Amendments to clinical trials
The Danish Medicines Agency receives many enquiries about amendments to ongoing clinical trials. It follows from section 4(1) of the Danish clinical trial executive order no. 295 of 26 April 2004 that the sponsor must apply to the Danish Medicines Agency for permission before they may amend the trial protocol when such amendments could impact:
1. the safety of the trial subjects,
2. the interpretation of the scientific documentation which the trial is based on,
3. the completion or management of the trial,
4. the quality or safety of the investigational medicinal products used in the trial,
or if the concerned amendments are otherwise deemed substantial.
It is the responsibility of the sponsor to assess if a change to a clinical trial represents a substantial amendment, but in case of doubt, we are happy to assist.
Notifications to the Danish Medicines Agency
Amendments that do not substantially impact the aspects listed above (non-substantial amendments) do not require approval by the Danish Medicines Agency prior to implementation. However, some of them should be submitted as a notification to make us aware of them. Consequently, amendments requiring neither authorisation nor submission as a notification should not be submitted to us
The Danish Medicines Agency must always be notified about the following:
- Extension of trial period relative to the date approved on the Danish authorisation.
- New trial sites/change of trial sites (including updated XML file).
- Change of principal/coordinating investigator (including updated XML file).
- Change of CRO/applicant
- When the trial ends in Denmark
These changes are not subject to approval by the Danish Medicines Agency.
Please be aware that substantial amendments of information that is subject to review by the ethics committee only should be submitted to the ethics committee only (recruitment material, etc.).
The following list shows the amendments that are considered substantial, i.e. subject to approval, and amendments either not requiring submission or requiring submission as a notification.
Applying to amend an ongoing clinical trial
An application to amend a clinical trial must contain the following (relevant) documents (covering letter is mandatory):
Covering letter detailing the following:
- Unambiguous identification of the affected clinical trial(s) (sponsor protocol numbers and EudraCT numbers).
- A short description of the substantial amendments indicating the location of the change within the submitted documents (page reference or a reference to the section ‘summary of substantial changes).
- A clear justification for any special circumstances related to the amendment including an indication of whether the amendment impacts the benefit-risk evaluation, participant information or the safety monitoring of the trial.
- In case of added/removed investigational medicinal products, a new sub-protocol or new populations in an adaptative/complex trial, it must be clearly justified how the amendments fit the overall purpose and design of the trial. This description must include the information detailed in section 5.2 of the CTFG’s recommendation paper on complex clinical trials.
- An application to extend a trial must always be specified in the covering letter indicating the reason/justification and a new expected national end of trial (EoT) date.
- A short description of any accompanying documents with non-substantial amendments, however, without describing any such amendments.
- List of enclosed annexes with version number and date if relevant.
- Name and signature of applicant.
Revised trial protocol or other modified documents (e.g. investigator’s brochure, investigational medicinal product dossier, participant information, etc.):
- The submission should include both a version in track changes clearly showing marked changes, omissions and additions and a version showing only the new wording.
- Comprehensive or extensive amendments warranting a new version of the document, should be listed in an additional table (summary of substantial changes). Identical changes can be grouped on this list, and the table should contain a short justification for each amendment.
- In case the Danish Medicines Agency has previously approved the same amendments in an application for another trial (e.g. the same version of the investigator’s brochure applied for in connection with another amendment), a reference should be included (case no. or EudraCT no.).
Updated EudraCT application form:
- If the protocol version has been updated, the new protocol version and date should be indicated in section A.
- If changes other than the protocol changes applied for have been made, this must be clearly indicated, e.g. highlighted in yellow.
- When the EudraCT application form is updated, this is not considered a resubmission. Consequently, the information regarding resubmission should not be changed under A.6.
- Both an updated XML file and PDF file should be attached.
Substantial Amendment Notification Form:
- The European Commission has drawn up a form for notification of substantial amendments that applicants can use:
Covering letter, forms and documents must be combined in one PDF file with bookmarks and should as far as possible be filled out electronically to enable text copying for the review process. The entire application can be sent directly to the clinical trials mailbox or via Eudralink. Please see this page for more information about Clinical trial applications via Eudralink.
Please also see section 3 on ’notification of amendments and related measures’ in the European Commission’s detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1)
Updated 5 November 2021 –Clarified that the list of examples of substantial and non-substantial amendments are only available in Danish.