How to Handle Adverse Events and Serious Adverse Events (SAEs) in Phase 2 Trials

Introduction

Adverse events (AEs) and serious adverse events (SAEs) are a core focus of safety monitoring in clinical trials, particularly in Phase 2 where investigational drugs are administered to patients with the target condition. The proper handling, documentation, and reporting of these events are not only critical for patient safety but also regulatory compliance and overall trial success. This tutorial provides a comprehensive guide on the processes, roles, and best practices for managing AEs and SAEs in Phase 2 clinical studies.

Definitions: AE vs. SAE

Adverse Event (AE)

An AE is any untoward medical occurrence in a clinical trial subject, which may or may not be related to the investigational product. It includes symptoms, lab abnormalities, or diseases that emerge during the trial period.

Serious Adverse Event (SAE)

An SAE is an adverse event that results in:

• Death
• Life-threatening situation
• Hospitalization or prolongation of existing hospitalization
• Persistent or significant disability/incapacity
• Congenital anomaly or birth defect
• Other important medical events (per the investigator’s discretion)

Sources of AE and SAE Identification

• Patient-reported symptoms
• Physical examinations
• Laboratory test results
• Vital signs or imaging results
• Hospital admissions or emergency visits

Grading and Severity Assessment

AEs and SAEs are graded based on severity using the CTCAE (Common Terminology Criteria for Adverse Events):

• Grade 1: Mild
• Grade 2: Moderate
• Grade 3: Severe or medically significant
• Grade 4: Life-threatening
• Grade 5: Death related to AE

Causality Assessment

The investigator must determine whether an AE or SAE is:

• Not related
• Possibly related
• Probably related
• Definitely related to the investigational product

This determination is based on temporal association, biological plausibility, and absence of alternative explanations.

Documentation of AEs and SAEs

Case Report Forms (CRFs)

All AEs and SAEs are recorded in the study CRF with details including:

• Date of onset and resolution
• Severity and seriousness
• Causality assessment
• Action taken (e.g., dose reduction, treatment withdrawal)
• Outcome (e.g., recovered, ongoing, fatal)

SAE Reporting Form

A separate SAE form is filled and submitted within 24 hours of awareness. It may include narratives, lab results, hospital notes, and autopsy reports (if applicable).

Timelines for SAE Reporting

• To Sponsor: Within 24 hours of site awareness
• To Regulatory Authorities:
  • Fatal or life-threatening SUSARs: Within 7 calendar days
  • All other SUSARs: Within 15 calendar days
• To Ethics Committees: Typically within 7 working days or as per local requirements

Management of Ongoing Adverse Events

• Provide medical care and monitor until resolution
• Adjust or discontinue investigational product if necessary
• Follow up to capture long-term outcomes
• Update documentation as new information becomes available

Examples

Example 1: Non-Serious AE

A subject reports mild nausea (Grade 1) on Day 3 after dosing. No treatment required. AE is recorded in the CRF and resolved by Day 5. Causality deemed “possibly related.”

Example 2: SAE – Hospitalization

A subject experiences acute chest pain on Day 14 and is hospitalized for cardiac evaluation. Event is recorded as a SAE and reported to the sponsor and IRB within 24 hours. Outcome is non-fatal; causality assessed as “unrelated.”

MedDRA Coding

All AEs and SAEs must be coded using the Medical Dictionary for Regulatory Activities (MedDRA). This ensures consistency in terminology and supports global regulatory submission requirements.

Responsibilities

Investigator Responsibilities

• Identify, evaluate, and report AEs and SAEs
• Provide medical care and follow-up
• Complete SAE forms and narratives

Sponsor Responsibilities

• Ensure 24/7 SAE reporting infrastructure
• Perform medical review and causality assessment
• Submit expedited reports to regulators and ethics boards
• Compile cumulative safety data for annual reports

Regulatory Expectations

• FDA: IND safety reports must be submitted promptly with safety narratives
• EMA: SUSARs must be reported through EudraVigilance
• CDSCO: SAE reports required within 14 days with ethics committee evaluation and compensation recommendations

Best Practices

• Train all study staff on AE/SAE reporting procedures
• Use standardized templates for SAE narratives
• Establish clear site-Sponsor communication protocols
• Predefine stopping rules for AE frequency or severity

Conclusion

Effective handling of AEs and SAEs in Phase 2 trials ensures subject protection, enhances trial credibility, and meets global regulatory expectations. Investigators, sponsors, and ethics committees must work collaboratively to create a reliable safety monitoring framework—one that emphasizes timeliness, accuracy, and patient-centered action at every step.