Within the framework of the conformity assessment procedure for an initial CE mark application for a Class III combined medical device, the manufacturer must submit a Technical File (TF) for the device to the notified body. Compared to the TF for a “non-combined” device, this one is different in that it comprises a specific section on the medicinal substance which is divided into five parts:

• Administrative information;
• Summaries of the file comprising the risk analysis, the rationale for the presence of the medicinal substance, the description of the modes of action of the components of the medical device, distinguishing between those linked to the device, to the medicinal substance and to the combination of the two; expert reports (quality, non-clinical and clinical);
• The quality part concerning the medicinal substance alone and the medicinal substance incorporated into the device;
• The pre-clinical part;
• The clinical part.

After checking the usefulness of the substance as a part of the device and taking account of the intended purpose of the device, the notified body asks one of the national competent authorities designated by the Member States or the EMA (European Medicines Agency) for a scientific opinion on the quality and safety of the medicinal substance, including on the benefit and/or risk linked with the incorporation of the substance into the medical device. These competent authorities or the EMA are referred to as the “medicinal products authority consulted”.

For those medical devices incorporating a medicinal substance that may be considered to be a medicinal product subject to a centralized market authorization procedure or a medicinal product derived from human blood or plasma, the EMA will be the medicinal products authority consulted.

For medical devices incorporating another medicinal substance, the medicinal products authority consulted may be either a competent national authority or the EMA. The medicinal products authority consulted then has 210 days from receipt of all the necessary documentation to assess the file and provide its scientific opinion, taking account of the manufacturing process and the data on the usefulness of incorporating the substance into the medical device, as determined by the notified body. The scientific opinion of the medicinal products authority consulted, and any update of that opinion, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion when making its decision. The notified body shall not deliver the certificate if the scientific opinion is unfavorable and shall convey its final decision to the medicinal products authority consulted.

I. Application form

This form contains, among other information, the name, address and contact details of the sponsor and, where they are different, those of the manufacturer of the device intended for clinical investigation. It also contains the title of the clinical investigation and a summary of the clinical investigation plan (for a first application), the details and/or references of the clinical investigation plan and a brief description of the device and its classification.

The sponsor must mention the Member States and third countries in which the investigation is to be conducted, as part of a multicenter or multinational study.

The sponsor shall provide a brief description of the investigational device, its classification and other information necessary for the identification of the device and device type.

If the notified body is already involved at the stage of the clinical investigation application, the sponsor must provide details to identify it.

II. Investigator’s brochure

The Investigator’s Brochure shall contain the clinical and non-clinical information on the investigational device that is relevant for the clinical investigation and available at the time of application for the authorization.

It must be clearly identified and contain in particular the following information:

• Data to identify and describe the device, including information on its intended purpose, classification, design and manufacture;
• The manufacturer’s instructions for installation, maintenance, maintaining hygiene standards (storage and handling requirements), as well as the available information to be placed on the label and instructions;
• A pre-clinical evaluation based on relevant pre-clinical testing data (notably biocompatibility, performance tests, sterilization validation, stability data, etc.) and experimental data;
• Existing clinical data, in particular from relevant scientific literature relating to the performance, clinical benefits to patients, design characteristics and intended purpose of the device , and all other relevant data;
• A summary of the benefit-risk analysis and the risk management, including information on known or foreseeable risks, any undesirable effects, contraindications and warnings;
• For combined medical devices incorporating a medicinal substance, detailed information on the medicinal substance and compliance with the GSPR, and on the specific risk management in relation to the substance, as well as evidence for the added value of incorporation of such substance in relation to the clinical benefit and/or safety of the device;
• A list detailing the GSPR, including the standards and common specifications applied, as well as a description of the solutions for fulfilling the GSPR when those standards or common specifications have not been fulfilled;
• A detailed description of the clinical procedures and diagnostic tests used in the course of the clinical investigation, and in particular information on any deviation from normal clinical practice.

III. The clinical investigation plan

The Clinical Investigation Plan sets out the rationale, objectives, design, methodology, monitoring and conduct of the clinical investigation, as well as record-keeping and the method of analysis for it.

In this document, the sponsor must indicate the single identification number of the clinical investigation, the identification of the sponsor and of the principal investigator at each investigational site. It describes how the clinical investigation is financed and the overall synopsis of the clinical investigation.

The plan sets out information identifying and describing the device, including its intended purpose, its manufacturer, its traceability, the target population, materials coming into contact with the human body, a review of the background literature, the current state of the art in clinical care in the relevant field of application and the proposed benefits of the new device.

The sponsor must provide information on the objectives and hypotheses of the clinical investigation, the design of the clinical investigation and general information such as type of investigation with the rationale for choosing it, its endpoints and its variables. It must also provide information on subjects, selection criteria, the size of investigation population and its representativeness in relation to the target population.

The Clinical Investigation Plan also contains a presentation of the different tests for statistical analysis.

It also presents a monitoring plan and a data management plan, a policy regarding follow-up and management of any deviations from the investigation plan at the investigational site and clear prohibition of use of waivers. It also contains a statement of compliance with the recognized ethical principles for medical research involving humans, and the principles of good clinical practice in the field of clinical investigations of devices, as well as with the applicable regulatory requirements. The informed consent of the patient must be presented.

The sponsor must describe the criteria and procedures for follow-up of subjects following the end, a temporary halt or the early termination of an investigation, for follow-up of subjects who have withdrawn their consent and procedures for subjects lost to follow-up. A description must also be provided of the arrangements for taking care of the subjects after their participation in the clinical investigation has ended, where additional care is necessary because of the subjects’ participation in the clinical investigation and where it differs from that normally expected for the medical condition in question.

Other information must also be included in the clinical investigation plan, such as the signed statement by the natural or legal person responsible for the manufacture of the device, the documents to be used to obtain informed consent, including the patient information sheet and the informed consent document.

IV. Timelines for appraisal of authorization applications

The sponsor of the clinical investigation shall submit an application to each Member State in which the clinical investigation is to be conducted, accompanied by the documentation referred to above. The Member State concerned shall have ten days to assess acceptability and the application that has been submitted. If it deems that the clinical investigation does not fall within the scope of the MDR or if the dossier is incomplete, it shall inform the sponsor to this effect. The sponsor then has ten days to comment or to complete its application. The Member State concerned may extend this period by a maximum of 20 days.

If the sponsor has not provided comments nor completed the application within the time limit, the application will be cancelled.

If the sponsor considers the application does fall under the scope of the MDR and/or is complete but the Member State concerned is not of the same opinion, the application shall be considered to have been rejected. The Member State concerned shall provide for an appeal procedure in respect of such refusal.

Within five days of receiving the comments or requested additional information, the Member State concerned shall notify the sponsor whether the clinical investigation is considered as falling within the scope of this Regulation and the application is complete. The date on which the sponsor is notified corresponds to the validation date of the application. If the sponsor is not notified, the validation date shall be the last day of the period set by the Member State concerned.

The sponsor may start the clinical investigation as soon as the Member State concerned has notified the sponsor of its authorization, and provided that the ethics committee in the Member State concerned has not issued a negative opinion in respect of the clinical investigation. The Member State shall notify the sponsor of the authorization within 45 days of the validation date.(4)

It should be noted that the MDR also makes provision for the possibility of a coordinated assessment procedure to obtain authorization to conduct clinical investigations (5).

V. The clinical investigation report

At the end of the clinical investigation, the sponsor must provide a report containing the results of the investigation. The clinical investigation report is the most important document in the evaluation of the safety and clinical performances of the medical device, as claimed by the manufacturer.