and the Introduction of CTIS

The CTR, which became fully applicable on January 31, 2022, replaced the Directive and introduced a single submission portal – CTIS – for all clinical trial applications. It harmonizes and centralizes the application, assessment, and decision-making process across EU countries, supporting both single- and multi-country trials.

Core Clinical Trial Insights for Multi-Country EU Studies

1. Single Dossier Submission Through CTIS

Under the CTR, sponsors submit a single dossier via CTIS, which includes:

• Part I: Common scientific documents assessed jointly by all concerned Member States (e.g., protocol, IMPD, IB)
• Part II: Country-specific documents (e.g., informed consent forms, recruitment materials)

This eliminates the need for parallel submissions in each country, creating a unified submission workflow.

2. Coordinated Assessment Process

In a multi-country trial, one Member State acts as the “Reporting Member State (RMS)” responsible for leading the Part I assessment. The other “Concerned Member States (CMS)” review and contribute to this assessment. After finalization, each Member State completes their Part II assessment independently.

Standard timelines include:

• Part I: 45 days (extendable for specific reasons)
• Part II: 45 days from validation, running in parallel with Part I
• Decision: Each country provides its decision after both assessments are complete

3. Harmonized Yet Flexible Ethics Review

Ethics Committees (ECs) are still governed by national regulations. However, they are expected to conduct their reviews within the CTR timeline for Part II. Member States such as Belgium and the Netherlands have aligned ethics processes to fit the CTR framework, while others are still adapting.

4. Language and Localization Challenges

Even under a centralized submission system, documents like informed consent forms must be adapted and translated into local languages. This creates logistical challenges and requires advance planning by the sponsor for each participating country.

5. Role of the Sponsor in Multi-State Coordination

Sponsors must ensure:

• Consistent documentation across Part I and II
• Clear communication with NCAs and ECs in each country
• Active monitoring of questions and deadlines in CTIS
• Transparency in resolving any issues flagged by individual Member States

6. Amending a Multi-Country Trial

Substantial modifications require re-submission of impacted sections through CTIS. Changes affecting only Part II documents may only require submission to affected Member States. However, if the protocol or IMPD is altered, the RMS must reassess the Part I section and initiate a coordinated review again.

7. Trial Timelines and Delays

Although CTR introduces predictable timelines, operational bottlenecks can occur due to:

• Internal review delays at ECs
• Incomplete or inconsistent document packages
• Differences in interpretation of regulatory requirements

Therefore, pre-submission consultations are recommended to align expectations and avoid rejections.

Best Practices for Multi-Country EU Trials

• Engage early with potential RMS to discuss timeline expectations
• Use standardized document templates with country-specific adaptations
• Plan translations and localizations in advance
• Leverage local CROs or affiliates for country-specific regulatory insights
• Train team members on CTIS workflows and timelines

Scientific and Regulatory Evidence

• Regulation (EU) No 536/2014 (Clinical Trials Regulation)
• EMA CTIS Reference Guides and Module Trainings
• ICH E6(R2) – Good Clinical Practice
• National Competent Authority guidelines (e.g., BfArM, ANSM, FAMHP)
• EU Commission Q&A documents on CTR implementation

Special Considerations

Multi-country trials involving pediatric populations, rare diseases, or advanced therapies (e.g., ATMPs) require careful coordination of additional regulatory layers. Sponsors must also be mindful of:

• Data privacy requirements under GDPR
• Local pharmacovigilance obligations during development
• Informed consent models accepted in each country

When Sponsors Should Seek Regulatory Advice

• Before selecting RMS – to ensure optimal review leadership
• When planning protocol complexity involving multiple regions
• Before submitting substantial amendments across jurisdictions
• When facing divergent questions from ECs or NCAs
• For clarification on CTIS technical submissions and user roles

FAQs

1. Can I select any country as the Reporting Member State (RMS)?

Yes, but the selected country must agree to serve as RMS. Many sponsors choose the country with the fastest ethics/NCA coordination and strong regulatory experience.

2. Do all countries need to approve a multi-country CTA?

No, Member States can issue different decisions. Approval in one country does not guarantee approval in another.

3. Is CTIS mandatory for all trials?

Yes, as of January 31, 2023, all new trial applications in the EU must be submitted via CTIS.

4. Can I run a mono-country trial under CTR?

Yes. CTR applies to both single-country and multi-country trials. However, the harmonized process is particularly beneficial for multi-country trials.

5. Do I need separate insurance policies for each Member State?

Yes, insurance must comply with each country’s requirements. Coverage amounts and conditions may differ.

6. What happens if timelines are missed in CTIS?

If deadlines are missed without a justified extension, the application may be withdrawn automatically or considered rejected.

Conclusion

Multi-country clinical trials in the EU are increasingly streamlined under CTR 536/2014 and CTIS. While harmonized regulatory timelines and coordinated reviews offer significant advantages, operational and cultural differences among Member States still require strategic planning. Sponsors must combine centralized submission strategies with localized expertise to navigate ethics, language, insurance, and pharmacovigilance variations. With the right preparation, the EU can be a highly efficient region for executing global clinical development programs.