The European Union Clinical Trial Regulation (EU CTR) went live on January 31, 2022. The first-year transition period ended on January 30, 2023, so using the Clinical Trial Information System (CTIS) is now mandatory for all initial submissions of interventional clinical trials involving one or more European Union (EU)/European Economic Area (EEA) member states (MS).
Trials approved under the EU Clinical Trial Directive (EU CTD) and not complete by January 30, 2025, will have to formally transition under EU CTR (national decision in place) by that date, but they may continue under the EU CTD regimen until then. This leaves the question of how to manage ongoing trials authorized under the EU CTD and the impact that EU CTR implementation may have on IMP labeling strategy and planning. So, what are the impacts of this second transition period (2023–2025) on IMP labeling activities?
Requirements and Supporting Guidance
Labeling requirements for clinical trials approved under the EU CTD are in Good Manufacturing Practices, Annex 13 (Investigational Medicinal Products) and their national transposition (as applicable). Requirements for clinical trials to be submitted under EU CTR are in Annex VI of the EU CTR itself (investigational medicinal products and auxiliary medicinal products), meaning that labeling requirements are now directly part of the EU CTR and do not rely on historic national transpositions.
From EU CTR Article 98: Transitional provision provides for a three-year transition period from EU CTR go-live (effectively from January 31, 2022, to January 30, 2025) to allow for trials submitted under the EU CTD to “continue to be governed by that Directive.”
Further insights into what may need to be considered to manage your activities during the transitional period are in section 11 of the Clinical Trials Regulation (EU) No. 536/2014 Questions & Answers document (version 6.3 dated December 2022 used for this blog). For IMP labeling in particular, the following entries are of specific interest:
• Question 11.9: when is the sponsor expected to update trial documents and labels?
505. Answer: the sponsor should bring documents related to the clinical trial in line with the CTR requirements (including the EUCT number) at the latest at the time of authorisation of the first Substantial Modification of a given document.
506. For the labelling of IMP and AxMP, it is expected that the sponsor updates the label for those batches that are (re)labeled after the authorization under the CTR. There is no need to pro-actively relabel released IMPs. (112)
This means that a pragmatic approach considering the actual relabeling/qualified person (QP) release of supplies in relation to the eventual date of transition to EU CTR can be used as a criterion for the timing of label updates and their actual use on clinical supplies.
• Question 11.8: What are the consequences of switching the regulatory framework applicable to a clinical trial?
[…] 503. As for GMP requirements, with the exception of labelling, the Commission Delegated Regulation (EU) 2017/1569 and the Implementing Regulation (EU) 2017/556 on the good clinical practice inspection procedures will become applicable once the trial is approved under the CTR. (For trials authorised under the CTD, Annex 13 remains applicable until 31/1/2025). […] (112)
This means that EU CTD requirements will remain valid for trials not yet transitioned.
Three Key Considerations for Planning IMP Labeling Activities for Ongoing Studies
Based on the information available, we can see that several points should be considered for adequate planning and execution of your labeling strategy during the remaining transition period for clinical trials running in EU/EEA countries.
#1 Conduct a Gap Analysis
Conduct a gap analysis of all labels (current and planned) for studies conducted in the EU/EEA falling under the scope of EU CTR. This will allow you to gather relevant information to determine what actions may be required for:
• The design/update of your supply labels depending on the regulatory framework under which your clinical trials will be (submitted under EU CTR when, if planned to be transitioned)
• Current labeling strategy (trial-specific or pooled supplies)
• Projections regarding new supplies manufacturing/QP release for transition trials in particular
#2 Adopt a Pragmatic Strategy
Adopt a pragmatic strategy that’s in line with current regulators’ expectations (as detailed in the Q&A document). In particular, the confirmation that no relabeling of already released IMPs for transitioned trials provides some leeway on the impact that EU CTR transition may have on clinical trials where no further manufacturing or labeling campaign is planned (which would be identified upfront via your gap analysis and supplies manufacturing/release projections).
#3 Align Your Strategy
Align your strategy between Clinical Operations/Regulatory Operations and Qualified Person(s) internally and for vendors (as applicable). As requirements are not as detailed and may be subject to specific interpretation, it is important for your QP(s) to be aligned with the operational implementation of the labeling strategy in the planning and execution of new and ongoing (to be transitioned) trials. Newly released supplies are of particular focus, as the timing of this QP release may need to consider either EU CTD- or EU CTR-approved documents (with an impact on the timing for submitted EU CTR-updated labels when considering transition).
Conclusion
In conclusion, it is of particular importance to assess if new manufacturing/batch releases are for trials potentially planned to transition under EU CTR, as this may trigger the need to use updated labels for those new supplies (triggering a need for their timely readiness and submission as part of the transition process). New clinical trials submitted directly under EU CTR should be fully compliant with EU CTR Annex VI from the start. Existing clinical trials authorized under EU CTD may retain their original labeling, as GMP annex 13 requirements remain applicable through the transition period. If a new manufacturing run/batch release of supplies is to take place, approved labels aligned with the legislative framework under which the clinical trial is approved should be in place to ensure the batch release remains compliant with the clinical trial regulatory framework and its approved documentation.
Contact us at labels@transperfect.com to learn how we can support fine-tuning your labeling strategy and processes under the new EU CTR framework.