SAE Reporting Workflow | GMPify Training

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SAE Reporting - Protecting Subjects Through Timely Safety Escalation

A serious adverse event report is the mechanism by which a single subject's experience becomes protective knowledge for every other subject in a trial, and every future patient who takes the product. ICH E2A defines the seriousness criteria, causality framework, and expedited reporting principles that apply across regions, while 21 CFR 312.32 and EU CTR 536/2014 set the specific regulatory timelines sponsors must meet. This map details the pathway from event identification through sponsor determination, expedited regulatory submission, and case follow-up to closure.

ICH E2A · 21 CFR 312.32 · EU CTR 536/2014 Art. 41-43 · ICH E2B(R3)

ICH E2A

21 CFR 312.32

EU CTR 536/2014

ICH E2B(R3)

Fatal / Life-Threatening SUSAR

Unexpected, serious, related event that is fatal or life-threatening. Shortest reporting clock of any category.

Initial report: 7 calendar days

Follow-up: +8 calendar days

Other SUSAR

Unexpected, serious, related event that is not fatal or life-threatening. Standard expedited timeline.

Initial report: 15 calendar days

Follow-up: As available

Expected Serious AE

Serious and related, but consistent with the reference safety information. Not expedited.

Reporting route: Periodic (DSUR)

Non-Serious AE

Does not meet seriousness criteria. Captured in the safety database only.

Reporting route: Routine periodic only

Phase 1

Event Identification and Initial Assessment

1Identify and document the adverse event

Investigator or site staff identifies the event through subject report, clinical observation, or laboratory finding, and documents it in the source record.

ICH E6(R2)

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2Determine seriousness per ICH E2A criteria

Event evaluated against the seriousness criteria: results in death, is life-threatening, requires hospitalization or prolongs existing hospitalization, results in persistent disability, is a congenital anomaly, or is another medically important event.

ICH E2A Section II.A

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3Investigator makes initial causality assessment

Investigator records their assessment of the relationship between the event and the investigational product using the trial's defined causality categories.

ICH E2A Section III.B

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4Submit initial SAE report to sponsor

Site submits the initial SAE report to the sponsor within 24 hours of becoming aware of the event, per the protocol and site agreement.

ICH E6(R2) Section 4.11

Phase 2

Sponsor Evaluation and SUSAR Determination

5Sponsor medical reviewer evaluates the case

Sponsor pharmacovigilance or medical safety function reviews seriousness and causality independently of the site's initial assessment.

ICH E2A Section III.C

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6Determine expectedness against reference safety information

Event compared against the current investigator's brochure or reference safety information to determine whether it is a listed, expected event.

ICH E2A Section III.A

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Is the event a Suspected Unexpected Serious Adverse Reaction (SUSAR)?

YES → Expedited regulatory reporting NO → Routine safety database entry

Phase 3

Regulatory Reporting and Notification

7Submit expedited report to regulatory authorities

SUSAR submitted within the required timeline: 7 calendar days for fatal or life-threatening events, 15 calendar days for all other SUSARs.

21 CFR 312.32 · EU CTR 536/2014 Art. 42

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8Notify IRB, Ethics Committee, and investigators

Relevant safety information distributed to the IRB or Ethics Committee and to investigators at all participating sites, per protocol requirements.

ICH E6(R2) Section 5.17

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9Update the reference safety information if needed

Investigator's brochure or reference safety information revised when a new SUSAR pattern indicates the current safety profile is no longer accurate.

ICH E2A Section III.A

Phase 4

Follow-Up and Case Closure

10Collect follow-up information

Additional clinical information gathered until the event resolves, stabilizes, or the subject's condition is otherwise fully characterized.

ICH E2A Section IV

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11Submit follow-up expedited reports

Follow-up reports submitted as significant new information becomes available, within 8 additional calendar days for fatal or life-threatening events.

21 CFR 312.32(c)

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12Include the event in aggregate safety reporting

Case summarized in the periodic Development Safety Update Report or equivalent aggregate report, providing cumulative safety context.

ICH E2F

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13Close the case record

Case record closed in the safety database once resolution is documented and all required reports have been submitted and reconciled.

ICH E2B(R3)

SAE Reporting Timeline Requirements

Fatal or Life-Threatening SUSAR

Initial report to regulatory authorities within 7 calendar days of sponsor awareness, followed by a complete follow-up report within 8 additional calendar days.

21 CFR 312.32(c)(1)(i)

Other SUSAR

Initial report submitted within 15 calendar days of sponsor awareness, with follow-up reports as new information becomes available.

21 CFR 312.32(c)(1)(ii)

Expected Serious Adverse Events

Not subject to expedited timelines. Captured in the safety database and summarized in periodic aggregate reports.

ICH E2A Section III.A

Causality Assessment Categories (Overview)

Unrelated Event clearly explained by another cause, such as the underlying disease or a concomitant medication, with no plausible link to the investigational product.

Unlikely Temporal relationship exists but another explanation is more probable, and a causal link to the investigational product is not well supported.

Possible Reasonable temporal relationship exists and a causal link cannot be ruled out, though other explanations are also plausible.

Probable / Definite Strong temporal relationship, no more likely alternative explanation, and in definite cases a positive dechallenge or rechallenge supports the investigational product as the cause.

Regulatory Notification Recipients (Overview)

National regulatory authorities FDA IND safety report or the applicable national competent authority, per the jurisdiction in which the trial is conducted.

EU safety database SUSARs occurring in EU trials reported to the applicable EU/EEA pharmacovigilance database per EU CTR 536/2014.

IRB / Ethics Committee Notified of SUSARs and other safety information relevant to the ongoing evaluation of subject risk at the site.

Participating investigators All investigators across a multi-site trial informed of SUSARs that may affect their site's risk assessment or informed consent process.

SAE Reporting Quality Elements

Initial 24-Hour Site Notification Site reports the SAE to the sponsor within 24 hours of first becoming aware, regardless of completeness of information at that point.

Investigator Causality Assessment Documented, investigator-level judgment of the relationship between the event and the investigational product, recorded independent of the sponsor's later review.

Sponsor Medical Review Independent medical evaluation of seriousness, causality, and expectedness performed by qualified sponsor safety personnel.

SUSAR Determination Formal classification combining seriousness, causality, and expectedness to determine whether expedited reporting is triggered.

Expedited Regulatory Timelines 7-day and 15-day clocks met consistently, measured from the date the sponsor first becomes aware of a reportable event.

IRB / EC Notification Safety information relevant to subject risk communicated to the overseeing ethics body per protocol and applicable regulation.

Follow-Up Reporting New clinically significant information captured and submitted as supplemental reports until the case is resolved.

Aggregate Safety Reporting Individual case data rolled into periodic Development Safety Update Reports, providing cumulative trend context beyond single events.

Never do this

Allow the 24-hour site notification clock to slip because information is incomplete. Delay SUSAR determination pending unrelated administrative review. Miss the 7 or 15 day expedited reporting deadline. Fail to notify all participating sites of a safety signal that could affect their risk assessment.

SAE vs AE

An adverse event is any untoward medical occurrence in a subject. A serious adverse event meets one or more specific seriousness criteria, such as death, hospitalization, or life-threatening risk. Seriousness, not severity, determines the regulatory reporting pathway.

Expedited vs periodic reporting

Expedited reporting applies to SUSARs and follows fixed regulatory clocks measured in days. Periodic reporting, such as the DSUR, aggregates all safety data including expected events on a scheduled annual or protocol-defined cycle.

Key regulations

ICH E2A - clinical safety data management definitions and standards. 21 CFR 312.32 - IND safety reporting requirements and timelines. EU CTR 536/2014 Art. 41-43 - EU safety reporting obligations. ICH E2B(R3) - electronic safety report data elements.