A clinical investigation can demonstrate a medical device’s safety and clinical performance. In December 2023, the Medical Device Coordination Group updated the guidance on clinical investigation, MDCG 2021-6. The new revision added different new questions and answers, while it updated some previous answers.

General questions on clinical investigation

Among the newly added answers, the Guidance explains several general requirements to conduct a clinical investigation according to the EU Medical Devices Regulation (MDR). Some of the key clarifications provided in the updated MDCG 2021-6 include:

• Q2 – Legislation other than MDR: The MDR allows, and for some aspects requires, Member States to apply national legislation for procedures, among others, for review and authorisation by ethics committees, responsibility for medical care, investigator qualifications, legally designated representative, damage compensation systems, designation of competent authority. Complying with the MDR does not remove the obligation of sponsors to comply with other relevant legislation. Thus, if any other applicable legislation exists, the sponsors must comply with the additional relevant legislation.

• Q4 – Not all clinical studies that involve the use of devices are considered clinical investigations as defined by the MDR. For example, when the clinical trial of a medicinal product involves the use of a medical device (e.g., to measure blood pressure), the safety or performance of the device is not under assessment and therefore, such studies would not be considered clinical investigations as per MDR.

• Q14 – In the case of a device incorporating medicinal substances which if used separately is a medicinal product with an action ancillary to that of the device, the sponsor has to perform the clinical investigation according to the MDR. On the contrary, if the action of the medicinal substance is principal and not ancillary to that of the device, the integral product shall be governed by Directive 2001/83/EC21 or Regulation (EC) No 726/2004. In the case of devices intended to administer medicinal products, the respective clinical studies are subject to the MDR requirements for clinical investigations. By contrast, if the device intended to administer the medicinal product and the medicinal product form a single integral product intended exclusively for use in the given combination, and is not reusable, then Directive 2001/83/EC21 or Regulation (EC) No 726/2004 applies to that single integral product.

• Q15 – Regulatory pathway for a medicinal product and a device: When a clinical study collects data for both a device and a medicinal product, the sponsor has to comply with the MDR regulatory requirements as well as the regulatory requirements for clinical trials of medicinal products.

• Q16 – There is no common EU procedure for combined studies with devices and medicinal products. Consequently, the MDR regulates clinical investigations of devices, Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) regulates clinical trials of medicinal products. Sponsors of combined studies have to comply with both regulations.

• Q17 – Usability tests as clinical investigations: There are several factors to consider when determining whether a usability test is also a clinical investigation, such as the scope and purpose of testing, and how the human subjects are exposed to the device. In their technical documentation, manufacturers should document their justification of why a usability test does not fall in the definition of a clinical investigation if human subjects are involved.

• Q18 – Retrospective clinical study as clinical investigations: If the study analyses performance or safety of the device retrospectively, separately from the decision to use the device, the study should not be considered as a clinical investigation according to the MDR. Nonetheless, there may be national provisions to consider.

Application content

• Q25, Q26, Q27 – Documents to submit per MDR article 62(1) and 74 (1): Sponsors can consult MDCG 2021-08 on clinical investigation application/notification documents. This guidance provides templates for clinical investigation applications and notifications created to support clinical investigation procedures. According to Article 74(1) of the MDR, the documentation to submit for a notification and for an application is the same.

• Q27 – Documents to submit per MDR article 82: Studies according to Article 82 follow national provisions. Thus, there is no general guidance for these studies’ documentation.

• Q28 – Content of the Investigator’s Brochure (IB): The IB should provide investigators with sufficient data on safety and performance of the investigational device. This includes data from pre-clinical testing or clinical investigations as well as justification on the human exposure to the investigational device. Section 2 in chapter II of Annex XV of the MDR lists the content. In addition, annex B of ISO 14155:2020 can also assist in the documentation preparation.

Timeline considerations for clinical investigations

• Q39 – Sponsors have to inform the Member States concerned when a clinical investigation is temporarily halted or terminated early. Starting from when the sponsor has decided to suspend or terminate the investigation, the Member State has to be informed within 15 days, or 24 hours if based on safety grounds.

• Q41 – The documentation must be kept for at least 10 years after the clinical investigation has ended or the device has been placed on the market. In the case of implantable devices, the period is at least 15 years.

• Q43 – For the mandatory summary of the clinical investigation report referred to in article 77(5), the template is Commission Guidance on the content and structure of the summary of the clinical investigation report.

Arrangements for the transitional period

• Q44 – The use of EUDAMED for Clinical Investigation and Performance Studies becomes mandatory after the 6 months starting from the announcement that EUDAMED is fully functional.

Legal representative

• Q48 – Role of the legal representative: Non-EU sponsors must appoint a legal representative in the EU. The legal representative is responsible for ensuring compliance with the sponsor’s obligations. The two parties can stipulate a contract that obliges the sponsor to provide the legal representative with all required information, and the legal representative to immediately notify the sponsor in case they become aware of any noncompliance with the Regulation. MDR chapter III of annex XV regulates the delegation of tasks related to the sponsor’s obligations.

• Q49 – The MDR does not specify how the legal representative can ensure compliance with the sponsor’s obligations. However, to perform this task, the legal representative would need access to the technical documentation of the device and clinical investigation documentation and be aware of specific aspects of the clinical investigation.

• Q50 – The documentation should be kept at the competent authorities’ disposal. This applies also in the case the sponsor goes bankrupt or ceases its activity before the end of the specified retention period (10 years or 15 years).

If you are a non-EU sponsor and want to conduct a clinical investigation in the EU, you need a legal representative.