Professor Dr Freimut Schliess, Director of Science & Innovation at the Profil Institut für Stoffwechselforschung GmbH, explores how the MDR will impact clinical trials
With the MDR [1], which has replaced the Medical Device Directive 93/42/EC (MDD) since 26th of May 2021, the European Commission intends to enhance the safety and quality of medical devices available in the European single market, in order to offer a high level of protection to patients, users and other persons (Whereas clause 101; Article 1). Randomised controlled clinical trials are usually considered the gold standard when it comes to providing scientifically proven evidence of safety, efficacy, and real-world effectiveness [2].
The MDR refers to three stages of clinical development
In the MDR, clinical trials are referred to as clinical investigations (Articles 2(45), 62-82; Annex XV). The MDR requirements for the execution of a clinical investigation include that “measures should be taken to minimise bias, such as randomisation, and management of confounding factors”. In addition, it specifically states that pivotal clinical trials shall be performed in “a clinical environment that is representative of the intended normal conditions of use of the device in the target patient population” (Annex XV). However, no particular trial designs are required by default. Rather, the MDR applies the principle of proportionality, i.e. a risk-based approach when it refers to three general stages of clinical development (see also ISO 14155:2020, Annex I).
Clinical investigations to demonstrate conformity of devices (Article 62). These are pivotal clinical trials conducted to prove the intended performance, the clinical benefits, as well as clinical safety of an investigational device. Such clinical investigation can start as soon as the Member State(s) grants an authorisation if an ethics committee has not issued a negative opinion in relation to the clinical investigation.
Post-market clinical follow-up (PMCF) clinical investigations (Article 74). PMCF clinical investigations where the trial participants are subject to additional procedures considered invasive or burdensome are conducted to further assess an already CE marked device within the scope of its intended purpose. They can start following notification of the Member States if an ethics committee has not issued a negative opinion.
Other clinical investigations (Article 82) include non-interventional (observational) PMCF investigations as well as proof-of-concept, first-in-human, early feasibility and traditional feasibility trials. The latter are conducted, for instance, to inform the design of a pivotal clinical investigation. Other clinical investigations are subject to scientific and ethical review.
The MDR stipulates the general requirements, the documents to be submitted for application and the obligations of the clinical trial sponsor and investigators.
When does a clinical investigation have to be conducted and when not?
The question of whether a clinical investigation needs to be conducted or not is answered within the wider context of the clinical evaluation (Articles 2(44), 61; Annex XIV). In case a device is CE marked and evaluated within the scope of its intended purpose in the absence of additional procedures considered invasive or burdensome for patients, no clinical trial is required in the framework of PMS and PMCF activities (Articles 74 and 84, ISO 20416:2020).
Class I, class I s/m and class IIa devices don’t need to undergo a clinical investigation to obtain a CE mark. If a class IIb and class III device is not yet CE marked, a pivotal clinical investigation is mandatory to prove conformity, unless sufficient clinical evidence comes from the clinical evaluation related to a device for which technical, biological and clinical equivalence with the device in question can be demonstrated (Annex XIV). However, for implantable and class III devices a proof of equivalence alone is not enough to exempt a clinical investigation, the MDR establishes extra specific requirements for these devices (MDCG 2020-5).
Critical appraisal and advice to manufacturers
The MDR takes a differentiated, risk-based approach to whether medical device manufacturers are required to implement clinical trials as part of their mandatory pre- and post-market clinical evaluation. The specification of real healthcare provision as the relevant environment for pivotal and PMCF clinical investigations can be expected to narrow the well-known gap between the efficacy of devices seen in well-controlled research environments and their effectiveness in real-world healthcare.
Clinical trials are recognised a valuable source of clinical data to be used in the clinical evaluation (including conformity assessment and PMS), which in turn is subject to continuous monitoring through the manufacturer’s quality management system (QMS). In this way, clinical trials help protecting patients in Europe from the circulation of non-effective and harmful medical devices.
The narrow definition of equivalence criteria will significantly increase the need for resource-intensive clinical trials, which require high financial investments. Therefore, manufacturers are advised to first conduct carefully designed proof-of-concept trials with the aim to validate the targeted patient population and to inform the design and sample size of the larger pivotal clinical investigations. In addition to the formal Clinical Study Report (CSR), clinical trial outcomes should be published in peer-reviewed scientific journals and presented to the relevant audiences at international conferences in order to fully leverage the return on the investment in a clinical trial program.
A multi-stakeholder dialogue, as it was recently started by the EIT Health Knowledge & Innovation Community1 would be most appropriate to evaluate the experiences gained with the current edition of the MDR. In particular, its impact on the availability of innovative devices for patients who urgently need them, and the positioning of European start-ups and SMEs in global competition should be reviewed in a timely manner. If necessary, rapid adjustments of the MDR should be made.
Footnotes
[1] EIT Health Think Tank: Are we MDR ready? Summary of research findings. June 2021.
This article is part of the RealWorld4Clinic innovation project that develops in compliance with the MDR 2017/245 a class III medical device for the remote cardiorespiratory health monitoring of heart failure patients (https://eit-health.de/en/realworld4clinic/).
RealWorld4Clinic is curated and financially supported by EIT Health (https://eithealth.eu/), a network of best-inclass health innovators that collaborates across borders and delivers solutions to enable European citizens to live longer, healthier lives. EIT Health is funded by the EIT (https://eit.europa.eu/), a body of the European Union.
The support of Tatiana Affini Dicenzo (Manager Science & Innovation at Profil Institute for Metabolic Research GmbH) in the creation of this article is greatly acknowledged.
Please note: This is a commercial profile
© 2019. This work is licensed under CC-BY-NC-ND.
