1. 18 th Meeting of FDA TSE Advisory Committee: 31 October 2005 Summary FDA Blood Products Advisory Committee 85 th Meeting 03 November 2005 Holiday Inn Gaithersburg MD David M. Asher, MD Laboratory of Bacterial, Parasitic and Unconventional Agents Division of Emerging & Transfusion-Transmitted Diseases Office of Blood Research & Review Center for Biologics Evaluation & Research US Food & Drug Administration

2. 18 th FDA TSEAC Agenda 1. BSE worldwide and USA: USDA update 2. TSE decontamination of surgical devices: CDRH update 3. CBER decisional issue 1. Advice on further development of FDA risk assessment for vCJD and plasma-derived factor VIII 4. CBER decisional issue 2. Validation criteria and possible label claims for devices to remove TSE infectivity from blood components

3. Recipients surviving >3yrs post transfusion of blood components from vCJD/CJD Donors (using data from UK TMER and US ARC look-back studies, S. Anderson, FDA TSEAC 14 Oct 2004) Fisher's Exact Test comparing rates of infection after transfusions from vCJD and CJD donors suggests a statistically significant difference between the two groups (  1.2% likelihood that the difference occurred by chance).  Risk of transfusion-transmitted vCJD >> sporadic CJD Infection No Infection CJD0116 vCJD213

4. vCJD : Non-UK = 27cases (October 2005 UK =158 ) from R. Knight/CJD SU Edinburgh FRANCE 15 ITALY1 NETHERLANDS1 PORTUGAL1 SPAIN1 REPUBLIC of IRELAND2  REPUBLIC of IRELAND2  USA1  CANADA1  JAPAN1  SAUDI ARABIA (source uncertain) 1 Probably acquired in UK  Probably non-UK

5.  Donor travel history UK, FR, Europe  Adjustments for duration & year traveled, donor age  Screening questionnaire  Plasma pool size  Quantity of vCJD agent in pool  Reduction of vCJD agent during manufacture  Percent contaminated vials  Amount vCJD agent per FVIII vial  Annual dose Factor VIII Module 1 vCJD Prevalence in UK Module 2 vCJD Prevalence in US Donors Module 3 FVIII Processing Module 4 Utilization of FVIII INPUTMODULEOUTPUT  Number US vCJD donors  Number vCJD donors post- screening  Total number vCJD donations  Percentage plasma pools / vials with vCJD agent  Quantity vCJD agent per FVIII vial  Annual exposure of FVIII recipients to vCJD agent  Estimate of vCJD prevalence in United Kingdom  UK surveillance data  Predictive modeling based on UK vCJD cases

6. Critical elements of vCJD risk assessment: Prevalence of vCJD in US Plasma UK vCJD prevalence US donor travel history Time of travel relative to UK BSE prevalence Travel: Source Plasma vs recovered plasma donors Risk reduction by donor deferral Effectiveness of donor deferral Residual risk: non-deferred (short-duration) travelers

7. Module 1 Prevalence of vCJD in United Kingdom Proposed Modeling Approaches Two sources of UK vCJD prevalence data: 1. Predictive models based on UK vCJD cases 2. Surveillance data based on examination of appendix samples Problem: Disparity ~ 10 to 100 fold between approaches

8. Module 1 Prevalence of vCJD in UK Predictive models based on observed cases of vCJD and “back calculation” method ______________________________________________ (1) Ghani et al 2003  vCJD estimated median 100 cases (10 to 2,600 - 95% CI)  Median 1 in 500,000  (2) Boelle et al 2003  vCJD UK estimated cases: 183 to 304  (3) Llewelyn et al 2004  vCJD UK est 1 in 15,000 to 1 in 30,000 or 1,000- 2,000 infections

9. Unique Pathology of vCJD (Chazot G & al. Lancet 1996;347:1181. Will RG & al. Lancet 1996:347:921-5. Hill AF & al. Lancet 1999;353:183-9)

10. Module 1 Prevalence of vCJD in UK Empirical appendix surveillance data (Hilton et al. 2004) 3 PrPres-positive samples in 12,674 samples tested  ~ mean of 1 positive in 4,225 individuals (mostly 20- to 30-yr-old patients) Approximately 13,000 vCJD infected UK individuals in UK Data should be further age-adjusted using reported UK vCJD case age profile Does not consider infected persons before appendix becomes positive for PrPres (e.g., last transfusion-transmitted infection in a PRNP-codon-129 met/val person)

11. Issue 1. Advice on Assumptions for vCJD FVIII Risk Assessment l UK Prevalence: Use empirical prevalence value based on UK PrPres tissue survey allowing for a pre-clinical/sub-clinical infectious state in donors of all PRNP- codon-129 genotypes

12. Issue 1. Advice on Assumptions for vCJD FVIII Risk Assessment l Screening sensitivity for vCJD risk: Advised against using estimates from analogous donor screening situations (showing 90-99% sensitivity of screening) and recommended instead 85% most likely l Source Plasma donor information: Encouraged obtaining survey data for travel by apheresis donors rather than extrapolating from a travel survey for donors of Whole Blood

13. Levels of vCJD infectivity in human plasma What infectivity range (in ID 50 /ml) should FDA select for human blood/plasma based on studies in animals? During what part of the incubation period? FDA proposed a triangular distribution:  Minimum = 0.1  Most likely = 10  Maximum = 310 FDA proposed assuming infectivity to be potentially present in blood throughout the entire incubation period.

14. From Dr RG Rohwer, Baltimore VAH  Infected Experimental TSEs: infectivity in blood |___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___| | | | | | | | | | | | | | 1 8 16 27 41 51 60 70 80 90 100 120 |___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|_ 0 1 2 3 4 5 6 7 8 9 10 15 20 25 30 35 __|___|___|___|___|___| 42       Weeks Clinical disease                                                                                                                 ? ?  Uninfected                         Days Clinical disease scrapie in mouse scrapie in hamster Eklund/5x10 7 im/ 30 ul blood clot ic 30 ul serum ic 2 exp. same result |___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___| 0 5 10 20 30 40 50 120                      Days Clinical disease scrapie in hamster Diringer/ 10 6 ip 200 ul blood equiv ic Cassacia/ 10 6 ip 200 ul blood equiv ic (214)(151) (186)(191) (108)(116)(114)(113)(128)(124)(131)(121)(132)(138) Numbers in parentheses are mean incubation times. file: Viremia6.ppt Robert G. Rohwer, Ph.D. |___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___| 0 1 2 3 4 5 6 7 8 9 10 15 20 25 CJD in guinea pig Manuelidis/ic inoc.1ml clinical/ 0.1ml buffy coat ic, ip, sc, im |___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___|___ 0 1 2 3 4 5 6 7 8 9 10 15                         Clinical disease Weeks GSS (  fCJD) in mouse Kuroda/3x10 4 ic inoc 30 ul buffy coat ic & 100 ul serum ip/ 100ul rc ip (281)(213)(156)(142)            Weeks Clinical disease                              (443) (463) (429) (308) (448) (504)(379) (396) (210)(343) (184) (307) (147) (447)

15. Infectivity in blood of terminally ill mice inoculated with mouse-adapted GSS (Fu-1) agent (Brown P et al. Transfusion 1999;39:1169-78) Infectivity in ic IU/ml Expt 1Expt 2 Pool 1 Expt 2 Pool 2 Buffy coat44NT106 Plasma103422

16. Titers of scrapie-infected hamster blood from clinically ill animals Infectious Doses/ml Splenectomies Individual Pools mean median From Dr RG Rohwer, Baltimore VAH

17. Infectious Dose/Unit 450 2700 90 2250 1800 1350 900 3150 0 From Dr RG Rohwer, Baltimore VAH

18. Issue 1. Advice on Assumptions for vCJD FVIII Risk Assessment l Infectivity level: Agreed that—based on rodent data—10 ID 50 /ml blood most likely and minimum of 0.1 ID 50 prudent, but offered mixed advice on upper level (100 to 1000 ID 50 mentioned) l Duration of infectivity in blood relative to incubation period: Agreed compromise advice estimating infectivity in last 50% of incubation period, modified if shown to be a critical parameter in sensitivity analysis

19. Issue 1. Advice on Assumptions for vCJD FVIII Risk Assessment l Pool size: Agreed with FDA-proposed “bimodal” distribution with pools of 20,000 and 60,000 donations considered most likely l Clearance of TSE infectivity by manufacturing processes: Agreed with FDA proposal to use three different ranges for various products

20. Issue 1. Plasma fractionation: FDA proposes 3 ranges of estimated vCJD infectivity clearance by manufacturing Range of reduction (log 10 ) Process Likely minimum 2-3 Single step with moderate clearance Mid-range4-6 Single step with higher clearance or Multiple additive steps Likely maximum 7-9 Multiple additive steps

21. Issue 1. Advice on Assumptions for vCJD FVIII Risk Assessment l Clinical use: Agreed with FDA that CDC databases for FVIII use (1993-98 survey of all HA pts in 6 states and Universal Data Collection Program [UCD]) were best available (but not enough—especially for von Willebrand’s disease) l Additional information needed: Agreed with FDA proposal to extrapolate from existing data to estimate use by year and use patient- based medical record data if needed to resolve inconsistencies

22. Issue 1. Advice on Assumptions for vCJD FVIII Risk Assessment l Cumulative risk from repeated exposures to “sub-infectious” doses: Agreed with FDA that experimental studies showing infection following frequent exposures of rodents to amounts of infectivity not infectious by single exposures or repeated at long intervals are a concern l Risk per annum: Agreed with FDA proposal to estimate vCJD risk per annum rather than per dose (but did not advise other modification to the risk model)

23. Issue 1. Advice on Assumptions for vCJD FVIII Risk Assessment Special concern: risk communication Risk of transmission by plasma derivatives is theoretical. (Even in UK, no case of vCJD has been recognized in a recipient of a plasma derivative.) Especially difficult to communicate highly uncertain theoretical risks Notification might cause adverse effects  Patient anxiety  Health care provider anxiety  Other Participation of patient groups helpful

24. TSEAC Decisional Issue 2. Validation criteria and possible label claims for devices to remove TSE infectivity from blood components UK regulatory authorities plan an independent evaluation of CE-marked blood filters purported to reduce TSE infectivity:  Expect minimal  3 log 10 reduction of spiked infectivity (demo by Western blot and bioassay) at ambient temp and 4 o C  Component (RBC) must maintain functionality at expiry by usual tests  Seek “surrogate” markers suitable for QA Three manufacturers described 3 promising devices for clearing TSE agents (one CE-marked)

25. TSEAC Decisional Issue 2. Validation criteria and possible label claims for devices to remove TSE infectivity from blood components TSEAC suggested modifications to FDA’s proposed criteria:  3 log 10 reduction of spiked infectivity (demonstrated by Western blot and bioassay)  Remove all detectable infectivity from endogenously infected animal blood  2 animal models and 2 strains of TSE agent  1 agent strain derived from cow with BSE or human with vCJD (rodent-adapted)  Filtered blood components should maintain functionality at expiry by usual tests

26. TSEAC Decisional Issue 2. Validation criteria and possible label claims for devices to remove TSE infectivity from blood components TSEAC suggested modifications to FDA’s proposed criteria for validation (continued):  Desirable to demonstrate that device removes all detectable endogenous TSE infectivity from whole units of blood of large animals (sheep scrapie/BSE; ?? primates—not yet available)  Since bioassays for residual infectivity by transfusing of animals of the same species, while ideal, are generally not feasible, may test in susceptible transgenic mice (although sensitivity relative to large animals not known)

27. TSEAC Decisional Issue 2. Validation criteria and possible label claims for devices to remove TSE infectivity from blood components TSEAC suggested modifications to FDA’s proposed criteria for validation (continued):  While reproducibility of results at separate study sites is desirable, it may be difficult to arrange for two labs with required equipment and TSE expertise  Study should be large enough for statistical validity  Studies described might support label claims for reduction of TSE infectivity (small animal models), ?? prevention of transfusion- transmitted TSE (only after large animal study)