1. Modeling Risk of vCJD in US Donors – Residual Risk and Efficiency of Donor Deferral Alan E. Williams, Ph.D. Director, Division of Blood Applications Office of Blood Research and Review CBER, FDA TSE Advisory Committee October 31, 2005

2. Estimation of Total* Donor Exposure to BSE/vCJD * (Before 1999 UK 6 mo. deferral)

3. Summary of FDA Recommendations Regarding Donor Deferral for Dietary BSE Risk u Guidance to Industry November 11, 1999 –Donor deferrals undertaken concurrent with a commitment to monitor the blood supply (estimated loss 2%) –Donor deferrals recommended for: »travel/residence in U.K. for >six months between 1980- 1996 »Receipt of bovine insulin sourced in the U.K. after 1980 –Product retrieval recommended if donor later discovered to have vCJD

4. Estimation of Donor Exposure to BSE/vCJD * (After 1999 UK 6 mo. deferral)

5. Summary of FDA Recommendations Regarding Donor Deferral for Dietary BSE Risk u Guidance to Industry January, 2002 > 3 months residence/travel in U.K. 1980 - 1996 > 5 years residence/travel in Europe  For donors of Source Plasma this criterion applies only to France (5-10% consumption of UK beef) > 6 months on certain US military bases in Europe between 1980- 1990 or 1980-1996 (up to 35% UK beef consumed) Transfusion in the U.K. 1980 – present Receipt of bovine insulin sourced in the U.K. after 1980

6. Estimated Incremental and Total BSE/vCJD Risk Reduction Following Implementation of January, 2002 Revised Guidance Total Risk Reduced 91%

7. Sensitivity of Current Donor Screening Procedures: Application to the FDA Risk Model u Two factors related to current donor screening procedures are considered in the proposed FDA model: a)Periods of dietary BSE/vCJD risk among donors that are less than the current deferral criteria. These are estimated from the original donor travel survey data (estimated as ~9% of total risk burden prior to any donor screening for BSE/vCJD risk). b)Sensitivity of current donor screening procedures to exclude “deferrable” BSE/vCJD risks among donors.

8. Sensitivity of Current Donor Screening Procedures: Application to the FDA Risk Model u In the absence of empirical measures, the proposed FDA risk model incorporates an estimate of 90 – 99% sensitivity for current donor screening procedures to exclude “deferrable” BSE/vCJD risk. u Due to donor population size and limited other risk-reduction measures, the impact of this factor on the model is large. u The balance of this presentation will concern the rationale behind the 90-99% sensitivity estimate.

9. Functional Components of Donor Screening u Reduction of entire population subsets, e.g. paid donors, prisoners u Self deferral before blood drive u Self-deferral at blood drive site u Deferral by staff during interview -------------------------------------------------------------------- u Post-Donation Information

10. Interview-based deferrals: UK Travel u Survey estimate of donor deferral –1999 recommendations - 2.4% –2002 recommendations - 5.0% u Recent on-site vCJD deferral experience* –American Red Cross (ARCNET Data Center) 0.37% (2004 Overall) 0.30% (no previous on-site exposure to vCJD question) 0.07% (previous on-site exposure to vCJD question) Source Plasma (PPTA) ~ 0.44% among candidate donors ~ 0.04% among qualified donors (*Note: most donor self-deferral occurs prior to on-site screening)

11. Specific Measures for Assessment of Sensitivity of Donor Screening for BSE/vCJD Risk u Not Possible –Reduction in donor seroprevalence –Reduction in recipient adverse events –Comparisons with risk levels in general population u Possible –Extrapolations from analogous situations with other TTD risk factors –Limited validation of screening procedure (e.g. cognitive assessment of questions)

12. Examples: Reduction of infectious disease marker prevalence/(incidence) in accepted blood donors 1) … compared with general population 0.47% HIV+ in donor-age general population (McQuillan, 1994) 0.03% HIV+ in FT Donors (REDS survey circa 1995)  93.6% reduction in HIV seroprevalence 2) … over time

13. Approximately 90% Reduction of PT HIV-1 Transmission in San Francisco Due to Donor Screening Prior to anti- HIV Screening (MP Busch 1992)

14. Reduction of infectious disease risk in accepted blood donors 1) … compared with general population 4.1% prevalence of MSM - past 5 yrs in male general population (Laumann 1994) 0.57% MSM-77 risk in accepted male donors (Williams 1997)  86.1% reduction

15. Reduction of infectious disease risk in accepted blood donors 2) … compared with general population 3.9% IDU since 1978 in general population ((Dallas Household Survey 1994) 0.51% IDU-ever among accepted donors (Williams 1997)  86.9% reduction

16. Prior Observations about False Negative Behavioral Screening of Donors u Data collected from donors after their acceptance for donation may identify behavioral risks that should have prevented the donation.

17. HIV Seropositive Donors by Exposure Category (N=410)(N=77)(N=130)(N=56) MalesFemales

18. Measurement of Deferrable Risk JAMA 1997;277:967-72 u In past year – Prostitute use (males) [0.5%] – Female sex with MSM [0.3%] – Syphilis/gonorrhea [0.1%] – Sex with IDU [0.4%] – Needle stick [0.3%] – Transfusion [0.03%] u Since 1977 – MSM [0.6%] u Ever – IDU [0.5%] u 1.9% of donors reported one or more risks u ~ 241,800 U.S. donors/yr.

19. Behavioral Science Perspective u Information about personal behaviors is inherently difficult to collect. –Social acceptability of information –Response rates are low/missing data and inconsistencies are frequent (regulated blood establishments are special case) –People tend to avoid careful reading –Improvement in quality with serial data collections (all qualified plasma donors and most WB most donors are repeat) u Donor forms own basis for risk assessment –Denial –Lack of respect for policy u External factors prevent correct self-deferral –Secondary gain from donation –Peer pressure and Environment –Comprehension –Question complexity

20. Conclusions: u Based upon limited data from analogous donor screening situations, we believe that the 90-99% estimate of screening sensitivity screening for vCJD risk is realistic. –90% lower bound supported by screening experience with other transfusion-transmitted infections –99% upper bound supported by behavioral factors, less likelihood of travel among plasma donors, and high proportion of repeat donors u Other limited evaluations may be possible –Targeted follow-up of reasons for PDI reports –Comparison of results from different donor screening modes (e.g. post-donation interview or survey) u TSEAC may wish to consider recommending new funded data collection efforts that will support future deliberations