CTIS and EU Clinical Trials in 2025: Maximizing the New System

The Clinical Trials Information System (CTIS) has fundamentally transformed clinical trial applications in the European Union. As we progress through 2025, sponsors are increasingly leveraging CTIS capabilities to streamline multi-country submissions, reduce timelines, and enhance regulatory efficiency under the Clinical Trials Regulation (EU) No 536/2014.

CTIS Evolution and Current State

From Transition to Maturity

January 31, 2025: The transition period officially ended, making CTIS the mandatory system for all new clinical trial applications in the EU. Legacy trials under the Clinical Trials Directive 2001/20/EC continue under national systems until completion.

System Capabilities

CTIS provides comprehensive functionality for:

• Initial clinical trial applications (CTAs)
• Substantial modifications
• Safety reporting (SUSARs and ASRs)
• End of trial notifications
• Public disclosure of results
• Inspection coordination

Clinical Trial Application Process

Part I and Part II Structure

Part I - Scientific Assessment (coordinated by RMS):

• Protocol and amendments
• Investigational medicinal product (IMP) information
• Non-clinical and clinical data
• Risk assessment and management
• Labeling and patient information

Part II - National Assessments (by each MSC):

• Informed consent procedures and documents
• Suitability of investigators and facilities
• Compliance with national requirements
• Ethics committee considerations

Member State Roles

Reporting Member State (RMS):

• Leads Part I assessment
• Coordinates with Member States Concerned (MSCs)
• Prepares assessment report
• Facilitates decision-making

Member States Concerned (MSCs):

• Conduct Part II assessments
• Provide input on Part I
• Make national authorization decisions
• Oversee trial conduct in their territory

Assessment Timelines

Standard Timeline

Part I Assessment: 45 days (RMS-led)

• Day 1-26: Initial assessment period
• Day 27-31: Consolidation of comments
• Day 32-38: Sponsor response period
• Day 39-45: Final assessment

Part II Assessment: Parallel with Part I

• MSCs conduct national assessments
• Ethics committee reviews
• National-specific requirements

Clock Stops: Additional time for sponsor responses to questions

Accelerated Procedures

For certain trial types:

• Low-intervention clinical trials (LICTs)
• Trials with prior positive opinions
• Trials in emergency situations

Optimizing CTIS Submissions

Pre-Submission Preparation

Strategic planning:

1. Select appropriate RMS based on expertise and capacity
2. Identify all MSCs early in planning
3. Prepare comprehensive documentation
4. Ensure protocol clarity and completeness
5. Address potential concerns proactively

Documentation excellence:

• Complete and accurate eCTD format
• Clear, concise protocol
• Comprehensive investigator’s brochure
• Well-designed informed consent documents
• Robust risk management plans

RMS Selection Strategy

Consider:

• Regulatory authority expertise in therapeutic area
• Historical approval rates and timelines
• Language capabilities
• Workload and capacity
• Previous experience with authority

Managing the Assessment Process

Responding to Questions

Best practices:

• Monitor CTIS daily for communications
• Respond promptly and comprehensively
• Provide clear, scientific rationale
• Include supporting data when relevant
• Maintain professional, collaborative tone

Common question areas:

• Protocol design and endpoints
• Safety monitoring and reporting
• Statistical methodology
• IMP quality and manufacturing
• Risk-benefit assessment

Coordinating with MSCs

Effective coordination:

• Address Part II questions promptly
• Ensure consistency across MSCs
• Facilitate ethics committee interactions
• Manage country-specific requirements
• Maintain clear communication channels

Substantial Modifications

Types of Modifications

Substantial modifications requiring approval:

• Protocol amendments affecting safety or scientific validity
• IMP changes
• Changes to informed consent
• Investigator or site changes (in some cases)

Non-substantial modifications: Notified but not requiring approval

Modification Assessment

Timeline: 38 days for substantial modifications

• Faster than initial applications
• Coordinated assessment by RMS and MSCs
• Potential for urgent safety measures

Safety Reporting in CTIS

SUSAR Reporting

Suspected Unexpected Serious Adverse Reactions:

• Electronic reporting through CTIS
• Harmonized timelines (7/15 days)
• Automatic distribution to all MSCs
• Simplified compared to previous system

Annual Safety Reports (ASRs)

Requirements:

• Submitted annually through CTIS
• Comprehensive safety data analysis
• Benefit-risk assessment
• Cumulative review of all safety information

Transparency and Public Disclosure

Clinical Trial Information

Public register:

• Trial details accessible to public
• Layperson summary required
• Regular updates mandatory
• Enhanced transparency vs. previous system

Results Disclosure

Mandatory requirements:

• Clinical study report within 12 months of trial end
• Layperson summary of results
• Public access through CTIS
• Compliance monitoring by authorities

Multi-Country Trial Strategies

Efficient Country Selection

Considerations:

• Patient population availability
• Site capabilities and experience
• Regulatory environment
• Recruitment timelines
• Cost considerations

Coordinated Trial Management

Best practices:

• Centralized trial management
• Consistent training across sites
• Harmonized monitoring approaches
• Unified safety reporting
• Coordinated communications

Common Challenges and Solutions

Technical Issues

CTIS platform challenges:

• System downtime or slow performance
• Document upload issues
• Validation errors

Solutions:

• Plan submissions with buffer time
• Validate documents before upload
• Maintain backup documentation
• Contact CTIS helpdesk promptly

Regulatory Challenges

Assessment variations:

• Differing interpretations between MSCs
• Country-specific requirements
• Ethics committee variations

Solutions:

• Proactive engagement with authorities
• Clear, comprehensive documentation
• Flexibility in protocol design
• Local regulatory expertise

Best Practices for 2025

Strategic Recommendations

1. Early Planning: Begin CTIS preparation 3-6 months before submission
2. Quality Documentation: Invest in comprehensive, clear documentation
3. Regulatory Intelligence: Stay current with CTIS updates and guidance
4. Expert Support: Engage experienced regulatory consultants
5. Technology: Utilize CTIS training and support resources

Operational Excellence

Key success factors:

• Dedicated CTIS-trained personnel
• Robust quality management systems
• Effective communication protocols
• Proactive risk management
• Continuous learning and adaptation

Future Developments

System Enhancements

Expected improvements:

• Enhanced user interface
• Additional automation features
• Improved search and reporting functions
• Integration with other EU systems
• Mobile accessibility

Regulatory Evolution

Anticipated changes:

• Refined guidance documents
• Harmonized interpretation across MSCs
• Streamlined procedures for specific trial types
• Enhanced support for complex trials

Conclusion

CTIS represents a paradigm shift in EU clinical trial regulation, offering unprecedented efficiency, transparency, and harmonization. Success in 2025 requires thorough understanding of the system, strategic planning, high-quality documentation, and proactive engagement with regulatory authorities.

Sponsors who master CTIS capabilities, invest in proper training, and adopt best practices position themselves for faster approvals, reduced administrative burden, and ultimately, more efficient delivery of innovative therapies to European patients. The system, while complex, delivers on its promise of a truly integrated European clinical trials framework.