Clinical investigation of medical devices: implementation rules set out in Italy

Specifically, the following were published on June 13, 2023:

• the decree of the Ministry of Health on “Administrative modalities of national relevance for the submission of the application for clinical investigation for medical devices not bearing the CE marking referred to in Article 16, paragraph 2 of Legislative Decree No. 137 of 2022”;
• the decree of the Ministry of Health on “Administrative modalities of national relevance for the submission of communications relating to clinical investigations for devices bearing the CE marking used in the context of their intended use as referred to in Article 16, paragraph 3 of Decree No. 137 of 2022.”

Both entered into force on July 13, 2023.

The following were published in the official gazette on June 14, 2023:

• the decree of the Ministry of Health on “Requirements for facilities suitable for conducting clinical investigations, in compliance with the provisions of Article 62(7) of Regulation (EU) 2017/745”;
• the decree of the Ministry of Health on “Provisions for the purpose of ensuring that the persons entrusted with evaluating and validating clinical investigation applications or making a decision thereon do not have a conflict of interest, are independent of the sponsor, the investigators involved, and the natural or legal persons financing the clinical investigation, and are free from any undue influence.”

This entered into force on the day following its publication.

Application for clinical investigation approval

Until the EUDAMED European database is fully operational, the decree of June 13—together with the technical specifications published on the ministry’s website—will establish the national procedure for submitting application for clinical investigation approval and the exchange of related communications and information (i) for devices not bearing the CE marking; (ii) for devices bearing the CE marking but used outside the scope of their intended purpose as set out in Art. 74(2) of the MDR.

Please find below the main rules:

(i) A digitally signed application for clinical investigations shall be submitted electronically to the Ministry of Health by the sponsor of the clinical investigation; if the sponsor is not the manufacturer, the sponsor is required to provide the ministry with the details of the natural or legal person responsible for manufacturing the device in question. If a sponsor is not established in the European Union, a representative established in the EU must be identified (Art. 62(2) of the MDR).

(ii) During the application process, all statements referring to the sponsor and its representatives are made, for residents of Italy or the European Union, pursuant to Article 47, Presidential Decree No. 445/2000 (Dichiarazioni sostitutive dell’atto di notorietà). Non-EU residents must present certificates or attestations issued by the authority of a foreign state, accompanied by a certified translation by the Italian consular authority, certifying their conformity to the original.

(iii) The templates adopted by the MDCG (Medical Device Coordination Group) published on the European Commission’s website are to be used for submission of clinical investigation applications.

Ethics Committee opinions and the launch of investigations

An application is to be accompanied by a favorable opinion issued by a TEC (Territorial Ethics Committee, see also the Ministerial Decrees of January 26 and January 30, 2023) or a NEC (National Ethics Committee) as per the Ministerial Decree of February 1, 2022.

To speed up the procedure, the sponsor may submit an application for investigation accompanied by a conditional EC opinion or a copy of a request for an opinion sent to the EC. In such a case, the ministry must receive the positive opinion of the related EC (i) within 30 days of validation of the application for clinical investigation of a class I device or a class IIa or IIb non-invasive device; within 45 days of validation of the application for investigation of a class IIa or IIb invasive medical device or class III device.

The start of the clinical investigation takes place after notification of the sponsor as follows:

• for clinical investigation of a class IIa or IIB medical device or class III device, after notification of authorization from the ministry;
• for clinical investigation relating to a class I medical device or non-invasive class IIa or IIB medical device, 30 days after the date of validation provided in Article 16(2), Legislative Decree No. 137/2022 (and Article 70 of the MDR).

Other communication about clinical investigations of medical devices

The ministerial decree of June 13, 2022, which is also pending the EUDAMED becoming fully operational, regulates communication regarding the conduct of clinical investigations on CE-marked devices used for their intended use. The ministerial decree establishes national administrative modalities for communication from the sponsor:

• to further evaluate a CE-marked device in the context of its intended use (Art. 74(1) MDR);
• for substantial modification of clinical investigations (Art. 75 MDR);
• for information provided at the end of a clinical investigation or in the event of temporary interruption or early termination (Art. 77 MDR).

Dedicated forms published on the website of the Ministry of Health must be used for the aforementioned communications.

Facility requirements

The ministerial decree identifies the types of facilities suitable for carrying out clinical investigations of medical devices without CE marking and medical devices that are CE marked but used outside the scope of their intended purpose as set out in Art. 74(2) of the MDR.

In general, a facility where a clinical investigation is conducted must (i) have documented expertise in controlled clinical trials, with experience in the specific field of the trial, supported by scientific publications or patents or other evidence of similar standing; and (ii) document established use of medical devices belonging to the same type and class as the medical device being investigated during normal clinical practice by qualified personnel at the facility where the trial is conducted.

In addition to the facilities listed in Article 1 of the decree—hospital groups, research institutes, accredited hospitals and care homes, and so on—clinical investigations of non-invasive class I or class IIa and IIb medical devices can also be conducted at specialist and multi-specialist national health service outpatient clinics and in the territorial facilities listed in Ministerial Decree No. 77/2022.

A facility’s legal representative must certify that the requirements are met by means of a declaration made in accordance with the model on the website of the Ministry of Health with appropriate supporting documentation attached. Moreover, if activities are conducted outside the facility using digital devices, the facility must guarantee suitable levels of quality and safety and set up mechanisms for reporting and managing any adverse events that occur outside the facility.

Conflict of Interest and independence of assessors

Pursuant to Art. 71(2) MDR and Art. 16(5) of Legislative Decree No. 137/2022, the decree of the Ministry of Health of June 14, 2023 identifies the modalities used to ensure that persons in charge of assessing and validating clinical investigation applications for medical devices not bearing CE marking and those bearing CE marking referred to in Art. 74(2) of the MDR or making decisions about them do not have conflicts of interest and are independent of the sponsors, the investigators, and the persons financing investigations.

These subjects are identified by the Ministry of Health, which may also consult with experts who meet the requirements set forth in Article 3 of the decree, including by relying upon those on lists drawn up according to the criteria and methods published on its website.

Identified persons must (i) declare annually their financial interests and any links to persons with respect to whom conflicts of interest may arise using the ministerial form,^[1] and (ii) refrain from participating in clinical investigation proceedings if they are in situations of potential conflict of interest and are subject to undue influence.

[1] This declaration, drawn up following the model on the institutional website of the Ministry of Health, is taken into account when assigning evaluation and validation tasks for each clinical investigation.