Clinical investigations of medical devices

Clinical evaluation of a medical device by a manufacturer

According to Regulation (EU) 2017/745 (MDR, the Medical Devices Regulation), in order to confirm that a medical device conforms to the general safety and performance requirements, to assess undesirable side effects and the acceptability of the benefit/risk ratio, the manufacturer is required to plan, carry out and document a clinical investigation consisting of a critical evaluation of the clinical data for the medical device, in relation to its characteristics and intended purpose (this is a continuous process which should be updated throughout the device’s intended lifetime).

Based on the clinical development plan, manufacturers use clinical investigations to generate any new or additional clinical data required to address unresolved issues.

Clinical investigation with a medical device

A clinical investigation involving one or more human participants consists of evaluating the safety or performance of a medical device in a specific clinical context.

Clinical investigations must be designed and conducted in such a way that the participants’ rights, safety, dignity and wellbeing are safeguarded, giving precedence to such considerations over all others, and in such a way as to ensure the clinical data generated are scientifically valid, reliable and robust. Clinical investigations are subject to a scientific and ethical review.

In Luxembourg, all applications for a clinical investigation or for a substantial change to a clinical investigation are also subject to the prior approval of the Ministry, based on the scientific and ethical decision of the Health Directorate and the National Research Ethics Committee (Comité national d’éthique de recherche - CNER) (Art. 27 of the Law of 8 March 2018 on hospitals and hospital planning).

Additional directives regarding the definitions and requirements of the MDR, the regulatory channels (including usability studies), submission documents, documentation of reports and studies, transitional periods etc. can be found in the documents of the MDCG (Medical Devices Coordination Group) – particularly MDCG 2021-6 Rev. 1.

Submitting an application for a clinical investigation

Pending the entry into force of the European Database on Medical Devices (EUDAMED), applicants should submit their applications for clinical investigations using the application form available as Annex I of the document MDCG 2021-08 to the Ministry of Health and Social Security using the following addresses:

• recherchebiomedicale@ms.etat.lu & meddevices@ms.etat.lu

The application may be written in one or more of the following languages: German, French, Luxembourgish or English.

The document MDCG 2024-3 includes instructions on the content of the clinical investigation plan (CIP) for clinical investigations of medical devices. The document MDCG 2024-5 includes instructions on the content of the Investigator’s Brochure (IB).

The information communicated to the participant, or their legal representative, must enable them to understand the nature and objectives of the investigation, their rights and guarantees in relation to their protection, the conditions and duration of the investigation, and any alternative treatments and follow-up measures. In this regard, it is important to provide French and German versions of all documents for the attention of participants (informed consent, questionnaires, recruitment material, etc.) in order to meet the linguistic expectations of the Luxembourg population.

Proof of insurance cover must be provided, referring to the project and the number of insured participants, and such cover must be in place for the full duration of the study.

Submitting an application for a substantial change to a clinical investigation

A non-exhaustive list of the changes that may be interpreted as substantial is provided in Annex II of document MDCG 2021-6 Rev. 1.

Within a period of one week, the applicant must:

• stipulate the reasons for and nature of the change;
• send the application using the form available in Annex I of document MDCG 2021-28 to the Ministry of Health and Social Security using the email addresses recherchebiomedicale@ms.etat.lu & meddevices@ms.etat.lu;
• attaching an updated version of the relevant documentation as referred to in Annex XV, Chapter II of MDR (with the changes clearly marked).

Notification of a clinical investigation being ended or suspended

Information regarding an investigation being brought to an end or suspended must be sent to the Ministry of Health and Social Security via recherchebiomedicale@ms.etat.lu & meddevices@ms.etat.lu, adhering to the instructions set out in the table below:

The clinical investigation summary and report must be sent to the Ministry of Health within one year of the end of the investigation or within three months of it being terminated early or suspended temporarily, using the following template: Commission Guidance 2023/C 163/06.

Notification of events linked to a clinical investigation

What is an adverse event?

Any harmful event, unintended illness or injury or any adverse clinical outcome, including an abnormal laboratory finding, in participants, users or other persons in the context of a clinical investigation, whether or not related to the medical device under clinical investigation.

What is a serious adverse event?

Any adverse event resulting in:

a) death;
b) a serious deterioration in the participant's state of health, leading to:

• a life-threatening illness or injury;
• a permanent impairment of an anatomical structure or function;
• hospitalisation or extension of the patient’s stay in hospital;
• medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment of an anatomical structure or function;
• a chronic illness;

c) foetal distress, foetal death, congenital physical or mental impairment or congenital malformation.

What is a device defect?

Any defect in the identity, quality, durability, reliability, safety or performance of a device under clinical investigation, including any malfunction, error of use or defect in the information provided by the manufacturer.

Further guidelines are available in the document MDCG 2020-10/1 Rev. 1.

Which events must be reported and how quickly?

The sponsor should report any event relating to a clinical investigation carried out in Luxembourg immediately, using the form available in the document MDCG 2020-10/2 Rev. 1 and sending it to meddevices.vigilance@ms.etat.lu:

• any serious adverse event with a proven or plausible causal link with the device being investigated, the comparator device or the investigation procedure;
• any failure of a device that could have resulted in a serious adverse event in the absence of appropriate measures or intervention, or in less favourable circumstances;
• any new element in relation to an event referred to in points 1) and 2).

The deadline for notifying the national authorities depends on the severity of the event. In order to report the event in a timely manner, the sponsor may, if applicable, submit an initial, incomplete report before submitting a full version.

Reporting of events linked to investigations into CE-marked medical devices

If the serious adverse event is linked to the investigation procedure, the notification process described above applies accordingly.

If the event is linked to a CE-marked device used within the limits of its intended purpose, notification in accordance with Article 87 of the MDR applies accordingly and must be sent to meddevices.vigilance@ms.etat.lu using the most recent version of the MIR (Manufacturer’s Incident Report) form available on the European Commission website.

With regard to the investigations pursuant to Article 74(1) of the MDR, it is recommended to consult section 5.1 of guideline MDCG 2020-10/1 Rev. 1.

Retrospective studies on medical devices

Retrospective studies, involving retrospective data for example, are not included in the scope of the MDR. However, such studies require the approval of the National Research Ethics Committee (CNER).