1. Preliminary Risk Assessment Model for U.S. Plasma Derivatives and vCJD 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 NAS (1983) I. Hazard identification Establishes causality between hazard and adverse effects II. Dose response (Hazard characterization) Probability of response – infection or illness III. Exposure assessment Frequency and level of exposure IV. Risk characterization Probability of occurrence, severity of adverse effects Uncertainty Sensitivity analysis

3. Risk Assessment Question l Given the recent probable transmission of vCJD via transfusion of non-leukocyte reduced RBC concentrates in the United Kingdom, what is the risk of potential exposure to the vCJD agent to the US population(s) that have received US- manufactured human plasma derivatives?

4. Risk Assessment l FDA has risk assessments underway for several plasma derivatives n FVIII n FIX n Immune globulins n Serum albumin l This presentation provides an overview of the concept model and assumptions for the risk assessments for the above products l The risk assessments have not been completed!

5. I. Hazard Identification l Two recent cases of probable transfusion- transmitted vCJD in United Kingdom l Raise possibility of transmission of vCJD via plasma derived products l To date vCJD transmission via plasma derivatives has not been observed

6. II. Dose response (or Hazard characterization) l Human data not available –On BSE dose(s) that cause vCJD –Quantity vCJD ID 50 causes infection by blood l Animal data limited –Multiple dose groups needed l Development of a dose response model not possible at this time l Predicting probability of vCJD illness is extremely uncertain ! Probability of infection 50% 100% 12 Quantity of agent

7. III. Exposure Assessment Plasma derivatives and vCJD Key aspects of exposure assessment: (A) vCJD in US population and plasma pool –Probability of agent in pool and –Quantity (dose) TSE agent in starting pool l (B) Plasma donation –Probability of deferral –Probability of agent in pool l (C) Reduction during manufacture –Reduction in Quantity (dose) TSE agent in product l (C) Dose per surgery or treatment(s) –Quantity of vCJD agent in final product –Amount of product used by patients

8.  Probability vCJD plasma pool  Screening questionnaire  Plasma pool size  Infectivity in plasma  Reduction of quantity vCJD agent during manufacture  Product yield  Percent contaminated vials  Amount vCJD agent per unit(s)/ vial(s)  Annual dose product Module A vCJD cases US Module B Plasma Donation Module C Processing Module D Utilization INPUTMODULEOUTPUT  Percentage of contaminated plasma pools  Quantity vCJD agent in contaminated plasma pool  Percentage units/ vials with vCJD ID 50  Infectivity units/ vials with vCJD ID 50  Annual exposure to vCJD agent  Theoretical estimate of potential annual number vCJD cases in the United States  UK vCJD cases  US vCJD risk dietary exposure to BSE US Plasma Derivatives Risk Assessment Exposure Assessment Overview

9. III.Exposure Assessment: Module A: Potential vCJD cases in US vCJD risk in US plasma donors possible from two sources: (1) Dietary exposure to BSE agent from US domestic beef consumption (2) Dietary exposure to BSE agent during extended travel to UK and Europe

10. III.Exposure Assessment: Module A: Potential vCJD cases in US (1) Dietary exposure to BSE agent from US domestic beef consumption  Evaluation of USDA BSE surveillance data in US cattle  Currently – estimated risk of domestically acquired vCJD in United States from this route is negligible  Model assumes zero cases from this source

11. III.Exposure Assessment: Module A: Potential vCJD cases in US (2) Dietary exposure to BSE agent during extended travel to UK and Europe Approach: Model estimates vCJD prevalence in UK population “Relative risk” of exposure to BSE agent in relation to UK risk is estimated for France and Europe vCJD risk then calculated for US plasma donors with history of extended travel to UK, France, and Europe

12. III.Exposure Assessment: Module A (2) Dietary exposure to BSE agent during extended travel to UK and Europe Calculation US donor vCJD risk based on: (a)Prevalence vCJD in UK (b)Relative risk of UK, France, Europe for BSE/vCJD (c)Percentage US donors with travel history UK, France & Europe (d)Duration of US traveler stay Potential cases vCJD in US = [(UK Prev vCJD) x (Rel Risk UK) x (% US donors) x (duration in UK)] + [(Fr Prev vCJD) x (Rel Risk Fr) x (% US donors) x (duration in Fr)] + [(EU Prev vCJD) x (Rel Risk Eu) x (% US donors) x (duration in EU)] + others

13. III. Exposure Assessment: Module A (2) Potential vCJD cases in US due to BSE dietary exposure during travel (a) Prevalence of vCJD in UK population  Tonsil/appendix surveillance study (Hilton, et al. 2004)  3 prion positive samples in 12,674 samples tested  Mean of 1 positive in 4,225 individuals

14. III.Exposure Assessment: Module A (2) Potential vCJD cases in US due to BSE dietary exposure during travel (b) Relative risk of UK, France, Europe for BSE/vCJD  UK > 3 months - 1980 – 1996  France, Europe > 5 years - 1980 - present  Model uses concept of “relative risk” presented at TSEAC at past meetings  to evaluate vCJD risk for US plasma donors with history of extended travel  Donor travel risk is evaluated in relation to UK vCJD risk

15. III. Exposure Assessment: Module A (2) Potential vCJD cases in US due to BSE dietary exposure during travel (b) Relative risk of UK, France, Europe for BSE/vCJD vCJD risk of UK citizens is assumed – equal to 1 Other country exposures are a fraction of the UK relative risk Based on potential exposure to BSE, vCJD prevalence, etc. US donor travel stay in UK: UK > 5 years (1980 to 1996) - relative risk 1 UK < 5 years - 1980 to 1996  Risk for stay for 3 months to 5 years pro-rated on a per year basis  Relative risk apportioned equally for each of 17 years between 1980 - 1996 US donor travel stay in France and Europe: France >5 years (since 1980) - relative risk 0.05 Europe >5 years (since 1980) - relative risk 0.015

16. III. Exposure Assessment: Module A (2) Potential Potential vCJD cases in US BSE dietary exposure during travel (c)Percentage US donors with travel history UK, France & Europe ~ 6% US residents - history of travel to UK and Europe during 1980s and 1990s ~ 3% US residents Military and dependents history of travel to UK and Europe 1.7% traveled to UK (1980 – 1996) for 3 month period 0.2% traveled to France since 1980 for 5 year period 0.7% traveled to Europe since 1980 for 5 year period

17. III. Exposure Assessment: Module A (2) Potential Potential vCJD cases in US BSE dietary exposure during travel (d) Duration of travel to UK, France and Europe  Travel history and duration of travel data was collected for blood donors using blood center surveys  Model assumes blood donor travel history data is same for plasma donors  However, plasma donors less likely to have history of travel to UK and Europe  Model may slightly overestimate vCJD risk for US plasma donors

18. III. Exposure Assessment: Module B Plasma Donation US donors with travel history Model incorporates information on: (1)Age specific plasma donation rates (2)Age specific vCJD rates (3)Probability of vCJD donation per plasma pool (4) Quantity iv ID 50 per plasma donation (5) Probability of donor deferral

19. III. Exposure Assessment: Module B Plasma Donation Age (in yrs) Percentage plasma donors by age < 25 42 % 25 - 34 28 % 35 - 44 19 % > 45 11 % (1) Model uses estimated age specific Source Plasma donation rates

20. (2) Age specific vCJD rates - Model assumes vCJD for US -similar age demographics to UK - Based on UK data (Knight et al 2004) III. Exposure Assessment: Module B Plasma Donation

21. (3) Probability of vCJD donation per plasma pool  Model uses equation to estimate vCJD donations per pool:  n = number donations  D pool = Total donations per pool  D C-prev = prevalence vCJD donation(s)

22. III. Exposure Assessment: Module B Plasma Donation (4) Quantity iv ID 50 per plasma donation  ic ID 50 per ml blood  Minimum 0.1  Most likely 10  Maximum 1,000  Model assumes 58% associated with plasma (Gregori, et al. 2004)  Model assumes source plasma donation is 800 mls  Assume adjustment 5 to 10 fold for efficiency of intravenous vs. intracerebral route exposure

23. III. Exposure Assessment: Module B Plasma Donation (5) Probability of donor deferral  Model assumes donor questionnaire is 90% - 95% effective

24. III. Exposure Assessment: Module C Processing Effect of processing on vCJD infectivity (1) Log 10 reduction ID 50 during processing Processing varies Reduction based on processing steps High purity – immunopurified product Intermediate purity - alcohol precipitation, chromatography, etc.

25. III. Exposure Assessment: Module C Processing : Example using Factor VIII Reduction during Manufacturing Parameter Log 10 reduction Minimum Most Likely Maximum High purity FVIII 3.05.06.0 Intermediate purity FVIII 2.03.04.0

26. III.Exposure Assessment: Module D Utilization: Example using Factor VIII l Probability and Quantity of exposure influenced by patient utilization of product(s) l Number sources of product utilization by patients l Three categories of Hemophilia A disease severity: n Severe n Moderate n Mild

27. III. Exposure Assessment: Module D Utilization: Example using Factor VIII Treatment Regimen for Severe Disease Mean 5 th percentile 95 th percentile Prophylaxis 236,800 u158,800 u314,600 u Episodic 95,200 u63,800 u126,400 u

28. III. Exposure Assessment: Module D Utilization of other plasma derivatives Factor IX, immune globulins, albumin l Concepts for utilization similar l Probability and Quantity of exposure influenced by patient utilization of product(s) l Number sources of product utilization by patients l Severity of disease and utilization l Frequent use l One or few occasions of use (albumin)

29. Exposure Assessment: Other plasma derivatives Factor IX, immune globulins, albumin l Many concepts in model similar: –Probability of vCJD in US –Probability contaminated plasma pool –Effectiveness screening questionnaire l Some processes vary: –Plasma pool size –Reduction vCJD ID 50 during manufacture –Product package sizes and amounts dispensed –Product utilization by patients

30. Data Gaps More data are needed on: Prevalence of vCJD in UK, USA, etc. Amount vCJD agent present in human blood & plasma Progression of vCJD and variability of levels of infectivity in blood & plasma Variability in reduction of vCJD agent during various processing steps Plasma product utilization Many other parameters

31. Acknowledgements Hong Yang, OBE Dorothy Scott, OBRR David M. Asher, OBRR Rolf Taffs, OBRR Mark Weinstein, OBRR Other Hematology and OBRR staff