Europe is a large, attractive market for clinical trials with 44 countries, 27 of which are in the European Union (EU). However, North American sponsors should be aware that Europe is not a single market and that on top of Europe-wide requirements, each country has its own operational and regulatory processes to follow. A deep dive into the country under consideration is needed to successfully navigate complex layers and cultural nuances, which can be quite different than in the North American market.
A good starting point is understanding the Clinical Trials Information System (CTIS), the EUâs centralized portal and database for managing clinical trial applications, approvals, amendments, and ongoing trial oversight within Clinical Trials Regulation (CTR) EU No. 536/2014. However, knowing the CTIS does not eliminate the need to understand country-specific regulatory considerations, national notifications, contracting complexity, local documentation requirements, language requirements, site-level negotiation, public hospital governance, or lifecycle obligations.
Variables in country selection
Country selection for clinical trials in Europe should also be grounded in:
- The specific indication and phase of the trial
- The competitive trial landscape
- CTIS applicability
- Regulatory and site activation timelines
- Expected patient enrollment
- Potential site interest
- Treatment access and reimbursement
- Local key opinion leaders (KOLs) or ambassador networks
- Interest in placebo-controlled studies: For example, in European countries with easily accessible biologic treatment, and for some indications like moderate-to-severe atopic dermatitis or psoriasis, placebo-controlled studies may not be accepted.
Patient recruitment & enrollment
As elsewhere in the world, European patient recruitment and enrollment rates are one of the biggest challenges to trial success, differing by where in Europe. For example, Central and Eastern Europe (CEE), including Poland, Czech Republic and Hungary, is associated with strong recruitment and lower competition. Western Europe is associated with slower recruitment due to high trial density and already reimbursed drugs on the market, and the Nordic countries have smaller patient pools, higher costs, and excellent data quality.
In each country, pay attention to patient density versus disease prevalence, competing enrollment efforts, patient willingness and trust in clinical research, and the referral culture and involvement of the general practitioner/family doctor. For example, high patient trust exists in CEE and in Spain. The UK and the Nordic countries have a strong patient advocacy presence, and consent procedures can be particularly detailed in Germany.
Trial startup feasibility
In the clinical trial feasibility phase are further differences between North America and Europe, and between European countries, including:
- Site contracting times
- Clinical trial agreement (CTA) document requirements (local language, format)
- Experience with global trials
- Use of master agreements versus site-by-site negotiation
Data quality & inspection risk
Variations in data quality and inspection risk will affect regulatory success and submission-readiness. There may be deviations in query rates and protocols, audit history, such as inspection frequency at the European Medicines Agency (EMA) compared to the US Food and Drug Administration (FDA) and variability in site documentation maturity.
For example, CEE has strong compliance with higher monitoring needs early on, allowing for quicker startup, but the region has variable documentation maturity. Resource-driven variability exists in high-volume Western European sites, and the Nordics have excellent data consistency.
Investigator & site quality
Data integrity and inspection-readiness depend on the quality of both investigators and sites. Factors include investigator experience with phase I-IV trials, Good Clinical Practice (GCP) compliance track record, and site infrastructure and staffing.
High specialization exists in Germany, Spain, the UK and the Netherlands. CEE countries tend to have higher patient throughput and fewer competing commitments, while Southern Europe has strong academic sties but variable resourcing.
Budget optimization and country selection will obviously also be affected by cost variability, investigator fees, per-patient cost, monitoring and travel expenses, and insurance and indemnity requirements.
Feasibility considerations
North American sites are part of a highly competitive, decentralized private and academic system; feasibility is driven by principal investigator (PI) interest and specialty, past performance (startup/enrollment KPIs), and site infrastructure. Sites actively compete in North America; PIs are thinking âwe want first patient in, we want more trials.â Budget is negotiated later; trial startup post-CTA is faster in North America.
In Western Europe, most trial sites are public hospitals and university research centers; in CEE it is about 40% public and 60% private sites. In the cases of public sites, the pace of feasibility moves accordingly. The PI is chosen by the department’s head at these centers, and evaluation includes administrative feasibility, contracting feasibility, budget appropriateness, legal and capacity considerations. European decisionmakers assess core clinical workload, staff allocation limits, research capacity guidance, and national strategies. Some European sites may request budget review before accepting feasibility. Language can also be an operational barrier, especially when Clinical Research Associates (CRAs) contact sites.
Contracting is the bottleneck
Despite there being a single regulatory entry point in Europe, contracting is a real bottleneck because the EU CTR did not harmonize legal contracts. Whether private or academic site, CTAs must be negotiated country by country, site by site. Negotiation is rarely PI-driven the way it may be in the U.S. Rather, European negotiations are driven by the legal department in public hospitals, who do not work for the PI, and at private sites, the lawyer is usually a third-party vendor.
Negotiation speed is not the only determinant of contracting timelines; it is also shaped by institutional governance, public healthcare procurement norms, local legal constraints, tax rules, language requirements, and mandatory wording.
A typical approval pathway in Europe involves the PI to the Research Office to Legal to Finance to Procurement to the Hospital Director and, if financial transparency is needed, to Ethics. Three to five rounds of redlines per site are normal in academic hospitals, while private sites may have a shorter pathway.
Most European contracting delays are caused by critical path items for sponsors that can affect activation timing; they include:
- Indemnity and liability insurance wording
- Governing law and country-specific templates
- Publication rights
- General Data Protection Regulation (GDPR), the EUâs privacy and data protection law
- Controller and processor roles
- Data transfer safeguards
- Retention language
- Value-added tax (VAT)
- Payment structure
One template will not work EU-wide. Country-specific master templates are tailored to legal requirements before sending the first CTA. Sponsors must agree to using the template unmodified with the national and site/regional-specific templates (unless modifications are optional).
Language and translation requirements are another important planning variable. Many European countries need CTAs who can work in the national language or in dual-language, and patient-facing documents must always be in the local language. Some European institutions require certified legal translation, not just professional translation. Sponsors should therefore plan translation and localization as part of the critical path, early, not as a late-stage document-management activity.
Waves of country activation
European country activation occurs in waves, triggered by the duration of budget and contract negotiations. For example, an active clinical trial application lasting 106 days could include a 28-day screening period, CTA and budget negotiations lasting five to seven and a half months (with summertime impact), and staged activation across multiple European countries.
Regulatory landscape
As well as complying with Europeâs CTIS, sponsors must respond where applicable to national body applications and notifications which, again, will differ between countries. Regulatory strategy will need to be built from the protocol, population, intervention, IMP, procedures, country-specific requirements (e.g., radiation, patient & public involvement, device components, translations), sample flows, data categories, local site requirements, and country mix.
Sequencing constraints
Ongoing application activity in CTIS has sequencing constraints. For example, submission of an Additional Member State Concerned (MSC) is not allowed until a decision is issued by all MSCs for the initial application, and certain substantial modification or non-substantial modification submissions are restricted depending on whether applications are under evaluation and whether member states have issued positive decisions.
For sponsors, this means that amendment strategy, new country additions, new site additions, and non-substantial changes must be planned with awareness of CTIS submission sequencing rules and ongoing evaluations.
Accelerated pathways
Mono-national accelerated approval routes exist in selected EU member states including Austria, Belgium, Bulgaria, Denmark, France, Germany, Hungary, Netherlands, and Spain. In each country, though, eligibility varies by trial phase, disease type, advanced therapy medicinal product status, monocentric design, seriousness of disease, first-in-class status, adolescent inclusion, and national law, policy, announcement, or experience.
Accelerated pathways are not universal. For example, selection criteria for the Facilitating and Accelerating Strategic Clinical Trials in the EU (FAST EU) pilot initiative include:
- Multinational trials
- Parallel Part I and Part II MSC submission strategy
- High numbers of MSCs
- Suitability of the proposed Reporting Member State (RMS), the EU Member State that leads the coordinated scientific assessment of a multinational clinical trial application
- Relevance such as life-threatening or rare diseases
- Complexity considerations
- Prior engagement in EU-level pre-assessment activities
- Overall workload across participating authorities
The advantage with FAST EU is shorter approval timelines and lessons learned, with an expected decision reduction of approximately 36 days.
Cultural and operational nuances
Last but not least, the interpersonal nuances of doing business in Europe, such as communication styles, can be different than in North America. For example, a European may give more direct feedback, such as âthis is problematic,â intending correction; a North American may hear this as conflict or escalation. The reverse is true; where a North American says âweâll try to improve this,â intending collaborative flexibility, a European might hear uncertainty in that statement. Neither of these styles are right or wrong; they just reflect differences in professional norms.
Operationally, Europeans tend to prefer a strong planning culture and scope discipline, versus North American comfort with an evolving scope. While the latter may prioritize speed of operations, Europeans have a high sensitivity to process deviations and an upfront expectation of reduced ambiguity. With a more hierarchical structure, Europeans want to know early on who owns each submission element, which decision points require country-level input, which timelines are dependent on hospital or authority review, and where written confirmation is necessary to prevent downstream misalignment.
Building relationships and trust also differs. While North Americans tend to build rapport quickly and use an informal tone early on in relations, Europeans prefer to build trust through credibility, and formality may last longer.
North American sponsors need to consider, one country at a time, the many levels of operational and regulatory complexity, variable factors affecting feasibility and budgeting, as well as cultural nuances in communications and processes. Europe can be highly productive for clinical development, but its value is unlocked when sponsors treat complexity as something to be planned for, and not as something to be solved after submission.
Europe rewards preparation.
About the Author
Mateusz Kozuch is Director, Country Strategy and Expert Engagement, for Indero. He has more than 13 yearsâ experience in pharmaceutical and CRO industries including in dermatology, rheumatology, and oncology therapeutic areas, with expertise in clinical operations, project management, and KOL/site networking. Based in Poland, Mateusz holds a master’s in biology science.
