Clinical Trials Series: Part 1 – First Steps into Europe: Key Considerations for Your First EU Clinical Trial

Published on: Jun 23rd, 2025

Embarking on your first clinical trial in Europe marks an important milestone for any biotech company. Whether your goal is to develop a rare disease treatment, enter a new market, or build a clinical package for global regulatory submission, Europe offers a complex but highly rewarding environment. With its harmonized regulatory pathway, vast patient populations, and diverse healthcare systems, the European landscape requires thoughtful, strategic planning from the very start. For first-time sponsors, success means understanding both the opportunities and the challenges.

Whether you’re an emerging biotech or expanding into Europe, here’s how to strategically plan your clinical trial and avoid common pitfalls.

Understand the regulatory requirements

One of the most important changes in recent years has been the implementation of Regulation (EU) No 536/2014, also known as the Clinical Trials Regulation (CTR). This legislation replaces the previous Clinical Trials Directive (Directive 2001/20/EC) and all national laws implementing its terms and introduces a centralized process for clinical trial applications across the European Union (EU) and European Economic Area (EEA).

At the heart of the CTR is the Clinical Trials Information System (CTIS), a centralized portal that serves as the single-entry point and communication solution for all stakeholders: sponsors to submit and manage their clinical trial applications in participating Member States (designated as Member States Concerned (MSC)), evaluators to issue evaluation queries (designated Requests for Information (RFI)), and public to browse clinical trial register. While the process is harmonized through CTIS, it is important to clarify that trial evaluations and authorizations remain the responsibility of each MSC and not the EMA or any EU central authority. This shift brings greater transparency and procedural consistency but also demands that sponsors align with both overarching EU requirements and specific national expectations.

What is different under CTR?

• One application across all participating EU/EEA countries
• Evaluations are conducted by Member States at once, and no longer by national competent authorities and ethics committees separately
• Two-part structure review: Part I (scientific and technical aspects) is assessed jointly by all MSC; Part II – one per MSC (heavily locally-regulated documentation such as consent, investigator and site qualification, financial disposals) is assessed nationally
• Fixed timelines for validation, assessment and response to RFI
• Mandatory public disclosure of some trial documents and data (under the CTR’s concept of “Transparency”)

While both the FDA and the EU/EEA aim to ensure patient safety and data integrity, the regulatory pathways differ significantly. Unlike the FDA’s single centralized review, the EU relies on a decentralized, multi-member state evaluation that includes local requirements unique to each country. Sponsors running parallel trials or transitioning from the US to Europe often overlook these distinctions, which can affect planning and timelines. Early strategic planning that accounts for these differences is crucial to avoid delays and ensure compliance across regions.

What do you need to do? Train to the essential CTR concepts, familiarize yourself with the CTIS structure early, appoint a High-Level Sponsor Administrator and a CTA Administrator, and establish clear internal workflows for validation, assessment, and RFI response. Address company-level confidentiality policies to prepare redactions of publicly disclosed documents and data sets ahead of submission, such as protocols, information leaflets and consent forms, or some RFI and their responses.

Choose your countries strategically

While the regulatory framework is harmonized under CTR, the operational reality remains more nuanced. Each country retains national processes for contract negotiation, import licensing and how ethics review is operationalized. Although ethics evaluation is part of the CTA submitted via CTIS, the structure and responsiveness of ethics committees still vary, introducing some variability in timelines start-up timelines, and investigational site availability can also vary significantly. A robust feasibility assessment is therefore critical to identify potential sites and investigators, but also to understand whether a country offers the right environment for your clinical trial’s success.

Language is another consideration that can impact both startup and execution. While English is generally adequate for the protocol and IB, patient-handed materials will generally need to be translated into national languages. For instance, informed consent forms are often subject to both local policies and country-specific ethical guidance.

Consider when selecting countries:

• Site maturity: choose centers with prior experience in clinical trials and expert in the therapeutic area.
• Patient population: ensure access to eligible participants.
• Start-up timelines: include time for contract negotiation.
• Import license timelines and local distribution steps following QP release (particularly for ATMPs or temperature-sensitive IMPs)

Seek scientific and expert advice early

In parallel, sponsors should engage with key stakeholders. In Europe, early scientific advice is available from both national regulatory agencies and the European Medicines Agency. This can be particularly valuable for complex studies, including those involving advanced therapy medicinal products (ATMPs), rare diseases, or pediatric populations. Early advice can help de-risk the development pathway by clarifying expectations around endpoints, safety monitoring, or manufacturing readiness.

Stakeholder engagement should extend beyond regulators. Inputs from clinical experts, patient advocacy groups, and key opinion leaders can shape a more relevant and meaningful protocol. For studies involving vulnerable populations or ultra-rare diseases, patient organizations may provide critical insights into disease burden, trial logistics, and patient retention strategies. Involving these voices early helps ensure that your study design is not only scientifically sound, but also patient-centric and operationally realistic.

Who should you speak with?

• EMA or national agencies for Scientific or Regulatory consultation
• Key Opinion Leaders (KOLs) for feasibility and clinical relevance
• Patient advocacy groups for input on recruitment, burden, and accessibility

Engaging stakeholders before finalizing your protocol improves trial success and ensures alignment with EU standards and operational feasibility.

Align internal teams and build strong CRO partnerships

With a clear regulatory roadmap and feasibility assessment in hand, sponsors can turn their attention to operational readiness. Selecting the right vendors, including contract research organizations (CROs), central laboratories, and drug supply partners, is one of the most consequential decisions for a first-time trial. Vendor experience with CTR submissions and active presence in your selected countries can make the difference between smooth approval and frustrating delays. It is essential to vet your partners carefully, with a focus on their knowledge of your therapeutic area, operational footprint in selected countries, and regulatory expertise.

The CTR introduces new responsibilities for sponsors, including those related to quality oversight and transparency. Your organization must have a defined quality management system (QMS) that addresses trial oversight, vendor management, safety reporting, and data integrity (This topic will be addressed in the 3rd blog post of our series). While ICH GCP provides broad standards for monitoring, the CTR, places greater emphasis on continuous, proactive oversight and requires sponsor to maintain real-time awareness of issues such as protocol deviations, serious breaches, and safety signals. This requires both documentation and organizational capacity.

Make sure to:

• Assign the High-Level Sponsor and CTA Administrators early
• Ensure robust oversight over CROs and third-party vendors
• Define roles and responsibilities between you and the CROs

Even if you outsource, sponsors retain responsibility so build clear governance and QMS pathways.

Budget with precision and flexibility

Sponsors must also ensure that there are adequate internal resources whether in-house or outsourced for regulatory compliance, data management, pharmacovigilance, and monitoring.

Don’t forget to budget for:

• CTIS preparation and training
• Translation of documents for each country
• Legal Representative if you’re non-EU based
• Insurance aligned with national requirements
• Redaction and publication costs

Be realistic in timelines and buffer costs and consider

Appoint an EU Legal Representative

Planning a clinical trial in Europe requires more than just covering site costs and CRO fees. Sponsors must account for a range of Europe-specific expenses: CTIS preparation and submission support, insurance coverage aligned with local laws, and the appointment of an EU Legal Representative. While the CTR technically allows for a waiver if all Member States involved agree and a local contact is designated, in practice this waiver is rarely granted. As such, for non-EU sponsors, appointing a Legal Representative remains the expected route, as this party bears legal accountability under the CTR. The LR is responsible for:

• Ensuring compliance with the sponsor’s obligations pursuant to this Regulation Communication with authorities
• Liability in case of non-compliance

Choose a partner who understands CTR—not just a mailbox service.

Summary: Get It right from the start

Launching a clinical trial in Europe no longer is about checking regulatory boxes. It is about building a well-integrated strategy that connects science, operations, compliance, and market understanding. The CTR may seem like a steep learning curve, but it also presents a unique opportunity, and shall be considered as a launchpad for innovative therapies to reach European patients more efficiently.

By investing early in operational readiness (i.e., site selection, contracting, document readiness, CTIS workflows) you will reduce delays

In conclusion, the EU/EEA continues to be a highly attractive environment for clinical research. Planning your first clinical trial in Europe is an investment in both time and resources. By engaging early with experts, and ensuring operational readiness, you can lay the foundation for a successful development program.

Key takeaways:

• Train and build internal understanding of the CTR processes and loopholes
• Select countries based on feasibility and readiness, not market size
• Budget beyond just operations include redactions, translations, insurance and legal fees
• Plan for transparency and legal representation
• Act early and monitor continuously, responsiveness is key in a dynamic environment
• Involve operational experts early, a robust study design and strategic planning are critical, not optional