Adverse Event Monitoring in Phase 1: Definitions, Reporting, and Grading

Table of Contents

Introduction

Adverse event (AE) monitoring is at the heart of Phase 1 clinical trials, where the primary objective is to establish the safety and tolerability of a new investigational product (IP). Because participants are often exposed to a drug for the first time in humans, detecting, assessing, and reporting AEs accurately is critical to protect subjects and comply with global regulatory standards.

This tutorial walks through key definitions, classification systems, reporting requirements, and grading guidelines used in early-phase AE monitoring.

What Is an Adverse Event?

An Adverse Event (AE) is defined as any untoward medical occurrence in a subject administered an investigational product, whether or not related to the product.

This includes:

Symptoms (e.g., headache, rash, nausea)
Abnormal lab values (e.g., elevated ALT, low platelets)
ECG abnormalities
Vital sign deviations (e.g., hypotension, tachycardia)

Even events that do not require treatment but deviate from baseline are captured as AEs.

Serious Adverse Events (SAEs)

A Serious Adverse Event (SAE) is any AE that results in:

Death
Life-threatening condition
Hospitalization or prolongation of existing hospitalization
Persistent or significant disability/incapacity
Congenital anomaly/birth defect
Any other event deemed medically significant by the investigator

SAEs must be reported immediately to the sponsor and regulatory authorities.

AE Classification by Causality

Causality assessment determines whether the AE is related to the investigational drug. The investigator is responsible for making this assessment based on timing, dose-response, dechallenge/rechallenge, and biological plausibility.

Typical causality categories include:

Not related
Unlikely
Possible
Probable
Definite

Causality assessments are documented in the source notes and CRFs and may influence further dosing decisions in dose-escalation trials.

Grading Severity of Adverse Events

The severity of an AE refers to intensity, not seriousness. It is usually graded using standardized scales:

CTCAE (Common Terminology Criteria for Adverse Events)

Used widely in oncology and early-phase trials, CTCAE provides a 5-point scale:

Grade 1 (Mild): Asymptomatic or mild symptoms; no intervention required
Grade 2 (Moderate): Minimal intervention; limiting age-appropriate activities
Grade 3 (Severe): Medical intervention required; hospitalization possible
Grade 4 (Life-threatening): Immediate intervention required
Grade 5: Death related to AE

DAIDS AE Grading Tables

Used in infectious disease trials and for lab-based abnormalities (e.g., hematology, liver enzymes). Similar grading structure based on numeric thresholds.

Recording AEs in Phase 1 Trials

All AEs should be documented in:

Source notes (site investigator’s records)
Case Report Forms (CRFs)
Safety databases (e.g., ARGUS, Oracle Clinical, MedDRA coded)

Each AE entry should include:

Onset and resolution dates
Severity grade
Causality assessment
Outcome (recovered, ongoing, fatal, etc.)
Actions taken (e.g., IP interruption, concomitant meds)

Real-Time Monitoring and Safety Oversight

1. Clinical Monitoring

On-site or remote CRA reviews AE entries regularly
Ensures AE-to-lab/vitals consistency

2. Investigator Role

Reviews labs and patient-reported symptoms
Performs causality and severity grading
Documents all medical interventions and outcomes

3. Medical Monitors and Safety Physicians

Provide sponsor oversight of SAEs and cumulative safety
Evaluate trends across cohorts or studies
Decide on pausing, dose adjustment, or escalation hold

4. Safety Review Committees (SRCs)

Review unblinded safety data at pre-defined milestones (e.g., after each cohort)
Make formal recommendations for escalation or study continuation

Reporting Timelines for SAEs

Recipient	Timeline
Sponsor (from site)	Within 24 hours of SAE awareness
Regulatory Authorities	Within 7–15 days for SUSARs
Ethics Committee	Immediate or within 7 days (local policy)

Common AEs in Phase 1 Trials

While most Phase 1 trials are conducted in healthy volunteers or patients with no active disease intervention, common AEs include:

Injection site reactions
Gastrointestinal discomfort (nausea, vomiting)
Headache, dizziness
Mild laboratory abnormalities (e.g., ALT elevation)
Transient changes in blood pressure or heart rate

Adverse Event Coding and MedDRA

All reported AEs must be coded using a standardized terminology system—most commonly MedDRA (Medical Dictionary for Regulatory Activities). Proper coding ensures:

Consistency across sites and studies
Regulatory acceptability for signal detection
Clean and analyzable data for DSURs, IBs, and regulatory submissions

Integration with Protocol and Study Design

Phase 1 protocols must include:

Definitions of AEs, SAEs, and DLTs
Grading criteria and source
Safety stopping rules
Reporting pathways and responsibilities

For example, in a SAD/MAD study, DLTs are often defined as any Grade 3 AE that is drug-related and persistent beyond 48 hours, or any Grade 4 SAE regardless of attribution.

Conclusion

Adverse event monitoring in Phase 1 is foundational to clinical safety evaluation. With small sample sizes and limited exposure data, each AE carries more weight in determining whether a compound is safe to proceed. By following standardized definitions, timely reporting practices, and globally accepted grading scales, clinical teams ensure both subject protection and regulatory compliance—paving the way for future trial phases built on trust and transparency.