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(Serious) adverse events and SUSARs

SAEs

SAEs include all serious events independent of whether they have a suspected causal relationship to the investigational medicinal product (IMP) or not.

The investigator shall record and document all adverse events and report all SAEs to the sponsor, unless the protocol provides differently. The reporting of  SAEs to the sponsor has to be done without undue delay but not later than within 24 hours of obtaining knowledge of the events, unless, for certain SAEs, the protocol provides that no immediate reporting is required.

Individual SAEs, except for SUSARs (refer to SUSARs) do not need to be reported in CTIS or Eudravigilance. The sponsor includes an aggregated table with all SAEs in the Annual Safety Report (ASR) which should be submitted in CTIS.

SUSARs

A SUSAR is a serious adverse reaction (SAR) of which, the nature, severity or outcome is not consistent with the reference safety information (RSI).

All SUSARs to investigational medicinal products or related to the same active substance occurring in a clinical trial from the same sponsor or another sponsor (part of the same parent company or joint development of medicinal product), should be reported electronically through Eudravigilance by the sponsor or another party on basis of a formal agreement with the sponsor of the trial.

SUSAR reporting in Eudravigilance

In principle, the sponsor of the study is responsible for reporting SUSARs in Eudravigilance. The sponsor needs to register with Eudravigilance. More information on the steps to be followed, can be found in the document Registration Eudravigilance.

When the sponsor does not have the means, the sponsor can request a waiver from the CCMO. The request should minimally contain a clear motivation, the expected number of SUSARs, the study synopsis and the Reference Safety Information (RSI). It can be sent to ctr@ccmo.nl referencing "waiver SUSAR reporting in Eudravigilance". The CCMO will then evaluate if the waiver can be granted. If the waiver is granted, the sponsor should report SUSARs to the CCMO by using the specific SUSAR reporting form. Instructions will be sent upon granting the waiver. Attention: waivers are only granted for a specific study with an authorized product and only for SUSARs which occurred in subjects on Dutch territory. For a multinational study, the competent authorities of the other concerned Member States should also be contacted to ask if they have the possibility for a waiver.

CCMO will no longer provide the above services at the end of the transition period. This means that from 30 January 2025, exemptions can no longer be applied for and granted exemptions will expire.

Reporting period SUSARs

The period for reporting SUSARs by the sponsor to Eudravigilance is:

  • Fatal or life-threatening SUSARs as soon as possible but no later than 7 days after the sponsor become aware of the reaction. The sponsor shall submit a completed report within an additional eight days.
  • Non-fatal or non-life threatening SUSARs as soon as possible but no later than 15 days after the sponsor become aware of the reaction.
  • SUSARs initially considered as non-fatal or non-life threatening but turn out to be fatal or life-threatening must be reported as soon as possible but no later than 7 days after the sponsor become aware of the reaction being fatal or life-threatening.

SUSARs to IMPs which are identified or come to the attention of the sponsor after the end of the trial have to be reported as well.

Note that comparators and placebo are IMPs. Therefore, SUSARs associated with comparators follow the same reporting requirements as for the test IMP. Events associated with placebo will usually not satisfy the criteria for a SUSAR and, therefore, neither for expedited reporting. However, where SUSARs are associated with placebos (e.g., reaction due to an excipient or impurity), the sponsor should report such cases.

Only unblinded SUSARs shall be reported in Eudravigilance. Therefore, it is important to have procedures in place to ensure  that unblinded information is only accessible to persons who need to be involved in the safety reporting to Eudravigilance, to Data Safety Monitoring Boards (DSMB), or to persons performing ongoing safety evaluations during the clinical trial.

Causality

In case of ARs assessed as ‘unknown’ or ‘not assessed’ for which the investigator cannot make a decision with regard to relatedness to the IMP the sponsor should consult the reporting investigator and encourage him/her to express an opinion. The causality assessment given by the investigator can be upgraded (from unrelated to related), but not downgraded by the sponsor. If the sponsor disagrees with the investigator’s causality assessment, the opinion of both the investigator and the sponsor should be provided with the report. If (despite all efforts) the causality assessment cannot be made, these SAEs should be considered to be related to the IMP and reported as SUSARs if they are not listed as an expected SAR in the RSI. In general, SAEs with “unknown causality” or “causality not assessed” will not be accepted to support the inclusion of expected SARs in the RSI.

When after the initial reporting, it is considered that the event is not a SUSAR, for example due to lack of causality, seriousness, or expectedness, a socalled 'downgrade' by the investigator should be considered as relevant information. However if the sponsor disagrees with the investigator’s causality assessment, the sponsor shall not downgrade the investigator assessment. The opinion of both the investigator and the sponsor should be provided in the narrative and in the relevant structured ICH E2B data elements of the report.

SUSAR reporting to investigators

The sponsor should promptly notify all concerned investigators/institutions of findings that could adversely affect the safety of the subjects and should expedite the reporting of all SUSARs to all concerned investigators/institutions (ICH E6). The most important thing is to inform investigators of safety profile changes, not of individual SUSAR reports. For example, information derived from SUSAR reports could be provided via investigators’ letters including both an updated benefit-risk evaluation and risk mitigation measures.

The safety information for investigators should be concise and practical. Whenever possible, the information on SUSARs should be at least a list of SUSARs that occurred at their MS, national territory, together with a summary analysis of safety profile and updated benefit risk for the ongoing clinical trials. See also question 7.30 of the Q&A CTR.

Auxilliary medicinal products

Safety reporting with regard to authorised AxMPs shall be made in accordance with Title IX of Directive 2001/83/EC.

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).