What doctors need to know about new processes for the regulatory approval of high risk medical devices

AUTHORS:

Dr Rory Durand, Dr JJ Coughlan, Professor Robert A. Byrne

Affiliations: Dept. of Cardiology and Cardiovascular Research Institute (CVRI) Dublin, Mater Private Network and RCSI University of Medicine and Health Sciences, Dublin, Ireland.

The authors acknowledgment funding to RCSI University from the European Union Horizon 2020 project, Grant Agreement 965246.

What doctors need to know about new processes for the regulatory approval of high risk medical devices

Introduction

Medical device development and manufacturing accounts for an increasing proportion of overall economic activity in Ireland.

Some estimates suggest that approximately one in every 100 to 120 workers in Ireland is employed in the medical device industry.

The number of workers in the medical device industry in Ireland per capita is many times higher than the European Union (EU) average and about three times as high as the EU country with the next highest ratio. In addition, for certain high-risk medical devices Ireland dominates global manufacturing capacity, with 80% of all coronary stents worldwide being manufactured in Ireland.

While progress in medical device innovation and manufacturing has contributed to the significant decline in death and disability from common medical conditions such as acute coronary syndrome, stroke and heart valve disease and improved the quality of life of millions of patients suffering from degenerative joint disease, some controversy has surrounded the processes for approval of medical devices in Europe in recent years.1 Cases involving patient harm due to implantation of substandard breast implants, hip on hip implants and vaginal meshes have received widespread coverage in the lay media and has focused the attention of the medical and political communities at a national and European level (see Table 1). In 2018 a worldwide investigation by journalists released information from the so-called 'Implant Files' detailed a catalogue of problems with certain medical devices, which had resulted in adverse outcomes for patients. This resulted in coordinated front page headlines in newspapers around the world on 26th November that year (see Figure 1).

Partly as a response to these issues, as well as the realisation that historical processes, which had developed somewhat organically over recent decades, had become outdated, a review of the approval and certification process in Europe was initiated as far back as 2008. This led to the drafting of new legislation and following negotiation and tripartite dialogue between the European Commission, European Parliament and member states represented via the Council of the European Union, the new Medical Device Regulation (MDR) was officially published in 2017.

In contrast to the older processes which were known as the Medical Device Directives (MDD) and had to be adopted individually by member states into law, the new processes were enshrined as a regulation – the MDR – which in common with other regulations, such as the general data protection regulation (GDPR), automatically becomes law in the individual member states of the EU. Due to the coronavirus pandemic, the regulation came into force in May 2021, one year later than had been planned at the time of publication of the legislation.

While the MDR has officially come into law in EU member states, the community finds itself now in a transition phase. This means that devices already approved under the older MDD can remain on the market until the end of the transition phase. However, new devices must be approved under the MDR pathways. Because of some difficulties encountered in the implementation of MDR (see below), the European Commission has agreed to extend the transition phase for the highest risk medical devices for a number of years, up until 2029 for certain classes of devices.

Overview of the regulatory landscape for medical devices in Europe

While the introduction of MDR brought in a number of important changes in the approval of medical devices, some key elements of the approval process remained unchanged. The central steps involved in the process – known as a conformity assessment – are shown in Figure 2. As the name suggests this process evolved as a legacy from the historical needs of device manufacturers to demonstrate adherence to common standards in the development and manufacture of their devices. Accordingly, the processes were often developed without direct input from practising clinicians or academia. This accounts in some respects for the lack of prominence given to assessment of clinical evaluation data under the MDD and the knock on effect that often high-risk medical devices were approved for use in Europe with a lesser quantity and quality of clinical trial data than was the case in other jurisdictions, such as the United States.

In simple terms, in Europe the manufacturer of a medical device is required to make a submission to a designated company known as a notified body; the notified body will review the submission dossier and has the power to authorise the device, granting a CE certificate of conformity and facilitating market access in the European Union and other countries aligned with the EU regulatory system. The code designating the name of the notified body that approved the device is usually available on the package of the device directly under the CE mark. The work of the notified bodies is overseen by national competent authorities, the regulatory authorities in each individual member state. In Ireland's case this is the Health Products Regulatory Authority (HPRA). Competent authorities coordinate activities related to medical devices amongst their members in each EU country through a competent authority for medical devices coordination group. At a European Commission level, legislative and guidance roles as well as coordination of medical device regulation lies within the department of the directorate general for health (DG Sante).

Did you know

The four-digit code designating the name of the notified body that approved the device is available on the package of the device directly under the CE mark.

Medical device classification according to risk

The degree of clinical evidence that is required by a notified body in order for CE certification to be granted depends on the risk category of the device. High risk medical devices must have supportive data available from clinical investigations to accompany their application. Interestingly, the general burden of proof as part of a conformity assessment in Europe was that the device should be safe and perform technically as intended. Considerations in relation to efficacy were not central to the process. This differs from approaches used in the United States, where high risk medical devices seeking approval would be expected to have evidence supporting both safety and efficacy. A new concept introduced under EU MDR is that devices should now be required to show evidence of clinical benefit, which may be interpreted to mean both safety and efficacy.

The system of rules that are used to classify any medical device into one of three risk categories is somewhat complicated to understand. In simple terms, however, devices are classified based on whether they are invasive or not, whether they are in contact with important body systems, such as circulatory or central nervous system, and whether or not the contact is transient, short-lived or permanent (as in the case of implants).

Examples of medical devices in each class are shown in the Table 2. The most commonly used highrisk medical devices in clinical practice are coronary stents, heart valves, pacemakers, and hip and knee implants. In recent years medical implants used for glucose monitoring and management of diabetes mellitus have also become common.

Problems with transparency and quality of clinical evidence for high-risk medical devices

We recently completed work as part of a European collaboration of stakeholders involved in medical device regulation, known as CORE-MD.2 This consortium was led by representatives of doctors professional societies, and also comprised representation from the European Commission, national regulatory authorities, notified bodies, patient organisations and public health authorities. Further details on the work of this project can be found at the website www.core-md.eu.

As part of this work, we surveyed the landscape of clinical evidence for high-risk medical devices approved for use in Europe, assessing the quality and transparency of evidence across three medical specialties, cardiovascular medicine, orthopaedics, and diabetes. Two reports have been published in the peer-reviewed literature.

For cardiovascular devices seven groups of Class III devices were predefined, encompassing 71 long term implantable devices marketed in the EU between the year 2000 and 2023.3 The identified groups were bioresorbable scaffolds, left atrium appendage closure devices, transcatheter aortic valve implantation systems, subcutaneous ICDs, surgical aortic and mitral valves, transcatheter mitral valve repair or replacement devices and leadless pacemakers.

The most commonly used devices, coronary stents, were not included as we had previously provided a detailed report on this area.4,5 Of the 308 identified studies, most were non-randomised (81%), 51% without a pre-registered study protocol and 61% without sufficient information on event adjudication. No randomised trial was performed prior to CE mark approval for any device.

A second systematic review was performed to give an overview of clinical investigations regarding hip and knee arthroplasty implants published in peer-reviewed journals before entry into force of the MDR.6 A random selection of 30 devices from the Orthopaedic Data Evaluation Panel (ODEP) and registry reports from European countries were included between years 1995 and 2021. There were no clinical investigations published in peer reviewed literature for any of the selected devices prior to CE marking and on average, only 5 publications within 20 years of CE marking.

In aggregate the CORE-MD led systematic review of the literature for high risk cardiovascular, orthopaedic and diabetes mellitus devices emphasised major issues with the quality and transparency of evidence in these domains. There was a high degree of variability between quality of clinical evidence from published studies across the same device classes, different device classes and between different medical fields. The quality tended to be limited by small sample size and non-randomised studies without a comparator group or subgroup analyses. Usually publication occurred after CE marking.

What are the key changes introduced by the Medical Device Regulation

Some of the deficiencies in quality and transparency of clinical evidence for high-risk medical devices identified by the systematic reviews discussed above are addressed by the change in legislation under MDR. At a high level, the aim of the medical device regulation was to improve and further standardise processes for the evaluation of medical devices with the goals of balancing access to novel treatments and fostering of innovation against enhancing safety for patients and overall confidence in the regulatory system.

The key changes introduced by MDR may be summarized as follows:

• Stricter pre-market control of high-risk devices

• Strengthening of the requirements for clinical investigations of high risk medical devices prior to their approval

• Establishment of expert panels of clinicians to review clinical evaluation assessment reports of notified bodies

• Enhanced scrutiny and monitoring of the work of notified bodies with requirement for redesignation of each notified body

• Increasing transparency by the development of a central EU database containing information on approved medical devices

• Enhancement of requirement for manufacturers for dedicated post-approval surveillance programmes for certain medical devices

• Improvements in safety reporting and notification of adverse device related events

• Improved device traceability system based on Unique Device Identification (UDI)

Fall out form the introduction of medical devices

The introduction of the new regulation has not been without controversy, and a number of problems in the implementation of the regulation have become apparent.

Firstly, only a small proportion of devices approved under MDD have received recertification under MDR. This has led to concerns that certain devices or groups of devices may disappear from the market, reducing treatment options for patients. The reasons for this are multifactorial but delays in recertification of notified bodies under the new more stringent regulations has played a role. Currently around 45 notified bodies have been redesignated successfully, whereas in the past there were more than 80 in operation.

Secondly, many device manufacturers have claimed that the new processes are overly burdensome in terms of paperwork and that in some cases the amount of clinical data that is required to support an application is unclear. One important development going forward would be the facilitation of an early dialogue process to enable manufacturers to receive direct feedback from regulators and notified bodies in relation to specifics of study design and size for the particular device in question. Such processes would probably result in improved predictability of clinical investigation programs for manufacturers of high risk medical devices, while ensuring that the enhanced safety of patiences, that is the focus of MDR, is not compromised.

Thirdly, it has become clear that specific measures will need to be introduced for certain types of high-risk medical devices used to treat rare or orphan conditions which are frequently encountered in the treatment of paediatric patients. It is extremely challenging to conduct clinical trials in these settings and alternative approaches to clinical evaluation may be necessary in these cases.

What are a doctors’ responsibilities for safety reporting and vigilance Medical practitioners continue to play an important role in the regulation of high-risk medical devices. Clinicians may be involved in some or all of clinical audit, national registry reports or dedicated post-marketing surveillance studies. In Ireland adverse device events should be reported immediately to the responsible local hospital medical device or quality and safety committee, the device manufacturer and the HPRA

(https://www.hpra.ie/homepage/ about-us/report-an-issue).

In recent years concerns about device performance in cardiovascular medicine were frequently first brought to light by individual clinicians or groups of clinicians using devices in daily practice (see case examples) and reporting results of case series or registries at specialty meetings and in the peer-reviewed literature.

Conclusions

The regulation of medical devices has undergone significant change in recent years. The publication of the Medical Device Regulation in 2017 represented the outcome of a root and branch review of the processes in Europe. The regulation became law in 2021 and introduces enhanced scrutiny of the regulation system and higher standards for clinical evidence which is particularly relevant for high-risk medical devices. Doctors continue to play a critical role in medical device vigilance, postmarket surveillance and safety event reporting.

References available on request