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

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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)

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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

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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

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

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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)

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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)

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)

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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.

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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

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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

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Examples of Hemovigilance-Related Elements Currently Operational in the United States:

Investigator-initiated research Major blood organizations (donors) Individual hospitals (recipients) MERS-TM

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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

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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)

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Transfusion-Related Fatality Reports by Complication, FY2005 through FY2007

0

10

20

30

40

Complication

Num

ber

of F

atal

ities

FY05 29 16 8 1 6 0 2

FY06 35 9 7 8 3 1 0

FY07 34 2 6 5 3 2 0

TRALI HTR (non-ABO)Microbial Infection

TACO HTR (ABO) Anaphylaxis Other

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Reports of TRALI by Implicated Blood Product, FY2005 through FY2007

0

5

10

15

20

25

Blood Product

Nu

mb

er

FY05 13 5 3 4 4

FY06 22 5 1 2 5

FY07 12 12 0 1 9

FFP RBC Plasma* Platelets Pheresis

Multiple Products

Examples of Hemovigilance Elements Currently Operational in the United States:

Voluntary “passive” reporting to FDA via

AERS/MedWatch

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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.

Products US Foreign Total

Fresh frozen plasma 4 1 5

Platelets 4 3 7

Red blood cells 14 1 15

Blood derivative 9 7 16

Whole blood + other components 3 3 6

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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

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New Initiatives in US Biovigilance

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

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

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

CDC NHSN/AABB Recipient Hemovigilance

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

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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)

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Case Definition Criteria

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

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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

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FDA’s Sentinel InitiativeFDA’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

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Use of CMS Database:

RAPID ANALYSIS OF GBS RATE vs. USE OF SEASONAL FLU VACCINE - 2006

DOSES

GBS rates

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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

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Harmonization on Hemovigilance: The Remaining Challenges

CDCand HHS Hemovigilance 1. 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

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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.