Transmissible Spongiform Encephalopathies Advisory Committee 23 rd Meeting Gaithersburg, MD – August 1, 2011

1. Transmissible Spongiform Encephalopathies Advisory Committee23rd 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 Recipients surviving > 5 yr post transfusion * Dorsey et al, Transfusion 2009 5|Gregori|TSEAC, August 1, 2011

6. CJD Infected Blood Poses a Theoretical Risk (1) • 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 Hewitt et al, Vox Sang 2006; Dorsey et al, Transfusion 2009 6|Gregori|TSEAC, August 1, 2011

7. CJD Infected Blood Poses a Theoretical Risk (2) • 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

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 toReduce 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 (PrPTSE 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 ProductsMay 10, 2010 www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/UCM213415.pdf 11|Gregori|TSEAC, August 1, 2011

12. Recommendations in the 2010 Guidance • 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

13. To Be Considered • 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

14. FDA Policy for Indefinite Blood Donor Deferral for vCJD Risks * Donors eligible to donate Source Plasma 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. 14|Gregori|TSEAC, August 1, 2011

15. FDA Policy for Indefinite Blood Donor Deferral for CJD and vCJD Risks * 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. 15|Gregori|TSEAC, August 1, 2011

16. Conclusions • 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

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