Article

Handling substantial modifications under the CTR

Xandra Neuberger

Understand when to make a clinical trial dossier fully CTR compliant, what the first substantial modification requires and how to plan your modifications.

Before the end of the transition period, there was some confusion among sponsors when it came to the transition of ongoing clinical trials to the CTIS to fit the Clinical Trials Regulation (CTR) requirements.¹ In particular, it was not always well understood when the dossier has to be made fully CTR compliant. While the dossier is harmonized and some formal adaptations are made for the purpose of transitioning, it is not required for companies to submit a substantial amendment, now called “substantial modification”, directly after the transition purely for the purpose of having a fully CTR compliant dossier.

Update, October 2026: The CTR transition period ended on Jan. 30, 2025. Since Jan. 31, 2025, the CTR has been fully applicable, all clinical trials in the EU must be managed under the CTR through CTIS, and transition procedures are no longer available.⁸ The considerations below about the first substantial modification remain relevant for sponsors of trials that were transitioned from the Clinical Trials Directive.

Per the Commission’s transition guidance, it is only with the first substantial modification under CTR, contingent on the study itself, that sponsors will need to update their dossier in line with the CTR.² Importantly, at that point the entire dossier part they belong in (part I and/or part II), not just the affected documents, will need to be updated to comply with CTR standards.

This will likely make the first substantial modification after transition more preparation-intensive than previous amendments under CTD or subsequent modifications under the CTR. This workload also depends on whether the CTD dossier has already been comprehensively transferred to CTIS or whether a transition with minimal dossier has been performed.

Importantly, CTIS training sessions and presentations by EMA, as well as practical experience, have made it clear that as part of their review of the first substantial modification, member states can request and review any documents that have previously been approved under CTD in addition to the documents comprised within the updated dossier. As with all substantial modifications, changes to any of those documents can be requested in order to make them CTR compliant.

When, how and if sponsors need to update the dossier to CTR requirements where no substantial modification is planned for reasons originating from the study should be reviewed closely from a strategic perspective. It may make sense to update and submit the dossier voluntarily shortly after the transition if time permits, for example, in order to facilitate an important substantial modification later in the trial’s lifecycle. Whether or not clinical trial dossiers have to be made fully CTR compliant if there is no need for a substantial modification contingent upon the study also depended on guidance from the European Medicines Agency that had not been published at the time of writing. It may well be that dossiers of studies that are close to completion, or long-term follow-up studies with little interaction with subjects and no project-derived need for modification, won’t have to be updated to CTR requirements at all. Sponsors are advised to check the latest official guidance.

Attention is required when sponsors intend to add member states to their clinical trial after it has been transitioned from CTD. Here, a part I substantial modification solely for updating the dossier to CTR standards is required before an additional member state application can be submitted.³

Some additional points that may help

Use of the templates published, for example for investigator CV and declaration of interest, is not mandatory.⁴ Equivalent documentation approved under CTD does not have to be exchanged.

For transitioned investigational sites, the site suitability form does not need to be prepared. This is only needed for sites added after the transition.

Even though updated labels must be submitted with the first substantial modification involving part I (where label updates are necessary for CTR compliance), IMPs and AxMPs do not need to be proactively relabeled. Use of the new labels is only required for batches (re)labeled anyway after the new label has been approved.²

General considerations for substantial modifications

When preparing for a substantial modification, sponsors should ensure they know whether just one part or both Part I and Part II are affected so the correct sections are selected when generating the substantial modifications in CTIS. For example, a protocol change (Part I) may necessitate a respective ICF adaptation (Part II). In that case, a combined Part I / II substantial modification would need to be submitted. Whereas, for instance, an amendment to the investigator’s brochure (Part I) that does not affect any other document would constitute a Part I only substantial modification.

There may also be times when it makes strategic sense to combine Part I and Part II modifications, even where the changes are not related, as it could save time to not submit both sequentially. However, there is a higher risk of having the entire substantial modification application rejected (for example, if one member state refuses to approve Part II) because the application cannot be authorized partially.⁵

Importantly, it is only possible to submit substantial modifications when there isn’t any review ongoing that might be impacted by or might impact the content of this SM dossier. For example, it is not possible to submit any SM while review of a Part I SM is ongoing, while it is possible to submit a Part II SM while another Part II SM is ongoing in another member state.⁶

At the time of writing, some system functionalities were not available, preventing sponsors from making substantial amendments in certain situations, even though this would be in line with CTR. Hence it was not possible to submit a part I modification until there was a final decision (including on part II) available from all of the participating member states. This means that for trials with one or more member states for which only part I had been submitted and approved (called “staggered application”), no part I modification can be submitted. If a Part I modification becomes necessary, sponsors either have to withdraw the member states with Part I only approval, or the respective parts II first have to be submitted and decided upon in order to enable part I SMs for the entire trial.⁷ As of October 2026, the CTR Q&A refers sponsors to a procedure for submitting Part I substantial modifications in member states where only Part I was submitted.⁹ Since April 27, 2026, a mandatory Clinical Trials Coordination Group (CTCG) procedure for staged submissions, the "Article 11 workaround," allows Part I substantial modifications before Part II has been submitted in all member states.¹⁰

Preparing for success

Planning is key to successful regulatory lifecycle management of clinical trials. Sponsors should therefore consider how best to manage substantial amendments with a view to not wasting time or impacting their ability to perform relevant adaptations by submitting less important changes first, or by not combining urgent substantial modifications. On the other hand, they should combine modifications wisely so as to not risk rejection of important changes by overloading the submission pack with less important or insufficiently designed changes.

Disclaimer:
The information in this article is intended to inform readers about a topic related to Cencora's capabilities and is not legal or purchasing advice. Cencora, Inc. encourages readers to review the cited references in this article and use their own knowledge and experience when making decisions.