Many US pharmaceutical companies seek to conduct clinical trials in the EU as it represents a large, diverse patient population. However, significant differences in clinical trial design, which can be driven by the nuanced differences in regulatory approaches, mean that a local understanding of EU requirements can be critical. This is even more pertinent now that the EU has implemented the Clinical Trial Regulation (CTR) and set up the Clinical Trial Information System (CTIS) for the submission of combined Clinical Trial Applications (CTA) and Independent Ethics Committee applications to EU countries.
In this expert guide, Chris Moore, Senior Clinical Project Manager at Boyds, shares 10 essential considerations for U.S. biotechs looking to set up successful clinical trials in Europe under the new Clinical Trials Regulation (CTR) and CTIS system.
- Understand the Clinical Trials Regulation (CTR).
The CTR replaces the EU Clinical Trials Directive and provides the requirements for conducting clinical trials in member states of the EU. The regulation aims to harmonize EU clinical trial requirements and has a single point for communication with the competent authorities in the EU.. Simultaneously, the CTIS platform has been implemented, creating a single entry point for CTA and IEC submissions, authorizations, and supervision for trials conducted in the EU.
The CTR provides significant advantages to U.S. organizations, enabling the parallel implementation of clinical trials in multiple EU countries at the same time. However, sponsors should be aware of the CTR review timelines, especially the timelines for Requests for Further Information on the initial submission, which are required to be responded to in 12 days and could require significant updates to documents that require both translation and redaction. By having one submission for all EU countries, any updates to key study documents that are made would be applicable for all EU countries at the same time, which mitigates the need for many country-specific protocols that can be all slightly different to meet the individual regulatory requirements. As a result, there is a reduced administrative burden, as well as a lower risk of error and increased consistency in the patient population and study data, as all countries would be working from the same study protocol and other key study documents.
- Decide your order of operations for site feasibility and selection.
One of the key changes with the CTR is the requirement to obtain more documents from the clinical sites to include in the submission package, including site investigator CVs, investigator declaration of interest forms, and statement of site suitability forms. Therefore, US sponsor companies should complete site feasibility early to assess the experience and knowledge of the CTR of the proposed sites. Sponsors may select sites with little experience in the CTR process, and subsequently should allow more time for them to provide the required documentation before submission. Alternatively, sponsors may elect to select experienced sites that have performed CTR submissions before and are generally quicker at providing the required documents and plan to have shorter timelines to complete site document collection. In practice, a combination of CTR experienced and CTR less experienced sites will often be the case and this should be factored into the planning of site set-up timelines.
Other indirect considerations of the CTR implementation, where early site feasibility and selection can assist, are in describing the participant identification and recruitment arrangements. Early discussions with sites and capturing how they identify and recruit patients will greatly assist with documenting how participant identification will be completed, and this can then be documented in the study protocol and/or in the applicable EU template form.
Once the sponsor has received the site’s documents and key contact information, the documents must be uploaded into CTIS, the portal for CTR submissions. It is important to have the details of every site to avoid delays in the whole submission process. Site information needs to be entered for each site into CTIS and it is much more efficient when the site is registered in OMS (Organisation Management System). It is possible to submit Part 1 (to the competent authority) and Part 2 (to the ethics committee) of the CTR separately to give more time to collect site information and documents, but both approvals are required to start the study. Adding additional countries and sites takes considerable time after approvals are received, so sponsors should include as many as they can at the beginning while balancing this with the risk of the whole submission being held up by unconfirmed information from individual sites.
- Appoint a European representative.
A US sponsor company must designate an organization or individual to undertake this task if it does not have its own EU entity or EU legal representative. EU legal reps carry significant responsibilities that directly impact the trial’s credibility and outcome and are key to protecting the rights, safety, and well-being of clinical trial subjects.
The EU legal rep assumes legal responsibility for the conduct of the clinical trial, ensuring that the sponsor meets their obligations under the clinical trials regulations and all relevant laws, regulations, and guidelines, as well as notifying the sponsor in the case of non-compliance. To become an EU legal representative, the organization or individual must be established within an EU member state and be familiar with good clinical practice (GCP) guidelines and ethical and regulatory principles.
The EU legal rep acts as a point of contact between the sponsor and regulatory bodies, including the ethics committees and research sites. Sponsors should establish a good working relationship with their EU legal rep so they can quickly notify the sponsor should they become aware of noncompliance with the CTR or other regulations impacting clinical trial conduct.
- Work closely with regulators.
Understanding the differences in regulatory processes between the U.S. and Europe is key to successfully delivering a clinical trial. There are key differences in the submission requirements, the review and approval timelines, and the required study documentation, which are important to understand as these can impact the data needed and predicted timelines. Sponsors should work closely with regulatory consultants or legal experts with experience in European clinical trials to ensure compliance with local laws, standards, and regulations, including the CTR and the EMA guidelines.
- Use a trusted clinical operations partner.
CROs that operate in Europe or clinical operations managers in the EU have in-depth knowledge of local regulations and, in particular, the different EU healthcare systems. Having a country expert mitigates the risk of missing country-specific nuances, such as country-specific templates or items outside of the CTR, including genetically modified organism (GMO) submissions for gene therapies. CROs typically have established relationships with a network of investigator sites across multiple EU countries, as well as local vendors, and can put together a study start-up team with the right expertise and strategic insight to enable expedited clinical trial setup.
A local CRO may also be able to provide logistical support, including investigational medicinal product (IMP) supply chain management. A well-established European provider may also be able to coordinate local project management, including monitoring visits and site management activities, to streamline trial operations and ensure efficient execution.
In addition to providing potential time savings, using an established CRO can provide significant cost advantages owing to the use of their own existing infrastructure and resources, which is often important to U.S.-based sponsors in the earlier phases of development, where managing cash flow is important to their success.
- Understand market access and reimbursement across the EU.
Market access and reimbursement are critical considerations for U.S. sponsors planning clinical trials in the EU. EU member states have diverse healthcare systems with varying processes for pricing, reimbursement, and market access and, as a result, may require different primary and secondary endpoints in their clinical trial as the EU tends to prefer endpoints that show quality of life, mortality and/or morbidity improvements. Understanding the nuances of each market is essential for successful product development.
Early consideration of a health technology assessment (HTA) is also important to incorporate relevant endpoints and comparator arms with alternative approved treatments and local standard of care practices, to maximize the probability of successful HTA review. Early dialogues with payers and local KOLs to understand local reimbursement prescribing practices can help. Many EU countries use reference pricing, where the price of a new medicine is compared to similar products already on the market. U.S. sponsors should then consider the pricing of existing therapies in their therapeutic area when setting prices for their products. Conducting supplementary health economics and outcomes research (HEOR) studies may be useful in providing evidence of the economic value of a new treatment, which is important for reimbursement negotiations with payers.
- Be aware of the differences between an IRB and Europe’s IECs.
In the EU, the equivalent of the institutional review board (IRB) in the U.S. is the independent ethics committees (IECs). Sponsors will need to obtain approval from each participating country’s IEC to proceed with the study after submission through CTIS. Although the CTR has standardized many parts of the submissions to EU IECs, there are still some local requirements that need to be adhered to that are non-standardized across all EU countries.
There are many subtle differences between the U.S. and the EU in the ethical considerations for clinical trial conduct. Sponsors need to ensure their clinical trial protocol aligns with the ethical standards and guidelines set by the EU and individual member states to obtain clinical trial approval. For example, in the EU, pre-screening is commonplace through separate screening protocols and established processes for approving consent documents for the purpose. In the U.S., the Health Insurance Portability and Accountability Act (HIPAA) imposes strict regulations on the use and sharing of patient data, limiting the scope of pre-screening activities. Understanding these nuanced differences can reduce delays in study setup and, therefore, patient recruitment within the EU.
In the U.S., patient involvement is also driven by other patient engagement initiatives such as the Patient Centered Outcomes Research Institute (PCORI). The use of patient advocacy groups is much more established as the primary mechanism of patient engagement in the EU compared to the US and the impact of participant feedback is now a requirement for the protocol as per the CTR. Patient engagement during early clinical development has been found to enhance study participant experience during clinical trials by ensuring the study is not overburdensome for the patient population in question and that the assessments provide data which may address real-life concerns of a patient population. Sponsors should aim to engage early with patient groups and advocates so they can get input on key aspects such as the study design and how information is presented in patient-facing documents. Studies with patient input have been shown to improve retention rates, increase protocol adherence, and inform the use of language in patient-facing leaflets to facilitate better understanding of the participants.
Early engagement with EU-based patient advocacy groups can help to shape the EU clinical development plan, as well as provide valuable feedback that is necessary for EU ethics committee approvals.
- Allot time and money for quality language and cultural translation services.
Cultural differences also can influence the understanding and sentiment of informed consent, so researchers should tailor their approach accordingly. While some essential documents (such as the protocol) may not need to be translated into the local language, a protocol synopsis, in lay language does need to be submitted in the local language(s). Patient-facing information such as informed consent forms, instructions, and advertisements will have to be translated into the local language(s) of participating countries.
Sponsors should allow adequate time for good-quality translation when developing and implementing timelines. EU ethics committees require a good-quality translation that keeps the language at a suitable reading level, is not too optimistic for early phase studies, and is not too technical. Using a vendor experienced in translating clinical trial documents will mitigate the risks of poor-quality translation.
- Get clinical trial insurance that meets the local requirements.
U.S. sponsors must obtain appropriate clinical trial liability insurance coverage to mitigate potential liabilities associated with conducting clinical trials in Europe. This may be part of the same policy covering existing U.S. trials or, more often, a separate policy. There can be minor differences in what is required for setting up the policy. For example, in the EU, the study sites may not need to be identified within the policy which is standardly included in US polices. Be sure to seek professional advice from someone experienced in organizing appropriate clinical trial liability insurance.
When inquiring about insurance policies, it is important to select one that meets the requirements specified by the CTR and relevant EU directives, as well as local requirements, as the amount of coverage required can differ by country and even within the sites selected.
- Adhere to data protection and privacy compliance laws.
Adherence to the General Data Protection Regulation (GDPR) when handling the personal data of study participants is crucial to clinical trial conduct within the EU. A U.S.-based sponsor needs to implement robust data protection measures and obtain informed consent from participants in compliance with GDPR. U.S. sponsors must also agree in their submission to treat data collected from EU participants in compliance with GDPR which may require internal review of their data handling processes to ensure they can meet any additional requirements to be GDPR compliant. Within the patient information, they must also make it clear within the consent process that should data be transferred to a country where GDPR is not a legal requirement (such as in the U.S.), compliance with GDPR is not enforceable. GDPR-experienced consultants can help navigate this process.
Set Up For Success In The EU
It has never been more critical for US sponsors to ensure compliance with the necessary regulations in the EU with the implementation of CTIS for combined submissions under the CTR. US biotechs or small pharma companies that may not be familiar with the CTR and its nuances can benefit from working with an external consultancy with strong local knowledge of the relevant requirements in both the U.K. and the broader EU region.
If you require any further support with setting up a clinical trial in Europe or tailored guidance on the CTR, CTIS, or EU trial strategy, get in touch at info@boydconsultants.com.
