Safety reporting | The Central Committee on Research Involving Human Subjects

During the trial, adverse events, such as potential side effects, may occur in trial participants. Adverse events must be recorded and documented. Depending on the seriousness of the adverse event, it must also be reported.

The sponsor of the study is required to report Suspected Unexpected Serious Adverse Reactions (SUSARs) on an expedited basis in EudraVigilance. Furthermore, an annual safety report (ASR) must be submitted to CTIS. The ASR contains an aggregated analysis of all safety information and includes all serious adverse events (SAEs), including all serious adverse reactions that occurred. In addition, additional obligations regarding the safety of the study participants apply. In some situations, for example, it may be necessary to take urgent safety measures (see Notifications).
The flowchart below provides an overview of the recording and reporting obligations for (serious) adverse events.

The process starts with the reporting of an adverse event by the participant, research nurse, participant's partner, etcetera to the investigator or by the investigator identifying an adverse event. Subsequently, the investigator records and documents the event, unless the protocol provides otherwise. Next, the seriousness of the event needs to be assessed.. If the event is not serious then it concerns an adverse event (AE). The investigator reports adverse events in line with the protocol to the sponsor (for example, via a Case Report Form (abbreviated CRF)). If the event is serious then it concerns a serious adverse event (abbreviated SAE). The investigator must report the event to the sponsor without undue delay but no later than 24 hours after becoming aware of it, including an assessment of the relationship and seriousness, unless the protocol specifies that for certain serious adverse events no immediate reporting is required. Subsequently, it should be determined whether there is a possible causal relationship with the investigational medicinal product. If the serious event is not considered related to the investigational medicinal product then it concerns a serious adverse event (abbreviated SAE). The sponsor must include all serious adverse events in an aggregated summary table in the annual safety report in CTIS. If the serious event is considered related to the investigational medicinal product then it should be assessed whether it concerns an unexpected event based on the Reference Safety Information (abbreviated RSI). If the serious event is not considered unexpected but expected based on the RSI then it concerns a Serious Adverse Reaction (abbreviated SAR). The sponsor lists all serious adverse reactions in the annual safety report in CTIS If the serious event is considered unexpected then it concerns a SUSAR (Suspected Unexpected Serious Adverse Reaction). The sponsor reports the SUSAR expeditely to EudraVigilance and the sponsor includes all SUSARs in the annual safety report in CTIS. Overall, the sponsor maintains a register of all adverse events (AEs, SAEs, SARs, and SUSARs).

Definitions

AE (Adverse Event): any untoward medical occurrence in a participant to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment.

SAE (Serious Adverse Event): any untoward medical occurrence in a patient or trial participant that regardless of the dose, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is life-threatening, results in death, or is considered serious based on medical evaluation.

SAR (Serious Adverse Reaction): a serious adverse reaction of which the nature, severity or outcome of the adverse reaction are consistent with the approved reference safety information (RSI).

SUSAR (Suspected Unexpected Serious Adverse Reaction): a serious adverse reaction of which the nature, severity or outcome of the adverse reaction are not consistent with the approved reference safety information (RSI).

The investigator must record and document all adverse events and reports all SAE to the sponsor, unless the protocol provides otherwise. SAEs must be reported to the sponsor without undue delay but no later than 24 hours of obtaining knowledge of the events unless the protocol specifies that immediate reporting is not required for certain SAEs.

Individual SAEs, with the exception of SUSARs (see SUSARs), but including SARs, do not need to be reported to CTIS or Eudravigilance. The sponsor includes an aggregated summary table of all SAEs in the Annual Safety Report (ASR) which should be submitted in CTIS. All SUSARs of the investigational medicinal product or related to the same active substance in a study by the same or a different sponsor (part of the same parent company or with whom the sponsor collaborates in the development of a medicinal product) must be reported electronically to Eudravigilance by the sponsor (or by another party based on a formal agreement with the sponsor of the study).

Auxiliary medicinal products

Safety reporting with regard to authorised AxMPs shall be made in accordance with Title IX of Directive 2001/83/EC. Related events should be reported to EudraVigilance (post marketing module) either via the marketing authorisation holder or via the national reporting system (Lareb for The Netherlands).

For non-authorised AxMPs, the same requirements as those provided for the IMP in the CTR should be applied with regard to the obligations of the investigators and the sponsors for the collection, recording, management and reporting of adverse events (see recommendations on auxiliary medicinal products in clinical trials). SUSARs related to non-authorised AxMPs must be reported in EudraVigilance (clinical trial module).