Mastering CTIS: Strategies for Multi-Country Submissions, Compliance & Operational Success

Date: September 23, 2025

Cromos Pharma hosted a webinar dedicated to exploring the complexities of the Clinical Trials Information System (CTIS) and the implementation of the new Clinical Trials Regulation (CTR 536/2014). Our experts shared practical tools and strategies to confidently manage multi-country submissions, minimize delays, and address country-specific regulatory requirements.

Webinar Recording

Questions & Answers

We received quite a few questions from the audience during the webinar. Please see our answers below¹.

Q: Is it possible to change the Reporting Member State after submission?

A: No, once the RMS is selected and the application is submitted, it cannot be changed for that trial. That’s why it’s important to carefully choose the RMS at the very beginning, ideally after checking experience in handling similar submissions.

Q: If we would like to change a CRO during the trial, how should we proceed in CTIS?

A: In this case, the Sponsor Administrator needs to update user access in CTIS.  The old CRO’s access can be removed, and the new CRO first needs to have an active EMA account. Once that’s in place, the Sponsor Administrator can assign the appropriate CTIS role to the new CRO so they can take over activities. It’s also important to check all trial documents in the system, because in some cases the CRO may be listed as the Legal Representative in the EU. If that’s the case, the documentation will need to be updated and re-submitted for approval before the change is effective.

Q: How do we know if our Annual Safety Report has been successfully submitted in CTIS?

A: After you submit, CTIS will generate a confirmation and you’ll see the status updated in the “Annual Safety Reporting” section. The report will also appear under submitted documents, and the system automatically keeps an audit trail. If authorities need anything further, they can raise an RFI in this section — for example, sometimes they ask for proof of payment for Annual Safety Reporting review. Proof of payments must be uploaded in the reply section.

Q: In the case of a change of PI, do we also have to submit Part I?

A: No. Principal Investigator’s change is regarded as Part II substantial modification for the particular Member State concerned. The change of a Principal Investigator in the clinical trial site, may only be implemented if it has been approved by the MSC.

Q: If an application for a clinical trial is submitted 3-4 Member State, does a sponsor need to wait for approvals for all Member States concerned, before commencing the trial in any of the Member States concerned?

A: No. The sponsor/investigator can commence a clinical trial in the Member State concerned if a positive decision on both Part I and Part II has been issued by the Member State concerned.

Q: Did you have cases when documents cannot be prepared within the established timelines? How did you manage this case?

A: We plan our submission strategies to meet the deadlines and be ready to submit within defined timelines. We focus on quality of the documents before the submission and discuss with the sponsor all items that are time-consuming and may be regarded as risks. We also proactively identify and mitigate risks to avoid delays, maintain continuous communication with authorities and sites, and apply lessons learned from previous submissions to further improve efficiency. However, if during the RFI response process with a limited period for reply the document is not available or it is not possible to obtain it within the RFI response timeline (e.g. Insurance or site documents, such as updated Suitability Form): The commitment to amend the document during the next round of review may be declared.

In this case the outcome may be:

• conditional approval;
• rejection;
• acceptance of commitment and approval.

Q: When application for adding a Member State can be submitted?

A: An application for the extension of a clinical trial to another Member State can only be submitted:

• after the decision of all MSC which received an initial whole or both Part I and II in the case of staggered application is notified or made by tacit approval and at least one of them authorized the trial.

So, in multi-country trials, the last Member State (for staggered applications this is the last MS that received a Part II) notifying its decision (or authorized the trial by tacit approval) determines when a subsequent addition of a Member State can be submitted (the “slowest” MS drives the process).

• if there is no ongoing assessment of a Part I or Part I/II substantial modification in any of the MSC meaning that all MSCs issued a decision on a previous substantial modification application or authorized it through tacit approval (the “slowest” MS drives the process).

An application for the extension of a clinical trial to another Member State can be submitted if there is an ongoing assessment of a Part II substantial modification in any of the other MSC.

Q: Can there be different decisions from different countries for a part I SM?

A: Yes. The CTR foresees an assessment of a substantial modification of an aspect covered by Part I. In case of multinational trials, all Member States jointly review the application. The Reporting Member State will assess the substantial modification and will submit a conclusion at the end of this assessment.

However, each Member State Concerned takes an individual decision and can disagree with a positive conclusion by the RMS. This might lead to the situation that for a given clinical trial, several versions of the Part I documents exist. The CTIS reflects these versions and contains both an overview of the document versions authorized at trial level and at Member State level.

In case of disagreement from one or several Member States to a positive conclusion of a Part I substantial modification, the Sponsor can submit subsequent Part I substantial modifications. The basis for these substantial modifications will be the authorized versions of the Part I document. Sponsors are encouraged to carefully review the considerations and justification of the MSC that disagreed on the previous Part I substantial modification in order to have one common version of the Part I dossier across the MSC.

Q: How can the amendments be done?

A: The Clinical Trials Regulation defines a substantial modification as “any change to any aspect of the clinical trial which is made AFTER notification of a decision referred to in articles 8, 14, 19, 20 or 23 and which is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial”.

Modifications to a trial are regarded as ‘substantial’ when they are likely to have a significant impact on the safety or rights of the subjects and/or the reliability and robustness of the data generated in the clinical trial.

Substantial modifications within CTIS are submitted as Part I, Part II or Part I/II applications, that depend on the type of amendment and can be implemented when authorization is in place (appropriate conclusion(s) and decision(s) are obtained).

Q: Can we expect to receive Part 2 RFIs before Part 1 RFIs? What if it will impact the documents between Part 1 and 2?

A: Yes. Part I and Part II assessment have defined timeframes, and it may happen that in multi-country trials Part II RFIs are issued when Part I assessment is still in progress. In this case, Part II RFI needs to be responded within its defined timeline. When Part I RFI is issued, and in case it requires change to Part II documentation, the sponsor may contact appropriate Competent Authorities and initiate raising Part II RFIs to address the changes accordingly.

Q: Is there any templated language for contractual definitions of responsibilities we should be using?

A: There is no single “official” EU template, but under the Clinical Trials Regulation (536/2014) it is standard practice to include contractual language clarifying the roles of the Sponsor and the EU Legal Representative. The wording usually specifies that the Legal Representative acts as the Sponsor’s agent in the EU and is responsible for ensuring that the Sponsor’s obligations under the CTR are fulfilled, while the Sponsor remains fully responsible for the initiation, management, and financing of the trial.

Q: What happens if the QP Declaration or GMP documents are incomplete? Is the whole submission rejected?

A: Under the CTR, the authority issues a Request for Information (RFI). If the missing information is not properly addressed, the outcome may be a conditional approval or even a rejection. This is why early involvement of the QP and thorough pre-checks of all documents are critical to avoid last-minute issues.

Q: Can one QP Declaration cover multiple clinical trials?

A: No. Each clinical trial requires its own QP Declaration. The declaration must specifically reference the batches intended for that particular study. Re-using a declaration from another trial is not accepted and almost always triggers an RFI.

Q: Why are QPs so “strict”? Why can’t they simply accept the documents provided by the manufacturer?

A: Because the QP carries personal legal – and in some countries even criminal – liability for product quality and patient safety. The QP must be certain that the product meets EU GMP standards before releasing it for clinical use. This is why they only accept fully verified and complete documentation. Their caution is not bureaucracy but a safeguard for trial participants.

Q: If the IP manufacturing site changes while the study is ongoing, what is the average time required for the new manufacturing site documentation to be submitted and approved? Does Cromos Pharma have experience in this regard?

A: If the investigational product (IP) manufacturing site changes while the study is ongoing, two timelines need to be considered:

• Preparation and submission readiness
  • Collecting the necessary documentation (updated IMPD-Q, GMP certificate, QP declaration, vendor approvals) typically takes 3–4 weeks if all documents are readily available.
  • If certain documents are delayed (e.g. a new GMP certificate or QP declaration), preparation may extend to 2–3 months or longer before the submission package can be finalized.
• Regulatory approval
  • Once submitted as a substantial modification under the EU CTR, the regulatory review and approval process normally takes around 6–8 weeks.
  • If requests for information are issued by authorities, or if documentation is incomplete, the total approval timeline may extend to 3–4 months.

In summary: From the point the new site is identified until approval is granted, the overall timeline is usually 2–3 months in the best case, but can extend to 4–6 months if key certificates or declarations are not yet available. Until approval is obtained, investigational product manufactured at the new site cannot be released to clinical sites. 

Cromos has proven experience in managing such submissions and helping sponsors minimize delays.