A UK scheme for reporting serious adverse events and reactions associated with ocular tissue transplantation
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Reporting and investigation of serious adverse events and reactions associated with tissue and cell transplantation is a fundamental aspect of ensuring adequate levels of safety and quality and is a requirement of the European Union Directives on tissues and cells. In the UK, a system for the reporting and analysis of events and reactions associated with ocular tissue transplantation is well established. It is operated by a network of individuals and organisations, each with clearly defined roles and responsibilities, following written procedures for reporting and investigation. Analysis of reports indicates that the most important adverse reactions associated with this type of tissue transplantation are endophthalmitis (0.58%) and primary graft failure (0.3%). This system allows the analysis of all types of events and reactions by the professionals involved so that trends can be identified and services improved. Tools to evaluate the severity and imputability of individual events or reactions, such as those developed by the EUSTITE project, can be utilised to facilitate the selection of those cases meeting the criteria for reporting to the Competent Authority. This vigilance model has been shown to be effective and could be applied in other fields of tissue or cell transplantation.
KeywordsAdverse Reaction Transplant Reporting Cornea Allograft
With the transposition of the EU Tissues and Cells Directives (EUTCD Directives 2004/23/EC, 2006/17/EC; 2006/86/EC) into national law in each European Union Member State, there is now a statutory requirement to report to each national Competent Authority serious adverse events and reactions (SAER) relating to tissue or cells for therapeutic purposes. In the UK, the Competent Authority for tissues and cells for transplantation is the Human Tissue Authority (the Human Fertilisation and Embryology Authority, HFEA, is the Competent Authority for tissues and cells applied in the assisted reproduction field). Prompt reporting of SAER is important for a number of reasons. Most importantly, it facilitates actions to prevent other recipients of tissues or cells or organs being affected by an event or from suffering a reaction that has happened with the index case. For example, rapid communication can lead to effective quarantining of material from the same donor or from tissue processed using the same reagents or clean room, depending on the circumstances. It may also provide rapid identification of a risk that has public health implications and, through escalation, can alert Competent Authorities in other Member States and beyond. This is necessary because tissues and cells are frequently supplied across national boundaries.
A serious adverse event is defined in the EUTCD as “any untoward occurrence associated with the procurement, testing, processing, storage or distribution of tissues or cells that might lead to the transmission of a communicable disease or to death or a life threatening, disabling or incapacitating condition for patients or which might result in, or prolong, hospitalisation or morbidity.”
An adverse event does not necessarily directly affect the health of the patient but has the potential to cause harm to a patient if the tissue were to be transplanted. There are potentially numerous types of serious adverse events that may occur at each stage during the procurement, testing, processing, storage or distribution of tissue or cells. If these are identified by the tissue establishment prior to issuing of the tissue or cells, the reporting of such events would start at the tissue establishment and not involve the transplant centre. Examples of serious events that are not recognised until the tissue has been issued to the transplant centre include tissue that has passed its expiry date, tissue that was damaged, scarred or, in the case of ocular tissue, showing signs of previous surgery, or may simply be the wrong tissue for a particular type of allografting procedure. It could also involve transplantation of tissue where there is a medical contraindication to donation that was unknown at the time of distribution from the tissue establishment or where donor test results are discovered to be invalid due a transcription error.
A serious adverse reaction is defined in the EUTCD as “an unintended response, including a communicable disease, in the donor or in the recipient associated with the procurement or human application of tissues and cells that is fatal, life threatening, disabling, incapacitating or which results in, or prolongs, hospitalisation or morbidity.” The mention of ‘donor’ in this context clearly refers to a living donor, such as a bone marrow donor but can also apply to other living donors such as femoral head donors (usually donating as part of an operative therapeutic procedure) or amnion donors who donate at the time they deliver their infants, often by caesarean section. This could also apply in the ophthalmic tissue and cell donation context if a related donor such as a syngeneic twin were to provide limbal stem cells for their sibling.
Serious adverse reactions include primary graft failure, transmission of a severe ocular or systemic viral, prion, bacterial or fungal infection or malignancy possibly attributable to the transplanted tissue.
SAER associated with ocular tissues
Limbal cell or tissue transplantation,
Amniotic membrane transplantation is included in the limbal cell or tissue transplantation category.
Primary graft failure.
Endophthalmitis or serious ophthalmic infection likely to be attributable to the transplanted tissue.
Graft failure due to donor tissue which was out of date, scarred, abnormal or otherwise damaged, or carried evidence of previous surgery.
Malignancy likely to be attributable to the transplanted tissue.
Systemic infection likely to be attributable to the transplanted tissue.
Limbal cell and or tissue transplantation (including amniotic membrane)
Graft failure due to donor tissue which was out of date, scarred, abnormal or otherwise damaged, or carries evidence of previous surgery.
Endophthalmitis or other serious ophthalmic infection likely to be attributable to the transplanted cells and or tissue.
Malignancy likely to be attributable to the transplanted tissue/cells.
Systemic infection likely to be attributable to the transplanted tissue/cells.
Endophthalmitis or other serious ophthalmic infection likely to be attributable to the transplanted tissue.
Malignancy likely to be attributable to the transplanted tissue.
Systemic infection likely to be attributable to the transplanted tissue.
Graft failure due to donor tissue which was out of date or otherwise damaged.
Vigilance in ocular tissue transplantation in the UK
The National Health Service Blood and Transplant (NHSBT) is a Special Health Authority in the NHS with responsibility for optimising the supply of blood, organs, plasma and tissues and raising the quality, effectiveness and efficiency of blood and transplant services. NHSBT’s responsibilities include: encouraging people to donate organs, blood and tissues; optimising the safety and supply of blood, organs and tissues; helping to raise the quality, effectiveness and clinical outcomes of blood and transplant services.
Organ Donation and Transplantation (ODT), previously known as UK Transplant, is a directorate within NHSBT with responsibility for organ and ocular tissue and cell donation and transplantation administered through the Duty Office.
The Designated Individual at the tissue establishment that supplied the allograft is the person with legal responsibility for ensuring compliance with the EUTCD and for co-ordinating the investigation of a SAER.
The duty officer at ODT. The ODT Duty Officer provides a 24 h service acting as the first point of contact for the notification of organ and eye donors and the registration of patients for organ and ocular tissue and cell transplants. Duty officers also offer organs to hospitals according to NHSBT allocation algorithms and accept requests for ocular tissue. They make the arrangements for moving organs between donor and recipient hospitals and for transporting ocular tissue and cells.
OTAG and the audit sub-group. OTAG is a professional group accountable to ODT and NHSBT. It is responsible for providing advice and guidance to maintain the standards of ocular tissue transplantation in the UK for all ocular tissue donations co-ordinated through the Duty Office. The audit sub-group is responsible for reviewing and auditing SAER and is accountable to OTAG.
The ODT Clinical Governance Monitoring Group (CGMG) is responsible for clinical governance within ODT.
NHSBT Governance and Audit Committee (GAC) is responsible for clinical governance and audit in NHSBT.
The Human Tissue Authority (HTA) is the Competent Authority in the UK for tissues and cells other than reproductive cells which are regulated by the HFEA.
This mechanism for vigilance in ocular tissue transplantation the CTS Eye Banks achieves a national scope by cooperation with other eye banks including the Moorfields Hospital Eye Bank.
The procedure for investigation of an SAER is as follows:
Part A: the initiation of an investigation
The person reporting the event or reaction.
The designated individual at the tissue establishment that supplied the allograft (in this case, the eye bank).
The duty officer at ODT.
The Ocular Tissue Advisory Group and the audit sub-group of the OTAG.
The ODT Clinical Governance Monitoring Group (CGMG).
NHSBT Governance and Audit Committee (GAC).
On recognising a serious event or reaction the responsible clinician telephones the duty officer at ODT.
- 2.The responsible clinician completes part A of the reporting form in triplicate which is sent to the:
Tissue establishment (eye bank),
ODT duty officer,
The recipient patient’s case notes.
At each stage there is cross reporting of events between the duty officer at ODT and the eye bank. This reduces the potential for missed events with multiple parties acting as comparators. For example, ODT confirms that the eye bank has acknowledged and reported the serious adverse occurrence.
Reporting of events that do not involve the transplant centre where the surgery is performed commences at the tissue establishment (in this case the eye bank). The designated individual at the tissue establishment reports the adverse event to the HTA, and reports back to ODT that the HTA has been informed. The designated individual at the tissue establishment is responsible for the investigation. At all stages it is imperative that any other agencies receiving tissue (or organs) from the same donor or where an event or reaction has implications for other tissues, that relevant tissue is quarantined and other tissue establishments that received tissue from the same donor are informed so that they can take immediate action to quarantine tissue whilst the investigation is completed. For example, if ophthalmic tissue from the other eye of the same donor were sent to another recipient, or where there were other tissues from that donor such as bone or heart valves or where, for example, a clean room or processing failure affected another donation, then appropriate warning of relevant clinicians and quarantining within the tissue facility could be undertaken (see Appendix).
Part B: the completion of an investigation
The designated individual at the tissue establishment (eye bank) is responsible for investigating the serious adverse event or reaction and reporting back to the HTA, ODT and to the reporting clinician (transplant surgeon). On completion of the investigation, part B of the reporting form is completed by that designated individual. Copies are again sent to each of the HTA, ODT and the clinician. The clinician files the copy in the patient’s case notes and takes any action deemed necessary locally depending on the outcome of the investigation.
NHS Blood and Transplant (Duty office) informs the OTAG audit group which collates figures and provides a 6 monthly report via OTAG to the Clinical Governance Management Group. It is proposed that advice from this group on the basis of audit figures is fed back to the HTA and to the NHSBT Board. Other agencies receiving relevant tissue or other clinicians who have transplanted relevant tissue may benefit from being informed of the outcome of the final investigation report. As all SAER are reported to the HTA including those involving tissue establishments outside of NHSBT, a decision is awaited on a proposal for the OTAG audit group to provide professional, as against regulatory review all SAER involving ophthalmic tissue reported to the HTA, in order to identify trends or patterns of SAER.
Determining the seriousness of SAER
It can be difficult to determine if an adverse event or reaction is serious. This can sometimes only be decided after completion of the investigation. A system within NHSBT is therefore in place to also allow the reporting and review of adverse incidents. A list of adverse incidents are collated by the tissue establishment (eye bank) with recommendations and then reported to the OTAG. An initial assessment is then made by the OTAG and if necessary after further review by the audit group of OTAG. This determination of the severity of the investigated event or reaction could be standardised by use of the EUSTITE tools and thereby ensure that there was easy comparison with reporting by other agencies within an individual member state and also at the supra-national, i.e. European Union, level.
Key data emerging from the vigilance system
Adverse reactions can be generic risks for any type of tissue, cell or organ transplanted such as transmission of a blood borne virus. Endophthalmitis, however, is a specific site of infection and which can complicate ophthalmic tissue transplantation. Between 1999 and 2006 there were 16,067 corneal transplants registered with UK Transplant (now ODT), of which 14439 (90%) have reported follow-up and of these 85 (0.58%) cases of endophthalmitis were reported. This represented an unchanged incidence on previous years. The risk of endophthalmitis occurring in a previously uninfected and/or un-inflamed eye is considerably less than the risk of developing endophthalmitis in an infected or inflamed eye.
Primary graft failure
Primary graft failure is defined as the corneal graft remaining oedematous or otherwise opaque after surgery and failing to clear. The rate of primary graft failure between 1999 and 2006 was 0.3% of 10167 corneal transplants.
As part of the audit subgroup review of these SAER (reporting system described above and in Fig. 1), factors relating to the development of endophthalmitis and primary graft failure are now the subject of an investigative study. The results of these studies, will then be reported to OTAG and following publication, may potentially lead to changes in practice to reduce the occurrence of these serious reactions.
The mechanisms for reporting of severe adverse events and reactions for ocular tissue in the UK, which have been developed by the OTAG Group, may be useful to other organisations that are considering how to initiate mechanisms for adverse event and reaction reporting. The OTAG scheme, which is described in this paper, has been submitted to the UK Competent Authority, the Human Tissue Authority (HTA), for their consideration. The submission includes the suggestion that the OTAG group undertakes review, audit and trend analysis of all ocular tissue severe adverse event and reaction reporting for the UK, whether the tissue were supplied by a CTS Eye Bank, other eye bank from within the UK, or an eye bank outside the UK. This would provide a professional overview as a supplement to the legislative requirement that all severe adverse events and reactions are reported to the HTA for subsequent annual reporting to the European Commission. Establishment of such a model could be extended to professional groups for other tissues, possibly with an overarching group which would then have the capability of determining SAER across different tissues or indeed organs with common donors, centres etc.
Tools for vigilance and surveillance of human tissue and cells provided for human application have been developed for assessing adverse events and reactions. These tools have been developed by EUSTITE, which is an EU funded project (Fehily et al. 2007www.eustite.org). In addition to the EUSTITE primary objective, to optimise and harmonise standards and methods applied by Competent Authorities in the Inspection and Accreditation of tissue procurement and tissue establishments within the EU, the project has a secondary objective (Fehily et al. 2007). This was to propose common systems for definition, classification and reporting of adverse events and reactions that are consistent with similar systems found elsewhere in the world. The project began by examining existing systems within EU member states and elsewhere. As a partner in the project, the World Health Organisation led the establishment of a vigilance and surveillance medical advisory committee which consulted widely and developed tools and guidance for reporting and management of SAER that were submitted to the European Commission in May 2008 and are available on the EUSTITE website (see earlier). EUSTITE launched a 1 year pilot scheme for adverse event and reaction reporting and management which will finish in June of 2009. Twenty-two Competent Authorities from 20 Member States, including both the HTA and HFEA, are participating in the pilot which will evaluate the feasibility of the proposed tools and guidance and make recommendations to the European Commission for future development of these activities.
The toolbox that was developed includes tools for assessing severity and imputability of adverse reactions, where imputability is an evaluation of the likelihood that the reaction was caused by the tissues or cells transplanted. An impact assessment tool for evaluating the broader systems impact of SAER has also been designed, along with criteria for reporting of adverse events, where no recipient reaction is involved, to the Competent Authority. The tools assist in discriminating between those which require reporting and escalation to the Competent Authority and those which can be handled locally or evaluated only by a professional group. The work is being led by the World Health Organisation to ensure global compatibility and relevance.
Clearly there is a role for both national Competent Authorities and the EUSTITE Project Partnership to focus on types of severe events and reactions that are reportable to Competent Authorities under the Tissue and Cell Directives (2004/23/EC, 2006/17/EC, 2006/86/EC) because they are serious. The success of a vigilance system, however, depends on the active participation of both the clinical users and the tissue establishments in order to detect, report and investigate all types of such events and reactions that might be associated with the application of human tissues and cells. This proposed UK scheme is necessary in order to provide the information that can be analysed in a wider context and collated with reports from other Member States.
Ocular tissue donation and transplantation is an important contributor to saving sight and relieving pain in recipients. The evolution of this surgical speciality has been described from its early history to evolving modern techniques which hold promise for further advances. Ensuring a sufficient supply is critical especially when matching of age or human leucocyte antigen (HLA) tissue types between donors and recipients is needed. No tissue transplantation is entirely free from complications and this paper describes a model for SAER reporting for ocular tissues and cells that has been developed in the UK to ensure compliance with both the EU Tissues and Cells Directive (EUTCD) and is also supplemented by professional peer review of adverse events and reactions in the field of ocular tissue transplantation. These rare occurrences need collation from large numbers of recipients and tissue banks because otherwise public health advantages and clinical governance requirements cannot be met. The EUTCD and the EUSTITE project represent significant advances in standardising approaches to vigilance and surveillance. The movement of tissue between EU Member States is now regulated under a common set of quality and safety standards, with which tissue imported from outside the EU must also comply. Partnership between users and providers of tissues and community participation in provision of grafts are all essential in ensuring the future safety and efficacy of such transplant programmes.
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