Lessons Learned from the EU Clinical Trials Regulation:

As of February 2023, the European Union Clinical Trials Regulation (EU CTR) No. 536/2014 has been in effect for a full year, repealing the EU Clinical Trials Directive 2001/20/EC. Lionbridge’s Life Sciences team reviews its first year providing translation services to customers impacted by this new EU clinical trials regulation. This blog will share our observations and best practices for supporting clients through submissions of clinical trial applications under this new EU clinical trials regulation.

Background on the new EU clinical trials regulation

The Clinical Trials Regulation (EU) No 536/2014 (“the CTR”) entered into application on January 31, 2022. The new regulation harmonizes the submission, assessment, and supervision of clinical trials conducted in both the European Union and the European Economic Area countries (EU/EEA). Implementation is facilitated via a Clinical Trials Information System (CTIS). This system is a single, centralized entry point for clinical trial information in the EU/EEA. There will be an ongoing transition period until January 31, 2025. However, as of January 31, 2023, all initial clinical trial applications must be submitted through the CTIS under the CTR requirements. Global translation readiness has become a critical contributing factor to the success of the application process. Translation readiness allows for timely preparation of a clinical trial application dossier and a rapid translation turnaround. This enablement is vital to helping companies meet the rigid deadlines of request for information (RFI) queries during evaluation of their application(s).

The EU clinical trials regulation’s language requirements for clinical trial applications

A complete clinical trial application consists of two parts. The first part includes the scientific and medicinal product information and documents. These documents could be the study protocol or content of the labeling of the investigational medicinal product. The second part comprises information relevant to the national aspects of the application, such as recruitment arrangements or information related to the informed consent procedure. Annex I of the CTR lists documents that must be included in Parts I and II of the application dossier.

The CTR states that the language of the application dossier should be determined by the respective Member States Concerned (MSCs). The clinical trials regulation offers some flexibility regarding choice of language. When submitting documentation that isn’t patient-facing, the CTR recommends using English. This recommendation is based on the fact that English is generally regarded as a lingua franca of the medical field.

MSCs currently agree that most documents submitted in Part I can be accepted in English. They allow for some exceptions where a national language is mandated.

• Annex II of the European Commission’s guidance document, titled “Questions and Answers Document — Regulation (EU) No 536/2014,” is published on EudraLex 10 (hereto referred to as the “Q&A document”). The Q&A document clarifies which documents from Part I can be accepted in English. It denotes which documents must be submitted in a mandated national language. In cases where English or national language can be accepted, trial sponsors should submit only one language version of the documents.

Each MSC defines language requirements for Part II documents.

• Annex III of the Q&A document includes a list of national websites and contact email addresses. This list helps trial sponsors with their queries about national requirements and individual parts of an application dossier.

Submission language requirements for PROs/ePROs

One confusing factor was submission language requirements for patient-reported outcomes/electronic patient-reported outcomes (PROs/ePROs) and other patient-facing documents linked to the endpoints of the clinical trial. The CTR doesn’t specifically refer to these types of documents among the content of the trial application dossier. As a result, sponsors trying to comply with the new regulation were unsure if those documents are required in a submission. Additionally, if these documents were required, sponsors were trying to determine which part of the application dossier to include them in. They were also trying to determine if there are specific language requirements for submission. Varying feedback sponsors received from individual MSCs exacerbated the lack of clarity surrounding these questions.

The Q&A document, published in September 2022, clarified that these patient-facing documents should be submitted as part of the study protocol in Part I. They needed to meet language requirements for the protocol. An additional logical caveat was added. The caveat specified that these documents (when used in trial) must be provided to clinical trial participants in a language they understand. The Q&A document also confirmed that the CTR did not provide a legal basis to request submission of these types of documents in Part II (nor could a translation be required).

As a response to all this confusion, a majority of MSCs indicated that the protocol could only be accepted for submission in English. By extension, this English-only language requirement applied to all patient-facing documents submitted as part of the protocol. Preparing such patient-facing documents for multinational trials is a complex and resource-intensive process. Submission schedules frequently push this complicated preparation. These factors made simplified, streamlined submission language requirements very helpful to trial sponsors (and all relevant involved stakeholders). A December 2022 update of the Q&A document revealed an emerging divergence on this matter. Several MSCs now require these documents to be provided in national language only. Some MSCs indicated that both English and national language must be submitted. Or, they specify that either English or national language can be accepted.

This change should remind trial sponsors that the Q&A document is a live document, constantly updated as new information is available. It’s crucial to check this document regularly and ensure language requirements are understood promptly. From a practical perspective, sponsors may want to take advantage of the option to submit their documents in English when an MSC offers it (or it applies to a particular trial). This tactic may even out translation readiness schedules and reduce associated pressures on sponsors and stakeholders’ teams.

Requests for information under the new EU clinical trials regulation

In the context of this new CTR, an RFI is a request for information regarding the submitted trial application. Reviewing authorities may raise an RFI to trial sponsors during evaluation of the application. Depending on the nature of an RFI, a sponsor’s response may require updated translated documents.

As per the CTR, RFI response time is notably limited and contingent on the stage when it’s raised. The regulation sets a maximum of:

• 10 days to respond to RFIs raised during validation of an application.
• 12 days to respond to RFIs raised during Part I and/or Part II assessment.

Within these time limitations, each MSC may set its own deadline. This deadline could reduce the response timelines further. The consequences of missing the deadline are serious. If the sponsor doesn’t answer within the period set by authorities, their trial application will be deemed lapsed.

MSCs may raise more than one round of RFIs, an experience some trial sponsors had. In these cases, efficient translation management for responses is crucial to support the sponsor comprehensively.

Managing tight deadlines created by the new EU CTR

Managing translation requirements within limited timeframes requires thorough advanced preparation. Depending on the sponsor’s organizational structure (or where other partners, such as clinical research organizations, may be involved as well), multiple stakeholders should work together. They should create a robust, reliable process to ensure timely turnaround of translation projects associated with RFI responses. These are some tips for developing an optimal translation response for RFI responses:

• Currently, RFIs can only be accessed from within the CTIS. There is no notification system outside of it. Therefore, responsible CTIS users should monitor the system daily and ensure that RFIs are promptly routed for processing.
• Your language service provider (LSP) likely receives a steady flow of many translation requests. Ensure translation requests for RFI responses are prioritized by agreeing with your LSP on a label (or other method) to identify them easily.
• Similarly, create a specific project gateway to facilitate dynamic processing of translation requests. Ensure that it’s different from your “usual” request method. For example, create a dedicated email alias.
• It’s vital for your LSP to be apprised of anticipated submission dates. Communicate dates when you submit a trial application. When possible, share the estimated time window for receipt of (potential) RFIs. This communication will enable your LSP to initiate mapping resources and swiftly activate your project once a translation request is received.
• All parties need to align on expectations. Discuss what is feasible within limited timelines. Detail the service(s) requested and agree on the operational performance metrics for this type of translation project. Confirm any specific requirements for the deliverables.
• Identify and remove potential roadblocks to slow down initiation of translation projects. For example, a delay in providing a purchase order to your LSP will delay initiation of the project. This delay could jeopardize timely delivery.
• In collaboration with your LSP, develop best practice guidance. Document everything agreed upon concerning this type of translation project. Provide a set of consistent recommendations regarding project management. Share this document with all relevant teams and stakeholders. Lastly, follow good documentation practices throughout the project’s life cycle. Good documentation ensures information is accurate, current, relevant, and accessible.

A well-defined translation strategy is necessary for the successful centralized submission of clinical trial applications under the new EU CTR. Think of your LSP as a key partner in achieving success. Consult with your LSP and involve them from the early stages of trial planning. This communication will help you streamline your global translation management, ease administrative burden on your teams, and fully benefit from your LSP’s external language expertise and technological capabilities.

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Need assistance complying with the new EU CTR? We have the deep experience, knowledge, and technology to help. Contact us today to find out more about Lionbridge’s Life Sciences translation services.