Transcript CBER Chagas Serological Lot Release Panel Development Hira L. Nakhasi, Ph.D. Director, Division of Emerging and Transfusion Transmitted Diseases, OBRR/CBER/FDA.

CBER Chagas Serological Lot
Release Panel Development
Hira L. Nakhasi, Ph.D.
Director, Division of Emerging and
Transfusion Transmitted Diseases,
OBRR/CBER/FDA
Challenge for Blood
Products
Enhance
Product Safety,
Purity and
Potency
and
Avoid Product
Shortages & Major
Increased Costs
Critical Path opportunities exist that could
improve blood product safety, efficacy and
availability while minimizing disruptions to the
blood system
FIVE LAYERS OF BLOOD SAFETY
FDA’s approach is to optimize each safety layer:
1. Donor screening and deferral based on geographic,
behavioral and medical risk factors (donor education,
self deferral, donor interview)
2. Laboratory testing and deferral (HIV-1, HIV-2, HBV,
HCV, HTLV-I, HTLV-II, WNV, Chagas, syphilis)
3. Deferral registries to prevent use of blood from deferred
donors
4. Quarantine controls to prevent unit release pending
verification of donor suitability
5. Investigation and correction of deviations
Impact on the US Public Health:
Blood Safety and Availability
• Millions of units are transfused
annually
• Risk of transmission of infectious
disease agents through transfusion
has been significantly reduced with
the introduction of donor screening
tests
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. testbased deferrals
Chagas Transmissions by Blood or
Organ Donations: U.S./Canadian
1987: California – Mexican blood donor
1989: New York City – Bolivian blood donor
Manitoba – 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 Mexico
Los Angeles – Heart donor born in El Salvador
Blood Screening ELISA Licensed
December, 2006 ORTHO T. cruzi ELISA Test
System approved for use as a blood
screening assay
Large blood centers implemented testing
Feb. 2007. FDA recommendations for
implementation under consideration.
Pre-release testing of kit lots is CBER
responsibility
CBER Lot Release Panel developed
Cross testing with manufacturers panels
T. cruzi Reactive Donors by State
of Residence (01/29/07 – 01/14/09)
Total Repeat Reactive
RIPA
Positive
RIPA
Negative/Ind
RIPA
Pending/NT
3071
749
2177 / 47
98
26
22
16
9
9
31
53
13
6
53
229
42
19
43
1
81
4
59
81
14
DC
119
16
37
38
27
2
17
39
8
482
73
52
26
65
21
96
31
24
46
18.9 million donations screened
0.015% RR rate
RR 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)
26
35
12
PR
30
57
26
78
30
36
365
* 3 RIPA pos samples represent
multiple positives from auto donor
and cord blood
Epidemiology of T.cruzi infection
among US blood donor
Confirmed positive (RIPA) donors:
–
–
–
–
25% US born
75% born in T.cruzi endemic countries
63% first time donors (increasing)
37% repeat donors (declining)
Potential autochthonous cases ~42
Chagas positive cases from 47 states
Look back has identified 0/88 of recipients*
– All donors are long term chronic asymptomatic (low parasitemia)
– Transfusions are rarely WB
– L/B have few platelet Transfusions ( > probability to transmit than
RBC)
– *On going investigations for a few cases possible T-T but rare
No true seroconversions have been identified
Current Status of T.cruzi testing
in the US
Continuation of universal blood screening
for T.cruzi to have a better evaluation of
epidemiology of the disease and
performance of the tests.
Need for licensed confirmatory test for
donor reentry
Blood established performed validation of
selective testing strategy (STS) to chart
future course of testing in the US
Public discussion of the STS
Standardization of Serological Testing
for Chagas’ Disease
Validation and licensing of new tests
– Analytical characteristics
Sensitivity, specificity and reproducibility
– Clinical characteristics
Random donor specificity trial
Known positive and High risk sensitivity trials
Testing lot to lot consistency of licensed
assays
T. cruzi Panel Development
Purpose
∙ Lot Release Panel to test lot to lot consistency
∙ Not a Reference Panel
∙ Not an International Standard
Objective
∙ Obtain T. cruzi positive specimens from various
geographical locations.
∙ Emphasis on immigration patterns found in the
U.S. donor pool from endemic countries.
*
Geographic Distribution
offromPanel
Members
Total Immigration
Chagas Disease
Endemic
Countries as of 2004
*
*
*
7%
*
7%
11.7%
*
7%
7%
17.7%
30%
3%
Mexico
El Salvador
Columbia
Guatemala
Ecuador
Honduras
Peru
Nicaragua
Brazil
Argentina
Venezuela
Panama
Chile
Costa Rica
Bolivia
Paraguay
Uruguay
10.7%
0.1%
9.8%
*
*Endemic countries
for CBER Panel
24%
3.9%
0.4%
N%-WHO estimate of prevalence,
1.2% 0.1%
*
Global burden of Chagas’ disease in the year 2000 DRAFT
A Moncayo, F Guhl, C Stein.
http://www.who.int/healthinfo/statistics/bod_chagas.pdf
Preliminary Formulation of Panel
Obtained/Purchased positive units and
tested neat for titers and co-infections
(e.g. HCV, HBsAg, HIV etc.)
Determined acceptable units for possible
panel manufacturing
∙ Highest Titers
∙ Largest Volumes
∙ Geographical Variation
Preliminary Formulation of Panel con’t
Chose Acceptable Units from Following Areas
∙ Mexico, Argentina, Nicaragua, and Brazil
Tested at CBER/DETTD with Serial Dilutions until
Non-Reactive
∙ Ortho T. cruzi ELISA Test System
Sent Serial Dilutions to Kit Manufacturers
∙ Ortho-Clinical Diagnostics
∙ Abbott Laboratories
Evaluate all results to construct final panel
Candidate CBER Lot Release Panel
10 Member Panel
– 2 Negatives
– 4 geographical units at 2 dilutions
∙ Consensus High Positive (S/CO >2.0)
∙ Consensus Low Positive (S/CO ~ 1.0)
500 ml Bulk, 500 ml for Final Vialing
Fill Volume 1.25 ml
Validation of Candidate Panel
CBER/DETTD Tested Final Vialing
∙ Ortho T. cruzi ELISA Test System
∙ Abbott PRISM Chagas
∙ Abbott Chagas Confirmatory Assay
Ortho-Clinical Diagnostics Tested
∙ Ortho T. cruzi ELISA Test System
Abbott Laboratories Tested
∙ Abbott PRISM Chagas
∙ Abbott Chagas Confirmatory Assay
CBER Panel Testing Results
Manufacturers
Testing
Manufacturers
Testing
CBER
Testing
CBER
Testing
Lot Release
Criteria
CBER and
Manufacturers
Testing*
Screening Test
A
Screening
Test
B
Screening
Test
A
Screening
Test
B
Screening
Tests
Confirmatory
Test
1 (Negative)
0.163
0.183
0.169
0.220
-
Negative
2 (Nic. High)
1.776
5.782
1.784
5.720
+
Positive
3 (Mex. High)
1.647
3.512
1.650
11.430
+
Positive
4 (Arg. High)
1.184
1.524
1.006
1.580
+/-
Positive
5 (Braz. High)
3.141
7.018
3.244
6.900
+
Positive
6 (Negative)
0.134
0.198
0.132
0.200
-
Negative
7 (Nic. Low)
1.131
2.641
1.100
3.560
+/-
Positive
8 (Mex. Low)
0.800
1.861
0.944
3.660
+/-
Positive
9 (Arg. Low)
0.606
0.812
0.642
1.010
+/-
Positive
10 (Braz. Low)
2.336
3.782
2.396
3.740
+
Positive
Panel Member
*Lot release criteria for the Confirmatory test will be determined after testing additional lots
Summary
Selection of panel members guided by
availability, antibody titer, geographic source of
specimens and origins of US immigrant blood
donor population.
Panel dilutions guided by multiple tests on two
testing platforms.
– 4 panel members mandatory positive (S/Co >2)
– 4 panel members low positive/high negative (S/Co~1)
– 2 negative
Acceptance criteria for each panel member as
negative, positive or positive/negative
determined by multiple testing of the diluted
specimens from final filled vials.
Acknowledgments
Robert Duncan
Steve Kerby
Kori Francis
Robin Biswas
Alain Debrabant
Leslyn Aaron
Karen Smith
Silvano Wendel- Brazil
CBER Lot Release Procedures
Manufacturer submits kit lot with testing data
for FDA review
– Manufacturer’s in-process test results
– Manufacturer’s release panel results
– Test results from 100 non-reactive specimens
– Manufacturer’s results from CBER panel
CBER tests kit with CBER panel
CBER approves/fails release of kit lot