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Blood Products Advisory Committee April 27, 2007 Dorothy Scott, M.D.

Update - Summary of TSE Advisory Committee Meeting (December 15, 2007): Discussion on Experimental Clearance of TSE Infectivity in Plasma-derived FVIII Products. Blood Products Advisory Committee April 27, 2007 Dorothy Scott, M.D. Office of Blood Research and Review/CBER.

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Blood Products Advisory Committee April 27, 2007 Dorothy Scott, M.D.

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  1. Update - Summary of TSE Advisory Committee Meeting (December 15, 2007):Discussion on Experimental Clearance of TSE Infectivity in Plasma-derived FVIII Products Blood Products Advisory Committee April 27, 2007 Dorothy Scott, M.D. Office of Blood Research and Review/CBER

  2. 4. Risk Characterization Importance Analysis (slide from S. Anderson) - +

  3. Topic II: Levels of TSE clearance in plasma-derived FVIII manufacturing • Amount of clearance by manufacturing processes is a major driver of risk – more clearance = less risk • TSEAC had discussed TSE clearance on September 19th, 2006 • Affirmed importance of bioassays in TSE clearance studies • Discussed limitations and advantages of TSE agent spiking of plasma vs. endogenously infected plasma as starting material for TSE clearance studies • Would a minimum TSE agent reduction factor enhance vCJD safety of products? • What TSE agent reduction factor is appropriate?

  4. Level of TSE Clearance ? • Analogy to viral safety studies – spiking of infectious agent into plasma or intermediate, and assessing removal • Viral clearance usually at least for the maximum amount of virus expected + “margin of safety” • TSE infectivity estimate in plasma (based on animal models): 2-30 IU/ml x 800 ml plasma = 3.2-4.4 log10 IU total in a plasma unit

  5. Level of TSE Clearance - Impact on mean potential vCJD risk/person/year (pdFVIII risk assessment table 5.3.A.) Log10 TSE Clearance * Available data suggests that all U.S.-licensed products are likely to have TSE clearance of > 4 log10

  6. Clearance Studies Update – PPTA Presentation • Reported summary TSE clearance study results from 6 pdFVIII manufacturers • TSE agent spiked into starting material • Bioassays or PrpTSE binding assays as readout • Types of steps studied: precipitations, chromatography, filtrations • Clearance levels for U.S. products (4) reported at least one step with estimated 3.5 – 4.0 logs of clearance • Mainly binding assay readouts • Varied study designs: TSE agent preparation, numbers of steps studied, readout

  7. TSEAC Question 1 Based on available scientific knowledge would a minimum TSE agent reduction factor, measured by bioassay, demonstrated using an exogenous spiking model in scaled-down manufacturing experiments, enhance vCJD safety of the products? - 15 yes, 2 abstentions

  8. TSEAC Question 1 • If yes, what TSE agent reduction factor is most appropriate? The committee did not identify a minimum TSE agent reduction factor - Uncertainties about current TSE clearance model

  9. Level of TSE Clearance - Impact on mean potential vCJD risk/person/year (pdFVIII risk assessment table 5.3.A.) Log10 TSE Clearance * Available data suggests that all U.S.-licensed products are likely to have TSE clearance of > 4 log10

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