Parvovirus B19 NAT Screening and Infectivity Mei-ying W Yu CBER/FDA SoGAT XVI Paul Ehrlich Institut July 03, 2003

1. Parvovirus B19 NAT Screening and InfectivityMei-ying W YuCBER/FDASoGAT XVIPaul Ehrlich InstitutJuly 03, 2003

2. B19 NAT/BPAC Sep 1999 • 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 • B19 NAT as an in-process test, unlike HIV/HCV/HBV NAT • Quarantine and destroy in-date units when possible (However, 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)

3. B19 NAT/Dec 2001 FDA NAT WKSP • Source Plasma Fractionators • High-titer B19 minipool NAT screening (105 to 107 geq/mL of original donation) as an in-process test • Reactive minipools are resolved to single donations • Results are used to reject reactive donations • Whole Blood Establishments • Would like to implement high-titer B19 NAT screening similar to that used by SP 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

4. B19 NAT/BPAC Mar 2002 (I) FDA’s Current Thinking on B19 NAT 1. 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. 2. 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.

5. B19 NAT/BPAC Mar 2002(II) 3. 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. 4. 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 (e.g., IDE).

6. B19 NAT/BPAC Dec 2002 BPAC Recommendations 1. Reduce the risks to transfusion recipients by withholding high-titer positive units (106 geq/mL) of Whole Blood (WB) and its components from use • However, the overall value of screening WB donors has not been established • Temporarily defer plateletpheresis donors, but not WB or Source Plasma donors • Potential medical benefits to close contacts of B19 infected donors warrant notification of high-titer donors • Only if donor notification can be completed within several weeks of donations

7. B19 Infectivity Studies 1. In-vitro model (UT-7/EPO) • Infectious • Anti-B19 (-) plasma with 104 geq/mL of B19 DNA • Anti-B19 IgM (+) plasma with 108 geq/mL • Not infectious • Anti-B19 IgG (+) plasma with 106 geq/mL 2. Investigated a case report received by the FDA for the possible transmission by a high-purity factor VIII concentrate • Causal relationship between the product and the recipient • Infection occurred when the seronegative recipient received 30,000 geq of B19 DNA