SUSARs

For each adverse event that occurs, it must be determined whether the event is serious, suspected and unexpected.

Whether an event is serious is determined based on specific criteria.

An event is serious if:

• it requires (prolongation of existing) hospitalisation;
• results in persistent or significant disability or incapacity;
• results in congenital anomaly or malformation;
• is life-threatening;
• results in death;
• is considered serious based on medical evaluation.

A causality assessment must be performed assessing the causal relation with the investigational medicinal product. Possible outcomes of this assessment are:

• not related;
• unlikely related;
• possibly related;
• probably related;
• definitely related.

Events deemed at least possibly related to an investigational medicinal product must be considered related.

In cases where an event is both serious and assessed as at least possibly related to an investigational medicinal product, it must subsequently be determined whether this serious adverse event (SAE) is expected or unexpected. To this end, the adverse event is compared with the reference safety information (RSI) of the investigational medicinal product. The RSI is either a separate section of the Investigator's Brochure (IB) or consists of section 4.8 Adverse effects of the Summary of Product Characteristics (SmPC). If the coded term of the serious adverse event is not included in the list of expected serious adverse reactions in the RSI, the serious adverse event is considered unexpected and classifies as a SUSAR. Only SARs listed in the approved RSI do not need to be reported as SUSARs in EudraVigilance.

SUSAR reporting in EudraVigilance

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.

The sponsor needs to register with Eudravigilance. More information on the steps to be followed, can be found in the document Registration Eudravigilance.

Timelines for SUSAR reporting

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 became 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 became aware of the reaction.
• SUSARs initially considered non-fatal or non-life threatening but which turn out to be fatal or life-threatening must be reported as soon as possible but no later than 7 days after the sponsor became aware of the reaction being fatal or life-threatening.

SUSAR reporting after end of trial

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.

Deblinding of SUSARs

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 a serious adverse events 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 so called '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's 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.

SUSARs for comparators and placebo

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.

SUSAR reporting to investigators

The sponsor should promptly notify all concerned investigators/institutions of findings that could adversely affect the safety of the participants 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 member state, national territory, together with a summary analysis of the safety profile and updated benefit risk for the ongoing clinical trials. See also question 7.30 of the Q&A CTR.