Safety Monitoring Boards and Safety Review Committees in Phase 1 Trials

Introduction

Safety is the cornerstone of every clinical trial, especially during early-phase drug development where human exposure to a new chemical or biological entity occurs for the first time. In Phase 1 studies, Safety Monitoring Boards (SMBs) and Safety Review Committees (SRCs) play vital roles in safeguarding participant wellbeing and guiding dose escalation. These groups serve as independent and/or internal oversight bodies that evaluate emerging safety, pharmacokinetic (PK), and pharmacodynamic (PD) data to determine whether a study should proceed, pause, or be modified.

Definitions and Purpose

Safety Review Committee (SRC)

An SRC is typically an internal or sponsor-appointed committee established before the start of a Phase 1 trial. Its role is to review safety data after each cohort, recommend dose escalation or adjustments, and assess adverse events (AEs) or dose-limiting toxicities (DLTs).

Data Safety Monitoring Board (DSMB)

A DSMB (also called a Data Monitoring Committee, or DMC) is an independent external board, often required for high-risk trials. While more common in Phase 2/3 studies, a DSMB may also be included in complex Phase 1 trials—such as those involving gene therapy, oncology, or multiple expansion cohorts.

When Are These Committees Required?

Required in Phase 1 When:

• The compound is first-in-class or high-risk
• The trial involves vulnerable populations (e.g., pediatric, oncology, CNS)
• There are multiple dose levels or complex adaptive designs
• The protocol includes sentinel dosing or staggered enrollment
• There are combination therapies with known overlapping toxicities

Optional/Not Typically Required When:

• The study involves healthy volunteers and non-cytotoxic agents
• The compound is a repurposed or well-characterized molecule
• Single-dose, low-risk exposures with built-in site-level safety reviews

Composition of SRC and DSMB

SRC Typical Members

• Principal investigator or medical monitor
• Sponsor clinical lead
• PK/PD analyst or clinical pharmacologist
• Biostatistician (optional)
• Project manager (non-voting)

DSMB Typical Members

• Independent clinical expert(s) in relevant therapeutic area
• Independent statistician
• Bioethicist (optional but recommended)
• Chairperson (usually not affiliated with sponsor)

Independence and Conflict of Interest

While SRCs are often internal or semi-independent, DSMBs must operate independently. Members must sign confidentiality and conflict-of-interest declarations. Independence ensures unbiased oversight and enhances regulatory credibility.

Functions and Responsibilities

For SRC:

• Review all adverse events and serious adverse events (SAEs)
• Evaluate dose-limiting toxicities (DLTs)
• Analyze interim PK/PD and laboratory data
• Make dose-escalation recommendations
• Assess protocol deviations or safety signals
• Recommend dose expansion, protocol modifications, or trial termination

For DSMB:

• Oversee aggregate data across multiple sites or countries
• Evaluate cumulative safety and efficacy signals in ongoing studies
• Recommend continuation, modification, or halting of the trial
• Issue official DSMB letters to regulatory authorities if applicable

SRC/DSMB Meeting Frequency

Type	Frequency	Mode
SRC	After each cohort or sentinel group	In-person or virtual
DSMB	Quarterly or based on milestones	Independent closed-door meetings

Key Documents and Tools

• SRC Charter: Outlines roles, responsibilities, quorum, and voting process
• DSMB Charter: Includes independence requirements, data access rules, and communication procedures
• Safety Data Review Package: AE/SAE listings, lab data summaries, narratives, dose logs
• Meeting minutes and decision reports: Required for audit trail and regulatory submission

Example Decision Path in a Phase 1 Oncology Trial

• Cohort 1: No DLTs → escalate to next dose level
• Cohort 2: 1 DLT in 6 → expand to 9 subjects
• Cohort 2 (expanded): 2 DLTs total → hold escalation, discuss stopping rule
• SRC meets → recommends intermediate dose or alternate schedule

Ethical and Regulatory Oversight

• Regulators such as the FDA and EMA expect clear SRC/DSMB plans in protocols
• ICH E6(R2): Good Clinical Practice requires risk-based monitoring and independent oversight where appropriate
• Ethics Committees/IRBs may request access to DSMB decisions or charter

Best Practices for SRC and DSMB Implementation

• Define structure, roles, and timelines in advance
• Ensure real-time availability of clean data before meetings
• Implement clear decision rules for escalation, hold, and expansion
• Train study team members on responsibilities and documentation standards
• Maintain full transparency while protecting trial integrity