Adverse event of special interest (AESI)

As per CIOMS VI, An adverse event of special interest (AESI) (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s product or programme, for which ongoing monitoring and rapid communication by the investigator to the sponsor could be appropriate. Such an event might require further investigation in order to characterise and understand it. Depending on the nature of the event, rapid communication by the trial sponsor to other parties (e.g., regulators) might also be warranted.

ICH Topic E2F Development Safety Update Report also indicated the importance of identifying the AESIs:

“If important and appropriate, the report should also include adverse reactions of special interest within the line listings and adverse events of special interest in summary tabulations. The basis for selection of such events/reactions should be explained. “

These adverse events may warrant collection of additional information across the entire study population to better characterise these events (e.g., particular laboratory parameters; vital signs; risk factors; concomitant therapies; and/or concomitant illnesses). For example, if gastrointestinal haemorrhage was an adverse event of special interest, one might want to proactively collect concomitant antithrombotic therapy across the entire study population

Reporting AESI is an emerging and more critical aspect related to characterising the safety profile of a compound in clinical trials. It is important to define clearly “adverse events of special interest” in the protocol and to specify close monitoring and prompt reporting to the sponsor of these types of events, even if the event is considered non-serious according to the usual regulatory criteria.

These non-serious AESIs might be precursors of more serious medical conditions; for example, muscle pain and elevated Creatine Phosphokinase (CPK) together may be indicative of potential rhabdomyolysis. Other types of non-serious events may be important in and of themselves, such as those that could affect quality of life in a meaningful way (e.g., impotence, hair loss). Such events examples of what are often referred to as adverse events of special interest, when there is evidence or suspicion of their potential importance. 

Toxicology studies and other non-clinical research may suggest the potential for serious adverse events in humans. Prior to initiation of clinical trials, the sponsor may identify adverse events of special interest from these data, or from experiences with similar compounds, and require special collection and reporting by the investigator.

For example, if a compound in development has been demonstrated to have the propensity to cause tachycardia in pre-clinical studies or if this is a concern with other compounds in the same class, it would be precursor to proceed with caution in any human trials. ECGs should therefore be monitored and tachycardia routinely reported by investigators to sponsors for all subjects/patients until the risk to humans is delineated. While animal studies may or may not be predictive of potential human toxicity, they cannot rule out all potential toxicity.

AESI should ideally be identified in the developmental safety plan and protocols for handling by investigators and sponsors as if they were serious, even though they do not necessarily meet the regulatory defi nition of serious.

Reporting requirements:

Prompt medical evaluation of all individual AESI cases regardless of attribution or expectedness, whether serious or not is mandatory and should be reviewed and assessed in aggregate on a continuous basis. The careful and thoughtful evaluation of one or more reports of AESI can be critical in detecting an emerging safety signal. 

Some authorities will ask sponsors to report events of special interest in an expedited manner regardless of causality or expectedness.

AESI in Vaccines:

Identification and assessment of AESI are a high priority in vaccines because when their frequency after vaccination increases they represent potential risks which will change benefit risk balance of vaccine or may require prompt communication with pubic by regulatory or public health authority.

Identification of AESIs:

Identifying AESI usually involve searching through PTs, pre-defined SMQs that can be extracted using MedDRA PTs, or the CMQs that are specific to a study but are not pre-defined w ithin MedDRA. 

It w ill also involve adjudication process that spreadsheet output created through the searches are submitted for medical/clinical confirmation. These spreadsheets are usually in specific structure so adequate information like subject ID, AE sequence number, verbatim term, PT, SOC, onset date, resolved date, seriousness, severity, SMQs, CMQs,…,etc.,are compiled to assist with the confirmation. 

Based on the adjudication process, additional flag variables can be checked by medical/clinical reviewers to confirm whether an AE included in the spreadsheet constitute an AESI.