development of fda recommendations for deferral of donors based on risk of bse exposure

Development of FDA Recommendations for deferral of donors based on risk of BSE exposureAlan E. Williams, Ph.D.Director, Division of Blood ApplicationsOffice of Blood Research and ReviewCBER, FDA

TSE Advisory CommitteeOctober 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 ModelLikelihood of dietary exposureLength of incubation period (mean and range)Prevalence of asymptomatic carrier statePresence of vCJD agent in blood during incubation period/carrier stateSusceptibility 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 AssumptionsData 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 SurveyProbability sample of accepted donors at twelve blood center sites - Winter, 1999.19,067 surveys - single page mailing with cover letter9,541 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 1980-1996 - 22.8%Range by blood center - 10.2 - 31.7%Higher travel with education, age, repeat status

Any European country with BSE in 1999 - 35.5%

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 ConcernsBlood Donor base~80% repeat donors (deferrals costly)Stressed by changing donor demographics and deferrals related to donor exposures and test results. AgingFewer large worksite collections

Elasticity of Supply3-5 % 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 uncertainCapability of monitoring supply impact

UK BSE Exposure/Donor Loss Analysis (Based upon 252,804 total UK person-days exposure)

UK 6 month deferralUK 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 novoUK p-d removed: 235,866/252,804 (93.3%)Residual total p-d: 16,938/252,804 (6.7%)


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%)


BSE Exposure/Donor Loss Analysis UK 1 month, given 3 month UK deferralAdditive 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

Chart2

-14.90

-6.40.2

-3.42

-2.26.7

-1.515.6

20.8

% of Blood supply lost

Theoretical Residual vCJD risk remaining

(1 year)

(6 months)

(3 months)

(1 month)

(1 week)

% Blood supply lost

Residual vCJD risk remaining

Time spent in U.K. and/or Republic of Ireland (days)

Sheet1

22.61.3539109545days

?nNPercentLow CIHigh CI173656205

> 5 Years313185260.40.250.5253651825

19.71.2943053678> 3 Years306185260.70.550.9233651095

> 1 Year379885261.20.931.41365365

> 9 Months1211085261.31.061.55930.4166666667273.75

> 5 Months6217285262.01.732.34530.4166666667152.0833333333

> 1 Month24641885264.94.455.38130.416666666730.4166666667

> 11 Days5921010852611.811.1712.5511111

> 4 Days6691679852619.718.8520.55414

11.81.0735760455> 1 Day2471926852622.621.7123.49111

total19265505852664.6

logintvlintvldays%logdays%log%intvlpersonsintvl-midptperson-days

0.30102999572.0122.6022.61.3539109545> 5 Years314014.5124449.549.4

0.845098047.0419.70.602059991319.71.2943053678> 3 Years301459.543785.017.4

1.305530496920.21111.81.041392685211.81.0735760455> 1 Year37729.526991.510.7

1.957846633790.8304.91.48311161844.90.6904309535> 9 Months12318.93826.51.5

2.3271885894212.41522.02.18208162272.00.3047831186> 5 Months62212.413169.85.2

2.5036204716318.92741.32.43735412781.30.1106473568> 1 Month24690.822324.58.9

2.8630252962729.53651.22.56229286451.20.079181246> 11 Days59220.211963.34.8

3.16420409931459.510950.73.03941411920.7-0.1454154933> 4 Days6697.04683.01.9

3.60363146234014.518250.43.26126286880.4-0.4393836345> 1 Day2472.0494.00.2

6205251687.2100.0

YXY given XX given YX given YYXY given X

%expregressexpregressexpregress%expregress

22.6233.81954596623.9908203212829.771.0716.3

19.7716.26962818995.0478557908253.27619695442.0307.0

11.820.20833333338.75868747112.0502356303126.51037438533.0903.7

4.990.753.642681285554.568238753577.30917235344.01802.4

2.0212.41666666672.2166061722249.556582702852.76197959335.02701.9

1.3318.8751.748375354536.450252584838.61560010556.03651.6

1.2729.51.0782173545607.294622880629.65854794317.07301.1

0.71459.50.71909751472.004214946723.59759109568.018250.6

0.44014.50.39821558794690.104412969319.28832667749.062050.3

effective c/oCum% CJD Risk RemovedResidual CJD Risk RemainingCum% Loss of Blood Supply

intrvl

211000.0-20.8

7499.80.2-18.1

201198.02.0-11.0

913193.36.7-4.5-14.97

21215384.415.6-1.9-6.430

31927579.220.8-1.2-3.490

73036577.822.2-1.1-2.2180

1460109567.132.9-0.6-1.5365

4015182549.250.8-0.3-0.31825

2.00.3047831186

1.30.1106473568

1.20.079181246

0.7-0.1454154933

0.4-0.4393836345

Sheet1

0

0

0

0

0

0

0

0

0

days visited UK/ROI

percent of donors

Sheet2

22.589725545433.8195459662

19.692704668116.2696281899

11.84611775748.758687471

4.90265071553.6426812855

2.01735866762.2166061722

1.29017124091.748375354

Power Regression

Cumulative number of days in U.K. and/or Republic of Ireland

Percent of donors

Sheet3

22.5897255454

19.6927046681

11.8461177574

4.9026507155

2.0173586676

1.2901712409

1.2

0.7154585972

0.3635937133

0

0

0

0

0

0

0

(1 week)

(1 month)

(3 Months)

(6 Months)

(9 Months)

(1 year)

(2 years)

y = 50.699x-0.5841R2 = 0.9722

Y given X expregress

Days of travel to U.K. and/or Republic of Ireland

Percent of donors

Percent Loss of Donors by Amount of Time Spent in the U.K. and/or Republic of Ireland

0

0

0

0

0

0

0

0

0

Days of Travel to the U.K. and/or Republic of Ireland

Percent of donors

Amount of Time Spent in the U.K. and/or Republic of Ireland Given a Percentage of Donor Loss

0

0.2

2

6.7

15.6

20.8

22.2

32.9

50.8

effective c/o

Minimum interval cutoff (days)

Residual vCJD Risk Remaining

00

00

00

00

00

00

0

0

0



% Blood supply lost



00

00

00

00

00

0



(1 year)

(6 months)

(3 months)

(1 month)

(1 week)

% Blood supply lost



Development of FDA Guidance issued November, 1999 June 2, 1999 TSEAC Guidance 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 Potential BSE/vCJD Risk Remaining After November, 1999 Guidance Implementation

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

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 BSEUK = 1.0Epidemic focus, index countryFrance = 0.05 UK beef imports; obs. BSE, vCJDOther Europe (incl. Euroblood) = 0.015 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, 2002June 18-19, 2001 TSEACGuidance to Industry January, 2002 (deferrals)> 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 Further BSE/vCJD Risk Reduction Following Implementation of January, 2002 Revised Guidance

Current Risk reduced 72 % (Total Risk Reduced 91%)Option #3 (FDA)

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


Sheet2

0

0

0

0

0

0

0

0

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

Sheet3

0

0

0

0

0

0

0

0

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

0

0

0

0

0

0

0

0

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


Sheet3

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% nationwideActual loss not directly measurableMajor component of industry more restrictive

Disproportionate impacts of travel deferralsCoastal cities: 50% donor loss (e.g. NYC and SF) Rural US: 50% impact New York area Euroblood lost by pan-European deferralMilitary basesTSEAC 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 precautionaryAdditional deferral of individuals with previous transfusion? (adaptation of vCJD agent)

Chart4

5.41

5.35

5.56

5.53

5.41

5.05

4.65

4.05

4.05

3.98

Overall

Donation Year

Percentage

Percentage of Donations Given by TransfusedAllogeneic Donors, 1991-2000

Sheet1

1991199219931994199519961997199819992000

Overall5.415.355.565.535.415.054.654.054.053.98

Sheet1

0

0

0

0

0

0

0

0

0

0

Overall

Donation Year

Percentage of Allogeneic Donations

Percentage of Donations Given by Transfused Allogeneic Donors, 1991-2000

Sheet2

Sheet3

Chart1

1.733.825.717.9810.9

1.593.65.497.8810.98

1.673.595.658.1311.41

1.563.435.538.0211.42

1.483.35.237.6911.31

1.333.044.77.1110.45

1.222.554.276.399.55

1.052.23.695.518.4

1.142.123.475.518.51

0.9723.395.328.39

=55

Donation Year

Percentage

Percentage of Donations Given by TransfusedAllogeneic Donors by Age, 1991-2000

Sheet1

1991199219931994199519961997199819992000

=5510.9010.9811.4111.4211.3110.459.558.408.518.39

Sheet1

00000

00000

00000

00000

00000

00000

00000

00000

00000

00000

=55

Donation Year

Percentage of Allogeneic Donations

Percentage of Donations Given by Transfused Donors Over Time

Sheet2

Sheet3

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 exposurerate 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 AreasNo 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

development of fda recommendations for deferral of donors based on risk of bse exposure

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