Safety of living donors is critical to the success of blood, tissue and organ transplantation. Structured and robust vigilance and surveillance systems exist as part of some national entities, but historically no global systems are in place to ensure conformity, harmonisation and the recognition of rare adverse events (AEs). The World Health Assembly has recently resolved to require AE/reaction (AE/R) reporting both nationally and globally. The World Marrow Donor Association (WMDA) is an international organisation promoting the safety of unrelated donors and progenitor cell products for use in haematopoietic progenitor cell (HPC) transplantation. To address this issue, we established a system for collecting, collating, analysing, distributing and reacting to serious adverse events and reactions (SAE/R) in unrelated HPC donors. The WMDA successfully instituted this reporting system with 203 SAE/R reported in 2011. The committee generated two rapid reports, reacting to specific SAE/R, resulting in practice changing policies. The system has a robust governance structure, formal feedback to the WMDA membership and transparent information flows to other agencies, specialist physicians and transplant programs and the general public.
Living donors are increasingly requested for life-saving procedures for patients in need. Annually over 25 000 allogeneic haematopoietic cell transplants (HCT) are performed for patients with blood disorders worldwide, with approximately one-third of those from related donors, and the balance using volunteer unrelated donors (VUD) or umbilical cord blood units. VUD are represented in a worldwide database (http://www.bmdw.org/), which currently lists >20 million donors. To ensure the continued viability of the global HCT enterprise utilising VUD, the donor health and safety is of critical importance. Because almost half of the haematopoietic progenitor cells (HPC) procured for transplantation cross international borders, optimal donor safety requires global strategies.
World Health Organisation (WHO) Guiding Principle 10 established the need for safe and efficacious procedures for living donors. It highlighted the need for quality and vigilance systems for all cells, tissues and organs for transplantation, nationally and across international borders, as well as requiring adverse event and reaction (AE/R) reporting (http://www.who.int/transplantation/Guiding_PrinciplesTransplantation_WHA63.22en.pdf). World Health Assembly Resolution WHA63.22, adopted in May 2010, extended these principles, and introduced the concept that the collection and analysis of all serious adverse events and reactions (SAE/R) should be collaborative and global.1
Although national competent authorities or regulatory agencies sometimes mandate donor SAE/R reporting, there are, to our knowledge, no examples of global reporting systems.
Global data collection is essential as it enhances the likelihood of recognition of relatively rare SAE/Rs, which may occur at such a low frequency, or not at all, in a single-donor registry or cord blood bank that recognition is otherwise unlikely. It also enables the tracking of trends or hazards. The analysis of AEs can lead to insights into the underlying system failures and be the basis for new recommendations and corrective and preventative actions. A further advantage is that global expertise and experience can be developed within formal structures resulting in the continuity of analysis of AEs and a global ‘institutional memory’ allowing for AE/Rs over several years to be rapidly accessible.
There are challenges associated with global data reporting such as inconsistency of definitions, duplication of or contradiction with national reporting systems, cost, infrastructure issues, availability of labour resources for data capture and processing and fear of reprisals or punishment. To this end, there are several requirements for a reporting system to be successful. This topic has been well summarised by Leap,2 but in brief the system should ensure confidentiality for the reporter and that the report is anonymous. In addition, the system should be independent and non-punitive and thus clearly separated from any regulatory or funding implications.
Also critical to the success of such a system is that the reports are reviewed and analysed in a timely manner by a review group comprising recognised experts in their field and, if possible, elected by and thus representative of the community. Finally, the review group must be responsive, having the power not only to generate reports and disseminate information, but also to make recommendations and to ensure that structures and processes are present to enforce such recommendations.
In this paper we describe the process undertaken by the World Marrow Donor Association (WMDA) to develop a global system for V&S in the unrelated donors of HPC for transplantation.
Developing a global reporting system: serious (product) events and reactions (S(P)EAR)
The WMDA is an international association based on the principle of the harmonisation of global practices in unrelated donor HCT and the protection of stem cell donors. The WMDA has developed guidelines and recommendations and has implemented a robust accreditation system for registries.
Although the donation of HPC, either by direct extraction from the BM under general anaesthesia or by apheresis following G-CSF administration, is a generally safe procedure, there are well-recognised, albeit rare, serious adverse reactions (SARs).3, 4, 5, 6 In addition, there may be more frequent product events, such as those associated with transportation or quality of the product.
In 2002, the Clinical Working Group of the WMDA recognised a need for centralised collection of SAE/R, termed Serious Events and Adverse Reactions (SEAR). This need was reinforced following the publication in 2004 and 20067, 8 of two studies raising concerns about the development of chromosomal abnormalities and haematologic malignancies in related G-CSF-mobilised PBSC donors.
In 2006, the European Union required its member States to report an AE if it influenced the quality or safety of the transplant (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:102:0048:0058:en:PDF). An AE could be attributed to procurement, testing, processing, storage and distribution. Therefore, the WMDA implemented a complementary system to collect product events: Serious Product Events And Adverse Reactions (SPEAR). At the outset these were voluntary schemes, and although many registries participated, the numbers of SAE/Rs reported were low. More recently, reporting has increased substantially for several reasons, including increased recognition by the membership of the benefits of a reporting system and increased awareness of the international reporting requirements and the rationale for such.
In 2008, the S(P)EAR reporting system was significantly altered to meet the needs and requirements of a global reporting system.
Registry membership responsibility
Reporting of S(P)EAR by all WMDA-accredited registries was mandated effective from 1 January 2011. Thereafter, a standard operating procedure (SOP) detailing the roles and responsibilities of donor registries was developed. This SOP covers the reporting procedure, including the registry requirements, timescales and the types of events to report. In the creation of these materials, the importance of harmonising definitions was recognised. The definitions of SAEs, SARs and imputability adopted for S(P)EAR reporting were the same as those agreed to by the Vigilance and Surveillance of Substances of Human Origin (SOHO V&S), an European Union-funded project led by the Italian Transplant Society (CNT) in collaboration with the WHO (NOTIFY project) (Table 1). By so doing, it is anticipated that these definitions will be equivalent to those required by the regulatory agencies and competent authorities, making the procedures for reporting to multiple agencies more straightforward.
The Committee recognised that the reporting procedure needed to be both simple and standardised. To this end, an online system was instituted, accessed directly from the WMDA AEs page (http://www.worldmarrow.org/). A report is generated and delivered to the WMDA office as well as to the Chair of the Committee and the reporting registry. The system also allows supplementary documents to be uploaded and made available to the committee.
The S(P)EAR report recommends the use of Common Terminology Criteria for Adverse Events (CTCAE) and International Code Designator-10 (ICD-10) codes (providing a link to these definitions). A guidance document gives an overview of what to report.
Reporting is also defined according to the temporal association with the donation. ‘Early’ was from the initiation of donation (first dose of GCSF or initiation of anaesthetic) to Day 30 post donation. ‘Late’ was any event/reaction occurring at any time after 30 days. The reporting of two main categories of ‘late’ reactions is required, namely autoimmune disorders and malignancies.
WMDA S(P)EAR review committee responsibility
For the reasons outlined in the introduction, it was recognised that the WMDA needed to develop a review committee to complete the S(P)EAR process.
The composition of the Committee was felt to be of great importance considering the important task at hand. Therefore, the membership of the group consists of elected representatives of the WMDA membership, the majority with clinical experience, including members of the Clinical, Ethics and Cord Blood Working Groups. In addition to these voting members, the committee also includes one non-voting Regulatory and Legal Affairs member, and one non-voting member from the WMDA Office. A long-term of 6 years (three renewable terms) may be served, and was felt to be desirable in order for committee members to build up expertise and experience, especially where there is a need to recognise very rare events.
It is the responsibility of the Committee to review each S(P)EAR report and to make a determination about the imputability of the S(P)EAR. The committee meets regularly, either face-to-face or by teleconference. Each S(P)EAR report is assigned to a specific voting member who reviews it before the meeting and leads the discussion of the event or reaction. Imputability assignment requires more than half of the voting members to agree and uses the previously agreed definitions. There are several possible outcomes of the review process that are outlined in Figure 1.
It is also the responsibility of the committee to periodically report back to the WMDA membership. This occurs during the bi-annual general membership meeting of the WMDA and, in addition, an annual report is produced by the Committee (in 2011, 203 S(P)EAR were reported to the committee). These reports are available on the WMDA website. A record of all committee materials and record of all S(P)EAR is held in a secure area on the WMDA website. The WMDA office holds a confidentiality agreement signed by each review committee member.
The committee does not take on a legal reporting role for SAE/R, and this system in no way replaces or removes the need for individual registries to comply with the legal reporting requirements of their national/competent authorities or other regulatory or pharmaceutical bodies.
Examples of feedback mechanisms and ‘rapid alerts’
The Chair of the Clinical Working Group (CWG) or a designee is required to review briefly each S(P)EAR within 7 working days of it being received by the WMDA office. In the majority of cases, formal discussion of this S(P)EAR will then occur at the next committee meeting. In the rare case of a donor death, or if the chair deems a S(P)EAR report to require expedited reporting, an ad-hoc meeting of the S(P)EAR committee will be called within 5 working days. If this group judges the impact of the S(P)EAR to be high, they will prepare a communication to be sent to all WMDA member organisations and all relevant members of the international community in contact with allogeneic (related and unrelated) donors and patients. This must be done in a timely manner, but may require investigation and thus it is not possible to specify a time scale. The Executive Board of the WMDA approves the subsequent communication.
Two real-life examples of the committee issuing a communication in this manner are described below:
The first occurred when the WMDA received several SPEAR reports describing the development of Takotsubo syndrome (‘shocked heart syndrome’) in recipients of double cord blood units for transplantation. The reporting registry had received reports of two cases, after which they had performed a ‘look back’ to see whether previous similar events had occurred. One previous report was uncovered. Owing to heightened awareness, four further cases were reported. It is not within the jurisdiction of the WMDA to investigate S(P)EAR, but pertinent information resulting from the investigation conducted and shared by the involved registry was disseminated to the WMDA membership. The membership of the WMDA represents the vast majority of cord blood banks shipping cord blood units nationally or internationally, and a letter was prepared for dissemination to all members. In addition, the letter was sent to the president of each of the national blood and marrow transplantation societies to disseminate to their members. In this way, the coverage was very thorough and, in fact, many individuals received the communication through more than one route. Following a formal investigation by the original reporting registry, the WMDA was able to circulate the findings to the same groups. These findings suggested that the problem arose due to procedural issues when preparing the umbilical cord blood for transplantation, and recommendations based on these assessments were disseminated.
A second example followed the report to the WMDA of a donor death (the only death that has thus far been reported of a VUD). The committee was immediately able to ascertain that the death was due to a rare but known complication related to the insertion of a central venous catheter (CVC). The committee therefore decided to gather as much information as possible before issuing a report. The specific details of the donor’s death, including the autopsy report, were collected. The committee also reviewed all previous SEAR reports of CVC complications (of which there were five non fatal SEAR, including bruising and pseudo-aneurysm formation) and the available published literature on the subject. All three of these aspects were included in the subsequent communication. The communication also made a set of recommendations about the insertion of CVCs. The key recommendation was that the WMDA standards be altered to include a requirement for each registry to have a written policy concerning CVC use (http://www.worldmarrow.org/fileadmin/Committees/STDC/20120101-STDC-WMDA_Standards.pdf). This recommendation was approved by the WMDA Executive Board and accepted by the standards committee. The communication was also sent to groups outside the WMDA who care for related donors. In this regard, the review committee also made an official recommendation to the Foundation for the Accreditation of Cellular Therapy and Joint Accreditation Committee-ISCT (Europe) and European Blood and Marrow Transplantation (EBMT) Society (FACT-JACIE) committee that a standard about CVC use be added to their accreditation process, which was approved by the medical director of JACIE.
In both of these situations it was obvious that a broad coverage of all interested parties was achieved and that new standards to protect patients and donors from these complications could be instituted.
Harmonisation with outside organisations
As previously mentioned, the optimal globalised S(P)EAR reporting system should be one which is publicly available to all, participated in by all relevant parties and which seeks to provide harmonised reporting, such as a common report form, for all of the international societies and competent authorities. The WMDA has made a concerted effort to begin to achieve these aims, and has cooperated with other organisations to do so.
WMDA has been working with SOHO V&S, an organisation that has developed a series of vigilance tools for tissues and cells resulting in Project NOTIFY, a major global initiative aimed at raising the profile of V&S of substances of human origin (under the umbrella of the WHO). Ultimately, final reports from the S(P)EAR registry will be anonymised and posted in the public domain (http://www.notifylibrary.org/).
WMDA has engaged the Worldwide Network for Blood and Marrow Transplantation (WBMT), a non-profit scientific organisation representing all associations relevant to the care of allogeneic patients and both related and unrelated donors, with the mission to promote excellence in SCT, stem cell donation and cellular therapy. The WMDA adopted the minimum essential data set9 agreed by the WBMT for donor follow-up, such that exactly the same data points and SAE/R will be reported by all WBMT members. Although not the direct mission of the WMDA, the authors recognise that it is highly desirable for a global reporting system to also attempt to include reports from related donors. It is recognised that SAE/R may be more common in related donors and that currently no system of reporting exists outside of individual countries. Individuals can report SAE/R to project NOTIFY, however, this is a voluntary scheme. The Centre for International Blood and Marrow Transplant Research is accruing related donors to a study (RDsafe) in which AE/Rs are collected and compared with those in unrelated donors. Professional societies such as the EBMT and FACT-JACIE are developing methods to both require, and assist in, the reporting of related donor SAE/R, but considerable efforts from the transplant community will be required to ensure that this occurs.
Conclusions and future goals
We report here the successful development of a truly global SAE/R reporting system for volunteer unrelated HPC donors in line with recent WHO recommendations. We believe this represents the first example of such a system on a global scale. In order to achieve these goals, we have partnered with as many complementary organisations as possible to assure harmonisation of definitions and procedures. Compliance with reporting as evidenced by increased numbers of reports continues to improve. Between 2003 and 2009, 50 or fewer S(P)EAR were reported per year, compared with 144 in 2010, 203 in 2011 and 137 in 2012. Since 2010, reporting registries facilitated >95% of donations globally. We have also demonstrated success by disseminating information on particular reactions/events widely and instituting new procedures to protect patients and donors. In so doing, we have demonstrated the benefit of this system to the international transplant and donor communities, thus enhancing compliance. Our challenge is to extend such systems to coverage of all living donors, a goal that we think is achievable by following this model.
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We thank the membership for their active participation in this reporting system. We also thank Florian Krouwel for his invaluable support in managing the system.
All authors were active in developing the S(P)EAR reporting system and in reaction and event review. All authors were involved in the drafting of the article or critical revision for important intellectual content.
The authors declare no conflict of interest.
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Cite this article
Shaw, B., Chapman, J., Fechter, M. et al. Towards a global system of vigilance and surveillance in unrelated donors of haematopoietic progenitor cells for transplantation. Bone Marrow Transplant 48, 1506–1509 (2013). https://doi.org/10.1038/bmt.2013.104
- unrelated donor
- vigilance and surveillance
- haematopoietic cell transplantation
- serious adverse event
- serious adverse reaction
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