Clinical investigations with medical devices and evaluation of the performance with in vitro diagnostic medical devices

A ‘clinical investigation’ is defined as any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device of a medical device;

A ‘performance study’ is a study undertaken to establish or confirm the analytical or clinical performance of a device;

‘Performance evaluation’ covers the assessment and analysis of data to establish and verify the scientific validity, analytical performance and, where applicable, clinical performance of an in vitro diagnostic medical device.

An ‘Investigational Device’ is a device being evaluated in the context of a clinical investigation.

A ‘(in vitro diagnostic) device for performance study‘ means a device intended by the manufacturer to be used in a performance study.

A device intended to be used for research purposes, without any medical objective, shall not be deemed to be a device for performance study.

‘Performance of a device’ (in vitro diagnostic medical device) means the ability of a device to achieve its intended purpose as claimed by the manufacturer. It consists of the analytical and, where applicable, the clinical performance supporting that intended purpose;

‘Analytical performance’ means the ability of a device to correctly detect or measure a particular analyte.

‘Clinical Performance’ means the ability of a device to yield results that are correlated with a particular clinical condition, a physiological or pathological process, or in accordance with the target population and intended user;

Clinical investigation endpoints:

(a) establishing and verifying whether the performance of the devices is as established by the manufacturer.

(b) establishing and verifying a device’s clinical benefits as specified by its manufacturer;

(c) determining any undesirable adverse reaction under normal circumstances of use and whether these are considered risks in relation to the device’s intended performance.

In order to approve the conduct of a clinical investigation, the sponsor/authorised representative submits an application to the NAMMDR; the form is available online: https://ec.europa.eu/health/sites/default/files/md_sector/docs/mdcg_2021-8_annex1.pdf. Depending on the risk class of the device, the existence of the CE mark and the purpose of the clinical investigation, this can be adapted.

The application is registered only if accompanied by proof of payment of the fee in line with Order of the Minister of Health no. 3467 of November 17, 2022, Annex 1, point 3 – Clinical investigation

((https://www.anm.ro/_/DM/Anexa%201%20tarife%20ANMDMR-DM.pdf))

The form for payment of the fee can be downloaded from the Forms and fees page:

https://www.anm.ro/dispozitive-medicale/formulare-si-tarife/

Following completion of the form for payment of the fee, this shall be submitted to the NAMMDR headquarters of 48 Aviator Maior Ștefan Sănătescu, Sector 1, 011478, Bucharest, and the respective request shall be invoiced by the NAMMDR. After making the payment and confirming it, you can register your application at the NAMMDR headquarters of 48 Aviator Maior Ștefan Sănătescu, Sector 1, 011478, Bucharest.

Upon registration of applications for the conduct of clinical investigations, performance studies and substantial modifications to them, the files must be complete, in accordance with the legislation in force and must include the ethical opinion issued by the National Bioethics Committee for Medicinal Products and Medical Devices (CNBMDM), in order to meet the evaluation deadline and avoid rejection of the applications.

The NAMMDR approves applications for conduct of clinical investigations and clinical performance studies only if accompanied by an ethical opinion issued by the National Bioethics Committee for Medicinal Products and Medical Devices (CNBMDM) and by the documents provided for in Annex XV of the MDR and Annex XIV of the IVDR, as required. The CNBMDM can be contacted at: http://www.bioetica-medicala.ro; https://www.adsm.ro/comisia-de-bioetica-a-medicamentului-si-a-dispozitivelor-medicale/; e-mail: comisia.bioetica@gmail.com.

The structure and the Regulation for organisation and operation of the National Bioethics Committee for Medicinal Products and Medical Devices (CNBMDM) are approved through Order of the Minister of Health no. 80/2023.

Clinical investigations with medical devices and clinical performance assessment studies with in vitro diagnostic medical devices are conducted in compliance with the principles of good clinical practice, in accordance with the SR EN ISO 14 155 and ISO 20 916 standards.

The NAMMDR assesses and validates the requests for changes and assesses and authorizes the files for clinical investigations with medical devices, as well as their substantial changes, according to:

• MDR, Articles 61- 82, Annexes XIV and XV of 26 May 2021;

• IVDR, Articles 56 –77, Annexes XIII and XIV of 26 May 2022;

• Emergency Government Ordinance no. 46/09.06.2021 on national rules on clinical assessment and clinical investigations with medical devices, Article 16.

• Government Emergency Ordinance no. 137/12.10.2022;

• Order of the Minister of health no. 330/13.02.2023.

Useful documents:

Guidelines approved by the Medical Devices Coordination Group (MDCG) of the European Commission, DG SANTE, available online at: https://health.ec.europa.eu/medical-devices-sector/new-regulations/guidance-mdcg-endorsed-documents-and-other-guidance_en:

• 2023/C 163/06 – Commission Guidance on the content and structure of the summary of the clinical investigation report, available online at: https://eur-lex.europa.eu/legal-content/RO/TXT/PDF/?uri=CELEX:52023XC0508(01)

• Guidance MEDDEVs – 2.7/1 rev.4 , available online at https://health.ec.europa.eu/system/files/2022-01/md_guidance_meddevs_0.pdf, available on the Directives webpage: https://health.ec.europa.eu/medical-devices-sector/directives_en

• MDCG 2021-6 ”Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation”, https://health.ec.europa.eu/system/files/2021-04/mdcg_2021-6_en_0.pdf.

• MDCG 2021-08 – ”Clinical investigation application/notification documents”, https://health.ec.europa.eu/system/files/2021-05/mdcg_2021-8_en_0.pdf.

• MDCG 2021-28 ”Substantial modification of clinical investigation under Medical Device Regulation”, https://health.ec.europa.eu/system/files/2022-01/mdcg_2021-28_en.pdf.

• MDCG 2020-10/1 ”Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745”, https://health.ec.europa.eu.

• ”MDCG 2020-10/2 – Form for SAE reporting”;

• MDCG 2020-7 ”Post-market clinical follow-up (pmcf) plan template a guide for manufacturers and notified bodies”, https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2020_7_guidance_pmcf_plan_template_en_0.pdf.

• MDCG 2020-8 ”Post-market clinical follow-up (PMCF) Evaluation Report Template A guide for manufacturers and notified bodies”, https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2020_8_guidance_pmcf_evaluation_report_en_0.pdf.

• MDCG 2022-10 ”Q&A on the interface between Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR)”, https://health.ec.europa.eu/system/files/2022-05/mdcg_2022-10_en.pdf.

• MDCG 2020-1 ”Guidance on Clinical Evaluation (MDR) / Performance Evaluation (IVDR) of Medical Device Software” https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2020_1_guidance_clinic_eva_md_software_en_0.pdf.

• MDCG 2019-11”Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR”, https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2019_11_guidance_qualification_classification_software_en_0.pdf.

• ”SR EN ISO 14155 – Clinical investigation of medical devices for human subjects – Good clinical practice.

• ISO 20 916 – In vitro diagnostic medical devices – Clinical performance studies using specimens from human subject – Good study practice”.

Medicinal product – medical device combinations

There are various types of medicinal product-medical device combinations, as referred to in the MDR – Article 1 (9), Art. 117 and in the IVDR – Articles 2, 4, Annex II.

An eloquent description of these, as well as recommendations for enforcement of legal provisions can be found in the following documents made available by the European Medicines Agency (EMA):

• Question-and-answer guidance on the implementation of these Regulations is available below, available online at https://www.ema.europa.eu/en/human-regulatory/overview/medical-devices .

• Questions & Answers for applicants, marketing authorisation holders of medicinal products and notified bodies with respect to the implementation of the Medical Devices and In Vitro Diagnostic Medical Devices Regulations ((EU) 2017/745 and (EU) 2017/746), available online at https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/questions-answers-implementation-medical-devices-vitro-diagnostic-medical-devices-regulations-eu/745-eu-2017/746_en.pdf.

• MDCG 2022 – 5 ”Guidance on borderline between medical devices and medicinal products under Regulation (EU) 2017/745 on medical devices” available online at https://health.ec.europa.eu.

Clinical trials for medicinal product –medical device combinations shall be submitted to the NAMMDR Clinical Trials Directorate (DSC). As the case may be, the DSC will either consult the DGDM for medical device documentation or the sponsor will have to submit in parallel an application for notification of the medical device of the combination to the DGDM. In most cases of medicinal product-medical device combinations, the latter (whether they are medical devices or in vitro diagnostic medical devices) must bear the CE marking.

Useful contacts:

dscdm@anm.ro, for SAE reporting as well

dsc@anm.ro, for clinical trials on medicinal products and combinations with medicinal products