3. Biovigilance

System is organized at national level. Due to law all medical providers must report SARE to National transplant organization.

National: 24/7 reactivity on the level of Slovenija transplant, reporting to and from donor and transplant centres, collecting data, investigation of cases, preparing corrective measures to increase quality and safety for patients in cooperation with clinicians, issuing annual reports,

Polish legal regulations are adapted to Directive. The regulations define SARE and the procedures by which SARE should be monitored (in organ donation, procurement, testing, preservation, distribution, and transplantation), impose registration requirements on donation and transplant centres and require reporting of SARE with detailed information describing events or reactions as well as the procedures enacted to resolve and prevent future problems. Poltransplant is the authority that refers and manages the data on SARE related to organ transplantation in web-netted tool. The National Transplantation Council appointed by the Minister of Health analyses the aggregate data on SAREs to evaluate its effect on the quality and safety of the transplantation system and submits proposals for improving the quality of the current system.

First alert sent by Eurotransplant; final report by Dutch Transplant Foundation for Dutch donors

An ad-hoc reporting function has been developed in the national transplant info system, where hospitals can report to Clinical Risk Manager and Regional Transplant Centre. A national protocol has been adopted for the purpose of reporting and managing adverse events and reactions.

The CA function is delegated through Department of Health to Organ Donation Transplant Ireland (Clinical) Health Product regulatory authority (Non-Clinical). Dual reporting to which then determine clinical/non-clinical status. Clinical reports are managed through the National Organ Donation Transplantation Advisory Group which oversees investigations, corrective/preventative actions and continuous improvement measures agreed.

Nationally and internationally as well in cooperation with Eurotransplant

There is another system for alerts. It is a 24/24 system managed by ABM (at CA level) in charge of allocation of the procured organs. There are operational links between vigilance system and alert system since an alert can lead to a vigilance notification (e.g., following a bacterial or viral contamination of the graft, following tumour identified on the graft). The purpose of both systems is complementary, one (ALERT) gives information to the clinician in charge of the recipients to help them quickly adapt the recipient care, second (VIGILANCE) is to improve the system (process, organization, etc.) and avoid recurrence of deleterious events.

In 2016, the Agence de la Biomédecine became the CA for Organs vigilance. The system is a national one: the CA coordinates vigilance organization at national level, develops tools, provides help for SAREs investigations, publishes an annual report, organizes training… Locally, there are local biovigilance coordinators (MD or a nurse under the responsibility of a MD) located in each health establishment in charge of organs procurement and transplantation. These vigilance coordinators must collect and notify to the CA, SAREs that occur along the chain from the selection of donors to the follow-up of the recipients. They are implicated in the investigations and whenever possible in the management of correctives measures.

FIMEA receives national SARE-reports from organ transplantation centre (Helsinki University Hospital) and all Scandinavian SARE-reports from Scandiatransplant.

The system is organized at three levels, as a mirror of the transplantation system and the healthcare system in the country. Cases appear at the hospital level but are transmitted bottom up for analysis and evaluation at the regional / national level, depending on the geographical and administrative distribution of the cases affected (whether it is within a particular region or affects several regions). The immediate measures are taken at hospital level and reported. The measures are agreed upon by the affected levels. The follow up contacts are made as per a national protocol agreed upon by all regions. A final report of every case is delivered. The system is advised by a committee of experts.

For organs, which are sent to other countries notification system was established by Scandiatransplant, so all transplant centres and competent authorities receive the first notification at the same time. Further communication and investigation depend on the countries involved.

All the SARE reports and final investigation reports are sent to State Agency of Medicines, where they are assessed and registered. Relevant information that may influence the quality and safety of organs is exchanged between transplant centres. All this must be covered with handler's biovigilance system. This is a national system and requirements are outlined in the law.

The SARE reporting are handled through the Scandiatransplant systems and reported to centres and CAs

The German organ procurement organization (Deutsche Stiftung Organtransplantation (DSO)) in close cooperation with Eurotransplant is responsible at the national level for reporting, investigating, documenting, and transmitting relevant and necessary information concerning serious adverse events and serious adverse reactions that may influence the quality and safety of organs in accordance with para.9 and para. 10 of the Regulation on the Quality and Safety of Organs under the Transplant Act. In case of cross-border organ exchange all centres from the different countries that received an organ are involved. The initial and final report is provided by the Competent Authority / Delegated Body of the respective donor country.

Every establishment (procurement organizations or transplantation centres), that has license to work in the field of transplantation of organs, tissues and cells has the obligation to report if a serious adverse reaction (SAR) or incident (SAE) occurs. All establishments send reports to the Medical Supervision Executive Agency, which is the competent authority in the field of organ, tissue and cell transplantation and assisted reproduction for Bulgaria. The Agency shall register, investigate, and inspect each individual case of SAR or SAE. If other Member States are involved, this case is reported through the RATC system (Rapid Alert Tissues Cells). Our system is organized at a national level.

The implementation works in line with the legal framework, between EOEO (Eurotransplant), the Competent Authority and the transplantation centres.

7.1 Please briefly outline how your reporting system works in practice. Please explain at what level the system is organised (e.g., EOEO, regional, or other):

7. Were there any changes to the reporting system for information concerning SARE since the last report?

National transplant organization is working at 24/365 basis. In case of SARE the duty office can connect every procurement and transplant centre. Also is in connection with transplant coordinators. Management goes on in close coordination with relevant medical and other actors.

Usually, Slovenija transplant is receiving first info. Based on the nature of case or situation the first report is sent to the target centre in Slovenia or to Eurotransplant. The collection of data is starting in cooperation with clinicians. If the situation is not urgent then we are collecting data and preparing final report in due time. If the situation is urgent, we send alarm to target centres and Eurotransplant to stop using organs, send to pathology and based on the results prepare the report. Our communication with all involved experts and centres is made on the non-blaming principle and we try to be precise and correct as much as it is possible.

Notified in the digital platform (Biovigilância), with a specific codex, to be analysed and validated by the competent authority.

As it is described in 7,1

We have only one procurement organization - P. Stradin's University Hospital, National Transplant Coordination Department, which manages all reports and SARE investigations. P. Stradin's University Hospital is also delegated body for tasks regarding Article 5,6, 7 of Directive 2012/25/EU including SARE reports) and acts as a 24/7 contact-point required by Directive 2012/25/EU (http://www.txcontactlist.eu/index.php?action=details&id=lv). In order to provide information also for State Agency of medicines (SAM) as the competent authority in the field of organ transplantation as per Directive 2010/53/EU Article 17, SAM maintains online SARE reporting (Annex I, and II of Directive 2012/25/EU; bilingual - Latvian, English) tool with possibility to download report in PDF after submitting and subsequently to send it to other transplant centres and procurement organizations in case of organ exchanges (https://dati.zva.gov.lv/biovg/?&t=org-bn-s and https://dati.zva.gov.lv/biovg/?&t=org-bn-f ).

carry out an investigation and notify the competent authority with reasons of SARE and conclusion.

If SARE happens, centre must inform competent authority and institution which took, distributed, or received organ, tissue, or cells without any delay. After that, centre should

All adverse events/reactions should be reported and classified in terms of seriousness/likelihood of recurrence. Actions by regional and national CAs are requested on the basis of higher scores. A panel of 6 experts at national level revises the self-evaluated scores and takes decisions about remedial action and audits (if necessary).

Currently notification is through the National Organ Donation Transplant Advisory Group and local centre procedures. The biovigilance system is currently undergoing review. Objective to further align with latest guidance and best practice.

All identified SAE/R cases are reported to the HNBTS, which investigate all cases, prepare reports that are sent to the Ministry of Human Capacities

Rapid alert from donor or transplant centres to NCA and Eurotransplant

Since 2021, CA organises training on vigilance for the LBCs. We also published a guide to help them in their biovigilance tasks.

Each LBC needs to provide an annual report summarizing relevant corrective measures implemented in their establishment.

In the application, the LBC can assess imputability and severity for SAR. For the SAE, the LBC can detail the steps where the SAE occurred and mention possible causes.

In the IT system, the local biovigilance coordinator (LBC) describes SAR or SAE. The CA can identify the donor or the recipient and can access us with additional information (like medical history) through living donors registry, deceased donors’ registry, or recipients’ registry. The application informs the concerned procurement or transplant centre that can follow each step of the investigation.

ABM’s IT application centralizes SAREs notifications and allows national analysis and publishes annual national vigilance report

Organ donation hospitals report all events to organ transplantation centre (Helsinki University Hospital). Organ transplantation centre reports all SARE to FIMEA (CA). Operating procedures for the notification are inspected regularly during official inspection.

The answer considers notifications bottom up, and top down. The donor transplant coordinator detects a possible case and makes an initial notification triggering the system. Initial measures are decided by the hospital and notified bottom up. Those include a notification to the centres possibly affected and to the Tissues and cells system. The biovigilance contact person fills up a predesigned form. After the analysis of the case at an upper level, the measures to be taken are decided, agreed upon, notified top down, and then carried out. The case is supervised and followed up as per a national protocol. A final report is made and issued to all the centres affected.

Direct and immediate reporting to any involved professional and authority

Urgent: E-mail is sent to CAs and E-mail + SMS is sent to all transplant coordinators at time of reporting

Non-urgent: E-mail is sent out the day after reporting at 10.00 to CAs and transplant coordinators

All the transplant centres in the Scandiatransplant area are in direct contact with each other 24/7 by phone, e-mail etc. as follows:

The DSO has – based on the German Transplant Act – issued guidelines for the reporting of SAEs and SARs by donor hospitals, laboratories/pathologies, and transplant centres to the DSO. After the initial reporting the DSO takes care of the work-up of the cases as described und 7.1

SARE have been implemented into Czech legislation through Regulation No. 111/2013 Coll. (on setting requirements for working procedures to ensure the system of quality and safety of human organs intended for transplantation) as of April 30, 2013. SARE has been implemented into practical procedure of reporting serious details of an adverse reactions/effects (SARE) on the special forms - reporting measures taken in respect of the incident. Both forms have been distributed to individual transplant centres, the centres were instructed how to report, and filled-in reports are being regularly checked by KST. Apart from that, empty forms are easily accessible on the website of KST. The Ministry of Health is informed about the most serious events.

In Bulgaria we have published normative acts in which it is defined in which case it is reported, there are published serious adverse reaction or event (SAR/E) forms, there are certain responsible persons who are responsible for reporting, deadlines and the sequence of actions are determined.

Each SARE coming in from Eurotransplant is discussed in a national workgroup

Additionally, there is an exchange of information in case of involvement of tissue procurement.

Notification of SARE must be done immediately with the report of the EOEO (Eurotransplant) and within three working days to the delegated body.

8.2 Please explain how this notification system works in practice:

8.1 Do you have operating procedures in place for the notification, in due time, of the management measures with regards to SARE to the Competent Authority?

8. Do you have operating procedures in place for the notification, in due time, of any SARE to the Competent Authorities and to the concerned procurement organisation or transplantation centre?

National transplant organization has the register of deceased and living donors of tissue and can connect the TE and transfer information and manage the SARE.

We have a common 24/7 on-call team for organs and tissues and cells vigilance system. In this way, the system is very rational and practical. For Slovenia is only realistic to organize a common system in order to cover requirements for being vigilant and able to react in all urgent cases.

Tissue donation from organ donors is coordinated by the same institution (Poltransplant). Info on SARE in organs are referred to Poltransplant and via this institution to tissue entities - and vice versa.

It is managed by the same biovigilance officers in SAM.

Same procedure of reporting SARE between organs and tissues and cells

A flow chart has been developed to ensure proper notification between different involved actors.

The Competent Authority in charge of both notification systems is the same.

There is an arrangement between both functions which will be further developed as a result of service review.

As many of organ donors are also tissue donors, we involve all tissue establishments, if they procured tissue

Agence de la Biomédecine is the CA for organs, tissues and cells, and the same biovigilance tool is used in all those fields.

All SARE (organ/tissue) reports are reviewed by same authority (same register) and same official.

The CA is the same, so, as soon as a case is reported, possible affected T&C recipients or tissue establishments are identified and notified as well as organ transplantation centres.

It's the same reporting system with the principal requirements outlined in the law. If SARE that may affect organs is found by tissue handlers, organ transplantation centre is also notified.

There is not an "automated electronic" link. Relevant information will be passed through phone or mail (see above).

According to para 40 subsection 3 of the Drug and Active Ingredient Manufacturing Regulation the tissue establishments are obliged to report SAE/SAR to the DSO, in case the tissue or cell donor had also donated organs. Respectively the DSO is obliged according to para. 9 subsection 3 of the Regulation on the Quality and Safety of Organs under the Transplant Act to report SAE/SAR to the tissue establishment in case the organ donor had also donated tissues or cells. For this purpose, a designated system has been established to allow a reliable linkage between the organ procurement organization and the different tissue banks in case a donor donated both organs and tissues or cells.

All establishments (procurement organizations or transplantation centres) send reports to the Medical Supervision Executive Agency, which is the competent authority in the field of organ, tissue and cell transplantation and assisted reproduction for Bulgaria. The Agency is one institution (Competent Authority) for organs, tissues and cells and there is no need to make a connection between them. We don’t have connection with Blood sector.

The information exchange is between the delegated body organs and tissue vigilance and is done by email.

Please specify how this interconnection is organised:

9. Is an interconnection in place between the reporting system for organ transplantation of Directive 2010/53/EU and the notification system established for the transplantation of tissues and cells in accordance with Article 11(1) of Directive 2004/23/EC?

10. Please describe the procedure for you to contact competent authorities/delegated bodies of other Member States in case of a related SARE within your country that might affect other Member States: 10.1 Please describe the procedure for you to be contacted by competent authorities/delegated bodies from other Member State(s) in case of a related SARE within the other Member State(s) that might affect your Member State:

AT The information exchange is done via EOEO (Eurotransplant). The information exchange is done via EOEO (Eurotransplant).

BE The transplantation/donor centre informs Eurotransplant which in turn the other centre or country Eurotransplant inform me which SARE from which country and I send the information to the transplant/donor centre

BG The Medical Supervision Executive Agency will report by the RATC system (Rapid Alert Tissues Cells). The Agency is going to create a new signal to the other affected Member States. When we receive a signal through the RATC system that includes our country, we register it, analyse it, investigate it, and take action, if necessary, in each case.

CY Communication between Cyprus MOH and the Competent Authority of the other member state regarding SARE

CZ NA

DE s. 7.1 – The key element guaranteeing the information and involvement of the CAs of all countries that either donated or received an organ in case of an SAE/SAR is the international organ allocation office Eurotransplant (Leiden/The Netherlands) Eurotransplant is responsible for the allocation of the organs and the documentation of all parties involved, allowing full linkage between donor and recipient. The individual donor country is responsible for the work-up of the case. Eurotransplant facilitates the process, so that the DBs/CAs of all countries are involved. The procedure is regulated in para. 10 of the Regulation on the Quality and Safety of Organs under the Transplant Act. s. 7.1

DK This is rarely - if ever - needed because the transplant centres in the Scandiatransplant area have well established procedures for such events. If needed the CAs can contact each other individually by phone or mail. Ensure that the relevant transplant centre is also informed in a relevant manner.

EE For organs, which are sent to other countries notification system was established by Scandiatransplant, so all transplantation centres and competent authorities receive the first notification at the same time. Further communication and investigation depend on the countries involved. Competent authorities/delegated bodies from other Member States will be contacted if there is a need for it. The decision to contact other Member States is based on the information in the initial report.

EL E-mail E-mail

ES It is established that the CA of other MS are notified, and any information transmitted as for a national centre. The procedure stated in Directive 2012/25/EU is fulfilled. Whenever an organ from a donor in Spain is transplanted abroad (EU MS) and a case of vigilance might affect this case, the biovigilance team at the ONT notifies the case to the corresponding competent authority. Updates of the situation as per protocol are communicated to the CA of the other MS. The other CA is also asked actively for information for a comprehensive analysis of the case. The final report is transmitted to the CA of the MS transplanting the organ. According to a national protocol, It is established that MS different from Portugal should contact and inform OCATT and this one informs ONT as NCA. Portugal must contact directly ONT as NCA to exchange information. ONT issues the information to the regions / hospitals, except Catalonia, which is informed by OCATT.

FI FIMEA informs Scandiatransplant which organize all organ exchange between Finland, Denmark, Sweden, Norway, Iceland, and Estonia. FIMEA receives all SARE reports from Scandiatransplant.

FR We have no specific procedure regarding vigilance information that must be shared with other competent authorities. The majority of organs are collected and transplanted in France. If needed, we contact directly known colleagues in the country concerned. It was the case notably during the COVID-19 pandemic crisis. A system like RATC/RAB might be a useful tool for information sharing between competent authorities regarding alert and vigilance events in the field of organs. It might be the same informal circuit described in the question 10.

HR Rapid alert from our donor or transplant centres to Eurotransplant Also, rapid alert from Eurotransplant through SARE national contact person who immediately reports our donor or transplant centres

HU It is always centrally managed by Eurotransplant. All initial and final reports are sent to them. It is also managed centrally via Eurotransplant

IE When an organ has a SARE reported, ODTI reports this out to the impacted transplant centres for immediate action. When further action is deemed necessary it is reported to the relevant competent authority in conjunction with the recipient centre. Reverse of 10 above.

IT The list of Competent Authorities for SARE linked to organs, available at http://txcontactlist.eu/, allows to alert other CA, that could be affected by a SARE within our country. The contacts of Italian National Transplant centre are available at http://txcontactlist.eu/

LT Other Member states about related SARE would be informed directly by phone and email Other Member states about related SARE would inform us directly by phone and email

LV http://www.txcontactlist.eu/index.php?action=details&id=lv RATC/RAB bilateral inquiry. http://www.txcontactlist.eu/index.php?action=details&id=lv RATC/RAB bilateral inquiry.

NL SAER alert is sent to Eurotransplant; Eurotransplant send the first alert SAER to each transplant centre that received an organ see 10

PL Phone and/or mail. The list of competent authorities is accessible on Poltransplant pages: https://ec.europa.eu/health/system/files/2020-02/competentauthorities_organs_en_0.pdf Phone and/or mail to Poltransplant coordinating office working 24/7

PT Portugal has an organ exchange agreement with a member state (Spain). This agreement follows Directive 2012/25/EU of October 9th, 2012, regarding information procedures for the exchange of organs including the report of serious adverse events and reactions. These procedures are also applied to the crossover kidney donation under the South Alliance for Transplantation (SAT). 1) Through ONT. 2)

SE - -

SI Notification goes via Eurotransplant, which is in charge to inform target country or countries. All next steps go as on the national level in all directions and with cooperation between responsible clinicians via competent authorities and Eurotransplant. The circulation of info goes in the same way if Slovenian patients are affected, or our country is only in the position to transfer info and data of the case. Sometimes we have just to check our patients if the results are ok and at the end, we distribute the results.