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Academy · Regulatory Affairs · AE vs SAE vs ADR
Adverse Event, Serious Adverse Event and Adverse Drug Reaction: Definitions Under ICH E2A and Their Implications for Expedited Reporting
These three terms are not synonyms ranked by severity. Each is defined by a specific criterion (causality, seriousness or neither), and these definitions determine when expedited reporting timelines apply in clinical trials.
An adverse event (AE) is any untoward medical occurrence in a trial participant, regardless of causal relationship to the investigational product. A serious adverse event (SAE) is an AE meeting specific seriousness criteria, regardless of causality. An adverse drug reaction (ADR) is an AE for which a causal relationship to the drug is at least a reasonable possibility. The three criteria — occurrence, seriousness, causality — are independent of each other.
Learning objectives
- The specific ICH E2A seriousness criteria that make an adverse event (AE) a serious adverse event (SAE).
- Why causality (ADR) and seriousness (SAE) are assessed independently, not on the same scale.
- Why expedited reporting timelines are triggered by the combination of seriousness and causality, not by either alone.
Common misconceptions
- “A serious adverse event is simply a severe adverse event.” ICH E2A defines “serious” by specific outcome-based criteria — results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is another medically important event — not by the intensity or severity of the symptom itself; a mild-intensity event that results in hospitalisation is still classed as serious, while a severe-intensity symptom that resolves without any of these outcomes is not.
- “Every adverse event that occurs during a trial is assumed to be caused by the investigational product.” ICH E2A defines an adverse drug reaction specifically as a response to a drug for which a causal relationship is at least a reasonable possibility — causality must be actively assessed, typically by the investigator, for each event; an AE occurring during a trial is not automatically presumed to be drug-related, and many AEs are unrelated intercurrent illness or events.
Definition of an adverse event
ICH E2A defines an adverse event as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment — meaning any unfavourable and unintended sign, symptom, or disease temporally associated with the use of the investigational product, whether or not it is considered related1. This is deliberately the broadest of the three categories, capturing everything observed before any judgement about cause or severity is made.
Criteria for classifying an event as serious
ICH E2A sets out specific, outcome-based criteria for seriousness, independent of symptom intensity: the event results in death; is life-threatening; requires inpatient hospitalisation or prolongs existing hospitalisation; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; or is another medically important event that may jeopardise the patient or require intervention to prevent one of the other outcomes1. Meeting any one of these criteria classifies the event as serious, regardless of how the investigator might otherwise describe its severity.
Separate assessment of causality and the triggers for expedited reporting
ICH E2A defines an adverse drug reaction as an adverse event for which a causal relationship to the drug is at least a reasonable possibility — a judgement made independently of, and in addition to, the seriousness assessment1. Expedited regulatory reporting obligations are triggered specifically by the combination of seriousness and an assessed causal relationship (a “serious and unexpected adverse drug reaction,” or SUSAR, when also not consistent with the known safety profile). An event that is serious but assessed as unrelated, or related but not serious, does not trigger the same expedited timeline; for this reason, both criteria must be assessed and documented for every event rather than inferred from each other.
Key points
Key points
Adverse event, serious adverse event, and adverse drug reaction are defined by three independent criteria — occurrence, specific seriousness outcomes, and assessed causality — and expedited regulatory reporting is triggered specifically by events that are both serious and causally related (and unexpected), not by severity or occurrence alone.
Practical application
Practical application
- Assess seriousness against ICH E2A's specific criteria for every AE, not against perceived severity. Each event should be checked explicitly against the defined seriousness outcomes (death, life-threatening, hospitalisation, disability, congenital anomaly, other medically important event).
- Document a causality assessment for every AE, separate from the seriousness assessment. The investigator’s causality judgement (related/not related, or a graded scale) should be recorded independently, with its own rationale.
- Identify SUSARs specifically for expedited reporting. Events that are serious, causally related and unexpected relative to the known safety profile should be flagged for expedited regulatory reporting, distinct from routine periodic safety reporting of other events.
Frequently asked questions
Yes. If it results in hospitalisation or meets another of the seriousness criteria defined in ICH E2A, it is classed as serious, regardless of how mild the underlying symptom was judged to be.
Typically the investigator makes an initial causality assessment, which may be reviewed by the sponsor's pharmacovigilance team and, in some cases, an independent safety monitoring committee.
An event is “unexpected” if its nature or severity is not consistent with the information already in the investigator’s brochure or product labelling. Expected serious, related events are still tracked, but SUSARs specifically require expedited reporting because they represent new safety information.
References
- International Council for Harmonisation (ICH). E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. read 10 October 2026. View ICH E2A Guideline
Every source above is a peer-reviewed article, a publisher’s record of one, or a standard issued by the body that owns it. Each carries the date it was last read. Where a standard moves, this article is revised rather than left up with a note.
How to cite this article
Pick your referencing style and copy it. Your university or target journal may vary the punctuation — check its guide if it has one.
Pubrica Academy. (2026, October 10). Adverse Event, Serious Adverse Event and Adverse Drug Reaction: Definitions Under ICH E2A and Their Implications for Expedited Reporting. Pubrica. https://pubrica.com/academy/concepts-definitions/adverse-event-sae-adr/
Pubrica Academy. “Adverse Event, Serious Adverse Event and Adverse Drug Reaction: Definitions Under ICH E2A and Their Implications for Expedited Reporting.” Pubrica, 10 Oct. 2026, pubrica.com/academy/concepts-definitions/adverse-event-sae-adr/.
Pubrica Academy (2026) Adverse Event, Serious Adverse Event and Adverse Drug Reaction: Definitions Under ICH E2A and Their Implications for Expedited Reporting. Pubrica. Available at: https://pubrica.com/academy/concepts-definitions/adverse-event-sae-adr/ (Accessed: 15 October 2026).
Pubrica Academy. “Adverse Event, Serious Adverse Event and Adverse Drug Reaction: Definitions Under ICH E2A and Their Implications for Expedited Reporting.” Pubrica. October 10, 2026. https://pubrica.com/academy/concepts-definitions/adverse-event-sae-adr/
Pubrica Academy, ‘Adverse Event, Serious Adverse Event and Adverse Drug Reaction: Definitions Under ICH E2A and Their Implications for Expedited Reporting’ (Pubrica, 10 October 2026) <https://pubrica.com/academy/concepts-definitions/adverse-event-sae-adr/> accessed 15 October 2026.
Pubrica Academy. Adverse Event, Serious Adverse Event and Adverse Drug Reaction: Definitions Under ICH E2A and Their Implications for Expedited Reporting. [Internet]. Pubrica; 2026 Oct 10 [cited 2026 Oct 15]. Available from: https://pubrica.com/academy/concepts-definitions/adverse-event-sae-adr/
Pubrica Academy, “Adverse Event, Serious Adverse Event and Adverse Drug Reaction: Definitions Under ICH E2A and Their Implications for Expedited Reporting,” Pubrica, Oct. 10, 2026. [Online]. Available: https://pubrica.com/academy/concepts-definitions/adverse-event-sae-adr/
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}This article is written to be learned from. Cite it if you are referring to what it says; if you are using the evidence behind it, cite the sources listed above instead.
AE/SAE/ADR classification check
Use when documenting and reporting an adverse event.
[ ] Event checked against ICH E2A's specific seriousness criteria [ ] Causality assessed and documented independently of seriousness [ ] Expectedness assessed against the investigator's brochure/product labelling [ ] SUSARs identified and flagged for expedited reporting on the correct timeline [ ] Non-serious and/or unrelated events tracked for routine periodic safety reporting
Pubrica AcademyWritten and maintained by Pubrica’s subject matter experts. Articles are revised when the underlying standards change, and each article states the date on which it was last reviewed.
How Pubrica can help
Pubrica structures safety reporting workflows to the ICH E2A definitions, so that seriousness and causality are assessed and documented correctly for every event.