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Before the European Clinical Trial Regulation (CTR) came into effect, the terms 'protocol deviation' and 'protocol violation' were used as an attempt to clarify when a deviation from the protocol had to be (or did not have to be) reported to the MREC. The terms were used as follows: if a researcher or assistant -unintentionally- diverged from the protocol, an assessment was done to determine whether this was 'just' a deviation (and therefore did not have to be reported to the MREC), or a violation (and indeed had to be reported). A violation was usually defined as a potential risk to patient safety or the integrity of the study and the data collected. However, formal definitions of a protocol deviation or protocol violation do not exist in the ICH-GCP or in the Clinical Trial Directive. Definitions can be found in the literature but differ considerably from each other. The terms deviation and violation do not appear on the CCMO website.

Clinical study into investigational medicinal products:

Reporting serious breaches for studies covered by the European Clinical Trial Regulation (CTR):

In the European Clinical Trial Regulation that came into force on 31 January 2023, the term 'serious breaches' is used. A clear definition of is given. A 'serious breach' is any deviation of the approved protocol version or the clinical trial regulation that is likely to affect the safety, rights of trial participants and/or data reliability and robustness to a significant degree in a clinical trial.

The GCP Inspector Working Group (ICH-IWG) of the European Medicines Agency (EMA) has drawn up a guideline for types of serious breaches and the reporting requirements: Guideline on reporting serious breaches. It describes what, when, by whom and where to report. Appendix 1 of the Guideline provides a list of examples of "serious breaches.". In short, a serious breach by the investigator (local principal investigator) must be reported immediately to the sponsor. The sponsor must then report this through CTIS without delay but no later than 7 days after becoming aware of the serious breach. In the Netherlands, the CCMO receives notifications of serious breaches via CTIS and, depending on the type of serious breach, the serious breach is assessed by the Health and Youth Care Inspectorate (IGJ), the MREC that approved the study, or the CCMO: Serious breaches | Investigators | The Central Committee on Research Involving Human Subjects (ccmo.nl)

Transitional period: notification of serious breaches under Directive 2001/20/EC:

The first three years after the entry into force of the CTR is the so-called transition period (31 January 2022 - 31 January 2025). During this period, clinical investigations with medicinal products can still be carried out under Directive 2001/20/EC. In fact, a provider carrying out clinical investigations with medicinal products under Directive 2001/20/EC is only obliged to report a serious breach to the recognized MREC or the CCMO if the breach is likely to result in unacceptable risks for the subject. For clinical studies into investigational medicinal products that are still being carried out under Directive 2001/20/EC during the transitional period of the CTR, the Health and Youth Care Inspectorate (IGJ) asks sponsors to report serious breaches to them by e-mail via gcp@igj.nl. This also applies to serious breaches involving electronic systems, for example hacks and/or ransomware.

Source: The Health and Youth Care Inspectorate (IGJ) website: https://www.igj.nl/zorgsectoren/geneesmiddelen/klinisch-onderzoek-gcp/regels-voor-klinisch-onderzoek/aandachtspunten-geneesmiddelenonderzoek/ernstige-inbreuken

Non-medicinal research governed by the WMO and research into medical devices or in vitro diagnostic medical devices (governed by the MDR and IVDR):

In contrast to the CTR, the WMO, MDR and IVDR do not define (serious) breach, protocol violation or protocol deviation. The applicable law and regulations also do not provide for a procedure for reporting serious infringements.

As long as there are no national or European frameworks, the MREC NedMec advises researchers and sponsors to follow the same procedures for these types of studies as for clinical studies into investigational medicinal products governed by the CTR. This means: the sponsor must determine and document the consequences of a (serious) breach (i.e. perform a so-called impact analysis), and report a serious breach only, to the MREC or CCMO if the breach may lead to unacceptable risks for the study subject and/or data reliability and robustness to a significant degree.

Minor changes, such as textual corrections, are generally only acknowledged by the review committee (MREC or CCMO). More substantial modifications, such as the addition of a new participating centre, require a further decision. This also applies to modifications that can affect the safety of the human subjects. These are considered substantial amendments.

• For more information, go to: 'CCMO Amendments'
• For submission instructions, go to: How to submit

Generally, the following applies: If a change is within the scope of the primary research question of the study, it will concern an amendment. If it is beyond the scope of the primary research question, it will concern a new study.

The MREC only assesses the Dutch information sheet and consent form. However, every test subject must be able to make well-informed decisions about participating in a study. If a person not sufficiently proficient in Dutch, is asked to participate in a study, the subject information sheet must be available in a language that the person is proficient in. As a standard, the study's sponsor is responsible for a good translation. The review committee does not require the translated subject information sheet; however  the corresponding translation certificate must be submitted. If a person who is not proficient in Dutch, is asked to participate in research unexpectedly and incidentally, a translation certificate is not required. In addition to providing adequate written information, the investigator must also ensure that oral information is provided (before and during the study) in a language that the subject is sufficiently proficient in.

Source: Central Committee on Research Involving Human Subjects (CCMO) website

Please refer to the English-language section in the decision letter. If this is not enough, we advise you to engage a sworn translator.

On May 26, 2021, the EU Medical Device Regulation (EU no 2017/745, MDR) entered into force. As a result, the rules for submission, review and conduct of clinical research with medical devices have changed. Please consult the CCMO website for information on research with medical devices as of May 26, 2021. There you will find, among other things, the definition of medical devices according to the Medical Devices Act, legal frameworks, review by an accredited MREC and notification to the Health and Youth Care Inspectorate (IGJ). 

Useful links

• MREC webpage on the European Medical Device Regulation (EU no 2017/745, MDR).
• For researchers of the UMC Utrecht: Medical Technology Connect page (MTKF department)
• Research with a medical device that is not subject to the WMO: see the explanation on the page Is review required?

For more information on reporting changes to non-WMO studies, go to: Is review required?

For information on obtaining local approval from your institution, visit the pages below:

• Antoni van Leeuwenhoek
• Princess Máxima Center
• UMC Utrecht