1. FVIII PRODUCT USAGE IN CLINICAL SETTINGS TSEAC October 31, 2005 Mark Weinstein, Ph.D. Office of Blood Research and Review CBER, FDA

2. Topics Issue: What data should be used to estimate how much FVIII is used by typical patients? Need to know: –Definition of typical patient –Dosage –Frequency of dosage –Period of time to be evaluated Background: patient characteristics Available estimates, data and limitations Proposal

3. Background: Hemophilia A and von Willebrand Disease (vWD)

4. Background: Hemophilia A and vWD Severity Clotting Factor Level (% activity) Bleeding Episodes U.S. Population (Est.) 2002 (% patients) Severe<1% Spontaneous bleeding, predominantly in joints and muscles 6200 (43%)* Moderate1% - 5% Occasional spontaneous bleeding. Severe bleeding with trauma, surgery 3600 (25%)* Mild6%- 30% Severe bleeding with major trauma or surgery 4600 (32%)* Type III vWD <1% vWF, 2-3% FVIII Mucosal, joint, muscle bleeding, Severe bleeding with trauma, surgery 250** *Soucie et al, Am J Hematol, 1998 **Universal Data Collection Project

5. Product Usage Most Hemophilia A patients use recombinant FVIII first licensed in 1991 Type III vWD patients use plasma derived products containing FVIII and vWF. Hemophilia A patients can use either FVIII or FVIII/vWF products Frequency and dosage of product are highly variable depending on patient weight, type of bleed, clinical severity of disease Frequency of usage –Prophylaxis: variable definition: e.g. 2 - 3.5 [i.e. on alternate days] x per week –Intermittent Prophylaxis: product used to prevent bleeding for certain events, followed by return to episodic treatment –Episodic: on demand in response to bleeding complications

6. CDC Data for Numbers of Patients Who Receive a Given Product 1993-1998 survey of all HA patients in six states. Data includes for each patient: –Severity of disease based on FVIII activity range –Total number of bleeding episodes per year –Estimate of amount of product used per year –Pattern of usage, e.g. prophylaxis –Number of weeks scheduled for prophylaxis –Brand of product(s) used Limitations: –Current usage may not be the same as in 1993-1998 –Extrapolations may not represent use in other states in the US –No information on vWD type

7. CDC Universal Data Collection Program (UDC) The UDC program started in 1998 in Hemophilia Treatment Centers. Data includes: –Numbers of HTC patients from start of program –Disease type: Hemophilia A, Severe, moderate, mild, Type III vWD –Treatment prescription: episodic; continuous or intermittent prophylaxis; immune tolerance –Product brand used by patient Limitations in use of available data for purposes of risk estimate –Amount of product used per patient was not collected –Not all patients visit HTCs –HTC patient population may differ from non-HTC population –Prophylactic or episodic are broadly defined with respect to amount of product used –Some patients use more than one product

8. Estimated Numbers of Hemophilia A Patients Using pd FVIII Derivatives (2002)* TREATMENTSEVEREMODERATEMILD Monoclonal purified FVIII Prophylaxis324500 Episodic1381350196 Other pd FVIII Products Prophylaxis3333 Episodic561462 TOTAL HA Patients620036004600 Percent pd FVIII Treated28.9%11.6%5.7% *Patient numbers are estimates, derived from CDC data obtained in 2002 from Hemophilia Treatment Centers as part of the Universal Data Collection Project and extrapolated to the total estimated hemophilia population for 2002

9. Estimated Number of Type III vWD Patients Using pd FVIII/vWF Derivatives (2002)* TREATMENT Type III Patient Number Episodic189 *Patient numbers are estimates, derived from CDC data obtained in 2002 from Hemophilia Treatment Centers as part of the Universal Data Collection Project and extrapolated to the total estimated hemophilia population for 2002

10. Estimated Range of F VIII Doses for Severe Hemophilia A Prophylactic Use (70 kg man) a : Episodic Use (70 kg man) b : 25 IU/kg 2 Doses/Wk 182,000 IU 50 IU/kg 3.5 Doses/Wk 637,000 IU a.) Personal Communications b.) Liesner RJ, 1996 12.5 IU/kg 0.08 Doses/ Week 3,500 IU 25 IU/kg 0.5 Doses/Wk 45,500 IU (Median # Doses) 53 IU/kg 1.38 Doses/Wk 267,120 IU

11. Reported Mean I.U. Factor VIII Prescribed for Hemophilia A Patients (1998) ++ SEVERITY TreatmentSevereModerateMild Prophylaxis199,160 IU*102,055 IU24,556 IU Episodic78,559 IU20,798 IU3,576 IU Linden et al, Transfusion, 2003 Based on 826 patients in New York State derived from a CDC 1993-1998 population-based study. ++ Includes both F VIII and F IX deficient patients *19% were prescribed more than 250,000 IU; 3.8% more than 500, 000 IU, and 1% more than 1,000,000 IU

12. Conclusions Regarding Clinical Use The existing data are limited and have not been analyzed for estimates of clinical use of specific brands of FVIII products in patient groups. We plan to analyze data from the ongoing UDC survey (1998-present) to estimate the numbers of patients using specific product brands, and the distribution of disease types, e.g.HA severe, moderate, mild; Type III vWD. We also plan to extrapolate data from the 1993-1998 survey in six states to estimate the total number of U.S. patients, and product consumption per patient, with stratification by clinical setting. If there is inconsistent information from these two analyses it will be reconciled using patient based medical record data.

13. Do Repeated Exposures to Low Doses of vCJD Infectivity Lead to Clinical Disease? Hamster Study (Diringer H, et al. 1998) –Hamsters fed one dose of scrapie infected Hamster brain for one day, one dose each day for 10 days, or one dose every four days for 10 exposures Fed 1 x (single dose) Every Day x 10 Every 4 days x 10 Cumulative death rate 1%8%4% Can a cumulative effect from repeated exposures to low doses of vCJD agent be incorporated in the risk model? Hamsters receiving a repeated standard infectious dose several times have a higher risk of developing scrapie than those receiving a single infectious dose. N= ~ 60 per Group

14. Do Repeated Exposures to Low Doses of vCJD Infectivity Lead to Clinical Disease? Fed once (dose equivalent to total spread out over 10 feedings for other test groups) Fed 1/10 th dose every day x 10 Fed 1/10 th dose every 4 days x 10 Risk of infection 11%8%4% A smaller risk of infection is associated with longer intervals between feeding Hamster Study (Diringer H, et al. 1998) Hamsters fed a dose of scrapie infected Hamster brain once, 1/10 th dose daily for 10 days, or 1/10 th dose every four days for 10 exposures N = ~ 60/ Group

15. Interpretation These findings suggest that exposure to repeated low doses of vCJD infectious material by the oral route increases the potential of infection, but that increasing the time between doses may decrease the risk.

16. Conclusions and FDA Proposal Conclusions: –The risk of vCJD infection may not be linearly related to cumulative exposure. –Nevertheless, despite possible low prevalence of vCJD in plasma donors and limitations to pool size, repeated dosing substantially increases potential risk of vCJD exposure in F VIII product recipients FDA Proposal –Based on these considerations, we propose to estimate the risk per annum in pd FVIII or vWF product users rather than the risk per dose Does the Committee concur with this approach?