DIA Europe 2022 

To comply with regulations, the pharmacovigilance team confirms whether or not the specific type of SAE is expected per the drug’s Reference Safety Information (RSI). Events which are not expected must be reported to regulatory agencies globally. Anticipated events that are not caused by study drug will never appear in RSI even if they occur frequently, and must be reported as expedited cases any time causality is unclear.  

As single cases, these events are not informative for the safety profile of the drug. FDA has proposed in the current “Draft Guidance: Sponsor Responsibilities – Safety Reporting …” that expedited reporting of anticipated events only occur when the event is more frequent than predicted. Sponsors are encouraged to propose a process for making this prediction.

The standard for an 'anticipated' adverse event to be considered a Suspected Adverse Reaction may depend on the study design. Some sections in the Guidance seem to suggest that it is only applicable to studies with a comparator design; in others the assessment is described as relative to "expected background rates in the study population" or to "the rate of the same SAE in a similar population not exposed." 

The Draft Guidance clarifies the distinction between anticipated events versus expected events. It explicitly states that "it is not expected that the list of anticipated events will cover all clinical events that may be background clinical events in the population...rather, such events should be carefully reviewed to determine if they meet the criteria for IND safety reporting when such a determination cannot be made based on a single case."

The initial sections of the draft Safety Reporting - Sponsor Responsibilities Guidance describe "safety reporting for INDs and BA/BE studies" and do not exclude studies of any size or design.  The focus of the Guidance is to create "an effective systematic approach by sponsors to safety surveillance, couple by limiting the scope of IND safety reports ... to suspected adverse reactions that are both serious and unexpected, [that] allows all parties to focus on important safety issues..."  

We conducted a survey to assess plans for implementing processes described in the guidance across small, medium, and large companies.  We also evaluated the range of exposures available at different stages of development and compared those to the background incidences of typical conditions representing 'anticipated events' in common populations. 

Aggregate analysis – the review of all safety data related to an unexpected medical condition observed in clinical trial subjects – can be resource-intensive, but becomes efficient with standard programming and processes for identifying subjects for review.