Clinical Trials Series: Part 3 – Design with the Mitigating Risk in Your First EU Trial: Operational, Regulatory, and Strategic Thoughts

Published on: Aug 8th, 2025

Risk management is an integral part of the set-up and management of clinical trials. While a global risk assessment is generally performed for the full trial, country or region-specific information should also be considered. This is especially true when venturing into the EU for the first time.

Starting your initial clinical trial in the EU may feel daunting at first, knowing the stringent regulatory requirements to adhere to. However, there are simple steps and considerations that can mitigate risks and set your study up for success, enabling you to fully reap the benefits of entering the EU market.

This blog post builds on earlier discussions around preparing for EU trials and designing patient-centric protocols. If you haven’t yet explored those topics, you might find it helpful to revisit Part 1 and Part 2 of the series.

• Part 1: First Steps into Europe – Key Considerations for Your First EU Clinical Trial
• Part 2: Design with the Patient in Mind – Building a Patient-Centric Protocol

Study Design

The first step in preparing your clinical trial for submission is, of course, to design it. Designing your study in a manner that considers EU specific expectations can help avoid approval delays, or costly amendments.

Risks

Protocol Not Approved – Unfavorable response on Clinical Trials Application or country specific submission.

Protocol amendment/update required – Due to inadequate protocol design, amendment required.

Inefficient use of vigilance resources – Unnecessary time and resources spent on collecting Serious Adverse Events that are not required from a safety perspective

Mitigation

Decentralized Trials

Careful consideration is needed when designing for a decentralized trial. Decentralised Clinical Trial (DCT) refers to a clinical trial where some or all trial-related activities are conducted at locations other than traditional clinical trial sites, such as the participant’s home or through digital platforms.

Core components include but not limited to:

• Home health visits by trained professionals
• Remote monitoring and diagnostics
• Direct-to-patient shipment of investigational medicinal products (IMPs)
• Electronic informed consent (eConsent)
• Teleconsultations and virtual follow-ups

There are significant restrictions in the EU when compared to US.

If you are including decentralized aspects in your study design, ensure what you have planned meets regulatory requirements in all EU countries where you are conducting your trial, particularly in regards to remote source data verification and e-consent.

Auxiliary Medicinal Product

If you are using other medicinal products for background treatments, as challenging agents, rescue medication or to assess end-points, these are considered as auxiliary medicinal products

It is useful to keep in mind that the documentation requirements set out in sections F and G of Annex I of the Clinical Trials Regulation (i.e., documentation relating to compliance with Good Manufacturing Practice (GMP) for the investigational medicinal product and Investigational Medicinal Product Dossier (IMPD)) also apply to auxiliary medicinal products.

Auxiliary Medicinal Product planning starts during protocol design and should be considered early on to ensure deadlines can be adhered to.

Protocol Amendments

Protocol Amendments in the EU can be quite time-consuming and costly (more so than in the US), therefore it is critical that you have a complete and well thought out study protocol that meets any country-specific requirements prior to submission.

Serious Adverse Events (SAE) Exceptions

In the EU, protocols can list events that should not be considered as Serious Adverse Events (SAE)

It is critical to give thoughtful consideration, and develop justifications, for which adverse events are expected and do not need to follow Serious Adverse Event Reporting

Considering this as part of the protocol design process can save time and resources on reporting that would not contribute to patient safety.

Study Start-up

Risks

Delays in submission timelines – If you do not have a clear understanding of the requirements in the EU and per country, you may not have all of the required components for your application prepared which can significantly delay approval.

Selecting an underqualified Principal Investigator (PI) – A PI that is not the right match for the study can result in insufficient oversight and causality errors which can impact vigilance resources and even study endpoints

Mitigation

Trial Applications

With only one Clinical Trial Application (CTA) per trial, versus one IND per product in the US, it is critical to consider your individual trial strategy carefully for your whole program, and to have a clear study plan established prior to beginning the CTA process

Country-Specific Requirements

In addition to general Clinical Trial Application requirements, there are also additional requirements for certain countries within the EU, particularly with regards to consent forms and ethics committee (IRB-equivalent) submissions

It is critical to map out in which countries you are planning to conduct the trial and to have a firm understanding of their specific requirements

As regulations can change, it is also important to stay informed of any updates on an ongoing basis and be prepared to adapt your strategies to stay complaint

EudraVigilance

To submit your Clinical Trial Application, you will need to enter Substance and Product registration numbers into the application form

To get these numbers, your active Substance will need to be registered within the EU Substance Management System and your Product will need to be registered within the extended EudraVigilance Medicinal Product Dictionary (xEVMPD)

To register, you will need to have:

• Registered your company location within the EU Organisation Management System
• Opened your EudraVigilance account by registering a EudraVigilance Responsible Person (EVRP)

Registering an EVRP is a process that requires having specific EMA certifications in XEVMPD and Individual Case Safety Report (ICSR) submissions via EudraVigilance.

It also requires a dossier made up of specific forms, cover letters on company letterhead, certificates, proof of company registration in the EU Organization Management System, and ID Cards and signatures from the EU Legal Representative, the EVRP and a person in a management position at the sponsor organization.

The end-to-end process can take up to 2 weeks, depending on the speed at which the dossier is able to be compiled. The European Medicines Agency has 1 week to process the request.

Investigator’s Decision on Causality

In Europe, it is the investigator who has the last say on the causality assessment for a Serious Adverse Event, determining whether the report should be classified as a Suspected Unexpected Serious Adverse Reaction (SUSAR)

It is really important to select the right Principal Investigator (PI), who is able to handle this responsibility, and who responds quickly to requests from the vigilance department to confirm missing pieces of information.

It is also critical to ensure that the Investigator is well-trained and understands the product, indication and underlying disease(s) fully, to avoid indicating product causality when it could be related to an underlying condition or other consideration, and vice versa.

Study Conduct

Risks

Reports not being accepted – If requirements for annual safety reports are not followed, the result may be the receipt of Requests for Information (RFI) which have very stringent timelines and can be costly to address.

Potential data breach – If GDPR is not understood or carefully adhered to it can result in a data breach which can have serious consequences for the study sponsor

Mitigation

Development Safety Update Report (DSUR) (Annual Safety Report)

When drafting your DSUR/ASR, you will need to consider the preparation of specific regional annexes, including:

• Cumulative summary tabulation of SARs
• List of subjects who died during the reporting period
• List of subjects who dropped out of clinical trials in association with an AE during the reporting period
• Safety signal review
• EuCT numbers of relevant trials are recommended to be listed in the annex of the ASR.

These annexes differ slightly to other regions where you may submit a DSUR, specifically the safety signal review annex.

This annex is required to contain a description of the safety signal review you are performing for the trial. It is, thus, recommended that you develop this process from the very beginning of your trial to ensure it is correctly implemented and bears results from the first DSUR/ASR preparation (at the latest)

Serious Adverse Event Reporting to Authorities

As described above, in the EU, it is the investigator’s causality assessment that is considered when determining reportability of an SAE.

If the investigator considers that the event is related to the product, an auxiliary medicinal product, a placebo or a comparator, the report must be submitted to authorities via EudraVigilance.

Reporting timelines remain consistent with most other countries for reports to competent authorities (7 days for death/life-threatening and 15 days for all other related and unexpected SAEs – or SUSARs)

Data Protection

It is important that you ensure you understand the differences between the Global Data Protection Regulation and HIPAA requirements for data management. See our next blog post for more information on GDPR.

You must have a firm grasp on country specific interpretation of GDPR requirements, as these do vary. It could also be worth contracting with a local partner who has this expertise.

Vendors should be confirmed to be knowledgeable and compliant in GDPR, as sponsors are ultimately responsible for data protection. This can be achieved through regular vendor management processes including questionnaires and audits.

Overall, you must stay aware of any changes in GDPR regulations.

Study Closure

Risk

Noncompliance – study results not being accepted because post study requirements are not adhered to

Mitigation

Archiving requirements

Ensure you understand overarching archiving requirements in the EU, and country specific requirements.

In the EU, clinical trial data must be archived for at least 25 years from the end of the trial, unless a longer period is mandated by national regulations.

Conclusion

Being aware of these specific risks associated with starting your first clinical trial in the EU and being prepared with a strategic plan as outlined above to mitigate those risks is key to a successful study from start to finish.

As discussed, most of the risks involve mitigation through careful screening of the changing regulations, a fundamental yet burdensome task. Choosing a qualified third party to handle these aspects guarantees you the expertise required to succeed each step of the way.

Whichever step you are on in your trial planning, it’s critical to plan your clinical trial strategy, including all aspects listed above, and to implement your risk mitigation steps.