Cell Therapy Liaison Meeting January 27, 2006 Industry – Outline of Issues and Data

1. Cell Therapy Liaison MeetingJanuary 27, 2006Industry – Outline of Issues and Data Susan L. Stramer, PhD American Red Cross representing multiple contributing Blood and HPC Centers Updated March 20, 2006

2. Issue and Goals • Mini-pool (MP) NAT for HIV-1 and HCV of HPC donation samples is not currently acceptable; testing must be performed by individual donation (ID) NAT (AABB/ISCT teleconference Nov 9, 2005) • Upon communication of this information from AABB (AABB Pulse Points, Nov 29, 2005), blood centers converted from MP to ID NAT with the goal of qualification of MP NAT for HPC donations in the future • Multiple communications within organizations to ensure compliance; e.g., ARC, Dec 7, 2005; AATB, Nov 17, 2005

3. Issues and Goals • “Specimens from other living donors (except whole blood, blood components or source plasma) and from cadaveric donors should be tested using the individual donor testing method only” • (GP insert, version IN0076-01 REV A) • Definition of a blood component: “product containing a part of human blood separated by physical or mechanical means” (21 CFR 1271.3(i)) • Interpretation was that donations from HPC donors (peripheral blood stem cells, maternal cord blood, bone marrow) meet this criteria

4. Issues and Goals • Analysis in support of MP NAT prospectively/retrospectively by comparing frequency of infectious disease markers in HPC donations to those of donations of whole blood (autologous and allogeneic FT/RPT donations; i.e., those already approved for MP NAT) • Data to be shared with FDA but will be submitted to manufacturers so that their package inserts may be modified to include a claim for MP NAT of HPC donations (assuming the data support such a modification)

5. Points to Consider • NAT clinical trials, and prospective use of the licensed assays, have included samples from the following donations in context of MP NAT: allogeneic FT/RPT, autologous, pheresis, HPCs • All samples from heart-beating donors meeting the sample suitability criteria of the clinical protocols/licensed inserts were considered suitable for pooling and testing • Only donations of organ and tissue donors have been tested by ID NAT due to sample suitability issues; testing frequently occurs in separate laboratories to segregate from samples tested by MP NAT • Hemodilution/hemolysis (not included in this presentation) • At request of FDA, separate analysis was performed post-licensure to include volunteer source pheresis; insert modified based on analyzed data

6. Points to Consider-False Positivity • Impact of ID NAT on lost donors/products • MP involves two rounds of testing in contrast to ID NAT • False positive rates since FDA licensure: • 1:40,000-1:100,000 (0.001-0.0025%) for MP NAT by site • 1:555-1:2150 for ID NAT by lot (0.08-0.18%; mean 0.13%) • 32-180X (80X mean) higher reactive rate for ID NAT • Decrease in specificity of 99% • Additional loss of 130 donors/donations for every 100,000 tested • Result is the loss of valuable, sometimes irreplaceable donors/donations

7. Points to Consider-Cost • Impact of ID NAT on cost • Additional $3-5 per donation for ID vs MP NAT • Current price approx $10.00 per MP NAT; additional $300,000-$500,000 for every 100,000 donations for ID NAT • One manufacturer (GP/Chiron) has agreed not to increase pricing until March 2006; then price will increase

8. Points to Consider-Logistics • Impact of ID NAT on logistics • Up to 8000 samples/day arrive in a consolidated testing lab • No automated systems to sort samples; performed manually based on visual examination of each tube and sorting based on WBN codes on tube labels • Procedures/processes developed to identify and test HPC donations by ID NAT • Error prone; what is impact of an HPC inadvertently tested by MP NAT? • Increase in staff needed for sorting/testing/QC • Cost not captured in this presentation

9. Analysis Goals • To determine the infectious disease marker prevalence/incidence rates for donations of Hematopoietic Progenitor Cells (HPC) donors to qualify these donations for MP NAT by demonstrating equivalence to blood donation types already included in the intended use statements for licensed NAT assays, and prove that the risks associated with MP NAT as compared to ID NAT for HPC donations are no greater than the difference between MP and ID NAT for donations of whole blood

10. Analysis Methods • Prevalence of HIV, HCV and HBV determined by antibody or antigen confirmed positive rates (using specific confirmatory tests or NAT, or repeat reactivity if none of the above exist, such as anti-HBc) • Incidence of each agent (including WNV) will be determined by NAT yield (antibody/antigen negative) • Included in the analysis are the test results for samples of donations of HPC donors collected from geographically distinct US collection facilities from the time of NAT licensure to the end of 2005 • Results from screening ARC whole blood donations from a similar period of time serve as the control

11. Analysis Methods • Spreadsheet distributed through AABB and ABC to collecting and testing sites (Nov 30, 2005) • Requested results for all infectious disease testing including: anti-HIV-1/2, HIV-1 NAT, anti-HCV, HCV NAT, HBsAg, anti-HBc, HBV NAT and WNV, as available • FDA licensed tests or testing using approved investigational protocols/reagents • Break out requested by HPC type • Peripheral blood stem cells (PS) • Bone marrow (B) • Maternal cord blood (C)

12. Analysis Methods • Data submitted to ARC to prepare a consolidated line listing and to perform analysis vs a control population already approved for MP NAT • ARC donor population: autologous and allogeneic donations from 4/1/04-3/31/05 • 6.55 million allogeneic and 1.066 million autologous donations • Data included in the analysis represent all donations that meet the licensed/investigational package insert sample suitability requirements

13. Data Collection from HPC Sites • Data received from 10 organizations, many with multiple organizations represented • e.g., NMDP has 72 submitting centers with 34 different testing sites • 171,619 HPC submitted data points having both NAT and serology results (next slide) • 139,654 HPC samples associated with a donation (removal of 31,965 “unknown types” not associated with a donation)

14. Donations Analyzed-update3/20/06

15. Submissions from All Submitting Sites Combined by HPC Donation Type; Complete Data for N=139,654 (3/20/06)

16. Frequencies of Marker Positives in Whole Blood DonationsARC; 4/1/04-3/31/056.55 million Allogeneic and 1.066 million Autologous Donations

17. Frequencies of Marker Positives in Whole Blood DonationsARC; 4/1/04-3/31/056.55 million Allogeneic and 1.066 million Autologous Donations

18. Frequencies of Marker Positives in Whole Blood DonationsARC; 4/1/04-3/31/056.55 million Allogeneic and 1.066 million Autologous Donations

19. Frequencies of Marker Positives in Whole Blood DonationsARC; 4/1/04-3/31/056.55 million Allogeneic and 1.066 million Autologous Donations

20. Frequencies of Marker Positives in HPC DonationsAll Submitting Sites; Date of Licensure-12/31/05139,654 HPC Donations vs Control Donations

21. Frequencies of Marker Positives in HPC DonationsAll Submitting Sites; Date of Licensure-12/31/05139,654 HPC Donations vs Control Donations

22. Frequencies of Marker Positives in HPC DonationsAll Submitting Sites; Date of Licensure-12/31/05109,286 HPC Donations vs Control Donations

23. Frequencies of Marker Positives in HPC DonationsAll Submitting Sites; Date of Licensure-12/31/0538,052 HPC Donations vs Control Donations

24. Comparisons by MarkerHPC vs Control Sample Sets Analyzing Controls as: Combined, Allogeneic and Autologous • HIV • Antibody => only significant difference observed was autologous > HPCs • 2.91 autologous vs 0.36 HPCs/10,000 donations • NAT => no HIV yield samples • HCV • Antibody => significant differences observed where autologous > all others • 105 autologous vs 15.40 HPCs/10,000 donations • NAT => no significant differences between autologous and HPC donations • Confirmatory data lacking for five of thirteen HCV NAT yield HPC donations

25. Comparisons by MarkerHPC vs Control Sample Sets Analyzing Controls as: Combined, Allogeneic and Autologous • HBV • Antibody => significant differences where autologous highest • 30 allogeneic, 36 combined, 274 HPCs vs 401 autologous/10,000 donations • HBsAg => significant differences where HPC highest • 1.29 allogeneic, 1.49 combined, 14.16 autologous vs 25.44 HPCs/10,000 donations • Impact of Ortho 3 false positivity unknown • 70% (196/278) of HPC positives Ortho 3 confirmed • NAT => no yield samples • WNV • NAT => no significant differences between any groups • Confirmatory data lacking for two of three WNV NAT yield HPC donations

26. Comparison of Prevalence Rates/10,000 donations *p<0.05 for one or multiple comparisons; ** Ortho System 3

27. Summary and Conclusions • Overall comparison of prevalence rates shows no difference between control groups and HPC donations • 3 of 4 cases autologous higher, 1 case of 4, HPC higher where Ortho 3 used only for HPC group • No significant differences in incidence (as determined by NAT yield) observed between control groups and HPC donations • With HPC NAT-reactives mostly unconfirmed • No additional risk of MP NAT for HPC donations as compared to the control groups for which MP NAT occurs

28. Next Steps • Share presentation with test kit manufacturers • Prepare line listings by submitting site/donation type, including analysis versus control population and provide to the NAT test kit manufacturers for labeling modifications to allow MP NAT of HPC donations • Next series of slides highlight the individual manufacturers’ data (3/20/06)