Clinical investigations with medical devices and assessment of performance with in vitro diagnostic medical devices
”Clinical investigation” – any systematic investigation involving one or several human subjects, conducted to assess the safety or performance of a medical device;
”Performance study” – a study conducted in order to establish or confirm the analytical or clinical performance of a device;
”Performance assessment” – assessment and analysis of data in order to establish or verify the scientific validity, the analytical performance and, where applicable, the clinical performance of a device;
”Device subject to investigation” – a device which is assessed in the context of a clinical investigation;
”In vitro diagnostic medical device subject to a performance study” – 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, is not considered a device subject to a performance study;
”Device performance” (for in vitro diagnostic medical devices) – the ability of a device to fulfil its intended purpose as indicated by the manufacturer. This consists of the analytical performance and, as the case may be, of the clinical performance which justifies the respective proposed purpose;
”Analytical performance” – the ability of a device to correctly detect or measure a particular analyte;
”Clinical performance” – the ability of a device to produce results correlated with a particular clinical condition or physiological or pathological condition or physiological or pathological process in accordance with the intended target population and 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 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/; email: firstname.lastname@example.org.
The NAMMDR and the Medical Devices assess and validate requests for changes and evaluate and authorize the files for clinical investigations, as well as their substantial changes, according to:
- MDR, Articles 61- 82, Annexes XIV and XVof 26 May 2021;
- IVDR, Articles 56 –77, Annexes XIII and XIVof 26 May 2022;
- Emergency Government Ordinance no. 46/09.06.2021on national rules on clinical assessment and clinical investigations with medical devices, Article 16.
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 :
- Clinical investigation and evaluation (the guideline on clinical evaluation), published by: https://health.ec.europa.eu/medical-devices-sector/new-regulations/guidance-mdcg-endorsed-documents-and-other-guidance_en#sec3
- MDCG 2021-6 “Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation”, available online at: https://health.ec.europa.eu/system/files/2021-04/mdcg_2021-6_en_0.pdf>.
- MDCG 2021-08 – ”Clinical investigation application/notification documents”, available online at: 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”, available online at: 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”, available online at: https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2020-10-1_guidance_safety_reporting_en_0.pdf.
- MDCG 2020-7 ”Post-market clinical follow-up (pmcf) plan template a guide for manufacturers and notified bodies”, available online at: 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”, available online at: 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)”, available online at: 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” available online at: 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”, available online at: https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2019_11_guidance_qualification_classification_software_en_0.pdf.
Medicinal product – medical device combinations
There are various types of medicinal product-medical device combinations, as referred to in the MDR – Article 1 (9) 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/system/files/2022-04/mdcg_2022-5_en_0.pdf.
In the case of combinations containing medicinal products, clinical trials for medicinal products are submitted to the NAMMDR Clinical Trials Directorate (DSC). On a case-by-case basis, the DSC will consult the DGDM for medical device documentation or the sponsor will have to submit a parallel application to the DGDM for notification of the medical device, which in such combinations must bear the CE mark.