Modeling Risk of vCJD in US Donors Residual Risk and Efficiency of Donor Deferral Alan E. Williams, Ph.D.Director, Division of Blood ApplicationsOffice of Blood Research and ReviewCBER, FDA

TSE Advisory CommitteeOctober 31, 2005

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

Total Exposure

78.6

4.3

3.6

13.6

Total R

Sheet1

UKEuropeEurobloodDoD Base

Total R794.33.613.6

Current R3213.611.242.9

TSEAC out05.4038.2

ARC out14.911.811.238.2

FDA out14.97.311.238.2

TSEAC res32.38.211.242.9

ARC res17.41.804.7

FDA res17.46.304.7

Sheet1

78.6

4.3

3.6

13.6

Total R

Total BSE/vCJD Exposure

Sheet2

32.3

13.6

11.2

42.9

Current R

Current BSE/vCJD Exposure

Sheet3

Summary of FDA Recommendations Regarding Donor Deferral for Dietary BSE RiskGuidance to Industry November 11, 1999Donor 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- 1996Receipt of bovine insulin sourced in the U.K. after 1980 Product retrieval recommended if donor later discovered to have vCJD

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

Chart2

32.3

13.6

11.2

42.9

Current R

Sheet1

UKEuropeEurobloodDoD Base

Total R794.33.613.6

Current R3213.611.242.9

TSEAC out05.4038.2

ARC out14.911.811.238.2

FDA out14.97.311.238.2

TSEAC res32.38.211.242.9

ARC res17.41.804.7

FDA res17.46.304.7

Sheet1

0

0

0

0

Current R

Current BSE/vCJD Exposure

Sheet2

Sheet3

Summary of FDA Recommendations Regarding Donor Deferral for Dietary BSE RiskGuidance 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 presentReceipt of bovine insulin sourced in the U.K. after 1980

Estimated Incremental and Total BSE/vCJD Risk Reduction Following Implementation of January, 2002 Revised Guidance

Total Risk Reduced 91%

Chart3

14.9

17.4

7.3

6.3

11.2

0

38.2

4.7

Sheet1

UKEuropeEurobloodDoD BaseUK outEur outDoD out

Total R794.33.613.6

Current R3213.611.242.9

TSEAC out05.4038.2

ARC out14.911.811.238.217.41.804.7

FDA out14.97.311.238.2

TSEAC res32.38.211.242.9

ARC res17.41.804.7

FDA res17.46.304.7

UK outUK leftEur outEur leftEbld outEbld leftDOD outDoD left

14.917.411.81.811.2039.24.7ARC

032.35.48.2011.238.24.7TSEAC

14.917.47.36.311.2038.24.7FDA

Sheet1

0

0

0

0

Current R

Current BSE/vCJD Exposure

Sheet2

Current BSE/vCJD Risk Removed by Option #2 (ARC)

Sheet3

Current BSE/vCJ-D Risk Removed by Option #1 (TSEAC)

Current BSE/vCJD Risk Removed by OPtion #3 (FDA Proposed)

MBD00164F82.xls

Chart1

78.6

4.3

3.6

13.6

Total R

Total BSE/vCJD Exposure

Sheet1

UKEuropeEurobloodDoD Base

Total R794.33.613.6

Current R3213.611.242.9

TSEAC out05.4038.2

ARC out14.911.811.238.2

FDA out14.97.311.238.2

TSEAC res32.38.211.242.9

ARC res17.41.804.7

FDA res17.46.304.7

Sheet1

0

0

0

0

Total R

Total BSE/vCJD Exposure

Sheet2

0

0

0

0

Current R

Current BSE/vCJD Exposure

Sheet3

Sensitivity of Current Donor Screening Procedures: Application to the FDA Risk Model Two factors related to current donor screening procedures are considered in the proposed FDA model:

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).

Sensitivity of current donor screening procedures to exclude deferrable BSE/vCJD risks among donors.

Sensitivity of Current Donor Screening Procedures: Application to the FDA Risk Model 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.

Due to donor population size and limited other risk-reduction measures, the impact of this factor on the model is large.

The balance of this presentation will concern the rationale behind the 90-99% sensitivity estimate.

Functional Components of Donor ScreeningReduction of entire population subsets, e.g. paid donors, prisoners

Self deferral before blood drive

Self-deferral at blood drive site

Deferral by staff during interview --------------------------------------------------------------------Post-Donation Information

Interview-based deferrals: UK TravelSurvey estimate of donor deferral1999 recommendations - 2.4% 2002 recommendations - 5.0%

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)

Specific Measures for Assessment of Sensitivity of Donor Screening for BSE/vCJD Risk Not PossibleReduction in donor seroprevalenceReduction in recipient adverse eventsComparisons with risk levels in general population

PossibleExtrapolations from analogous situations with other TTD risk factorsLimited validation of screening procedure (e.g. cognitive assessment of questions)

Examples: Reduction of infectious disease marker prevalence/(incidence) in accepted blood donors

1) compared with general population0.47% 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

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

Reduction of infectious disease risk in accepted blood donors

1) compared with general population4.1% 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

Reduction of infectious disease risk in accepted blood donors

2) compared with general population3.9% IDU since 1978 in general population ((Dallas Household Survey 1994)

0.51% IDU-ever among accepted donors (Williams 1997)

86.9% reduction

Prior Observations about False Negative Behavioral Screening of Donors

Data collected from donors after their acceptance for donation may identify behavioral risks that should have prevented the donation.

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

Measurement of Deferrable RiskJAMA 1997;277:967-72 In past yearProstitute 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%]Since 1977MSM [0.6%]EverIDU [0.5%]

1.9% of donors reported one or more risks

~ 241,800 U.S. donors/yr.

Behavioral Science PerspectiveInformation 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)

Donor forms own basis for risk assessmentDenialLack of respect for policy

External factors prevent correct self-deferralSecondary gain from donationPeer pressure and EnvironmentComprehension Question complexity

Conclusions: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 infections99% upper bound supported by behavioral factors, less likelihood of travel among plasma donors, and high proportion of repeat donors

Other limited evaluations may be possible Targeted follow-up of reasons for PDI reportsComparison of results from different donor screening modes (e.g. post-donation interview or survey)

TSEAC may wish to consider recommending new funded data collection efforts that will support future deliberations