Since May 25, 2017, the In Vitro Diagnostic Medical Device Regulation (IVDR) has been in force, which has now replaced the previous IVD Directive (98/79/EC, IVDD). There are significant differences between the IVDR and IVDD.
This article presents these differences. In doing so, it provides manufacturers who placed their devices under the EU directive (IVDD) on the market with an overview of the "gaps" that need to be closed. It also helps health institutions that have not yet been affected by the IVDR, such as medical laboratories.
It is widely rumored that the breast implant scandal was the catalyst for the revision of medical device legislation. However, most of those involved now deny this. It is, therefore, largely unclear who initiated the new regulation and for what reason.
Directive 98/79/EC on in vitro diagnostic medical devices (IVDD) will be replaced by a separate regulation (In vitro Diagnostic Medical Device Regulation (IVDR), number 2017/746).
Read more about the Medical Devices Regulation, MDR.
The EU regulation is divided into ten chapters and 14 annexes. While the IVDD contained 24 articles, the IVDR comprises 113 articles, indicating that the IVDR has been written from scratch.
The IVDR has retained some concepts. For example, the regulation continues to recognize "essential requirements," which are now called general safety and performance requirements.
The performance parameters to be demonstrated also hardly differ between the IVDD (Annex I, Section 3) and the IVDR (Annex I, 9.1.). Only a better distinction is made between analytical performance characteristics (Annex I, 9.1.a) and clinical performance characteristics (Annex I, 9.1.b).
Manufacturers still have to demonstrate that they and their devices meet these requirements by means of a conformity assessment procedure. The IVDR has also not changed the fact that conformity must be expressed by a CE mark.
In contrast to the IVDD, the IVDR regulates devices manufactured and used only within health institutions, the so-called in-house IVDs (also known as lab-developed tests or LDTs). This means that medical laboratories must comply with the requirements of the IVDR.
For the classification of IVDs, the IVDR introduces risk-based classification rules. (Under the IVDD, classification was based on a list system.) For each device, an IVD manufacturer must go through all of the implementing and classification rules in Annex VIII to assign a device to one of the four classes:
The IVDR distinguishes other types of in vitro diagnostic medical devices:
Under the IVDR, conformity assessment is no longer carried out by the manufacturer himself but by a notified body. Only manufacturers of non-sterile class A devices may still declare conformity themselves. There is still no central regulatory authority (like the EMA for medicinal products).
According to the general obligations for manufacturers according to Article 10 of the IVDR, IVD manufacturers must implement and enforce a quality management system that meets the requirements of the IVDR, Article 10, and ISO 13485 as harmonized standard. For all devices, regardless of their class, manufacturers must prepare product-specific technical documentation according to Annex II as well as technical documentation on post-market surveillance according to Annex III.
The IVDR essentially distinguishes between three conformity assessment procedures:
For devices intended as near-patient testing (point-of-care tests, POCT) or for self-testing by lay persons, the IVDR imposes specific requirements, as it does for companion diagnostics (CDx). Class D devices must involve reference laboratories and, if common specifications (CS) are not available, expert panels.
Manufacturers should continue to use harmonized standards. The EU Commission also reserves the right to define so-called common specifications (CS) with which manufacturers must comply. These serve to provide a uniform specification of safety and performance requirements, particularly for high-risk products.
The first essential activity includes defining a precise intended purpose. The information that must be specified can be found in Annex II, Section 1.1 and Annex I, Section 20.4.1.c – a valuable source for both IVD manufacturers and users.
Manufacturers and also medical laboratories developing and using in-house IVDs quickly realize that without a precise formulation of the intended purpose, neither a targeted regulatory strategy is possible nor the scope for the performance evaluation can be determined.
However, it is the performance evaluation that the IVDR focuses on. It describes the requirements for performance evaluation documentation in much greater detail than the IVDD. It devotes attention to the three elements of performance evaluation: scientific validity, analytical performance, and clinical performance (Annex XIII, Part A).
The IVDR indicates that performance - as well as risks - must be monitored throughout the life cycle of a device and that performance evaluation is not a one-time thing. Therefore, the regulation requires post-market performance follow-up (PMPF) after placing a device on the market, in accordance with Annex XIII, Part B.
That performance evaluation and PMPF have a special place in the conformity assessment of an IVD is also demonstrated by the focus of the notified bodies during the assessment of the technical documentation.
This, in turn, is in line with the requirement that only devices that can demonstrate their clinical benefit are on the market. And in the case of IVDs, this lies in particular in "providing accurate medical information on patients" (IVDR, preamble (64)).
The term "accurate" refers to, i.e., analytical and clinical accuracy including trueness and precision of the results.
Whereas the requirements for risk management previously originated more from ISO 14971, the IVDR now defines them in more detail in Annex I.
Comparable to the MDR, the requirements for documenting and conducting (clinical) performance studies have multiplied. This is evidenced by Article 57 and Annex XIII, Section 2, or Article 58 et seq. and Annex XIV. The latter impose further requirements on certain performance studies that are associated with a risk to the patient.
In 2019, the ISO 20916 was published as standard defining the special requirements for performance studies with IVDs. The standard is referenced in the preamble of the IVDR.
Read this article on sample size planning for performance studies with IVD.
The IVDD addressed software very poorly. For example, it did not formulate any concrete requirements for the software life cycle. The IVDR changes that:
Overall, these are not surprising requirements. Rather, they reflect what IEC 62304 and, in part, ISO 13485 specify more concretely.
As with other medical devices, manufacturers are required to clearly label the devices using a UDI and to upload information in EUDAMED.
Every(!) manufacturer of an IVD medical device must have a quality management system (QM system). This applies regardless of the conformity assessment procedure. However, the IVDR only requires an assessment of the QM system by a notified body for the conformity assessment procedures according to Annex IX and XI.
The requirements for the quality management system are comprehensive and specified both via the obligations as a manufacturer in Article 10 of the IVDR and by ISO 13485 as a harmonized standard. The QM system must address, among other things:
Once you have described and implemented all these procedures, it is not a big step to compliance with ISO 13485:2016.
The IVDR requires notified bodies to perform an unannounced audit at least every five years for a chosen conformity assessment procedure according to Annex IX and Annex XI.
As in ISO 13485:2016, the IVDR places increased emphasis on adequate qualification of personnel. The Person Responsible for Regulatory Compliance is a new, explicitly required role.
To overcome the differences in the requirements of IVDR and IVDD, you, as a manufacturer, should take the following steps:
The IVDR is significantly more comprehensive than the IVDD. This is mainly due to the more specific requirements for documentation in the IVDR.
Essential differences are the risk-based classification rules and the conformity assessment by notified bodies for all class B, C, and D devices.
That the IVDR will lead to greater safety for patients, users, and third parties through the necessary clinical evidence and performance evaluation of devices cannot be doubted. However, it is questionable whether the IVDR, just like the MDR, could not have managed with less bureaucracy, as this has the effect of inhibiting innovation.
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