6.1 Governments

In France, the field of bio-vigilance was incorporated into the law on 21 December 2003 with the publication of Decree no.° 2003-1206. Its scope ranged from human organs, human tissues and cells to human cellular therapy preparations and ancillary products. The aim of bio-vigilance is to supervise and assess the risk due to the occurrence of adverse events attributable to products and activities in the field, and from adverse reactions to the living donor or recipient. It is based on the notification of adverse events and adverse reactions linked or possibly linked to human organs, tissues, cells and ancillary products and activities.

The European Union has three pieces of legislation addressed specifically to ensuring the quality and safety of human tissues and cells. The primary Directive (2004/23/EC) establishes standards from donation to distribution. The two implementing Directives set out specific technical requirements for donations, procurement and testing (2006/17/EC) and others for traceability, the notification of serious adverse occurrences as well as processing, preservation, storage and distribution (2006/86/EC). The publication of the legislation, however, is only the beginning of a process to ensure a common European standard and approach. The major challenge lies in the implementation, maintenance and
updating of the legislative requirements.

Significant progress toward this end was made during the EUSTITE (European Union Standards and Training in the Inspection of Tissue Establishments) project, which was co-financed by the European Commission. EUSTITE addressed issues in support of the requirements for tissue and cell establishments to have systems in place for the monitoring and reporting of serious adverse occurrences. It established criteria for reporting adverse incidents to competent authorities and developed not only a severity grading system but also one for imputability for cases where donors or recipients have been harmed, with guidance on which level to report. Guidance documents were prepared on how to use
these tools and on the management of adverse occurrences that have cross border implications.

A EU sponsored project entitled Vigilance and Surveillance of Substances of Human Origin (SOHO V&S) developed more detailed vigilance guidance. One of the main objectives of the project was to increase awareness among clinicians of the importance of vigilance and surveillance of tissues and cells. The V&S Guidance for Clinicians developed in the project aims at promoting vigilance and surveillance and helping to define the roles and responsibilities of clinical users in the traceability, recognition, reporting, and investigation of adverse occurrences in hospitals, as well as the management of recalls.

EFRETOS – the European Framework for the Evaluation of Organ Transplants – was a project funded by the European Union (EU) aimed at promoting the development of a pan-European registry of registries on the follow-up of patients who have undergone organ transplantation. It included recommendations on the implementation of a vigilance system as an integral part of the monitoring of such patients.

Vigilance in the EU links three levels: the European Commission, which plays inter alia a coordinating and supportive role and maintains the rapid alert system for tissues and cells, the European Centre for Disease Control (ECDC), which monitors health threats; national Competent Authorities that ensure that the requirements of the EU Directives are followed including annual reporting of their adverse reports to the EC; and local tissue and cell establishments that are in the forefront when there are adverse occurrences.
Tissue Establishments must report adverse occurrences to the regulator in each Member State and each Member State must send an annual summary of reports received to the European Commission. With respect to the collection and reporting of adverse occurrences in relation to activity data, problems do exist with several countries only able to provide partial activity information, thus making it difficult to allow estimation of frequency at the EU level. Consequently, incomplete data and different interpretations and reporting practices among Member States obviate any safe conclusions regarding frequency at this moment. With the further development of common data collection and reporting at the national level, a more consistent estimation of frequency is expected in the coming years.

In the United States, The Food and Drug Administration (FDA) is one of a number of agencies involved in biovigilance within the Department of Health and Human Services.
The Center for Biologics Evaluation and Research (CBER) is the center within FDA with responsibility for regulating biological products for human use including vaccines, blood and its components and derivatives, cell and gene therapies, tissues, related devices including certain IVDs, xenotransplantation products and allergenic products.

As part of its activities, CBER reviews adverse reactions. An adverse reaction is defined as a noxious and unintended response to any HCT/P for which there is a reasonable possibility that it caused the response. For the ‘361’ HCT/Ps (HCT/P's Regulated under 21 CFR 1271.3(d)(1) and Section 361 of the US Public Health Service Act), manufacturers must investigate any adverse reaction involving a communicable disease related to an HCT/P they made available for distribution and report it to the FDA if it was fatal, life-threatening, caused permanent impairment/damage or required medical or surgical intervention. Although reporting is voluntary for clinicians, they are encouraged to submit reports directly to the manufacturer and to the FDA. With regard to voluntary reporting, underreporting is likely, and manufacturers may remain unaware of safety issues if clinicians fail to report cases.
Organ oversight and biovigilance in the United States was legislated in 1984 with the signing by the President of the National Organ Transplant Act (NOTA). It set out the framework for matching organs with individuals included in the waiting list as well as the equitable distribution of organs nationwide among transplant patients, and established standards for preventing the acquisition of organs that are infected with the etiologic agent for acquired immune deficiency syndrome (AIDS). The United Network for Organ Sharing (UNOS) / Organ Procurement and Transplantation Network (OPTN) are operated under contract with the Health Resources and Services Administration (HRSA), a division of the Department of Health and Human Services along with the FDA. Within UNOS a Disease Transmission Advisory Committee (DTAC) evaluates reports of potential disease transmission.

Furthermore the activities of the CDC, another division of HHS, include collaboration on investigations of possible disease transmission as the result of reports from diverse sources, such as State and local health departments, transplant clinicians, infectious disease specialists, pathologists, as well as patients and their families. CDC is neither a regulator nor an oversight authority, and investigates events through the assistance of local and state authorities. CDC works collaboratively with U.S. Public Health Service (PHS) agencies that have regulatory oversight over organs, tissues, and cells, including the FDA and HRSA.
For the future of biovigilance in the U.S., there are many gaps to fill, which will require coordination among blood/organ/tissue communities through public-private partnerships, both nationally and globally.
In Brazil, the Organs, Tissues and Cells Office (GTOR) of the National Health Surveillance Agency (ANVISA) is responsible for vigilance and surveillance of substances of human origin. Under the ANVISA Act, it became mandatory in 2010 for industries to report adverse events involving drugs and medical devices. The NOTIVISA information system was upgraded the following year. It is anticipated that organs, tissues and cells will be included in VIGIPÓS in 2012 and in NOTIVISA in 2013.
In Singapore, reportable events include:

  • Patient death or serious disability associated with haemolytic reaction due to administration of ABO/HLA-incompatible blood or blood products;
  • Transmission of diseases following blood transfusion, organ transplant or transplant of tissues;
  • Incidents associated with assisted human reproductive procedure which has, or may have, resulted in:

- Death, life-threatening condition, incapacitating condition, prolonged hospitalisation;
- Transmission of communicable disease;
- Loss or damage to embryos;
- Gamete or embryo misidentification or mix-up.

WHO plays a coordinating role in the promotion of vigilance and surveillance systems globally, sharing the experiences of those countries with existing programs with those who are at earlier stages in the development of such systems. Guiding Principle 10 can be summarised firstly as calling for reporting and analysis of short and long-term, donor and recipient outcomes, and secondly the development and implementation of quality systems, traceability, vigilance and adverse event reporting. In taking up GP10, however, recognition has to be given to the disparities in access and the systems – which are largely created by professionals through their societies and associations – that exist today to
record and analyse the outcomes of donors and recipients on waiting lists and after transplantation.