Publications

• Which regulatory pathway should a Sponsor follow to conduct a clinical investigation in the pilot stage (i.e. first in human, early feasibility) in accordance with the Regulation (EU) 2017/745 (MDR)?

The MDR describes different types of clinical investigations that follow different regulatory pathways. The choice of the appropriate regulatory pathway must take into account the clinical development plan and the proposed use of clinical data. In general, if the clinical data will be used to support conformity assessment (necessary for obtaining CE mark), the clinical investigation is subject to Article 62 of the MDR, otherwise another regulatory pathway may be chosen (Article 74 or 82 of the MDR).

Since pilot-stage clinical investigations are conducted to collect preliminary safety and/or performance data, which in the future are most likely to be used to design studies to obtain the results supporting conformity assessment necessary for medical device CE marking, the application of Article 62 of the MDR Regulation should be anticipated.

• A CE marked medical device is planned to be further investigated in a clinical investigation – how does a Sponsor determine the regulatory pathway for this clinical investigation?

Firstly it is important to understand what the intended purpose of the device is and to check whether the planned use in the clinical investigation is within its intended purpose. This will help to determine the regulatory pathway for studies with CE marked devices.

Following points determine the appropriate regulatory pathway when it has been determined whether the investigational medical device will be used within its intended purpose:

• When the CE marked device is further assessed, for safety or performance within the intended purpose it is a post-market clinical follow-up (PMCF) investigation. Where the investigation would involve submitting subjects to procedures additional to those performed under the normal conditions of use of the device and those additional procedures are invasive or burdensome, this is a subject of article 74(1) of the MDR. In this regulatory pathway the sponsor shall notify the member state(s) concerned at least 30 days prior to its commencement. If the sponsors are uncertain whether such additional procedures are considered invasive or burdensome, they are encouraged to request the opinion of the relevant authority in the Member State(s) prior to commencement of the investigation. It is worth to notice that when a CE marked device is modified by a health institution (that conditions in Article 5(5) of the MDR are met and any national provisions are adhered to), Article 74(1) of the MDR is not applicable.
• If safety and performance of a CE marked device is being further investigated and article 74(1) of the MDR is not applicable, article 82 of the MDR may apply. It is also necessary to check and follow national regulations of the Member State where the clinical investigation will be conducted. Registration in a publicly available database of clinical investigations falling under article 82 of the MDR is encouraged.
• When the CE marked device is assessed outside the intended purpose, article 74(2) of the MDR foresees that the requirements for pre-market clinical investigation apply (articles 62 to 81 of the MDR). If the clinical investigation is not performed for conformity purposes, article 82 of the MDR applies.
• When the CE marked device is used in a clinical study but the device itself is not assessed for safety or performance, this is outside the scope of the MDR definition of clinical investigation, and it is necessary to check national provisions in the Member State where the clinical study will be conducted.

• How can a Sponsor assess if the planned use of a medical device in the clinical investigation is covered by the intended purpose?

First, the Sponsor should determine the device’s intended purpose, which could be identified by reviewing the instructions for use, and if available, documents such as: the clinical evaluation report, the labelling supplied by the manufacturer, the EU declaration of conformity and the CE conformity certificate, but only if applicable to such device.

Secondly the Sponsor should assess how the device will be used in the clinical investigation, which means reviewing the clinical investigation plan. This will help to determine the details of the planned use of the medical device and also target population, the indications/contraindications, anatomical location where the device will used, the duration of use, the planned procedures, and the planned users.

Next, according to instructions of use, usage of the device by intended user has to be checked and that instructions of use cover all necessary information.

All above documents have to be compliant and Sponsor has to ensure that planned use of the device during a clinical investigation is consistent with the medical device’s intended purpose.

• What is a pilot clinical investigation?

Typically, a limited number of subjects participate in pilot stage clinical investigations. The aim of this kind of clinical investigation is to evaluate a medical device at early stage of its development in terms of initial clinical safety and performance (e.g. device functionality).

During or after termination of this kind of clinical investigation, the device design may require further changes and modifications which may be critical to the initial design. Also, the data obtained from pilot stage clinical investigation may influence the design of a subsequent clinical investigation.

The data generated in pilot stage clinical investigations are in general insufficient to CE mark the device.

A pilot clinical investigation is usually an early-stage clinical investigation, which includes the following types:

• First in human clinical investigation
• Early feasibility clinical investigation
• Traditional feasibility clinical investigation

This kind of investigation is also described in the standard ISO 14155:2020