Safety reporting in clinical trials
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 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).
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 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 and transitional period
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. This obligation remains in force throughout the trial.
*IMP refers to an active substance in the context of annual safety reporting
During the CTR (Clinical Trials Regulation (EU) 536/2014) transitional period of 31 January 2022 to 31 January 2025, the following shall also be observed:
1. If all the clinical trials with the IMP* are ongoing under the Directive 2001/20/EC, shall annual safety reporting be carried out according to section 10g of the Medical Research Act (as amended in Act 295/2004); the sponsor shall annually submit to Fimea and to the Ethics Committee a list of all suspected serious adverse reactions which have occurred in the trial during the period concerned (or alternatively a DSUR, Development Safety Update Report). At the same time, the sponsor shall submit a brief report on the safety of the subjects participating in the clinical trial. The report shall take into account all the facts relating to the trial, not only the safety of the investigational medicinal product.
The list/DSUR together with the report on the safety shall be submitted to Fimea electronically at FI-CTA (at) fimea.fi. The sponsor shall also inform the investigators and Fimea without delay of any significant new findings concerning the safety of the investigational medicinal product. (Nat. Reg 8/2019)
2. In case even one clinical trial is ongoing in alignment with the CTR while others with the same IMP are ongoing under the Directive 2001/20/EC, an ASR (Annual Safety Report) should be submitted to the CTIS portal as specified in the regulation article 43. (CTR QUESTIONS & ANSWERS version 5; question 7.49). The ASR will then be evaluated in co-operation with EU member states, including Fimea (983/2021 26§) and as specified in the regulation 536/2014 article 44. Commission Implementing Regulation (EU) 2022/20 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 (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.
In this case, sponsors are not obliged to submit the list/DSUR nor the report on the safety to Fimea. However sponsors are still obliged to submit those documents to the Ethics Committees according to national legislation (488/1999 10g §; Act 295/2004) and within the transition period.
3. At the end or during the CTR transitional period, when all the clinical trials with the same IMP have been transitioned, ASRs should be submitted to the CTIS portal as specified in the regulation article 43. In this case, sponsors are not obliged to submit the list/DSUR nor the report on the safety to Fimea or to the Ethics Committees any more.
Regulation 536/2014: Chapter VII, Articles 40–43 and Annex III
EudraLex Vol 10 (particularly Chapter V Q&A – Reg 536/2014, Chapter 7)
Commission Implementing Regulation (EU) 2022/20
EudraVigilance website of the European Medicines Agency
ICH guideline E2B (R3) on electronic transmission of individual case safety reports (ICSRs) - data elements and message specification - implementation guide
ICH guideline E2F on development safety update report
CTIS training module 18: How to create and submit an annual safety report and respond to related requests for information