Biovigilance in the United States: Efforts to Bridge a Critical Gap in Patient Safety and Donor Health

Abstract

A comprehensive review of current surveillance and adverse event reporting systems for blood; human cells, tissues, and cellular and tissue-based products (HCT/Ps); and organs was undertaken by a task group of the Public Health Service (PHS) Biovigilance Working Group (BWG). This white paper review included relevant PHS agencies (Centers for Disease Control and Prevention, Food and Drug Administration, National Institutes of Health, and Healthcare Resources Services Administration and the Center for Medicare and Medicaid Services). The PHS BWG carefully considered the various roles and missions of the PHS agencies play in program oversight and product regulation. The PHS BWG found in its review that at the present time, biovigilance in the US is a patchwork of activities, not a cohesive national program. Although this patchwork is functional, some of these activities are redundant, while others are limited in scope, resulting in inefficiency and gaps. Each HHS agency has created some means of data collection for outcomes and adverse events in support of its mission and objectives, including regulatory obligations. Professional organizations have also implemented standards for quality systems, which require investigation of adverse outcomes and errors. Recommendations on biovigilance systems and partnerships to fill existing gaps are complicated by the lack of a national policy and a pluralistic approach to the safety and availability of blood, tissue, and organs. Both voluntary and mandatory systems are needed. Integration of systems with both public and private sector support and joint governance of national biovigilance collaborative is vital.

Full text

BIOVIGILANCE IN THE UNITED STATES:
EFFORTS TO BRIDGE A CRITICAL GAP
IN PATIENT SAFETY AND DONOR HEALTH
This report is a work product of the Public Health Service (PHS)
Biovigilance Task Group in response to recommendations of the
HHS Advisory Committee on Blood Safety and Availability

2
Acknowledgements
The PHS Biovigilance Working Group was formed to respond to the ACBSA’s
recommendations to the Department of Health and Human Services (HHS).
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;
Karen Deasy, CDC; Bernard Kozlovsky, HRSA; Ellen Lazarus, FDA; and
Susan Leitman, NIH.

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UNITED STATES BIOVIGILANCE: EFFORTS TO BRIDGE A
CRITICAL
DONOR AND PATIENT SAFETY GAP
Table of Contents
Acknowledgements .................................................................................................... 2
Table of Contents........................................................................................................ 3
Abbreviations Used in this Document............................................................... 7
1.0 EXECUTIVE SUMMARY ................................................................................. 10
1.1 Issue..................................................................................................................... 10
1.2 Objectives.......................................................................................................... 10
1.3 Methods.............................................................................................................. 10
1.4 Summary............................................................................................................ 11
1.4.1 Blood ............................................................................................................ 11
Gap 1: Patchwork and sometimes fragmented system of various
adverse event reporting.................................................................................... 11
Gap 2: Likely under-reporting of transfusion adverse events .............. 11
Gap 3: Challenges with FDA-required reporting.................................... 11
Gap 4: Need for accurate recipient denominator data, precise
definitions, and training............................................................................... 11
Gap 5: No national surveillance of donor serious adverse events other
than fatalities..................................................................................................... 11
Gap 6: Need for accurate donor denominator data, precise definitions,
and training ....................................................................................................... 11
Gap 7: Need for accurate tracking of all donor infectious disease test
data ...................................................................................................................... 11
Gap 8: Need for timely analysis of reported data ................................... 11
1.4.2 Tissues ......................................................................................................... 11
Gap 9: Limited information on the potential for HCT/Ps to transmit
infectious disease............................................................................................... 11
Gap 10: Ability to ascertain that reported infections in HCT/P
recipients can be attributed to the tissue is limited................................... 11
Gap 11: Regulations concerning HCT/P adverse reaction reporting do
not extend to the level of the healthcare facility or healthcare provider 11
Gap 12: Current mechanisms for tracking HCT/P grafts to the level of
the recipient are limited. ................................................................................. 11
Gap 13: Adverse reaction reporting for HCT/Ps regulated solely under
Section 361 of the PHS Act is limited to infectious diseases ................... 11
Gap 14: Information about adverse reactions in other recipients of
HCT/Ps from an implicated donor may not be readily available ......... 12
1.4.3 Organs ......................................................................................................... 12
Gap 15: Lack of nationwide common organ/tissue donor network
system for real-time reporting, data collection, communication, and

4
analysis of donor transmitted diseases in organ and tissue transplant
recipients, including a common donor identifier necessary for linkage
back to implicated donor of both organs and tissues. ............................... 12
Gap 16: No Requirement to retain donor and recipient samples ........... 12
1.5 Recommendations: ........................................................................................ 12
2.0 BIOVIGILANCE IN THE UNITED STATES ............................................ 13
2.1 Purpose .............................................................................................................. 13
2.2 Background ...................................................................................................... 13
2.3 Definition of Biovigilance .......................................................................... 14
2.4 Surveillance: Sentinel Event Reporting vs. Adjusted Rate
Benchmarking........................................................................................................ 15
3.0 GLOBAL MODELS OF COMPREHENSIVE HEMOVIGILANCE.... 16
Table 1. Comparison of adverse reporting requirement of countries
represented in the European Haemovigilance Network (EHN) ............ 17
Figure 1. Governance models of various hemovigilance systems in
various countries............................................................................................... 18
4.0 HEMOVIGILANCE EFFORTS IN THE UNITED STATES: A
PATCHWORK OF BLOOD SAFETY PROGRAMS ....................................... 20
4.1 Blood Recipients and Transfusion-Related Adverse Events ...... 20
4.1.1 Federal Government Activities................................................................. 20
Table 2. Donor, recipient, and linked donor-recipient repositories in the
US......................................................................................................................... 25
4.1.2 Public/Private and Private Sector Activities........................................ 26
4.1.3 US Transfusion Hemovigilance Initiatives to Date............................. 28
4.2 Gaps in Current US Transfusion Recipient Adverse Reaction
Reporting Systems ............................................................................................... 29
Gap 1: Patchwork and sometimes fragmented system of various adverse
event reporting................................................................................................... 29
Gap 2: Likely under-reporting of transfusion adverse events................. 29
Gap 3: Challenges with FDA-required reporting....................................... 30
Gap 4: Need for accurate recipient denominator data, precise
definitions, and training............................................................................... 32
Gap 5: No national surveillance of donor serious adverse events other
than fatalities..................................................................................................... 33
Gap 6: Need for accurate donor denominator data, precise definitions,
and training ....................................................................................................... 36
Gap 7: Need for accurate tracking of all donor infectious disease test
data ...................................................................................................................... 37
Gap 8: Need for timely analysis of reported data....................................... 38
4.3 Emerging Threat Assessment: Looking Beyond Known
Transfusion-Related Events............................................................................. 38
4.4 A New Initiative: A Public-Private Partnership in
Hemovigilance Surveillance Reporting...................................................... 39
4.4.1 Public/Private Initiatives in Recipient Hemovigilance...................... 40

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4.4.2 Public/Private Initiatives in Donor Hemovigilance ........................... 41
4.4.3 Future Challenges, Including Integration of Private and Public
Hemovigilance Efforts.......................................................................................... 42
Figure 2. The current patchwork of biovigilance ...................................... 43
Figure 3. Portal concept of biovigilance reporting ................................... 44
Figure 4. Potential Model of Electronic Health Record (EHR)
Exchange Interoperability.............................................................................. 44
5.0 BIOVIGILANCE EFFORTS IN THE US: ADVERSE EVENTS
ASSOCIATED WITH HUMAN CELLS, TISSUES, AND CELLULAR
AND TISSUE-BASED PRODUCTS..................................................................... 45
5.1 Background ...................................................................................................... 45
Table 3. Federal Oversight/Regulation of Hematopoietic Progenitor
Cells* ................................................................................................................... 46
5.2 HCT/P Biovigilance Concerns .................................................................. 47
Figure 5. Tissue Donors Recovered in US in the first part of 21
st
Century ............................................................................................................... 47
Figure 6. Musculoskeletal grafts distributed in US in the first part of
21
st
Century ....................................................................................................... 48
5.3 Efforts in HCT/P Biovigilance .................................................................. 49
5.3.1 Global Biovigilance .................................................................................... 49
5.3.2 HCT/P Biovigilance in the United States............................................. 50
5.3.2.1 Federal Reporting ......................................................................... 50
5.3.2.2 Private Sector Reporting ............................................................. 53
5.4 Gaps in Current HPC/T Adverse Reaction Reporting Systems . 55
Gap 9: Limited information on the potential for HCT/Ps to transmit
infectious disease................................................................................................... 55
Gap 10: Ability to ascertain whether reported infections in HCT/P
recipients can be attributed to the tissue is limited....................................... 55
Gap 11: Regulations concerning HCT/P adverse reaction reporting do not
extend to the level of the healthcare facility or healthcare provider........... 55
Gap 12: Current mechanisms for tracking HCT/Ps to the level of the
recipient are limited. ............................................................................................ 56
Gap 13: Adverse reaction reporting for HCT/Ps regulated solely under
Section 361 of the PHS Act is limited to infectious diseases ....................... 56
Gap 14: Information about adverse reactions in other recipients of
HCT/Ps from an implicated donor may not be readily available ............. 56
6.0 BIOVIGILANCE EFFORTS IN THE US: ADVERSE EVENTS
ASSOCIATED WITH SOLID ORGANS ............................................................. 57
6.1 Solid Organ Adverse Event Reporting ................................................. 57
6.2 Gaps in Current Organ Adverse Reaction Event Reporting
Systems...................................................................................................................... 61
Gap 15: Lack of nationwide common organ/tissue donor network system
for real-time reporting, data collection, communication, and analysis of
donor transmitted diseases in organ and tissue transplant recipients,

6
including a common donor identifier necessary for linkage back to
implicated donor of both organs and tissues .................................................. 61
Gap 16: No Requirement to retain donor and recipient samples ............... 62
7.0 POLICY CHALLENGES................................................................................... 64
7.1 Historical Background ................................................................................ 64
7.2 Mandates for a Comprehensive Biovigilance Program ................ 65
7.3 Mandatory vs. Voluntary Adverse Event Reporting ...................... 65
7.4 Public/Private Partnership ....................................................................... 66
7.5 Conclusions ...................................................................................................... 66
7.6 Recommendations ......................................................................................... 68
8.0 APPENDICES ...................................................................................................... 69
APPENDIX 1: Blood Action Plan.......................................................................... 69
FY98 ........................................................................................................................ 69
FY99 ........................................................................................................................ 70
FY00 ........................................................................................................................ 71
FY01 ........................................................................................................................ 72
FY02 ........................................................................................................................ 72
FY04 ........................................................................................................................ 73
FY05 ........................................................................................................................ 73
FY06 ........................................................................................................................ 73
FY07 ........................................................................................................................ 74
FY08 ........................................................................................................................ 75
APPENDIX 2: Office of the Secretary’s Office of Public Health and Science
Draft Strategic Plan................................................................................................. 76
APPENDIX 3: Tissue Transplant Record (Northwest Tissue Services) ..... 94
APPENDIX 4: NMDP Form 701 .......................................................................... 95
APPENDIX 5: NMDP Form 760 .......................................................................... 96
APPENDIX 6: Cell Therapy Adverse Event Form (University of California
San Diego Medical Center)..................................................................................... 97
9.0 References............................................................................................................. 98

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Abbreviations Used in this Document
AABB Formerly the American Association of Blood Banks
AATB American Association of Tissue Banks
ABC America’s Blood Centers
ACBSA Advisory Committee on Blood Safety and Availability
AE Adverse Event
AERS Adverse Event Reporting System
AHA American Hospital Association
AHRQ Agency for Healthcare Research and Quality
AIDS Acquired Immunodeficiency Syndrome
ARC American Red Cross
ASH Assistant Secretary for Health
BASIS Blood Availability and Safety Information System
BCP Blood Centers of the Pacific
BPDR Biological Product Deviation Report
BWG Biovigilance Working Group
CAP College of American Pathologists
CBER Center for Biologics Evaluation and Research
CBS Canadian Blood Services
CDC Centers for Disease Control and Prevention
CDRH Center for Devices and Radiological Health
CLIA Clinical Laboratory Improvement Amendments of 1988
cGMP Current Good Manufacturing Practice
cGTP Current Good Tissue Practice
CIBMTR Center for International Blood and Marrow Transplant
Research
CMS Centers for Medicare & Medicaid Services
DRCP Donor and Recipient Complications Program
DoD Department of Defense
DPSMC Donor and Patient Safety Monitoring Committee
DRG Diagnosis-related Groups
DTAC Disease Transmission Advisory Committee
EBAA Eye Bank Association of America
EC European Commission
EHR Electronic Health Record
EHN European Haemovigilance Network
EID Emerging Infectious Diseases
EUSTITE European Union Standards and Training for the Inspection of
Tissue Establishments
FACTS Frequency of Agents Communicable by Transfusion Study
FD&C Federal Food, Drug and Cosmetic Act

8
FDA Food and Drug Administration
FDAAA Food and Drug Administration Amendments Act of 2007
GLPR General Leukocyte and Plasma Repository
GSR General Serum Repository
GVHD Graft Versus Host Disease
HBV Hepatitis B Virus
HCT/P Human Cells, Tissues, and Cellular and Tissue-based Product
HCV Hepatitis C Virus
HHS Department of Health and Human Services
HHV-8 Human Herpesvirus 8
HIV Human Immunodeficiency Virus
HMO Health Maintenance Organization
HPC Hematopoietic Progenitor Cells
HRSA Health Resources and Services Administration
HTA Human Tissue Authority
IBMTR International Bone Marrow Transplant Registry
IHN International Haemovigilance Network
IND Investigational New Drug
IRB Institutional Review Board
ISBT International Society for Blood Transfusion
LCMV Lymphocytic Choriomeningitis Virus
MAB Medical Advisory Board
MedSun Medical Product Safety Network
MERS-TM Medical Event Reporting System for Transfusion Medicine
NAT Nucleic Acid Test
NBCUS National Blood Collection and Utilization Survey
NCBI National Cord Blood Inventory
NHLBI National Heart, Lung, and Blood Institute
NHSN National Healthcare Safety Network
NIH National Institutes of Health
NMDP National Marrow Donor Program
NOTA National Organ Transplant Act
OARRS Online Adverse Reaction Reporting System
OCTGT Office of Cellular, Tissue and Gene Therapies
OBRR Office of Blood Research and Review
OCBQ Office of Compliance and Biologics Quality
OPDIV Operating Divisions of the Department of Health and Human
Services
OPTN Organ Procurement and Transplantation Network
PBSC Peripheral Blood Stem Cells
PDI Post Donation Information
PHS Public Health Service

9
PLT Platelets
PPTA Plasma Protein Therapeutics Association
PVD Presumed Viremic Donors
RADAR Retrovirus Epidemiology Donor Study Allogeneic Donor and
Recipient
RBC Red Blood Cells
REDS Retrovirus Epidemiology Donor Study
RFID Radio Frequency Identification
SAE Serious Adverse Events
SENV SEN virus
SHOT Serious Hazards of Transfusions
SRR Safety Reporting Rule
TACO Transfusion Associated Circulatory Overload
TJC The Joint Commission (formerly the Joint Commission on
Accreditation of Healthcare Organizations [JCAHO])
TRALI Transfusion Related Acute Lung Injury
TRIP Transfusion Reactions in Patients
TSO Transfusion Safety Officer
TSS Transfusion Safety Study
TST Tissue Safety Team
TTD Transfusion Transmitted Diseases
TTVS Transfusion Transmitted Viruses Study
UBS United Blood Services
UCB Umbilical Cord Blood
UK United Kingdom
UNOS United Network for Organ Sharing
US United States
VCA Vascularized Composite Allografts
vCJD variant Creutzfeldt-Jakob Disease
WB Whole Blood
WHO World Health Organization
WNV West Nile virus

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1.0 EXECUTIVE SUMMARY
1.1 Issue
The Advisory Committee on Blood Safety and Availability (ACBSA)
recommended in August 2006 that the Department of Health and Human
Services (HHS) coordinate Federal actions and programs to support and
facilitate biovigilance in partnership with private sector initiatives. The
ACBSA has defined “biovigilance” as 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, cells, tissues, and organs. The ACBSA
recommended that biovigilance should be considered as a potential system to
improve patient safety. They recommended that a biovigilance program
should be outcome driven with the objectives of providing early warning
systems of safety issues, exchanging of safety information, and promoting
education and the application of evidence for practice improvement. The
ACBSA further recommended that the government form a Biovigilance Task
Group to perform a gap analysis of the current systems and make
recommendations for a public-private partnership in biovigilance.
1.2 Objectives
The objectives of this report are to review current biovigilance efforts in the
US and recommend a national plan for biovigilance in the future, including
review of the current status of hemovigilance and biovigilance system
infrastructure and gaps for blood; human cells, tissues, and cellular and
tissue-based products; and organs. Finally, the report will conclude with a
summary of system needs and recommendations for a national biovigilance
plan, consistent with the charges given by ACBSA.
1.3 Methods
A comprehensive review of current surveillance and adverse event reporting
systems for blood; human cells, tissues, and cellular and tissue-based
products (HCT/Ps); and organs was undertaken by a task group of the Public
Health Service (PHS) Biovigilance Working Group (BWG). This white paper
review included relevant PHS agencies (Centers for Disease Control and
Prevention, Food and Drug Administration, National Institutes of Health,
and Healthcare Resources Services Administration and the Center for
Medicare and Medicaid Services). The PHS BWG carefully considered the
various roles and missions of the PHS agencies play in program oversight
and product regulation.

11
1.4 Summary
The PHS BWG found in its review that at the present time, biovigilance in
the US is a patchwork of activities, not a cohesive national program.
Although this patchwork is functional, some of these activities are redundant,
while others are limited in scope, resulting in inefficiency and gaps. Each
HHS agency has created some means of data collection for outcomes and
adverse events in support of its mission and objectives, including regulatory
obligations. Professional organizations have also implemented standards for
quality systems, which require investigation of adverse outcomes and errors.
Recommendations on biovigilance systems and partnerships to fill existing
gaps are complicated by the lack of a national policy and a pluralistic
approach to the safety and availability of blood, tissue, and organs. Both
voluntary and mandatory systems are needed. Integration of systems with
both public and private sector support and joint governance of national
biovigilance collaborative is vital.
1.4.1 Blood
Gap 1: Patchwork and sometimes fragmented system of various adverse
event reporting
Gap 2: Likely under-reporting of transfusion adverse events
Gap 3: Challenges with FDA-required reporting
Gap 4: Need for accurate recipient denominator data, precise definitions,
and training
Gap 5: No national surveillance of donor serious adverse events other
than fatalities
Gap 6: Need for accurate donor denominator data, precise definitions,
and training
Gap 7: Need for accurate tracking of all donor infectious disease test data
Gap 8: Need for timely analysis of reported data
1.4.2 Tissues
Gap 9: Limited information on the potential for HCT/Ps to transmit
infectious disease
Gap 10: Ability to ascertain that reported infections in HCT/P recipients
can be attributed to the tissue is limited.
Gap 11: Regulations concerning HCT/P adverse reaction reporting do not
extend to the level of the healthcare facility or healthcare provider
Gap 12: Current mechanisms for tracking HCT/P grafts to the level of the
recipient are limited.
Gap 13: Adverse reaction reporting for HCT/Ps regulated solely under
Section 361 of the PHS Act is limited to infectious diseases

12
Gap 14: Information about adverse reactions in other recipients of
HCT/Ps from an implicated donor may not be readily available
1.4.3 Organs
Gap 15: Lack of nationwide common organ/tissue donor network system
for real-time reporting, data collection, communication, and
analysis of donor transmitted diseases in organ and tissue
transplant recipients, including a common donor identifier
necessary for linkage back to implicated donor of both organs and
tissues.
Gap 16: No Requirement to retain donor and recipient samples
1.5 Recommendations:
1. We recommend government resource support for a national
biovigilance program to monitor and enhance safety of blood, organs,
and HCT/Ps.
2. We recommend integration of systems within the government and
those within the private sector, involving blood, organs, and HCT/Ps,
including all related voluntary and mandatory adverse event reporting
systems.
3. We recommend steps to enhance mechanisms for surveillance,
including sentinel reporting and investigation, and comprehensive
surveillance that features benchmarking.
4. We recommend developing an HHS action plan to support the above
three recommendations.

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2.0 BIOVIGILANCE IN THE UNITED STATES
2.1 Purpose
The Advisory Committee on Blood Safety and Availability (ACBSA)
recommended in August 2006 that the Department of Health and Human
Services (HHS) Secretary coordinate Federal actions and programs within
the United States (U.S.) to support and facilitate biovigilance in partnership
with private sector initiatives. A PHS BWG was formed to identify the
vision, goals, and processes needed to advance these objectives. The PHS
BWG was charged with producing an analysis and operational report
incorporating both public and private sector efforts to include:
• A gap analysis regarding the effectiveness of the current activities;
• The need for mandatory versus non-mandatory, and regulatory versus
non-regulatory reporting;
• The scope of reporting with regard to product problems, medical errors
and clinical adverse events including recognized and novel events;
• Database centralization versus data sharing;
• Database governance, ownership and accessibility;
• Format and standards for data reporting including confidentiality;
• Potential for coordination with non-US safety reporting systems;
• Funding mechanisms for a sustainable system; and,
• Design and feasibility of suitable pilot programs to determine the
characteristics of a value-added system.
The objectives of this report are to review current biovigilance efforts in the
US and recommend a national plan for biovigilance in the future. First, we
will review the current status of hemovigilance and biovigilance system
infrastructure and gaps nationally; global systems will also be briefly
reviewed in order to provide perspective. The review will be separated into
biovigilance systems for blood; human cells, tissues, and cellular and tissue-
based products (HCT/Ps); and organs. Identification and analysis of system
gaps will also be included for each section. Finally, the report will conclude
with a summary of system needs and recommendations for a national
biovigilance plan, consistent with the charges given by ACBSA.
2.2 Background
Advances in science and healthcare technology have led to more biologic
products being collected to sustain and improve the quality of human life. In
the United States (US) in 2007, over 30 million units of blood or blood
products, 28,000 organs, and two million tissue allografts were transfused or
transplanted. Despite these large numbers, demand often exceeds

14
availability, particularly for organs. Challenges exist to monitor and ensure
appropriate access to and availability of safe products, both in the domestic
and global arenas. Efforts to increase the availability of these products also
may increase the opportunities for transmission of infectious pathogens,
including viruses, bacteria, parasites and prions. These risks are multiplied
when there are multiple recipients from a common donor. Examples of
diseases or organisms transmitted through blood, organs, or other tissues
include Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV),
hepatitis C virus (HCV), human T-cell lymphotrophic virus types I and II
(HTLV-I/II), West Nile virus (WNV), rabies virus, lymphocytic
choriomeningitis virus (LCMV), Group A Streptococcus, Mycobacterium
tuberculosis, malaria, babesiosis, variant Creutzfeldt-Jakob Disease (vCJD),
and Trypanosoma cruzi (the etiologic agent of Chagas disease). Transmitted
malignancies have been reported primarily through organ transplantation.
Beyond disease transmission, other concerns include adverse immunologic
response, reaction to toxins, or decrease in expected function. These non-
infectious events may be due to deficiencies in the product, or a mismatch
between the product and recipient immunologic profile, but consequences
may be as severe as for infectious disease transmission events.
Biologic-based products or technologies are likely always to carry an inherent
risk. While solid organs cannot be altered to reduce infectivity, some tissues
can be processed with chemicals or radiation, and blood can be modified, e.g.
through leukocyte filtration or irradiation. However, no process can
completely eliminate the inherent risks of transfusion and transplantation.
The role of patient safety efforts is to drive that risk to the lowest level
reasonably achievable without unduly decreasing the availability of these life
saving resources, so that the overall benefit outweighs risk.
2.3 Definition of Biovigilance
The ACBSA has defined “biovigilance” as 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, cells, tissues, and organs. The program should
be outcome driven with the objectives of providing early warning systems of
safety issues, exchanging of safety information, and promoting education and
the application of evidence for practice improvement. Donor biovigilance is
integral to the total biovigilance program since donors provide the “raw
materials” for biologic treatments, and because safety of living donors is a
related and important public health issue in itself.
Biovigilance incorporates a program to maximize the safety of blood, organs,
and HCT/Ps. Some experts have framed the basic elements of biovigilance as

15
consisting of adverse event monitoring (for recipients and donors), product
quality assurance (including processing controls and error management),
emerging threat assessment using epidemiologic and laboratory data (e.g.,
bioinformatics, repositories), and measurement of availability and
appropriateness of use. There are two main types of approaches to these
issues, one utilizing data analysis to uncover trends in aggregate data to
reveal new concerns or the efficacy of interventions in traditional
surveillance, and the other utilizing a “sentinel” approach that quickly
detects singular events that pose potential public health threats.
2.4 Surveillance: Sentinel Event Reporting vs. Adjusted Rate
Benchmarking
The World Health Organization (WHO) guideline on adverse event reporting
emphasizes that the effectiveness of surveillance systems should be measured
not only by data reporting and analysis but also by the use of such systems to
improve patient safety through active response to data generated (1).
In examining frameworks for implementation of biovigilance systems,
including the use of such systems for quality improvement, one must consider
what type of event is the target of capture. For instance, in order to capture
rare events that are of significant singular importance for patient safety, a
sentinel system should be 1) extremely sensitive, perhaps at the expense of
specificity, 2) operated in real time in order to allow immediate registry of
events, and 3) configured so that communication about the event allows
critical response actions to take place.
An effective biovigilance program should be operationally capable of
providing the core tools, infrastructure, and logistics necessary to support
timely communication of critical information to the right people in order to
make essential real-time interventions to avert clinical catastrophe.
On the other hand, surveillance of more common events of interest may be
more comprehensive. Capture of more common events also may allow
benchmarking through comparison of event rates between facilities, which
are most helpful if they are adjusted for factors that are not the focus of
comparison. Such risk-adjusted rates allow valid comparisons and analysis,
so that a quality program can be implemented and continuously evaluated,
either before, during, or after an intervention takes place.

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3.0 GLOBAL MODELS OF COMPREHENSIVE HEMOVIGILANCE
Hemovigilance systems arose as a response to the threat of emerging
infections to the safety of the blood supply. The recognition of the Acquired
Immunodeficiency Syndrome (AIDS) epidemic, which resulted in the deaths
of thousands of recipients of blood and plasma products worldwide, led to
public debates, commissions of inquiry, and legal prosecution stemming from
management of the nascent HIV risk of the 1980s. The epidemic also
provided additional stimulus to assess the safety of transfusion services
through ongoing risk assessment measures. Hemovigilance was developed
first by France in 1993 and featured mandatory reporting; the United
Kingdom (UK) developed the first voluntary system in 1996. The European
hemovigilance efforts were empowered with the European Blood Directive
2002/98/EC (2).
Subsequently, global solutions to the challenge of hemovigilance represent a
spectrum of responses including national blood policies, governance models,
and reporting systems that are either mandatory or voluntary. Most
developed and developing countries have a national blood policy and a
national blood system for collecting blood and making it available to hospital
transfusion services. These nationalized structures facilitate the
establishment of hemovigilance efforts.
Countries that have developed hemovigilance programs have created and
implemented systems as a hybrid of mandatory and voluntary approaches
(Table 1), operating under a variety of governance models (Figure 1).
Hemovigilance systems, depending on the country, are governed either by
regulators (e.g., France, Germany, Switzerland), blood manufacturers (e.g.,
Japan, Singapore, South Africa), medical societies (e.g., Netherlands, UK), or
public health authorities including regulators (e.g., Canada). Figure 1 is a
graphic representation of these programs. Some of these reside within, and
derive reporting mandates from, a national ministry of health (3, 4) while
others are primarily organized through professional societies or the country’s
blood collection system with sharing of data to all concerned parties (2, 5, 6,
7, 8).
The European Union currently requires implementation of a
hemovigilance system in each member state with reporting to a central office
(9, 10, 11).
Outside the European Union, the more recently formed Canadian system is of
particular interest as an example of a public health-driven model with data
flow to the public health regulators. Within Canada, Héma-Québec, a non-
profit organization that manages the blood supply for the Canadian province
of Québec has placed Transfusion Safety Officers (TSO) within each medical
facility. Surveillance in Québec is more active and comprehensive with the

17
TSO concept in place and perhaps due to this unique characteristic, Québec
has a high rate of transfusion adverse event reporting (4). Although each of
the existing hemovigilance systems has characteristics unique to the
country’s own healthcare and transfusion systems, the systems bear multiple
similarities and have yielded similar benefits.
With the implementation of hemovigilance systems in Europe, it became
apparent that individual countries were using different definitions for events
and incidents and there was a wide diversity in methods and systems of
reporting. This led to the establishment of the European Haemovigilance
Network (EHN) in 1998 with the goal of developing uniform standards and
definitions (12).
Table 1. Comparison of adverse reporting requirement of countries
represented in the European Haemovigilance Network (EHN)
Country Reporting
Requirement
Haemovigilance Reporting to
Ministry of Health or Regulator
Austria Unable to determine Yes, but some SAEs reported in
annual report
Belgium Voluntary Yes
Croatia Voluntary Unable to determine
Denmark Voluntary No
Finland Mandatory Yes
France Mandatory Yes
Greece Voluntary Unable to determine
Iceland Voluntary No
Ireland Voluntary Irish Blood Transfusion Service
Italy Unable to determine Unable to determine
Luxembourg Mandatory Report is to blood service of Red
Cross but MOH is also notified
Malta Unable to determine Unable to determine
Netherlands Voluntary No
Norway Unable to determine Unable to determine
Portugal Voluntary No
Slovenia Unable to determine Unable to determine
Sweden Unable to determine Unable to determine
Spain Unable to determine Unable to determine
UK Voluntary Reported through SHOT

18
Haemovigilance
Governance
Regulators
e.g. France,
Switzerland, &
Germany
Medical Societies
e.g. United Kingdom,
Netherlands
Blood
Manufacturer
e.g. Singapore,
Japan &
South Africa
Public Health
e.g. Canada
Private-Public
Partnership
Figure 1. Governance models of various hemovigilance systems
in various countries
The EHN defines haemovigilance as a set of surveillance procedures covering
the entire transfusion chain (from the donation of blood and its components
to the follow-up of recipients of transfusions), intended to collect and assess
information on unexpected or undesirable effects resulting from the
therapeutic use of labile blood products, and to prevent the occurrence or
recurrence of such incidents (2).
The European blood directive 2002/98/EC established the definitions for
Haemovigilance, Serious Adverse Events and Serious Adverse Reactions (13).
The EHN initially defined grading for severity, imputability and clinical and
biological signs (9), which have been modified and expanded by the
International Society for Blood Transfusion (ISBT) Working Party.
Nevertheless, variability still exists in some definitions, terminology,
standardized reporting, etc. Also, the scope of various countries’ systems is
varied. For example, the UK’s Serious Hazards of Transfusion (SHOT)
focuses only on serious hazards and does not report mild febrile or urticarial
reactions and since most non-hemolytic transfusion reactions show mild
signs, reports from SHOT demonstrate a very low incidence of overall adverse
events compared to France (14). Others have published the value of
reporting near misses (15, 16). The differences from country to country have
been recently reviewed (6).

19
Since the founding of the EHN, the network has expanded to include
countries outside of Europe including Canada, New Zealand and Singapore.
In addition, the International Society for Blood Transfusion (ISBT) has
played a leading role in standardization. Working parties were created in
2002 within ISBT to establish definitions in order to make data comparable
between members. There are more than 50 members from 34 countries
represented in the EHN. Recently, EHN changed its name to the
International Haemovigilance Network (IHN).

20
4.0 HEMOVIGILANCE EFFORTS IN THE UNITED STATES: A
PATCHWORK OF BLOOD SAFETY PROGRAMS
4.1 Blood Recipients and Transfusion-Related Adverse Events
4.1.1 Federal Government Activities
Although national hemovigilance systems are well established in most
developed countries, in the US, there is no single program of centralized
blood safety monitoring. Ensuring the safety of the US blood supply is a
public health responsibility designated to the Assistant Secretary for Health
(ASH) as the Nations Blood Safety Officer. Coordinated safety and public
health efforts are shared among operating divisions of HHS, including the
Centers for Disease Control and Prevention (CDC), Food and Drug
Administration (FDA), National Institutes for Health (NIH), and Centers for
Medicare and Medicaid Services (CMS) (17). Together, these HHS agencies
identify and respond to potential threats to blood safety, develop safety and
technical standards, monitor blood supplies and help industry provide an
adequate supply of blood and blood products. However, by their design, the
existing systems focus primarily on reporting of sentinel events. The existing
systems do not provide comprehensive baseline surveillance reporting of
known events in relation to blood product exposures. Thus, in the US,
currently it is not possible to routinely monitor adverse event rates outside of
limited, specially designed studies.
The FDA has regulatory responsibility for blood and blood products, and
takes on most of the work of risk management. In the US, blood and plasma
is collected, processed and distributed by a private industry that is regulated
by the FDA primarily under the authority of two national laws. The Public
Health Service Act (PHS Act) (42 USC 201 [check] et. seq.) has two relevant
sections. Section 351 sets forth the authority for licensure and regulation of
biological products while Section 361 defines authorities for communicable
disease control. The second national law is the Federal Food, Drug, and
Cosmetic Act (FD&C Act) (21 USC 201 et. seq.), which provides authority for
the regulation of medical products, including drugs and medical devices.
Biological products fall within the scope of the FD&C Act because they also
are drugs or medical devices. In September 2007, Congress passed the Food
and Drug Administration Amendments Act of 2007 [FDAAA]), giving the
FDA additional authorities over FDA-regulated products, including biological
products. Blood collection and transfusion organizations also comply with
State laws and voluntary standards developed by stakeholder organizations
such as the AABB (formerly the American Association of Blood Banks) and
the PPTA (Plasma Protein Therapeutics Association). Interstate distribution
of biological products (including distribution outside of the US) is only

21
permissible under FDA license. There are approximately 1090 FDA-licensed
blood collection establishments and 374 FDA-licensed plasma collection
establishments. Approximately 770 unlicensed, but registered whole blood
facilities collect and manufacture blood components for intrastate
distribution. Within FDA, the Center for Biologics Evaluation and Research
(CBER) regulates the collection of blood and blood components used for
transfusion. CBER also regulates blood products derived from blood and
blood components, such as clotting factors, and CBER establishes reference
standards for many of the products. CBER also regulates related products
such as cell separation devices, blood collection containers and HIV and other
infectious disease screening tests that are used to prepare blood products or
to ensure the safety of the blood supply. CBER develops and enforces quality
standards, inspects blood establishments prior to licensure of new products,
and monitors mandatory and voluntary reports of errors, accidents and
adverse clinical events. Post-market inspections of blood establishments are
conducted by the FDA Office of Regulatory Affairs, in conjunction with the
CBER Office of Compliance and Biologics Quality (OCBQ) and other FDA
Offices, including the Office of Blood Research and Review (OBRR).
In 2006, CBER formed the Blood Safety Team (BST) with membership from
several CBER offices. The BST’s goals are to improve the FDA responses to
blood safety issues through defined interoffice collaboration within CBER; to
create increased sensitivity to safety signals; to improve the value of safety
information; to establish roles and responsibilities in the management of
blood safety issues; to broaden public and regulated industry access to the
information; to improve the processing of blood safety information through
establishment of a forum for review and evaluation of events; and to enhance
external outreach, evaluation and risk communication. Although activities of
the BST promote effective interagency cooperation, BST participation does
not extend outside FDA.
Regulatory oversight of hospital transfusion services occurs through CMS or
accredited organizations granted deemed status under the Clinical
Laboratory Improvement Amendment of 1988 (CLIA). Although transfusion
services are subject to applicable FDA regulations, they are not required to
register with FDA unless they also manufacture blood or blood components
and they are not routinely inspected by FDA. However, hospital transfusion
service laboratories are required to be certified by the CLIA program, and
they are routinely surveyed for CLIA compliance. These surveys are
addressed in a Memorandum of Understanding between CMS and FDA.
CLIA regulations require laboratories to report transfusion fatalities to FDA,
and CMS and FDA routinely cooperate in the investigation of these
fatalities. CLIA regulations directly reference certain FDA regulations that
apply to transfusion services.

22
In 1997, the FDA initiated the Blood Action Plan to increase the effectiveness
of its scientific and regulatory actions, and to ensure greater coordination
within PHS. The Action Plan addressed focused areas of concern such as
emergency operations, response to emerging infections, and updating of
regulations. The plan was adopted by HHS as a whole and progress has been
remarkable with many outcomes (Appendix 1)
In 2005, the ACBSA made recommendations on the development of a
strategic plan for the blood system as a follow-up to the 1998 Blood Action
Plan. A key element of the ACBSA recommendations was development of a
biovigilance system. In October 2008, elements of the ACBSA
recommendations were incorporated into the Secretary’s Office of Public
Health and Science strategic plan (Appendix 2).
Reporting to FDA is required for blood and blood components when a fatal
adverse event occurs related to donation or transfusion (18). Based on data
collected in 2008, the top five leading transfusion related fatality categories
were transfusion related acute lung injury TRALI (35%); ABO blood group
hemolytic transfusion reactions (22%); non-ABO hemolytic transfusion
reaction (15%); microbial infection (15%) and transfusion associated
circulatory volume overload (TACO) (7%). Collection of information from the
currently required FDA fatality reports for disorders such as TRALI have led
to increased understanding of the possible role of plasma and anti-HLA and
anti-leukocyte antibodies in TRALI pathogenesis.
In addition, there is a requirement for licensed and registered blood
establishments and transfusion services to file biological product deviation
reports (BPDRs) when a deviation from standards, such as a variation in
current Good Manufacturing Practice (cGMP), may affect the safety, purity or
potency of a blood product and the unit leaves the facility’s or a contracted
facility’s control before the problem is identified and rectified. For non-fatal
adverse events, blood collection and transfusion facilities are required to
conduct investigations and maintain records and reporting to FDA is
encouraged, but not required, and is uncommon.
Medical device manufacturers must submit adverse event (AE) reports to
FDA involving deaths and serious injuries or illnesses connected with the use
of medical devices used for the collection or administration of blood
components for patient treatment or diagnosis.
For voluntary reporting related to any FDA-regulated product, patients,
family members, physicians, pharmacists and any other reporter can submit
information to FDA’s Adverse Event Reporting System (AERS)/MedWatch

23
(19). This system gathers information on a variety of products including
drugs, devices and other medical and nutritional products.
CDC’s mission is to collaborate with state and local health departments to
create the expertise, information, and tools needed to protect public health
through health promotion, disease prevention, and preparedness for new
health threats. Areas of focus concerning blood, organ, and tissue safety at
CDC include public health investigation, surveillance, research, prevention,
and risk communication. A stated CDC goal objective is to improve
surveillance for adverse events associated with use of biologic products (e.g.,
blood, organs, and tissues), vaccines, drugs, or devices by coordinating HHS
efforts to enhance rapid detection and implementation of novel prevention.
Proposed measures and actions include implementation of transfusion and
transplant adverse event surveillance. One CDC system for healthcare-
related event surveillance is the National Healthcare Safety Network
(NHSN). NHSN is a secure, internet-based surveillance system that collects
data from voluntarily participating healthcare facilities in the United States
to permit benchmarking of adverse events, including healthcare-associated
infections, among patients and healthcare personnel.
CDC has had in place since 1998 a blood safety monitoring system in
the bleeding disorder community, the Universal Data Collection program,
managed by the Division of Blood Disorders, that provides annual testing for
hepatitis and HIV and stores blood specimens in a serum bank for use in
future blood safety investigations [MMWR 2003]. CDC works with local state
health departments to investigate any seroconversions to rule out
transmission from blood products used to treat hemophilia and other
bleeding disorders. A similar system has been established in several
centers in the U.S. that treat patients with thalassemia who depend on
frequent blood transfusions for survival. Currently there are over 70,000
plasma specimens on patients with bleeding disorders (primarily hemophilia)
and about 1,000 specimens on patients with thalassemia in the CDC bleeding
disorder repository.
The Office of Blood, Organ, and Other Tissue Safety operates within the
Division of Healthcare Quality Prevention in the Coordinating Center for
Infectious Diseases. The Office functions are to coordinate CDC activities to
prevent disease transmission and other adverse events; develop, implement,
and evaluate CDC’s agenda for blood safety; direct CDC representation on
standing HHS and industry committees to determine blood safety policy; and
chair the Blood, Organ, and Other Tissue Safety Working Group.
The Blood, Organ, and Other Tissue Safety Working Group is composed of
division representatives of the Coordinating Center for Infectious Diseases

24
and liaison members from other areas of CDC, including the Division of Blood
Disorders. Functions are analogous to the BST at FDA/CBER to enhance
investigation coordination. In addition, the working group coordinates
current and planned projects; identifies gaps and priorities for intervention;
and develops an agenda to enhance transfusion and transplant safety, in
collaboration with HHS and external partners.
The National, Heart, Lung, and Blood Institute (NHLBI) of NIH is
responsible for funding basic, translational, and clinical research related to
transfusion. NHLBI funds biospecimen collections (Table 2). A vast majority
of these collections are maintained at the NHLBI Biologic Specimen
Repository. Research is also conducted by intramural FDA, CDC, and NIH
scientists.
Within the Office of the Secretary of HHS, the ASH has been designated as
the Nation’s Blood Safety Officer. This role was established as an outcome of
an internal review of the Institute of Medicine’s report in the mid 1990s. The
ASH carefully considers public discussion of issues and recommendations
from the ACBSA. In addition, the ASH participates in internal discussions
with the Blood Safety Council (BSC), which often provides input and
recommendations on blood policy matters. The BSC consists of senior
executive representatives from FDA, NIH, CDC, HRSA, and CMS. The BSC’s
role is currently being reviewed and a new charter has been proposed to
expand the BSC’oversight to organs and tissues. Monitoring of the blood
supply and demand is obtained through voluntary reporting through the
Blood Availability and Safety Information System (BASIS).

25
Table 2. Donor, recipient, and linked donor-recipient repositories in the US.
Name of
study
*
Timeframe
of
funding
Sample
population
Sample
type
Number of
samples
Major agents
studied
NIH-
Clinical
Center
1968-97
Donor-
Recipient
Serum 29,055
donations
3,429 recipients
HCV,
HGV/GBV-C,
TTV, SENV
TTVS 1974-79 Donor-
Recipient
Serum 5,655 donations
1,533 recipients
HCV, HBV,
HHV-8
TSS 1984-85 Donations Serum 201,212
donations
HIV, HTLV
FACTS 1985-91 Recipients Serum 11,494
recipients
HIV, HTLV,
HCV, HHV-8,
T. cruzi
REDS
GSR/GLPR
1991-94 Donations Serum
(GSR)
Plasma;
frozen
whole
blood
(GLPR)
508,151
donations
(GSR)
147,915
donations
(GLPR)
HBV, CMV,
HHV-8
VATS 1995-99 Donor-
Recipient
Plasma;
frozen
whole
blood
3,864 donations
531 recipients
HIV, CMV,
HBV, HCV,
HGV, HTLV
REDS
RADAR
1999-2003 Donor-
recipient
Plasma;
frozen
whole
blood
13,201
donations
3,574 recipients
Parvovirus
B19
TRIPS 2001-
ongoing
Donor-
recipient
Plasma;
frozen
whole
blood
4,401 donations
879 recipients
HIV, HBV,
HCV, HHV-8,
CMV, EBV,
Parvovirus
B19
* All the collections in the table are housed at the NHLBI Biologic
Specimen Repository except the NIH-Clinical Center and the FACTS
repositories which are retained by the primary investigators.

26
4.1.2 Public/Private and Private Sector Activities
Unlike the national blood systems that are in place through much of the
developed world, the US blood and plasma supply is collected by privately
owned and operated facilities that are regulated by FDA. Whole blood for
interstate distribution is collected by 135 not-for-profit FDA-licensed blood
establishments operating 1,090 fixed community blood collection centers. It is
estimated that the American Red Cross (ARC) collects approximately 42% of
the US red blood cell (RBC) supply through its network of 35 regional blood
centers and operates under a single FDA license. An additional 52% of the
RBC supply is estimated to be collected by 77 independently licensed blood
establishments that are members of America’s Blood Centers (ABC). The
remaining 6% of the RBC supply is collected by hospitals (approximately 5%),
and the Department of Defense (1%). Blood for intrastate use only is collected
by 710 hospitals and other entities that are not licensed, but are registered
with and inspected by the FDA and must follow all applicable laws and
regulations. Source Plasma is collected in the US by 57 licensed
establishments at 373 collection facilities.
The professional organization, the independent blood collectors association
and the ARC have also engaged in gathering safety data for assessing risks.
The professional organization is represented by the AABB, of which nearly all
blood collection establishments and most transfusion services are members;
while the ABC represents collaboration among independent, community-
based blood programs.
HHS sponsors the National Blood Collection and Utilization Survey (NBCUS)
through competitive contract to assess the amount of blood collected and
transfused, and hospital activities involving tissues and cellular therapies in
the US. The facilities surveyed include all non-hospital-based blood collection
centers, a statistically representative sample of hospitals from the American
Hospital Association (AHA) database and a similar sampling of cord blood
banks. The data obtained by this survey are vital in determining estimated
numbers of collections and transfusions as well as trending of utilization.
Some data on adverse events, defined as numbers of events that require
diagnostic or therapeutic intervention, are also collected (20). The national
data are helpful in determining the denominator for comparison of activities
and events.
Blood collection centers also operate their own reporting systems. ABC,
through its alliance of independent blood centers, conducts a variety of
surveys among its members on a periodic basis and shares outcomes and best
practices through online reports to its participating members. Some members
of ABC are blood collection centers that also function as transfusion services

27
and collect and monitor adverse reactions in a fashion similar to hospital
based transfusion services (21). These activities however are for internal use
and quality control and are, in general, not shared publicly. Individual blood
centers are also required by FDA to document errors and adverse events,
perform investigations, document corrective action when warranted, and
report to FDA any biologic product deviations that are present in products
that are made available for release from the manufacturing facility.
The 35 ARC regional blood centers actively solicit reports of infectious and
noninfectious complications in recipients of blood components. When
transfusion reactions are reported within ARC, investigations are performed
locally and then by region. Regional medical directors evaluate the
investigations and assign probability scores. Outcomes are compiled and
entered into the Donor and Recipient Complications Program (DRCP)
database. This provides the ability to track and analyze trends in
complications at each region and across the ARC system to provide
opportunities for process improvement. Specific outcomes are also published
periodically through peer-reviewed journals (22).
Mandatory reporting requirements from some state health departments also
exist. For example, since 1989, the New York State Department of Health
has required the reporting of all transfusion-associated incidents in the state
that pose a significant risk to the donor or to the recipient, whether or not an
incident results in an adverse outcome (23). Approximately 250 New York
hospitals use action and root-cause analysis results and delineation of
corrective actions taken. Compliance is verified during biennial inspections.
For transfusion-related events, reports are assessed for completeness, and
missing information is sought. The observed rate of giving incorrect ABO
blood group and type is reported to be 1/19,000 transfusions. This rate is
very similar to the 1/18,000 reported by SHOT; however the true error rate
may be much higher.
In 1996, The Joint Commission (TJC, formerly the Joint Commission on
Accreditation of Healthcare Organizations) an organization responsible for
accreditation of healthcare facilities in the US, established a sentinel event
reporting system in support of its mission to continuously improve the safety
and quality of health care (24). TJC reviews organizational responses to
sentinel events as a part of its accreditation process. Sentinel events are
defined as an unexpected occurrence involving death or serious physical or
psychological injury, or the risk thereof. Serious injury specifically includes
loss of limb or function. The phrase “or the risk thereof” includes any process
variation for which a recurrence would carry a significant chance of a serious
adverse outcome. The Sentinel Event Policy requests the organization to
transmit its root cause analysis, action plan, and other sentinel event-related
information to TJC electronically (25). Transfusion errors, primarily

28
misidentification of patient or product, are expected to be reported as sentinel
events should they lead to severe harm.
4.1.3 US Transfusion Hemovigilance Initiatives to Date
While there is no formal hemovigilance program in the US, mandatory and
voluntary reporting requirements exist within healthcare facilities. For
example, most hospitals have a transfusion reaction reporting system that
reports to the hospital transfusion service. A transfusion committee made up
of various department representatives (26, 27) may review the reports or in
some facilities this may be an additional responsibility of the Pharmaceutical
and Therapeutic Committee. This control at the local level is important since
it offers the opportunity for a uniformity of practice at the hospital level,
including common definitions, and implementation of corrective actions when
system problems are identified within a specific facility or hospital system
(17, 28). However, benchmarking to external institutions is lacking in this
model. The French experience has demonstrated the benefits of comparison
to other hospitals for participation in a national hemovigilance program (29,
30).
Prototypes have also been created to detect transfusion errors. The Medical
Event Reporting System for Transfusion Medicine (MERS-TM) was
developed under the leadership of Columbia University, New York, with
funding from NHLBI to collect, classify and analyze events that could
compromise the safety of transfused blood and to facilitate system
improvement (31). MERS-TM defines a medical event as any error, incident,
deviation, variance, or sentinel/adverse event related to blood components
and transfusion procedures. An avoidance or prevention of an unwanted
consequence through some action that identified and corrected the potential
failure is considered a near miss.
The MERS-TM system was designed to function within existing quality
assurance programs using descriptive classification schemes and FDA coding.
The system was tested within blood centers and transfusion services.
Currently functioning, this small system provides mechanisms for
approximately 20 hospitals to submit reports anonymously to a central
database, which supports analysis of an individual hospital’s data as well as
comparisons to that of the aggregate data (32, 33). This approach has
demonstrated that, for the facilities participating, 90% of reported events are
near misses of which 10% were detected after product issue, but before
transfusion.

29
4.2 Gaps in Current US Transfusion Recipient Adverse Reaction
Reporting Systems
Gap 1: Patchwork and sometimes fragmented system of various adverse
event reporting
The responsibility of hemovigilance, and more broadly biovigilance, within
the federal sector has been divided by HHS agencies based on their specific
mission and regulatory authority. There is currently no comprehensive HHS
system to share data among the HHS operating divisions, or externally.
The US blood collection and transfusion system is comprised of a network of
private sector blood establishments and hospitals that maintain strong
affiliations with accreditation and trade organizations. Adverse event
reporting is conducted within individual facilities and sometimes shared
within the larger organizations, but lacks uniformity of definitions,
procedures, and assessments. There is also limited information exchange
between stakeholders. In many cases, data are considered proprietary until
they are published in the scientific literature.
Gap 2: Likely under-reporting of transfusion adverse events
Despite reporting requirements and an existing patchwork of systems, there
are many challenges in effectively detecting transfusion reactions in
recipients. First, separating complications of transfusion in recipients from
conditions due to the underlying illnesses that prompted the need for
transfusion is difficult. The development of computerized health services
data could improve the quality and availability of recipient data. This type of
initiative would require significant investment in infrastructure. Evaluation
of international systems (such as SHOT in the UK) and standards could
prove useful in identifying possible modifications and improvements to the
US system.
It is likely that there is under reporting to FDA, even for required adverse
events (i.e., fatality reporting for blood and blood components)). This under
reporting (“numerator” deficiencies) has been attributed to a number of
factors, including uncertainty about the relationship of the fatality to a
transfusion event, the time and effort required for filing a report, or concern
by a potential reporter about resulting regulatory actions. As an example,
TRALI remains the most frequent cause of US fatalities following transfusion
with 34 cases reported to FDA in 2007 for a reported rate of 1.2 TRALI cases
per million transfusions (all components)(34). This is a substantially lower
rate than reported by SHOT prior to the institution of male only plasma (35).

30
According to the 2005 NBCUS Report, there were 32,128 medically
significant transfusion-related adverse reactions in 2004. After adjusting for
the survey response rate, one can estimate that there are over 50,000
significant transfusion reactions per year in the US, many of which are
preventable. The 2007 NBCUS report registered 71,994 transfusion reactions
in 2006 for an overall reaction rate of 1:320 transfusions for all components
(36). This is about one half of the 1:150 rate overall reported by the active
hemovigilance system in Québec, Canada (7). Extrapolation of the Québec
estimates would translate into nearly 120,000 adverse events in the US
based on 2004 red cell utilization data (20). Including other blood components
would significantly increase that number.
Finally, increased knowledge about the potential risks of transfusion to
recipients could lead to more careful assessment of the need for transfusion of
blood and blood components and reduction in the number of transfusions that
do not meet accepted practices.
Gap 3: Challenges with FDA-required reporting
Current FDA regulations 21 CFR 606.170 require that blood collection or
transfusion establishments investigate adverse reactions resulting from blood
collection or transfusion. The establishments must investigate these adverse
reactions and maintain records of their investigation at their facility. If it
were determined that the blood caused the transfusion reaction, then the
report must be forwarded to the blood collection facility. Currently, blood
establishments are not required to submit these reports to FDA, although
FDA can review these reports on inspection. FDA has proposed reporting
requirement for serious adverse events related to blood collection and
transfusion, in the proposed Safety Reporting Rule (SRR), published on
March 14, 2003 in the Federal Register. (http://frwebgate5.access.gpo.gov/cgi-
bin/waisgate.cgi?WAISdocID=906650192596+0+3+0&WAISaction=retrieve).
FDA currently is considering the comments received and a timeline for final
publication of this rule is not currently available.
Important trends in the data submitted under regulatory requirements may
not always be identified or understood because of the limitations placed upon
data that are reported to the federal government. Biologic Product Deviation
Reports (BPDRs) required by 21 Code of Federal Regulations (CFR) 600.14
and 21 CFR 606.171 are examples. There is a need to develop more
sophisticated analyses of the data collected BPDR reports, but this ability is
hampered by the lack of more detailed characterizations of reported product
deviations within the reports themselves. More detailed analyses would
better define underlying reasons for deviations, provide useful benchmarks,
and provide additional incentives for changes in practices in blood

31
establishments and transfusion services. As a hallmark of the future,
electronic reporting for BPDRs has significantly reduced the paperwork
burden for both regulated industry and the FDA associated with reporting,
receipt, and analysis of BPDR reports. Arguably, the burden of BPDR
reporting is in need of examination to focus reporting and analytic efforts on
the manufacturing deviations that have the highest predictive value to
identify unsafe units and then share this information proactively to help
improve quality control and quality assurance efforts at the manufacturing
level. FDA is actively reviewing certain categories of post donation
information (PDI) and has recently removed the requirement for reporting
donor history of cancer.
It should be noted that FDA-required serious adverse event reporting will not
provide for the collection of incidents related to less serious events, or near-
misses that can detect safety signals for further investigation. These are
important signals that are effectively captured by more broadly-based
hemovigilance systems.
A Sentinel Initiative, recommended by the 2006 Institute of Medicine Report,
currently under early development in the FDA Office of Critical Path
Initiatives will establish data mining capability across HHS (e.g. CMS) and
non-government sites (e.g. pharmaceutical manufacturers) and aims to
develop a national, electronic network to link data on 100 million patients from
multiple existing health care data systems by 2012 in order to conduct post-
licensure safety monitoring of FDA-regulated medical products.
Blood products,
particularly plasma derivatives dispensed by pharmacies, as well as blood-
related devices will be studied in the same fashion as drugs, vaccines, and
other medical products. (See, for example, the extensive research methods
and record of the CDC Vaccine Safety Datalink at
http://www.cdc.gov/vaccinesafety/vsd/
). In addition to facilitating
pharmacoepidemiologic safety signal searching, safety hypothesis refinement,
and safety hypothesis testing studies, the systematic study of special hazards
of blood and blood products will likely become much more efficient because a
range of information resources at participating sites will be potentially
accessible. As one example, acute hemolytic transfusion reactions can follow
mistakes in matching products to patients. These human errors might be
possible to track by time of day, day of week, and other variables that could
point to opportunities for development of additional preventive methods.
ICD-9 and ICD-10 discharge diagnoses are often useful in finding patients
who have particular diseases, and then blood bank, pharmacy, and other
linked records can clarify when some of these "case patients" had been
exposed to medical products that might have contributed to their illness.
Patients with babesiosis can be identified, for example, and then their prior
transfusion history will be available for analyses.

32
Additional information about the Sentinel Initiative is available at these
sites: http://www.fda.gov/oc/initiatives/advance/reports/report0508.html
http://www.fda.gov/oc/initiatives/advance/sentinel/factsheet.html
Gap 4: Need for accurate recipient denominator data, precise definitions,
and training
The potential pitfalls of any adverse event reporting system include
fragmented reporting, incomplete reports, lack of control groups (e.g., those
not transfused but with similar adverse events) to establish causal
relationships, incomplete or absent denominator information, and a passive
and voluntary surveillance system with under-reporting, biases and
confounding factors.
For rates to be accurately calculated there is a need to determine the precise
number of units of blood and blood components produced and distributed by
blood establishments and transfusion services in the US as a “denominator”.
With this information, adverse reaction reports, BPDRs, fatality reports, and
safety signals can be put into perspective on a national, regional, and local
level. The availability of a denominator facilitates the interpretation of
reports and the evaluation of potential sentinel events. Potentially, data
could be obtained from hospital outpatient services or from CMS records if
diagnostic-related group (DRGs) were revised to capture use of blood and
blood components as a separate category. BASIS provides nationally
representative current usage information. BASIS could also be used to
survey specific safety issues through targeted initial data collection from
participants. Mathematical modeling can be developed and used to predict
blood use and availability, an indirect measure of the denominator.
Whether dealing with clinical events, such as transfusion reactions, or near-
miss incidents, a clear and precise set of definitions is lacking throughout the
US. The recent experience with the utilization of definitions recommended by
a 2004 Canadian Consensus Conference for TRALI (37) is a case in point. An
AABB survey carried out 2 years later demonstrated a wide variability in
procedures and policies related to the diagnosis, donor investigation and/or
management of TRALI cases (38). The working party of ISBT has developed
definitions of transfusion reactions that could be used to achieve commonality
and facilitate meaningful comparisons of data between countries.
The multiplicity of laboratory information systems can also be an impediment
in implementation of a comprehensive national framework. To be successful,
in addition to the issues mentioned above, simplicity and ease of use are
important elements. Building interfaces to existing reporting systems need to

33
be considered from the beginning. Optimally, a national hemovigilance
system would be interfaced to a facility’s internal error management software
(such as MERS-TM) and be able to accept the report of the necessary
elements of a case automatically. Most hemovigilance systems have not
reached this level of sophistication.
Finally, healthcare providers need more awareness of transfusion adverse
events. For any reporting system to be reliable, those charged with capturing
the event must be cognizant of the commonly recognized signs and symptoms
of transfusion reactions as well as unusual events during or after a
transfusion. Unfortunately, those responsible for transfusion are not always
adequately trained to recognize such events, and provider education and
practices vary from hospital to hospital.
As mentioned before, Canada, particularly Québec, has moved forward with
TSOs, but other countries, including those in Europe, are wrestling with the
concept of hiring TSOs in every hospital due to cost constraints. The
appointment of at least some personnel associated with quality assurance to
be tasked with transfusion outcomes would greatly improve education and
process improvement at the transfusion facility.
In summary, gaps in the current system can be addressed by improving
reporting compliance, enhancing oversight though increased reporting
requirements, improving data analysis, improving data feedback and
education, and creating standardization within and between interfaces at the
facility level.
Gap 5: No national surveillance of donor serious adverse events other than
fatalities
Overall surveillance of donor serious adverse events other than fatalities is
not conducted systematically in the US. However, several large efforts to
collect donor adverse event data have been initiated among major blood
collection organizations.
Most blood centers collect data on reactions of various types but there is no
universally accepted set of definitions for comparative purposes. ISBT lists 25
categories of events, ARC has 15 and ABC has 9. A primary charge to the
AABB donor biovigilance working group is to harmonize these definitions if
possible. As previously mentioned, individual center data reports have been
useful in focusing on particular areas of concern but no national database, or
even standard definitions, exist.

34
Donor events are particularly complicated in precisely defining the focus of
adverse events of interest. One can examine 1) adverse reaction occurring
from donation, 2) donor screening markers, or 3) post-donation outcomes.
Data on adverse events in blood donors have not been included in national
hemovigilance systems until recently and are thus not as well developed as
recipient adverse event reporting. Studies have been reported from single
centers in the US (39-42) and in Europe (43), and comprehensive national
data have been reported from France and Denmark (44, 45). In 2004, a joint
working group from the ISBT and EHN was established, and has proposed a
classification and a set of definitions of complications related to blood
donation to form the basis for a registry.
Regulatory oversight of donors includes determination of donor eligibility and
extends to protections of donor health and safety. Donation-related fatalities
must be reported to FDA (21CFR606.170 (b)) within seven days after a
thorough investigation (21CFR606.170 (a)). Aspects of this process are
clarified in Guidance for Industry: Notifying FDA of Fatalities Related to
Blood Collection or Transfusion (September, 2003). Data analysis at FDA is
largely descriptive and is accomplished through specific follow-up
investigations and epidemiologic trending of fatality reports.
In the US, the ARC initiated a comprehensive hemovigilance system in 2003
that includes complications of blood donations (42). The program
prospectively monitors donor complications associated with allogeneic whole
blood (WB), apheresis platelet (PLT) and automated 2-unit red cell collection
(R2) procedures in 35 blood collection regions. All regions follow standard
operating procedures including recording all adverse reactions on the blood
donation record according to a standardized classification scheme and
captured in a central electronic database. There are 15 reaction categories
which incorporate a severity rating (minor, major) for reaction types in most
categories, and every category is further divided into whether the donor
received outside medical care. All major reactions at the time of donation
and all reactions that are reported to the blood center after the donor leaves
the collection site are captured on a standard case report form, investigated,
and reviewed by the blood center physician and reported in a tally on a
monthly basis to the National Medical Office which compiles and analyzes
data. Complication rates for different procedure types and among different
age groups are compared by calculating odds ratios and 95% confidence
intervals.
In 2006, the American Red Cross performed a total of 6,014,472 whole blood
collections in the US: 209,815 were associated with adverse reactions (349
per 10,000 donations or 3.5%). Minor events (e.g., pre-faint or vasovagal-
type) reactions accounted for the majority of reactions (258.3 per 10,000

35
collections)(42).
The second largest blood collector in the US is Blood Systems, Inc. (BSI)
which consists of United Blood Services (UBS), Blood Centers of the Pacific
(BCP), Tri-Counties Blood Bank in California, United Blood Services Central
Coast California, Community Blood Bank, Rancho Mirage, CA and is
affiliated with Inland Northwest which has collections in Washington and
Idaho. Operating procedures and software are not the same at UBS and
BCP. BSI collected 941,357 whole blood units in 2006. Blood donor reactions
are classified as mild, moderate or severe (46). Mild reactions are noted on
the donation records. Each center provides information on reactions using a
standardized adverse reaction reporting form. These paper records capture
incidents related to needle insertion such as bruises and hematomas; and on
moderate and severe reactions include descriptions such as time and
duration, symptoms, monitoring and management of the reaction. Data is
entered into a database for further analysis. BSI reported an overall reaction
rate of 1.43% for 2006 which is lower than previous reports (42, 47).
America’s Blood Centers (ABC) is a trade organization with members from 77
community-based blood centers around the US and Canada. ABC members
collect more than 9 million units of whole blood – half of the US blood supply
and all of Canada’s volunteer donor blood supply. Recently ABC established
a data warehouse initiative, which includes a comprehensive plan for data
collection, benchmarking and sharing of best practices. Although the ABC
membership is not required to participate in the data warehouse, the
initiative is meant to streamline current activities, combine efforts, reduce
member and staff workload, and establish a formal policy governing use of
surveys and data. The initiative includes design, development, validation,
and implementation stages for accumulating, organizing and reporting on the
collected data including donor adverse reactions. Local decisions will
determine quantity of data entered into the data warehouse. This data
collection tool is built so that very detailed information can be collected on
each donor reaction, including demographic information on the donor and
signs/symptoms. The final phase of the project will be to establish a method
to download donor incident data stored either in the Blood Center mainframe
computer or in the ABC Donor Reaction Tracker into the ABC Data
Warehouse.
Previous efforts to establish reporting on donor events have focused on
specific emerging infectious diseases through results of donor testing. This
has been limited specifically to WNV and Chagas testing through AABB. The
epidemic outbreak of WNV resulted in establishment of a public-private
partnership between AABB and several government agencies to collaborate
on the response to this emerging public health disease threat. The task force

36
included representatives from AABB, Department of Defense (DoD), ARC,
ABC, Canadian Blood Services (CBS), BSI and HHS operating divisions
(CDC and FDA). This AABB Inter-organizational Task Force carried out
weekly monitoring of transfusion related cases, prevalence of reactive WNV
Nucleic Acid Test (NAT) results and discussions of public health policy
including reporting of outcomes (48).
In 2006, an electronic data network for capturing WNV test results from each
blood collector was established. The tool was intended to support and
enhance the identification and tracking initiative in partnership between
HHS and the blood industry when WNV first became a public health concern.
The data posted on the AABB Web site is provided by blood collection and
testing agencies and provides a unique perspective of the continental
distribution of West Nile Virus in blood donors in North America. The WNV
Biovigilance Network collates data on donors (blood, tissue and hematopoietic
progenitor cells) with suspected WNV infection in the United States and
Canada. Data are collected from donor screening tests performed by NAT.
The data are reported to the AABB site by facilities responsible for testing
virtually all blood donations in the United States and Canada. The reports,
provided on a map of North America, illustrate the geographic and temporal
distribution of WNV infection as reflected by presumed viremic donors
(PVDs) during the peak season (49).
In 2007, a similar effort was established for tracking and mapping of donors
screening positive for Trypanosoma cruzi, the etiologic agent of Chagas
disease. Tracking and mapping of this apparent emerging disease was done
in an effort to determine both the prevalence and geographic status of
potentially infected donors.
Gap 6: Need for accurate donor denominator data, precise definitions, and
training
Even within a single blood system, such as the ARC, with standardized
definitions of donor complications and operating procedures, there is
considerable variability in reported reaction rates among different regional
blood centers. Some of this variability relates to donor demographics
including age and differences in rates during the spring and fall compared to
summer and winter (50). Nevertheless, ARC has demonstrated that regional
variability exists because of the inherent subjectivity in evaluating and
recording donor complications. This subjectivity in evaluation and
imprecision in coding undoubtedly contributes to regional reporting
variability (42).

37
The limitations of these programs include a lack of systematic collection of
data and provide opportunities for future improvements. Many centers focus
on moderate and severe reactions, which are the most medically relevant.
However, minor reactions can provide important information if rates predict
more serious outcomes. Interventions which result in a small reduction in
reaction rates locally would require a large dataset to achieve statistical
significance, translating into reductions in absolute terms nationally. This,
along with identification of rare events, may only be enhanced by a national
reporting system with standardized definitions. Furthermore, small blood
centers that lack the resources for monitoring any reactions can benefit from
practices that establish improved safety measures on a national scale and
result in standards setting for the benefit of the donors. Although elimination
of all risks to healthy volunteer donors is not possible, reduction in the rate of
complications will not only benefit the health and well being of donors but
also enhance the likelihood of future donations.
Similar to the need for denominator information about transfusion recipients,
donor hemovigilance would benefit from accurate donor denominator
numbers, donation frequencies, and broader demographic and other relevant
information about the overall pool of donors.
Enhancements in national oversight of those who donate and the donation
process could have major benefits, These include: increased donor safety,
increased numbers of donors and the resultant size of the blood supply,
improved public confidence in the process, and development of devices and
software that increase the safety margin for donation. Increased costs
associated with enhancements should be balanced by increased public
confidence in the donation process and an absolute increase in the number of
donors.
Gap 7: Need for accurate tracking of all donor infectious disease test data
Efforts to aggregate blood donor screening markers nationally, beyond WNV
and Chagas to include HIV, HBV, and HCV are now underway through
collaboration between HHS, AABB’s Transfusion Transmitted Diseases
Committee (TTD), and the major blood collection centers. At the present
time, these data are available but not collected outside of the blood or plasma
collection facilities. An attempt was made during the 2007 NCBUS to collect
these data, however, methodologies need to be validated (e.g. whether test
results should be included in the numerator total results, reactive results, or
confirmed test results). It has been proposed to the AABB TTD that a unified
national system ideally should track data reflecting whole blood collections,
plasma for further manufacture and possibly HCT/Ps. Data for apheresis
should also be considered separately due to the unique characteristics of this

38
critical donor subset and the higher frequency of collections.
Although planning is in place for national coordination, questions remain
concerning funding, data ownership and management, maintenance of
database and donor elements, and use of the collected data.
Gap 8: Need for timely analysis of reported data
Timeliness of analysis is a major problem with the data currently collected.
For example, the NBCUS is conducted every two years but the report may be
delayed for publication by up to three years for use by the blood community
and the public. Likewise BPDR and MedWatch reports, while collected
shortly after an observed event, are summarized and collectively reported,
which may result in delays. Information obtained from these data systems
could potentially facilitate internal quality audits if analysis of the events
and magnitude and incidence of the problems could be reported in a timelier
manner.
4.3 Emerging Threat Assessment: Looking Beyond Known
Transfusion-Related Events
There is a need to develop informatics and laboratory repository capabilities
to meet the challenges presented by emerging infectious diseases (EIDs) and
other threats. For example, the NHLBI has sponsored two multi-center
Retrovirus Epidemiology Donor Studies (REDS-I and the current REDS-II)
that carry out investigator-initiated investigations of transfusion-transmitted
viral and non-viral infections, non-infectious complications of transfusion,
and other aspects. Several targeted specimen repositories were established by
REDS-I, including a matched donor-recipient cell and serum collection
(REDS Allogeneic Donor and Recipient - RADAR) that included seven blood
centers and eight hospitals. The use of these repositories has been reported in
peer-reviewed journals (51). REDS-II has initiated targeted studies of TRALI
and other important transfusion-related outcomes.
Rapid worldwide information exchange is also needed to assess the potential
impact on means of transmission regarding new or re-emerging agents.
Repositories, such as those maintained by funded NHLBI studies and CDC’s
Universal Data Collection bleeding disorder community repository, may be
very useful in defining the onset of human infection with a new EID and
learning about its epidemiology and natural history, but vital epidemiologic
data must be gathered from global sources before such studies can be put into
place. The EID subgroup of the PHS Interagency Working Group for Blood
Safety and Availability (i.e., PHS Blood) provides an ongoing platform for
information exchange among the PHS agencies; however these efforts need to

39
be translated into a rapid response plan that will ensure timely protection of
the Public Health when an EID appears. More sophisticated real-time
informatics methods are needed for timely detection of potential threats to
transfusion and transplant recipients.
4.4 A New Initiative: A Public-Private Partnership in Hemovigilance
Surveillance Reporting
The national patchwork of reporting systems for blood safety in the US,
although providing valuable information, falls short of the advances being
made in Europe related to the existence of integrated national reporting
systems. As a result, there has been growing interest in development of
national programs to improve communication across a variety of reporting
systems, collect adverse event and incident data and improve patient and
donor safety.
The realization of the shortcomings of the US infrastructure in
hemovigilance, as well as the growth and needs of the tissue transplantation
field led AABB, in 2006, to incorporate a Biovigilance Network initiative into
its strategic plan. This Network is envisioned to enhance cooperation with
government and other interested agencies to incorporate transfusion and
transplantation (tissue and organ) recipient and blood donor adverse event
and incident reporting (27). Due to the multiplicity of both public and private
agencies with a stake in such a network, an Inter-organizational Task Force
was created to provide representation and input into the process. From this
Task Force, a Steering Committee was created with representatives from the
private sector AABB, ABC, ARC, BSI and the College of American
Pathologists (CAP) and HHS, FDA, NIH and CDC serving in liaison roles
from the federal government. The Steering Committee defined the vision,
mission/purpose and charges to two working groups representing recipient
and donor hemovigilance to provide technical input to allow the development
of working surveillance systems in collaboration with the Federal
government. The working groups consisted of individuals with expertise in
various operational aspects of transfusion services and blood collection. Both
groups included corresponding members from the EHN to provide guidance
and experience from other systems.
As mentioned as the impetus for this report, also in 2006, the ACBSA
recommended that HHS should coordinate Federal government actions and
programs to support and facilitate biovigilance in partnership with initiatives
in the private sector, including the AABB Interorganizational Task Force on
Biovigilance, to advance public health in this effort.

40
At this time, the opportunity arose to develop a different type of partnership,
which recognized the global uniqueness of American healthcare. This
partnership marries the benefits of the subject matter expertise available in
the private sector with the public health knowledge, ability for data
protection, and resource capacity available from the public sector.
Hemovigilance is a public health responsibility, but with privacy,
confidentiality, and regulatory concerns present on many levels; an
independent perspective must be maintained for hospital participation to be
maximized.
4.4.1 Public/Private Initiatives in Recipient Hemovigilance
As an example of one product of this collaboration, the AABB and the CDC
have entered into a public-private partnership to develop a national
hemovigilance infrastructure for transfusion recipient monitoring, as a
module of NHSN. Other NHSN modules currently operating include
surveillance in over 2,000 hospitals as of May 2009 for the reporting of
patient nosocomial infections and healthcare personnel adverse events. The
NHSN system overall is a voluntary, confidential, non-punitive third party
reporting service. It focuses on improving patient safety and corrective
action, is managed by experts with the ability to analyze data and to
understand implications for the medical community-at-large both at an early
warning/detection level and for long term continuous improvement. There is
data access for external analysis, periodic data feedback to participants, and
where possible, incorporation into existing systems.
The NHSN hemovigilance system will capture both adverse events (post-
transfusion untoward outcomes) and incidents (deviations from standard
procedures or other unusual events that did or might have resulted in an
adverse event or suboptimal outcome), which will be captured with a simple
web portal for rapid manual entry of data. Eventually the system could allow
for automatic transfer of data from local systems to the national system.
Registration (and annual updates of basic institutional and demographic
data) will provide the denominators with which rates of adverse events and
incidents can be calculated. The details of these events will be captured
through selection from pull-down menus and other simple systems to speed
entry. Data will be stored in this secure database that will allow generation
of standardized as well as user-defined reports (tabular or graphical) with or
without comparative data from the system. Training modules are being
prepared to ensure that all can take rapid advantage of the system’s
capabilities.
The hemovigilance module has been designed to incorporate useful features
that have been tested though other systems. The system developed though

41
the Public Health Agency of Canada has been an excellent model of utility,
using the event classification system developed by Dr. Harold Kaplan and
colleagues to support the MERS-TM system. The assistance of Canadian
representatives on the AABB Working Group has been critical to the rapid
development of the US system. The definitions of transfusion reactions that
will be used by the network are those developed by the ISBT Working Party
on Hemovigilance. As these definitions are being widely adopted around the
world, the data generated in the US can be compared with those generated
elsewhere, extending the power of the US efforts.
In addition to the participating institutions having access to their own and
comparative system data, and compilation of an annual report by CDC on
behalf of NHSN participants, a variety of targeted expert analyses and
surveillance tracking systems can be utilized. The collection of comprehensive
national data for the first time will allow clinicians, researchers and policy
makers to view the impact of interventions on the transfusion system both
locally and nationally. The system’s database design has the capability to
evaluate the effect of new interventions, allowing for the exploration of more
complex interrelations.
Separately under the guidelines of a Patient Safety Organization (PSO),
AABB could query a database derived from consenting NHSN facility
participants via the NHSN group function. The PSO goal is to develop
recommendations for improved practices to improve transfusion recipient
outcome. These analyses would be made available to the PSO membership so
that local (i.e., hospital) or regional (i.e., blood center) implementations of
improved practices could be designed and undertaken by those closest to the
operation as part of their commitment to continual process improvement.
4.4.2 Public/Private Initiatives in Donor Hemovigilance
AABB is also working with HHS in an effort to establish a national donor
biovigilance network. Their initial efforts are focused on agreement on
definitions of donor adverse reactions including those developed by the ISBT
with the objective at arriving at a global set of definitions to facilitate
benchmarking around the world.
The greatest impediments to establishing a national system for donor events
will be in reaching agreement on definitions and determining how data that
are already being collected electronically can be easily transferred to a
national database. Even if established, it will be of equal importance that
data be captured in such a way that it leads to continuous improvement.
Such a system must be easy to use, flexible and responsive to developments
in transfusion medicine, and forward looking to justify the expense and effort

42
in developing and maintaining a national program.
4.4.3 Future Challenges, Including Integration of Private and Public
Hemovigilance Efforts
HHS and non-government partners have made substantial progress on
national biovigilance collaborations based upon voluntary reporting. This
design offers many opportunities for improvements in US national
biovigilance capability, including time trending based upon highly refined
definitions and imputations, availability of benchmarking data to allow
comparative assessment of errors and adverse events at the institutional
level, and establishment of national data for comparisons with other
hemovigilance systems worldwide.
Any large hemovigilance system faces future challenges, and efforts are
underway to address, for example:
1) The precise parameters for sustained public/private shared partnership
have yet to be defined. Although there are many opportunities created
by a public-private venture, there also need to be clear pathways for
long-term governance, including how data is collected, analyzed, and
disseminated to improve practice.
2) As part of a national biovigilance effort, the voluntary hemovigilance
programs described here must be integrated meaningfully with other
systems that are under development, including publicly-funded
investigator-initiated research which may offer the most rigorous and
efficient design for intervention research.
3) Similarly, biovigilance efforts must also be designed to complement
reporting with the proposed FDA Safety Reporting Rule (SRR). Serious
adverse events among donors and blood recipients will form a key
element of data collection for all of these efforts.
Work has already begun to develop an interface between NHSN facility
participants and the FDA MEDWATCH adverse event data collection form,
so that at an early stage, anonymous surveillance reports to the NHSN
hemovigilance program can be fed to FDA (at the reporter’s option) on an
identity-linked basis. This will facilitate the identification and investigation
of failures related to FDA-regulated products and the identification of
sentinel events. As both data collection efforts mature, it is anticipated that
the NHSN data collection will increasingly be collected automatically from
reporting institutions under HL-7 data standards and that these reports will
then form the basis of reporting to FDA through the future MEDWATCH-

43
PLUS adverse event reporting system (again at the discretion of the
reporting institution). While the functionally anonymous system will be
optimized for benchmark quality comparisons and trending, the FDA system
will permit rapid investigation and intervention based upon observations
that may have a time-sensitive impact on public health. Similarly, the
existence of FDA-required reporting, implemented through a common data
portal, will help to encourage the overall level of reporting.
The current biovigilance patchwork system environment is complex and non-
integrated. Since the broadest interpretation of biovigilance represents an
umbrella for multiple public and private surveillance and reporting
mechanisms, one could imagine a common portal through which systems
could be accessed depending on either interest or requirement. As electronic
health records (EHR) and information exchange become more widely adopted,
electronic exchange of information directly from EHR systems for biovigilance
reporting should be integrated (Figures 3-5). It will, in part, be the role of
HHS to identify and address these challenges and create a sustainable
biovigilance effort of the highest quality to support the public health needs of
our donors and blood recipients.
Hospital or
Point of Care
FDA
CDC
HRSA
PSO
CMS
Common Data Elements
Quality Indicators
OPTN
Recipient Data (NHSN)
Blood Disorder UDC
MedSun
MedWatch
Figure 2. The current patchwork of biovigilance

44
Hospital or
Point of Care
FDA
CDC
HRSA
PSO
CMS
Portal
Common Data Elements
Quality Indicators
OPTN
CDC Blood Disorder
MedSun
MedWatch
Blood Donor Data
TTSN
Recipient Data (NHSN)
Figure 3. Portal concept of biovigilance reporting
Hospital or
Point of Care
FDA
CDC
HRSA
PSO
CMS
EHR
Common Data Elements
Quality Indicators
OPTN
CDC Blood Disorder
MedSun
MedWatch
Blood Donor Data
TTSN
Recipient Data (NHSN)
Figure 4. Potential Model of Electronic Health Record (EHR) Exchange
Interoperability

45
5.0 BIOVIGILANCE EFFORTS IN THE US: ADVERSE EVENTS
ASSOCIATED WITH HUMAN CELLS, TISSUES, AND CELLULAR
AND TISSUE-BASED PRODUCTS
5.1 Background
FDA regulates human cells, tissues, and cellular and tissue-based products
(HCT/Ps), defined as articles containing or consisting of human cells or
tissues that are intended for implantation, transplantation, infusion, or
transfer into a human recipient. Examples of HCT/Ps include bone,
ligament, skin, dura mater, heart valves, cornea, tendon, oocytes, semen, and
hematopoietic progenitor cells (HPCs) derived from peripheral and umbilical
cord blood (UCB). Minimally manipulated bone marrow for homologous use
and not combined with a drug or a device is not considered an HCT/P, and is
not regulated by FDA. HRSA has oversight of minimally manipulated bone
marrow from unrelated donors. This oversight is executed through the Bone
Marrow Coordinating Center, a component of the CW Bill Young Cell
Transplantation Program, by contract with the National Marrow Donor
Program (NMDP). Minimally manipulated bone marrow for homologous use
that is not combined with another article and is for autologous or related use
is not subject to Federal oversight. For the most part, the collection and
infusion of these products occurs in establishments that manufacture HPCs
that are subject to oversight. Table 3 summarizes PHS agency responsibility
for Federal oversight/regulation of HPCs.
The PHS WG did not perform a gap analysis on reproductive HCT/Ps.
Reproductive HCT/Ps have unique issues related to their use, and FDA
regulation of reproductive HCT/Ps currently is limited to registration of
facilities and listing of products, as well as donor eligibility requirements.
The PHS WG also did not include a gap analysis on HCT/Ps subject to pre-
market review and licensure by FDA. HCT/Ps subject to licensure must
comply with additional regulations; must demonstrate safety and efficacy;
and are subject to a comprehensive set of event reporting requirements.
Examples of HCT/Ps that are or will be subject to licensure are peripheral
blood stem cells (PBSC), UCB from donors unrelated to the recipient, and
somatic cellular therapies. Table 3 summarizes PHS agency responsibility for
Federal oversight/regulation of HPCs.

46
Table 3. Federal Oversight/Regulation of Hematopoietic Progenitor Cells*
Source Marrow
Peripheral
Blood
Cord Blood
Autologous No Federal
regulation
FDA regulation
as HCT/P
FDA
regulation as
HCT/P
Related allogeneic
(first-degree or
second-degree blood
relative)
No Federal
regulation
FDA regulation
as HCT/P
FDA
regulation as
HCT/P
Unrelated allogeneic HRSA
oversight of
Program
HRSA oversight
of Program;
FDA regulation
as HCT/P
HRSA
oversight of
Program;
FDA
regulation as
HCT/P
*minimally manipulated, for homologous use, and not combined with another
article such as a drug or device
HRSA = Health Resources and Services Administration; FDA = Food and
Drug Administration; Program = C.W. Bill Young Cell Transplantation
Program
Certain HCT/Ps recovered before May 25, 2005 are regulated by FDA under
21 CFR Part 1270, while those HCT/Ps recovered on or after May 25, 2005
are regulated under 21 CFR Part 1271, the current tissue rules in effect as of
May 25, 2005. 21 CFR Part 1271 requires establishments that manufacture
HCT/Ps to register and list their products with FDA; screen and test donors
for relevant communicable disease agents or diseases; and follow good tissue
practices to prevent the introduction, transmission, or spread of
communicable diseases by HCT/Ps. All foreign establishments importing
HCT/Ps to the US also must register and list their products with FDA and
follow the applicable regulations. However, it should be noted that the HCT/P
regulations apply only to manufacturers, and, for those HCT/Ps regulated
solely under 21 CFR Part 1271, the scope is limited to the prevention of
transmission of communicable diseases.

47
HCT/Ps must meet the following criteria, as described in 21 CFR Part
1271.10(a), to be regulated solely under section 361 of the PHS Act (which
pertains to the prevention of transmission of communicable diseases):
1. Minimally manipulated
2. Intended for homologous use
3. Not combined with a drug, device or other article (with limited
exceptions)
4. Does not have a systemic effect (exceptions are autologous use, use in a
first- or second-degree blood relative, or reproductive use).
An HCT/P that fails to meet any one of these criteria and that does not
qualify for exceptions specified in the HCT/P rules is subject to regulation as
a drug, device, and/or biological product, and additional regulations would
apply.
5.2 HCT/P Biovigilance Concerns
Modern day tissue banking was initiated in the U. S. Navy in 1949. Many of
today’s standards are due to this early experience (52) , as well as the efforts
of the American Association of Tissue Banks (AATB) over several decades.
AATB has reported substantial growth in tissue recovery and distribution.
This is illustrated in Figure 5 and 6 (53).
Tissues Recovered
0
5000
10000
15000
20000
25000
30000
2000 2003 2007
Years
Tissues
Figure 5. Tissue Donors Recovered in US in the first part of 21
st
Century

48
Figure 6. Musculoskeletal grafts distributed in US in the first part of 21
st
Century
A major difference between blood, organs, and HCT/Ps is that many HCT/Ps
undergo processing to disinfect; effectiveness of these methods varies by
processor, tissue type, and method employed. Although manufacturers
validate their methods and have standard procedures, methods are not
required to be FDA approved, and the eventual risk of contamination of final
products is not well-quantified, although understood to be quite low for many
types of product and disinfection procedures. Better quantification of the
potential risk based on the effectiveness of disinfection procedures will help
investigators decide if reported infections should be attributed to implanted
tissues.
The current understanding of the risk of tissue-associated disease
transmission largely is derived from what is learned from case reports. For
example, in 2001, CDC investigated a case involving a musculoskeletal
tissue
allograft recipient who died as the result of clostridium infection from a
contaminated graft. In the course of its investigation, CDC identified a total
of 14 patients with Clostridium infections associated with musculoskeletal
tissue allografts from this and other donors (54). As a result of this case,
FDA published guidance for immediate implementation that emphasized
existing regulatory requirements for the prevention of tissue contamination
during processing. In a 2005 article, investigators described transmission of
HCV to several organ and tissue recipients from a donor that was antibody
negative but later determined to be infected with HCV. This case generated
Musculoskeletal Grafts Distributed
0
500,000
1,000,000
1,500,000
2,000,000
2,500,000
2000 2003 2007
Years
Grafts Distributed

49
much publicity because of the numbers of organs and tissues (44 transplants
into 40 recipients) produced from this single donor. Through genetic
comparison of isolates from donor and recipient serum, investigators
determined that 8 recipients (three organ recipients and five tissue
recipients) were infected with HCV transmitted by the donor. Two of the
tissue recipients and one organ recipient were diagnosed with HCV several
months before many of the tissues were transplanted. Some of the
subsequent tissue recipient infections would have been prevented if donor
transmission had been recognized and communicated to the tissue
establishments at the time of diagnosis of the three initial cases (55).
Another issue of significant concern is tracking of HCT/Ps to the level of the
recipient. During 2005 and 2006, HHS became aware of two HCT/P recovery
firms committing serious violations of Federal regulations. An FDA
investigation found that the firms were recovering tissues from donors in a
manner that did not prevent the transmission of communicable disease.
Other violations included creating and maintaining inaccurate and
incomplete records related to: the medical/social history interview with next
of kin; medical history, including place, time, and cause of death; and
communicable disease screening and testing. These practices presented a
danger to public health, and the FDA ordered the firms to cease
manufacturing operations and retain tissues in inventory. In the first case,
tissue had been sent to a number of processors, then processed, distributed
and sub-distributed. Tissues from over 1,000 donors were recovered during a
three-year period of time. An estimated 25,000 tissues were distributed to
hospitals and other healthcare providers in the U.S. and internationally for
transplantation. The magnitude of distributions puts in perspective the
current difficulties of timely tracking of HCT/Ps, something that is
particularly important when there is concern about safety. A system such as
the recently piloted Transplantation Transmission Sentinel Network (to be
described in Section 6.1) may help to address issues related to tracking.
5.3 Efforts in HCT/P Biovigilance
5.3.1 Global Biovigilance
Development of vigilance and surveillance systems for tissues and cells used
in transplantation is a recent undertaking in most of the world. The
European Union Standards and Training for the Inspection of Tissue
Establishments (EUSTITE), co-funded by the European Commission, is
assisting member states by providing guidance documents and training in
the areas of inspection and adverse event and reaction reporting for tissue
and cells. The project is developing vigilance and surveillance tools consistent
with and complimentary to those existing, such as hemovigilance systems,

50
and under development globally, led by the Department of Essential Health
Technologies at the WHO. A survey completed in January 2007 on the status
of such systems found that 10 member states had a reporting system in place,
while the other 17 member states still have not established reporting
systems, although a few were currently planning their systems and would be
launching their systems shortly. Member states gave various responses
regarding the types of adverse events/reactions which would be considered to
be reportable in their member states.
Health Canada requires that source establishments investigate and submit
reports of certain adverse reactions, errors, and accidents involving cells,
tissues, and organs to the Canada Vigilance Program. Health professionals
and consumers also may submit voluntary reports to the Canada Vigilance
Program.
The Center for International Blood and Marrow Transplant Research
(CIBMTR), a division of the Medical College of Wisconsin, brings together the
International Bone Marrow Transplant Registry and the Autologous Blood
and Marrow Transplant Registry (IBMTR/ABMTR) and the NMDP to
facilitate large clinical studies of blood and marrow transplantation.
Through CIBMTR, researchers have access to large clinical databases on
autologous, related, and unrelated donor HPC transplants. CIBMTR reports
that 50,000 transplants are performed worldwide annually, and about two-
thirds are autologous.
5.3.2 HCT/P Biovigilance in the United States
5.3.2.1 Federal Reporting
An adverse reaction, as defined in 21 CFR Part 1271.3(y), means a noxious
and unintended response to any HCT/P for which there is a reasonable
possibility that the HCT/P caused the response. HCT/P manufacturers must
investigate any adverse reaction involving a communicable disease related to
an HCT/P they made available for distribution. Manufacturers must report to
FDA an adverse reaction involving a communicable disease if:
• Fatal
• Life-threatening
• Causes permanent impairment/damage, or
• Necessitates medical or surgical intervention
For reportable adverse reactions, manufacturers must submit a report
through FDA’s MedWatch Adverse Event Reporting Program within 15 days
of receipt of information about the reaction. Manufacturers must submit a
follow-up MedWatch report within 15 days of receipt of new information from

51
the investigation. The adverse reaction reporting requirements apply only to
products recovered on or after May 25, 2005 (the effective date of the current
tissue rules). Manufacturers are encouraged to submit voluntary reports
related to products recovered prior to May 25, 2005, as well as product
problems that do not involve infectious disease transmission. Manufacturers
are not required to report adverse reactions that do not involve infectious
disease.
The definition of an adverse reaction requires that a manufacturer decide
that there is a reasonable possibility that the HCT/P caused the response. It
is likely that different manufacturers have different thresholds for
attributing causality to the HCT/P. Also note that, while HCT/P
manufacturers are required to report serious adverse reactions to FDA,
reporting is voluntary for clinicians. Clinicians are encouraged to submit
reports directly to the manufacturer and to FDA through the MedWatch
program, but underreporting is likely. Manufacturers may remain unaware
of safety issues if clinicians fail to report cases.
Factors such as an infection with an unusual organism or temporal proximity
between implantation and onset of infection may suggest that the HCT/P
could be the cause. However, it often is difficult for clinicians to distinguish
between a graft-attributable infection and an unrelated post-operative
infection. If infections are reported to the manufacturer or FDA, a full
investigation that includes review of donor and manufacturing records still
may fail to produce evidence linking the HCT/P to the infection, particularly
for common organisms. Certain information could implicate the HCT/P as
transmitting the infection such as: similar infections reported in more than
one recipient of HCT/Ps from the same donor; a very unusual organisms
identified in pre-processing (recovery) cultures and the recipient;
contamination in the processing environment with the same organism; or
evidence of the same infection in the HCT/P donor. However, in the absence
of factors such as these, as is the case for most reported infections, the cause
of the infection is indeterminate.
In 2004, CBER formed the Tissue Safety Team (TST), composed of
representatives from several offices within the center. The TST was formed to
provide a coordinated process for the review, analysis and follow-up of
adverse reaction reports received by CBER; to efficiently and effectively
respond to emergencies; and to strategically identify policy and outreach
needs and opportunities and implement solutions. A subgroup of the TST
evaluates every MedWatch HCT/P adverse reaction report submitted (56).
For reports involving infections in HCT/P recipients, TST generally contacts
the HCT/P manufacturer for donor and processing related information and, if
additional data is needed on the clinical case, the recipient’s transplant

52
surgeon or other health care professional involved in the case. As needed, the
TST collaborates with points of contact at other offices within FDA (such as
OBRR when the HCT/P donor or recipient received blood or blood products),
and other HHS agencies (such as CDC and HRSA).
HCT/P manufacturers also must investigate all deviations related to a
distributed HCT/P for which they performed a manufacturing step. They
must report to FDA, within 45 days of the discovery of the event, those
deviations related to core CGTP requirements (specified in 21 CFR Part
1271.150(b)). The term "HCT/P deviation" is defined in 21 CFR 1271.3(dd) as
an event that represents a deviation from applicable regulations or from
applicable standards or established specifications that relate to the
prevention of communicable disease transmission or HCT/P contamination;
or that is an unexpected or unforeseeable event that may relate to the
transmission or potential transmission of a communicable disease or may
lead to HCT/P contamination. Deviations must be reported to the Director of
the Office of Compliance and Biologics Quality in CBER on a standardized
BPDR form (Form FDA-3486).
FDA’s Center for Devices and Radiological Health (CDRH) launched the
Medical Product Safety Network (MedSun) in 2002 to identify and share
information about problems with the use of medical devices. MedSun
(www.medsun.net) is a targeted surveillance program that involves AE
reporting from a sentinel network of around 350 healthcare facilities
throughout the country. FDA currently is operating a sub-network involving
a subset of MedSun sites, called TissueNet, for the reporting of adverse
reactions and other events related to HCT/Ps. TissueNet is the first
enhanced surveillance program for HCT/P-related adverse reactions and
boosts the numbers of voluntary reports submitted for these products.
MedSun sub-networks like TissueNet build relationships between
MedSun/FDA and the front-line product users in specific “high-risk” clinical
care areas. TissueNet enhances CBER’s understanding of the use of HCT/Ps
and provides a resource for communication with the clinical tissue and cell
transplant community. The objectives are to describe the frequency and types
of reports following HCT/P transplants; identify potential causes or “near
misses”; and improve the safety of HCT/Ps. TissueNet sites use MedSun to
report HCT/P-related AEs or product problems to FDA via a secure, internet
based data entry portal. The data entry screens are based on items on the
MedWatch Form, and MedSun translates the data into a completed
MedWatch form. The first report from this system was generated in 2005
and the project is funded to operate through September 2009.

53
5.3.2.2 Private Sector Reporting
Several professional organizations also perform tissue biovigilance activities.
Federal agencies collaborate with these organizations to foster harmonization
of standards and the exchange of information to address safety issues. Some
of these efforts are described below.
The Joint Commission (TJC) accredits and certifies more than 15,000
healthcare organizations and programs in the US. In 2005, TJC published
standards related to tissue storage and issuance. These standards require
the assignment of responsibility for handling tissue within a hospital to a
single coordinating entity. The oversight responsibility includes: supplier
certification; incoming inspection and logging in of tissue; traceability and
recordkeeping; storage temperature monitoring; investigation of adverse
outcomes; reporting tissue related infections to the tissue supplier;
sequestering tissue reported by the supplier as contaminated; the notification
of surgeons and recipients if tissue donors are subsequently found to harbor
infection; and compliance with federal and state regulations if supplying
tissues to any other facility. The College of American Pathologists has
adopted similar standards.
Many hospitals have turned to their blood bank where many of the
capabilities for tissue management already exist. As a result, the AABB
established a tissue task force to begin to develop guidance documents and
assistance to hospital blood banks to prepare for managing tissue within
their facilities. The AABB Tissue Task Force, which later in an attempt to
better understand how tissues were being managed within hospitals,
prepared and distributed a survey to hospital institutional members. The
survey contained questions on tissue types handled, the breadth of
responsibility, and facilities within hospitals responsible for tissue. Of the
904 institutional members invited to participate, 402 gave interpretable
responses; 325 reported the use of allogeneic or autologous human tissue.
The survey indicated that the department of surgery was the most likely
hospital department to have any responsibility for tissue use, followed by the
blood bank. Surgery departments were most frequently responsible for tissue
handling, documenting use, and for adverse event reporting; for the latter
category only 23% reported infection control responsibilities (57).
The AABB survey was corroborated by the 2007 NBCUS that of hospitals
reporting, 14% responded that blood banks and 80% responded that
operating rooms had responsibility for tissue management (36). Adverse
events were reported in this survey. Although limited to hospital transfusion
service data on facility events, there were 43 AE reports, including bacterial
and viral infections and graft failures, from 229,115 grafts implanted for a

54
rate of 1:5,300. Since healthcare facilities do not have reporting
requirements (unless they are performing a manufacturing step and subject
to FDA reporting regulations), one is left to extrapolate the actual number of
AEs occurring.
The AATB has been publishing standards since 1984. AATB Standards state
that tissue banks establish policies and procedures regarding adverse
outcomes and recalls, and have a process for sharing information with other
tissue banks known to have recovered or received tissue from the same donor.
Tissue banks must document and investigate all reported or suspected
adverse outcomes potentially related to an allograft. Tissue banks must
assure that tissue can be tracked to the consignee, and must notify the
consignee of its responsibility to maintain records traceable to the recipient.
Typically, tracking to the recipient is facilitated through graft implant cards
that accompany each allograft that is distributed. These cards contain
information about the graft, and space for recording information about graft
use (such as facility, surgeon, and recipient). Manufacturers ask hospitals
and healthcare providers to return these records following transplants, but
there is no enforceable requirement for the return of the implant cards.
Compliance with return of these cards varies considerably from bank to bank
depending on the degree to which the tissue bank pursues their return. A
recent AATB survey, to which only 15 of over 100 banks responded, reported
an average return rate of just over 50% with a wide range from less than 10%
to as high as 95% (53). Information about graft disposition and adverse
outcomes can provide context for assessing the potential risk of tissue
allograft transplantation.
The Eye Bank Association of America (EBAA) implemented its Medical
Advisory Board (MAB) in 1991 in response to a 1990 requirement for all eye
banks to seek three to twelve month follow-ups of all patient outcomes.
EBAA’s Online Adverse Reaction Reporting System (OARRS) was redesigned
in 2005. The MAB reviews results on a biannual basis. Eye banks provide
institutions with self-addressed envelopes to complete and return follow up
forms. Persons who submit reports on OARRS must provide information on
the adverse reaction, surgery, microbiology results, tissue mate status, donor,
and method of transporting the tissue from the source eye bank.
HRSA awarded CIBMTR a contract to establish and maintain the Stem Cell
Therapeutic Outcomes Database (SCTOD) component of the C.W. Bill Young
Cell Transplantation Program. Transplant centers must submit data
annually to CIBMTR on all allogeneic transplant recipients. Although most
data are focused on outcomes, some data also relate to adverse events such as
early and late graft failures, risk factors for graft versus host disease

55
(GVHD), prevalence of microbiologically contaminated hematopoietic stem
cell products, antibodies to the graft, infections and second cancers.
NMDP collects data on donor adverse events and post-donation symptoms
(Appendix 5 and 6). Data collected include serious and minor complications
following marrow and peripheral blood stem cell collections, such as
mechanical injury to tissue, anesthesia reactions, infection, seizures,
excessive pain and delayed return to normal work functions. Minor side
effects such as hypotension, syncope and collection site pain are reported in
75% of marrow donors. Peripheral blood stem cell (PBSC) donors are also
monitored for adverse events specific to filgrastim administration and central
intravenous catheter placement, such as more serious degrees of headache,
fatigue, bone pain, hypotension, vomiting, central line placement
complications, or more serious cytopenias. HRSA personnel are informed of
adverse events that are serious and unexpected and FDA is also notified if a
serious and unexpected adverse event occurs in a PBSC donor.
5.4 Gaps in Current HPC/T Adverse Reaction Reporting Systems
Gap 9: Limited information on the potential for HCT/Ps to transmit
infectious disease
Risks of disease transmission by HCT/Ps are not well characterized for all
known and emerging communicable disease agents, and for all types of cell
products and tissues. Improvements in donor screening and testing, and in
methods for processing some tissues, have made these products safer than in
the past. However, un-quantified risks remain.
Gap 10: Ability to ascertain whether reported infections in HCT/P
recipients can be attributed to the tissue is limited.
Post-operative infections occur at a small but appreciable rate, independent
of allograft use. The majority of reported infections in HCT/P recipients are
likely due to local contamination or some other cause typical of post-operative
infections and not attributable to the HCT/P. Although each report deserves
thorough evaluation, this leads to a low predictive value for a given report.
Infections with common organisms are particularly difficult to attribute to
implicated HCT/Ps. Multiple recipients with infections involving the same
organism would suggest potential HCT/P-related transmission and require
further evaluation.
Gap 11: Regulations concerning HCT/P adverse reaction reporting do not
extend to the level of the healthcare facility or healthcare provider

56
The HCT/P regulations apply only to manufacturers; hospitals and
healthcare providers (e.g. transplant surgeons, dentists) are not required
under these regulations to report adverse reactions experienced by their
patients who received HCT/Ps. Surveillance for recipient infection depends
largely on voluntary reporting by clinicians, and it is likely that an unknown
number of events are undetected and/or unreported. HCT/P manufacturers
are unable to investigate adverse reactions of which they are not aware.
Although TJC tissue standards include reporting of adverse events,
compliance with the reporting standards is not enforced and TJC standards
do not extend to physician and dentist offices or other facilities not accredited
by TJC.
Gap 12: Current mechanisms for tracking HCT/Ps to the level of the
recipient are limited.
Tissue establishments request that healthcare providers convey back to them
information about the final disposition of the graft; e.g. through return of
graft implant cards. However, hospitals and healthcare providers are not
subject to enforcement actions for failure to convey this information.
Voluntary compliance with return of implant cards is relatively low in some
cases. Lack of information about final graft disposition hinders investigation
of adverse reactions and allograft recalls.
Gap 13: Adverse reaction reporting for HCT/Ps regulated solely under
Section 361 of the PHS Act is limited to infectious diseases
The scope of adverse reaction reporting required for HCT/Ps regulated solely
under the authority of Section 361 of the PHS Act is limited to the prevention
of transmission of communicable diseases. HCT/P manufacturers are not
required to report adverse reactions that do not involve potential
transmission of a communicable disease, and healthcare facilities and
healthcare providers are not required to submit any reports. However,
reports of non-infectious events potentially could reveal other safety concerns.
Gap 14: Information about adverse reactions in other recipients of
HCT/Ps from an implicated donor may not be readily available
HCT/Ps recovered from a single donor may be sent to multiple
establishments for processing. While FDA regulations require that
manufacturers maintain complaint files related to HCT/Ps they made
available for distribution, this information may not be readily available to
other manufacturers of HCT/Ps from the same donor.

57
6.0 BIOVIGILANCE EFFORTS IN THE US: ADVERSE EVENTS
ASSOCIATED WITH SOLID ORGANS
6.1 Solid Organ Adverse Event Reporting
Transmission of infectious agents, both known and unknown, from an organ
donor represents a particular hazard to the transplant recipient because,
unlike a recipient of blood transfusion, the immunosuppression regimen
(required to prevent organ rejection) weakens the patient’s host defense
mechanisms against invading organisms. The resulting infection is thus more
likely to result in devastating, and sometimes fatal, consequences. As such,
biovigilance takes on added importance in the setting of solid organ
transplantation. Although it is estimated that the risk of acquiring an
infectious disease through organ transplantation is an infrequent occurrence,
it is still higher than through blood or tissue transplantation. This risk is
balanced against the life saving indications for transplantable organs and the
substantial number of patients that die each year due to the lack of organs.
There is a need to capture more complete data on transmission of infectious
diseases and malignancies of donor origin. Several factors make the task of
identifying potential transmissible infections in deceased solid organ donors
more problematic than for blood donors: (1) information about medical
history and social/behavioral risk factors of deceased organ donors is often
incomplete and suboptimal (usually obtained from family or acquaintances);
(2) potential organ donors are typically admitted to the hospital emergently
with catastrophic medical or traumatic events, and may receive multiple
transfusion products with the small risk of transfusion transmitted disease;
(3) organ recovery often is done urgently (due to the donor’s deteriorating
clinical status) and the retrieved organs must be transplanted within hours
of recovery, limiting the amount of time available to obtain the results of
donor screening tests or perform extensive confirmatory lab testing of any
abnormal test results prior to transplant of the organs; and (4) because the
number of patients waiting for organ transplants far exceeds the number of
available organs, it is important that screening tests for infectious agents in a
potential organ donor are accurate to avoid unnecessarily discarding useable
organs. In addition, because of the limited supply of organs, even individuals
known to have risk factors for infectious diseases may be accepted as organ
donors. Hence, the transplant community, including potential transplant
patients, must balance the risk of acquiring an infection or other disease from
a potential donor against the potential for death or morbidity if an organ
from a particular donor is rejected.
The HRSA, Division of Transplantation oversees the transplantation of
human organs, including kidney, liver, heart, lung, pancreas, and intestine.

58
The National Organ Transplant Act (NOTA) of 1984 established the Organ
Procurement and Transplant Network (OPTN), resulting in a national
computerized system to maintain a waiting list and allocate organs, including
a 24 hour organ-recipient matching operations center. In 1986, the United
Network for Organ Sharing (UNOS) was awarded the first contract to
operate the OPTN, and has held the contract since then through a
competitive award process. UNOS has developed an online database system,
called UNet for the collection, storage, analysis and publication of all OPTN
data pertaining to the patient waiting list, organ matching and transplants.
The OPTN final rule became effective in March of 2000. The rule established
a regulatory framework for operation of the OPTN, including requirements
for policy development and member compliance with these policies, including
policies consistent with the recommendations of the Centers for Disease
Control and Prevention for the testing of donors and follow-up of transplant
recipients to prevent the spread of infectious diseases. The Division of
Transplantation of HRSA also administers the Scientific Registry for
Transplant Recipients contract, as well as various grant programs and
initiatives to increase organ donation and transplantation.
Through its oversight role, HRSA monitors the activities of the OPTN to
include member compliance with NOTA, the OPTN Final Rule and other
applicable Federal law. The OPTN Final Rule requires the OPTN, with the
assistance of the OPTN contractor, to review member compliance with
Federal law and regulations and the policies and bylaws of the OPTN. The
OPTN, with the assistance of the OPTN contractor, is also required to
conduct periodic and special compliance reviews of OPTN members.
Members that are not found to be in compliance are referred to the
Membership and Professional Standards Committee (MPSC) for review.
Unlike the on-site inspections conducted by the professional State Facility
Surveyors under CMS, much of the OPTN oversight, generally carried out
through confidential peer review conducted by the MPSC, may also conduct
on-site peer reviews with audit teams. The OPTN has the authority to take
certain actions against OPTN members that are not in compliance, including
issuing letters of warning, letters of admonition, letters of reprimand; placing
the member on ‘Probation’ and making the member a ‘Member Not in Good
Standing.’ Both ‘Probation’ and ‘Member Not in Good Standing’ are public
actions, which in the case of transplant programs, may impact the program’s
ability to receive contracts from insurance companies. In addition to actions
that may be taken by the OPTN, particularly egregious non-compliance
issues may be referred by the OPTN Board of Directors to the Secretary of
HHS for further action, including removing a transplant program’s ability to
receive donor organs and ability to participate in Medicare and Medicaid.

59
Solid organ transplant programs that participate in the Medicare program
are required by the CMS to comply with the following Conditions of
Participation (per 42 CFR Part 482.96) regarding Adverse Events:
The actual regulations, 42 CFR 482.69(b), are as follows: (b) Standard:
Adverse events. A transplant center must establish and implement written
policies to address and document adverse events that occur during any phase
of an organ transplantation case.
1) The policies must address, at a minimum, the process for the
identification, reporting, analysis, and prevention of adverse events.
2) The transplant center must conduct a thorough analysis of and
document any adverse event and must utilize the analysis to effect
changes in the transplant center's policies and practices to prevent
repeat incidents.
The regulation clearly states that “unintended transmission of infectious
disease to a recipient” is an example of an Adverse Event under “Definitions”
in 42 CFR 482.70.
CMS has various options at its disposal to ensure transplant program
compliance with these Conditions of Participation.
In response to increasingly recognized adverse events due to diseases
transmitted through organ transplantation, there are relatively new policies
in place to require reporting of suspected disease transmission. These efforts
include the creation of an OPTN/UNOS Disease Transmission Advisory
Committee (DTAC) to facilitate and monitor reports of organ donor-derived
diseases in organ recipients; the reports are required under new
OPTN/UNOS policy. As a result, documented incidence has increased every
year since reporting has been required and in 2007 the donor-derived disease
transmission incidence was 0.96% of deceased donor donations. (58)
Recent CDC investigations have identified causes of multiple illness clusters
in organ transplant recipients, including WNV, rabies, LCMV, Chagas
disease, and tuberculosis. Following these investigations of disease
transmission events associated with transplantation, CDC sponsored an
organ and tissue safety workshop in 2005 to promote a better communication
network within and between the organ and tissue community. From that
workshop came a number of recommendations to both government and the
tissue/organ community, including the development of a unique donor
identification system linking organs and tissues, clear mechanisms for
adverse event reporting by health-care facilities, stronger information
dissemination systems to a broader array of clinicians and health
professionals as well as patients, and a notification algorithm for trace-back

60
and trace-forward tracking. This system, developed by UNOS and other
organ and tissue community partners in a cooperative agreement with CDC,
is called the Transplantation Transmission Sentinel Network (TTSN). The
purpose of the network is to provide a system for detecting emerging
infections among organ and tissue allograft donors and recipients and aid
healthcare personnel in detecting, communicating, tracking and preventing
the transmission of infections.
To guide its development, UNOS organized a TTSN Advisory Committee
made up of organizations with a stake in this process. The Advisory
Committee identified five key parts for development of a working
communication network: registration or search for donors (Part A);
registration of recipients (Part B); reporting of adverse events (Part C);
dissemination of information to appropriate regulatory and public health
agencies (Part D); and education within the community (Part E). In addition,
UNOS identified a group of tissue banks, eye banks, organ procurement
organizations, and healthcare facilities to pilot the system. After piloting, a
quality assessment will be performed to evaluate the development process
and to determine next steps for national implementation. The national
implementation of systems to enhance tracking and communication
concerning adverse events involved organs and tissues, such as TTSN, will be
an important step forward in allograft patient safety.
Three recent changes in organ donor procurement practices and
transplantation have heightened interest in an effective nationwide
biovigilance system that includes solid organ transplantation.
First, due to the ever-expanding waiting list of patients in need of
transplantable organs, deceased donors with various behavioral and social
risks, which would categorized them as “high risk” donors, are being accepted
with the expectation that all available information will be provided to all
involved. Although donors are screened and tested for infectious diseases,
the inherent limitations of less-than-perfect screening tests for infectious
agents have increased the potential for missing a potentially serious infection
in such “high risk” donors. Screening tests are not identical to those used in
blood and tissue donors, in part because of concerns over timeliness and false
positive results, potentially impacting availability. A fully operational
nationwide biovigilance system can improve the capabilities to detect and
respond swiftly to such transmissible agents when these events occur thus
minimizing the consequences in all recipients of organs from that affected
donor.

61
Second, in an attempt to further increase the number of organs, especially
kidneys, available from individuals with a demonstrated wish to donate, the
transplant community is pursuing organ procurement following cardiac
arrest and failed cardiopulmonary resuscitation in both the hospital and
community settings. This has been termed Uncontrolled Donation after
Circulatory Death (UDCD) or Donation after Cardiac Death (DCD). In these
still infrequent situations, it may be difficult to procure suitable screening
test specimens prior to death. How this might affect disease transmission
from UDCD solid organ donors remains to be seen.
Third, a recent advance in the field is the transplantation of vascularized
composite allografts (VCA), a variety of body parts composed of multiple
types of tissues transplanted as an anatomical unit. The most notable types
of VCAs to date have been hand and face transplants. Given the anticipated
increase in VCA transplants, HRSA published a Request for Information
(RFI) on March 3, 2008 in the Federal Register for the purpose of soliciting
feedback from stakeholders and the public as to whether VCAs should be
included within the definition of organs covered by the OPTN final rule
and/or added to the definition of human organs covered by section 301 of
NOTA (73 Federal Register 11420). Through this RFI, HRSA invited the
public to attend a meeting on April 4, 2008 to discuss the issues described
above. The meeting provided a venue for interested stakeholders to provide
input and generate discussion. Interested parties were invited to submit
written comments to HRSA by July 2, 2008. Further action is still pending at
this time. Federal authorities must determine the appropriate level of
oversight/regulation to address safety concerns without unduly restricting
access.
6.2 Gaps in Current Organ Adverse Reaction Event Reporting
Systems
Gap 15: Lack of nationwide common organ/tissue donor network system
for real-time reporting, data collection, communication, and
analysis of donor transmitted diseases in organ and tissue
transplant recipients, including a common donor identifier
necessary for linkage back to implicated donor of both organs and
tissues
One donor may provide organs and tissues to be used in dozens of recipients.
Currently there is no unique donor identifier that links a common donor for
both organs and tissues. While the OPTN uses a unique donor identifier for
each organ donor, and FDA requires a unique donor identifier for each tissue
donor, these organ and tissue donor identifiers are not necessarily the same.
A unique donor identifier that links all of the organs and tissues from a

62
common donor may facilitate the rapid identification of all allografts from
that donor in the event of a public safety concern.
Although the recently implemented OPTN DTAC now facilitates real-time
coordination of communication and notification of potential donor
transmitted diseases (including infections and malignancies) for organs,
there is still some time lag between incident identification, event reporting,
notification, and follow up. Also, a nationwide reporting network for organ
and tissue events may aid tissue establishments in sharing information
pertaining to potential disease transmissions identified in tissue recipients.
There currently is no published comprehensive analysis of the prevalence and
incidence of various diseases in organ donors as there is for blood
transfusions. Implementation of a nationwide common organ/tissue donor
system, such as TTSN, would facilitate a comprehensive analysis of the
prevalence and incidence of various diseases in these donors and the
potential for transmission to recipients. Although it is estimated that the
risk of acquiring an infectious disease through organ transplantation is
higher than through blood or tissue transplantation, this risk is balanced
against the life saving indications for organ transplantation and the
substantial number of patients that die each year due to lack of organs.
Gap 16: No Requirement to retain donor and recipient samples
Given that several factors make the task of identifying potential
transmissible infections in deceased organ donors difficult (such as
inaccurate medical/social history, incomplete donor testing prior to
transplantation of the organs), it would be valuable if retained donor and
recipient specimens were available for testing. Although OPOs and
transplant hospitals do keep these specimens for various lengths of time
following organ procurement and transplant surgery, there is no requirement
for specimen retention and current retention practices are variable. There is
no system with a consistently applied uniform policy for specimen retention
time, storage, and retrieval capable of supporting a nationwide biovigilance
program.
Having acknowledged these recognizable gaps identified above, it is
important to keep the potential for donor-transmissible disease in context
with respect to the life-saving benefit these organs provide for severely ill
patients waiting for transplant. Humar and Fishman (59) sum it best:
“First, it should be emphasized that these events continue to be
very uncommon and that current screening practices have a
remarkable track record for maintaining safety in

63
transplantation, considering the number of potential organ and
tissue donors that are screened each year. Second, we should
realize that the screening of organs for pathogens is about risk
mitigation and not about risk elimination. It is unlikely we will
ever be able to completely eliminate the risk of disease
transmission associated with transplantation. Such a goal is
unrealistic with present technology. However there is room to
improve donor screening and the detection of such events when
they occur, to improve communication regarding transmission
events, and to deploy therapies and public health investigations
more quickly than is possible at present. The process of donor
screening must continue to evolve with our knowledge about the
ever-changing field of infectious diseases.”

64
7.0 POLICY CHALLENGES
7.1 Historical Background
Blood establishments in the US were launched after World War II in many
communities to support the medical needs of the local populations. As a
result of this community approach, the US blood supply became isolated and
fragmented. In the 1970’s, HHS, then called the Department of Health,
Education and Welfare, attempted to establish a national blood policy to
unify a national strategy for blood safety and availability. However, the
private sector was very concerned about the potential impact of a national
blood policy and a policy was never established. The previously proposed
national blood policy was reviewed by the ACBSA in January 2004 and the
Committee acknowledged the draft policy generally captured many of the
present day concepts. However the US still is without a national blood policy
although there are FDA regulations codified to ensure Good Manufacturing
Practices.
The infrastructure for policy on solid organ transplantation, organ recovery,
and equitable allocation of organs through a single national network (i.e.,
OPTN) was founded in Federal legislation through the National Organ
Transplant Act (NOTA), enacted in 1984.
This legislation was amended in 2000 (60). In accordance with the NOTA,
policy in the organ transplantation community is established by the OPTN
and if it is to be enforceable the policy must be approved by the Secretary of
HHS. The only policy currently approved by the Secretary and enforceable
under Federal law is reporting of data on Office of Management and Budget
(OMB) forms. These data are on transplant candidates, recipients and all
living and deceased donors. Within the organ transplantation community,
oversight of policy and bylaws by the OPTN is recognized as key to a
successful solid organ transplant program in the US. The current oversight
system relies on confidential peer review of compliance in contrast to policy
enforcement (61).
Human tissue became regulated under FDA in 1993. FDA’s current rules for
HCT/Ps, in effect since 2005, are more comprehensive than the earlier rule.
They cover a wider range of tissues and cellular products, including, for
example, reproductive tissues and HPCs, a more extensive and continually
updated list of relevant communicable diseases, and require registration of
all establishments that manufacture HCT/Ps in the US or for import to the
US as well as compliance with Current Good Tissue Practices. Reporting
requirements under the new rules include mandatory reporting of
manufacturing deviations and adverse reactions relating to communicable
disease transmission.

65
The Stem Cell Therapeutic and Research Act of 2005 (Stem Cell Act 2005)
was passed by Congress and signed by President Bush in December 2005 as
Public Law 109-129. The Stem Cell Act 2005 is managed by HRSA. The Stem
Cell Act 2005 includes the C.W. Bill Young Cell Transplantation Program
and the National Cord Blood Inventory (NCBI). The cell transplantation
program is named after Congressman C.W. Bill Young who is a long-time
supporter of bone marrow transplantation and helped start the National
Bone Marrow Donor Registry. The C.W. Bill Young Cell Transplantation
Program expands upon the previous requirements to increase the number
of marrow donors and cord blood units and continues to serve patients who
need a bone marrow or cord blood transplant. The NCBI will also provide
cord blood units for research.
7.2 Mandates for a Comprehensive Biovigilance Program
The rapid growth and evolution in the scientific and technical fields of
transfusion and transplantation call for a comprehensive biovigilance
program. Specifically, AE monitoring for recipients and donors, quality
assurance, and emerging threat assessment are critical components in a
comprehensive system. As identified in this report, the AE reporting can
either be active or passive depending on timeliness of data collection and
analysis. Ideally, all adverse events and outcome reporting should be active
in terms of data collection but this may not be practical in all sites nationally
for every product.
7.3 Mandatory vs. Voluntary Adverse Event Reporting
For blood and blood products, there is a robust regulatory structure from
collection to transfusion and accrediting organizations active in emphasizing
patient safety, but coordinated surveillance for AE event policy on reporting,
particularly for non-fatal events, is lacking, both in donors and in recipients.
For other tissues (i.e., HCT/Ps), regulation is narrower in scope, being limited
to control of communicable diseases, but with no government regulation
extending to the end user in the clinical setting.
Common processes for data collection, analysis and evaluation are either
lacking or underdeveloped in both the private and public health communities.
Compounding the lack of common processes is the lack of understanding of
transfusion and transplant safety risks across the spectrum of products.
Surveillance for a wider array of AE is needed for blood and blood products.
Voluntary reporting of AE may increase reporting if there are no punitive
consequences to the facility, but such systems must be implemented widely to

66
have an impact. CDC’s NHSN hemovigilance module is expected to have
such as impact. In addition, serious AE reporting required by the proposed
Safety Reporting Rule (SRR) will help broaden the hemovigilance data that
FDA collects.
Mandatory reporting for HCT/P manufacturers, excluding reproductive tissue
establishments, consists of adverse reaction reports involving communicable
disease transmission, and deviations in manufacturing that may introduce
risks of communicable disease transmission or contamination. For HCT/Ps
also regulated as licensed biologics, mandatory reporting requirements are
more extensive. Under the MedWatch program, FDA receives voluntary
reports of other types of adverse events from healthcare providers and
recipients.
Finally, for solid organs, for which transmission risks are highest, oversight
mechanisms feature an excellent database infrastructure through the OPTN,
but such systems currently are focused on patient outcome, not disease
transmission or other adverse events. A system such as the prototype TTSN
attempts to strengthen connections between organ and tissue recovery
organizations and healthcare providers to solve multiple problems
simultaneously. However, TTSN is unlikely to be successful as a purely
voluntary system without specific resources allocated for implementation.
7.4 Public/Private Partnership
Industry, led by AABB, initiated its efforts at collaboration on biovigilance at
about the same time biovigilance was incorporated into the ACBSA
recommendations (September 2005 and August 2006) as a priority for a
federal government national strategic plan. In addition CDC and UNOS
recently completed a cooperative agreement to develop a prototype for
surveillance of transplant-transmitted diseases, the TTSN. Progress made
by government and industry has created valuable momentum toward a
lasting public-private partnership in this area. However, although current
initiatives for blood, organ, and tissue safety, such as HHS partnerships with
AABB and UNOS, represent a potential to fill gaps for blood, organs, and
some HCT/Ps, resources are lacking for system maintenance and expansion.
7.5 Conclusions
Blood products, organs, and HCT/Ps are obtained and managed by
independent local blood collectors, organ procurement organizations, and
tissue establishments. Federal oversight includes monitoring through facility
inspections or accreditation, e.g., by FDA, CMS or CMS granted deemed
status by an accrediting organization. Industry generally supports safety

67
efforts, but encourages the Federal government to minimize requirements to
reduce burden and duplication of efforts. Thus, voluntary reporting of AE
would be more palatable but may hinder implementation of biovigilance
without adequate enforcement.
A uniform biovigilance system may not be possible in the US, given
differences in oversight and regulation of these different products, but these
differences should not be an obstacle to a common coordinated national
program. Therefore, a concerted effort is needed for coordination among
PHS agencies in the federal government and organizations in the private
sector to assure safe and available transfusion and transplantation. Systems
need to avoid overlap in order to minimize reporting burden. However,
mandatory regulatory components alone will not be sufficient, as data cannot
be shared from these sources, emphasizing the need for voluntary non-
regulatory components in parallel. Uncoordinated efforts without a clear
governance plan may be the greatest threat to patient safety related to
biovigilance, as progress may cease. Importantly, systems need to be aligned
with FDA, HRSA, and CMS reporting requirements and AHRQ-mandated
PSO data elements to minimize data reporting burden; public health
surveillance should be coordinated with CDC; research priorities should be
coordinated with NIH.
A comprehensive biovigilance program should bridge both regulatory and
organizational gaps to meet public health needs. The first step is to develop a
new HHS action plan that includes blood, HCT/Ps, and organs. The absence
of a road map for HHS is a notable deficiency, and stalls momentum for its
agencies (i.e., AHRQ, CDC, CMS, FDA, HRSA, and NIH) to develop their own
strategic plans. Regular assessment and evaluation of current measures is
needed to determine risks to patient safety. Disease transmission and other
adverse events associated with transfusion and transplantation constitute
risks that are evident but unevenly quantified, depending on the biologic.
Although patient safety is paramount, the need to assess availability also
needs to be taken into consideration.
After a strategic plan for biovigilance is developed, to assure the appropriate
scope, participation, and a common architecture, details can be finalized on
the resources and partners needed to accomplish the task. Well-defined
transparent governance of a private/public partnership for biovigilance is in
the best interest of the American people.

68
7.6 Recommendations
Given these policy challenges, the PHS Biovigilance task group developed
the following recommendations:
1. We recommend government resource support for a national
biovigilance program to monitor and enhance safety of blood, organs,
and HCT/Ps.
2. We recommend integration of systems within the government and
those within the private sector, involving blood, organs, and HCT/Ps,
including all related voluntary and mandatory adverse event reporting
systems.
3. We recommend steps to enhance mechanisms for surveillance,
including sentinel reporting and investigation, and comprehensive
surveillance that features benchmarking.
4. We recommend developing an HHS action plan to support the above
three recommendations.
END OF REPORT TEXT

69
8.0 APPENDICES
APPENDIX 1: Blood Action Plan
ACCOMPLISHMENTS TO DATE
FY97
• Team Biologics – Insuring Compliance of Plasma Fractionators, 10/97
• FDA Response to Emergencies and Class I Recalls, 10/7/97
• Workshop: Potency and Dosage of Von Willebrand Factor Concentrates,
9/26/97
• Workshop: The Biologics License Application (BLA) for Blood Products
and Reporting Changes to an Approved Application, 12/2/97
• Workshop: Current Topic in Immunohematologic Testing, 12/10/97
FY98
• Draft Guidance for Industry: In the Manufacture and Clinical Evaluation
of In Vitro Tests to Detect Nucleic Acid Sequences of Human
Immunodeficiency Virus Type 1, 7/10/98
• Draft Guidance for Industry: Current Good Manufacturing Practices for
Blood and Blood Components: (1) Quarantine and Disposition of units
from Prior Collections from Donors with Repeatedly Reactive Screening
Tests for Antibody to Hepatitis C Virus (anti - HCV); (2) Supplemental
Testing, and the Notification of Consignees and Blood Recipients of Donor
Test Results for Anti-HCV, 9/23/98
• Draft Document: United States Industry Consensus Standard for the
Uniform Labeling of Blood and Blood Components using ISBT 128,
11/27/98
• Draft Guidance for Industry: Gamma Irradiation of Blood and Blood
Components: A pilot Program for Licensing, 12/8/98
• Workshop: Nucleic Acid Testing for HCV and other Viruses in Blood
Donors, 9/16/98
• Workshop: Evaluation of In Vivo Efficacy of Platelet Transfusion Products
and Platelet Substitutes, 9/28/98
• Workshop: Blood Donor Suitability, 11/23/98
• Workshop: Pilot Program for Streamlining the Licensure of Blood and
Blood Components. 2 Topics: Gamma Irradiation/RBC Immunization,
12/9/98

70
FY99
• Guidance for Industry: For the Submission of Chemistry, Manufacturing
and Controls (CMC) and Establishment Description Information for
Human Plasma-Derived Biological Products, Animal Plasma or Serum-
Derived Products, 2/17/99
• Guidance for Industry: Content and Format of Chemistry, Manufacturing
and Controls (CMC) Information and Establishment Description
Information for a Biological In Vitro Diagnostic Product, 3/8/99
• Guidance for Industry: For the Submission of Chemistry, Manufacturing
and Controls (CMC) Establishment Description Information for Human
Blood and Blood Components Intended for Transfusion or for Further
Manufacture and for the Completion of the FDA From 356h, 5/10/99
• Direct Final Rule and Companion Proposed Rule: Revisions or
Requirements Applicable to Albumin (Human), Plasma Protein Fraction
(Human), and Immune Globulin (Human), 5/14/99
• Draft Guidance for Industry: Current Good Manufacturing Practices for
Blood and Blood Components: (1) Quarantine and Disposition of Prior
Collections from donors with Repeatedly Reactive Screening Tests for
Hepatitis C Virus; (2) Supplemental Testing, and the Notification of
Consignees and Transfusion Recipients of Donor Test Results for Antibody
to HCV (Anti-HCV), 6/17/99 [Replaces 9/23/99 Guidance]
• Guidance for Industry: Platelet Testing and Evaluation of Platelet
Substitute Products. 5/20/99
• Guidance for Industry: Efficacy Studies to Support Marketing of Fibrin
Sealant Products Manufactured for Commercial Use, 5/20/99
• Draft Guidance/Implementation for Industry: Revised Precautionary
Measures to Reduce the Possible Risk of Transmission of Creutzfeld-
Jakob Disease (CJD) and new variant Creutzfeld-Jakob Disease (nvCJD)
by Blood and Blood Products, 8/99 [Final Guidance 11/23/99]
• Direct Final Rule and Companion Proposed Rule: Revisions to the
Requirements Applicable to Blood, Blood Components and Source Plasma,
8/19/99
• Proposed Rule: Requirements for Testing Human Blood Donors of
Evidence of Infection Due to Communicable Disease Agents, 8/19/99
• Proposed Rule: General Requirements for Blood, Blood Components and
Blood Derivatives; Notification of Deferred Donors, 8/19/99
• Advanced Notice of Proposed Rulemaking: Plasma Derivatives and Other
Blood-Derived Products; Requirements for Tracking and Notification,
8/19/99
• Draft Guidance for Industry: Application of Current Statutory Authority
to Nucleic Acid Testing of Pooled Plasma, 11/26/99
• Database for Emerging Infectious Diseases, 4/99

71
• Workshop: Potential Transfusion Transmission of Tick Borne Agents,
1/14-15/99
• Workshop: Blood Donor Suitability Workshop: Donor History of Hepatitis,
7/21/99
• Workshop: International Workshop on Clearance of TSE Agents from
Blood Products and Implanted Tissues, 9/13-14/99
• Workshop: Bacterial Contamination of Platelets, 9/24/99
• Workshop: Criteria for Safety and Efficacy Evaluation of Oxygen
Therapeutics as Red Cell Substitutes, 9/27-28/99
• Workshop: Plasticizers: Scientific Issues in Blood Collection, Storage and
Transfusion, 10/18/99
• Workshop: Standards for Inactivation and Clearance of Infectious Agents
in the Manufacture of Plasma Derivatives from Non-Human Source
Materials for Human Injectable Use, 10/25/99
• Open Public Meeting: Public Comment during the Comment Period of 4
recently Published Documents. ANPR-Tracking and Notification/DFR-
Requirements for Blood/PR-Donor Notification/PR-Testing, 11/22/99
• Workshop: Blood Donor Suitability, 12/9/99
• Workshop: Universal Leukoreduction, 12/10/99
• Workshop: NAT Implementation, 12/14/99
FY00
• Draft Guidance to Industry: Changes to an Approves Application:
Biological Products: Human Blood and Blood Components Intended for
Transfusion or for Further Manufacture 1/3/00
• Revision of Requirements Applicable to Albumin (Human), Plasma
Protein Fraction (Human), and Immune Globulin (Human); Confirmation
in Part and Technical Amendment; Final Rule - 3/14/00
• Final Guidance for Industry: Pilot Program: Gamma Irradiation, 3/15/00
• Final Guidance for Industry: Recognition and Use of a Standard for the
Labeling of Blood and Blood Components, 6/6/00
• Draft Guidance: Pilot Program: CBER Pilot Licensing Program for
Immunization of Source Plasma Donors with Immunogen Red Blood Cells
Obtained from an Outside Supplier, (July 18, 2000)
• Revision or Requirements Applicable to Albumin (Human), Plasma
Protein Fraction (Human), and Immune Globulin (Human), (August 28,
2000)
• Reporting Biological Product Deviations in Manufacturing, (November 7,
2000)
• Proposed Rule: Current Good Manufacturing Practices for Blood and
Blood Components: Notification of Consignees and Transfusion Recipients

72
Receiving Blood and Blood Components at Increased Risks of
Transmitting HCV Infection (Lookback), (November 16, 2000)
• Draft Guidance: Variances for Blood Collection from Individuals with
Hereditary Hemochromatosis, December 20, 2000)
• Workshop: Donor Incentives, (February 28, 2000)
• Workshop: CDC- Public Meeting on Donor Suitability Standards (June 26-
27, 2000)
• Workshop: Donor Recruitment Practices, (July 6-7, 2000)
• Workshop: TSE Diagnostics, (September 21-23, 2000)
• Workshop: Streamlining the Blood Donor Questionnaire, (September 29,
2000)
FY01
• Revisions to the Requirements Applicable to Blood, Blood Components,
and Source Plasma; Conformation in Part and Technical Amendment,
(January 10, 2001)
• Donor Incentives (Draft Compliance Policy Guide), (January 16,2001)
• Pre-Storage Leukocyte Reduction of Blood and Blood Components – Draft
Revised Guidance, (January 23, 2001
• Final Rule: Requirements for Testing Human Blood Donors for Evidence
of Infection Due to Communicable Disease Agents, (June 11, 2001)
• Final Rule: General Requirements for Blood, Blood Components and Blood
Derivatives; Notification of Deferred Donors, (June 11, 2001)
• Reporting Form and Database for Reporting Biological Product Deviation
in Manufacturing (June 18, 2001)
• Final Guidance: Pilot Program: CBER Pilot Licensing Program for
Immunization of Source Plasma Donors with Immunogen Red Blood Cell
Obtained from an Outside Supplier, (July 11, 2001)
• Revisions to the Requirements Applicable to Blood, Blood Components,
and Source Plasma, (August 6, 2001)
• Draft Guidance to Industry: Reporting Biological Product Deviation in
Manufacturing (2 Guidance Documents), (August 11, 2001)
• Final Guidance: Variances for Blood Collection from Individuals with
Hereditary Hemochromatosis, (August 22, 2001)
FY02
• Draft Guidance: Streamlining the Donor Interview Process:
Recommendations for Self-Administered Questionnaires, (April 19, 2002)
• Final CPG: Donor Incentives, (May 17, 2002)
FY03

73
• Final Guidance: Streamlining the Donor Interview Process:
Recommendations for Self-Administered Questionnaires, (July 7, 2003)
• Proposed Rule: Revisions to Labeling and Storage Requirements for Blood
and Blood Components, Including Source Plasma, (July 29, 2003)
• Final Guidance: Notifying FDA of Fatalities Related to Blood Collection or
Transfusion, (September 22, 2003)
• Final Guidance: An Acceptable Circular of Information for the Use of
Human Blood and Blood Components (December 9, 2003)
• Proposed Rule: Revisions to Labeling and Storage Requirements for Blood
and Blood Components, Including Source Plasma (July 30, 2003)
FY04
• Final Guidance: Use of Nucleic Acid Tests on Pooled and Individual
Samples form Donors of Whole Blood and Blood Components (including
Source Plasma and Source Leukocytes) to Adequately and Appropriately
Reduce the Risk of Transmission of HIV-1 and HCV, (October 21, 2004)
• Workshop on Plasma Standards (August 31, 2004)
• Workshop on Use of Radiolabled Platelets for Assessment of In Vivo
Viability of Platelet Products (May 3, 2004)
FY05
• Final Guidance: Assessing Donor Suitability and Blood and Blood Product
Safety in Cases of Known or Suspected West Nile Virus Infection (June
23, 2005)
• Draft Guidance: Nucleic Acid Testing (NAT) for Human Immunodeficiency
Virus Type 1 (HIV-1) and Hepatitis C Virus (HCV): Testing, Product
Disposition, and Donor Deferral and Reentry (July 19, 2005)
• Workshop on Biological Therapeutics for Rare Plasma Protein Disorders
(June 13, 2005)
• Workshop on Leukocyte Reduction of Blood and Blood Components (July
20, 2005)
FY06
• Final Guidance: Gamma Irradiation of Blood and Blood Components: A
Pilot Program for Licensing; Withdrawal of Guidance (April 10, 2006)
• Draft Guidance: Pilot Program for Immunization of Source Plasma Donors
Using Immunogen Red Blood Cells Obtained from an Outside Supplier;
Withdrawal of Guidance (April 11, 2006)
• Draft Guidance” Amendment (Donor Deferral for Transfusion in France
Since 1980) to “Guidance for Industry: Revised Preventive Measures to

74
Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease
(CLD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood
Products” (August 8, 2006)
• Final Guidance: Implementing a Collection Program for Source Plasma
Containing Disease-Associated and Other Immunoglobulin (IgG)
Antibodies (August 8, 2006)
• Final Guidance: Recognition and Use of a Standard for Uniform Blood and
Blood Component Container Labels (September 22, 2006)
• Final Guidance: Biological Product Deviation Reporting for Blood and
Plasma Establishments (October 18, 2006)
• Final Guidance: Implementation of Acceptable Full-Length Donor History
Questionnaire and Accompanying Materials for Use in Screening Donors
of Blood and Blood Components (October 27, 2006)
• Workshop on Behavior-Based Donor Deferrals in the NAT Era (March 8,
2006)
• Workshop on Testing for Malarial Infections in Blood Donors (July 12,
2006)
FY07
• Final Guidance: Informed Consent Recommendations for Source Plasma
Donors Participating in Plasmapheresis and Immunization Programs,
(June 20, 2007)
• Final Guidance: “Lookback” for Hepatitis C Virus (HCV): Product
Quarantine, Consignee Notification, Further Testing, Product Disposition,
and Notification of Transfusion Recipients Based on Donor Test Results
Indicating Infection with HCV, (August 24, 2007)
• Final Guidance: Adequate and Appropriate Donor Screening Tests for
Hepatitis B; Hepatitis B Surface Antigen (HBsAg) Assays Used to Test
Donors of Whole Blood and Blood Components, Including Source Plasma
and Source Leukocytes (November 21, 2007)
• Final Guidance: For Industry and FDA Review Staff; Collection of
Platelets by Automated Methods (December 17, 2007)
• Final Rule: Current Good Manufacturing Practice for Blood and Blood
Components; Notification of Consignees and Transfusion Recipients
Receiving Blood and Blood Components at Increased Risk of Transmitting
Hepatitis C Virus Infection (July 24, 2007)
• Direct Final Rule: Revisions to Requirements Applicable to Blood, Blood
Components and Source Plasma (August 15, 2007)
• Proposed Rule: Requirements for Human Blood and Blood Components
Intended for Transfusion or for Further Manufacturing Use (November 8,
2007)
• Workshop on Licensure of Apheresis Blood Products (August 15, 2007)

75
• Final Guidance: For Industry and FDA Review Staff: Collection of
Platelets by Automated Methods (December 17, 2007)
FY08
• Draft Guidance: Use of Nucleic Acid Tests to Reduce the Risk of
Transmission of West Nile Virus from Donors of Whole Blood and Blood
Components Intended for Transfusion and Donors of Human Cells,
Tissues, and Cellular and Tissue-Based Products (HCT/Ps), (April 25,
2008)
• Draft Guidance: Requalification Method for Reentry of Blood Donors
Deferred Because of Reactive Test Results for Antibody to Hepatitis B
Core Antigen (Anti-HBc), (May 20, 2008)
• Draft Guidance: Nucleic Acid Testing (NAT) to Reduce the Possible Risk
of Parvovirus B19 Transmission by Plasma-Derived Products, (July 30,
2008)
• Workshop to Consider Approaches to Reduce the Risk of Transfusion-
Transmitted Babesiosis in the United States (September 12, 2008)

76
APPENDIX 2: Office of the Secretary’s Office of Public Health and Science
Draft Strategic Plan

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94
APPENDIX 3: Tissue Transplant Record (Northwest Tissue Services)

95
APPENDIX 4: NMDP Form 701

96
APPENDIX 5: NMDP Form 760

97
APPENDIX 6: Cell Therapy Adverse Event Form (University of California
San Diego Medical Center)

98
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2. Faber JC. Worldwide overview of existing hemovigilance systems.
Transf Apher Sci 2004;31:99-110.
3. Michlig C, Vu D-H, Wasserfallen J-B, Spahn DR, Schneider P, Tissot
J-D. Three years of haemovigilance in a general university hospital.
Transfus Med 2003; 13:63-72.
4. Robillard P, Nawej KI, Jochem K. The Quebec hemovigilance system:
description and results from the first two years. Transfus Apher Sci
2004; 31:111-22.
5. Engelfriet CP, Reesink HW. Haemovigilance systems. Vox Sang 1999;
77:110-20.
6. Engelfriet CP, Reesink HW. Haemovigilance. Vox Sang 2006;90:207-
41.
7. Beckers EA, Dinkelaar RB, te Boekhorst PA, van Ingen HE, van
Rhenen DJ. Reports of transfusion incidents: experiences from the first
year of hemovigilance in the region of the former ZWN (South West
Netherlands) blood bank in Rotterdam. Ned Tijdschr Geneeskd
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8. Espinosa A, Steinsvåg CT, Flesland Ø. Hemovigilance in Norway.
Transfus Apher Sci 2005; 32:17-9.
9. Commission Directive 2005/61/EC of 30 September 2005 implementing
Directive 2002/98/EC of the European Parliament and of the Council
as regards traceability requirements and notification of serious
adverse reactions and events. Official Journal of the European Union.
10. Faber JC. Haemovigilance procedure in transfusion medicine.
Haematol J 2004;5:S74-82.
11. Faber JC. The European blood directive: a new era of blood regulation
has begun. Transfus Med 2004; 14:257-73.
12. Faber JC. Work of the European Haemovigilance Network (EHN).
Transfus Clin Biol. 2004; 11(1): 2-10.
13. Directive 2002/98/EC of the European Parliament and of the Council
setting standards of quality and safety for the collection, testing,
processing, storage and distribution of human blood and blood
components and amending Directive 2001/83/EC; published in the
Official Journal of the European Communities on 8 February 2003.

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14. Stainsby D, Jones H, Asher D, Atterbury C, Boncinelli A, Brant L,
Chapman CE, Davison K, Gerrard R, Gray A, Knowles S, Love EM,
Milkins C, McClelland DBL, Norfolk DR, Soldan K, Taylor C, Revill J,
Williamson LM, Cohen H, on behalf of the SHOT Steering Group.
Serious hazards of transfusion: a decade of hemovigilance in the UK.
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15. Callum JL, Kaplan HS, Merkley LL, Pinkerton PH, Rabin Fastman B,
Romans RA, Coovadia AS, Reis MD. Reporting of near-miss events for
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16. Kaplan HS. Event reporting systems: MERS-TM, surveillance--seeing
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17. Busch M, Chamberland M, Epstein J, Kleinman S, Khabbaz R, Nemo
G. Oversight and monitoring of blood safety in the United States. Vox
Sang 1999;77:67-76.
18. Title 21 Code of Federal Regulations 606:170(b), 2006.
19. FDA MedWatch; http://www.fda.gov/medwatch/index.html
20. Department of Health and Human Services. The 2005 Nationwide
Blood Collection and Utilization Survey Report. 2006.
21. Centralized Transfusion Services: Models and Systems, (Simpson,
M.P., ed.) AABB Press, Bethesda, MD, 2006.
22. Eder AF, Kennedy JM, Dy, BA, Notari, EP, Weiss, JW, Fang, C.T.,
Wagner, S., Doff, R.Y., Benjamin, R.J. Bacterial screening of apheresis
platelets and the residual risk of septic transfusion reactions: the
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