SAE reporting - from non-serious AE to serious AE - one event or two events?

An adverse event is any undesirable experience associated with the use of a medical product in a patient. The event is serious (therefore serious adverse event (SAE)) and should be reported when the patient outcome is:

Death

Report if you suspect that the death was an outcome of the adverse event, and include the date if known. 

Life-threatening

Report if suspected that the patient was at substantial risk of dying at the time of the adverse event, or use or continued use of the device or other medical product might have resulted in the death of the patient.

Hospitalization (initial or prolonged)

Report if admission to the hospital or prolongation of hospitalization was a result of the adverse event.

Emergency room visits that do not result in admission to the hospital should be evaluated for one of the other serious outcomes (e.g., life-threatening; required intervention to prevent permanent impairment or damage; other serious medically important event).

Disability or Permanent Damage

Report if the adverse event resulted in a substantial disruption of a person's ability to conduct normal life functions, i.e., the adverse event resulted in a significant, persistent or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities and/or quality of life.

Congenital Anomaly/Birth Defect

Report if you suspect that exposure to a medical product prior to conception or during pregnancy may have resulted in an adverse outcome in the child.

Required Intervention to Prevent Permanent Impairment or Damage (Devices)

Report if you believe that medical or surgical intervention was necessary to preclude permanent impairment of a body function, or prevent permanent damage to a body structure, either situation suspected to be due to the use of a medical product.

Other Serious (Important Medical Events)

Report when the event does not fit the other outcomes, but the event may jeopardize the patient and may require medical or surgical intervention (treatment) to prevent one of the other outcomes. Examples include allergic brochospasm (a serious problem with breathing) requiring treatment in an emergency room, serious blood dyscrasias (blood disorders) or seizures/convulsions that do not result in hospitalization. The development of drug dependence or drug abuse would also be examples of important medical events.

In clinical trial setting, there are two layers of SAE reporting:

The investigational site reports the SAE to the trial sponsor:

According to ICH E6 (Good Clinical Practice), the SAEs should be reported immediately to the sponsor when the site staff become aware of the occurrence of a SAE. 'Reported immediately' is generally interpreted as 'reported within 24 hours'. The clinical trial protocol typically includes a statement "Sites must report SAE information regardless of causality or expectedness to the Sponsor within 24 hours of awareness of an SAE." 

The sponsor or designee reports the SAEs and SUSAR to the regulatory authorities (FDA):

SAEs need to be reported to regulatory agencies and IRBs/ECs in narrative format (so called SAE narratives). According to 21CRF part 312.32 Safety Reporting, here are the requirements:

SUSUR stands for serious and unexpected suspected adverse reaction. FDA guidance "Safety Reporting Requirements for INDs and BA/BE Studies" provided the definition for SUSAR and specified the reporting requirement. 

SUSAR determination and subsequent reporting are typically handled by the drug safety or pharmacovigilance group, which has access to treatment assignment information. When a SUSAR event is reported, the drug safety or pharmacovigilance group may unblind the individual subject to determine if they are in the active drug group or the placebo group. If the subject is in the placebo group, it will not be considered a SUSAR.

SUSAR events that involve unexpected fatal or life-threatening suspected adverse reactions must be reported to the FDA within 7 days through the submission of a "7-day IND safety report." Here is what is said in 21CFR part 312.32 IND Safety Reporting:

In practice, it is common for adverse events to initially present as non-serious (not meeting the criteria for defining a serious adverse event), but with the event worsening, they may evolve into a serious adverse event. For example, a subject may experience an adverse event that eventually requires hospitalization, meeting the criteria for a serious adverse event.

There is a common (but inappropriate) approach to handling this situation by splitting the event into two separate entries: one for the initial non-serious adverse event and another for the subsequent serious adverse event. Some sponsors provide instructions to record the non-serious adverse event with a stop date, mark the outcome as 'Not recovered/not resolved,' and create a new entry for the serious adverse event with the start date when the seriousness criteria are met. The stop date of the non-serious adverse event should be the same date or the day prior to the start date of the serious adverse event. While this approach aligns with SAE reporting and is considered conservative, it artificially divides the same episode into two separate events, which will cause the problem when writing the SAE narratives. We can not just write a SAE narrative without including the non-serious part - they are essentially the same event. 

In general, when an adverse event initially presents with non-serious symptoms and later progresses to meet the criteria for a serious adverse event (SAE), it is typically reported once as an SAE. This is because the serious adverse event designation takes precedence over the non-serious symptoms.

It's important to note that the onset date of the SAE should be the date when the symptoms started, not the date when the SAE criteria are met. Reporting of SAEs should be based on the date when the SAE criteria are met and when the site staff becomes aware of the SAE.

In situations where an adverse event starts as non-serious and progresses to serious, it is appropriate to report the event as an SAE.

When an adverse event evolves into a serious condition, such as requiring hospitalization or meeting other predefined criteria for seriousness, it is considered a new phase or stage of the same event. Reporting it as an SAE captures the escalated severity and ensures appropriate attention, monitoring, and reporting to regulatory authorities.

When an adverse event (AE) starts as non-serious and progresses to a serious state, it should be reported solely as a serious adverse event (SAE). In this situation, there are three potentially relevant dates: the "serious adverse event start date," "adverse event becomes serious," and "the site staff became aware of the serious adverse event." These terms are associated with the reporting and monitoring of adverse events in clinical trials or medical research. Here's a comparison of these terms:

Serious Adverse Event Start Date: The serious adverse event start date refers to the specific date when an adverse event initially occurred or began in a participant during a clinical trial or medical research study. It marks the beginning of the event's timeline and is often recorded to establish the temporal relationship between the event and the study procedures.

Adverse Event Becomes Serious: An adverse event refers to any unfavorable or undesirable medical occurrence experienced by a participant during a clinical trial or medical research study, regardless of its seriousness. When an adverse event becomes serious, it means that the event has worsened in intensity, severity, or clinical impact. The criteria for determining whether an adverse event is considered serious may vary, but they generally include outcomes such as death, life-threatening situations, hospitalization or prolonged hospital stay, significant disability, congenital anomalies, or other important medical events.

The Site Staff Became Aware of the Serious Adverse Event: This phrase signifies the point at which the staff at the clinical trial site or research facility becomes aware of the occurrence of a serious adverse event in a participant. It is crucial to promptly report and document the event to ensure participant safety and adhere to regulatory requirements. The site staff's awareness triggers subsequent actions such as assessment, documentation, reporting to the appropriate authorities, and potential modifications to the study protocol or participant management.

In summary, when an adverse event starts as non-serious and progresses to a serious state, it should be reported solely as a serious adverse event (SAE). The serious adverse event start date marks the initial occurrence of the event, while the "adverse event becomes serious" indicates the worsening of its intensity or impact. The "site staff became aware of the serious adverse event" signifies the point when the research facility staff acknowledges the occurrence and initiates the necessary actions for reporting and participant safety.