Development of FDA Recommendations for deferral of donors based on risk of BSE exposure Alan E. Williams, Ph.D. Director, Division of Blood Applications Office of Blood Research and Review CBER, FDA TSE Advisory Committee October 14, 2004

Goals: Effective response to the spread of vCJD in Europe and the potential threat to blood safety Optimal balance between vCJD risk reduction and blood supply preservation Implementation plan that is sensitive to the dynamics of donor recruitment and blood resource sharing Coherent and uniform national policy

“Empirical ” vCJ-D Risk Model Likelihood of dietary exposure Length of incubation period (mean and range) Prevalence of asymptomatic carrier state Presence of vCJD agent in blood during incubation period/carrier state Susceptibility of recipient population  VERY LIMITED DATA, THEREFORE AN EMPIRICAL MODEL IS NOT POSSIBLE

“Linear” vCJD Risk Model Risk of exposure to BSE/vCJD is linear and related to the duration and likelihood of dietary exposure –Concept previously endorsed by TSEAC –Assumptions Data regarding travel and residence in BSE-endemic country is a valid surrogate for: –dietary exposure to BSE –subsequent potential to transmit vCJD via blood

1999 Blood Donor Travel Survey Probability sample of accepted donors at twelve blood center sites - Winter, ,067 surveys - single page mailing with cover letter 9,541 anonymous responses (~ 50%) UK (European) travel, sex, age, FT/Rpt, education Data requested by TSEAC and presented extensively at previous meetings. Note: Donor survey estimates are reproducible, but are based upon self-report and have not been validated by other independent measures. Short survey - numerous data extrapolations.

Any Blood Donor Travel/Residence: UK and any European Country with endemic BSE in 1999 Any UK Travel/residence % Range by blood center % Higher travel with education, age, repeat status Any European country with BSE in %

Possible Donor Exposures to BSE/vCJD Person-Days Exposure - Derived from total estimated cumulative time spent by donors in a defined geographic area Donor loss - Estimated proportion of donors who spent time in a geographic area  cut-off value

Blood Supply Concerns Blood Donor base –~80% repeat donors (deferrals costly) –Stressed by changing donor demographics and deferrals related to donor exposures and test results. Aging –Fewer large worksite collections Elasticity of Supply –3-5 % maximum donation loss experience (1986 anti-HBc; 2000 ear/finger stick + UK deferral) –Limited supply during Summer and holidays (esp. 2002) Public responds to appeals - long term impact uncertain Capability of monitoring supply impact

UK BSE Exposure/Donor Loss Analysis (Based upon 252,804 total UK person-days exposure) UK 6 month deferral UK p-d removed: 217,411/252,804 (86.0%) Residual total p-d: 35, 393 (14.0%) Donor loss: 2.2% % p-d removed/1% donor loss: 39.1

BSE Exposure/Donor Loss Analysis UK 3 months de novo UK p-d removed: 235,866/252,804 (93.3%) Residual total p-d: 16,938/252,804 (6.7%) Donor loss: 3.4% % p-d removed/1% donor loss: 27.4

BSE Exposure/Donor Loss Analysis UK 1 month de novo UK p-d removed: 245,978/252,804 (97.3%) Residual total p-d: 6826/252,804 (2.7%) Donor loss: 6.4% % p-d removed/1% donor loss: 15.2

BSE Exposure/Donor Loss Analysis UK 1 month, given 3 month UK deferral Additive UK p-d removed (based on total): 10,112/ 252,804 (4.0%) Total p-d removed: 245,978/304,406 (97.3%) Residual total p-d: 6826/252,804 (2.7%) Addl. donor loss: 3.0% % residual p-d removed /1% donor loss: 1.3

Residual vCJD Risk (Theoretical) vs. Percent of Blood Supply Lost

Development of FDA Guidance issued November, 1999 June 2, 1999 TSEAC 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 Receipt of bovine insulin sourced in the U.K. after 1980 –Product retrieval recommended if donor later discovered to have vCJD

Estimation of Potential BSE/vCJD Risk Remaining After November, 1999 Guidance Implementation

FDA/CDC “Weighted“ Linear Risk Model for Estimating Possible Donor Exposure to BSE/vCJD Risk weighted by geographic exposure based on observations of UK beef imports, vCJD cases, and indigenous BSE UK = 1.0 Epidemic focus, index country France = 0.05 UK beef imports; obs. BSE, vCJD Other Europe (incl. Euroblood) = Indigenous BSE, uncertain surveillance, reporting, food controls (Note: Travel/residence in France calculated as ~ 0.7 UK based on overall travel prevalence)

FDA/CDC “Weighted“ Linear Risk Model for Estimating Possible Donor Exposure to BSE/vCJD DoD active duty and dependents stationed on European bases = 0.35 (US bases supplied with ~ 35% UK beef)

Development of Revised FDA Guidance issued January, 2002 June 18-19, 2001 TSEAC Guidance to Industry January, 2002 (deferrals) > 3 months residence/travel in U.K > 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 or (up to 35% UK beef consumed) Transfusion in the U.K – present Receipt of bovine insulin sourced in the U.K. after 1980

Estimated Further BSE/vCJD Risk Reduction Following Implementation of January, 2002 Revised Guidance Current Risk reduced 72 % (Total Risk Reduced 91%) Option #3 (FDA)

Revised FDA Guidance issued January, 2002 Advantages: Deferral tied to BSE observational data. Ratio of 3 mo. (UK) to 60 mos. (Europe) reflects “worst case” 5% European dietary estimate relative to UK. (3 mo. deferral for all of Europe in absence of weighting would add additional 7-8% donor loss) Impact on NY area blood supply was severe, but was expected to be modulated by lesser impact elsewhere in US Pilot provision allows flexibility for stricter policies Some protection for human-human passage of vCJD Recognizes food chain protections

Revised FDA Guidance issued January, 2002 Disadvantages: At the time, transfusion-transmission of vCJD was theoretical Donor screening questions are complex Estimated 4-6% US donor loss exceeded past experience. Ability of rest of US to compensate for severe impact in NY area was untested.

Observed Impact of 2002 Guidance on US Donor Base BSE/vCJD Deferrals phased in during May and October, 2002 –Projected loss 5.0% nationwide –Actual loss not directly measurable –Major component of industry more restrictive Disproportionate impacts of travel deferrals –Coastal cities: 50%  donor loss (e.g. NYC and SF) –Rural US: 50%  impact –New York area “Euroblood” lost by pan-European deferral –Military bases –TSEAC requested supply monitoring and assessment Seasonal and regional blood shortages persist

Potential Future Challenges Recent documentation of transfusion-transmission during vCJD asymptomatic incubation period Deferral for UK transfusion in 2001 was precautionary –Additional deferral of individuals with previous transfusion? (adaptation of vCJD agent)

Estimated Donor Loss Related to History of Transfusion in UK, France and Europe Assumptions: – 5% prevalence of transfusion in US donors overall (REDS data) – >/= 5 yr travel/residence CONSERVATIVELY approximates lifetime transfusion exposure –rate of tx among long term residents/travelers to Europe and UK = overall US donor prevalence –prevalence of travel to France = 0.7 x travel to UK Hx tx (UK - deferral already accomplished) 0.4 x 0.05 = 2/10,000 Hx Tx (any Europe, excl. UK) 0.7% x 0.05 = 3/10,000 Hx Tx (France) 0.4 x 0.7 x 0.05 = 1.4/10,0000

Spread/Recognition of BSE/vCJD in New Geographic Areas No exposure data available for donors beyond UK and European BSE Countries Despite limitations, survey data provided a framework for risk:donor loss estimates TSEAC may wish to consider new data collection efforts that will support future deliberations