Substantial modifications - MDR

A change to a clinical investigation which is likely to have a substantial impact on the safety, health or rights of the subjects or on the robustness or reliability of the clinical data generated by the clinical investigation, is considered a substantial modification.

Additional guidance on what may be considered substantial modifications is available in the Medical Devices Coordination Group guidance document with questions and answers regarding clinical investigation.

Submit a substantial modification notification

Use the e-service for notification of substantial modifications.

You may also submit substantial modifications by email or on DVD/CD or USB by mail.

Email: registrator@lakemedelsverket.se 

Mail:

Läkemedelsverket
Box 26
751 03 Uppsala 

Documentation

The reasons for the substantial modifications shall be clearly indicated in the notification.

Complete the form for substantial modification under the MDR.

To facilitate the assessment of the modifications, the documents that were previously submitted to the Swedish MPA and that are affected by the change must be submitted in two versions, one with tracked changes and one clean version.

Evidence showing that the investigators and investigational sites are capable of conducting the clinical investigation according to the clinical investigation plan must be provided by sponsor for each new site.

The qualifications of the investigator shall be demonstrated by a CV, this is applicable for the principal investigator at each investigational site.
It should be confirmed by a certificate from the responsible person at each investigational site, that the site is capable of conducting the clinical investigation.

A CV needs to be provided for a new principal investigator at an already approved investigational site.

Also remember to attach an updated invoicing document for the notification of substantial modification.

Handling

For clinical investigations that have been initiated under the MDR (i.e. investigations where the initial application or notification to the Swedish MPA was made after 25 May 2021, and the required authorisations granted) the Swedish MPA will issue a confirmation of receipt.

The Swedish MPA may contact the sponsor during the handling period if the notification needs to be amended in any aspect. The Swedish MPA may also extend the handling period by a further 7 days. The sponsor will be notified if such an extension is applicable.

The sponsor needs to wait 38 days (or 45 days if the handling period is extended by 7 days) after the notification, or for the Swedish MPA to issue an approval letter (which may be done prior to the end of the handling period) before the modification is implemented.

Ethical review of substantial modification subject to coordinated handling

Before a substantial modification is implemented it also needs to undergo ethical review. For all notifications of substantial modifications regarding clinical investigations initiated under the MDR the Swedish MPA coordinates the assessment with the Swedish Ethical Review Authority. No separate submission to the Ethical Review Authority is required for these investigations.

As of 26th of May 2024, the Swedish MPA and the Swedish Ethical Review Authority coordinates the handling of all notifications of substantial modifications, regardless of whether the initial application or notification of the clinical investigation followed a coordinated authorisation procedure or not.

The form "Ansökan om ändring – medicintekniska produkter", which is available on the Ethical Review Authority website, has to be completed and enclosed with the notification to the Swedish MPA.

Web page in Swedish.

The Swedish MPA forwards all relevant documents regarding the substantial modification to the Ethical Review Authority for assessment. The Ethical Review Authority opinion is then provided to the Swedish MPA.

The Swedish MPA will need to take the opinion issued by the Ethical Review Authority into account before deciding whether the substantial modification can be implemented or not. The decision covers both the review made by the Swedish MPA and the Ethical Review Authority.

If no decision letter has been issued when 38 days (or 45 days if the handling period is extended by 7 days) have passed after a notification of substantial modification has been submitted to the Swedish MPA, this implies a tacit approval, and the modification of the clinical investigation may, according to the MDR provisions, be implemented without decision from the agency.

Non-substantial modifications

It is the responsibility of the sponsor to assess whether a planned change is a substantial modification or a non-substantial modification on the basis of Article 75(1) of the MDR and additional guidance document MDCG 2021-6 Rev. 1 – Questions & Answers regarding clinical investigation.

Sponsors are encouraged to document their assessment of whether a planned modification is considered substantial or non-substantial, including the justification for the assessment.

Sponsors may make non-substantial modifications to a clinical investigation without notifying the Swedish MPA. The non-substantial modification shall be included in the relevant study documents and the documents versioned to ensure traceability of what has been changed when. 

When the sponsor later has reason to submit documentation to the Swedish MPA (e.g. in connection with the notification of a substantial modification), the previously introduced non-substantial modification must also be clearly marked, e.g. as tracked changes in the concerned study documents.

Clinical investigations authorised under the previous (directive’s) legislation

Regarding clinical investigations that were notified before 26 May 2021 and subsequently were authorised by the Swedish MPA there is no dedicated form and no legally defined timeline for the agency’s handling of notifications of substantial modifications. The applicant needs to wait for the MPA decision on the substantial modification before it is implemented.

No confirmation of receipt is issued for these notifications of substantial modifications. However, the Swedish MPA will notify the sponsor if the notification is not considered valid with information on what documentation needs to be amended.

The reasons for the proposed changes should be clearly stated, either in the revised documents or in a separate cover letter provided with the notification.

To facilitate the assessment of the amendment notification, a clean version and a version with tracked changes should be submitted for all updated documents. If the information in the initial notification form is affected by the changes, this should be updated and attached as well.

The notification of amendments made to the investigation plan must be dated and signed by the sponsor and the relevant principal /coordinating investigator.

A notification of a new investigational site shall include a CV of the principal investigator at the new site. A CV should also be provided for the new principal investigator when a notification of investigator change is made for an already approved investigational site.

For these older clinical investigations, there is no coordination of the assessment with the Ethical Review Authority, so the entity responsible for the research may need to make a separate amendment application to the Ethical Review Authority.

Webpage in Swedish.