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Risk Analysis for TSE and Plasma Derivatives Steven Anderson, PhD, MPP

Risk Analysis for TSE and Plasma Derivatives Steven Anderson, PhD, MPP Office of Biostatistics & Epidemiology Center for Biologics Evaluation and Research U.S. Food and Drug Administration. Elements of Risk Assessment. Hazard identification Source(s) of risk and details of adverse effects

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Risk Analysis for TSE and Plasma Derivatives Steven Anderson, PhD, MPP

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  1. Risk Analysis for TSE and Plasma Derivatives Steven Anderson, PhD, MPP Office of Biostatistics & Epidemiology Center for Biologics Evaluation and Research U.S. Food and Drug Administration

  2. Elements of Risk Assessment • Hazard identification • Source(s) of risk and details of adverse effects • Exposure assessment • Frequency and Level of exposure • Hazard characterization • Dose-response relationship • Risk characterization • Probability of occurrence, severity of adverse effects • Uncertainty • Sensitivity analysis

  3. Quantitative Risk Assessment • Foundation is a computer model • “Link” relevant data together in a meaningful way • Estimate potential exposure / risk • Framework to identify critical elements where research will improve model • Understand key elements that “drive” risk

  4. Issues for Modeling TSE & plasma risks • Uncertainty exists for certain parameters • Little or no data available • Few replicates of some data • Variability • Variability among processing steps • Is reduction real? • Detection and measurement may be difficult • Especially when reduction is small (<1 or 2 logs)

  5. Objectives of Risk Modeling • Quantitate the relative contributions of parameters in the model • Identify critical elements for additional research in order to improve the model • Provide improved estimates of risk for making regulatory decisions

  6. Modeling allows “What if” Analysis • CJD in donor population • (rate of 1 per million) • Potential for vCJD in U.S. donor population • We assumed a rate of 1 per million for vCJD in the U.S. • UK rate ~0.3 – 0.4 million

  7. “What if” Analysis (cont’d) • Standard for viral clearance is > 4 Log10 per processing step • difficult to achieve that level for TSEs Therefore we modeled and evaluated risk for all processing steps with : • > 2 Log10 reduction of TSE ID50 • > 3 Log10 reduction of TSE ID50

  8. Scope of the Risk Assessment • 3 Products : • Albumin, Immune Globulin, Factor VIII • What is the potential exposure / risk posed by CJD and vCJD? • What level of reduction occurs for each type of product?

  9. Sporadic CJD Mean age ~65 yr Mean duration ~ 4 mo Presentation: confusion, sometimes ataxia Variant CJD Mean age ~29yr (19 to 52) Mean duration ~ 12 mo Presentation: abnormal behavior, dysesthesia Sporadic CJD and vCJD(modified from Will & al. Lancet 1996;347:921)

  10. Considerations of CJD Risk Assessment Models • Prevalence of CJD / vCJD in the donor pool • Asymptomatic CJD / vCJD cases • Sources of uncertainty in the model

  11. Plasma & TSE Risk Model Contaminated pools Amount ID50s Characterization Donor population Age & Frequency Prevalence CJD / vCJD Recovered Source Pools Pools TSE-positive Pools Percent / Number Quantity of Agent Plasma processing & Reduction levels All pools Amount TSE agent Production / Utilization Exposure / Risk?

  12. Data Inputs for the Model • Census data - Population by age group • Age-specific U.S. CJD deaths and vCJD data for U.K. • Age-specific plasma donations • Assumptions regarding screening and processing • Assumptions / Data on quantity of TSE agent in plasma • Data process specific clearance / reduction of TSE agent • Data on amounts of manufactured products and utilization

  13. Parameters in TSE Plasma Model

  14. Parameters for AlbuminBased on SNBTS Process for fractionation(Foster et al, Vox Sang 2000; 78:86-95 1999) * ( ic ID50 Log10 )

  15. Model Results for Albumin • ~ 95,000 Kg Albumin distributed in U.S. • 25 grams albumin per liter plasma • Approximately 5.2 million donors (source plasma) • Number of pools (60,000 donors) • Recovered plasma– 880 pools • Source plasma- 220 pools • Utilization is difficult to estimate • Albumin used in many products / procedures • Model predicted: • Potential for CJD infectivity in up to 72% of all pools • Potential for CJD + vCJD infectivity in up to 85% of all pools

  16. Albumin: Results – Potential ID50per gram

  17. Parameters for Immunoglobulin Based on SNBTS Process for fractionation(Foster et al, Vox Sang 2000; 78:86-95 1999) * ( ic ID50 Log10 )

  18. Model Results for Immunoglobulins • ~23,000 Kg Immunoglobulins distributed in U.S. • 3 grams Immunoglobulin per liter starting plasma • Approximately 9 million donations (source plasma) • Number of pools (60,000 donors) • Recovered plasma– 640 pools • Source plasma- 160 pools • Utilization estimate • Recipients get IG every 3 weeks (~400mg/kg) • 120 lb person may receive 380 – 400g annually • Model predicted: • Potential for CJD infectivity in up to 72% of all pools • Potential for CJD + vCJD infectivity in up to 85% of all pools

  19. Immunoglobulins: Results – Potential ID50per gram

  20. Immunoglobulins: Results – Potential ID50per 380 grams

  21. Parameters for Factor VIII Based on SNBTS Process for fractionation

  22. Model Results for Factor VIII • ~ 375,000,000 units (IU) distributed in U.S. • 150 IU per liter of starting plasma • Approximately 3 million donations (source plasma) • Number of pools (60,000 donors) • Recovered plasma– 220 pools • Source plasma- 55 pools • Utilization estimate • Product is used on an episodic basis • Product can be used prophylactically ~ 80,000 IU • Model predicted: • Potential for CJD infectivity in up to 72% of all pools • Potential for CJD + vCJD infectivity in up to 85% of all pools

  23. Factor VIII: Results Potential ID50 per 250 units

  24. Factor VIII: Results Potential ID50 per 80,000 units

  25. Summary of Modeling findings • On a per gram / unit basis : • Albumin - 10-9 to 10-11 iv ID50 • Immunoglobulins - 10-5 to 10-8 iv ID50 • Annual treatment - 10-3 to 10-5 • Factor VIII (250 IU) - 10-4 iv ID50 • Annual treatment - < 10-2

  26. Data Gaps More data are needed on: • the amount of CJD / vCJD agent that is present in blood & plasma • the progression of CJD / vCJD and the variability of levels of infectivity in blood & plasma • the variability in reduction of CJD / vCJD agent that might occur during various processing steps • Plasma product utilization

  27. Acknowledgements • Dorothy Scott, OBRR • David M. Asher, OBRR • Rolf Taffs, OBRR • John Finlayson, OBRR • Mark Weinstein, OBRR • Donor data provided by: • Westat • REDS-National Heart Lung Blood Institute (2001)

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