CBER OBRRDivision of Blood Applications

Alan E. Williams, Ph.D. Director, Division of Blood Applications

Office Review of ResearchJuly 22, 2005

OBRR Division of Blood Applications (DBA)

Critical Path Principal Staff

Blood an d P lasm a Bran chA ctin g C h ief

S h ary n O rton , P h .D .

D evices R ev iew Bran chC h ief

S h ery l K och m an , M T (A S C P)

R egu latory P ro jectM an agemen t Bran ch

C h iefS ay ah N ed j ar, P h .D .

M edical O ffi cersM an ette N i u , M .D .

L esl i e H o l n ess, M .D .

Q u al i ty C on t rol an d L i ai sonJ u d y C i aral d i , BS , M T (A S C P )SB B , C Q A (A S Q )

D irectorA l an E . W i l l i am s, P h .D .

D ep uty D irectorS h ary n O rton , P h .D .

DBA Regulatory Functions

Application Management and Review:DBA Blood and Plasma BranchBlood Establishment Licenses and License Supplements

Source Plasma Licenses and License Supplements

DBA Device Review BranchBlood Establishment Computer Software (BECS)

Immunohematology In-Vitro Diagnostics

DBA Regulatory Project Management BranchApplication management – All DH and DETTD scientific reviews

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

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 issuesStrategize interactions with sponsorGoal: 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.

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

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 5 th ed. F.A. Davis Company, Philadelphia

Examples of DBA Contributions to the

Critical Path

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

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.

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

Residual Dietary vCJD Risk vs. Percent of Blood Supply Lost

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(1 year) (6 months)(3 months)

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Blood Safety and Adequacy – Goal 2

Improve emergency preparedness through accurate assessment of blood shortages

TRANS-Net Blood 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)

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

Improvements to Donor Screening

• Donor History Questionnaire Task Force

• Cognitive Testing of Donor History Questions:– Focus groups

– FDA-sponsored 1:1 cognitive interviews

• Abbreviated Questionnaire Working Group

Targeted Epidemiological Studies

West Nile VirusIssue: 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.

Targeted Epidemiological Studies

Blood Donation IncentivesIssue: 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

Targeted Epidemiological Studies

HCV Incident (New) InfectionIssue: 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.

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.

Ongoing Fatality Surveillance

Donor Fatalities Issue: Eighteen donor fatalities reported in 2002-2003 prompted FDA

investigation.

Response: BPAC review of available data in December, 2003Collaboration 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.

TRALITRALI Fatalities vs. Total Transfusion Fatalities Reported

010203040506070

8090

100

1996 1998 2000 2002 2004

TRALI Fatalities

Total TransfusionFatalities Reported

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.