Transitioning an ongoing trial into the Clinical Trials Regulation
A trial authorised under the EU Clinical Trials Directive and still running after January 2025 had to move onto the Clinical Trials Regulation and its information system. The move calls on the medical writer for harmonised documents, a minimum dossier with redacted versions, a view of what is commercially confidential and when, care with licence-protected material and with national differences, and work that continues after approval.
The deadline and the cost of missing it
From 31 January 2025 only the Regulation and its delegated acts apply to trials in the EU, ending the three-year transition that began when the Regulation became applicable on 31 January 2022. Every ongoing trial governed by Directive 2001/20/EC and expected to continue in the EU or EEA after 30 January 2025 must transition to the Regulation, following the European Commission's guidance, and use the Clinical Trials Information System ahead of that cut-off. A trial that has not done so by then is non-compliant and in breach of the Regulation, and its sponsor can face corrective measures and penalties from member states and civil and criminal liability under Article 77.
From 31 January 2025, every clinical trial in the EU, including ongoing trials approved under the Directive, is governed by the Regulation, which marked the end of a three-year transition during which more than 5,000 trials were transitioned to the Regulation through submission to the system. Trials still ongoing after 30 January 2025 that were not moved to the system may be subject to corrective measures by member states. From that date transition procedures are no longer available, and sponsors of ongoing trials under the Directive must submit a new application through the system.
The transition application
The sponsor of a trial expected to continue after the deadline must submit a transition application, and practitioners strongly advise submitting it promptly, at the earliest date, so that there is time for approval. The transition application is an administrative process: the member states' assessment is reduced to the minimum needed to ensure compliance with the Regulation, its transparency requirements included. To streamline multinational applications, the member states were to run, where possible, an expedited, harmonised evaluation agreed by the Clinical Trials Coordination Group, open until 16 October 2024. The agency scheduled an information day on transition for 17 October 2024, the day after that window closed, to give practical guidance on the transition and the steps after it, with questions answered live by the agency, national authorities and industry. By May 2024 the Commission had issued Version 4 of its transition guidance, which, compared with Version 3 of March 2024, clarified the consequences of not complying with the transition requirements, added as Annex II a decision tree for the administrative transition of a trial, clarified the interface with medical devices and in vitro diagnostics and the matter of active sites, and made minor amendments on the system's transparency rules.
Harmonised or consolidated documents
Before a transition application, the first step is to evaluate whether the trial is in line with the Regulation's principles, and any document harmonisation requirements for a multinational trial must be considered early. Documents common to all member states and covered by the Part I assessment report, such as the protocol, the investigator's brochure and the investigational medicinal product dossier, must be either harmonised or consolidated. In the coordination group's guidance, a harmonised document is identical, with the same trial procedures, across all member states, and a consolidated document is a single identical document that sets out substantial member-state differences in its text or in an appendix. Where harmonisation is needed, it must first be submitted as a substantial amendment under the Directive, before the transition application. The medical writer's part is to help the regulatory submission team make the documents meet these requirements before transition.
The minimum dossier and its redacted versions
The minimum dossier's general documents are the cover letter, a statement of compliance with the General Data Protection Regulation, proof of payment where applicable, and the EU application form, completed in the system. Its Part I documents are the latest harmonised or consolidated protocol, investigator's brochure and investigational medicinal product dossier, documents relevant to good manufacturing practice such as the manufacturer's importation authorisation, and the latest approved documents on any non-investigational medicinal products. Its Part II documents are the latest approved subject information sheets and informed consent forms. The protocol, the brochure, the dossier and the participant documents are the affected clinical documents that medical writing teams write, and annex 1 of the transition guidance gives country-specific requirements.
A transitioned trial has to meet the Regulation's obligations, and the documents submitted with the transition application fall under its transparency requirements and are made public. When a minimum dossier is transitioned, the team has to prepare redacted versions of the protocol, the subject information sheets and the informed consent forms, in addition to the unredacted versions the member states have already approved. This applies to every trial category except category 1, for which a redacted protocol alone is enough, in line with the revised transparency rules.
The rules for redacting personal data are clear, anchored in the General Data Protection Regulation and the Clinical Trials Regulation, but the scope of commercially confidential information to redact is a significant challenge in preparing dossiers for publication. A collaborative approach involving medical writing, regulatory, transparency and often legal teams is essential, because what is confidential is unique to each company and often to each product or study. A clear definition provided early lets the writing team draft documents that minimise confidential content. But the protocols, subject information sheets and consent forms of active trials transitioning to the system were rarely composed with confidentiality considered from the outset. The most significant hurdle in a transitioning trial is balancing the risk of over-publication, which could reveal too much confidential information, against over-redaction, which frequently comes from a sponsor's limited understanding of what in its documents is confidential.
Commercial confidentiality over time
The revised transparency rules removed the deferral mechanism, and with that change it is important for a transitioning trial to distinguish what was confidential in an earlier development phase, when the application was submitted, from what is confidential during the trial's life cycle.
With transitioning trials under way, data are more likely to be published prematurely, particularly on sponsor websites, in conference presentations and in the sponsor's own scientific articles. Information the sponsor wishes to redact that is even partly in the public domain can affect the planned redaction strategy for an information-dense document such as a protocol. For example, a dose-escalation scheme for one cohort, presented at a scientific conference and made publicly available as slides, could compromise the sponsor's intention to protect the overall dose-escalation plan as confidential. The transparency rules introduced with the system have heightened awareness of the importance of appropriate timing in disclosing any full or segmented information about an active trial.
Licence-protected material
Standard clauses between sponsors and vendors usually approve the use of copies of the vendor's intellectual property in regulatory submissions. Some transitioning trials signed those contracts before the sponsors knew that all patient-facing material related to the trial's endpoints would become public once the trial was posted, so those contracts are unlikely to include a standard clause providing for public availability. The vendors agreed to regulatory review of their property but may not have been told of, or consented to, the same material becoming available to the public. Public disclosure could undermine their economic interest or competitive position, so their standing under these new circumstances has to be reassessed.
The protection that should be applied to such service providers, vendors of scales and questionnaires for example, does not fall under commercial confidentiality, but it is a highly sensitive matter for transitioning trials. The agency recognised the issue by letting sponsors upload a placeholder for licence-protected material where the sponsor and the third party have written agreements that expressly establish that patient-facing documents cannot be disclosed publicly.
Differences between member states
The industry has noted that member states continue to impose national requirements on submission documents, a practice that extends to the transparency rules for transitioning trials, even though a minimum dossier requires a minimum number of documents. Reimbursement and insurance amounts in subject information sheets and consent forms are one example: most member states approve redacting them, and some require them to be disclosed. Practitioners hold that applying different redaction strategies to the same document types, which will all eventually be available on the public portal in the same package, cannot be good transparency practice.
Resourcing the transition and the work after approval
Transition increased the documentation burden on sponsors. Study teams, medical writers and transparency specialists included, must work together to assess the time the transition application package needs, to consolidate or harmonise the documents, and to apply the redactions the Regulation's transparency requirements demand. Clear communication and a well-defined understanding of responsibilities are crucial, particularly in planning redactions and keeping to strict timelines, and especially when answering a request for information, which has a maximum response window of 12 days. A rapid response team that includes medical writers should be available to update documents so that translations and redactions are done within that window.
The work does not end once transition is completed: preparing the first substantial modification takes a substantial amount of work, especially where a minimum dossier was submitted for transition. After a transition application is approved, at the trial's next substantial modification, redacted versions for publication of the documents within the scope of the revised rules, as Annex I lists them, must replace the minimum-dossier documents. Resources must therefore be budgeted for the next substantial modification as well as for the transition application.