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The In Vitro Diagnostic Medical Devices Regulation is here — a closer look at what you need to know

Posted: 06/07/2022


This analysis was originally published on Lexis PSL on 25 May 2022 and can be found here (subscription required).

Industry has been preparing for the new medical devices regime since 2017. How do you feel the MDR (Medical Devices Regulation) has been received by the medical devices industry one year later and what similarities or distinctions do you anticipate for the reception of the IVDR (In Vitro Diagnostic Medical Devices Regulation) by the medtech industry?


As with Regulation (EU) 2017/745, the Medical Devices Regulation (MDR), which simultaneously celebrates its one-year anniversary since its application from 26 May 2021, the IVDR intends to provide comprehensive and harmonised regulation of the supply of in-vitro diagnostic medical devices (IVD) such as blood glucose monitors, tests for coronavirus (Covid-19) and cancer screening in the EU (and Northern Ireland under the Northern Ireland Protocol).The IVDR brings with it a raft of fundamental regulatory changes that manufacturers, notified bodies, the newly defined roles of importer and distributor, and other stakeholders will need comply with.

It is clear that the MDR and IVDR place significant regulatory burdens on all stakeholders involved compared to the previous regimes and that, in spite of the lead-in time between coming into force in 2017 and the dates of application (delayed due to the pandemic in the case of MDR), the industry and even those responsible for the framework are not fully prepared for the changes involved.

The medical device industry is fully aware that the regulatory regimes implemented under the previous directives required amendment and update, but although there were long periods for transition, compliance has still been slow and difficult. Discussed below, the lack of notified bodies for both MDR and IVDR is the starkest example of the lack of preparedness for the transition to the MDR and IVDR with their significantly increased requirements for certification.

A MedTech Europe survey of its members, estimated to represent about 90% of the market, produced some fairly pessimistic conclusions as to the effect of the introduction of the IVDR. They predicted that the IVDR will mean the discontinuation of at least 22% tests, the highest proportion of IVD losses coming from small and medium sized manufacturers, and were concerned that 53% of manufacturers (as at September 2021) do not yet have a notified body. The truth of these predictions remains to be seen but the joint implementation and preparedness plan (JIPP) produced by the Medical Devices Coordination Group (MDCG) does not seem to allay these concerns (see below).

The increased compliance requirements may prompt a shift away from the historic trend to launch devices in the EU before the US, particularly for companion diagnostics, given the potential complexity in navigating combined regulatory regimes.

What are the main outstanding issues the industry is facing?


Lack of notified bodies
As mentioned, the IVDR will require significantly greater notified body involvement and it is therefore a serious concern that a lack of capacity of and engagement with notified bodies will cause shortages and disruption in the supply of critical IVDs. There are currently only seven notified bodies designated under the IVDR and according to data provided by notified bodies as of September 2021 only 31 IVDR certificates had been issued (see: LNB News 04/05/2022 97).

Addressing the issue of a lack of notified bodies features as the second of 11 top priorities listed by the Commission and MDCG in their recently updated JIPP. They also note the risk that coronavirus restrictions have, and may continue to, seriously affect the notified bodies’ ability to fulfil their role and meet their requirements, particularly where travel or home-working restrictions may impede the necessary first-time audits of many manufacturers under IVDR.

The MDCG and Commission note that better understanding the obstacles faced in designating notified bodies, fulfilling their requirements under IVDR and recruiting the necessary professionals for these roles must be one of their highest priorities.

European database on medical devices (EUDAMED)
The IVDR provides for the establishment of a EUDAMED which will combine a series of electronic systems to allow for electronic registration of devices, a database of unique device identifiers (UDIs) and general digital management of the regulatory regime prescribed by the IVDR.

The MDCG has acknowledged in its updated JIPP, however, that EUDAMED will not be fully functional by 26 May 2022.

The main practical implications of this are twofold:

  • The requirement to comply with art 26(3) (requirement for manufacturer to enter certain information as at section 2 of part A of annex VI into EUDAMED) and art 51(5) (requirement for notified bodies to enter information on certificates issued into EUDAMED) do not apply until 27 November 2023.
  • Requirements under other articles listed at art 113(3)(f) which deal with the registration of devices and economic operators, notified bodies, vigilance, post-market surveillance, market surveillance are only postponed, insofar as they relate to EUDAMED, until six months after notice is given of EUDAMED becoming fully functional. The expectation to comply as far as possible using existing systems nevertheless applies from 26 May 2022.

The MDCG recognises that further guidance is urgently needed on how this will work in practice until EUDAMED is launched. For more information see practice note: The EU Medical Devices Regulation and In Vitro Diagnostic Medical Devices Regulation— EUDAMED and economic operators.

Delegated and implementing acts
Under article 108 of Regulation (EU) 2017/746, the IVDR, the Commission has retained powers to adopt delegated acts for a number of specific purposes, for example, amending the tasks of expert panels and EU reference laboratories, though according to a Commission report dated April 2022, no delegated acts have yet been adopted as the need has not yet arisen.

This power lasts for five years from 25 May 2017 though may be tacitly extended for further periods of five years provided the Commission does not object. The Commission clearly considers the need for these delegated acts may arise in future since the same report notes the need to extend this power as it approaches the end of the first five year period.

The Commission may also use implementing acts to exercise a number of powers provided in the IVDR. Unlike the delegated acts, the Commission has exercised a number of these (as listed here), though it has the power to exercise many more and has not yet done so, such as adopting common specifications (art 9), specifying detailed arrangements for the UDI system (art 24), designating EU reference laboratories (art 100) and many others.

The lack of EU reference laboratory designation (see below) is a particular concern for implementation of the new requirements for class D devices although an implementing act setting out the tasks and criteria for EU reference laboratories is currently in draft form.

Outstanding guidance and templates
There are quite a number of further guidance and template documents expected from various MDCG subgroups which have not yet been completed. The JIPP raises a number of these as top priorities, particularly guidance on dealing with the impacts of coronavirus or another health crisis while implementing IVDR, guidance for notified bodies, EU reference laboratories, expert panels and, as mentioned, guidance for stakeholders until EUDAMED is fully functional. To keep updated on progress see practice note: The EU MDR and IVDR implementing acts and guidance tracker.

Given the change in treatment of companion diagnostics and recognition that development of the companion diagnostic device is inextricably linked to that of the medicinal product, the MDCG acknowledges in their JIPP that more guidance is also required on this point. The European Federation of Pharmaceutical Industries and Associations’ report on the assessment pathway for companion diagnostics flags the need for guidance for in-vitro diagnostics which already guide treatment decisions and which may require recertification as well as for follow on diagnostics (new diagnostic tests for existing precision medicines already on the EU market that were originally approved with a CDx test).

The report highlights the need to ensure coordination between the relevant national competent authority/European Medicines Agency/notified body so that the regulatory processes, and particularly the timeframe for approval, for both the medicinal product and the CDx are aligned.

This is the second and final major piece of legislation to complete the application of the new EU regime for medical devices. In summary, what are the key changes introduced by the IVDR?


Although the IVDR applies from 26 May 2022, as noted below, a number of transitional provisions will continue to apply, and the industry still faces substantial challenges before being able to implement the IVDR requirements in full.

The key changes are:

A new classification system
The IVDR introduces a new, expanded, risk-based classification system comprising classes A, B, C and D, with class A being the most low risk and class D the most high risk devices, and provides detailed rules for classification at annex VIII.

Classification is based on the ‘intended use’ of a device, as set out in any documentation or instructions which accompany the device and will determine the relevant conformity assessment procedure to be followed as set out in annexes IX–XI, as well as a number of other compliance requirements. See practice note: The EU Medical Devices Regulation and In Vitro Diagnostic Medical Devices Regulation—scope, classification of devices and Notified Bodies.

There are detailed rules and guidance as to which class applies but the key distinguishing features are as follows:

Device class

Key parameters

Class D

 

·       Devices relating to blood transfusion, cell, tissue or organ transplantation or administration.

·       Devices for the detection of a transmissible agent causing life threatening disease with high risk of propagation.

·       Devices intended to determine the infectious load of a life threatening disease where monitoring is critical to patient management.

 

Class C

 

·       Devices intended to be used for blood grouping and others, except when used for certain markers which are class D.

·       Devices intended for detecting a sexually transmitted agent.

·       Devices intended for detecting the presence in cerebrospinal fluid or blood of an infectious agent without a high or suspected high risk of propagation.

·       Devices intended for detecting the presence of an infectious agent, where errors might cause death or severe disability.

·       Devices intended for pre-natal screening of women.

·       Devices intended for determining infective disease status or immune status, where errors are life threatening.

·       Devices intended to be used as companion diagnostics.

·       Devices intended to be used for disease staging, where errors are life threatening.

·       Devices intended to be used in screening, diagnosis, or staging of cancer.

·       Devices intended for human genetic testing.

·       Devices intended for monitoring of levels of medicinal products etc where errors are life threatening.

·       Devices intended for management of patients suffering from a life threatening disease or condition.

·       Devices intended for screening for congenital disorders in the embryo or foetus.

·       Devices intended for screening for congenital disorders in newborn babies where failure to detect and treat such disorders could lead to life threatening situations or severe disabilities.

·       Devices for self testing, except for certain exceptions which are class B.

 

Class B

 

·       Devices not covered by the other rules/classes.

·       Devices which are controls without quantitative or qualitative assigned value.

 

Class A

 

·       Products for laboratory use, instruments to be used in IVD procedures, specimen receptacles.

 

See practice note: Introduction to the EU Medical Devices Regulation and In Vitro Diagnostic Medical Devices Regulation.

New definitions and expansion of classification
There are many changes to the definitions included in the IVDR as opposed to directive 98/79/EC (the In Vitro Diagnostic Medical Devices Directive (IVDD)) and the treatment and classification of software as an IVD is one of the most significant. Under the IVDD, most software was classified as class I (lowest risk). Annex VIII now specifically states that ‘software, which drives a device or influences the use of a device, shall fall within the same class as the device’, and ‘[if] software is independent of any other device, it shall be classified in its own right’. This opens up the possibility of a single device falling within multiple classifications in which case IVDR clarifies that the rules applying to the higher classification shall apply.

The definition of ‘accessory’ has also been slightly amended as being an article which, though not itself an IVD, is intended by the manufacturer to be used with an IVD for its intended purpose or to assist the medical functionality of the IVD. Notably, the IVDR now provides that any accessory must be classified in its own right, separately to the device with which it is used.

Companion diagnostic devices
Companion diagnostic devices (CDx) are devices which are essential for the safe and effective use of a corresponding medicinal product to make certain treatment decisions. Under the IVDR, these will be in class C (the second most risky class) and will therefore require conformity assessments by a notified body, including increased clinical evidence (previously CDx could be self-certified).

Importantly, the conformity assessment procedure for CDx will require the notified body to consult a competent authority in a Member State (a medicinal product authority) or the European Medicines Agency (art 48(3)) regarding the suitability of the device in relation to the medicinal product concerned. This marks the first regulatory link between the approval of a medicine and its companion diagnostic and will require significantly closer collaboration between the relevant regulatory bodies.

Increased notified body involvement
Stakeholders have estimated that, whereas under the IVDD around 10% of all IVDs placed on the market (only self-tests and devices listed in annex II of the IVDD) needed notified body involvement, under the new IVDR, this will rise to 80–90% of IVDs due to the new classification system.

The conformity assessment procedures (see the detailed provisions at annexes IX–XI) for all class A sterile devices and class B, C and D devices will require proportionate notified body involvement. Article 48(10) clarifies that for class A sterile devices, notified body involvement will be limited to aspects that relate to establishing, securing and maintaining sterile conditions only.

Nevertheless, the scope for notified body involvement is significantly increased, requiring capacity on their part to fulfil these roles—an issue causing substantial concern as discussed above.

Common specifications
The IVDR has introduced the concept of common specifications, defined as ‘a set of technical and/or clinical requirements, other than a standard, that provides a means of complying with the legal obligations applicable to a device, process or system’. The European Commission may adopt these by means of implementing acts when no or insufficient harmonised standards exist.

Importantly, although adopting common specifications is optional, devices that conform with common specifications will be presumed to conform with the relevant IVDR requirements and will exempt devices covered from the additional step of expert panel consultation (see below).

EU reference laboratories
The IVDR enables the Commission to designate an entirely new type of independent scientific body, the ‘EU reference laboratories’, who will be responsible for carrying out additional tests on class D devices that fall within their scope. They will verify compliance with any common specifications and carry out sample or batch tests on CE-marked class D devices before they are placed on the market.

This will assist with bottlenecks for compliance, however, it appears that there will be no EU reference laboratories identified until at least 2023.

Expert panels
As part of the broader emphasis on clinical evidence of devices and setting three specific elements of performance evaluation which must be met (scientific validity, analytical performance and clinical performance) expert panels have been introduced as an additional step in the conformity assessment process.

While class D devices must be verified by an EU reference laboratory, notified bodies must consult expert panels on the performance evaluation report for very ‘novel high-risk devices’. This is likely to be in cases where there are no common specifications for a class D device and where it is the first certification for that type of device, though the MDCG notes that guidance is required as to what exactly this means.

Considering the impact of the coronavirus pandemic and the serious shortage of notified bodies, the transitional provisions of the IVDR were amended in January 2022—what do they provide?


The newly introduced transitional provisions under article 110 allow for a number of grace periods for compliance by most IVDs that were already placed lawfully on the EEA market prior to 26 May 2022 as follows (see LNB News 23/05/2022 40):

  • Certificates issued by notified bodies under the IVDD before 25 May 2017 may remain valid until the end of the period on the certificate, except certificates issued under annex VI of the IVDD (EC Verification) in which case they shall become void by 27 May 2025 at the latest.
  • Certificates issued by notified bodies under the IVDD after 25 May 2017 may remain valid until 27 May 2025.
  • Devices that will switch to a risk class requiring notified body involvement for the first time under the MDR and for which a declaration of conformity was drawn up prior to 26 May 2022 will enjoy a grace period and may still be placed on the EEA market under strict conditions (Article 110(3) of the IVDR). The relevant grace period differs per class as follows:
    • Class D—26 May 2025
    • Class C—26 May 2026
    • Class A (sterile) and class B—26 May 2027
  • Devices lawfully placed on the market under the IVDD before 26 May 2022 may continue to be made available on the EEA market or put into service until 26 May 2025.
  • Devices lawfully placed on the EEA market after 26 May 2022 may continue to be made available on the market or put into service until:
    • Class D—26 May 2026
    • Class C—26 May 2027
    • Class A (sterile) and class B—26 May 2028

The condition to these grace periods is that no significant changes are made to the intended purpose or design of the devices. Importantly, therefore, changes made to anything other than the intended purpose or the design, or any changes which are non significant can be implemented within the grace period.

Note, too, that where a notified body has issued a certificate under the IVDD which a manufacturer relies on in order to benefit from any grace period, this notified body remains responsible for ongoing surveillance and approval of any changes (as contractually agreed between the notified body and manufacturer) to ensure that the certificate remains valid.

The MDCG has issued some helpful and detailed guidance as to what significant changes to intended purpose or design might be in practice, including flowcharts to assist with decision making (see: LNB News 04/05/2022 66). A brief summary is below:

  • Changes other than to intended purpose or design—administrative changes (change of manufacturer’s name, relocation of sites, change to supplier) or changes to the manufacturing process are probably not caught, provided they do not impact the design/intended purpose of the device or the conditions under which conformity assessment certification was granted.
  • Significant changes to intended purpose—these include any extension of the intended purpose: adding to what is detected/measured, additional functionality, extension of the target population (for CDx) or addition of specimen type, as well as any other major change to intended purpose: change of assay type, change from professional user to lay user.
  • Significant changes to design—these include:
    • Changes to the device’s operating principle (the overall assay or testing method, mechanism or principle including the detection principle which the device uses to achieve its purpose). An example of this is changing from immunofluorescence to ELISA.
    • Changes that adversely affect the safety or performance and negatively affect the risk/benefit ratio of the device. An example of this is changing the instructions for use to refer to reduced sensitivity based on post-market surveillance data.
    • Significant changes to software.
    • Changes to ingredients or materials which affects either of the first two bullet points. Examples of this include changes to primers for PCR, capture antibodies/antigens for immunoassay, or substitution of a chemical substance which adversely affects device performance.
    • Changes to sterilisation including changing from non-sterile to sterile conditions.

It is important to note that the IVDR is applicable from 26 May 2022 regardless of the transitional periods. Consequently, the post market surveillance obligations, the vigilance obligations and the specifications regarding monitoring by competent authorities apply. The requirement for manufacturers based in Great Britain or another country outside the EU to appoint an importer also applies from 26 May 2022 and economic operators are urged to register on EUDAMED.

What does this mean for the UK?


The position is also very difficult for manufacturers looking to sell in Northern Ireland (where the EU regulatory regime applies) as well as the rest of the UK (where the former directives as implemented into UK law are still in force).

To add even greater uncertainty, the Medicines and Healthcare products Regulatory Agency (MHRA) launched a consultation in September 2021 as to the future of the medical devices regime in the UK. However, the proposals under the consultation move the UK’s regime to be more consistent with both the MDR and the IVDR as well as other global regulatory regimes, which is a welcome approach. See news analysis: Consultation on the future regulation of medical devices in the United Kingdom.

There remains an opportunity for the UK to become a favourable manufacturer’s market but if there is significant divergence from other global regulatory regimes, this may equally add a further burden of compliance with distinct regulatory requirements, with the additional risk of discrepancies in device safety and efficacy. See news analysis: Medical Devices and the Limits of UK Regulatory Autonomy.

It remains to be seen whether the attempts to create a regime of enhanced safety and harmonisation under the new MDR and IVDR, particularly the digitalisation of the system via UDIs and EUDAMED, will, once the market has adapted to the changes, prove their worth. The MHRA has the benefit of assessing the MDR and IVDR regimes to draw its own conclusions on their impact before changing our regulatory system under the Medicines and Medical Devices Act 2021 (MMDA 2021).

The MHRA consultation results will provide a fascinating picture of the views of the industry on how the MHRA’s regulatory regime under MMDA 2021 should be amended. Whether the MHRA moves away from its proposals based on those responses remains to be seen.

In the EU there is no going back, after five years of transition, the IVDR will apply from 26 May 2022 despite the lack of notified bodies and with the associated challenges for compliance for both the development of new in-vitro diagnostic devices and the new requirements for certification of existing in-vitro diagnostic devices.


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