CBER Chagas Serological Lot CBER Chagas Serological Lot Release Panel DevelopmentRelease Panel Development

Hira L. Nakhasi, Ph.D.Hira L. Nakhasi, Ph.D.Director, Division of Emerging andDirector, Division of Emerging and

Transfusion Transmitted Diseases,Transfusion Transmitted Diseases,

OBRR/CBER/FDAOBRR/CBER/FDA

Challenge for Blood Challenge for Blood ProductsProducts

Avoid Product Shortages & Major Increased Costs

and

Enhance Product Safety,

Purity and Potency

Critical Path opportunities exist that could improve blood product safety, efficacy and availability while minimizing disruptions to the blood system

FIVE LAYERS OF BLOOD SAFETYFIVE LAYERS OF BLOOD SAFETY

FDA’s approach is to optimize each safety layer:FDA’s approach is to optimize each safety layer:

1. Donor screening and deferral based on geographic, 1. Donor screening and deferral based on geographic, behavioral and medical risk factors (donor education, behavioral and medical risk factors (donor education, self deferral, donor interview)self deferral, donor interview)

2. Laboratory testing and deferral (HIV-1, HIV-2, HBV, 2. Laboratory testing and deferral (HIV-1, HIV-2, HBV, HCV, HTLV-I, HTLV-II, WNV, Chagas, syphilis)HCV, HTLV-I, HTLV-II, WNV, Chagas, syphilis)

3. Deferral registries to prevent use of blood from deferred 3. Deferral registries to prevent use of blood from deferred donorsdonors

4. Quarantine controls to prevent unit release pending 4. Quarantine controls to prevent unit release pending verification of donor suitabilityverification of donor suitability

5. Investigation and correction of deviations5. Investigation and correction of deviations

Impact on the US Public Health:Impact on the US Public Health:Blood Safety and AvailabilityBlood Safety and Availability

• Millions of units are transfused Millions of units are transfused annuallyannually

• Risk of transmission of infectious Risk of transmission of infectious disease agents through transfusion disease agents through transfusion has been significantly reduced with has been significantly reduced with the introduction of donor screening the introduction of donor screening teststests

Evolution of Testing and Deferral

What happens when an emerging pathogen threatens the safety of the blood supply?

1. We introduce deferral criteria based on epidemiologically determined risk factors (medical, geographic or behavior-related exposures) as an initial safety measure

2. Where feasible, tests are developed, but deferral is maintained as an overlapping safeguard

3. Test sensitivity and specificity generally improve. However, risk-based deferrals are usually retained as an overlapping safeguard, especially when data are lacking on the relative safety contribution of risk-based vs. test-based deferrals

Chagas Transmissions by Blood or Chagas Transmissions by Blood or Organ Donations: U.S./CanadianOrgan Donations: U.S./Canadian

1987: California – Mexican blood donor

1989: New York City – Bolivian blood donorManitoba – Paraguayan blood donor

1993: Houston – unknown blood donor

1999: Miami – Chilean blood donor

2000: Manitoba – German/Paraguayan blood donor

2001: Three organ recipients – Central American organ donor

2002: Rhode Island – Bolivian donor

2006: Los Angeles – Heart donor traveled to MexicoLos Angeles – Heart donor born in El Salvador

Blood Screening ELISA LicensedBlood Screening ELISA Licensed

December, 2006 ORTHO December, 2006 ORTHO T. cruziT. cruzi ELISA ELISA Test System approved for use as a blood Test System approved for use as a blood screening assayscreening assayLarge blood centers implemented testing Large blood centers implemented testing Feb. 2007. FDA recommendations for Feb. 2007. FDA recommendations for implementation under consideration.implementation under consideration.Pre-release testing of kit lots is CBER Pre-release testing of kit lots is CBER responsibilityresponsibilityCBER Lot Release Panel developedCBER Lot Release Panel developedCross testing with manufacturers panelsCross testing with manufacturers panels

T. cruzi Reactive Donors by State of Residence (01/29/07 – 01/14/09)

26

2678

365

27119

96

229

19

65

59

73

42

26

17

30

482

30

PR

21

31

12

57

37

46

81

6

53

81

16 9

52

53

43

38

26

35

14

31

39

36

24

22

13

8

4

9

18.9 million donations screened0.015% RR rateRR from 47 states (-DE)RIPA pos (25%) from 38 states (+PR, DC)

61% from FL and CA (1:3800-1:7600)Overall: 1:27,600 (Source: AABB)

16

* 3 RIPA pos samples represent multiple positives from auto donor and cord blood

DC

2

1

Total Repeat ReactiveTotal Repeat ReactiveRIPA RIPA

PositivePositiveRIPA RIPA

Negative/IndNegative/IndRIPA RIPA

Pending/NTPending/NT

30713071 749749 2177 / 472177 / 47 9898

Confirmed positive (RIPA) donors:Confirmed positive (RIPA) donors:– 25% US born25% US born– 75% born in 75% born in T.cruziT.cruzi endemic countries endemic countries– 63% first time donors (increasing)63% first time donors (increasing)– 37% repeat donors (declining)37% repeat donors (declining)

Potential autochthonous cases ~42Potential autochthonous cases ~42Chagas positive cases from 47 statesChagas positive cases from 47 statesLook back has identified 0/88 of recipients*Look back has identified 0/88 of recipients*– All donors are long term chronic asymptomatic (low parasitemia)All donors are long term chronic asymptomatic (low parasitemia)– Transfusions are rarely WBTransfusions are rarely WB– L/B have few platelet Transfusions ( > probability to transmit than L/B have few platelet Transfusions ( > probability to transmit than

RBC)RBC)– *On going investigations for a few cases possible T-T but rare*On going investigations for a few cases possible T-T but rare

No true seroconversions have been identifiedNo true seroconversions have been identified

Epidemiology of Epidemiology of T.cruziT.cruzi infection infection

among US blood donoramong US blood donor

Continuation of universal blood screening Continuation of universal blood screening for for T.cruziT.cruzi to have a better evaluation of to have a better evaluation of epidemiology of the disease and epidemiology of the disease and performance of the tests.performance of the tests.

Need for licensed confirmatory test for Need for licensed confirmatory test for donor reentrydonor reentry

Blood established performed validation of Blood established performed validation of selective testing strategy (STS) to chart selective testing strategy (STS) to chart future course of testing in the US future course of testing in the US

Public discussion of the STS Public discussion of the STS

Current Status of Current Status of T.cruziT.cruzi testing testing in the USin the US

Standardization of Serological Testing Standardization of Serological Testing for Chagas’ Diseasefor Chagas’ Disease

Validation and licensing of new testsValidation and licensing of new tests– Analytical characteristicsAnalytical characteristics

Sensitivity, specificity and reproducibilitySensitivity, specificity and reproducibility

– Clinical characteristicsClinical characteristicsRandom donor specificity trialRandom donor specificity trial

Known positive and High risk sensitivity trialsKnown positive and High risk sensitivity trials

Testing lot to lot consistency of licensed Testing lot to lot consistency of licensed assaysassays

T. cruziT. cruzi Panel Development Panel Development

PurposePurpose

∙∙ Lot Release Panel to test lot to lot consistencyLot Release Panel to test lot to lot consistency

∙ ∙ Not a Reference PanelNot a Reference Panel

∙ ∙ Not an International StandardNot an International Standard

ObjectiveObjective

∙ ∙ Obtain Obtain T. cruziT. cruzi positive specimens from various positive specimens from various geographical locations.geographical locations.

∙ ∙ Emphasis on immigration patterns found in the Emphasis on immigration patterns found in the

U.S. donor pool from endemic countries.U.S. donor pool from endemic countries.

Geographic Distribution of Panel MembersGeographic Distribution of Panel Members

*

*

*

7%

0.1%

24%

1.2%

0.4%

9.8%

10.7%

30%

3%

3.9%

0.1%

17.7%11.7%

7%7%

7%

Total Immigration from Chagas Disease Endemic Countries as of 2004

Mexico

El Salvador

Columbia

Guatemala

Ecuador

Honduras

Peru

Nicaragua

Brazil

Argentina

Venezuela

Panama

Chile

Costa Rica

Bolivia

Paraguay

Uruguay

N%-WHO estimate of prevalence, Global burden of Chagas’ disease in the year 2000 DRAFTA Moncayo, F Guhl, C Stein. http://www.who.int/healthinfo/statistics/bod_chagas.pdf

*Endemic countries for CBER Panel

*

*

**

*

Preliminary Formulation of PanelPreliminary Formulation of Panel

Obtained/Purchased positive units and Obtained/Purchased positive units and tested neat for titers and co-infectionstested neat for titers and co-infections(e.g. HCV, HBsAg, HIV etc.)(e.g. HCV, HBsAg, HIV etc.)

Determined acceptable units for possible Determined acceptable units for possible panel manufacturingpanel manufacturing∙ ∙ Highest TitersHighest Titers

∙ ∙ Largest VolumesLargest Volumes

∙ ∙ Geographical VariationGeographical Variation

Preliminary Formulation of Panel con’tPreliminary Formulation of Panel con’t

Chose Acceptable Units from Following AreasChose Acceptable Units from Following Areas ∙ ∙ Mexico, Argentina, Nicaragua, and BrazilMexico, Argentina, Nicaragua, and Brazil

Tested at CBER/DETTD with Serial Dilutions until Tested at CBER/DETTD with Serial Dilutions until Non-ReactiveNon-Reactive∙ ∙ Ortho Ortho T. cruziT. cruzi ELISA Test System ELISA Test System

Sent Serial Dilutions to Kit ManufacturersSent Serial Dilutions to Kit Manufacturers∙ ∙ Ortho-Clinical DiagnosticsOrtho-Clinical Diagnostics∙ ∙ Abbott LaboratoriesAbbott Laboratories

Evaluate all results to construct final panelEvaluate all results to construct final panel

Candidate CBER Lot Release PanelCandidate CBER Lot Release Panel

10 Member Panel10 Member Panel– 2 Negatives2 Negatives– 4 geographical units at 2 dilutions4 geographical units at 2 dilutions

∙ ∙ Consensus High Positive (S/CO >2.0)Consensus High Positive (S/CO >2.0)∙ ∙ Consensus Low Positive (S/CO ~ 1.0)Consensus Low Positive (S/CO ~ 1.0)

500 ml Bulk, 500 ml for Final Vialing500 ml Bulk, 500 ml for Final Vialing

Fill Volume 1.25 mlFill Volume 1.25 ml

Validation of Candidate PanelValidation of Candidate Panel

CBER/DETTD Tested Final VialingCBER/DETTD Tested Final Vialing∙ ∙ Ortho Ortho T. cruziT. cruzi ELISA Test System ELISA Test System

∙ ∙ Abbott PRISM ChagasAbbott PRISM Chagas ∙ ∙ Abbott Chagas Confirmatory AssayAbbott Chagas Confirmatory Assay

Ortho-Clinical Diagnostics TestedOrtho-Clinical Diagnostics Tested∙ ∙ Ortho Ortho T. cruziT. cruzi ELISA Test System ELISA Test System

Abbott Laboratories TestedAbbott Laboratories Tested∙ ∙ Abbott PRISM ChagasAbbott PRISM Chagas ∙ ∙ Abbott Chagas Confirmatory AssayAbbott Chagas Confirmatory Assay

CBER Panel Testing ResultsCBER Panel Testing ResultsManufacturers Manufacturers

TestingTestingManufacturers Manufacturers

TestingTestingCBER CBER

TestingTesting

CBER CBER

TestingTesting

Lot ReleaseLot Release

Criteria Criteria

CBER andCBER and

ManufacturersManufacturers

Testing*Testing*

Panel MemberPanel Member

Screening Screening TestTest

AA

Screening Screening TestTest

BB

Screening Screening TestTest

AA

Screening Screening TestTest

BB

Screening Screening

TestsTests

ConfirmatoryConfirmatory

TestTest

1 (Negative)1 (Negative) 0.1630.163 0.1830.183 0.1690.169 0.2200.220 -- NegativeNegative

2 (Nic. High)2 (Nic. High) 1.7761.776 5.7825.782 1.7841.784 5.7205.720 ++ PositivePositive

3 (Mex. High)3 (Mex. High) 1.6471.647 3.5123.512 1.6501.650 11.43011.430 ++ PositivePositive

4 (Arg. High)4 (Arg. High) 1.1841.184 1.5241.524 1.0061.006 1.5801.580 +/-+/- PositivePositive

5 (Braz. High)5 (Braz. High) 3.1413.141 7.0187.018 3.2443.244 6.9006.900 ++ PositivePositive

6 (Negative)6 (Negative) 0.1340.134 0.1980.198 0.1320.132 0.2000.200 -- NegativeNegative

7 (Nic. Low)7 (Nic. Low) 1.1311.131 2.6412.641 1.1001.100 3.5603.560 +/-+/- PositivePositive

8 (Mex. Low)8 (Mex. Low) 0.8000.800 1.8611.861 0.9440.944 3.6603.660 +/-+/- PositivePositive

9 (Arg. Low)9 (Arg. Low) 0.6060.606 0.8120.812 0.6420.642 1.0101.010 +/-+/- PositivePositive

10 (Braz. Low)10 (Braz. Low) 2.3362.336 3.7823.782 2.3962.396 3.7403.740 ++ PositivePositive

*Lot release criteria for the Confirmatory test will be determined after testing additional lots

SummarySummary

Selection of panel members guided by Selection of panel members guided by availability, antibody titer, geographic source of availability, antibody titer, geographic source of specimens and origins of US immigrant blood specimens and origins of US immigrant blood donor population.donor population.Panel dilutions guided by multiple tests on two Panel dilutions guided by multiple tests on two testing platforms.testing platforms.– 4 panel members mandatory positive (S/Co >2)4 panel members mandatory positive (S/Co >2)– 4 panel members low positive/high negative (S/Co~1)4 panel members low positive/high negative (S/Co~1)– 2 negative2 negative

Acceptance criteria for each panel member as Acceptance criteria for each panel member as negative, positive or positive/negative negative, positive or positive/negative determined by multiple testing of the diluted determined by multiple testing of the diluted specimens from final filled vials.specimens from final filled vials.

AcknowledgmentsAcknowledgments

Robert DuncanRobert DuncanSteve KerbySteve KerbyKori FrancisKori FrancisRobin BiswasRobin BiswasAlain DebrabantAlain DebrabantLeslyn AaronLeslyn AaronKaren SmithKaren SmithSilvano Wendel- BrazilSilvano Wendel- Brazil

CBER Lot Release Procedures CBER Lot Release Procedures

Manufacturer submits kit lot with testing data Manufacturer submits kit lot with testing data for FDA reviewfor FDA review– Manufacturer’s in-process test resultsManufacturer’s in-process test results– Manufacturer’s release panel resultsManufacturer’s release panel results– Test results from 100 non-reactive specimensTest results from 100 non-reactive specimens– Manufacturer’s results from CBER panelManufacturer’s results from CBER panel

CBER tests kit with CBER panelCBER tests kit with CBER panel

CBER approves/fails release of kit lotCBER approves/fails release of kit lot