Q&A: The role of the IVDR conformity assessment in genetic diagnostics

Now that the regulation on in-vitro diagnostic devices (IVDR) explicitly regulates in-house devices, or laboratory-developed tests (LDTs), in the European Union, the selection of properly CE-labeled devices is increasingly important to health institutions like genetic testing laboratories.

In this Q&A, Sonja Strunz, head of the regulatory affairs department at Limbus Medical Technologies in Germany, explains the classification of devices under IVDR and what it means for manufacturers, users, and patients. Strunz, a bioinformatician by training, is one of the persons responsible for regulatory compliance (PRRC) at Limbus. She and her team have recently completed the conformity assessment by a notified body of a software solution intended for genetic testing using next-generation sequencing.

What does the new device classification scheme in the IVDR look like?

The new classification scheme of IVDR is risk-based. This is fundamentally different from the scheme of the previous legislation, which was simply based on a fixed list of devices. This list had been created back in the 1990s and did not even consider software as a device in its own right. Many important types of IVD devices were not on that list and therefore were only subject to the lowest level of regulatory oversight.

The current IVDR classification scheme consists of four classes, ranging from Class A, the lowest risk classification, to D, the highest risk classification. As a general rule, the higher the risk for the patient and the larger the number of potentially affected individuals, the higher the risk classification of the device. Diagnostic devices, except for most in Class A, are required to undergo a conformity assessment by an independent third party, called the notified body.

How is the classification of a device determined?

IVDR requires that the manufacturer determine the classification of a device based on its intended purpose. A correct classification is therefore first and foremost the responsibility of the manufacturer. The correctness of the classification is not reviewed for all types of devices. This only happens automatically if an external conformity assessment for Classes B, C, or D is completed.

How should IVD devices intended for use in genetic diagnostics be classified under IVDR?

The classification rules are laid out in Annex VIII of the IVDR. There are also additional guidelines like MDCG 2020–16 that provide more details and examples. Applications such as genetic testing, prenatal testing, and cancer diagnostics are explicitly mentioned in the IVDR. The classification of devices intended for any of these purposes is therefore quite straightforward, and rule 3 (h), (i), or (l) may be applied. These paragraphs refer to cancer diagnostics, genetic testing, and prenatal screening, and they require that devices intended for use in these applications be classified as Class C.

This is an important improvement over the previous legislation, which did not really address genetic diagnostics, nor did it require particular regulatory oversight for devices intended for this purpose.

What does the conformity assessment for a Class C device entail?

Class C devices are subject to a conformity assessment by an independent notified body. The conformity assessment is a two-step process. The first step comprises an assessment of the manufacturer’s quality management system. The second step comprises the assessment of the technical documentation of the device.

In the assessment of the technical documentation, a manufacturer must demonstrate compliance with the General Safety and Performance Requirements (GSPR) and all other requirements derived from them. In the case of software devices, manufacturers must prove that the software has been developed in accordance with the state of the art. This is typically done by demonstrating compliance with international standards like IEC 62304, IEC 82304, and others. It also concerns the IT security aspects of the software.

A special focus is placed on the performance of the device, such as the sensitivity and specificity of a diagnostic function. In general, the IVDR imposes more detailed and stricter requirements on manufacturers for the performance evaluation of a device.

Many laboratories in genetic diagnostics deploy in-house tests. How is it an advantage for them to use IVDR-certified components in such a test?

Such in-house tests had been considered under the previous legislation only in certain national implementations. The IVDR changes that by specifically addressing the case of in-house development or in-house use within health institutions in Article 5. Health institutions are assigned responsibilities like manufacturers. This is now the uniform rule of law across the entire European Union.

For example, health institutions must now demonstrate compliance with the GSPR. This can be extremely difficult in the case of a complex software solution in genetic testing if the responsible institution is not the developer of the software.

It is a great simplification for the laboratory to use a software device that has already been IVDR certified because it can simply refer to the certificate and the existing technical documentation of the software.

So many devices in genetic diagnostics are labeled “for research use only” (RUO). What does that mean? How can they be used for diagnostic purposes?

In general, such devices cannot be used for diagnostic purposes on patients without any further qualification. If they are nevertheless used for diagnostic purposes, this may mean that the health institution using it assumes responsibility for the device under IVDR.

Why is an early certification of conformity under IVDR so important?

The IVDR allows manufacturers to continue to use declarations of conformity for Class C devices in a transitional period until 2028 if they had been issued under the previous legislation before 2022. Manufacturers who make use of these transitional provisions are, however, very restricted in the type and the extent of changes they are allowed to apply to their devices. The restrictions have a particularly strong impact on software because software is typically developed in short cycles and changes in the design are frequently required just to keep up with the general state of the art.

An important restriction during the transition period is that manufacturers may not change the intended purpose of their devices. This certainly puts any significant innovation on hold.

There are IVD devices that have been classified as Class A and are clearly intended for the purpose of genetic diagnostics. How can that be?

The classification of a medical device is derived from its intended use. The manufacturers of a Class A device must have defined the intended use of the device in such a way that it does not fall under the classification rule for Class C devices. Laboratories must carefully consider the intended use of the device. If an IVD device is not used according to its intended purpose, the declaration of conformity becomes void and the laboratory assumes the responsibilities of a manufacturer.

What will IVD device users like laboratories have to look out for?

Obviously, it makes a difference if a device has been subject to a notified body conformity assessment or if a manufacturer has declared the conformity of the device without the involvement of a notified body. The actual intended purpose and its scope are crucial information. Since the IVDR imposes stricter rules, manufacturers may reduce the scope of the intended purpose of their devices to facilitate the initial review by a notified body or to achieve a lower device classification. For example, software intended for use in genetic testing may exclude the bioinformatics processing altogether and simply provide functions to classify variants. This increases the burden of compliance to the laboratory and is a big difference from solutions that cover both secondary and tertiary analysis like the varvis® genomics platform from Limbus Medical Technologies.