SOP-500
Adverse Event Identification, Assessment and Recording
- Number
- SOP-500
- Category
- Safety
- Edition
- Reference Edition 1.3
- Approx. pages
- 7
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1. Purpose
This SOP describes how [SITE NAME] identifies, assesses, documents and records adverse events (AEs) in clinical trials, and how investigators provide medical care for participants who experience them. Serious adverse events and expedited reporting are covered in SOP-501.
2. Scope
This SOP applies to all drug, biologic and device trials conducted at [SITE NAME], at all locations and during remote or home visits. It covers AEs, abnormal test results, adverse device effects and device deficiencies from the start of the protocol-defined collection window until the end of follow-up.
Out of scope: expedited reporting of serious adverse events (SOP-501), reporting to the IRB (SOP-502) and pregnancy reporting (SOP-503).
Follow the protocol, sponsor safety instructions or IRB requirement where it is stricter than or more specific than this SOP. The protocol's definitions, grading scale and collection window govern each trial.
3. Responsibilities
| Role | Responsibilities |
|---|---|
| Principal Investigator (PI) | Holds overall responsibility for participant safety and AE assessment. Assesses or confirms seriousness, severity and causality for each AE. Provides or arranges medical care for AEs. Reviews and signs abnormal results. Keeps responsibility for safety reporting even when tasks are delegated. |
| Sub-Investigator (Sub-I) | Assesses AEs and causality when delegated on the Delegation of Authority Log and qualified to do so under the protocol. Provides trial-related medical care within their licensure. |
| Clinical Research Coordinator (CRC) | Elicits and collects AE information at each contact, records it in source, completes F-500-01 for the investigator's assessment, enters AE data in EDC, and tracks follow-up to resolution. Does not assess causality or clinical significance. |
| Research Pharmacist or IP Manager | Reports to the CRC and PI any AE or device deficiency learned of during dispensing, accountability or IP returns. |
| Quality Lead | Includes AE documentation in QC reviews (SOP-700) and trends AE-related findings for CAPA (SOP-703). |
| All Research Staff | Pass any participant health complaint or safety information to the CRC or an investigator the same day it is received. |
4. Definitions
| Term | Definition |
|---|---|
| Adverse Event (AE) | Any unfavorable medical occurrence in a trial participant administered the investigational product, whether or not considered related to it. Includes any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with use of the investigational product. The protocol may extend collection to events occurring before dosing (for example, from consent). |
| Adverse Drug Reaction / Suspected Adverse Reaction | An AE for which there is a reasonable possibility that the investigational product caused it, meaning there is evidence to suggest a causal relationship (21 CFR 312.32(a)). |
| Serious Adverse Event (SAE) | An AE that 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 (21 CFR 312.32(a)). 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; full definition in SOP-501). |
| Severity | The intensity of an event (for example, mild, moderate, severe, or a CTCAE grade) as defined in the protocol. A clinical measure, not a regulatory one. |
| Seriousness | Whether the event meets SAE criteria. Determines reporting obligations. A severe event is not necessarily serious, and a serious event is not necessarily severe. |
| Causality (relatedness) | The investigator's judgment of whether there is a reasonable possibility that the investigational product (or a study procedure, where the protocol asks) caused the event. |
| Expectedness | Whether the nature, severity or specificity of an event is consistent with the reference safety information (RSI) for the product. The sponsor makes the regulatory expectedness determination. |
| Reference Safety Information (RSI) | The section of the Investigator's Brochure (IB), or the approved package insert or device risk analysis where the protocol names it, used to judge expectedness. |
| Clinically significant (CS) | An abnormal test result that, in the investigator's judgment, indicates a new or worsened medical condition, requires intervention or further evaluation, or leads to IP interruption or discontinuation, or that the protocol defines as an AE. |
| Medical history | Conditions present before the start of the AE collection window, recorded as baseline. |
| Adverse Device Effect (ADE) | An AE related to the use of an investigational medical device, including events from inadequate instructions for use, deployment, implantation, installation, operation or malfunction, and events resulting from use error or intentional misuse (ISO 14155). |
| Device Deficiency | An inadequacy of an investigational medical device with respect to its identity, quality, durability, reliability, usability, safety or performance, including malfunctions, use errors and inadequate labeling (ISO 14155). |
| Source record | The original record or certified copy in which a clinical finding or observation is first recorded (see SOP-306). |
5. Procedure
5.1 Study start-up preparation
5.1.1
Before the first participant is consented, the Lead CRC extracts from the protocol and safety manual the following and records them on the study-specific page of F-500-01:
- AE and SAE collection windows (start and stop points)
- the severity grading scale (for example, CTCAE version, mild/moderate/severe)
- causality categories the CRF requires
- events the protocol excludes from AE recording or defines as endpoints
- protocol rules for abnormal laboratory values, vital signs and ECGs
- the RSI document and version
- AE-related EDC and safety-system instructions
5.1.2
The PI confirms at the site initiation visit (SOP-205) which investigators will assess AEs. Only investigators listed for AE assessment on F-302-01 (SOP-302) assess causality and clinical significance.
5.1.3
The Regulatory Coordinator files the current IB, package insert or device risk documents in the ISF and routes each new version to the PI for review (SOP-204). The PI signs and dates the acknowledgment before applying the new RSI.
5.2 Collection window and baseline
5.2.1
The CRC starts AE collection at the point the protocol specifies. Common patterns are from signing of consent (often for SAEs) or from first dose of IP (often for non-serious AEs). Where the protocol is silent, the CRC asks the sponsor in writing and files the answer in the ISF.
5.2.2
Before the collection window opens, the CRC records all current and past relevant conditions, ongoing symptoms and concomitant medications as medical history, with onset dates where known.
5.2.3
Events that occur after consent but before the AE collection window opens are recorded as medical history unless the protocol requires them to be reported (ICH E6(R3) Annex 1, 2.7.2(a)).
5.2.4
A pre-existing condition that worsens in frequency, severity or character after the collection window opens is recorded as an AE (for example, "worsening of hypertension"). A stable baseline condition is not an AE.
5.3 Eliciting and identifying AEs
5.3.1
At every visit, phone contact and remote visit, the CRC or investigator asks the participant an open, non-leading question about their health since the last contact (for example, "How have you been feeling since your last visit?"), followed by questions about medical visits, hospital stays, emergency visits and medication changes.
5.3.2
The CRC also identifies potential AEs from:
- physical examination, vital signs, ECGs and other assessments
- laboratory, imaging and other test results
- participant diaries and electronic patient-reported outcome alerts
- concomitant medication changes (each new or changed medication should have a matching indication)
- outside medical records, pharmacy records and EHR notifications
- calls from the participant, caregiver or other providers between visits
- IP accountability and device returns
5.3.3
Any staff member who learns of possible safety information between visits records it in the source the same day and informs the CRC or an investigator. If the information could meet SAE criteria, staff follow SOP-501 immediately.
5.3.4
The CRC records the AE as a diagnosis where one is known. Where no diagnosis is yet available, each sign or symptom is recorded separately and updated to the diagnosis when it is made, following the sponsor's CRF instructions.
5.4 Abnormal laboratory and test results
5.4.1
The CRC routes each laboratory, ECG, imaging or other test report to an investigator on receipt. The investigator reviews it within the timing set in SOP-101 5.4.4.
5.4.2
The investigator reviews each out-of-range value, marks it CS or NCS, and signs and dates the report (wet ink or compliant electronic signature per SOP-401). The review date in the source must allow the investigator to act on the result.
5.4.3
A CS abnormal value is recorded as an AE unless it is part of a condition already recorded as an AE or medical history and has not worsened, or the protocol states otherwise. The investigator records the diagnosis where one explains the abnormality (for example, "anemia" rather than "low hemoglobin").
5.4.4
Values that meet protocol-specified thresholds (for example, liver test elevations meeting Hy's Law criteria, or QTc limits) are handled exactly as the protocol directs, including any expedited reporting or IP interruption.
5.4.5
Critical or alert values are communicated to an investigator by phone the same day they are received. The CRC records the time of notification and the action taken.
5.5 Investigator assessment
5.5.1
For each AE, an investigator assesses and records on F-500-01 or in an equivalent source note:
- seriousness (yes or no, and which criterion; see SOP-501)
- severity using the protocol scale
- causality in relation to the IP, and to study procedures where the protocol asks
- action taken with the IP (none, dose reduced, interrupted, permanently discontinued)
- other treatment given
- outcome
5.5.2
The investigator bases causality on temporal relationship, biological plausibility, known product profile in the RSI, dechallenge and rechallenge information, and alternative explanations such as underlying disease or concomitant medication. The investigator assesses causality as if the participant received active product. The investigator does not unblind to assess causality (see SOP-305).
5.5.3
Expectedness: the investigator compares the event with the RSI and records an assessment if the protocol or CRF asks for one. An event is unexpected if its nature, severity or specificity is not consistent with the RSI (for example, hepatic necrosis when the IB lists only elevated hepatic enzymes). The sponsor makes the final regulatory expectedness determination.
5.5.4
Severity and seriousness are recorded separately. A severe headache can be non-serious. A mild event that leads to hospitalization is serious.
5.5.5
If the investigator's assessment differs from the CRC's initial capture (for example, an event reclassified as medical history), the investigator documents the reason in the source.
5.5.6
Causality and clinical significance assessments are made only by an investigator delegated for AE assessment. The CRC may record a provisional entry, but it is not complete until the investigator signs.
5.6 Source documentation
5.6.1
The source record for each AE contains, at a minimum:
- AE term (diagnosis, or signs and symptoms)
- onset date (and time where the protocol requires it)
- how the site learned of the event and the date site staff first became aware
- description, including relevant signs, symptoms and test results
- seriousness, severity and causality, with the assessing investigator's name, signature and date
- action taken with the IP and any treatment, including concomitant medications given
- outcome (recovered or resolved, recovering, not recovered, recovered with sequelae, fatal, unknown) and stop date
5.6.2
F-500-01 Adverse Event Assessment Worksheet is used for each event unless the site's EHR or eSource captures every element in 5.6.1 with an investigator signature. Records follow ALCOA+ principles (SOP-306).
5.6.3
Outside medical records obtained for an AE are filed in the participant's research record and reviewed and signed by an investigator.
5.7 EDC entry
5.7.1
The CRC enters AE data in the EDC within the timeline in SOP-307 or the sponsor's data-entry timeline, whichever is shorter.
5.7.2
EDC entries match the source. Changes in severity are recorded per the sponsor's CRF rules (some sponsors require a new AE record for each change in grade).
5.7.3
Related records (concomitant medications, IP dosing, IP discontinuation, withdrawal) are updated at the same time so that the CRF is internally consistent.
5.8 Medical care obligations
5.8.1
A qualified physician (or other qualified licensed healthcare professional where local law and the protocol allow) who is the PI or a Sub-I is responsible for trial-related medical care and decisions (ICH E6(R3) Annex 1, 2.7.1(a)).
5.8.2
During and after participation, the investigator makes sure adequate medical care is provided for any AE related to the trial, including clinically significant laboratory values. This may be treatment at the site within the investigator's scope, or referral to the participant's own physician, urgent care or emergency services.
5.8.3
The investigator tells the participant when medical care is needed for an intercurrent illness the investigator becomes aware of, even if it is not trial related (ICH E6(R3) Annex 1, 2.7.1(c)).
5.8.4
With the participant's agreement, the investigator informs the participant's primary physician about the participant's involvement in the trial (ICH E6(R3) Annex 1, 2.7.1(d)). The CRC documents the participant's choice.
5.8.5
Each participant receives written 24-hour contact details for the site, including how to reach an investigator after hours, and instructions to seek emergency care first in an emergency.
5.8.6
Participant injury costs and billing for treatment of research injuries follow the CTA and SOP-202.
5.9 Follow-up to resolution
5.9.1
The CRC follows each AE at each subsequent contact until it resolves, stabilizes, returns to baseline, is otherwise explained, or the participant is lost to follow-up, or until the end of the protocol-defined follow-up period.
5.9.2
AEs ongoing at the participant's end of study or withdrawal are followed as the protocol requires. Where the protocol does not require further follow-up, the investigator documents the arrangement for ongoing care.
5.9.3
Each update is recorded in source and EDC, including changes in severity, seriousness or causality. An AE that becomes serious is reported under SOP-501 from the date the site became aware it met SAE criteria.
5.9.4
If a participant withdraws consent for further participation, the CRC follows SOP-309 regarding continued safety follow-up and use of data already collected.
5.10 Investigational devices
5.10.1
In device trials the investigator assesses each AE for relationship to the device and, where the protocol asks, to the procedure.
5.10.2
Site staff record every device deficiency (malfunction, use error, labeling problem) whether or not it caused an AE. The record includes device identifier, lot or serial number, date, description, and whether it led to or could have led to a serious adverse device effect if action had not been taken or circumstances had been less fortunate.
5.10.3
Device deficiencies and any related AEs are reported to the sponsor within the protocol timeline. Device deficiencies that led to or could have led to a serious adverse device effect, and serious ADEs, are handled under SOP-501.
5.10.4
A deficient device or component is kept, labeled "Do Not Use: Device Deficiency", segregated from usable stock and returned to the sponsor as instructed (SOP-304). It is not discarded or repaired by site staff.
5.10.5
Records of adverse device effects, whether anticipated or unanticipated, form part of each participant's case history (21 CFR 812.140(a)(3)(ii)).
5.11 Quality checks
5.11.1
Before each monitoring visit, the CRC reconciles for each participant the AE log, concomitant medications, unscheduled visits, and abnormal results marked CS, and resolves gaps.
5.11.2
The Quality Lead includes AE completeness and investigator sign-off in QC reviews using F-700-01 (SOP-700). Repeated late or missing assessments are handled as deviations (SOP-308) and, where systemic, through CAPA (SOP-703).
6. Related Forms and SOPs
- F-500-01 Adverse Event Assessment Worksheet
- F-302-01 Delegation of Authority Log
- F-306-01 Note to File
- F-700-01 Internal QC Review Checklist
- SOP-202 Medicare Coverage Analysis and Research Billing Compliance
- SOP-204 Essential Documents and the Investigator Site File
- SOP-205 Site Qualification, Initiation and Study Activation
- SOP-302 Delegation of Authority
- SOP-304 Investigational Product Management
- SOP-305 Randomization, Blinding and Emergency Unblinding
- SOP-306 Source Documentation and Data Integrity (ALCOA+)
- SOP-307 Case Report Forms, EDC Entry and Query Resolution
- SOP-308 Protocol Deviations and Noncompliance
- SOP-309 Participant Retention, Withdrawal and Lost to Follow-Up
- SOP-401 Computerized Systems and Electronic Records
- SOP-501 Serious Adverse Event and Expedited Safety Reporting
- SOP-502 Unanticipated Problems and Reportable New Information
- SOP-503 Pregnancy Reporting in Clinical Trials
- SOP-700 Internal Quality Control and Quality Assurance Audits
- SOP-703 Corrective and Preventive Action (CAPA)
- SOP-904 Shared Staff, Cross-Site Coverage and Central Services (Model N only)
- Appendix B Central and Site Responsibility Matrix (Model N only)
7. References
| Reference | Title |
|---|---|
| 21 CFR 312.32(a) | IND Safety Reporting: Definitions |
| 21 CFR 312.62(b) | Investigator Recordkeeping: Case Histories |
| 21 CFR 312.64(b) | Investigator Reports: Safety Reports |
| 21 CFR 812.140(a)(3) | Investigator Records: Case Histories and Adverse Device Effects |
| 21 CFR 812.150(a) | Investigator Reports |
| ICH E6(R3) Annex 1, 2.7 | Participant Medical Care and Safety Reporting |
| ICH E6(R3) Glossary | Adverse Event, Adverse Drug Reaction, Serious Adverse Event, Reference Safety Information |
| 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 (2009) | Investigator Responsibilities: Protecting the Rights, Safety, and Welfare of Study Subjects |
| FDA Guidance (December 2025) | Investigator Responsibilities: Safety Reporting for Investigational Drugs and Devices |
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