Questions and answers CTR – The Netherlands

For clinical trials submitted via CTIS according to the rules of the CTR, the ABR form and EudraCT form expire. For currently ongoing clinical trials, the ABR form and EudraCT form will continue to exist as long as these studies have not been transferred to CTIS. See our website for more information about the transition period.

For studies submitted in EudraCT, and not yet transferred to CTIS, a Frequently Asked Questions document is available. It also contains information about the transition to CTIS as of 31 January 2025. See the frequently asked questions about EudraCT on the European Medicines Agency website.

No, the CTR does not provide for this. In order to be able to continue to ensure that the agreements with regard to the publication and termination of the clinical trial are in accordance with the Richtlijn Beoordeling Onderzoekscontracten (CCMO Directive on the assessment of clinical trial agreements), questions on these two matters have been included in the form 'Compensation for trial participants, investigator, funding clinical trial and other arrangements' (research dossier Part II). This form can be found on Financial and other arrangements.

No, an independent expert is no longer required under the CTR.

The CCMO templates are mandatory with the exception of the template CV of the investigator.

In the Netherlands the CV may be submitted without a signature in CTIS. This does not apply to the Site Suitability Declaration (Verklaring Geschiktheid Onderzoeksinstelling, VGO). A validated digital signature is accepted for this document. In CTIS, two versions must be submitted: one with and one without signature. The redacted version is made public in the public part of CTIS.

Documents, such as questionnaires and diaries, used to record study endpoints must be described in the study protocol and can be added as annexes to the protocol. Validated standard questionnaires, such as the quality of life questionnaire SF36, do not need to be included. See also the page on the protocol.

For clinical trials submitted before 1 November 2021, the Research Declaration (Onderzoeksverklaring) can be used for the new sites. The use of the Site Suitability Declaration (Verklaring Geschiktheid Onderzoeksinstelling, VGO) is voluntary for studies submitted before 1 November 2021.

No, it is enough to mention the EU Clinical Trial number without the last two digits in the documents. The last two digits refer to whether it concerns a first submission (EU clinical trial number ends with -00) or a re-submission of the same dossier (EU clinical trial number ends with -01 or higher). By leaving these last two digits out in the documents, the EU clinical trial number in the documents do not have to be changed when re-submission is required.

Only the centers for which the set of documents is complete should be submitted in CTIS. This means a signed VGO, a CV and a declaration of interests of the principal investigator.

Each affiliate must be registered separately in the OMS system and receives an unique ID. The OMS distinguishes between Organization IDs and Location IDs, where Organizations are country specific and locations under an Organization are located in that same country. For each country you create an Organization with Location (s). For more information, see the document on EMA's website.

The organizations that need to be registered in OMS to be available for CTIS are sponsors or co-sponsors, third party contractors (e.g. CRO), EEA trial sites, and Marketing Authorisation Holders.

The EudraVigilance product database (XEVPMD) applies to medicines authorised in the EU (AMPs) and to IMPs used in clinical trials. The active substances have to be registered as well. See also paragraph 5 (Product management in CTIS) of the Sponsor Handbook. See for more detailed information the document on EMA's website.

No. The addition of a new participating center is a substantial amendment (of Part II). A substantial part II amendment can only be submitted in a Member State if:

• the Member State concerned has issued a positive decision on the clinical trial, and
• no other substantial amendment to the same clinical trial is being assessed in the Member State concerned.

For more information on substantial modifications, see Submission of a substantial modification.

No, the marginal review by the competent authority (CCMO or Ministry of Health, Welfare and Sport) shall be repealed for clinical trials submitted in CTIS.

For CTR clinical trials all SUSARs must be reported via Eudravigilance. This means that every sponsor of a clinical trial must have access to EudraVigilance or must apply to the EMA for such an access. If a sponsor does not have the possibility to report SUSARs in Eudravigilance due to a lack of resources, the CCMO can be contacted. The annual safety report (ASR/DSUR) must be submitted in CTIS.

For CTD clinical trials all SUSARs must also be reported via Eudravigilance. If a sponsor does not have the possibility to report SUSARs via Eudraviglance, he can report this in the SUSAR module of ToetsingOnline. The competent authority will report SUSARs occurring in the Netherlands in Eudraviglance. In addition, the obligation to report all SUSARs to the MREC remains. SUSARs no longer need to be reported to the competent authority. However, the annual safety report (ASR/DSUR) has to be submitted to the MREC and to the competent authority.

This is the same as under the old legislation (Directive 2001/20/EC (CTD)). The investigator must report the SAE to the sponsor within 24 hours of it being discovered. The protocol defines the type of SAE that does not require immediate notification. The sponsor shall include an aggregated table of SAEs in the Annual Safety Report (ASR) to be submitted in CTIS. Individual SAEs are not reported in CTIS. If a SAE is suspected to be related to the IMP and is not described in the Reference Safety Information, the SAE should be reported as a SUSAR. SUSARs must be submitted via Eudravigilance.

No, SUSARs always have to be submitted to Eudravigilance.

When a clinical trial has been submitted in accordance with the old legislation (Directive 2001/20/EC (CTD), in the Netherlands the WMO) a new research site can still be submitted as an amendment under the CTD (WMO) the first three years after the CTR came into force, i.e. until 31 January 2025. From 31 January 2025, this will no longer be possible and all amendments must comply with the CTR. In order to continue the clinical trial after this date, the clinical trial has to be switched to the CTR.

The addition of a member state to a clinical trial authorised under the CTD is only possible in the first year of the transition period. Adding a new member state after this first year of the transition period can only be done when the clinical trial is switched to the CTR. The addition of a new country then has to be submitted according to the procedure 'Add new Member State'.

The Q&A CTR questions 11.5, 11.6, and 11.7 describe the documents needed to transition a clinical trial approved under the Clinical Trial Directive (CTD). For the transition of a clinical trial, first only the latest versions of the following documents approved under the CTD should be placed in CTIS:

• Protocol (a consolidated or harmonized version in case of a multinational clinical trial)
• Investigator’s Brochure
• Good manufacturing Process (GMP) documents
• IMPD (and AxIMPD if applicable)
• Subject information sheet and informed consent form

In CTIS a blank document should be uploaded in the placeholders for the remaining documents (where document upload is required). The title of these documents must include the term “blank document”.

The cover letter should include:

• A declaration that the clinical trial is in line with the requirements for transition trial (as set out in question 11 of the Q&A CTR) and that the clinical trial is still in line with the authorisation given under the CTD.
• The name of the ethics committee who has given a positive opinion on the clinical trial under CTD.

There will be no assessment during the transition of a CTD clinical trial to CTIS. Therefore, the Netherlands does not want to receive any documents other than those mentioned above during the initial transition.

After the initial transition, the dossier must be completed at some point. The replacement of the blank documents can be done at the first substantial modification (SM). If the SM only concerns Part I, then only Part I documents must be completed. For a SM relating solely to Part II, only the mandatory Part II documents must be supplied. Remarks:

• The site specific documents need to be supplemented only for those sites that are still active in the clinical trial.
• Recruitment arrangements: This document may be omitted if the recruitment of new trial participants has stopped.
• CV (resume): The previous CV’s (used in the CTD application) can be provided. Please note that in CTIS a redacted version (without personal details and signature) should be submitted.
• Declaration Site Suitability [VGO]: If this is the previously used Research Declaration under the CTD, then this can be submitted, and it is not necessary to supply a new VGO. Please note that a redacted version should also be submitted (without personal details and signature).

It is EMA’s intention that the CTIS public portal will be a WHO registry, however, this application is not yet finalized.

No, CTIS is specifically for the submission and assessment of clinical trials conducted in the European Union.