Handling substantial modifications under the CTR

There has been some confusion among sponsors when it comes to the transition of ongoing clinical trials to the CTIS to fit the Clinical Trials Regulation (CTR) requirements 1. In particular, it is 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.  

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 our 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 life cycle. 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 will also depend on guidance from the European Medicines Agency, which is yet to be published. 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 keep an eye out for official guidance information.  

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 include: 

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 pro-actively re-labelled. Use of the new labels is only required for batches (re)labelled 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.

There are also some system functionalities that are not currently available, preventing sponsors from making substantial amendments in certain situations, even though this would be in line with CTR. Hence it’s currently not possible to submit a part I modification until there is 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 has been submitted and approved so far (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.

Preparing for success  

Planning is key to successful regulatory life-cycle 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. 

Are you struggling with knowing when your dossier has to be made fully CTR compliant? Or are the requirements associated with the first substantial modification creating concern for your organization? We would be interested in hearing about your approach and concerns with regard to the first substantial modification.  

About the author: 

Xandra Neuberger is Associate Director Regulatory Affairs and international service lead for clinical trial applications at PharmaLex, leveraging her extensive experience with clinical trial applications and life cycle management to support the industry.  She also handles project and team coordination in her role. Xandra is a registered pharmacist in Germany and has also practiced pharmacy in the UK. 


1 Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance, EUR-Lex. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32014R0536

2 Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation, Dec 2023. https://health.ec.europa.eu/document/download/10c83e6b-2587-420d-9204-d49c2f75f476_en?filename=transition_ct_dir-reg_guidance_en.pdf

3 Best practices guide. https://www.hma.eu/fileadmin/dateien/HMA_joint/00-_About_HMA/03-Working_Groups/CTCG/2023_11_CTCG_Best_Practice_Guide_for_sponsors.pdf

4 EudraLex – Volume 10 – Clinical trials guidelines, European Commission. https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-10_en

5 Clinical Trials Regulation, Q&A, Substantial Modifications, Q 3.4, Version 6.7. EMA. Dec 2023. https://health.ec.europa.eu/document/download/bd165522-8acf-433a-9ab1-d7dceae58112_en?filename=regulation5362014_qa_en_0.pdf

6 Clinical Trials Regulation, Q&A, Substantial Modifications, Q 3.5.

7 Clinical Trials Regulation, Q&A, Version 6.7., EMA. Dec 2023.


This blog is intended to communicate PharmaLex’s capabilities which are backed by the author’s expertise. However, PharmaLex US Corporation and its parent, Cencora, Inc., strongly encourage readers to review the references provided with this article and all available information related to the topics mentioned herein and to rely on their own experience and expertise in making decisions related thereto as the article may contain certain marketing statements and does not constitute legal advice. 

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