1. Risk assessment: The Safety of Blood Products presented by Dr. Thomas R. Kreil Baxter BioScience on behalf of the PPTA Pathogen Safety Steering Committee Technical meeting with FDA April 29, 2003

2. 29.04.03 2 The safety of blood products  Risk assessment considerations – Plasma viremia – Infectious virus titer of positive units – Prevalence of viremia in the population – Resulting plasma manufacturing pool loads – Reduction by manufacturing processes – Further relevant features

3. 29.04.03 3 Symptomatic Individuals – 10 2 – 10 5 iu/ml: in patients with underlying malignant disease CM Southam & AE Moore, Am J Trop Med Hyg [1951] 31: 724 – 2.5 x 10 6 c/ml: 3 days after onset of neurological symptoms C Huang et al., http://www.cdc.gov/ncidod/EID/vol8no12/02-0532.htmhttp://www.cdc.gov/ncidod/EID/vol8no12/02-0532.htm Otherwise Healthy Donors – 1-5 x 10 3 c/ml: FDA BPAC briefing package, March 13, 2003 – 2 x 10 5 c/ml: 1 in 7,107 (out of samples 75% targeted for risk ) A Conrad / NGI, BPAC March 13, 2003  worst case: 2 x 10 5 PCR copies/ml West Nile Virus - Viremia

4. 29.04.03 4 Infectious virus titer of positive units – Mean PCR detectable amount of virus: 0.00289 pfu/mL (0.001640 – 0.005099 pfu/mL) A Conrad / NGI, BPAC March 13, 2003; CDC WNV panel (Lanciotti) – Assuming that already ONE copy is PCR detectable:  1 infectious virus particle per 346 (196-610) genomes – Viremia of max. 2x10 5 PCR detectable genomes, at only 1 infectious particle per 196 genomes:  worst case: max. 1,020 infectious units per ml West Nile Virus

5. 29.04.03 5 Prevalence of viremia in the population  Modeling approach – US average risk: 0.36 per 10,000 donors – US maximum risk: 1.55 per 10,000 donors (peak epidemic) – Michigan: about 4 per 10,000 donors (during the epidemic) – Michigan: about 10 per 10,000 donors (peak epidemic, Sept 1) – Detroit: up to 20 per 10,000 donors (peak epidemic, Sept 1) Dr. Lyle Petersen / CDC: BPAC, March 13, 2003 http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3940t1.htm West Nile Virus

6. 29.04.03 6  Verification by testing (viremia study) – Samples from Cleveland and Detroit: i.e. highest risk areas – Obtained during the first three weeks of September 2002: i.e. highest risk period – model: estimated risk ~ 8.2 per 10,000 in that population. – TaqMan PCR: 6 / 5,761 samples positive, i.e. viremia prevalence:  worst case: 10.4 per 10,000 Dr. Sue Stramer / ARC: BPAC, March 13, 2003 http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3940t1.htm Prevalence of viremia in the population West Nile Virus

7. 29.04.03 7 Max. viremic donor prevalence: 10.4 per 10,000  i.e. approx. 1 per 1,000 Max. viremia levels: 1,020 infectious units / ml Dilution of viremic donations into manufacturing pools:  maximum of 1 infectious unit per ml, assuming the  highest potential load, and the  highest prevalence  WORST CASE (earthquake during a hurricane) Resulting plasma pool loads West Nile Virus

8. 29.04.03 8  Plasma viremia: 1-5 x 10 3 c/ml (FDA BPAC info) assume mean of 3,000, statistically  Infectious virus titer of positive units: ~10 units/ml 1 infectious virus particle per 346 genomes, i.e. mean of determined range  Prevalence of viremia in the population: 2/10,000 average risk throughout the U.S., during peak epidemic  Resulting plasma manufacturing pool loads:  ~0.001 units/ml  PLUS: reduction by manufacturing processes ! Base case West Nile Virus

9. 29.04.03 9 WNV would be below the limit of detection for current virus assays Inconsistent with current practice for HIV, HCV and HBV Resulting plasma pool loads West Nile Virus

10. 29.04.03 10 ALL dedicated virus inactivation steps which have been investigated so far resulted in  complete inactivation of WNV reduction factors ranging between >5.5 and >8.2  very rapid inactivation kinetics of WNV  verification of the fact that WNV behaves exactly like predicted from model virus (BVDV, TBEV) data !! Reduction by manufacturing processes West Nile Virus

11. 29.04.03 11 Besides dedicated virus inactivation steps, other steps contribute to virus reduction during manufacturing process. – only dedicated steps considered For manufacturing process, the overall virus reduction capacity is determined by a combination of virus inactivation and virus removal. – only inactivation investigated Reduction by manufacturing processes ? West Nile Virus

12. 29.04.03 12 Acute self-limiting infection: life-long test-based donor deferral is only prudent for chronically-infected persons  No medical benefit to the donor  No public health benefit from WNV testing Further relevant features West Nile Virus

13. 29.04.03 13 Conclusions:  Donation loads below limit of detection for current test strategies  Typical flavivirus characteristics  Effective viral reduction by existing processes West Nile Virus