Transition of Ongoing Clinical Trials in the EU
From Directive 2001/20/EC to Regulation 536/2014: Key Considerations
Author:
Badrudiin Olow
Consultant
Introduction.
In the evolving landscape of clinical research and regulatory frameworks, Regulation 536/2014, also referred to here as the Clinical Trials Regulation (CTR), marks a significant milestone set to transform the conduct and oversight of clinical trials.
Please see our previously published whitepaper “Clinical Trial Regulation: A New Chapter for EU Clinical Trials”, prepared in collaboration with FGK Clinical Research, for a comprehensive resource detailing the framework for new clinical trial applications and clinical trial maintenance under the new Regulation 536/2014.
With the enactment of the CTR, stakeholders across the pharmaceutical and healthcare sectors now face the mandatory task of harmonising and transitioning ongoing clinical trials from the existing Clinical Trials Directive 2001/20/EC (CTD) to the new CTR framework in advance of the 30th January 2025 deadline.
This whitepaper serves as a comprehensive guide aimed at providing recommendations for navigating the transition process from CTD to CTR for active clinical trials. It delves into the fundamental changes brought forth by the CTR and outlines the requisite steps and considerations for ensuring a seamless transition whilst upholding regulatory compliance and patient safety.
As of the April 2024 CTIS Newsflash, sponsors have submitted 1,243 transitional submissions to CTIS, out of an estimated 4000 to 6000 trials that need to be transitioned. Scendea anticipate potential delays in Agency review in the coming months due to the anticipated rush from sponsors needing to transition before the January 2025 deadline, and the resulting backlog issues. Therefore, we strongly recommend submitting the transitional application as soon as possible.
Background.
Directive 2001/20/EC, also referred to here as the Clinical Trials Directive (CTD), was a regulatory framework established by the European Union in 2001 to govern the conduct of clinical trials involving medicinal products. It provided a legal basis for the regulation of clinical trials across EU member states, aiming to harmonize standards for the safety, quality, and efficacy of investigational medicines.
The CTD outlined procedures for obtaining regulatory approval, reporting adverse events, and ensuring the ethical conduct of trials involving human subjects. However, the CTD faced criticism for its complexity, bureaucratic hurdles, and variations in interpretation and implementation among the member states, leading to delays in trial initiation and hindering collaboration between EU member states. Clinical trial applications were assessed entirely independently by the respective National Competent Authorities, leading to divergent assessment conclusions. Procedural timelines also varied widely between EU member states.
In response to these challenges, the European Union introduced the Clinical Trials Regulation (CTR), Regulation 536/2014, to replace the CTD. The CTR, adopted in 2014 and becoming fully applicable in 2022, aims to streamline and simplify the regulatory process for clinical trials while enhancing patient safety and fostering innovation.
Unlike the CTD, which was based on the “Directive” framework, thereby mandating a goal for EU member states to achieve whilst leaving it to individual countries for how this would be implemented in national law, the CTR is a “Regulation”, meaning it is a legal act directly applied across all EU member states.
The move to a “Regulation” framework offers a more harmonized and standardized approach to the regulation of clinical trials within the European Union.
The CTR introduces several key changes in comparison to the CTD, including simplified procedures for obtaining regulatory approval, enhanced transparency, public access to trial data, strengthened reporting requirements for adverse events, and the establishment of a single online portal, the Clinical Trias Information System (CTIS) for the submission and assessment of clinical trial applications. The clinical trial application process is now harmonised with a single application submission sent to all concerned EU member states.
Additionally, the CTR introduces new provisions for the oversight and monitoring of clinical trials, including the designation of a single rapporteur member state responsible for coordinating the assessment of multinational trials (the reporting member state [RMS]) and the introduction of stricter requirements for the conduct and reporting of clinical trials, aimed at ensuring the reliability and integrity of trial data.
Overall, the CTR represents a significant overhaul of the regulatory framework for clinical trials in the European Union, designed to promote innovation, protect patient rights, and facilitate the development of safe and effective medicines.
Table 1 - Comparison of Directive 2001/20/EC and Regulation 536/2014
Please refer to the previously published whitepaper titled “Clinical Trial Regulation: A New Chapter for EU Clinical Trials” for additional insights into the CTR and detailed information regarding the submission of initial clinical trial applications and the associated clinical trial maintenance procedures.
Transitioning to the Clinical Trials Regulation.
For new clinical trials, the CTR became applicable in January 2022, offering standardized procedures for trial authorization, enhanced transparency, and improved patient safety measures. All new clinical trial applications submitted after January 2022 have been submitted under the Regulation 536/2014.
Ongoing trials conducted under the CTD must transition to the CTR before the deadline on 30th January 2025, adhering to updated regulatory requirements and ensuring alignment with the new framework. This transition period is intended to allow stakeholders to navigate the regulatory changes effectively and ensure compliance while upholding the highest standards of research integrity and patient welfare. The transition application is intended to be an administrative process which should not involve reassessment of documents already approved under the CTD.
The consequences for sponsors who are not able to complete transition of their ongoing trial are outlined in Article 77 of Regulation 536/2014 and include provision for EU member states to revoke authorisation of the trial, suspend the trial, or require the Sponsor to modify any part of the trial.
An expedited transition procedure involving the submission of a minimal dossier has been established to facilitate transitions and allow for ongoing trials to transition to CTR by limiting the scope of the review to purely a validation procedure, intended to ensure compliance with CTR rules relating to factors such as transparency and trial category. This procedure will be available only until 16th October 2024.
However, while the CTR transition guidance published by the European Commission assures sponsors that this is an administrative procedure and documents approved under the CTD will not be reassessed, Sponsors have reported receiving administrative and technical questions from competent authorities relating to these documents. Sponsors should therefore be prepared to receive Requests for Information (RFIs) in relation to Part I and Part II documents submitted as part of the transition application.
As stated previously, according to the April 2024 CTIS Newsflash, sponsors have submitted 1,243 transitional submissions to CTIS, out of an estimated 4000 to 6000 trials that need to be transitioned. Scendea anticipate potential delays in review in the coming months due to the anticipated rush from sponsors needing to transition before the 30th January 2025 deadline, and the resulting backlog issues. Therefore, we strongly recommend submitting the transitional application as soon as possible.
Requirements for a trial to transition to CTR.
Before initiating the application process to transition an ongoing trial to the CTR, sponsors must fulfil certain prerequisites. All pending or ongoing assessments, such as Substantial Amendments, under the CTD must be concluded in all EU/EEA countries prior to transition.
Moreover, if a clinical trial does not currently adhere to the Regulation’s requirements, a Substantial Amendment must be submitted under the CTD to ensure readiness for submission. A mono-national trial can transition once all pending or on-going assessments under the CTD are fulfilled. Multi-national trials may need additional preparation ahead of transition, such as consolidation or harmonisation of the study protocol.
Under the Directive 2001/20/EC, country-specific versions of documents for multinational trials were feasible as applications were submitted and assessed by individual EU member states. However, with the transition to the CTR, a single application is now sent to all relevant EU member states, eliminating the possibility of country-specific versions for Part I of the application dossier. Part II documents may still have country-specific versions.
While Part I documents must be harmonised across the EU for the most part, it is possible to transition to the CTR with a protocol with some country-specific aspects. According to EU guidance, the protocol may either be harmonized or consolidated prior transitioning a multinational trial. A harmonized protocol is identical across all EU member states, while a consolidated protocol allows for some procedural differences but maintains a core identical protocol. Furthermore, approval under the CTD may not be necessary for a multinational trial with a consolidated protocol, and sponsors should proceed with the transition application without the need to harmonise the protocol via Substantial Amendment submissions.
Scendea would advise that all other Part I documents should be harmonized, including the Investigator’s Brochure (IB), Investigational Medicinal Product Dossier (IMPD), and Good Manufacturing Practice (GMP) documentation.
A consolidated IB or IMPD may be submitted if a Sponsor cannot achieve full harmonisation. Similar to the consolidated protocol, the consolidated IB/IMPD must reflect the common core provisions and capture the differences as regards to each nationally authorised trial.
Prior to transition, a consolidated IB or IMPD does not require a Substantial Amendment under the CTD if the document properly reflects the scope and conditions of the authorisations of the clinical trial in each of the MSCs and complies with the CTR.
Scendea would strongly advise harmonising the IB and IMPD prior to transition and would anticipate heightened Agency scrutiny regarding a consolidated IB/IMPD in comparison to a consolidated protocol.
Sponsors should anticipate extensive total timelines for these pre-CTR transition activities. Sponsors may need to complete submission of Substantial Amendments in multiple member states, and respond to Requests for Information (RFIs), ahead of obtaining approval under the CTD to ensure compliance of the trial with the CTR before transition. Sponsors developing ATMPs should anticipate significantly increased review timelines, up to an additional 30 days, for the approval of any Substantial Amendment. Therefore, it is crucial for sponsors to commence these pre-CTR Transition activities as early as possible.
Documentation for a transition to the CTR.
Once sponsors have met the requirements for transitioning to the CTR, they should proceed with submission of the transition application as a partial expedited transition application with a minimal dossier.
While certain clinical trial sponsors may prefer to submit a complete dossier of all clinical trial documents previously approved under the CTD in their transition application, Scendea understands that member states are increasingly inclined towards insisting on the minimal dossier, thereby mandating the expedited process.
The expedited transition simplifies compliance with the new CTR by necessitating less documentation and featuring a shorter transition timeline.
It should be noted that following completion of the expedited transition procedure, the first submission by the Sponsor after approval must consist of the completion of the full application dossier via submission of a Substantial Modification. Crucially, this substantial modification can be submitted after the transition deadline on 30th January 2025.
The following section outlines the documentation required for the expedited transition application to the CTR. Once approved, the submission ensures that the sponsor and ongoing trial align with the requirements of the CTR.
Note that due to the CTR transparency rules, redacted versions of some documents, such as the protocol, will be required.
Table 2 - Documentation required for the Expedited Transition Application
from Directive 201/20/EC to Regulation 536/2014 - Minimal Dossier
GMP = Good Manufacturing Practice; IB = Investigator’s Brochure; ICF = Informed Consent Form;
IMPD = Investigational Medicinal Product Dossier
Process and Timeline for transition to CTR.
The expedited transition application process entails fewer documentation requirements and a shorter review timeline.
Although the expedited transition procedure offers the promise of a shorter review timeline without the need for reassessment of documents, it’s essential to note that EU member states may not consistently adhere to the expedited review timeline and may not refrain from reassessing documents already approved under the CTD. Therefore, sponsors should anticipate potential delays in the review process and be prepared for the possibility of reassessment of previously approved documents.
The minimum review timeline for a transition application with a minimal dossier is outlined below.
Expedited Transition Application with Minimal Dossier - Timeline
Standard Timeline Minimum (no queries) = 10 + 7 + 5 = 22 calendar days
Standard Timeline Maximum (with validation queries) = 10+ 15 + 7 + 5 = 37 calendar days
Worst Case Scenario = Expedited transition timeline/lack of assessment of Part I and Part II is not
guaranteed – review timeline could be up to 106 days or longer for some IMPs
Key Considerations for Stakeholders Intending to Transition.
Revised CTIS Transparency Rules
Since the publication of our previously released whitepaper “Clinical Trial Regulation: A New Chapter for EU Clinical Trials,” prepared in collaboration with FGK Clinical Research, notable revisions have been made to the transparency rules regarding the publication of documents submitted to CTIS as part of the initial clinical trial application (CTA)/transition application.
Previously, all non-Quality related information was subject to public disclosure, with sponsors having the option to request deferral for certain categories of information, such as the protocol, IB, responses to RFIs (non-Quality related), and the patient information sheet.
However, the revised CTIS transparency rules have eliminated sponsors’ ability to defer publication of clinical trial-related documents. Publication has been restricted to the protocol, SmPC, and patient-facing materials, with the IB no longer being made publicly available.
While the implementation of these rules will begin on 18 June 2024, the new transparency rules can currently be applied for all submissions.
CTIS will allow the upload of placeholder documents in place of documents that would previously have been published.
Ensuring Compliance with the CTR
An ongoing trial featuring several country-specific versions of a protocol or IMPD may necessitate Substantial Amendment submissions in multiple countries under the CTD before commencing the transition procedure. This could lead to significant delays of several months, underscoring the urgency for sponsors to promptly initiate the harmonization/consolidation process to ensure compliance with the CTR before transitioning.
CTR Transition Procedure - Reassessment of Documentation
While guidance pertaining to the transition of clinical trials from the CTD to the CTR assures sponsors that the transition application is purely administrative, Scendea understands that technical questions may still arise regarding Part I documents previously approved under the CTD. Sponsors should therefore be prepared to address technical questions, in addition to any validation queries.
CTR Transition Procedure - Lack of Consolidated RFIs
The designation of a single rapporteur member state responsible for coordinating the assessment of multinational trials (the reporting member state [RMS]) was intended to ensure sponsors would not experience the complexity, bureaucratic hurdles, variations in interpretation and implementation, and divergent assessment conclusions seen under the CTD.
Subsequent to the initial CTA or transition application, all requests for information (RFIs) from concerned member states are to be centralized by the RMS. However, Scendea notes that some sponsors have experienced a lack of consolidation of RFIs among the concerned member states by the RMS. Consequently, sponsors should anticipate the possibility of a similar RFI procedure as that of the CTD, as some EU National Competent Authorities may not uniformly adhere to the CTR requirements.
Good Laboratory Practice (GLP) Compliance under EU CTR
The Clinical Trials Coordination Group (CTCG) has released a recommendation paper outlining principles of Good Laboratory Practice (GLP) for CTAs under the CTR. The paper emphasizes that GLP facilities should have undergone inspection within a 3-year timeframe either side of the point at which pivotal non-clinical safety studies were conducted. Additionally, the CTCG advise inclusion of a statement confirming the OECD GLP status (or equivalent) of the non-clinical studies submitted to support clinical trials, unless this information is already included in the IMPD or IB. The absence of this information or incomplete documentation will lead to a Request for Information (RFI) to the sponsor and, if not resolved, to the rejection of the CTA.
Based on these recommendations, Scendea continue to advise sponsors to ensure that pivotal non-clinical safety studies are conducted in countries compliant with OECD standards.
Transition Application - Upcoming Deadline
As of April 2024, only 1,234 ongoing clinical trials out of a potential 4,000 - 6,000 have transitioned. As the 30th January 2025 deadline approaches, more sSponsors will seek to transition, potentially leading to backlog issues and delays among concerned member states. The expedited transition procedure will also only be available until 16th October 2024.
Sponsors should also be mindful of the 18-day winter clock stop, during which the evaluation of all clinical trial applications will halt from December 22nd, 2024, and resume on January 8th, 2024. Considering these factors and the EU CTR transition guidance published by the European Commission indicating that the transition procedure can take up to 3 months, Scendea would advises sponsors to submit transition applications no later than September 2024, to ensure compliance with the CTR before the 30th January 2025 deadline.
Conclusion.
In conclusion, navigating the transition of ongoing clinical trials from the CTD to the CTR represents a crucial undertaking for sponsors of ongoing trials within the European Union in the coming months.
Throughout this whitepaper, we have explored the key changes introduced by the implementation of the CTR, recent procedural and regulatory updates, and the complexities and considerations inherent in the transition process, emphasizing the importance of proactive planning to ensure a trial is ready to transition.
As the 30th January 2025 deadline approaches, we have outlined the crucial pre-requisite steps for sponsors to complete, such as Part I document harmonisation under the CTD via Substantial Amendment submissions, and the timelines associated with these pre-CTR transition activities.
As we enter this new era of clinical trials regulation, Scendea remain dedicated to providing expertise and guidance to facilitate a seamless transition and drive forward progress in medical research and innovation.