BIOVIGILANCE IN THE UNITED STATES: EFFORTS TO BRIDGE A CRITICAL GAP IN PATIENT SAFETY AND DONOR HEALTH

1. BIOVIGILANCE IN THE UNITED STATES: EFFORTS TO BRIDGE A CRITICAL GAP IN PATIENT SAFETY AND DONOR HEALTH Alan E. Williams, Ph.D. Office of Blood Research and Review CBER, FDA Pharma Conference January 27-29, 2010

2. Biovigilance • Biovigilance ….a comprehensive and integrated national patient safety program to collect, analyze and report on the outcomes of collection and transfusion and/or transplantation of blood components and derivatives, tissues, organs, and cellular therapies. (ACBSA 2006)

3. Public Health Goals for a Comprehensive Biovigilance System • Benchmarking and Quality Assurance • Adverse outcome measurement • Sentinel signal detection • Surveillance • Incident tracking (“e.g. near misses”) • Enhanced power to detect problems • Intervention evaluation (experimental studies) • Regulatory oversight • Rapid action to remove unsafe products/practices

4. Biovigilance Gap Report • Drafted in response to 2006 ACBSA recommendations (and concurrence by Assistant Secretary of Health): • that DHHS coordinate Federal actions and programs to support and facilitate biovigilance in partnership with private sector initiatives • that DHHS form a task group to perform a gap analysis of current systems and make recommendations for public-private partnerships in biovigilance (blood, cell, tissue, and organ therapies). • Hemovigilance is the blood-specific aspect of biovigilance

5. HHS Biovigilance Gap report:Key Deficiencies of Hemovigilance in the United States • Absence of………. • Long-term stability • National scope • Multicenter design • Common definitions • Broad data access and sharing • Real Time Data Availability • Active use to document practice improvement

6. Biovigilance Design Options(All have advantages and disadvantages depending on perspective) • Single Institution vs. Aggregated Data • Voluntary vs. Required Reporting • Functionally Anonymous vs. Identity-Linked Reporting • Sentinel vs. Surveillance • Severe Adverse Events vs All Incidents • Government vs. Private vs. Partnership • Commonality of data systems (HL7)

7. International Hemovigilance Global Models • 1993 Hemovigilance (France) • Mandatory Reporting • 1996 SHOT (UK) • First voluntary system • Made key observation: TRALI relationship to female plasma • European Blood Directive 2002/98/EC(2)

8. International Hemovigilance Global Models (cont.) • Some hemovigilance systems are governed by regulations (France, Germany Switzerland) • Some are managed by blood manufacturers (Japan, Singapore, South Africa) • Others are managed by Medical Societies (Netherlands, UK) or Public Health Authorities (Canada)

9. International Hemovigilance Global Models (cont.) • Hema-Quebec (non-profit blood establishment serving Quebec) • Established transfusion safety officers (TSOs) in each medical facility • High rate of transfusion AE reporting.

10. International Hemovigilance Global Models (cont.) • Recognized need for uniformity in definitions of adverse events and incidents • International Hemovigilance Network (EHN/IHN) • 50 members, 34 countries. includes most EU Nations • Defined grading for severity, imputability, and clinical signs (subsequently modified and expanded by the ISBT hemovigilance working party) • US may soon join the IHN

11. US National Hemovigilance: The Hurdles Complexity of the effort Uncertainty of future funding Differing definitions Wide variety of Data Systems Potential for inter-organizational competition FDA AE reporting regulations not finalized

12. Examples of Hemovigilance-Related Elements Currently Operational in the United States: • Investigator-initiated research • Major blood organizations (donors) • Individual hospitals (recipients) • MERS-TM

13. Examples of Hemovigilance-Related Elements Currently Operational in the United States: • Federally sponsored multi-center epidemiological studies NHLBI REDS and REDS-II RADAR, FACTS other repositories National Blood Collection and Utilization Survey (NBCUS) Marker positive donor interview studies

14. Examples of Hemovigilance Elements Currently Operational in the United States: FDA Blood Safety Mandatory Reporting Fatalities (donors & recipients) Product deficiencies Biological product deviation (BPD) reports Medical device reports (Note: mandatory FDA drug AE reporting is far more comprehensive)

15. Transfusion-Related Fatality Reports by Complication, FY2005 through FY2007

16. Reports of TRALI by Implicated Blood Product, FY2005 through FY2007

17. Examples of Hemovigilance Elements Currently Operational in the United States: Voluntary “passive” reporting to FDA via AERS/MedWatch

18. AERS Reports for BloodCalendar Year 2007 Query for blood and components as primary or secondary suspect products. Total = 44; some patients received blood components and derivatives.

19. The Deficiencies in US Biovigilance have Explanations • Absence of national blood system • Strong programs of investigator-initiated and federally-funded research programs • Barriers to data-sharing • Lack of targeted investment - especially “real-time” data analysis/interpretation • Legal liability • Regulatory liability

20. New Initiatives in US Biovigilance

21. HHS/AABB Donor Hemovigilance Funded by DHHS Focus on Donor Adverse Reactions Key Participants – DHHS, AABB, ARC, DoD, BSI, Coffee Memorial, Mayo, PPTA, Canadian Blood System, KBS

22. HHS/AABB Donor Hemovigilance • National Standards for Donor Reaction Data Collection • Data Elements and Definitions • Reactions and Reaction Categorization • Systemic, Standard Mechanism to Calculate Donor Reaction Rates • Trends at Facility, Organization, Region and Nation Levels • Comparison With Peers, Region and Nation

23. HHS/AABB Donor Hemovigilance • Predictive and Causality Analysis • Analyze Variables (Age, Sex, Weight, BP) Affecting Donor Reaction Rates • Device and Kit Analysis • Analyze Associations between Policies, Procedures of Organizations and Donor Reaction Rates • Intervention Analysis and Management

24. CDC NHSN/AABB Recipient Hemovigilance

25. http://www.cdc.gov/ncidod/dhqp/nhsn_biovig.html

26. Adverse Reactions Allergic reaction Acute hemolytic transfusion reaction Delayed hemolytic transfusion reaction Delayed serologic transfusion reaction Hypotensive transfusion reaction Febrile non-hemolytic transfusion reaction Post transfusion purpura Transfusion associated circulatory overload (TACO) Transfusion associated dyspnea TA- Graft versus host disease TRALI Transfusion associated infection (bacterial, viral, parasitic, other)

27. Case Definition Criteria http://www.cdc.gov/ncidod/dhqp/nhsn_biovig.html

30. For More Information http://www.aabb.org/biovigilance 8101 Glenbrook Road Bethesda, MD 20814-2749 Phone: +1.301.215.6574 Fax: +1.301.907.6895 biovigilance@aabb.org

31. FDA’s Sentinel Initiative Need to improve ability to detect low frequency adverse events in populations receiving approved biologics. Development of a nationwide electronic safety monitoring system Under FDAAA, section 905, FDA is required to link to disparate sources of safety data in order to access 25 million patient records by 2010 and 100 million by 2012

32. DOSES Use of CMSDatabase: RAPID ANALYSIS OF GBS RATE vs. USE OF SEASONAL FLU VACCINE - 2006 GBS rates

33. Initial FDA Vision of Sentinel • Data sources remain with original owners behind existing firewalls Owners would run queries—FDA-requested or other—(or could opt out) and convey the results of their queries to the network for analysis according to strict privacy and security safeguards System will enable FDA to partner with existing data owners (e.g., insurance companies with large claims databases, owners of electronic health records) • New system Will strengthen FDA's ability to monitor postmarket performance of a product – Will augment, not replace, existing functionality

34. Harmonization on Hemovigilance: The Remaining Challenges • CDCand HHS Hemovigilance • Voluntary • Unlinked • Surveillance design • Pilot → → National roll-out • FDA Adverse Event Data Needs (Drugs and Biologics) • Identity Linked (for follow-up) • Sentinel (and surveillance) design • Real time (to extent possible) • Voluntary and Mandatory • Early Middle stages of development (Patient Safety Rules, SENTINEL) Overall goal : Establish a comprehensive System for Simultaneous End-User Reporting in Support of Multiple Applications

35. PHS Biovigilance Task Group* • The PHS Biovigilance Working Group was formed to respond to the ACBSA’s recommendations to the Assistant Secretary for Health (ASH). The working group included: Matthew Kuehnert (chair), CDC; Jonathan Goldsmith (co-chair), formerly of FDA currently with NHLBI; Alan Williams (co-chair), FDA; James Bowman, formerly of CMS currently with HRSA; Simone Glynn, NIH, NHLBI; Harvey Klein, NIH; Laura St. Martin, FDA; Robert Wise, FDA; Jerry Holmberg, HHS/OPHS; James Burdick, formerly of HRSA; Elizabeth Ortiz-Rios, HRSA; Jay Epstein, FDA; Robyn Ashton, HRSA; and Karen Deasy, CDC. • Our thanks to others who contributed to this white paper, including D. Michael Strong, Barbee Whitaker and Kathy Loper, AABB; Tom Lane, University of California at San Diego; Anne Eder, American Red Cross; Peter Tomasulo, Blood Systems, Inc; Jim AuBuchon, Puget Sound Blood Center; and Susan Leitman, NIH.