1. FDA Risk Management Strategy for Potential Exposure to vCJD from Plasma Derivatives TSE Advisory Committee December 15, 2006 Dorothy Scott, M.D. OBRR/CBER

2. Plasma-derived Clotting Factors and vCJD To date, there are no reports of vCJD transmission by any plasma derivatives, including clotting factors In the UK, three cases of vCJD infection have been reported in transfusion recipients who received non- leukocyte reduced red blood cell concentrates from donors who later developed vCJD Plasma of experimentally infected animals contains TSE infectivity In the U.S., 3 vCJD cases diagnosed –2 long-term residents of U.K. –1 patient with prior residence in Saudi Arabia till 2005 No history of travel to Europe Not a blood donor or recipient Reported by CDC November 29, 2006, at http://www.cdc.gov/ncidod/dvrd/vcjd/other/vCJD_112906.htm

3. From: INCIDENCE OF VARIANT CREUTZFELDT-JAKOB DISEASE ONSETS AND DEATHS IN THE UK at http://www.cjd.ed.ac.uk/vcjdq.htm.http://www.cjd.ed.ac.uk/vcjdq.htm N J Andrews, Senior Statistician, Statistics Unit, CDSC, Health Protection Agency, 19th January 2005 Variant CJD Epidemic is Declining in the U.K.

4. Multitiered Risk Management Approach for Plasma Derivatives Plasma donation – donor deferrals Manufacturing - clearance Final product - withdrawal for vCJD donation Risk communication – product labeling –Recommended labeling for potential CJD risk –TSE clearance labeling based on submission of experimental data (voluntary) Risk assessment –Beginning with upstream manufacturing processes – clotting factor products –Identifies most important contributors to risk –Estimates risk to patients under various scenarios and communicates uncertainties Anticipating future risk mitigation measures, by developing: –Paradigms for TSE filtration device licensure (TSEAC 10/2005) –Strategies for evaluation of donor tests (TSEAC 9/2006) –Standard preparations to facilitate testing (TSEAC 9/2006)

5. RISK MANAGEMENT STRATEGY: Deferral of blood and plasma donors at increased risk of vCJD; product withdrawal for vCJD* Deferral of donors who: –visited or resided in countries where BSE exposure is higher (e.g. UK, France, rest of Europe; some European military bases); –used UK-sourced bovine insulin; –Received transfusions in the UK or France since 1980 * Withdrawal of products made from plasma of a donor with vCJD Encourage reporting of donors with possible vCJD (CJD diagnosis and age < 55) * FDA Guidance to Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products, a t http://www.fda.gov/cber/gdlns/cjdvcjd.htm, and draft amendment at http://www.fda.gov/cber/gdlns/cjdfrance.htm http://www.fda.gov/cber/gdlns/cjdvcjd.htm

6. RISK MANAGEMENT STRATEGY: Recommended Labeling In WARNINGS section for plasma derivative products, “Because this product is made from human blood, it carries a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.” –Captures uncertain, but still possible, risk Reduction of risk, if based upon scientific demonstration by clearance studies, reflected in DESCRIPTIONS section

7. RISK MANAGEMENT STRATEGY: Evaluation of Voluntary TSE Clearance Studies for Labeling Claims Discussed by TSEAC on 2/2003 Committee agreed that FDA may consider granting a labeling claim for TSE clearance if a sponsor submits detailed study data of the specific manufacturing process and demonstrates ability of that process to reduce TSE infectivity To date, several plasma derivatives have been approved for a TSE clearance labeling claim –Carimune® NF, Panglobulin® NF, Gamunex®, Thrombate III®

8. TSE Clearance Labeling (1) In DESCRIPTION section: “Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.”

9. TSE Clearance Labeling (2) In DESCRIPTION section “Several of the individual production steps in the [product name] manufacturing process have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include [process][(logs)]), [process][(logs)], [etc.]. These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.”

10. ADDITIONAL RISK MITIGATION MEASURES Developing licensure strategies for –Filtration devices to remove TSE infectivity from blood components –Candidate donor screening and diagnostic tests for vCJD and other TSEs Collaborations to develop standard preparations for use in candidate tests and clearance studies Facilitating development, validation, and information sharing regarding the performance of manufacturing processes in clearance of TSE agents from blood products.

11. RISK ASSESSMENT and RISK COMMUNICATION FOR U.S. PLASMA- DERIVED FVIII  Risk assessment for plasma-derived FVIII products  Identifies most important contributors to risk  Risk communication  Providing risk estimate and its uncertainties  Informing patients and physicians about the current scientific understanding regarding vCJD risk from blood products, to better inform treatment decisions

12. QUESTIONS TO THE TSEAC Does the Committee have any comments on the technical aspects of FDA’s risk assessment, including the risk estimates and uncertainties, for pdFVIII from US donors? Does the Committee agree that the Key Message and Additional Information as described –a) capture the essential points of the Risk Assessment, –b) provide a suitable and understandable interpretation of the results? Please comment on the communication strategy regarding the risk assessment and its interpretation.

13. FDA’s Risk Assessment for Potential Exposure to vCJD in Human Plasma- derived FVIII, and Communication Materials Risk Assessment and Interpretation – Steven Anderson, Ph.D., OBE/CBER Overall Risk Communication Approach – Mark Weinstein, Ph.D., OBRR/CBER Input from Patient Advocates –National Hemophilia Foundation – Val Bias, Board Member –Hemophilia Federation of America – Janice Hamilton, Director –Committee of Ten Thousand – Richard Colvin, M.D., Ph.D. –World Federation of Hemophilia – Mark Skinner, President