Outline

1. Parvovirus B19 NAT for Whole Blood and Source Plasma Introduction and BackgroundMei-ying W Yu, PhDDH/OBRR/CBER/FDA75th Blood Products Advisory Committee

2. Outline • Introduction and Background • Overview of Parvovirus B19 Infection • Kevin Brown, MD, NHLBI/NIH • Industry Data Presentations • Update data presented at Dec 2001 FDA NAT Workshop • Data for NAT sensitivity, testing algorithm, time to resolve to single donation/donor, prevalence and levels of both B19 DNA and anti-B19 antibodies, and profiles in serial bleeds, if any • FDA perspectives and Questions for the Committee

3. Background Information • Sep 1999 BPAC • Dec 1999 FDA NAT WKSP • Dec 1999 NHLBI Parvovirus B19 WKSP • Dec 2001 FDA NAT WKSP • Mar 2002 BPAC Update • FDA’s current thinking on B19 NAT for Blood and Plasma • July 2002 Ad Hoc PHS Panel • Conclusions on medical benefits to donors and close contacts

4. Parvovirus B19 NAT as an In-Process Test (I) • BPAC Sep 1999 agreed that “pending a policy on screening Whole Blood donations, FDA need not require studies to validate the clinical effectiveness of NAT for B19 DNA under IND for plasma for further manufacturing.” • Unlike HIV/HCV/HBV NAT as a donor screening test • BPAC did not recommend resolving to the single donation/donor. For S/D Treated Pooled Plasma, the reactive 20-unit subpools were discarded (when tests completed, labile components had expired). • Quarantine and destroy in-date units when possible.

5. Parvovirus B19 NAT as an In-Process Test (II) • FDA requires that the test be reviewed under Biologics Licensing Application (BLA) mechanism for the manufactured product and that the test be validated as an analytical procedure with respect to sensitivity, specificity, and reproducibility.

6. Parvovirus B19 NAT as an In-Process Test (III) • At both FDA NAT WKSP and NHLBI Parvovirus B19 WKSP held in Dec 1999, a strategy for standardizing B19 NAT was outlined. FDA also proposed a B19 DNA limit, <104 geq/mL, for manufacturing pools. • B19 transmissions associated with S/D Treated Pooled Plasma in a phase 4 study in healthy donors • <104 geq/mL in non-transmitting lots • Viral complexing/neutralizing by anti-B19 in large pools • Viral clearance by manufacturing procedures

7. Minipool B19 NAT for Source PlasmaDec 2001 FDA NAT WKSP • Fractionators are performing high-titer B19 minipool NAT screening by in-house methods to lower the viral load in manufacturing pools. • Sensitivities of NAT assays used to exclude donations range from 105 to 107 geq/mL (original donation). • Reactive minipools are resolved to single donations. • Test results are used to reject reactive donations.

8. Minipool B19 NAT for Whole BloodDec 2001 FDA NAT WKSP • Establishments collecting Whole Blood would like to implement high-titer B19 NAT screening similar to that used by Source Plasma fractionators. • Phase I: not resolve to single donations; labile components would have expired. • Phase II: resolve to single donations by a free-standing test kit.

9. March 2002 BPAC UpdateFDA’s Current Thinking on B19 NAT (I) Recommendations that FDA is considering Plasma: When identified, high-titer B19 reactive units should not be used for further manufacturing into injectable products. This is to ensure that the FDA’s proposed limit, <104 IU of B19 DNA/mL, for manufacturing pools destined for making plasma derivatives can be met. Whole Blood: When feasible, B19 reactive minipools should be resolved to identify the individual reactive donors prior to release of components for transfusion; units from reactive donors should not be used for transfusion.

10. March 2002 BPAC UpdateFDA’s Current Thinking on B19 NAT (II) • Whole Blood: When testing is done subsequent to product release, in-date components from potentially reactive donors should be retrieved and discarded so that they are not used for transfusion or further manufacturing into injectable products. • Even when performed as an “in-process” test (i.e., not performed pre-release as part of a determination of donor eligibility or product labeling),testing and identification of the individual reactive donor constitutes medical diagnostic testing.Therefore, such testing would require the use of an FDA-approved investigational mechanism.

11. March 2002 BPAC UpdateFDA’s Current Thinking on B19 NAT (III) • Informed consent should be obtained from blood and plasma donors subjected to such high-titer NAT testing. Reactive donors should be identified, be informed of their reactive status, and be provided with medical counseling. • Because of the transient nature of the infection and rapid development of the immune response, such donors would be suitable to donate when they test non-reactive.

12. March 2002 BPAC Discussion • Largely focused on an apparent lack of medical benefits that might justify donor notification. • Consequently, FDA convened an Ad Hoc PHS panel in July 2002. • NIH: H Klein and K Brown • CDC: L Anderson, M Chamberland, B Evatt • CBER representatives

13. Conclusions/PHS Panel • Regarding the donors, there is no medical benefit in identifying high-titer B19 NAT positive donors, informing them of their reactive status, and providing medical counseling. • Regarding close contacts of the high-titer B19 NAT positive donors, there are potential medical benefits to donors’ contacts, especially those at risk, e.g., persons with certain anemias, pregnant women, and immune deficient (suppressed or compromised) individuals.

14. Issues • FDA is taking a step-wise approach in resolving B19 NAT issues concerning Whole Blood and Source Plasma. • At this meeting, FDA is seeking advice on: • the need to reduce the risks to transfusion recipients by withholding high-titer positive units of Whole Blood and its components from use • the need to temporarily defer the high-titer donors • whether potential medical benefits to close contacts of B19 infected donors warrant notifying high-titer donors. If so, what would be the time frame for notification?

15. Questions for the Committee (I) 1. If donations of Whole Blood are tested for the presence of human parvovirus B19, are risks to transfusion recipients sufficient to warrant withholding high-titer positive units (³ 106 geq/mL) from use for transfusion? 2. Is temporary deferral of positive donors warranted in the setting of: a. Whole Blood donation? b. Apheresis donation?

16. Questions for the Committee (II) 3. Do potential medical benefits to contacts of parvovirus B19 infected donors warrant identification and notification of positive donors? 4. If yes to question 3, should donor notification be limited to settings where testing and notification can be completed within several weeks of donation?