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Changes to the research file (amendments)

Minor changes, such as textual changes, are generally only noted by the reviewing committee (MREC or CCMO).

Substantial amendments must undergo further review. Substantial amendments are changes to any aspect of the study that may substantially affect the safety or rights of the subject, or the reliability and robustness of the generated data. 

A few examples of substantial amendments are:

  • a new participating center,
  • a new research procedure for the primary endpoint,
  • a change in study design,
  • new version of the subject information sheet,
  • a new subject insurance.

For an amendment, you need to submit to the review committee a signed cover letter, and all changed and/or new documents in which clearly is stated what changes are made. You can do this in the cover letter or in a summary of changes for each document. Please submit both a clean version and a track changes version for each document. If the information in the ABR-form also changes because of the amendment, you have to create a new version of the ABR-form and submit as well. In the case of research with a medicinal product subject to the Dutch WMO Act, you always have to submit an EudraCT Notification of Amendment Form (B5), and, if applicable, also a modified EudraCT Application Form (B3).

Summarizing, in the case of an amendment you have to submit the following documents to the reviewing committee (MREC or CCMO):

  • Cover letter (A1) containing a description of the modification(s) and an oversight of all the documents you are submitting.
  • The modified and/or new documents, if applicable supplemented with a summary of changes for each document (in particular for protocol, IB, IMPD/IMDD and subject information sheet).
  • A track changes version of the modified document.
  • If the content of the information in the ABR-form (B1) changes, you also have to create a new version of the ABR-form and submit it as well.
  • Only in case of research with a medicinal product that is subject to the Dutch WMO Act (see below for more information) you have to submit an EudraCT Notification of Amendment Form (B5) and, if applicable, also a modified EudraCT Application Form (B3).
  • If the change concerns the subject information sheet, and subjects have already been included in the study, a summary of the changes can be of value to the subjects. If such an addendum is used, this document must be submitted to the reviewing committee as well.

For the way of submitting, see How to submit to the review committee.

The review committee decides if a further decision is necessary. Ask the accredited MREC in question or the CCMO about their policy. A further decision is subject to the so-called ‘reasonable timeline’ of 8 weeks as stated in the General Administrative Act Law (Algemene wet bestuursrecht, Awb). This timeline can be extended with a maximum of 8 weeks.

The Penaly and Appeal Act (Wet Dwangsom en beroep bij niet tijdig beslissen) applies when a request for a further decision is not reviewed within the legal timeline by an accredited MREC or the CCMO. If you do not agree with a decision made by an MREC then you can, as an interested party and under certain conditions, submit an administrative appeal to the CCMO. If you do not agree with a decision made by the CCMO then you can submit an objection to the CCMO.

Clinical investigations with medical devices

Information on how to submit adjustments of the research file for clinical investigations with medical devices can be found at Adjustments of the research file (amendments).

Research with a medicinal product

In the case of research with a medicinal product subject to the Dutch WMO Act (previous legislation) the sponsor determines if the amendment is substantial or not. See for more information the guidance document of the European Commission.

A further review is only necessary for a substantial amendment. The documents you are required to submit to the review committee are listed above. A timeline of 35 days applies to the review of an amendment. Non-substantial amendments do not have to be submitted to the reviewing committee. 

In the case of research with a medicinal product that is subject to the Dutch WMO Act (under previous legislation), the substantial amendment must, inaddition to the review committee, also be submitted to the competent authority (CCMO or Ministry of Health, Welfare and Sport) for a ‘No grounds for non-acceptance’. Please note: You are required to submit only the following documents to the competent authority:

  • Cover letter, see the template cover letter amendment to the competent authority (A1)
  • An EudraCT form notification of amendment (B5)
  • If applicable, a changed EudraCT clinical trial application form (B3), digitally in the form of a pdf and in xml format in ToetsingOnline.

How to submit:

Any other documents do not have to be submitted to the competent authority. Note: the competent authority does not send a confirmation of receipt. The review timeline of maximum 35 days starts on the day after the competent authority has received the complete submission. If the competent authority has no objections, a ‘No grounds for non-acceptance’ is issued per e-mail. The e-mail is sent to the registered user for the file concerned in ToetsingOnline. If it concerns a research which started before the 1st of March 2006 and which is not registered in ToetsingOnline, then an e-mail is sent to the submitting party.

Addition of a participating centre

Addition of a new participating centre is considered a substantial amendment and must be submitted for review to the reviewing committee (MREC or CCMO). If it concerns research with a medicinal product that is subject to the Dutch WMO Act (previous legislation), the substantial amendment must also be submitted to the competent authority.

The following applies to a submission to the reviewing committee: is the centre already mentioned in the ABR form and/or the EudraCT Application Form (Annex 1)? Then it is still considered a substantial amendment. However, in this case you do not have to submit a changed ABR form and/or new EudraCT Application Form. The Research Declaration (I2) (with cover letter) and the EudraCT form notification of amendment (B5) (previously Annex II ) is sufficient.

The competent authority (in the case of research with a medicinal product that is subject to the Dutch WMO Act under previous legislation) only has to receive the cover letter and the EudraCT form notification of amendment (B5). The Research Declaration does not have to be submitted. The submission of EudraCT forms is only necessary for research with a medicinal product.

For the way of submitting, see:

The procedure for the review of substantial amendments is slightly different for certain types of research (in the case of research that is subject to the Dutch WMO Act under previous legislation):