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.

All serious adverse events shall be reported in the annual safety report as a cumulative summary from the beginning of the trial.

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.

The sponsor must be aware that authorities may ask a question at any time via the CTIS portal if additional information about a SUSAR (Suspected Unexpected Serious Adverse Reaction) is requested or measures are required as a result. Therefore, the sponsor shall monitor the CTIS portal also during periods when no significant change is taking place if SUSARs have been reported to the EudraVigilance system.

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 (ASR, Annual Safety Report)

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.

EU-level guidance for annual reporting is available in the EU Commission’s Questions and Answers (pdf) compiled by the European Commission.
The Clinical Trials Coordination Group (CTCG) has prepared a Q&A guidance document on safety reporting (ASRs, Annual Safety Reports), unexpected events that change the benefit-risk balance of the trial, and the resulting urgent safety measures over the course of the trial. The Q&A also describes how changes to the reference safety information are handled. CTCG’s Question and Answers on safety related issues in amendment of the Commission’s QnA section 7 on safety, Eudralex Vol 10 (www.hma.eu, pdf)

Simplified ASR (Annual Safety Report), Non-commercial sponsors

Non-commercial sponsors conducting a single clinical trial using medicinal products with a marketing authorisation in any EU/EEA Member State and where summaries of product characteristics are used as RSI (Reference Safety Information) may submit a simplified annual safety report to Fimea. The annual safety report can include all the substances being investigated, and it is trial-specific.

The annual safety report shall include a benefit-risk evaluation and a conclusion on safety based on all SAE (Serious Adverse Event) and SAR (Serious Adverse Reaction) cases observed during the reporting period, as well as a list of the observed SAR cases.

When the trial is only being conducted in Finland, a report template (pdf) for mononational trials can be used.

When the trial is being conducted in several countries (multinational), even if only products with marketing authorisation are used, the Simplified ASR (Annual Safety Report) template prepared by the CTCG (Clinical Trial Coordination Group) shall be used. Please note that it may not be possible to fill in all the sections for non-commercial trials. These sections shall be marked “not applicable” or equivalent.

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.

The trial-specific annual safety report submitted by a non-commercial sponsor is evaluated by the RMS (Reporting Member State) responsible for evaluation of the trial. In the case of a trial conducted only in Finland, the RMS is always Finland.

Submitting an annual safety report in the CTIS system

Detailed instructions for submitting an ASR are available on the EMA website: Clinical Trial Information System (CTIS) user guidance on the sponsor’s
workspace, CTIS Handbook for clinical trial sponsors.

The authority may present questions related to the annual safety report, in which case an RFI (Request for Information) is submitted to the CTIS system. A response to the RFI shall be provided by the deadline. Separate information about an RFI is not sent outside the CTIS system to the party that submitted the ASR, and therefore the sponsor must monitor the system for this.

Fees

Fimea sends an invoice for evaluation of the annual safety report submitted by a commercial sponsor when the active substance in the trial medication is within the scope of Finland’s saMS (safety assessment Member State) duties.

When the sponsor does not receive external funding for their trial (non-commercial sponsors, investigator-initiated trials), Fimea does not charge a fee for assessing the annual safety report. In this case, the ASR shall be accompanied by an application for exemption from payment stating that the sponsor is non-commercial and does not receive external funding. If necessary, Fimea will ask an additional question about this before the actual evaluation has been completed. A response to this must be provided by the deadline and the actual evaluation questions monitored separately.