Safety Reporting – Adverse Events
This page provides answers to common or important questions about safety reporting in clinical trials on medicinal products for human use, with a focus on adverse events. If you do not find here an answer to your question, we kindly ask you to consult other relevant sources before contacting us, in particular EudraLex – Volume 10.
How to report SUSARs from clinical trials not falling within the scope of Regulation (EU) No 536/2014 but within the scope of the German Medicinal Products Act (Arzneimittelgesetz) in the version in force on 26 January 2022 (corresponding to Directive 2001/20/EC)?
As communicated in the sponsor handbook on the Clinical Trials Information System (EMA/923413/2022 – v. 3.01, 20 December 2022, section 9.1), SUSARs should be reported to the EudraVigilance database only, even if they occurred in clinical trials falling within the scope of the German Medicinal Products Act (Arzneimittelgesetz) and the German GCP Ordinance (GCP-Verordnung) in the versions in force on 26 January 2022 (corresponding to Directive 2001/20/EC). The notification obligations towards the higher federal authorities according to section 13(2) and (3) of the GCP Ordinance in the version in force on 26 January 2022 are also considered fulfilled in case of indirect notification. We kindly ask you to refrain from reporting SUSARs to the receiver ID of the respective higher federal authority.
The notification obligations towards the other bodies mentioned in section 13(2) and (3) of the German GCP Ordinance, i.e., the competent ethics committee, the competent authorities of other member states of the European Union and other contracting states to the Agreement on the European Economic Area in whose territory the clinical trial is conducted, as well as the investigators involved in the clinical trial, remain unaffected by this.
How to report SUSARs from compassionate use programmes?
In contrast to SUSARs from clinical trials, SUSARs from compassionate use programmes must be reported to the competent higher federal authority according to section 6(6)(1) of the German Ordinance on Medicinal Products for Compassionate Use (Arzneimittel-Härtefall-Verordnung, AMHV). Notification of these suspected cases should be made to the EMA's EudraVigilance database; upon notification to the EudraVigilance database, the obligation to notify the BfArM pursuant to Section 6 (1) AMHV is deemed to have been fulfilled.
How to report SUSARs in case of a failure of the EudraVigilance database or other technical issues?
Generally, in case of a system failure or other technical issues, SUSARs can be reported via the joint portal for reporting adverse reactions by healthcare professionals of the BfArM and the PEI after prior consultation with the BfArM. However, the sponsor must make up electronic reporting via the EudraVigilance database immediately as soon as the technical issues have been solved.
What to do in case of missing acknowledgment (ACK) for a SUSAR report?
The EMA is responsible for ACK transmission and this can take up to 48 hours. Before inquiring the status of ACK, please wait at least three working days. The sender should also check whether a “Message Disposition Notification” (MDN) is available, which is automatically generated by the EudraVigilance database. If the MDN is missing, it can be assumed that the SUSAR report was not transmitted. In such cases, the EMA should be contacted directly.
Further information on the EudraVigilance database can be found on the EMA web page: https://www.ema.europa.eu/en/human-regulatory/research-development/pharmacovigilance/eudravigilance.
Which scale should be used to determine a causal relationship between an event and an investigational medicinal product?
We recommend the use of a binary scale that only distinguishes between “related” and “not related”. See also: Council for International Organisation of Medical Sciences (CIOMS): Management of Safety Information from Clinical Trials: Report of CIOMS Working Group VI. Geneva, 2005.
How long shall adverse events be recorded, documented and reported to the sponsor?
According to article 41(2) of Regulation (EU) No 536/2014, investigators shall record and document all adverse events and report all serious adverse events to the sponsor, unless the protocol provides differently. The start and end time for documentation and reporting of adverse events should be specified in the protocol, taking into account, among other factors, the elimination half-life and the duration of action including any late effects of the medicinal products. Further details can be found in the ICH guidelines E19 and M11 (the latter not yet in force at the time of updating the FAQ). After the end time specified in the protocol, investigators do not need to actively monitor subjects for adverse events (section 1 of annex III of Regulation (EU) No 536/2014) and shall only report serious adverse events with a suspected causal relationship to an investigational medicinal product (article 41(4) of Regulation (EU) No 536/2014).
According to section B.11 of annex I of Regulation (EU) No 536/2014, the cover letter shall indicate where to find the reference safety information (RSI) in the application dossier. Should reference be made to a specific version of the investigator’s brochure (IB) or summary of product characteristics (SmPC) or to the version valid at the time of SUSAR reporting?
Reference should not be made to a specific version of the IB or SmPC, but to the most recently approved version at the time of SUSAR reporting, so the information remains valid even in case of subsequent amendments to the IB or SmPC. If, in contrast, reference is made in the application dossier – in the cover letter or, as some sponsors do, also in the protocol – to a specific version of the IB or SmPC, an amendment to the IB or SmPC also requires corresponding information in the cover letter (section B.3.d of annex II of Regulation (EU) No 536/2014) and/or a corresponding amendment to the protocol.