses a Theoretical Risk (2)

8. History of FDA Policies to Reduce CJD and vCJD Risks (1) 1978 & 1983. Evidence of infectivity in buffy coat of rodents experimentally infected with CJD and GSS agents 1983. FDA recommended withdrawal of CJD-implicated blood components (post-donation diagnosis of CJD in a donor) 1987. FDA recommended deferring donors treated with human cadaveric pituitary growth hormone, later other donors at increased TSE risk 1991 & 1996. FDA recommended withdrawal of in-date plasma derivatives manufactured from pooled plasma containing donation from an individual with CJD or at increased risk of CJD. This recommendation was rescinded in 1998 8|Gregori|TSEAC, August 1, 2011

9. History of FDA Policies to Reduce CJD and vCJD Risks (2) 1996. First cases of vCJD reported from UK and France 1999. FDA recommended deferral for  6 mo total residence in UK 1980-1996 2000. First report of transfusion-transmitted BSE in sheep 2002. FDA recommended enhanced geographic vCJD deferrals—retained in the current guidance (including donors transfused in UK since 1980) 2003-2007. UK reported 4 cases of presumptive transfusion-transmitted (TT) vCJD 9|Gregori|TSEAC, August 1, 2011

10. History of FDA Policies to Reduce CJD and vCJD Risks (3) 2006. FDA published draft guidance for comment to defer blood/plasma donors transfused in France after 1980 2009. UK reported evidence (PrP TSE in spleen) of elderly man with haemophilia treated with UK plasma-derived FVIII 2010. CBER issued revised guidance to defer blood donors with history of transfusion after 1980 in France 10|Gregori|TSEAC, August 1, 2011

11. Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt- Jakob Disease (CJD) & Variant Creutzfeldt- Jakob Disease (vCJD) by Blood and Blood Products May 10, 2010 www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryI nformation/Guidances/UCM213415.pdf www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryI nformation/Guidances/UCM213415.pdf 11|Gregori|TSEAC, August 1, 2011

12. Recommendations for donor deferral, product retrieval, quarantine and disposition Based on risk in the donor and product Effect that donor deferral and product withdrawal might have on the supply Indefinite deferral for individuals at increased risk for CJD or vCJD CJD includes all familial CJD-like diseases such as GSS and FFI 12|Gregori|TSEAC, August 1, 2011 Recommendations in the 2010 Guidance

13. Balance between “benefit of risk reduction compared with potential adverse effects of a decreased availability of the blood supply” 13|Gregori|TSEAC, August 1, 2011 To Be Considered

14. 14|Gregori|TSEAC, August 1, 2011 FDA Policy for Indefinite Blood Donor Deferral for vCJD Risks ResidenceTime of Residence UK≥ 3 mo from 1980-1996 History of blood transfusion France≥ 5 y from 1980-present Europe* (UK and France not included) ≥ 5 y from 1980-present US military bases North of the Alps ≥ 6 mo from 1980-1990 US military bases South of the Alps ≥ 6 mo from 1980-1996 Albania, Austria, Belgium, Bosnia-Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Finland, Germany, Greece, Hungary, of Ireland, Italy, Liechtenstein, Luxembourg, Macedonia, Netherlands, Norway, Poland, Portugal, Romania, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, and [former] Federal Republic of Yugoslavia. * Donors eligible to donate Source Plasma

15. 15|Gregori|TSEAC, August 1, 2011 FDA Policy for Indefinite Blood Donor Deferral for CJD and vCJD Risks Increased risk for all CJD Diagnosis of any form of CJD including vCJD and all familial TSE such as GSS and FFI ≥ 1 blood relatives diagnosed with CJD* Recipients of dura mater or human-derived pituitary growth hormone Users of UK bovine-derived insulin since 1980 (vCJD risk) * A donor is eligible for reentry if either it can be concluded that CJD was iatrogenic (or non-familial) or testing of the donor excludes a mutation associated with familial CJD.

16. Donor deferral is the only current action available to protect the US blood supply from transfusion- transmitted CJD and related diseases including vCJD Current US policies would not have deferred the US or Canadian Saudi cases 16|Gregori|TSEAC, August 1, 2011 Conclusions

17. Acknowledgements Steven Anderson OBE David Asher OBRR Jay Epstein OBRR Melissa Greenwald OCTGT Ginette Michaud OBRR Pedro Piccardo OBRR Martin Ruta OBRR Jennifer Scharpf OBRR Alan Williams OBRR Hong Yang OBE 17|Gregori|TSEAC, August 1, 2011