CBER OBRR Division of Blood Applications

1. CBER OBRRDivision of Blood Applications Alan E. Williams, Ph.D. Director, Division of Blood Applications Office Review of Research July 22, 2005

2. OBRRDivision of Blood Applications (DBA)Critical Path Principal Staff

3. DBA Regulatory Functions Application Management and Review: DBA Blood and Plasma Branch Blood Establishment Licenses and License Supplements Source Plasma Licenses and License Supplements DBA Device Review Branch Blood Establishment Computer Software (BECS) Immunohematology In-Vitro Diagnostics DBA Regulatory Project Management Branch Application management – All DH and DETTD scientific reviews

4. Regulatory Management Initiatives: (MDUFMA/PDUFA III) • Goal: OBRR-wide improvement in review process, including timelines, efficiency, consistency, documentation • Major accomplishments: • Documentation of procedures • QC of archival records • Improved sponsor meeting paradigm • Faster guidance document development • Monthly OBRR Regulatory Forum training • Internal review management metrics

5. OBRR Review Management Metrics DCC STN Filing log-in entry letter Mid-cycle Final Action | | | | | STN # 0000001 ▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒▒ ** *** ** Mid-cycle review meeting (date, attendamce, written/concurred discipline review) Identify all major review issues Strategize interactions with sponsor Goal: First cycle approval/clearance where possible ***T-10 Sponsor interactions and final review memos complete and documented 10 days before “final action date” Goal: Circulation for sign-off with sufficient time for management review/comment.

6. DBA Emergency Response Functions • Internal SOP for OBRR Crisis Response • Staff Responsibilities (back-up) • Initiation/documentation of response • Internal and external contact information • Continuity of Operations Plan (COOP) • Agent-specific emergency response preparedness

7. DBA External Liaison Activities • AABB Interorganizational Donor History Task Force • AABB Standards Committee • AABB Technical Manual Committee • AABB Medical Affairs Committee • Interorganizational TF on Disasters • AABB ad hoc Donor Fatality Committee • WNV Task Force • Update of current regulatory policies for blood in major transfusion medicine textbook Ciaraldi JE, and Williams AE. Transfusion Safety and Federal Regulatory Requirements in Harmening D M, et al, Modern Blood Banking and Transfusion Practices 5th ed. F.A. Davis Company, Philadelphia

8. Examples of DBA Contributions to the Critical Path

9. Definition of standards: Products Immunohematology IVD reagents and platforms • Specificity comparisons (esp. in face of potential reagent shortages ) • Platform migration Blood establishment Computer Software (BECS) • Standards and 510k designation for first CASI donor screening systems • EMI and EMC Standards for RFID

10. Definition of standards: Procedures Statistical Basis of Quality Control (OBRR and OBE) Ongoing development of practical statistical approaches to quality control of blood components and other biological products • Binomial • Likelihood ratio based on negative binomial • Scan statistics Lachenbruch PA, Foulkes MA, Williams, AE, Epstein JS. Potential use of the scan statistic in the quality control of blood products J Pharm Statistics. 2005 15:353-366.

11. Blood Safety and Adequacy – Goal 1. Maintain an informed balance between regulatory intervention and blood supply adequacy (e.g. v-CJD, SARS, WNV) • Risk modeling • Blood supply impact assessment

12. Residual Dietary vCJD Risk vs. Percent of Blood Supply Lost

13. Blood Safety and Adequacy – Goal 2 Improve emergency preparedness through accurate assessment of blood shortages

14. TRANS-NetBlood Shortage Reporting System • Web-Based Reporting of blood, reagent, supply shortages (esp. Transfusion Services) • Assessment of medical impact • Ad hoc situation assessment • TRANS-Net design made available to DHHS as “turn-key” system for implementation in Secretary’s Operations Center (SOC)

15. TRANS-Net Pilot: Characteristics of post-holiday blood supply 1/6 - 2/28/2003 TRANS-Net Reported Shortage Criteria (by transfusion service reporting days/ total = 191) Delay of emergency or elective surgery – 0 Use of strategic reserve – 11 Delay of elective surgery- 0 Delay of medically necessary treatment – 1 Support of Rh- patients with Rh+ blood – 24

16. Improvements toDonor Screening • Donor History Questionnaire Task Force • Cognitive Testing of Donor History Questions: • Focus groups • FDA-sponsored 1:1 cognitive interviews • Abbreviated Questionnaire Working Group

17. Targeted Epidemiological Studies West Nile Virus Issue: Donors implicated in first known transfusion-transmissions of WNV showed symptoms that were possibly predictive in absence of WNV screening. Data: Case control study of WNV+ vs. FP controls for WNV symptoms. Headache/fever not predictive Orton SL, Stramer SL, Dodd RY. Self-reported symptoms associated with West Nile Virus infection in RNA-positive blood donors.. Transfusion, In Press.

18. Targeted Epidemiological Studies Blood Donation Incentives Issue: Donation incentives are common. Data addressing incentive impact on donation encouragement and safety are very limited . Data: Health-related incentives encourage future donation. Compensatory incentives encourage younger donors but also discourage future donation among a subset of overall donors. Glynn SA, Williams AE, Nass CC et al. Attitudes toward blood donation incentives in the United States: implications for donor recruitment Transfusion 2003 43(1):7-16

19. Targeted Epidemiological Studies HCV Incident (New) Infection Issue: Recent HCV exposure is of interest among accepted blood donors very recently screened for donation eligibility Data: Incident (HCV NAT+/HCV Ab negative ) infection in donors is highly associated with recent IDU. Orton SL, Stramer SL, Dodd RY, Alter MJ. Risk factors for HCV infection among blood donors confirmed to be positive for the presence of HCV RNA and not reactive for the presence of anti-HCV. Transfusion, 2004 44(2):275-81.

20. Targeted Epidemiological Studies White Particulate Matter (WPM) Issue: In early 2003 “abnormal” white particles were observed in RBC units at several blood establishments. Early analysis did not associate WPM with a known cause. However, patient adverse event (AE) monitoring was also necessary to rule out a safety threat to transfused patients. Data: Collaborative cohort study of AE after observed WPM in distributed products failed to show patient AE or diminished RBC LR effectiveness. Orton SL, Leparc GF, Rossmann S, Lewis RM. Particulate matter phenomenon: adverse event data and the effect of leukofiltration.Transfusion, 2004 44(7): 973-6.

21. Ongoing Fatality Surveillance Donor Fatalities Issue:Eighteen donor fatalities reported in 2002-2003 prompted FDA investigation. Response: BPAC review of available data in December, 2003 Collaboration among CBER staff, AABB Donor Fatality Task Force led to development of standardized data reporting form with 36 hour basis for donation association. Donor fatality dropped to two reports in the past year. Recipient Fatalities • Ongoing review and assessment of transfusion-related fatalities reported to FDA. TRALI Outreach via “Dear Doctor” health alert letter in October, 2001.

22. TRALITRALI Fatalities vs. Total Transfusion Fatalities Reported

23. Closing thoughts: Critical Path efforts in DBA/OBRR DBA staff working in concert with internal and external collaborators have successfully identified and pursued unique critical path opportunities through a multidisciplinary response. The DBA critical path response has utilized management science, risk modeling, and targeted epidemiological investigations leading to key measurable advances in public health and transfusion safety.