SOP-501
Serious Adverse Event and Expedited Safety Reporting
- Number
- SOP-501
- Category
- Safety
- Edition
- Reference Edition 1.3
- Approx. pages
- 8
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On this page
1. Purpose
This SOP describes how [SITE NAME] recognizes serious adverse events (SAEs), reports them to the sponsor within the required time, follows them to resolution, reports unanticipated adverse device effects (UADEs), and receives and processes safety information sent by sponsors (IND safety reports, SUSAR letters and device safety notices).
2. Scope
This SOP applies to all drug, biologic and device trials at [SITE NAME]. It covers investigator-to-sponsor expedited reporting and site handling of sponsor safety communications.
Out of scope: identification and assessment of all AEs (SOP-500), reporting to the IRB (SOP-502), pregnancy (SOP-503), and sponsor-investigator obligations to FDA under an IND or IDE held by a site investigator (SOP-800).
Follow the protocol, sponsor safety instructions or IRB requirement where it is stricter than or more specific than this SOP. Sponsor timelines in this SOP are described only so that site staff understand why sponsors set short site timelines. They are sponsor obligations, not site obligations.
3. Responsibilities
| Role | Responsibilities |
|---|---|
| Principal Investigator (PI) | Holds overall responsibility for SAE reporting. Assesses or confirms seriousness and causality, reviews and signs each SAE report, provides or arranges medical care, reviews sponsor safety reports, and decides whether participants need to be told new information. |
| Sub-Investigator (Sub-I) | Assesses and signs SAE reports when the PI is unavailable and the Sub-I is delegated for safety assessment on F-302-01. |
| Clinical Research Coordinator (CRC) | Records the awareness date, gathers information, completes and submits the SAE report and follow-ups within the protocol timeline, obtains outside records, maintains F-501-01, and files correspondence. |
| Regulatory Coordinator | Logs and files sponsor safety reports, obtains PI acknowledgment, submits safety information to the IRB when IRB policy requires (SOP-502), and files IRB acknowledgments. |
| Research Pharmacist or IP Manager | Quarantines and returns investigational devices or IP involved in an event as the sponsor directs. |
| Site Director | Makes sure investigator coverage is in place so an investigator can assess an SAE within the reporting window, including weekends and holidays. |
| Quality Lead | Reviews F-501-01 for timeliness in the SOP-700 quarterly metrics review (5.11.2) and opens CAPA (SOP-703) for repeated or systemic late reporting. |
| All Research Staff | Report any information suggesting an SAE to the CRC or an investigator immediately, the same day it is received. |
4. Definitions
| Term | Definition |
|---|---|
| Serious Adverse Event (SAE) | An AE that, in the view of the investigator or sponsor, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or is a congenital anomaly or birth defect. Important medical events may be considered serious when, based on appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of these outcomes (21 CFR 312.32(a); ICH E2A). |
| Important medical event | An event that may not be immediately life-threatening or result in death or hospitalization but that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes above. Examples: allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in hospitalization, development of drug dependency or drug abuse. |
| Life-threatening | The event placed the participant at immediate risk of death at the time it occurred. It does not include an event that might have caused death had it been more severe. |
| Suspected Unexpected Serious Adverse Reaction (SUSAR) | A serious adverse reaction that is suspected (reasonable possibility of causal relationship) and unexpected (not consistent with the reference safety information). |
| IND safety report | The sponsor's expedited report to FDA and all participating investigators of potential serious risks under 21 CFR 312.32(c). Sites often receive these as SUSAR letters or line listings through a sponsor portal. |
| Awareness date (Day 0) | The date any member of the site research staff first receives information indicating that an event meets SAE criteria, from any source. |
| Initial report | The first SAE report sent to the sponsor, containing the minimum information the sponsor requires, even if details are incomplete. |
| Follow-up report | Any later report that adds, corrects or updates information on a reported SAE. |
| Adverse Device Effect (ADE) / Serious Adverse Device Effect (SADE) | An AE related to the use of an investigational device; a SADE is an ADE that meets SAE criteria (ISO 14155). |
| Unanticipated Adverse Device Effect (UADE) | Any serious adverse effect on health or safety, or any life-threatening problem or death, caused by or associated with a device, if not previously identified in nature, severity or degree of incidence in the investigational plan or application; or any other unanticipated serious problem associated with a device that relates to the rights, safety or welfare of participants (21 CFR 812.3(s)). |
| Device Deficiency | An inadequacy of a device related to its identity, quality, durability, reliability, usability, safety or performance, including malfunction, use error and inadequate labeling (ISO 14155). |
| Protected Health Information (PHI) | Individually identifiable health information as defined in 45 CFR 160.103. |
5. Procedure
5.1 Regulatory basis for site timelines
5.1.1
Under 21 CFR 312.64(b), the investigator must immediately report to the sponsor any SAE, whether or not considered drug related, including those listed in the protocol or IB, and must include an assessment of whether there is a reasonable possibility that the drug caused the event. Study endpoints that are SAEs (for example, all-cause mortality) are reported as the protocol specifies, unless there is evidence suggesting a causal relationship between the drug and the event, in which case the investigator reports immediately. Non-serious AEs are recorded and reported on the protocol timetable.
5.1.2
ICH E6(R3) Annex 1, 2.7.2(b) states the same principle: all SAEs are reported immediately after the investigator reasonably becomes aware of them, with a causality assessment, unless the protocol identifies SAEs that do not require immediate reporting (for example, deaths or other events that are endpoints).
5.1.3
For investigational devices, the investigator must report any UADE to the sponsor and to the reviewing IRB as soon as possible, and no later than 10 working days after the investigator first learns of the effect (21 CFR 812.150(a)(1)). Device protocols usually set a much shorter sponsor timeline for all serious events and device deficiencies. The site follows the shorter timeline.
5.1.4
Sponsor obligations, for context only:
- IND safety reports to FDA and all participating investigators as soon as possible and no later than 15 calendar days after the sponsor determines the information qualifies (21 CFR 312.32(c)(1)).
- Unexpected fatal or life-threatening suspected adverse reactions to FDA no later than 7 calendar days after the sponsor's initial receipt of the information (21 CFR 312.32(c)(2)).
- Device sponsors must immediately evaluate any UADE (21 CFR 812.46(b)(1)) and report the results to FDA, all reviewing IRBs and participating investigators within 10 working days after first receiving notice (21 CFR 812.150(b)(1)). If a UADE presents an unreasonable risk, the sponsor terminates the affected investigations no later than 5 working days after that determination and no later than 15 working days after first notice (21 CFR 812.46(b)(2)).
5.1.5
These sponsor clocks start when the sponsor receives information. Late site reports shorten the sponsor's time to act and to protect participants at other sites.
5.2 Study start-up preparation
5.2.1
Before activation, the Lead CRC records on the study page of F-501-01:
- the protocol SAE reporting timeline for initial and follow-up reports (set by the protocol; typically within 24 hours of awareness)
- the reporting method (EDC SAE form, sponsor safety portal, email or fax to the sponsor's safety department) and backup method if the system is down
- the SAE collection window and post-study reporting rule
- protocol-defined exclusions (planned hospitalizations, endpoint events, disease progression rules)
- the sponsor's medical monitor and safety contact details
- device-specific reporting rules (SADE, UADE, device deficiency) where applicable
5.2.2
The PI confirms that each delegated investigator, and each CRC delegated SAE reporting on F-302-01, has completed the sponsor's safety reporting training and has access to the reporting system before the first participant is enrolled.
5.2.3
The Site Director confirms that investigator coverage for the reporting window exists for weekends and holidays.
5.3 Recognizing an SAE and setting Day 0
5.3.1
Any staff member who receives information suggesting an SAE (participant call, caregiver call, hospital notification, EHR alert, outside record, monitor finding) records it in the source the same day, including the date and time of receipt and the source of the information, and informs the CRC and an investigator immediately.
5.3.2
The awareness date (Day 0) is the date the first site staff member received the information. The reporting clock starts then, not when the CRC or PI later reviews it. Information received after hours or at weekends counts from the date received.
5.3.3
The investigator decides whether the event meets any SAE criterion, including important medical event. When in doubt, the event is treated as serious and the sponsor's medical monitor may be consulted. Seriousness is not downgraded to avoid a report.
5.3.4
Hospitalizations: the CRC records the admission and discharge dates and admission status. Whether an emergency department visit, observation stay or planned procedure counts as hospitalization follows the protocol definitions. Admissions for procedures planned before the collection window opened, and for social reasons, are excluded only where the protocol says so.
5.4 Initial report
5.4.1
The CRC completes the initial SAE report within the protocol timeline from Day 0, even if information is incomplete. The minimum information is usually: participant ID, an identifiable reporter, the event term, and suspect IP. The sponsor's form sets the full content.
5.4.2
An investigator assesses seriousness and causality and reviews the report before or at submission. The investigator's assessment of causality is part of the initial report.
5.4.3
The investigator does not break the blind to report an SAE. Emergency unblinding for participant management follows SOP-305.
5.4.4
If the sponsor's electronic system is unavailable, the CRC uses the sponsor's paper or backup method, then enters the report electronically when the system returns.
5.4.5
The CRC records on F-501-01: participant ID, event term, Day 0, date and time reported, method, sponsor acknowledgment, and the name of the person who submitted.
5.4.6
The CRC files the submitted report and sponsor acknowledgment (or system confirmation) in the participant research record or ISF safety section, as the record location map on F-204-01 specifies (SOP-204).
5.4.7
The CRC enters the event as an AE in EDC in accordance with SOP-500 and SOP-307 and keeps the SAE form and the AE record consistent.
5.5 Supporting records and PHI
5.5.1
The CRC requests records needed to describe the event (discharge summary, history and physical, relevant laboratory and imaging results, procedure reports) from treating facilities. The request relies on the participant's HIPAA authorization (SOP-400).
5.5.2
Before sending any record to the sponsor, the CRC redacts and checks it under the single redaction rule in SOP-400 5.4.1 (what is redacted, coded participant ID, second-person check and record of what was sent).
5.5.3
Unredacted PHI sent in error is handled as a privacy incident under SOP-400 using F-400-01.
5.5.4
Outside records obtained are reviewed and signed by an investigator and filed in the participant research record.
5.6 Hospitalizations outside the site
5.6.1
The CRC instructs participants at consent and at each visit to tell any treating provider that they are in a clinical trial, to carry the participant wallet card, and to call the site as soon as possible after any emergency visit or admission.
5.6.2
When the site learns of an admission to an outside hospital, an investigator contacts the treating team where appropriate to share relevant trial information (IP, emergency unblinding route, sponsor 24-hour medical contact).
5.6.3
The CRC tracks the admission and discharge and obtains records under 5.5.
5.7 Deaths
5.7.1
A death during the reporting window is reported as an SAE within the protocol timeline. The event term is the cause of death where known; "death" is the outcome.
5.7.2
The CRC requests the death certificate, autopsy report and terminal medical records where available, and the investigator supplies the sponsor and IRB with any additional information they request (ICH E6(R3) Annex 1, 2.7.2(c)).
5.7.3
The CRC records contact with the family in the source. Staff do not press grieving relatives for information. Any outreach to family follows the participant's consent and authorization and IRB-approved processes.
5.7.4
Deaths that are protocol endpoints are reported as the protocol specifies, unless there is evidence of a causal relationship with the IP, in which case they are reported immediately (21 CFR 312.64(b)).
5.8 Follow-up reports
5.8.1
The CRC submits follow-up reports when significant new information is received (for example, new diagnosis, change in outcome, causality change, discharge, resolution, death), within the protocol follow-up timeline (typically within 24 hours of receiving the new information).
5.8.2
The CRC answers sponsor safety queries within the sponsor's timeline and records them on F-501-01.
5.8.3
Each SAE is followed until resolved, stabilized, explained, or the participant is lost to follow-up, as the protocol requires, and the final outcome is reported.
5.8.4
SAEs that the investigator learns of after the participant's end of study are reported if the protocol requires, or if the investigator considers them related to the IP.
5.9 Investigational devices
5.9.1
Serious adverse device effects, SAEs and device deficiencies that could have led to a SADE are reported to the sponsor within the protocol timeline, using the sponsor's device forms.
5.9.2
If the investigator considers that an event may be a UADE, the investigator (with the CRC preparing the submission) reports it to the sponsor and to the IRB as soon as possible and in no event later than 10 working days after the investigator first learned of it (21 CFR 812.150(a)(1)). Where the sponsor makes the UADE determination, the CRC confirms in writing which party will submit to the IRB and files the confirmation. If no confirmation exists, the site submits to the IRB.
5.9.3
The device, component or packaging involved is retained, labeled, segregated and returned to the sponsor as instructed. The Research Pharmacist or IP Manager records the return on the device accountability log (SOP-304). If the device has been explanted, the investigator coordinates retrieval with the treating facility according to sponsor instructions.
5.9.4
If the sponsor notifies the site that it is terminating the investigation because of a UADE that presents an unreasonable risk, the PI stops device use immediately except where stopping would itself endanger a participant, and follows SOP-601 section 5.11. A significant risk device study terminated for this reason may not resume without IRB and FDA approval (21 CFR 812.46(c)).
5.10 Receiving and processing sponsor safety reports
5.10.1
The Regulatory Coordinator logs each IND safety report, SUSAR letter, device safety notice, Dear Investigator letter and periodic line listing on receipt, and routes it to the PI for review [DEFAULT: within 5 business days of receipt; same day for urgent safety notices].
5.10.2
The PI reviews each report and records the review (signature and date, or the portal's electronic acknowledgment) and decides:
- whether any enrolled participant needs immediate action (for example, additional monitoring, IP hold)
- whether participants need to be told and reconsented (SOP-301)
- whether the information meets the IRB's definition of reportable new information (SOP-502)
5.10.3
The Regulatory Coordinator files each report and its acknowledgment in the ISF safety section (or confirms that the sponsor portal is the agreed repository and the site has continued access through record retention; SOP-204).
5.10.4
FDA's December 2025 investigator safety reporting guidance states that the investigator must submit IND safety reports to the IRB (21 CFR 312.66), because FDA considers information that meets the IND safety reporting criteria to be an unanticipated problem. Where the protocol or sponsor states that the sponsor submits IND safety reports to the IRB on the investigator's behalf, the Regulatory Coordinator obtains confirmation that the sponsor has sent each report, files it, and does not send a duplicate; the arrangement is documented on F-502-01. Otherwise the Regulatory Coordinator submits each IND safety report to the IRB under SOP-502. Other sponsor safety information (line listings, device safety notices, DSMB reports) goes to the IRB when the IRB's policy requires it. The IRB's written procedures govern how and when reports are submitted.
5.10.5
Urgent safety measures from the sponsor (for example, an immediate dosing hold) are actioned on receipt, documented, and reported to the IRB under SOP-502.
5.11 Late reports and quality review
5.11.1
Any SAE reported after the protocol timeline is recorded as a protocol deviation (SOP-308) with the reason, and reported to the IRB if it meets the IRB's criteria (SOP-502).
5.11.2
The Quality Lead reviews F-501-01 for timeliness as part of the quarterly metrics review in SOP-700 5.7.1, and opens CAPA where a trigger in SOP-703 5.1.2 is met (for example repeated or systemic late reporting).
6. Related Forms and SOPs
- F-501-01 SAE Reporting Tracker
- F-500-01 Adverse Event Assessment Worksheet
- F-302-01 Delegation of Authority Log
- F-400-01 Privacy Incident Report
- F-308-01 Protocol Deviation Log
- SOP-204 Essential Documents and the Investigator Site File
- SOP-301 Informed Consent Process and Documentation
- SOP-304 Investigational Product Management
- SOP-305 Randomization, Blinding and Emergency Unblinding
- SOP-307 Case Report Forms, EDC Entry and Query Resolution
- SOP-308 Protocol Deviations and Noncompliance
- SOP-400 Participant Privacy and HIPAA in Research
- SOP-500 Adverse Event Identification, Assessment and Recording
- SOP-502 Unanticipated Problems and Reportable New Information
- SOP-503 Pregnancy Reporting in Clinical Trials
- SOP-601 Study Closeout
- SOP-703 Corrective and Preventive Action (CAPA)
- SOP-800 Sponsor-Investigator Responsibilities (IND/IDE Holder)
- SOP-903 Network Oversight of Member Sites (Metrics, Central QA, Escalation) (Model N only)
- SOP-904 Shared Staff, Cross-Site Coverage and Central Services (Model N only)
- SOP-905 Network Data, Systems, Privacy and Records Across Sites (Model N only)
- Appendix B Central and Site Responsibility Matrix (Model N only)
7. References
| Reference | Title |
|---|---|
| 21 CFR 312.32 | IND Safety Reporting |
| 21 CFR 312.64(b) | Investigator Reports: Safety Reports |
| 21 CFR 812.3(s) | Definition: Unanticipated Adverse Device Effect |
| 21 CFR 812.46(b), (c) | Monitoring Investigations: Unanticipated Adverse Device Effects; Resumption of Terminated Studies |
| 21 CFR 812.150(a)(1), (b)(1) | Reports: Unanticipated Adverse Device Effects |
| 45 CFR 164.508 | Uses and Disclosures for Which an Authorization Is Required |
| ICH E6(R3) Annex 1, 2.7 | Participant Medical Care and Safety Reporting |
| ICH E6(R3) Annex 1, 3.13 | Safety Assessment and Reporting (sponsor) |
| ICH E2A | Clinical Safety Data Management: Definitions and Standards for Expedited Reporting |
| ISO 14155 (current edition) | Clinical Investigation of Medical Devices for Human Subjects: Good Clinical Practice |
| FDA Guidance (December 2025) | Investigator Responsibilities: Safety Reporting for Investigational Drugs and Devices |
| FDA Guidance (December 2025) | Sponsor Responsibilities: Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies |
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