What Benefits Does IVDR Bring to Manufacturers and Laboratories?

Compared to companies in the pharmaceutical and medical technology sectors, diagnostics manufacturers and medical laboratories had significantly lower regulatory effort. This view has changed since May 2017, when the new IVDR came into effect that is compulsory from May 2022. This new European regulation controls the manufacture of medical products and in-vitro diagnostics. This is many times stricter and involves considerably greater time and effort.

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In the past, IVD manufacturers were able to self-declare around 90 per cent of their CE products without an external review of the required documents and records. This review was generally carried out as part of the standard audits by the certification bodies. With the new regulation, the number of certifiers will be significantly reduced, upgraded to the “notified body”, with tighter regulations.

Regulatory experts are therefore predicting a restructuring of the IVD market and laboratory environment. A symposium of the AWMF in February 2020 in Lübeck (Link 1) once again confirmed it: in laboratories there is great uncertainty surrounding the new IVDR. “We have a lack of clear answers and official statements. We do not really know what it means for our laboratory and, above all, how we should best prepare for it. This is a thoroughly unsettling situation,” a participant at the symposium concluded. “We have a lack of statements and guidance from the appropriate bodies to highlight the regulatory tasks for medical laboratories in a transparent and uniform way.”“But, as manufacturers, we also face major challenges to comply with the IVDR 2017,” said Dr. Ralf Fischer, in charge of Regulatory Affairs at Chromsystems and responsible for implementing the new IVDR in the company. The companies are already dealing with additional, not yet conclusively manageable regulatory, personnel and financial costs for implementing the required regulations.

Dr. Ralf Fischer, Head of Regulatory Affairs at Chromsystems

“But, as manufacturers, we also face major challenges to comply with the IVDR 2017,” said Dr. Ralf Fischer, in charge of Regulatory Affairs at Chromsystems and responsible for implementing the new IVDR in the company. The companies are already dealing with additional, not yet conclusively manageable regulatory, personnel and financial costs for implementing the required regulations.

To date at Chromsystems newly developed methods are comprehensively and carefully validated. The conformity of the background processes are evaluated on a regular basis via external audits, which the notified body carries out on site. “We have realised many audits, including from TÜV Süd, from the US health authorities FDA, the Korean authorities and the Brazilian ANVISA, which all confirmed our conformity in accordance with all individual and country-specific regulations. This won’t change, but there will be additional duties.” Chromsystems had issued the CE declaration of conformity for each product themselves when it had fulfilled the relevant criteria and completed the processes for the development of a CE-IVD. “Soon it will no longer be possible to do it this way,” says Dr. Fischer.

This is because under the new regulation, each kit has to complete a re-classification and re-registration, meaning that self-certification will only be possible in exceptional cases. Instead, virtually each certification is completed via the notified body. This leads to a stricter documentation involving greater time and effort, but also to better monitoring after products are placed into the market. Unique Device Identification (UDI) has been introduced for improved traceability, and is mandatory from 2024: each product will require a UDI number, which will be displayed on the label, amongst other locations, and ensures that the product is easier to trace.

Fig.1: While previously 90 per cent of all IVDs were CE self-declared, and no notified body was involved, the landscape will soon change with the new regulation.

Fig.2: The clinical evidence is made up of three components: scientific validity as well as analytical and clinical performance.

The clinical evidence rests on three pillars: scientific validity, analytical performance and clinical performance (see fig. 2). For scientific validity, manufacturers like Chromsystems have to present a considerable amount of documentation to the notified body which provides evidence on the plausibility of a test: when is it making sense to determine a certain parameter, can I use it to diagnose diseases and, if yes, which ones? Is it making sense to carry out therapeutic drug monitoring for a certain drug and what evidence can I as a manufacturer provide for this? For some parameters, that is easy because there is already a wealth of scientific literature available. The analysis of biogenic amines, for example, for the diagnosis of tumours is documented by a multitude of studies. In other cases it’s a different story, such as for metabolic disorders. “If it’s possible to determine more than 40 amino acids with one assay, then studies on the significance and sensitivity are required for each of these parameters and for each disease that I would like to employ the assay for. This must then also be reflected in the intended use of the assay,” says Dr. Fischer. “This is where the manufacturer specifies what the laboratories can use the IVD test for and what not.”

Then the cut-off value for each amino acid and each disease must be defined in such a way that the test guaranteed to deliver 0 per cent false negative results while at the same time delivering a minimum of false positives. (see fig. 3). A second tier test then provides the confirmation analysis in the case of a positive test.

If a laboratory wants to use the kit or the analysis method for further applications other than those that are listed in the kit manufacturer’s intended use, then the laboratory is responsible for the medical and diagnostic performance and for the documentary obligations. The test then becomes a lab developed test (LDT).

Fig.3: In newborn screening, the cut-off value must be defined such that the test delivers
0 % false negative samples while also delivering as few false positive samples as possible.