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TSE Advisory Committee October 31, 2005 Dorothy Scott, M.D. OBRR/CBER/FDA

Progress Report on FDA’s Risk Assessment for Potential Exposure to vCJD in Human Plasma-derived Antihemophilic Factor (FVIII) Products. TSE Advisory Committee October 31, 2005 Dorothy Scott, M.D. OBRR/CBER/FDA. Rationale for Risk Assessment. Plasma may have risk:

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TSE Advisory Committee October 31, 2005 Dorothy Scott, M.D. OBRR/CBER/FDA

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  1. Progress Report on FDA’s Risk Assessment for Potential Exposure to vCJD in Human Plasma-derived Antihemophilic Factor (FVIII) Products TSE Advisory Committee October 31, 2005 Dorothy Scott, M.D. OBRR/CBER/FDA

  2. Rationale for Risk Assessment • Plasma may have risk: • Transfusion transmission of vCJD reported in the U.K. • Plasma infectious in animal models – no vCJD infections diagnosed in plasma derivative recipients • Risk estimates provide a basis for examining adequacy of current measures to protect blood and plasma derived products • Assessment may trigger threshold for actions: risk management, communication, surveillance; and contributes to public health decisions

  3. TSEAC 2/08/05 • Risk assessment model presented by FDA • TSEAC asked to comment with regard to: •  The U.S. risk assessment model per se, and • Any additional information that is needed to improve risk estimates for the various plasma derivatives

  4. TSEAC 2/08/05 Comments on FDA Risk Model • Approved of FDA’s risk assessment model framework • Additional refinements should be made as more input information is collected • Different products may have different risk levels • Donor travel history is important to consider • The 1-month exposure in the UK by a Japanese traveler who later developed vCJD suggests that there may be residual vCJD risk in donors with brief travel to the U.K.

  5. Elements of Risk Assessment Prevalence of vCJD in U.S. Plasma • Amount of vCJD infectivity in plasma • TSE Clearance by Plasma Derivative Manufacturing Processes • Patient exposure (product use)

  6. Outcomes of Risk Assessments • Main Parameter: Exposure per patient per year to 1 ID50 or more (1 ID50 = 50% risk of infection in animal models) • Identification of Sources of Uncertainty • Uncertainty increases with model complexity and when data is lacking for multiple input parameters • Sensitivity analysis: identifies input parameters that have the most impact on outcomes • Can focus data collection efforts

  7. Risk Assessment Issues • Uncertainties and ranges important to recognize – probabilistic • Data gaps should be communicated with risk assessment to provide context • Input parameters need to be adjusted over time to reflect scientific findings • Risk assessment outcomes should be compared to observed risk over time

  8. Risk Assessment Input Parameters • Review of FDA Risk Assessment Model – Steven Anderson, PhD, OBE/CBER • Update on vCJD in the UK and other countries: Estimates of prevalence – Azra Ghani, PhD, London School of Hygiene and Tropical Medicine, and Richard Knight, MD, Director, CJD Surveillance Unit, Edinborough • Modeling risk of vCJD in US donors – residual risk and efficiency of donor deferrals – Alan Williams, PhD, OBRR/CBER

  9. Risk Assessment • vCJD infectivity of plasma – estimates from experimental models – David Asher, MD, OBRR/CBER • Review of TSE clearance in FVIII product manufacturing – Dorothy Scott, MD, OBRR/CBER • FVIII product usage in clinical settings – Mark Weinstein, PhD, OBRR/CBER

  10. Risk Assessment: Questions to the Committee • What estimate(s) should be used to reflect the prevalence of vCJD in the U.K.? • How effective are current donor deferrals for geographic risk of vCJD? • What intravenous infectivity range (in ID50) should be selected for plasma, based on animal studies? • Is there sufficient evidence to estimate when during the incubation period human plasma is infectious? 5. Does the committee agree with FDA’s proposed approach for estimating clearance of vCJD infectivity from FVIII by manufacturing processes?

  11. Risk Assessment: Questions to the Committee 6. What experiments might enable refinement of these [clearance] estimates and allow comparison of clearance offered by various steps in the methods used to manufacture plasma-derived FVIII? 7. What data should be used to estimate how much FVIII is used by typical patients? 8. What is the effect of plasma pool size (I.e number of donors per final product) for FVIII recipients? 9. Can a cumulative effect from repeated exposures to low doses of the vCJD agent be incorporated into the risk model?

  12. Risk Communication: Question to the Committee 10. Given the present scientific uncertainties in the underlying assumptions of the FVIII risk assessment, does the Committee believe that the risk assessment model could provide a useful basis for risk communication to patients, their families, and health care providers?

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