In-vitro Diagnostic Device Regulation IVDR

Introduction IVDR

With the IVDR, the EU has issued a 157-page regulation which supersedes the IVD-Regulation (98/79/EC). The number of articles increased almost fivefold from 24 to 113.

In this article, you will learn which requirements were amended by IVDR, which requirements remained the same and how to get ready for the new regulation.

Since 25 May 2017, the EU regulations, MDR and IVDR are in effect.

Download

Here, you can find the final version of the IVDR in German as a HTML-file, as a HTML-file (with links) and as a PDF and in English as a HTML-file and as a PDF.

Further information

Click on this link to download the free Starter Kit providing you with an overview of the regulatory landscape and illustrating the 6 steps to your medical device's "approval".

IVDR at a Glance

a) Validity and Applicability

The IVDR feels responsible for the entire EU in-vitro diagnostics market: from development to market surveillance to usage. Hence, it is equally applicable to manufacturers, importers, users, notified bodies and national authorities.

In particular, the IVDR lays down the conditions ("essential requirements") to be fulfilled by in-vitro diagnostic products.

b) IVDR's Chapter Structure

The regulation is divided into 10 chapters and 14 annexes. Download image as PDF.

What the IVDR did not change

The IVDR still knows "essential requirements". However, they are now denoted "general safety and performance requirements". As pursuant to IVDD, manufacturers must provide evidence for their compliance with those requirements as part of conformity assessment procedures.

Furthermore, there are still classes in which products are classified. Conditional to the class, manufacturers may choose the conformity assessment procedure.

Likewise, the IVDR did not change that notified bodies are to be involved in conformity assessment procedures - except for uncritical devices - and that conformity has to be indicated with a CE label.

Important Amendments by IVDR

Even though the IVDR has maintained many concepts such as conformity assessment procedures, notified bodies' being involved and the essential requirements, some partly significant modifications have been made.

a) Dividing Devices into four Classes instead of two Lists

IVDR's Annex VIII now defines four classes In lieu of the previous lists A and B.

  • Class D: highly critical data, e.g. for transfusion medicine or determination of life-threatening or infectious diseases
  • Class C: critical data, e.g. human genetic testing, determining levels of medicinal products, detecting infectious or inherited diseases in the embryo or foetus. Most self-tests (performed by the patients) fall within class C.
  • Class B: less critical parameters such as glucose or leukocytes. Class B is also the default class for all parameters which do not fall within the scope of any of the stated rules.
  • Class A: uncritical devices such as washing solutions or general culture media are classified as class A.

IVDR even divides in-vitro diagnostic products into further categories:

  1. devices for near-patient testing
  2. devices for self-testing
  3. companion diagnostic devices which are essential for the safe and effective use of a corresponding medicinal product. An example would be a genetic test verifying whether a cytostatic is effective.

b) Conformity Assessment Procedures

The number of possible conformity assessment procedures has been reduced. Basically, the IVDR only distinguishes three procedures:

  1. For class A products without the requirement of a sterile condition, the technical documentation is sufficient for the product (Annex II) and for post-market surveillance (Annex III).
  2. All other products can be placed on the market subject to complete quality management system (Annex IX). As for the review of technical documentation, IVDR differs between assessment per product category (class B), device group (class C) or product (class D).
  3. Alternatively, manufacturers may opt for a conformity assessment procedure comprising a type examination (Annex X) and quality assurance techniques at the manufacturing stage (Annex XI).

Just as for companion diagnostics, IVDR stipulates specific requirements for devices intended for near-patient or self-testing.

If applicable, reference laboratory and expert panels shall get involved when assessing class D devices.

c) Common Standards

Manufacturers may continue to comply with harmonised standards. Now, the EU Commissions reserves the right to adopt so-called "common specifications" with which manufacturers must comply.

The Commission grants itself considerable rights. It may define requirements at its own discrection with virtually no involvement of the parliament.

d) UDI-System

As required for other medical devices, manufacturers are onyl obliged to clearly mark their devices using a UDI and to store the information in Eudamed.

Further Informationen

Read more articles on the UDI and Eudamed here.

 

e) QM-System

Each (!) manufacturer of an IVD must have a quality management system, irrespectible of the conformity assessment procedure. However, the IVDR requires a certification by a notifed body for conformity assesment procedures pursuant to Annex IX and XI.

The requirements for the quality management are comprehensive, though. It must comprise:

  • organisation, processes, responsibilities (including the management)
  • strategy to ensure conformity
  • identification of requirements
  • resource management
  • handling communication with suppliers
  • risk management
  • evaluation of the devices' performance
  • development
  • manufacturing
  • administration
  • post-market surveillance
  • UDI
  • CAPA

If you have described and implemented all of those procedures, you can also obtain certification according to ISO 13485:2016.

IVDR stipulates that notified bodies shall conduct an unannounced audit at least every five years. All manufacturers with a certified QM system are affected.

f) Technical Documentation

Manufacturers are obligated to describe what the device is supposed to do and how they ensure the actual performance of the device without unacceptable risks very precisely. Performance date comprises, for example, "analytical sensitivity, analytical specificity, trueness (bias), precision (repeatability and reproducibility), accuracy (resulting from trueness and precision), limits of detection and quantitation, measuring range, linearity, cut-off" etc.

Requirements for performance assessment are correspondingly extensive.

f) Software

IVDD put the issue of software in second place. For example, no requirements for the software life-cycle were defined. IVDR changes this:

  • Software must be developed taking into account software life-cycle processes, including verification and validation.
  • Requirements for interoperability must be specified in detail and their fulfillment must be verified. By the way: the latest version of ISO 13485:2016 requires this, too.
  • Risk management must consider even risks caused by problems with interoperability.
  • Runtime environment, operating system and hardware must be defined likewise.
  • The regulation even addresses mobile platforms. In this context, screen size and usage environment are to be determined, too.
  • Essential requirements also include IT security and protection against unauthorised access.
  • Manufacturers must provide a documentation which indicate the components, algorithmy and technologies.
  • The software itself is subject to Unique Device Identification UDI.
  • The staff must also be competent in the matter of software.

All in all, those requirements do not come as a surprise. Rather, they reflect what the IEC 62304 and, in part, the ISO 13485 specify more precisely.

g) Staff

Just as ISO 13485:2016, the IVDR attaches more importance to sufficient qualification of staff. The "Compliance Officer" is a new, explicitly required role.

f) And Much More

Among the additionally notable amendments and tightenings by die IVDR are:

  • Post-Market Surveillance: Manufacturers must precisely plan and carry out post-market surveillance. IVDR lays down the requirements in more details, among others in the Articles 78 et seqq. and in Annex III.
  • Clinical Performance Studies: Very comparable to the MDR, requirements for carrying out clinical performance studies increased dramatically. This is shown by Articles 57 et seqq. and Annex XIV.
  • Labeling: In paragraph 20 of Annex I, IVDR describes by the pageful what manufacturers must consider regarding manuals, warnings and other indications.
  • Risk Management: While requirements for risk management were rather laid down in ISO 14971 so far, IVDR now defines what has to be done in this regard.

Preparation for IVDR

Manufacturers are recommended to promptly start with their homework:

  1. Bring your QM system up to date (ISO 13485:2016)
  2. Form a task force for defining your UDI strategy including your development, logistics and production department.
  3. Determine your devices' classification.
  4. Carry out a gap analysis regarding your technical documentation and post-market system.
  5. Close the gaps.
  6. Coordinate your timetable with your notified body. 

Commission proposal on transitional periods

The IVDR entered into force on May 25, 2017 and is scheduled to become mandatory on May 26, 2022. This would make a high proportion of the declarations of conformity issued under the IVDD invalid from May 2022. 

However, on October 14, 2021, the EU Commission published a proposal that could give manufacturers of IVD medical devices more time.

a) Proposal on transitional periods

Under the Commission's proposal, the date the IVDR will start to apply will not change from May 26, 2022. However, manufacturers who have placed their IVD medical devices on the market in compliance with the IVDD will be given more time to demonstrate compliance with the IVDR. 

As with the MDR, there will be transitional periods. These periods do not just apply for IVDmedical devices for which a certificate was issued by a notified body under the IVDD but also for devices classified as “other IVD medical devices” that do not require the involvement of a notified body under the Directive. 

The new transitional periods for “other IVDs” would depend on the risk class according to the IVDR.

Please note that this is currently only a (non-binding) proposal from the European Commission!

b) IVD medical devices for which a certificate was issued by a notified body under the IVDD 

  • For IVD medical devices for which a certificate has been issued by a notified body under the IVDD, the proposal amends Article 110(2) as follows: 
    • Certificates issued by notified bodies in accordance with the IVDD prior to May 25, 2017 shall remain valid until the end of the period indicated on the certificate. So, for these devices, there is no change.
    • Certificates issued in accordance with Annex VI of the IVDD shall become void at the latest on May 27, 2025. 
      (Previously: 2024 – 1 year extension)
    • Certificates issued by notified bodies in accordance with the IVDD afterMay 25, 2017 shall become void by May 27, 2025. 
      (Previously: 2024 – 1 year extension)

c) “Other IVD medical devices” already placed on the market under the IVDD

  • For IVD medical devices for which manufacturers issued the declaration of conformity themselves (according to IVDD) without the involvement of a notified body before May 26, 2022 and which, under the IVDR, must undergo a conformity assessment procedure with a notified body in accordance with the IVDR classification rules, the following new transitional periods would apply:
    • May 26, 2025 for class D IVDs
    • May 26, 2026 for class C IVDs
    • May 26, 2027 for class B IVDs
    • May 26, 2027 for class A IVDs that are placed on the market in sterile condition
  • Therefore, depending on the risk class of the IVD medical devices, these existing devices can continue to be placed on the market after the IVDR starts to apply on May 26, 2022, provided that the devices comply with the requirements of the IVDD and there are no significant changes to the design and intended purpose.  
  • However, manufacturers should be aware that even for devices for which the proposed transitional periods would apply, the requirements of the IVDR with regard to post-market surveillance (PMS), market surveillance, vigilance and registration of economic operators and devices must still be complied with. 

d) Laboratory developed tests (LDT)

For devices manufactured and used only within a health institution, the proposal also provides for some more leeway. The main purpose of this is to relieve the burden on health institutions, such as laboratories, that have been hit hard by the coronavirus pandemic.

Article 5(5) of the IVDR provides special regulations for such devices. The deadline for the implementation of subsections (b) and (c), and (e) through (i), is now May 26, 2024. For d), the deadline is now May 26, 2028.

d) says:

 

“the  health institution justifies in its documentation that the target patient group's specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market”

Article 5(5)(a) is excluded from the extended deadlines. Therefore, from May 26, 2022, all lab developed tests in the EU must meet the general safety and performance requirements set out in Annex I and may not be provided to another legally independent facility – legal requirements that are already established in Germany in the Medizinproduktegesetz (MPG).

e) “Normal” (non-sterile) class A devices and “new” IVDs

However, the extensions proposed by the Commission would NOT apply to two device groups: 

  • “Normal” (non-sterile) class A devices 
  • “New” IVDs

For non-sterile class A devices, manufacturers will have to provide proof of conformity according to the IVDR before May 26, 2022 in all cases. 

Similarly, the proposed extensions do not apply for “new” in vitro diagnostic medical devices. The Commission considers in vitro diagnostic medical devices whose conformity has not been certified under the IVDD as “new” devices.

For these devices, manufacturers will also have to demonstrate conformity according to the IVDR before May 26, 2022 in all cases.

f) Reasons for the proposal

The Commission has justified its proposal primarily with reference to the impacts of the coronavirus pandemic that is tying up a lot of resources, making it almost impossible to implement necessary measures quickly. 

However, the current impact of the MDR on the medtech market is also likely to play a role. The aim is to avoid the kind of device culling caused by the MDR with in vitro diagnostic medical devices. Various actors have been sounding the alarm for months already.

  • Several stakeholders from politics, the medtech industry, notified bodies, medical professionals, scientists and non-profit organizations have warned about the dangers of the too-short deadlines in the IVDR.
  • On May 11, 2021 and June 15, 2021, respectively, various parties and the Council of Health Ministers approached the Commission to request a new regulation.

The Commission also recognizes the urgency of the situation in its proposal:

  • There are currently only six notified bodies in the whole of Europe that can work with the IVDR (there were 18 under the IVDD).
  • At the same time, notified bodies now have to be involved with a considerably higher number of in vitro diagnostic medical devices: previously, their involvement was needed for about 8% of IVDs on the market. Under the IVDR, just under 78% (approx. 24,000 IVDs in total) would require the involvement of a notified body.
  • According to a survey by MedTech Europe, if the deadlines were not extended, from 2022, around 22% of in vitro diagnostic medical devices would disappear from the market (there are currently approximately 40,000 IVDs on the market, i.e., 9,000 would disappear).
  • However, Covid-19 has shown just how important reliable in vitro diagnostic medical devices are.
  • Around 70% of clinical decisions are taken with the help of in vitro diagnostic medical devices.

g) What this means for manufacturers

  • For now: nothing. It is only a proposal.
  • The proposal must be discussed and passed by the EU Parliament and Council. Until then, it has no validity and could well still come to nothing.
  • Therefore, it is important that manufacturers stick to their implementation plan to ensure that their IVDs become IVDR-compliant in time.
  • Manufacturers should not waste any time, particularly in light of the scarce resources.
  • Manufacturers should be clear about the risk class of their IVD. If the proposal is adopted, the transitional period and the conformity assessment procedure will both depend on it.

Conclusion

IVDR has considerably raised the bar. The regulation's defined own objective is to enable small, innovate companies market access with finite effort. This target was clearly missed. The set of rules became too extensive for this to be reached. Consequently, a "Compliance Officer" became nearly inevitable for IVD manufactuerers.

If the IVDR results in higher safety of patients, users and third party is extremely doubtful. It is relatively certain that the IVDR has lead to more bureaucracy and less innovation.

Author:

Dr. Sebastian Grömminger

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