1. Management of Donors and Units that Test HBV NAT Positive: Current Considerations July 21, 2005 BPAC Meeting Robin Biswas, M.D. FDA/CBER/OBRR/DETTD

2. Issue u FDA seeks Committee advice on management of donors* and units, and on a proposed algorithm to permit reentry of some donors, when a donor tests positive for: Hepatitis B Virus (HBV) DNA by a Nucleic Acid Test (NAT) ------------------------------------ *Donors of Whole Blood and blood components for transfusion (WB) and Source Plasma (SP) for manufacture into injectable plasma derivatives

3. Background u FDA recently licensed an HBV NAT (COBAS AmpliScreen HBV Test) for WB & SP donations u Currently HBV NAT donor testing is optional u It could be recommended in the future

4. Current Donor Testing for HBV Consistent with current regulations and guidance documents: u Whole Blood/Components for transfusion is tested for - Hepatitis B surface antigen (HBsAg) - Antibody to hepatitis B core antigen (anti-HBc) u Source Plasma for further manufacture is tested for - HBsAg

5. HBV Donor Testing Performed by Centers that Implement HBV NAT u Whole Blood/Components for transfusion: HBsAg, anti-HBc, and HBV NAT u Source Plasma for further manufacture: HBsAg, and HBV NAT Centers will need to make decisions regarding donor/unit management based on test result combinations

6. HBV Testing for Centers that implement HBV NAT, contd. FDA’s current position: u If a unit tests HBV NAT negative: - Donor/unit management is c/w current FDA requirements and recommendations for HBsAg and anti-HBc. - Units that test NAT and serology negative used. u If a unit tests HBV NAT positive: - Units that test NAT and /or serology positive not used. - Donor indefinitely deferred.

7. HBV NAT and Donor Reentry Proposal: An algorithm can be developed to determine eligibility of donors who test HBV NAT positive, based on subsequent negative HBV NAT and serologic test results.

8. CategoryHBV NATHBsAg Anti-HBcDonor and Unit 1 PositiveRepeat Reactive/ neutralized Non-ReactiveUnit Not Used, Donor Permanently Deferred 2 PositiveRepeat Reactive/ neutralized Repeat Reactive 3 PositiveRepeat Reactive/ Not neutralized Repeat Reactive 4 PositiveNon-ReactiveRepeat Reactive 5 PositiveNon-Reactive Unit Not Used, Donor Indef Deferred, May be reentered 6 PositiveRepeat Reactive/ Not neutralized Non-Reactive Whole Blood and Blood Components for Transfusion (overview)

9. Whole Blood and Blood Components for Transfusion, contd. CategoryHBV NATHBsAg Anti-HBc Donor and Unit 1PositiveRepeat Reactive/ Neutralized = Positive Non- Reactive Unit not used, Donor perma- nently deferred 2PositiveRepeat Reactive/ Neutralized = Positive Repeat Reactive

10. Whole Blood and Blood Components for Transfusion, contd. CategoryHBV NATHBsAg Anti-HBc Donor and Unit 3PositiveRepeat Reactive/ Not Neutralized Repeat Reactive Unit not used, Donor perma- nently Deferred 4PositiveNon-ReactiveRepeat Reactive

11. Whole Blood and Blood Components for Transfusion, contd. CategoryHBV NATHBsAg Anti-HBc Donor and Unit 5PositiveNon Reactive Unit Not Used, Donor Indefinitely Deferred, Possible Reentry 6PositiveRepeat Reactive/ Not neutralized Non Reactive

12. Source Plasma for Further Manufacture into Plasma Derivatives CategoryHBV NAT HBsAgDonor and Unit 1 PositiveRepeat Reactive/ Neutralized = Positive Unit not used, Donor Permanently Deferred 2 Positive Non ReactiveUnit not used, Donor Indefinitely Deferred, Possible reentry 3 Positive Repeat Reactive/ Not Neutralized

13. Donor Reevaluation for Possible Reentry u During clinical trials of Roche’s COBAS AmpliScreen HBV NAT under IND, - seroconversion studies showed that the maximum period of time that HBV DNA preceded HBsAg detection was 143 days. - donor follow-up studies showed that the maximum period of time that HBV DNA preceded HBsAg detection was 17 days, and anti-HBc detection was 48 days. u Additional data will be presented.

14. Donor Reevaluation for Possible Reentry, contd. u Therefore, FDA is considering recommending a minimum 6-month waiting period after a positive HBV NAT result with negative serology results prior to retesting, to ensure that, if a true infection exists, seroconversion to HBsAg and/or anti-HBc occurs

15. Donor Reevaluation for Possible Reentry, contd. u A sample (not a donation) is collected at least 6 months after the index donation u For Whole Blood/Components for transfusion donors, sample tested for HBsAg, anti-HBc, HBV DNA by individual sample NAT u For Source Plasma donors, sample tested for HBsAg and HBV DNA by individual sample NAT

16. Donor Reevaluation > 6 Months After Index Donation Category HBV DNA by Individual Sample NAT HBsAg and/or Anti-HBc Donor a PositiveAny test resultPermanently Deferred b Negative Non reactiveEligible for reentry Further evaluation, as described in FDA recommendations c Negative Repeat reactive

17. Donor Testing Before the End of 6-Month Waiting Period u May be performed for notification or medical reasons u If positive NAT obtained, donor should be permanently deferred, irrespective of serology results u Negative/non-reactive results may be used for counseling u Only negative individual NAT and negative serologic test(s), collected at least 6 months after the index donation, qualifies the donor for reentry

18. Donor Reevaluation for Possible Reentry, contd. u A sample (not a donation) is collected at least 6 months after the index donation u For Whole Blood/Components for transfusion donors, sample tested for HBsAg, anti-HBc, HBV DNA by individual sample NAT u For Source Plasma donors, sample tested for HBsAg and HBV DNA by individual sample NAT

19. Questions for the Committee 1. Based on the scientific data, does the Committee agree with FDA’s proposal that a) A donor of Whole Blood and blood components for transfusion, who tests HBV NAT positive, anti-HBc non-reactive and HBsAg non-reactive or HBsAg repeatedly reactive /not confirmed by neutralization, may be reentered, if after a minimum period of 6 months a sample from the donor tests negative for HBV DNA by individual sample NAT, non-reactive for anti-HBc and non-reactive for HBsAg, ….

20. Questions for the Committee, contd. 1. Based on the scientific data, does the Committee agree with FDA’s proposal that b) A donor of Source Plasma for further manufacture into plasma derivatives, who tests HBV NAT positive and HBsAg non-reactive or HBsAg repeatedly reactive /not confirmed by neutralization, may be reentered, if after a minimum period of 6 months a sample from the donor tests negative for HBV DNA by individual sample NAT and non-reactive for HBsAg?

21. Questions for the Committee, contd. 2. Please discuss any alternative approaches FDA should consider.