Medical Device Regulation

On 5th April 2017, the European Parliament voted to adopt the new Regulation (EU) 2017/7451 on medical devices (MDR) that came into force and repealed Directives 93/42/EEC (Medical Device Directive (MDD)) and 90/385/EEC (Active Implantable Medical Devices Directive 90/385/EEC (AIMDD)) on 25th of May 2017. After a transition period, the MDR went into force on 26th May 2021, and medical devices must now meet the requirements of the MDR to be placed on the European Union market.

The MDR's comprehensive framework imposes stringent requirements on manufacturers, importers, and distributors, ensuring that medical devices meet the highest standards of quality, safety, and efficacy. The new regulation impacts all manufacturers of medical devices (Class I – III) and certain manufacturers producing devices without an intended medical. Consequently, these manufacturers are obligated to modify their Quality Management Systems (QMS), Risk Management (RM), and Technical Documentation (TD).

One of the key highlights of the MDR is its focus on a lifecycle approach, from design and production to post-market surveillance. This approach emphasizes continuous monitoring and adaptation to technological advancements, fostering innovation while safeguarding public health. The regulation introduces a centralized EU database, EUDAMED, aimed at improving the transparency and traceability of medical devices throughout their lifecycle.

On 15th March 2023, amendments (Regulation (EU) 2023/607) were made to the MDR, incorporating an updated transitional period outlined in Article 120(3). This revision introduces staggered deadlines based on the risk class of the device extending the compliance timeframe until 2028. In detail, this extension applies to devices undergoing the transition from the MDD to the MDR within the following timelines:

  • Until 26 May 2026 for Class III implantable custom-made devices.
  • Until 31 December 2027 for Class III and implantable Class IIb devices.
  • Until 31 December 2028 for non-implantable Class IIb devices, Class IIa devices, Class I sterile devices, or Class I devices with a measuring function; Class I devices under the directives that need the involvement of a Notified Body (NB) in the conformity assessment process under the MDR.

To be eligible for the transition extension and to place the medical devices on the market or put into service until the above-mentioned dates, the medical devices must meet the following conditions:

Those devices continue to comply with Directive 90/385/EEC or Directive 93/42/EEC, as applicable.

There are no significant changes in the design and intended purpose.

The devices do not present an unacceptable risk to the health or safety of patients, users, or other persons, or to other aspects of the protection of public health.

Further, manufacturers must put in place a QMS in accordance with Article 10(9) and lodge a formal application with a NB for conformity assessment no later than 26 May 2024, and by no later than 26 September 2024, the manufacturer must have signed a written agreement the NB.

Clinical Evaluation

The clinical evaluation is one of the key elements of a manufacturer's TD and a core requirement of the MDR (Article 61, Annex II 6.1(c)). As a systematic and planned process, the clinical evaluation generates, collects, and analyses all available clinical evidence data to demonstrate the conformity of the medical device under evaluation with the applicable general safety and performance requirements (GSPRs) (Annex I and Article 2(44)). Crucially, carrying out a clinical evaluation, including performing Post-Market Clinical Follow-Up (PMCF) activities, is a general obligation for any manufacturer and a fundamental part of a manufacturer's quality management system (QMS) (Articles 10(3) and 10(9)(f)).

The MDR has designated a pivotal role to clinical evaluation, imposing substantial requirements on manufacturers to ensure adherence to regulatory standards. The main purpose of the clinical evaluation is to demonstrate the safety and performance of the medical device, including its clinical benefits, when used as indicated by the intended user. Manufacturers are obligated to assess all potential adverse effects comprehensively, accompanied by a detailed analysis of the acceptability of the benefit-risk ratio, as stipulated in Article 61(1). The clinical evaluation must be performed following a defined and methodologically sound procedure focusing on a systematic scientific literature review to appraise all available clinical evidence. Further, the manufacturer must evaluate all available performed pre-market and post-market clinical investigations and provide a critical consideration of alternative treatment options for the medical device under evaluation (Article 61(3)). Generally, the manufacturer is required to update the clinical evaluation throughout the lifecycle of the medical device (Article 61(11)).

Importantly, the manufacturer must ensure that the clinical evaluation is performed thoroughly and objectively considering both favorable and unfavorable data to avoid any biased results regarding the benefit-risk ratio assessment. This takes into consideration the risk class, intended purpose, residual risks, and the clinical benefits of the medical device (Annex XIV (2)).

The clinical evaluation is performed following these distinct stages: Stage 0: Scope of the clinical evaluation (described in the Clinical Evaluation Plan (CEP)).Stage 0: Scope of the clinical evaluation (described in the Clinical Evaluation Plan (CEP)).

  • Stage 0: Scope of the clinical evaluation (described in the Clinical Evaluation Plan (CEP)).
  • Stage 1: Identification of pertinent data (described in the CEP).
  • Stage 2: Appraisal of pertinent data (described in the CEP and results detailed in the Clinical Evaluation Report (CER)).
  • Stage 3: Analysis of data (described in the CEP and results detailed in the CER).
  • Stage 4: Summary of stages 0, 1, 2, and 3 (CER document).

  • Clinical Evaluation Plan

The CEP, outlined in MDR Article 61(12) and Annex XIV, Part A, defines the scope of the clinical evaluation focusing on the specification of the GSPRs that require clinical data for the medical device under evaluation, the intended purpose, and intended target groups including indications and contraindications. Moreover, the CEP describes the medical device's intended clinical benefits, specifying relevant clinical outcome parameters for both qualitative and quantitative evaluations of safety and performance. Additionally, the CEP must address an indicative list and specifications of parameters crucial for determining the acceptability of the benefit-risk ratio. The CEP identifies all pertinent data available from data generated and held by the manufacturer such as any pre-market and post-market clinical investigations, PMS reports or PMCF activities, data retrieved from the scientific literature, and how to appraise and analyze them (demonstration that the available data are sufficient to demonstrate compliance with the GSPRs) regarding their suitability for establishing the safety and performance of the device. An important purpose of the CEP is to define the systematic scientific literature review in different databases and in detail to outline the objectives, sources of data, selection criteria, and data appraisal. The literature search not only includes the current State-of-the-Art (SOTA) but also scientific literature regarding similar benchmark devices or equivalent medical devices and the medical device under evaluation.

  • Clinical Evaluation Report

The clinical evaluation, including its outcomes and the clinical evidence derived from methodologies outlined in the respective CEP, must be systematically documented in a CER in accordance with MDR Article 61.12. as an integral part of the manufacturer's TD. The CER aims to confirm the conformity with relevant GSPRs under the normal conditions of the intended use of the device and evaluates the undesirable side effects and the acceptability of the benefit-risk ratio.

Post-Market Clinical Follow-Up

In accordance with the MDR definition specified in Annex XIV (5), Post-Market Clinical Follow-up (PMCF), incorporated within the manufacturer's Post-Market Surveillance (PMS) plan, is a continual proactive process to provide ongoing updates to the clinical evaluation. The PMCF activities aim to collect and evaluate clinical data from the use in or on humans of the medical device under evaluation with the aim of confirming the safety and performance throughout the expected lifetime of the device, of ensuring the continued acceptability of identified risks and of detecting emerging risks based on factual evidence.

  • PMCF Plan

The PMCF plan defines the methods and procedures, based on the results of the clinical evaluation, to identify and monitor previously unknown side-effects as well as contraindications, analyze emerging risks, ensure the acceptability of the benefit-risk ratio, and identify possible systematic misuse of the medical device (Annex XIV (6)). Among other requirements, the PCMF plan must define general and specific activities. While the general activities have a broader perspective focusing on, for example, feedback from users or screening of scientific literature databases, the specific activities aim to answer distinct aspects or questions to collect sufficient clinical evidence data for conformity with the GSPRs. Here, the manufacturer defines, for example, surveys, registries, or PMCF studies in a retrospective or prospective setting (Annex XIV (6.2)). The PMCF plan needs to be written according to the MDCG 2020-7 document.

  • PMCF Report

The findings of the PMCF activities laid out in the corresponding PMCF plan need to be documented in a PMCF evaluation report (Annex XIV (7)) according to the MDCG 2020-8 document. Importantly, the conclusions of the PMCF evaluation report need to be considered to update the upcoming clinical evaluation report and the manufacturer's RM (Annex XIV (8)).

PMS Report (Class I)

According to MDR Article 85, manufacturers of Class I devices should establish a PMS report to summarize and conclude the results of the PMS data analyses and a description of any implemented preventive and corrective actions. The PMS report is to be updated when necessary and made available to the competent authority upon request.

Periodic Safety Update Report (Class IIa, IIb, III)

According to MDR Article 86, manufacturers of Class IIa, IIb, and III devices should prepare a Periodic Safety Update Report (PSUR) for each medical device and, where relevant, for each category or group of devices. The PSUR summarizes and concludes the results the of the post-market surveillance data gathered referring to the conclusions of the benefit-risk determination, the main findings of the PMCF activities, the volumes of sales of the device, and an estimated evaluation of the size and other characteristics of the population using the device and, where practicable, the usage frequency of the device.

Crucially, manufacturers of Class IIb and Class III devices are required to revise the PSUR at least annually. For Class IIa devices, updates to the PSUR should be made when necessary and, at a minimum, every two years.

Summary of Clinical Safety and Performance

According to MDR Article 32, the manufacturer of implantable devices or Class III devices (other than custom-made or investigational devices) must establish a Summary of Clinical Safety and Performance (SSCP) document, which should be objective and clear to the intended healthcare users and, if relevant, to patients, and it must be accessible to the public. The Summary of Safety and Clinical Performance (SSCP) provides a condensed overview of the device's safety, clinical data, and performance, encompassing both favorable and unfavorable data. Subsequently, it undergoes assessment and validation by the NB. Following validation, the NB is responsible for uploading the validated summary to Eudamed. The manufacturer is required to indicate on the label or instructions for use where the summary can be accessed.