Questions and answers CTR – The Netherlands

For questions about the assessment of clinical trials with medicinal products in the Netherlands, please email: ctr@ccmo.nl.

In that case, you may contact the representative for clinical trials in the relevant UMC. The email addresses for questions on clinical trials with medicinal products of the seven UMCs in the Netherlands are listed below.

It is not necessary to ask informed consent for this again. Participants that are still in the trial could for instance be informed about this upon the next update of the ICF. It can also be communicated in different ways, such as verbally or via a website, there are no guidelines for this.

For new clinical trials submitted via CTIS, there is no ABR form or EudraCT form. For transition trials authorised under the Clinical Trial Directive and transitioned to CTIS, the ABR and EudraCT forms are not part anymore of the CTIS application.

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, a signature is required for the Site Suitability Declaration (Verklaring Geschiktheid Onderzoeksinstelling, VGO) submitted in CTIS. A validated digital signature is also accepted for this document. A signature is not required for the CV of the principal investigator, preferrably a CV without signature is submitted. A signature is considered personal data. Any document with a signature and to be published based on the transparency rules for CTIS should be redacted (see: Redacted and unredacted documents).

On 18 June 2024 revised transparency rules were published for CTIS (see: Transparency rules: general information). Based on these revised transparency rules, CV and VGO are no longer published in the public portal 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. They can also be submitted as separated documents in the Protocol section in CTIS (document code D4). 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.

No, this is not allowed. 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.

During validation, it is verified whether all required quality information is available to allow a scientific assessment. The acceptability of this information is evaluated during the assessment phase.

If essential quality information is missing and is not provided following a request for additional information, the application will be negatively validated.

Yes. For each unauthorised medicinal product (IMP and AxMP), batch analysis data and available stability data from at least one representative batch must be provided, where applicable. This batch must have been manufactured using a process representative of the intended clinical product, taking into account the applicable GMP requirements.

If no representative batch has been manufactured or the corresponding batch analysis data are missing, the application will generally be considered incomplete. A commitment to provide these data after submission is insufficient.

Yes. When reference is made to an ASMF for a drug substance, at least the Applicant's Part (open part) must be available at submission.

If this information is missing, the application will be considered incomplete. A reference to an ASMF alone is insufficient.

The necessary Chemistry, Manufacturing and Controls (CMC) information on critical starting materials and raw materials must be available at submission, where applicable. This information must be sufficient to allow a scientific assessment of the quality of the product.

If essential information is missing, the application will generally be considered incomplete.

When using a separate IMPD-Q-only application, the sponsor trial must contain sufficient information to allow a risk-based assessment of the product in the intended clinical trial.

For biological medicinal products and ATMPs, relevant information concerning, for example, the drug substance, novel excipients and viral vectors must be available in the sponsor trial.

If this essential information is only available through a separate IMPD-Q-only application, the sponsor trial cannot be positively validated. A separately submitted Reference Safety File (RSF) does not replace essential quality information missing from the sponsor trial.

The required GMP documentation must be available at submission, including, where applicable, a valid Manufacturing and Importation Authorisation (MIA), GMP certificate or QP declaration.

If the required documentation is missing, for example because a manufacturing site has not yet been inspected by the Dutch Health and Youth Care Inspectorate (IGJ), the application cannot be positively validated. A commitment to provide this documentation after submission is insufficient.

For activities falling under Article 61(5) of the CTR, a specific procedure applies regarding the CTR declaration.

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. Exceptions can only be made if the reviewing ethics committee has given a favorable opinion classifying the study as a low-intervention trial. In all other cases, the study must comply with all requirements of the CTR that apply to regular clinical trials. This also applies to drug accountability. No exceptions are permitted.

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.

A temporary replacement of a principal investigator (PI) should be reported as a Substantial Modification on Part II, containing the CV and Declaration of Interest (DoI) of the temporary PI. The details of the original PI should be maintained in the Trial Sites section in CTIS, and their CV and DoI should not be deleted. This way, no changes in CTIS are required when the PI returns. It is not necessary to report the return of the PI, it is sufficient to mention this in the cover letter of the next Substantial Modification. 

No, this requirement does not exist anymore for clinical trials under the CTR.

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. The annual safety report (ASR/DSUR) must be submitted in CTIS.

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.

Yes, the CTIS public portal is a WHO primary registry that meets the requirements for prospective registration set by the International Committee of Medical Journal Editors (ICMJE) for publication in scientific journals.
 

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