A SUSAR represents a particularly significant safety finding in clinical trials, combining three critical elements: the event is serious according to regulatory definitions, there is a reasonable possibility that the investigational product caused the event, and the nature or severity of the event is not consistent with the applicable reference safety information. This convergence of seriousness, suspected causality, and unexpectedness triggers the most stringent regulatory reporting requirements in drug development.

The reference safety information, typically contained in the Investigator's Brochure for investigational products or the Summary of Product Characteristics for authorized products, defines the expected adverse reaction profile against which new events are assessed. An adverse reaction that has not been previously observed or documented, or that occurs with greater severity or frequency than expected, qualifies as unexpected. This expectedness determination is crucial because regulatory authorities prioritize learning about new safety signals that were not anticipated based on prior knowledge.

Expedited reporting of SUSARs to regulatory authorities is mandated by regulations worldwide, with timelines typically requiring notification within seven calendar days for fatal or life-threatening SUSARs and fifteen calendar days for other SUSARs. Sponsors must also notify all investigators conducting trials with the investigational product, enabling them to assess the implications for their own participants and to update informed consent processes if warranted. The aggregation and analysis of SUSARs across all trials of an investigational product forms a key component of the ongoing safety evaluation throughout development.