February 8, 2005 Mark Weinstein, Ph.D. Office of Blood Research and Review CBER, FDA

1. Possible vCJD Risk from Investigational Coagulation Factor XI Manufactured Prior to 1998 from the Plasma of Donors Residing in the United Kingdom (UK) February 8, 2005 Mark Weinstein, Ph.D. Office of Blood Research and Review CBER, FDA

2. Issue • Some factor XI concentrate made from UK plasma was used under IND in the US between 1989 and 1997 to treat a relatively small number of patients • FDA seeks the Committee’s advice on a risk assessment model for potential vCJD exposure from this product

3. Background • UK notified bleeding disorder and congenital ATIII deficient patients that they might be at increased risk of vCJD from plasma derivatives • Products were manufactured from UK donors, and distributed between 1980-2001. • UK manufacturers stopped using UK plasma in 1999. • Last expiry date for UK products was 2001

4. UK Concerns and Recommendations • Increased concern of vCJD infectivity in plasma derivatives because of the probable transmission of vCJD through transfusion of non leukocyte reduced red blood cells from donors who later developed vCJD. • Recommendations: • Notify all patients who received coagulation/ATIII products. • Advised not to donate blood, tissues, or organs • To control potential infection, inform their surgeons and dentists of their increased risk, so that special arrangements can be made for surgical and dental instruments. • To inform their families so that surgeons could be informed in case of emergency surgery

5. US Situation • In the United States, no licensed product was made from UK plasma. • Small number of FXI deficient patients were treated under several IND protocols between 1989 - 1997 • No factor XI product used in the US was manufactured from a pool containing plasma from any donor known to have become ill with variant CJD, but such a lot may be identified in the future.

6. Factor XI Utilization Factor XI Deficiency • Very rare bleeding disorder • Estimates 1 in 30,000 to 1,000,000 • Variable bleeding tendencies • Disorder usually manifested during surgery • Bleeding usually mild • Most patients have little or no bleeding • Most IND product was used to control bleeding associated with surgery or dental bleeding • Relatively little product was used

7. Speakers • Risk Assessment Methods and Assumptions in U.K. Risk Model – Kate Soldan, Ph.D., Epidemiologist, U.K. Health Protection Agency • Translation of vCJD risk assessment for plasma derivatives to public health policy and assessment of risk to patients in the U.K. – Anna Molesworth, Ph.D., Epidemiologist, U.K. Health Protection Agency • Elements of TSE risk assessments and risk assessment for U.K. FXI - Steven. Anderson, Ph.D., OBE, FDA • Current public health recommendations on management of surgical instruments used on patients with TSE or TSE risk - Lynne Sehulster, Ph.D., CDC

8. Request to the Committee • Please comment on the FDA vCJD risk assessment for FXI manufactured from U.K. plasma, with regard to • The model as applied to FXI • Any additional information that is needed to improve risk estimates for this FXI product.