ICH E6(R2): Good Clinical Practice Updates

Introduction

The ICH E6(R2) addendum to Good Clinical Practice guidelines introduces important updates focusing on risk-based approaches to clinical trial management, quality management systems, and enhanced oversight of clinical trials. These changes reflect modern clinical trial practices and technological advances.

What is ICH E6(R2)?

ICH E6(R2) is the revised Good Clinical Practice guideline that builds upon the original E6(R1) by introducing risk-based approaches to clinical trial management, quality management systems, and enhanced requirements for oversight and documentation.

Key Changes in ICH E6(R2)

1. Risk-Based Quality Management

The addendum introduces a systematic approach to quality management based on risk assessment:

• Identification of critical to quality factors
• Risk-based monitoring strategies
• Proportionate approaches to trial oversight
• Focus on factors essential to human subject protection and data reliability

2. Quality Management System

Sponsors must implement quality management systems that include:

• Quality planning and assurance
• Quality control and improvement
• Corrective and preventive actions (CAPA)
• Management review of quality metrics

3. Enhanced Investigator Responsibilities

Clarified expectations for investigators regarding:

• Oversight of delegated trial-related duties
• Supervision of trial conduct at site
• Ensuring adequate resources and facilities
• Medical care and decisions for trial subjects

Risk-Based Monitoring

ICH E6(R2) allows flexible monitoring approaches based on trial risks:

Monitoring Methods

• On-site monitoring: Traditional site visits
• Centralized monitoring: Remote data review and analysis
• Risk-based monitoring: Targeted monitoring based on risk assessment
• Combination approaches: Mix of methods based on trial needs

Monitoring Plan Requirements

The monitoring plan should describe:

• Rationale for monitoring strategy
• Monitoring methods to be used
• Frequency and extent of monitoring
• Roles and responsibilities
• Documentation requirements

Essential Documents

E6(R2) updates requirements for essential documents including:

• Electronic records and signatures
• Audit trails for electronic systems
• Data integrity requirements
• Archiving of electronic records

Implications for Clinical Trials

For Sponsors

• Implement quality management systems
• Develop risk-based monitoring strategies
• Ensure adequate training on E6(R2) requirements
• Update SOPs and trial procedures

For Investigators

• Enhanced oversight of delegated tasks
• Improved documentation of supervision
• Understanding of quality management principles
• Adaptation to new monitoring approaches

For CROs

• Implementation of risk-based monitoring tools
• Quality management system integration
• Training of monitoring staff
• Updated monitoring procedures

Practical Implementation

For Sponsors

Steps to implement ICH E6(R2):

• Conduct gap analysis against current practices
• Develop or update quality management system
• Implement risk-based monitoring approaches
• Update SOPs and training materials
• Establish quality metrics and KPIs

For Sites

Investigators should:

• Understand enhanced oversight responsibilities
• Ensure adequate delegation documentation
• Maintain oversight of delegated tasks
• Adapt to new monitoring approaches

Benefits of ICH E6(R2)

Under the EU Medical Device Regulation (MDR 2017/745), manufacturers must compile comprehensive technical documentation that demonstrates conformity with regulatory requirements. The structure includes:

• Device description and specifications
• Information supplied by the manufacturer
• Design and manufacturing information
• General safety and performance requirements
• Benefit-risk analysis and risk management
• Product verification and validation
• Clinical evaluation
• Post-market surveillance

Comparative Analysis

Clinical Evidence Requirements

CTD: Requires extensive clinical trial data with detailed Clinical Study Reports following ICH E3 guidelines. Emphasis on randomized controlled trials demonstrating efficacy and safety.

MDR: Clinical evaluation can include clinical investigations, literature reviews, and post-market clinical follow-up. Equivalence to existing devices may be demonstrated in some cases.

Quality Documentation

CTD Module 3: Detailed chemistry, manufacturing, and controls information including drug substance and drug product specifications, manufacturing processes, and stability data.

MDR: Design and manufacturing information including materials, manufacturing processes, quality management system, and compliance with harmonized standards (e.g., ISO 13485).

Risk Management

CTD: Risk management integrated into Module 2.5 (Clinical Overview) and Module 2.7 (Clinical Summary) as part of benefit-risk assessment.

MDR: Comprehensive risk management file required following ISO 14971, with detailed risk analysis, evaluation, and control measures as a standalone section.

Post-Market Requirements

CTD: Post-marketing data included in periodic safety update reports (PSURs) and risk management plans (RMPs), submitted separately from the initial CTD.

MDR: Post-market surveillance plan and post-market clinical follow-up plan must be included in the initial technical documentation and continuously updated.

Similarities

• Both require comprehensive safety and performance data
• Both emphasize risk-benefit analysis
• Both require quality management system documentation
• Both need to demonstrate compliance with applicable standards
• Both require ongoing post-market monitoring

Practical Implications

For Combination Products

Products that combine drugs and devices (e.g., drug-eluting stents, prefilled syringes) must address requirements from both frameworks. The primary mode of action determines which regulation takes precedence, but documentation must satisfy both sets of requirements.

For Companies Working Across Sectors

Organizations operating in both pharmaceutical and medical device sectors should:

• Develop expertise in both regulatory frameworks
• Establish separate but coordinated documentation processes
• Leverage common elements (e.g., quality systems, risk management)
• Ensure teams understand the distinct requirements