EU Devices & Diagnostics Regulatory Outlook to May 2021
What can medtech expect for the rest of 2020 and into 2021, in these unprecedented times? Medtech Insight explores.
Change, change and more change: Is timely compliance with the EU's MDR and IVDR still possible?
One-Stop Shop: EU Devices and Diagnostics Regulatory Outlook through May 2021
What can medtech expect for the rest of 2020 and into the first half of 2021, in these unprecedented times? Medtech Insight explores.
During the first nine months of 2020, politics and pandemic panic heavily influenced the regulatory momentum of the medtech sector. Companies flexible enough and with sufficient resources to adapt to the changing demands and landscape are most likely to weather these storms.
But we are constantly warned that not all will. Many feel battered by constant change and are unprepared. That is especially the case among SMEs, which make up 90-95% of medtech companies.
So where are we now? And how can industry best prepare for eight months until 26 May 2021, the date of full application of the EU Medical Device Regulation (MDR)?
Firstly, it is worth remembering that up until late April this year, the medtech sector was expecting the MDR to fully apply by 26 May 2020.
If that had happened, many in the sector would have experienced problems, some companies even failing to be compliant in time because of the lack of guidance and notified body capacity, and due to the ongoing absence of fundamental elements of the infrastructure, such as the Eudamed medical device database and standards.
The one-year delay to the full application date of the MDR to 26 May 2021 mean the problems foreseen have been averted – for now.
But the big question is whether these problems will be solved by the one-year delay, or whether they will they resurface again next May, when the deadline hits.
EU Regulations: Ever More Complex
The implementation of the MDR and IVDR were always going to be multi-layered and complex. But the COVID-19 pandemic, in addition to the upheaval caused by Brexit and Swixit, are making it even more so. There are many regulatory balls that industry needs to juggle while keeping an eye on unexpected developments. This article aims to summarize how recent events have impacted the outlook for successful compliance with the new regulations on time, and to speculate how they are likely to shape the nine months remaining before the MDR’s full application.
Topics covered are: MDR Delay; Virtual Audit Solution; Virtual MDR Initial Audits; Critical Documents and Planning – Guidance, Implementing Acts; More Documents To Come; The IVDR; Notified Body Developments; Standards Request Rejected; The Eudamed Medical Device Database Delayed; Expert Panels; Persons Responsible for Regulatory Compliance (PRRC) Challenges; Brexit, Swixit and Turkey.
A delay in the full application of the MDR was something industry had long lobbied for. The European industry association, Medtech Europe, was convinced that the sector was not sufficiently ready in the early part of 2020. And it was not alone; even representatives of EU competent authorities and the US Food and Drug Administration had been adding their voice to the plea for extra time. All feared that products essential for health care would have to be pulled from the market on 26 May 2020.
But the European Commission was not convinced by this argument; it continued to make plans based around its original 2020 timetable, confident its program of designating notified bodies and posting MDR guidance documentation would be sufficient for successful – even if not fully complete ̶ implementation to take place on time.
It was not until COVID-19 struck and overwhelmed the devices sector that the priorities and ways of working of medtech stakeholders – authorities, notified bodies and manufacturers, as well as the commission itself ̶ had to shift. At this point, the commission conceded to the need for a one-year delay to the MDR, making the new deadline 26 May 2021. (Also see "EU’s MDR One-Year Delay Now Official As Amending Regulation Is Published In EU Official Journal" - Medtech Insight, 24 Apr, 2020.)
But the postponement is not the solution many had wished it would be. This is for many reasons, including:
- The one-year delay applies only to the MDR and not the IVDR;
- This means that there will be just one year between full application of the MDR on 26 May 2021 and the IVDR on 26 May 2022, putting pressure on those players who have staff working on both, including at authority and even commission level:
- The grace period, which allows many MDR products, and some IVDR products, to remain on the EU market until 26 May 2024 (where compliant with the current medical device directives), has not been extended, meaning the grace period will be three years, instead of four, for products under the MDR and remain two for those under the IVDR. So, auditing under the new regulations will need to be concentrated into less time;
- The Eudamed medical device database, a critical factor in transparency and traceability, is not likely to be fully ready until 26 May 2022;
- Because COVID-19 has resulted in social distancing and travel restrictions, physical audits of notified bodies by designating authorities and physical audits of manufacturers by notified bodies are generally not taking place. This is placing obstacles in the way of notified bodies auditing products against the new MDR and IVDR – and this is likely to remain the status quo for the near- to mid-term too, creating a potential paralysis in certification against the MDR which is only nine months away; and
- Dealing with COVID-19 products is going to continue to be a major feature of notified body work over the near future.
In other words, it was COVID-19 and its challenges that brought about the MDR’s one-year delay. But the problems around trying to address the coronavirus crisis are also the most likely obstacle to the successful full implementation of the MDR next May too.
The EU seems to be on the brink of a possible second wave as cases start to climb rapidly again in many countries, such as France, Germany and Spain, meaning that physical audits of and by notified bodies will continue to be impacted.
Virtual Audit Solution
Indeed, for those new products that must comply with the MDR by 26 May 2021 that cannot benefit from the grace period and that need the involvement of a notified body, EU rules require physical audits.
But these are not taking place generally because of COVID-19 social distancing rules and ongoing travel restrictions around the EU.
There are cases where virtual audits are permitted; but this is mainly for products that are already CE-marked under the MDD as well as for emergency products needed to treat patients with COVID-19.
The European Commission’s Medical Devices Coordination Group (MDCG), which supports the commission with implementation, has issued Guidance 2020-4 on permitting surveillance, recertification audits and audits triggered by changes under the existing medical device directives (the active implantable, medical device and IVD directives) virtual. But it does not really address audits under the MDR, many of which are likely to be initial audits.
This means that timely compliance for a whole swathe of innovative and often high-tech devices will depend on how COVID-19 spreads and on social distancing and travel rules; this is particularly the case because it can take nine months to be assessed and receive conformity assessment by a notified body ̶ and there are only nine months left until the MDR fully applies.
The Grace Period: Which Products Must Comply By 26 May 2021?
For those devices that can benefit from the grace period and whose certificates are up to date or able to be reassessed in time by a notified body under the Medical Devices Directive (MDD), full compliance with the MDR can be delayed up until 2024.
But medical devices that will need to comply by the 26 May 2021 deadline are:
- All class I products that are not being upclassified (although the majority of these do not need the involvement of a notified body);
- Products that fall under the MDR for the first time, such as Annex XVI products that do not have an intended medical purpose (although these may be held up by the lack of common specifications, see below); and
- Products in classes IIa, IIb and III that which undergo “significant changes in the design and intended purpose.”
The vast majority of IVDs, which will require the involvement of a notified body for the first time, will also need to have a conformity assessment certificate from a notified body by 26 May 2022, and not be able to benefit from the grace period and the extension until 26 May 2024.
Virtual MDR Initial Audits
While there are no signs yet of the European Commission extending virtual audits to include initial audits under the MDR, it acknowledges that months of activity have been lost by notified bodies because of COVID-19, so it has put in place a series of measure to monitor device availability to prevent or remedy potential device shortages.
In other words, while the date of application has been delayed for a year, fears over devices suddenly becoming unavailable have not gone away, particularly given the current restrictions on notified body activities caused by the COVID-19 pandemic.
But while the commission is monitoring the situation now and will over coming months, it has not responded to the plea made by industry for MDR virtual audits to be allowed.
This is despite MedTech Europe having issued a position paper stating that the medtech sector will not derive any benefit from the one-year delay because of COVID-19 travel restrictions and social distancing, which have made on-site audits nearly impossible for now.
MedTech Europe says: “This leads to situations where manufacturers who aim to transition to the new regulations as early as possible are currently held back by notified bodies’ assumptions that audits under the MDR/IVDR must be conducted at the manufacturer’s premises, ie on-site…”.
Critical Documents And Planning
Despite the obstacles for the sector in making productive use of the MDR one-year delay, there is some good news. The pace of guidance being published has really stepped up and many more documents are in the wings and due to be published soon.
There are now some 60 guidance documents on the European Commission’s MDR guidance webpage to support the implementation of the MDR, some of which has already been revised.
This guidance, most of which has been endorsed by the European Commission’s Medical Device Coordination Group, supports the interpretation of the MDR with respect to unique device identification (UDI); the Eudamed medical device database (Eudamed); the European Medical Device Nomenclature (EMDN); notified bodies; clinical investigation and evaluation; new technologies; and other topics.
The European Commission also has a page on its website detailing ongoing guidance development within the MDCG subgroups, which was last updated in July 2020. There are 42 items on this list with estimated dates of when the documents will be endorsed by the MDCG.
While manufacturers and other stakeholders are hungry for guidance to better understand how to comply with the new regulations, far more guidance is being produced than had originally been expected. Indeed, when the MDR and IVDR were first drafted – accompanied by much astonishment at how much more detailed they were than the directives ̶, the authorities argued that existing guidance under the medical device directives had been absorbed into the regulations.
But now the need for guidance to explain the regulations has meant that a huge amount of additional guidance has been written, and much more is still being drafted.
The MDR and IVDR foresaw that some of the regulations would need to be explained in subsequent implementing or delegated acts. Drafting these acts is a lengthy procedure. While there are some 80 acts, 12 have been prioritized as needing to be ready by the time the MDR fully applies.
But the only acts that are ready so far are: the Commission Implementing Regulation on the definition of the list of codes and corresponding types of device for specifying the scope of designation of notified bodies, which was adopted and published on 24 November 2017; the Commission Implementing Decision on the designation of one or more entities to operate the system for the assignment of unique device identifiers, published on 7 June 2019; and the more recent Commission Implementing Regulation on Common Specifications (CSs) for the reprocessing of single use devices (SUDs).
More Documents To Come
The European Commission’s MDR/IVDR Roadmap gives an overview of all the work that has been planned under the two regulations, along with a high, medium or low priority grading.
In early July this year, competent authority expert Thomas W. Møller explained how work on a third of the implementation tasks remained to be started. “Of the 165 separate items listed, 50 have been completed, while 47 are ongoing and 68 have not even been started yet,” Møller said at that time. He is section manager of medical devices at the Danish Medicines Agency, and newly elected as chair of the executive board of the EU’s CAMD (Competent Authorities for Medical Devices) group.
Having these 165 activities ready for the 26 May 2021 MDR application date is just not tenable, he told Medtech Insight in summer 2020. “We have grouped these remaining activities as ‘necessary, important, or nice to have,’ to create a prioritized list moving forward towards the implementation date,” he said at that time. (Also see "Competent Authorities Warn EU Industry Not To Expect All MDR Implementation Tools In Time" - Medtech Insight, 2 Jul, 2020.)
The late timelines will be particularly tight for the much-needed common specifications, detailed technical requirements, which are being developed, among other products, for medical devices without a medical purpose, known as the Annex XVI products. Annex XVI products include dermal fillers, liposuction equipment, breast implants, skin resurfacing equipment and brain stimulation products.
This means that these products, which are being regulated for the first time at EU level, may struggle to be compliant by 26 May 2021. Many of these products are coming under regulatory control for the first time as they are not regulated nationally, so any delays leave patients exposed to risks that the commission, European Parliament and Council of the EU were keen to avoid by regulating these products under the MDR.
The expected timelines for other much needed documents under the MDR and IVDR is being continually updated in the European Commission’s MDR rolling plan which is available via its website.
The expected publication date of implementing acts with the highest priority are as follows:
Description of Implementing Act
Common specifications (CSs) for products without a medical purpose
CSs for groups of products listed in Annex XVI of the MDR, which address application of risk management and, where necessary, clinical evaluation regarding safety. Manufacturers of these products cannot apply for conformity assessment review until these CSs are adopted
Setting up of expert laboratories
Designation of expert laboratories; the designation of expert laboratories is not mandatory
CSs for IVD Class D
CSs for IVD Class D in the context of the scrutiny mechanism for high risk devices
Rules for EU reference laboratories (EURL)
Rules to facilitate application of IVDR EURL tasks. Date of application of the act may not be earlier than 25 November 2020, according to the IVDR
Fees for EURL services
Definition of rules for fees for the advice/testing activities performed by EURL. Date of application of the act may not be earlier than 25 November 2020 according to IVDR
EU reference laboratories
Designation of EU reference laboratories. Designation may take place no earlier than 25 November 2020. Nominations are in preparation
Although medical devices and IVDs are being regulated under the same broad framework, the sectors have their own EU regulation because of the differences in the nature of the products and, therefore, require different approaches.
So, while many of the problems that are besetting the medical device industry which needs to comply with the MDR are also impacting the IVD industry, the IVD industry has its own challenges in ensuring it is compliant by the IVDR full application deadline of 26 May 2022. The scale of these is particularly great and there is growing concern among experts in the industry that the IVD industry is slow to understand the urgency with which it needs to begin compliance activities:
These are the some of the issues the IVD industry is facing:
- There has been no delay to the full date of application to the IVDR; it will now follow merely a year after the 26 May 2021 full application date of the MDR;
- Some 85-90% of IVDs do not need the involvement currently of a notified body under the EU IVD Directive. But under the IVDR, about 85-90% will, meaning a steep learning curve for manufacturers and notified bodies alike and considerably more work;
- Given that 85-90% of IVDs will need to involve a notified body for the first time, these products will not be eligible to benefit from the grace period, which is two years for products under the IVDR where it applies; and
- IVDs will be subject to performance evaluation for the first time, the IVDR equivalent of clinical evaluation under the MDR.
As there has been a one-year delay to the date of full application of the MDR, the IVD industry is still hopeful that it will benefit from the same kind of delay. It is also lobbying for a greater number of IVDs to be able to benefit from the grace period.
It is encouraged by the recent concession granted by the European Commission to class I upclassified medical devices under the MDR, which were latterly included in the list of products have been able, latterly, to benefit from this grace period in addition to other products already listed in the original regulation.
Readers can expect strong lobbying to continue, in a bid to seek a “stay of execution” for these products.
COVID-19 has had an enormous impact on many manufacturers’ ability to transition to the IVDR according to their original plans and timelines Some companies who were as ready as they could have been at this stage in terms of IVDR compliance have had plans their heavily impacted. This might have been, for example, because audits cannot go ahead with their notified body or because they were expecting their notified body to be designated under the IVDR this year and the timeframes are no longer clear.
Many IVD manufacturers now have clinical studies on pause too, because of COVID-19, and some estimates suggest it could be nine months before they can restart them. This obviously delays when they can file for conformity assessment.
MedTech Europe is also frustrated that the EU chose not to opt for the possibility of pan-European derogations from the need for full conformity assessment procedures for IVDs intended to help in the COVID-19 pandemic as well as for medical devices, within the amending regulation. This means that manufacturers must seek national derogations in every member state where their product is to be marketed and this could cause them to prioritize the bigger markets.
Notified Body Developments
As of mid-August, there were now 20 notified body designations in total, 16 under the MDR and four under the IVDR. These include two designations for BSI UK ̶ under the MDR and the IVDR. BSI is due to lose its designation status on 31 December at the end of the EU/UK Brexit withdrawal period, which means just 18 of the current designations will remain valid from the beginning of next year.
The hope is that there will be more designations in the meantime. But notified bodies cannot even begin testing under the MDR and IVDR before they are designated, so each day of delay could further threaten their ability to finalize the conformity assessment of MDR products before the 26 May 2021 deadline. There are, of course, many other factors that are compromising the likelihood of timely compliance (for example the appointment of expert panels in the case of higher risk products).
The figure of 20 notified bodies under the MDR and IVDR compares with over 80 designations under the Medical Devices Directive at its height (there are 54 now), and 22 under the IVD Directive.
The European Commission had originally promised 20 designations under the MDR and IVDR by the end of 2019. But it has defended its record by stating that the larger notified bodies were among the first designated and therefore there has not been the kind of capacity issue shortfall at notified bodies that such a number would suggest.
But industry said its own experience suggests otherwise.
It is also noteworthy that there are already six notified bodies based in Germany that have been designated against the MDR and three in the Netherlands. But no other country has more than one designation.
Questions arise over whether there is likely to be a hiatus now in the nomination of notified bodies designated under the MDR and IVDR due to COVID-19 and due to the challenges for joint assessment teams to carry out audits of notified bodies at a time when social distancing is enforced.
Sources close to the commission told Medtech Insight that the majority of current applications have passed the on-site assessment stage, as is indicated in the information on state of play of the designation process presented recently to the European Commission’s Medical Device Coordination Group (MDCG) and stakeholders.
In other words, although the travel restrictions imposed as a result of the pandemic have had an impact on the scheduling of on-site assessments relating to the receipt of new preliminary assessment reports (PARS) since the outbreak, the subsequent steps of the designation process, for example, the review of the corrective and preventive action (CAPA) plans, notification and designation, have not been affected, and continue to progress.
Standards Request Rejected
In yet more news about delays in the infrastructure that is critical to the full implementation of the MDR and IVDR, late June saw the European standards bodies CEN and CELENEC reject the European Commission’s already late standards request.
The existing standards under the current medical device directives need to be aligned with the new regulations so that industry can cite compliance with the updated standards as evidence that it should be in compliance with the General Safety and Performance Requirements (the MDR equivalent of the MDD’s Essential Requirements).
It looks unlikely that a new standards request will be presented to CEN and CENELEC before the first quarter of next year, meaning that one of the cornerstones of the new EU medical device regulations will simply not be ready on time.
EU medtech industry association MedTech Europe was already pre-empting the lack of availability of standards earlier this year, and has come up with a pragmatic way forward based around existing standards.
But with nothing yet official, industry is effectively in a legal limbo.
The Eudamed Medical Device Database Delayed
The new version of the European medical device database, Eudamed 3, is being designed to support the implementation of the MDR and IVDR and has six main modules: actor registration; unique device identification (UDI)/device certificate registration; notified body certificates; clinical investigations; market surveillance; and vigilance.
It is a cornerstone of the new MDR and IVDR, providing critical transparency and traceability. Its six main modules are interlinked and will provide an unprecedented oversight of which products are on the EU market where, how they are performing and how safe they are.
While Eudamed 3 was intended for launch at the same time as the full application of the MDR, the database has been beset by the type of delay that was predicted by many experts who cite historic problems with the vast majority of EU databases developed by the European Commission..
The database is now due to go live in its entirety in May 2022. The notice to trigger the go-live will be published in 2022, after a positive independent audit to assess that Eudamed has achieved full functionality and meets the functional specifications..
After much debate over whether individual modules of the database could go live before the database goes live in its entirety, the commission has now agreed that from 1 December this year, medtech manufacturers should be able to register – voluntarily ̶ in the actor registration module.
Authorized representatives, importers, and system/procedure pack producers will also be able to register from that date. The Single Registration Numbers (SRNs), which each Eudamed user must have, are also due to be available by then to support registration.
So now, an important document to look out for during the third quarter of this year is an implementing act providing detailed arrangements for setting up and maintaining Eudamed 3, as well as news on other modules going live early.
July saw progress, at last, on the appointment of members to the expert panels, with the aim of nominations being made public by the end of July.
These panels need to be in place for notified bodies to be able to complete conformity assessment of certain high-risk devices.
These panels have a variety of roles in supporting the more technical and product-specific aspects of implementation, and need to be in place for notified bodies to be able to complete conformity assessment of certain high-risk devices by performing a review of the notified body clinical evaluation consultation procedure (under the MDR) and performance evaluation consultation procedure (under the IVDR) for certain high-risk devices, namely class III implantables and class IIb active devices intended to administer and/or remove a medicinal product and Class D IVDs under the IVDR.
The next step will be to establish expert panels for the MDR’s clinical evaluation consultation procedure and IVDR’s performance evaluation consultation procedure.
Notified bodies that assess class III implantables and class IIb active devices intended to administer and/or remove a medicinal product should, except in certain cases, be obliged to request expert panels to scrutinize their clinical evaluation assessment reports and submit an opinion on them.
The process, known as the Clinical Evaluation Consultation Procedure (CECP), in the case of the MDR, can take up to 60 days, and must happen before notified bodies are able certify new products as conforming to EU requirements.
Because of the delays in setting up the expert panels, there will now be a build-up of applications for clinical evaluation of these innovative devices.
It could therefore take some considerable time before certificates are issued, especially because notified bodies’ auditing activities are being hampered by social distancing and travel restrictions and they are only able to conduct virtual audits.
Guidance so far states that initial audits should generally not be carried out virtually but should be conducted in person. (Also see "Manufacturers That Are Nearly MDR-Ready May Lose Their Advantage Unless Audits Can Take Place Virtually" - Medtech Insight, 7 May, 2020.)
The challenges inherent in the new role, under the MDR and IVDR, of the Person Responsible for Regulatory Compliance (PRRC) meant that the launch of a not-for-profit European association representing those taking on this role in June attracted a high level of interest.
The MDR and IVDR require that the supervision and control of the manufacture and the post-market surveillance and vigilance activities of medical devices are carried out within the manufacturer’s organization, and also at the level of authorized representatives and importers, by a PRRC, who, among other things, oversees manufacturing.
With many unknowns regarding new this role, a new association, TEAM-PRRC, has taken on the remit of supporting its members by analyzing available relevant requirements and guidance and trying to influence related developments. It aims to promote greater security of the PRRC professionals themselves, given that the function carries considerable responsibility and potentially weighty personal liability.
Brexit, Swixit and Turkey
It is already clear that the medtech sector has some very big technical and political challenges ahead and is swimming in uncertainty and in urgent need of greater clarity.
But the political situations between the UK and the EU and between Switzerland and the EU, as well as Turkey and the EU, have made implementation of the MDR and IVDR even more complex.
The UK’s future regulatory pathway was still under discussion up until Medtech Insight was going to press and a new announcement was made. This meant that it had been unknown whether the UK would essentially continue to falling into line with EU rules after 31 December and the end of the EU/UK Brexit withdrawal period, or whether it would choose to apply its own rules or even associate itself with the rules of a different market, like the US, for example.
At last there are more clues about how the UK will move forward. The latest news, just published by the UK regulator, the Medicines and Healthcare products Regulatory Agency (MHRA), is that the UK will continue to use and recognize the CE marking for medical devices and IVDs until 30 June 2023. Certificates issued by notified bodies based in the European Economic Area will, therefore, continue to be recognized in the UK until that date.
This puts an end to the previous UK position, and to concerns that if the UK still leaves the EU with at the end of the year with no deal that EU notified bodies and their certificates would no longer be recognized in the UK.
Ironically, this would have included the only remaining UK notified body, BSI UK.
This will be a welcome reprieve for BSI, although it had already set up a Dutch notified body to which most BSI UK medtech and IVD certificates have been transferred. BSI Netherlands is designated against the medical device directives and the MDR and IVDR. BSI UK had been among the first of the EU notified bodies to be designated under the MDR and the IVDR.
Also announced by the MHRA is that there will be a new UK regulatory pathway and product marking from 1 January 2021 for products being placed on the UK market for those that wish to use it. This will be enforced from 1 July 2023, when companies will have to meet new UK requirements and place a UKCA mark on devices launched in Great Britain. (Also see "UKCA Mark Will Be The Post-EU Route To The British Medtech Market In January 2021" - Medtech Insight, 2 Sep, 2020.)
This means that there will be new rules that industry will be able to choose to comply with, and these are still under discussion in the context of the UK's Medicines and Medical Devices Bill.
From 1 January 2021, the MHRA will be able to designate UK conformity assessment bodies (CABs) to conduct assessments against UK requirements for the purpose of the UKCA mark. UK notified bodies, known as "Approved Bodies," with designations under the MDD, IVDD or AIMDD, will have their designations rolled over automatically, without having to undergo a new designation process.
Switzerland, meanwhile, is still trying to work out the basis for its future relationship with the EU, and indeed the UK. It currently has one notified body, SQS ̶ Schweizerische Vereinigung für Qualitäts- und Managementsysteme, designated under the MDD (although none under the IVD Directive), and no new Swiss notified bodies are expected to be designated under the new EU regulations until the Swiss-EU mutual recognition agreement is finalized.
And, because of a similar political issues, no Turkish organization can apply to be a notified body under the MDR or IVDR until the Turkish customs agreement has been signed. This is a potentially big hit to notified body numbers, as Turkey has five notified bodies under the MDD and one under the IVDD but none can be designated under the IVDR or the MDR until the Turkish customs agreement is finalized.
So, in conclusion, the next eight months are critical for the medtech sector. Is this a time when as many obstacles as possible are going to be removed so that the sector can focus whole-heartedly on compliance, rather than on the politics and uncertainties?
Or are we now at a stage where deadlines are going to need to be continually put back while COVID-19 wreaks havoc on the industry?
EU Post-Market Clinical Follow Up
What Manufacturers Need To Know
EU Post-Market Clinical Follow Up: What Manufacturers Need to Know
The EU's new medtech regulations introduce much more comprehensive post-market clinical follow-up requirements for device and diagnostics companies. What do they entail, and why are there problems in understanding what will be required? Consultant Sarah Sorrel offers insights in an interview with Medtech Insight.
Post-market clinical follow-up (PMCF) is a relatively new requirement for the EU medtech sector. It is detailed for the first time in the EU's new Medical Device and IVD Regulations.
Sarah Sorrel, MedPass International
In this interview, Sarah Sorrel, a leading EU expert and consultant on clinical data issues, discusses with Medtech Insight what PMCF will entail. Sorrel, president of MedPass International, also addresses how slow implementation of the new regulations is making it difficult for manufacturers to put post-market plans into place and to leverage the potential value of PMCF to help obtain recertification of devices under the new regulations.
MedTech Insight: To what extent is post-market clinical follow-up required under the MDR and how does this compare to what is currently required under the EU directives?
Sarah Sorrel: Without the delegating acts, it is not entirely clear when PMCF will be mandatory under the MDR. This is a problem for manufacturers who need to plan now and to decide whether the cost of PMCF would warrant taking certain products off the market in view of the increased cost of compliance.
There is a new safety reporting requirement for all devices (except class I) called the Periodic Safety Update Report, PSUR. The PSURs are required at least every year for class III devices and class IIb implantables and at least every two years for class IIa devices and class IIb non-implantables. According to the regulation, the PSUR is based on the PMCF, so in theory a PMCF would be required for all of these classes of device. On the other hand, elsewhere in the regulation, it is stated that some products can be exempt from PMCF if duly justified. Clarification is needed urgently to address this apparent contradiction.
It is important to note, however, that the requirement for PMCF under MDR does not necessarily mean that clinical studies will be required in all cases to collect clinical data, which is what is currently understood as PMCF under the current directives due to the wording in the meddev guidance document. Under the MDR, the definition is much broader and relates to all types of clinical information. PMCF under the regulations is much broader and includes any clinical information, such as vigilance, complaints, technical information and publicly available information whereas PMCF under the directives is very much focused on PMCF studies and clinical data. It is important to understand this difference especially in the context of lower classes of devices. Indeed, it is vital to take in this distinction as it can make communication difficult if people do not understand the semantic differences.
The notion of PMCF was first introduced in the guidance document on post market clinical follow-up studies meddev 2.12 rev 2 and this is the background for how it was introduced in the context of the directives.
What The EU MDR Says
"PMCF shall be understood to be a continuous process that updates the clinical evaluation … and shall be addressed in the manufacturer's post-market surveillance plan. When conducting PMCF, the manufacturer shall proactively collect and evaluate clinical data … 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 on the basis of factual evidence."
Is there an equivalent requirement to PMCF for IVD products under the IVDR?
Sorrel: Yes, the IVDR introduces the notion of clinical evidence based on clinical performance. It is referred to as post-market performance follow-up, PMPF. In the case of IVDs, PMPF studies are usually only needed in the case of novel products because for most other IVDs, clinical performance can be established through analytical testing and literature reviews.
What happens if a company has a legacy product. Does it need to perform PMCF?
Sorrel: A legacy product is one that will have been on the market for a long time. It is typically one that has been CE marked based on the market history of the product and on equivalence to other similar products. This creates problems under the MDR, especially in the case of the higher-risk class III and class IIb implantables because when manufacturers recertify their products under the MDR, they need to present "sufficient" clinical evidence. The problem is that we do not know what constitutes "sufficient" clinical evidence. The Clinical Investigation and Evaluation (CIE) working group is working on guidance to explain this term and it could not be ready soon enough. Information that is obtained through what would effectively now constitute PMCF is critically useful in such cases. For legacy products, manufacturers must search for all data on their products and weigh up and see if it meets the MDR requirements for sufficient clinical evidence. This means that they will need to do an inventory as soon as possible of whatever clinical data is available on their device. This could come, for example, from national registries of implants, investigator reports, sponsored studies, other clinical studies performed on the product in other geographic jurisdictions. Once they have this, they need to do a gap analysis between what clinical data they have and what is needed and then put into place a PMCF study.
"This creates problems under the MDR, especially in the case of the higher-risk class III and class IIb implantables because when manufacturers recertify their products under the MDR, they need to present "sufficient" clinical evidence. The problem is that we do not know what constitutes "sufficient" clinical evidence."
Are there any clear exceptions to these PMCF requirements for any products?
Sorrel: It is important to point out that PMCF is very much related to risk and the biggest challenges are for the highest risk class III and IIb implantables. But there is a whole group of class IIb implantables, known as "well-established technologies" that are listed as exempt from clinical investigation for CE marking under the MDR, and therefore presumably from PMCF. These are sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips or connectors for which the clinical evaluation is based on sufficient clinical data and is in compliance with the relevant product-specific common specifications, where such a CS is available (Article 61). But, then again, there is an issue with what is “sufficient clinical evidence.” The MDR says that the European Commission will adopt delegated acts to amend the list in Article 61 so we can hope that the Commission will be realistic and extend this list to the maximum. But it is difficult for companies to move forward while this list is not complete, while the common specifications are not yet available, and we have no idea of the timing when these will be ready.
What type of studies can be considered for PMCF? Can off-label use in the post-market phase be used to extend indications?
Sorrel: Many manufacturers are very keen to use off-label use of products in their clinical data but this is totally excluded. Indeed, off-label use is banned in both the directives and the MDR and under the MDR one specific goal of PMCF is listed as detecting off-label use. So, if a company believes there is merit in what they have witnessed in unregulated off-label use, then it needs to do a pre-market investigation to obtain relevant clinical data and its study must be designed to meet the objectives of the PMCF plan too.
What about investigator-sponsored studies?
Sorrel: The most important thing is that a study is properly designed to collect the clinical information that is needed. When it comes to investigator-sponsored studies, one of the difficulties is that the sponsor, or manufacturer, may not necessarily be in control of how the study is being run, exactly what is being done and if the product is being used correctly. Such studies are therefore hazardous for the manufacturer as they may not result in the appropriate basis for producing valid data, and this would be particularly risky in the case of data being produced for class III or class IIb implantable devices, which had already been CE marked under the directives based on equivalence and not on clinical data produced by the manufacturer. We have already heard of one notified body refusing the data from an investigator-sponsored study as it was not conducted in strict compliance with the international clinical investigations standard, ISO 14155.
What happens if a company has a novel product that was approved on equivalence? Is PMCF required?
Sorrel: A PMCF study, sponsored by the manufacturer, is required for a novel product that was CE marked based on clinical data from an “equivalent” device. Manufacturers should be aware that the clinical data from the PMCF study in such cases will be crucial to ensuring that the product can be recertified under the MDR without further clinical data. This is particularly critical for class III and IIb products which may be subject to the added need for "scrutiny" of the clinical data by experts appointed by the European Commission, another factor to bear in mind is what will be needed to pass this scrutiny. But there is not enough information yet. We don't know what sort of a trial design and what end-points are needed where products are subject to scrutiny nor how to get validation for a study for a novel product for such cases. This will all be down to the what is decided by the European Commission's Medical Device Expert Group. But this group was only recently set up and has not produced any such information yet – although more clarity is expected by the time the MDR is in full effect. There is a particularly urgent need for this information since it takes a long time to design, gain approval and implement a clinical study. Indeed, this entire process can take from six to nine months or more.
"We don't know what sort of a trial design and what end-points are needed where products are subject to scrutiny nor how to get validation for a study for a novel product for such cases. This will all be down to the what is decided by the European Commission's Medical Device Expert Group."
What do companies need now to help them prepare for PMCF/PMPF ie forms, guidance, implementing acts, Eudamed? How far can they prepare for compliance without these being available?
Sorrel: For medical devices, the latest European Commission guidance document on clinical evaluations, Meddev 2.7/1 rev 4, goes about 80% of the way toward helping companies understand clinical data requirements of the Medical Devices Regulation, so manufacturers can make extensive use of this document in their preparation. But they need to be aware that the key item that is missing is an explanation of what is "sufficient clinical evidence". For IVDs however, there is no similar guidance at all under the current regulations The best advice is for manufacturers to read the new regulations, reassess all their clinical data in the light of these, and then identify any gaps which might be filled now under PMS or PMCF.
PMCF is one aspect of monitoring safety of devices in the post-market phase. How does this feed into the requirements for periodic updates to Clinical Evaluation Reports and Periodic Safety Update Reports (PSURs)?
Sorrel: The results of PMCF under the MDR are an input into the PSUR, which also includes a re-evaluation of the risk-benefit profile of the device and the volume of sales. This sales volume puts into perspective the accuracy of the risk-benefit evaluation. We would advise having a clinical expert review and sign off on PSURs as this is a key document demonstrating compliance with the regulations and which also must be made public on the EUDAMED database.
Differences in Clinical Evaluations and Investigations under the EU MDR
Differences in Clinical Evaluations and Investigations under the EU MDR
EU MDR COMPARED TO THE EU MDD
The EU MDR officially replaces the Active Implantable Medical Device Directive  and the Medical Device Directive  for medical devices. The EU MDR has a key objective of ensuring health and safety of EU citizens by making the medical device regulation more stringent with respect to the requirements for clinical investigation and evaluation. The definition (Article 2 EU MDR ) regarding the term ‘medical device’ has been modified in the EU MDR as against the definition in the MDD. For example, terminologies such as the Unique Device Identifier (Definition 15), clinical data (Definition 48), clinical evidence (Definition 51), and serious incident (Definition 65) have been affected by the changes in the EU MDR. Clinical evaluation for medical devices is necessary to receive a CE mark which is imperative to market medical devices in the European Economic Area.
In the MDD, there was a single article, Article 15, covering the theme of “clinical Investigation”, which is now replaced by 20 articles in Chapter VI (articles 62-82). In the EU MDR, the requirements are addressed to the “Sponsor”, and not the “Manufacturer” as in the MDD. While MDD lays down the requirement to “notify” the regulatory authorities of an intention to perform a clinical investigation, it has been replaced by the requirement to submit an application to conduct a clinical investigation in the EU MDR. For devices with a ‘low risk’, the sponsor can proceed with the clinical investigation if the application is not refused and therefore, the EU MDR is not likely to cause delays, at least for the low risk devices.
With the EU MDR, it is the manufacturer who determines the level of clinical evidence that is required, based on the characteristics and intended purpose of the medical device. The manufacturer should identify and appraise all available clinical data to establish sufficiency and only in cases where the available data is insufficient, a clinical investigation needs to be planned to address the gaps in data.
Clinical investigations are a must for implantable and class III devices, but the legislation makes it possible that in specific cases, the requirement to conduct clinical investigation can be exempted.
The transition from MDD to EU MDR affects multiple evaluation procedures of medical devices and the impact on clinical evaluation is important with respect to the following points:
1. Scrutiny Process
The regulatory authorities have the say in the re-review process of the technical documentation of high-risk devices prior to approval as per the EU MDR. In accordance with Article 44, they must submit new technical review reports. The procedure may result in extension of submission timelines due to the additional requirements. Clinical Evaluation Reports (CER) need to be reassessed considering limitations on equivalent devices, and the state of the art, and updated to withstand a higher level of scrutiny at the NB level and by the competent authorities. Updates to CERs may also trigger updates to ‘Instructions for Use’ requiring an alignment on the part of the manufacturer.
2. Reclassification of Medical Devices
Under the EU MDR, medical devices may be reclassified, which is expected to be largely based on the clinical evaluation data. The MDD classification is based on associated risk i.e. Class I (low risk) to Class Active Implantable Medical Devices (AIMD) (implanted cardiac pacemakers). Transition to the EU MDR may require that the in vitro diagnostic devices under a general classification (not subject to Notified Body (NB) approval) may be reclassified to Annex II List A (requiring NB approval and additional audits and reviews). Evaluation of all class A devices will also require the approval of the NB.
Classification to a higher risk category: devices such as in vitro fertilization diagnostics, spinal devices, and AIMDs will be reclassified as Class III devices or a software deemed as Class IIa “devices”.
3. Comparative Evaluations
As per the EU MDR, comparative evaluations between medical devices is expected to be more stringent as against the MDD. Extra data requirements for establishment of product safety and performance need to be considered while planning clinical investigations. This will also involve a rigorous interpretation of the data from comparative evaluations. Furthermore, data requirements also state that the use of data from a comparator will require an approval from the manufacturer of the comparator device.
4. Introduction of the New Clinical Evaluation Consultation Procedure with Respect to Class III and Class IIB Devices
The EU MDR introduces a clinical evaluation consultation procedure, which will be coordinated by an independent expert panel and shall be based on the clinical evaluation assessment report of the NB (Article 54). Annex I specifies the general safety and performance requirements, while Annexes II and III specify the makeup of the technical documentation.
5. Redefining the Scope of the Quality Management System (QMS)
As per Article 10 paragraph 9 of the EU MDR, the QMS system for medical devices will also include the clinical evaluation and post-marketing clinical follow-up (PMCF). Additionally, there is a requirement for a clinical evaluation plan, which must precede the clinical evaluation as per Annex XIV, Part A of the EU MDR.
6. Reinforcement of the Requirement for Clinical Evaluations
As per Chapter VI of the EU MDR, additional requirements for clinical investigations form one of the major group of changes in the EU MDR in comparison to the MDD.
Similar to the MDD, it includes collation of already available clinical data from the literature studies, and setting up of any additional, necessary clinical investigations. The concept of equivalence with other device-existing clinical data is still possible, but only in a limited number of cases and under more stringent conditions as per Article 61 paragraphs 4, 5 and 6. More specifically, Article 62 and Annex XV lay out the precise conditions for clinical investigations. Especially with respect to implantable Class III medical devices, all devices must go through clinical investigations with only some exceptions.
For all Class III devices, and for Class IIb devices intended to administer a medicinal product, the manufacturer has the option to consult a group of European experts to review its intended clinical development strategy (Article 61 paragraph 2). For the devices placed on the market in sterile condition, clinical evaluations may be required for aspects covering the establishing of sterile conditions, securing and maintaining sterile conditions.
7. Requirement of a ‘Summary of Safety and Clinical Performance’
As per Article 32 of the EU MDR, manufacturers of Class III and implantable devices will have to produce a summary of the safety and clinical performance of the concerned device in a form that is understandable for the intended users/patients, where applicable, and this summary has to be a part of the technical documentation sent to the NB.
8. Obligations for Manufacturers
The EU MDR requires medical device manufacturers to have the risk (paragraph 2) and quality management (paragraph 9) systems in place; to conduct clinical evaluations (paragraph 3); compile technical documentation (paragraph 4); and apply a conformity assessment procedure (paragraph 6). Manufacturers will also be liable for the medical devices once the devices are placed on the market (paragraphs 12, 13, 14). Furthermore, in light of the scandals affecting the medical device industry in recent past, the device manufacturers will also have to have systems in place to cover their financial responsibility for harm caused by defective devices (paragraph 16). The EU MDR, will require Notified Bodies (NBs) (Chapter IV) to be designated and meet stringent criteria, especially with respect to clinical competence. A database for all NBs (NANDO) is also enlisted. A manufacturer must verify if the NB concerned with its medical device is designated under the EU MDR. It is also necessary to start working early with the NB to plan the timing of certification for the product portfolio considering factors such as the availability of the NB and the requirement for additional data on devices.
Conformity assessment for CE marking depends on the risk class and specific features of devices and NB intervention is needed for all Class IIa, IIb and III devices, as well as some specific Class I devices and may need planning with respect to the timelines.
9. Post Market Clinical Follow-Up
The EU MDR requires an update on all clinical evidence for existing medical devices which has to be made publicly available. Additionally, CERs and summaries of safety and clinical performance for implantable devices and Class III devices should be updated at least once every year. The frequency of CER updates must be justified by the manufacturer considering factors such as risks involved, scientific developments, and design changes.
UNDERSTANDING WHAT COMPETENT AUTHORITIES AND NOTIFIED BODIES ARE LOOKING FOR
The rationale behind the EU MDR is to make medical devices safe for the general public, while enhancing the traceability and transparency in the EU. While generation of clinical evidence for medical devices is not new, under the MDD, lower risk devices were required to have CERs and higher risk devices needed clinical data. CERs are still required but with changes to content requirements and acceptability conditions with the MDR (EU MDR Annex XIV, Part A). Additionally, a public summary of safety and clinical performance is required, as per the MDR, for certain types and classes of devices. This summary is to be prepared considering the therapeutic/diagnostic options addressed in the CER and available alternatives. Class III and implantable devices should have clinical data from clinical investigations conducted under the supervision of a sponsor.
NBs now must provide a clinical evaluation assessment report (CEAR), which will be subject to a mandatory analysis by an “expert panel”. The Competent Authorities expect to be notified of any device receiving a certificate post-conformity assessment involving an expert panel, to develop Common Specifications for higher risk devices.
NBs will have a higher level of oversight and scrutiny and therefore, CERs must be reassessed considering limitations on equivalent devices and state of the art. CERs should be updated to meet the higher level of scrutiny from the NBs. Updates to CERs may also trigger updates to the ‘Instructions for Use’. It is also expected of the manufacturer to have an integrated program incorporating the risks in the labeling in order to limit the number of reportable events. Events need to be reported if they are not identified as a ‘known risk’ in the concerned device. The reporting timeline has also been reduced to 15 days.
EXAMINING THE INTERPRETATION AND DEFINITION OF “SUFFICIENT CLINICAL EVIDENCE”
The EU MDR mentions a term ‘sufficient clinical evidence’, but there is no specific definition or the extent to which data will be expected to meet this criterion. There is no ‘one solution fits all’ when it comes to this criterion, and each device must be investigated independently to satisfy the requirement for ‘sufficient clinical evidence’ expected on the manufacturer’s behalf.
As each device has a different predefined intended use, target populations, performance, safety profile, and claims, all these factors affect the quantity and quality of clinical evidence required to meet the criteria of sufficiency.
The definition of “sufficient clinical evidence” can be found in the guidance document on clinical evidence as per MEDDEV 2.7/1, revision 4, page 8, which states that sufficient clinical evidence: an amount and quality of clinical evidence to guarantee the scientific validity of the conclusions . The definition is derived from the evidence-based medicine and is based on the following characteristics:
The data collated should be enough data to support the performance and safety requirements for a medical device. The quantity of data required may be different to establish the aspects related to performance and safety respectively. Furthermore, it can be interpreted that the CER should justify the quantity of data presented for the performance and safety of a medical device. The quantity aspects cover questions related to the sample size chosen for the clinical evidence generation, evaluation of rare adverse events, conducting meta-analysis, and statistically relevant safety and performance analysis when patient subgroups are involved.
The quality of clinical data presented in the CER must be as per the acceptable clinical standards (ISO 14155), ethical standards (Declaration of Helsinki), and in accordance with the region that the clinical data is produced. Quality aspects cover questions related to the design of the clinical trial, relevance to the selected patient population, the intended use, risk of bias, trial execution and any ethical concerns.
3. GUARANTEE SCIENTIFIC VALIDITY OF CLINICAL EVIDENCE:
Considering dealing with statistical probabilities to derive a conclusion of a clinical evidence, the design, data analysis and data interpretation of clinical evidence for a specific medical device, statistical analysis must validate the available clinical evidence.
CER should include inputs from risk analysis, claims, state of the art, PMS data, sales data (e.g., experience on the market) etc. If there is no alignment between clinical performance claim and the available clinical evidence, it generates a gap in the CER that must be compensated with additional data or may require a change in the ‘claims’ statement.
ASSESSING THE REQUIREMENTS FOR LEGACY DEVICES UNDER THE MDR
Once the EU MDR is fully implemented, it is likely to affect reclassification of several medical devices across all classes. It is important for the manufacturers to determine if this reclassification will impact their device, as it could trigger a requirement for additional preparation and allocation of resources to demonstrate compliance with MDR for already approved devices. Medical devices that are reclassified to a higher class will require a detailed review by the NBs, and therefore, may extend the timelines to achieve the necessary additional conformity assessment procedures. Reclassified devices will also have to undergo a higher level of scrutiny with respect to the available clinical data review by the NB (also applicable to implantable devices without any changes to the class level). Reclassification to a higher class is likely to affect implants in the orthopedic space, and active therapeutic devices, such as automated external defibrillators among others. The MDR also lays down the classification rules for software and devices incorporating nanotechnology.
While it is possible to place devices on the market that are compliant with the MDR before the end of the transitional period, devices subject to the “clinical evaluation consultation procedure“, or those reclassified into Classes IIb and III, may not be placed on the market before the Medical Device Coordination Group (MDCG) and the expert panels have been established.
EVALUATING AND RATIONALIZING PRODUCT PORTFOLIOS
When the EU MDR is fully implemented, the device manufacturer must have a comprehensive plan to ensure the maintenance of its CE marked devices in accordance with the full requirements of the EU MDR. It is practical to consider the products in the development pipeline for compliance with the EU MDR, as this review can provide an opportunity to rationalize the product portfolio and possibly eliminate marginal products from the portfolio.
Portfolio review and assessment needs to be critically evaluated by the manufacturer against the requirements of the EU MDR. The manufacturer clearly needs to assess which products will be affected by reclassification and therefore attract a higher scrutiny from the NBs. For example, a product previously classified as an accessory may as well be classified as a medical device as per EU MDR. Others may be reclassified to a higher risk category and may require clinical evidence generation. The EU MDR also provides a huge opportunity to assess the impact of EU MDR on the need to redesign the product or develop a new manufacturing process. The manufacturer can also negotiate new supplier agreements and evaluate the opportunities to diversify its portfolio through acquisitions to meet the demands of the EU MDR.
KEY CHALLENGES AND OPPORTUNITIES WITH THE NEW CLINICAL REQUIREMENTS
The EU MDR poses several challenges and provides a great opportunity to reform the medical device industry in the EU. Challenges are expected in the transitional phases when the NBs will be required to undergo the process of recertification and retraining of personnel. From the manufacturer’s point of view, the kind of clinical evidence to be generated which requires the definition of ‘sufficient’ remains one of the toughest challenges. As the generation of ‘sufficient clinical evidence’ will require an assessment by a clinical expert (i.e. a medical doctor), the manufacturer will need to consider consulting with experts in the field. The same level of expertise will also be required from the NBs and the competent authorities.
The evaluation procedure for clinical evidence in the EU MDR involves a 3-tier process with the following steps:
The clinical evaluation team of the manufacturer, who prepares the CER.
The clinical expert team performing the evaluation at the NB level.
The clinical expert panels advising the Competent Authority.
Evidently, the evaluation process can be nonhomogeneous, and the same device analyzed by 2 different groups of clinical experts can lead to different outcomes. It is important to address this issue across tier levels such that the terms used to evaluate clinical evidence are harmonized across tiers. The EU MDR places the burden of classification of medical devices on the manufacturer who then must evaluate the regulations and understand its impact on their portfolio.
As NBs must apply for designation under the MDR, the process can be time consuming, increasing the risk that NBs currently designated under the MDD may not achieve designation under the EU MDR, restricting their capacity to create backlogs towards the end of the transition period.
For manufacturers who have experience in conducting clinical investigations for their medical devices, the new EU MDR will not have much of an impact on the timelines, considering that their Quality System is compliant to the MDD/AIMDD, ISO 14155:2011 and Declaration of Helsinki. It can be seen as an opportunity, as the manufacturers who transition early to align with the requirements of the EU MDR can gain larger market share for devices, in comparison to those who transition closer to the deadline of 2020.
The EU MDR introduces EUDAMED, the centralized electronic system for the registration of clinical investigations, which will capture registration details of the devices, accredited NBs, Serious Incidents, Safety and Clinical Performance Reports (SSCP), Periodic Safety Update Reports (PSUR), Surveillance Activities and Clinical Investigation Data. It is likely that EUDAMED will ease the coordination between the manufacturers, NBs and the competent authorities with respect to the data requirements for compliance with the EU MDR.
1. EU, COUNCILDIRECTIVE of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices (90/385/EEC). Official Journal of the European Communities, 1990. L189/17.
2. EC, COUNCIL DIRECTIVE 93/42/EECof 14 June 1993 concerning medical devices. L 169, 1993.
3. EC, REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC Official Journal of the European Union, 2017. L117.
4. EC, GUIDELINES ON MEDICAL DEVICES: CLINICAL EVALUATION: A GUIDE FOR MANUFACTURERS AND NOTIFIED BODIES UNDER DIRECTIVES 93/42/EEC and 90/385/EEC 2016.