By Dr Catarina Carrao
What do we all dream when putting a medical device on the market?
That it is safe, has good performance, and benefits the user. This is also what the EU Medical Device Regulation (MDR) asks of manufacturers when applying for approval. But what does this mean in practical terms?
Questions remain: What exactly is meant by "sufficient clinical evidence"? What data sources can be used? What about legacy products?
Even though it is mentioned in Article 2 (51) and Article 61, unfortunately “sufficient clinical evidence” is not defined in the MDR. However according to the published guidelines by the Medical Device Coordination Group (MDCG) it is understood that “sufficient clinical evidence” is “the present result of a qualified assessment which has reached the conclusion that the device is safe and achieves the intended benefits”1.
This conclusion encompasses the amount and quality of clinical evidence derived from state-of-the-art capabilities and accepted in good clinical practice, based on relevant consolidated findings of science, technology and experience.
The caveat is that providing “sufficient clinical evidence” is not a moment in time, but part of a lifecycle approach to medical devices. As such, the new regulations demand that a systematic and planned process needs to be set in place upon approval to continuously generate, collect, analyse and assess the clinical data pertaining to the device in order to verify the safety and performance, including the device clinical benefits, when the product is used as intended by the manufacturer1.
Also the consideration of alternative treatment options for the acceptability of the benefit-risk ratio needs to be taken into account (Article 61.3.c), and must also be based on clinical evidence and data (Art. 61.1 & Annex III)1.
Safety and performance information from a device can be generated from (1) its usage and sourced from direct clinical investigations by the manufacturer; or, (2) other studies reported in the scientific literature from the device itself or an equivalent; or, (3) reports published in peer-reviewed scientific literature2.
Also valid, is (4) clinically relevant information coming from Post-Market Surveillance (PMS), particularly Post-Market Clinical Follow-up (PMCF) generated for the purpose of MDD/AIMDD in the case of legacy devices (MDD, European Medical Devices Directive 93/42/EEC; AIMDD, Active Implantable Medical Devices Directive 90/385/EEC)1,2.
As such, it is important to identify all available sources of clinical data from both the pre-market and post-market phases generated and held by the manufacturer; but also, clinical data of equivalent or similar devices that is published in credible sources. Unpublished reports are not a valid source of clinical data under the new MDR1, but may provide informative context for the clinical evaluation of legacy devices, for example.
Since legacy devices currently on the market have been subjected to conformity assessment; and, therefore, are presumed to have been supported by clinical data (except where non-clinical testing was demonstrated to be adequate), then post-market clinical data together with the clinical data generated for the conformity assessment under the MDD/AIMDD will be the basis of the clinical evaluation process. On top of that, an analysis with respect to the General Safety and Performance Requirements (GSPRs) is essential to determine if additional data is needed to support the clinical evidence; which could be achieved either through a gap analysis, or by creation of an entirely new analysis specifically for the MDR.
Legacy devices are not excused from the additional requirements in MDR concerning PMS and PMCF. The MDR compliant clinical evaluation for a legacy device must contain the identification of available clinical data, as well as their appraisal / analysis / evaluation; and, shall lead to a demonstration of conformity to the GSPR based on a lifecycle approach of sufficient clinical evidence1. Preferentially, this should be created while the device still has a valid MDD/AIMDD certificate; and, such reports need to be updated, as soon as the certificates loose legitimacy.
It is also fundamental to check where a legacy device fits in the new perceived risk classification and revise the conformity assessment accordingly. As such, devices are divided into classes I (low risk), IIa (medium risk), IIb (medium/high risk), and III (high risk) taking into account the intended purpose3. Low risk class I medical devices are further sub-divided into four sub-classes depending on whether the device is provided sterile (Is), has a measuring function (Im) or is a reusable surgical instrument (Ir) – for these, the involvement of a Notified Body is required for approval to market4.
The MDR sets out 22 rules for determining risk classes (Annex VIII) and special attention should be paid to rules regarding invasive devices, surgically invasive devices and implantable devices (Section 5: Rules 5 to 8); active devices (Section 6: Rules 9 to 13, for example, software now falls under Rule 11); devices utilising tissues and cells (Rule 18); devices incorporating nanomaterials (Rule 19); and devices composed of substances (Rule 21)5. Particularly important in today’s world is that standalone software is classified in its own right as a medical device if the software fulfils a medical purpose, whether it is used in a medical setting or not2. If the intended use of data from an app includes the interpretation and analysis of data (e.g., dosage recommendations based on individual data analysed in the platform), then the software qualifies as a medical device and is regulated under EU MDR. Additionally, if wearable devices incorporate algorithms that analyse data and make clinical recommendations, again this is considered a Software as Medical Device (SaMD) and is regulated.
For certain Class III and Class IIb devices there is a new clinical evaluation consultation procedure that needs to be carried out by an independent expert panel based on the clinical evaluation assessment report of the Notified Body (Article 54). For all Class III devices and for Class IIb devices intended to administer a medicinal product (or remove it from the body), the manufacturer has the option to consult a group of European experts to obtain an upstream review of its intended clinical development strategy (Article 61 paragraph 2). The views expressed by the expert panel need to be considered by the manufacturer, and such consideration shall be documented in the clinical evaluation report5.
At this point, it is fundamental to make a critical re-evaluation of legacy devices, where low scientific value, or any form of bias from previous studies, should be considered because the device will be on a path of rejection. The “sell-off” provision of the EU MDR limits the time during which devices that are compliant with the Directives and have already been placed on the market may be available; as such, any devices that are not EU MDR compliant and are still within the supply chain until 27th May 2025, will no longer be marketable and must be withdrawn5. So, clinical study randomization, independent monitoring/auditing, statistical power, data collection methods that do not bias data integrity, and objectivity endpoints of the clinical studies of legacy devices will be fundamental points for continuous approval under EU MDR; and these need to be further compliant with the updated ISO 14155 standard6.
Even though the principles of Good Clinical Practices (GCP) as well as the way clinical trials are reported remain mostly the same, there are some new components in the updated ISO 141557. The main changes are the reinforcement of risk management in all phases of trial conduct, and further alignment with the International Council for Harmonization (ICH) and GCP. The updated ISO 14155, references the need to register the trial in a publicly accessible database; and, it also explains how the standard can be applied to post-market studies of different designs, with risk-based monitoring (ISO 14971) and considerations when outlining the monitoring plan.
Included are also advice on statistical considerations of clinical studies; guidance for Ethics Committees and audits; and, clarifications on clinical quality management with applicability of GCP to different clinical development stages8.
Another requirement of the new ISO 1455 is the usage of a compliant method of data collection and processing, such an Electronic Data Capture System (EDC), where all data is generated and maintained in a way that enables control and traceability9. Point 7.8 of ISO 14155 adds reliability and integrity to EDCs, as well as validation of electronic clinical data systems used to evaluate authenticity, accuracy, reliability and consistent intended performance of the data system. These requirements impact both the data generated and held by manufacturers, as well as those generated in the setting of Investigator Initiated Studies (IIS). Both sponsor-generated and IIS-generated data must be collected and processed using compliant data capture systems and case-report forms (CRFs). As such, in this context, using an established EDC vendor that offers a fully validated and compliant system, as well as the opportunity to validate study-specific CRFs is not money gone to waste7-9.
There are exceptions that can be used to justify not performing a clinical investigation in the case of certain devices, which are concretely detailed in the regulation (Article 61). If the device has been designed by modifications of a device already marketed by the same manufacturer, or the modified device is considered equivalent to a currently marketed product, or if the clinical evaluation is sufficient to demonstrate conformity with the modified device, then the exemption can be presented. In this case, the Notified Body only checks if the PMCF plan is appropriate and that the post-market studies can demonstrate the safety and performance of the device in continuum.
In addition, clinical investigations need not be performed in the cases of implantable devices and class III devices which have been placed on the market in accordance with Directive 90/385/EEC or Directive 93/42/EEC, and for which there exists sufficient clinical data in compliance with common specifications (CS) of the particular product. If there are not harmonized standards in place to guide the product, particularly the ones without a concrete medical purpose or single-use, then CS will be implemented according to the regulation10.
A manufacturer of a device demonstrated to be equivalent to an already marketed device not manufactured by him, may also rely on Article 61 paragraph 4, in order not to perform a clinical investigation if the following conditions are fulfilled: the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis; and, the original clinical evaluation has been performed in compliance with the new regulation11. Of course, the manufacturer of the second device needs to provide clear evidence of such agreement to the notified body.
Since the MDR places more emphasis on a life-cycle approach to safety backed up by clinical data, the investment needs to be made with eyes on the future. Which medical device products check the “dream-box” (safety, performance, risk-benefit), and on top will drive a profit? Those are the ones that need the necessary systems and funding to handle clinical evaluation, quality management, post-market surveillance and possible liabilities.
Dr Catarina Carrao gained a PhD in Biochemistry from Northeastern Ohio Medical and Pharmacy University and an M.Phil in Biochemistry at the University of Beira Interior. She has worked as a researcher at Max F. Perutz Laboratories, Yale Cardiovascular Center at Yale University School of Medicine, and the Center Cardiovascular Research (CCR) at Charité Medical University.
1 MDCG. Regulation (EU) 2017/745: Clinical evidence needed for medical devices previously CE marked under Directives 93/42/EEC or 90/385/EEC, a guide for manufacturers and notified bodies https://ec.europa.eu/health/sites/default/files/md_sector/docs/md_mdcg_2020_6_guidance_sufficient_clinical_evidence_en.pdf MDCG 2020-6, Medical Device Coordination Group (2020).
MDCG. Guidance on Clinical Evaluation (MDR) / Performance Evaluation (IVDR) of Medical Device Software. https://ec.europa.eu/health/sites/default/files/md_sector/docs/md_mdcg_2020_1_guidance_clinic_eva_md_software_en.pdf 2020-1, EU (2020).
EU. MDR – Article 51 – Classification of devices. https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745 Official Journal of the European Union (2017).
EU. Factsheet for Class I Medical Devices. https://ec.europa.eu/health/sites/default/files/md_topics-interest/docs/md_mdcg_2021_factsheet-cl1_en.pdf Assessed 6th September 2021 (2021).
EU. Factsheet for Manufacturers of medical devices. https://ec.europa.eu/health/sites/default/files/md_newregulations/docs/md_manufacturers_factsheet_en.pdf Assessed 6th September 2021, doi:10.2873/66341 (2020).
Pelgrim, L. Do you have sufficient clinical evidence for future EU-MDR compliance? https://www.qservegroup.com/eu/de/i97/do-you-have-sufficient-clinical-evidence-for-future-eu-mdr-compliance Assessed: 3rd Septemebr 2021 (2017).
Postma, W. The new ISO14155 standard for Good Clinical Practice is now published! https://www.qservegroup.com/eu/de/i718/the-new-iso14155-standard-for-good-clinical-practice-is-now-published Assessed: 3rd September 2021 (2020).
ISO. ISO 14155:2020, Clinical investigation of medical devices for human subjects — Good clinical practice. https://www.iso.org/obp/ui/#iso:std:iso:14155:ed-3:v1:en Assessed: 3rd September 2021 (2020).
Derks, S. The Impact of ISO 14155 on PMCF Investigations Under the MDR. https://www.castoredc.com/blog/iso14155-pmcf-mdr-impact/ Assessed: 3rd September 2021 (2020).
Mezher, M. European Commission sets common specifications for reprocessing single-use devices. https://www.raps.org/news-and-articles/news-articles/2020/8/european-commission-sets-common-specifications-for RAPS (2020).
EU. MDR – Article 61 – Clinical evaluation. https://www.medical-device-regulation.eu/tag/mdr-article-61/ Assessed 7th September 2021 (2017).
