Safety reporting in clinical trials

Monitoring of adverse events

The investigator shall record and document all adverse events or laboratory abnormalities identified in the protocol as critical to the safety evaluation. An adverse event is a serious adverse event (SAE) when it requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death. A serious adverse event shall be reported to the sponsor not later than within 24 hours of the investigator obtaining knowledge of the event. The sponsor shall keep records of all adverse events reported to it by the investigator.

In the report, the investigator shall comment on whether a causal relationship can be established between the adverse event and the investigational medicinal product* (whether at issue is a case of an adverse reaction to the investigational medicinal product) and whether the adverse event is expected or unexpected (whether the nature orseverity of the adverse event is consistent with the reference safety information).

*In a clinical trial, an investigational medicinal product means both the medicinal product being tested and the medicinal product used as a reference or as a placebo.

Suspected unexpected serious adverse reaction (SUSAR)

The sponsor shall report to the authority any fatal or life-threatening suspected unexpected serious adverse reactions as soon as possible, and in any case not later than seven days after the sponsor became aware of the reaction. Any additions to the report shall be submitted within eight days of the submission of the first report. Any non-life-threatening or non-fatal suspected unexpected serious adverse reactions shall be reported not later than 15 days after the sponsor became aware of the reaction.

The causality assessment given by the investigator shall not be downgraded by the sponsor. If the sponsor disagrees with the investigator's causality assessment, the opinion of both the investigator and the sponsor shall be provided with the report. The treatment allocation of a subject shall be unblinded in the course of a clinical trial only if unblinding is relevant to the safety of the subject.

EudraVigilance

EudraVigilance is a system designed by the European Medicines Agency (EMA), for collecting reports of suspected adverse reactions. These reports are used for evaluating the benefits and risks of medicines during their development and monitoring their safety following their authorisation in the European Economic Area (EEA). Registration with EMA’s EudraVigilance is mandatory for commercial sponsors. Registered sponsors are required to submit the aforementioned reports on adverse reactions electronically to the Clinical Trial Module of the EudraVigilance database (recipient code EVCTMPROD).

Non-commercial trials

In the case of non-commercial trials, where the academic investigator or team of investigators acts as the sponsor of the trial, the sponsor’s responsibilities for adverse reaction reporting mentioned in this section shall also apply to them. If the sponsor is not registered with EudraVigilance, the suspected unexpected serious adverse reactions that occurred in Finland shall be reported by secure e-mail (Eudralink or Fimea’s secure mail service) to FI-CTA (at) fimea.fi. Fimea will then transfer the information to EudraVigilance on the investigator's behalf.

The details of the adverse reaction can be submitted in free form using the CIOMS-I form (pdf) or equivalent. However, at least the following information must be included in the report:

a valid EU trial number (EudraCT number or the number assigned by the EU CTIS system* or both);
a sponsor study number (protocol number) ;
an identifiable coded subject (age and the trial code identifying the subject);
an identifiable reporter (investigator’s contact details);
a suspected unexcepted serious adverse reaction, its start and potential end date or the subject’s date of death;
a suspect investigational medicinal product and the name of the active substance;
a causality assessment ;
the receive date of the initial information from the primary source

* The Clinical Trial Information System (CTIS) is a portal and database maintained by the European Medicines Agency where clinical trial applications are processed as of 31 January 2022 by the authorities and ethics committees of the various Member States.

Annual reporting

The sponsor shall submit annually a report on the safety of each investigational medicinal product (IMP*) used in a clinical trial for which it is the sponsor. In non-commercial trials, the sponsor (the investigator or the academic group) may submit a single safety report on all investigational medicinal products used in the trial (see “Simplified ASR” below). This obligation remains in force throughout the trial.

*IMP refers to an active substance in the context of annual safety reporting

The transition period defined in Regulation (EU) 536/2014 has ended on 30 January 2025. For clinical trials approved in accordance with Directive 2001/20/EC, the annual reporting obligation to Fimea under the Medical Research Act has been in force as long as the study has been ongoing in Finland.

For clinical trials ongoing in alignment with the CTR, an ASR (Annual Safety Report) should be submitted to the CTIS portal as specified in the regulation article 43. The ASR will then be evaluated in co-operation with EU member states, including Fimea (983/2021 26§ (Finlex)) and as specified in the regulation 536/2014 article 44. Commission Implementing Regulation (EU) 2022/20 (pdf) is specifiying the rules and procedures for the cooperation of the Member States in safety assessment of clinical trials. Any issues or requests related to the safety of the trials will be processed within the CTIS-portal.

The ASR shall be compiled in accordance with the CTR Q&A section 7d and the ICH E2F (pdf) (especially the section 3.5 requirement to list all member states with either ongoing or ended clinical trials for that IMP in question should be noted). According to Article 43 of the CTR, an ASR is required for all IMPs (ie. tested or used as a refence) other than placebos.

The obligation for annual safety reporting ends with end of the last clinical trial conducted by the sponsor with the investigational medicinal product.

Simplified ASR (Annual Safety Report)

Simplified ASR template is for non-commercial sponsors conducting a single clinical trial on IMPs with a marketing authorisation in any of the EU/EEA member states and where SmPCs are used as RSIs.
Any sponsor submitting a simplified ASR must still comply with the overall objective of the ASR, which is to present a comprehensive, thoughtful annual review and evaluation of pertinent safety information collected during the reporting period. The focus should be on new safety findings that could have an impact on the overall benefit-risk ratio of the clinical trial and the assessment of these findings. In addition, data analyses may require or have had required risk minimisation measures, which should be addressed in simplified ASRs, too. Non-commercial sponsors investigating an IMP without a marketing authorisation, conducting several trials on the same IMP or not using the SmPC as RSI are still expected to submit a regular ASR in accordance with ICH E2F.

ASR should always be written in English.