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The Medical Device Coordination Group (MDCG), a voluntary association of national regulating authorities collaborating to improve the regulatory framework for medical devices further, has published a guidance document dedicated to clinical investigations.

In particular, the document describes in detail the applicable regulatory requirements set forth under the Regulation (EU) 2017/745 (Medical Devices Regulation, MDR), as well as additional recommendations to be considered by the parties responsible for clinical investigations.

Application Content for Clinical Investigations under MDR

According to the guidance, submitting applications for clinical investigations under the MDR, following Article 62(1), requires a comprehensive set of documents outlined in Chapter II of Annex XV of the MDR.

A separate guidance document provides templates for both application and notification purposes.
These templates are designed to streamline and support clinical investigation procedures in compliance with the MDR’s requirements.

However, it is vitally essential for applicants to not only rely on these templates but also to visit the website of the relevant competent authority in the country where the clinical investigation is intended to be conducted.

This step is essential to ensure compliance with any additional national requirements regarding application content.

Regarding clinical investigations that fall under Article 74(1) of the MDR, the documentation requirements are similar to those set forth under Article 62(1).

The same level of detail and compliance, as specified in Annex XV, Chapter II of the MDR, is expected.
MDCG 2021-08 guidance document provides the necessary templates for the parties involved.

As in the previous case, the MDCG encourages the applicants to consult the website of the competent authority in the respective country to ascertain any specific national requirements for notification content.

As further explained in the document, the situation is more complex in the case of clinical investigations regulated under Article 82 of the MDR.

Article 82 stipulates the minimum requirements for clinical investigations not performed for the purposes listed in Article 62(1).
The general guidance for submission requirements for these studies is not provided due to their dependence on national provisions.

Applicants are advised to seek information from the relevant competent authority and/or the appropriate ethics committee in the country where the clinical investigation will occur.

Content Expectations for Key Documents

The Investigator’s Brochure (IB) is a critical document designed to provide investigators with essential data about the safety and performance of the investigational device.

This information is typically derived from pre-clinical testing or other clinical investigations. The required content of the IB is detailed in Section 2 of Chapter II in Annex XV of the MDR.

Adherence to Annex B of ISO 14155:2020 is also recommended.
For more comprehensive guidance, the MDCG document on the content of the IB should be reviewed.

Similarly, the Clinical Investigation Plan (CIP) must be well-structured, clearly outlining the objectives and endpoints of the investigation.
It should provide a sound justification for the proposed design based on scientific and ethical principles.

The content requirements for the CIP are outlined in Section 3 of Chapter II in Annex XV of the MDR, with additional recommendations to adhere to Annex A of ISO 14155:2020. The MDCG document offers detailed guidance on the content of the CIP.

Modifications to Clinical Investigations

Another essential aspect addressed in the guidance relates to modifications to clinical investigations and associated regulatory requirements.
As explained by the MDCG, defining what constitutes a substantial modification becomes vitally important when it comes to alterations in clinical investigations.

According to the document, a substantial modification is typically one that significantly impacts the safety, health, or rights of the subjects or affects the robustness or reliability of the clinical data.
This definition encompasses changes to the CIP, IB, subject information sheet, and other relevant documents.

Sponsors are responsible for assessing whether a modification is substantial, considering its impact on the investigation’s design and scientific outcome. The procedure for notifying a considerable modification is outlined in Article 75 of the MDR.

It is also important to mention that for the submission of a substantial modification notification, timing is of the essence.
Notifications can be submitted once a clinical investigation is permitted to start under the MDR.

However, it is advised against submitting a new substantial modification while an assessment of a previously submitted one is still underway. National procedures may also influence the handling of these modifications.

Changes to the investigational device generally fall under the category of substantial modifications.
This includes changes that alter the device’s risk profile or introduce new risks.

In some cases, these modifications are so significant that a new clinical investigation application may be necessary.
The aspect of equivalence, as guided by MDCG 2020-5, should be considered when determining if a device modification warrants a new clinical investigation application.

According to Article 75 of the MDR, the sponsor must notify the Member State within one week of issuing updated documents like the CIP or IB.

Implementing changes to a CIP might necessitate updates to other documents, such as patient information, which can be submitted collectively when the last affected document is updated.

However, the implementation of these changes should not commence until the expiration of the deadline set in Article 75 of the MDR or until an authorization letter is issued by the Competent Authority and/or Ethics Committee, as per national provisions.

A sponsor can start implementing a substantial modification after 38 days from the notification date to the Member State, provided that an Ethics Committee issues no negative opinion.

This period may be extended by an additional seven days for expert consultation. Moreover, sponsors need to ensure that updated documents related to a substantial modification are submitted to both the Competent Authority and the Ethics Committee, keeping in mind that national provisions may apply.

Finally, the handling of non-substantial modifications is currently subject to variation due to the unavailability of EUDAMED.

Until harmonized approaches are established, it is crucial to check national requirements, especially those about the notification and review of non-substantial modifications to Ethics committees.

Conclusion

In summary, the present guidance provides a comprehensive overview of the procedural requirements and documentation expectations for clinical investigations under the MDR, emphasizing the need for compliance with both MDR and national guidelines to ensure the safety and effectiveness of medical device investigations.

Source

https://health.ec.europa.eu/system/files/2023-12/mdcg_2021-6_en.pdf

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