Finding our way in the In Vitro Diagnostic Medical Devices Regulation: a discussion paper from the European Bioanalysis Forum

The EU In Vitro Diagnostic Medical Devices Regulation (IVDR) [1] was published on 5 April 2017, becoming applicable on 26 May 2022. At first, the European Bioanalysis Forum (EBF) was not concerned whether the regulations would impact the work in regulated bioanalytical laboratories, as it was our interpretation that the regulated bioanalysis community would only be involved from the sideline and in rare cases only. However, we rapidly noticed an overinterpretation by our community, our stakeholders, and by some regulatory bodies, bringing many biomarkers used in earlier phases of clinical development into the IVDR scope. This stimulated the EBF to get involved in the discussion in trying to bring what we saw as scope creep and the consequences thereof to the table. Hence, the EBF recently intensified informal discussions on the potential impact of the IVDR on activities and assays performed in regulated bioanalytical labs, since a number of EBF member company representatives increasingly voiced concern that some biomarker, immunogenicity and potentially even pharmacokinetic (PK) assays being performed in their labs to support clinical trials of investigational medicinal products were being (rightfully or not) interpreted to fall in scope of the IVDR. Of notable relevance to the EBF community were the increasing number anti-viral capsid antibody assays, biomarker assays, anti-drug antibody (ADA) assays and PCR shedding assays, where bioanalytical data might be used to support patient treatment (medical management) decisions such as inclusion/exclusion, treatment group allocation or discontinuation of post-study monitoring, rather than the traditional end point analysis that most bioanalytical laboratories were accustomed to supporting.

Learning from the scientific community

Upon publication of the Medical Device Coordination Group Document MDCG 2022-10, on the interface between clinical trials and the IVDR [2] in May 2022, a number of those concerns were confirmed, with a clear statement that clinical trial assays used for patient selection, allocation and/or monitoring were indeed considered to be within scope of, and required compliance to, the IVDR. At this point, EBF discussions solidified into a first presentation at an external meeting showing our engagement to the external scientific community to join the discussion, i.e., at the EBF Autumn Focus Workshop on “Biomarkers/Context-of-Use: Sharing Experience through Examples”, held in Malaga, Spain on 29–30 September 2022. The presentation was entitled “Spotlight on CLIA and recent IVDR – when is it relevant for biomarkers and COU?” [3] and discussed the evolving, and increasingly complex, regulatory landscape that bioanalytical labs were attempting to navigate and raised awareness of the (relatively small number) of bioanalytical assays that do fall in scope of the IVDR, the US Clinical Laboratory Improvement Amendments (CLIA) and/or Companion Diagnostic (CDx) regulatory requirements/pathways, and importantly cautioned not to overreact and apply such requirements to assays that do not fall in scope. At the time of the EBF Autumn 2022 Focus Workshop, the full impact of the IVDR on bioanalytical and biomarker laboratories and scientists was still uncertain, which it remains to this day. In early summer 2023, the EBF provided collaborative support to an Open Scientific Discussion (OSD) online meeting organized by the AAPS Precision Medicine community, faced with the same challenges. In continuation, the EBF included a discussion on the impact of IVDR on the bioanalytical community at their 16th Open Symposium in November 2023, further refining the potential role of regulated bioanalysis for the IVDR [4].

Intended scope of the IVDR

The IVDR governs in vitro diagnostic medical devices (IVDs) within the European Union, replacing the previous In Vitro Diagnostic Medical Devices Directive (IVDD), and introducing more stringent requirements for manufacturers, importers, and distributors of IVDs. In Section 1 of the IVDR, the scope of the regulation is stated as “This Regulation lays down rules concerning the placing on the market, making available on the market or putting into service of in vitro diagnostic medical devices for human use and accessories for such devices in the Union”. The regulation aims to enhance patient safety, ensure the reliability of diagnostic results, and facilitate the free movement of these devices within the European market.

It is clear that the IVDR was never written with specific considerations for measuring the drug concentration of an investigational medical product for pharmacokinetic (PK) evaluation, or for assessing the immunogenicity of a biotherapeutic. For establishment and validation of such assays, the bioanalytical laboratory should be well aware of the expectations within the ICH M10 guideline [5] and the regional immunogenicity guideline/guidance documents [6,7].

Only in highly unusual circumstances do the IVDR become relevant for a bioanalytical scientist. Each IVD assay is validated and documented for a specific intended use, in the same way that each PK, immunogenicity, and biomarker assay is developed and validated for its context-of-use (CoU).

Since the EBF Autumn 2022 Focus Workshop, EBF member companies as well as The European Federation of Pharmaceutical Industries and Associations (EFPIA) have reported significant delays in some clinical trials in Europe. EFPIA recommends implementing complementary policies that would alleviate some of the barriers created by the implementation of the IVDR and improve access to clinical trials for European patients [8]. These recommendations include:

• Delaying the application of the IVDR for clinical trials using an IVD,

• Organizing voluntary coordination processes at Member State level to improve the assessment procedure,

• Developing new guidance clarifying the assessment process,

• Considering a risk-based approach to avoid assessing IVDs that are low risk for patients,

• Accepting on a case-by case basis, and with agreement of Member States involved, to not conform with IVDR requirements if certain conditions are fulfilled,

• Clarifying the scope of in-house testing to broaden it.

It has become clear that the IVDR included limited considerations for the implications for clinical trial assays, particularly those assays used to support early clinical development of therapeutics. The IVDR focuses on manufacturing of the analytical test and putting it on the market for diagnostic purposes. Assays used in clinical trials range from fully approved IVDs, such as assays used by central laboratories and safety laboratories, to laboratory developed tests and kits labelled as research use only (RUO) that are rarely meant to be developed as IVDs.

Several questions remain, especially the need for new IVDs in early phase I and phase II clinical studies. Although the scope of the IVDR can become relevant for bioanalytical scientists in studies including rare populations, e.g., where current IVD assays do not include an intended use for inclusion or exclusion or as management of a patient [9], it is EBF's general recommendation not to expand valid scientific concerns in exceptions to become the rule for all.

To prevent assays becoming inadvertently pushed into an IVDR direction, a suggestion could be that for new drug programs and clinical studies, the intended use (CoU) of each bioanalytical test included in a given clinical study is described appropriately in the clinical trial protocol or associated documentation. A well described intended use and appropriate justifications should limit the number of tests in scope of the IVDR and thus decrease the current ambiguity and delays in clinical trials.

Conclusion

In line with our goal and mission, the EBF will continue to engage with all stakeholders involved in a diligent implementation of the IVDR regulations while raising our concerns and to bring awareness to the bioanalytical scientists involved in supporting the development of IVD, to ensure we only follow the IVDR path if it is really in the intended scope of the regulations, or, in simple words, “if it's not in scope, don't put it in scope”. We observe there is a growing risk of scope creep, i.e., applying IVDR across the board of all clinical studies, e.g., pharmacokinetic, immunogenicity, AAV or biomarker evaluation. In early clinical development, we do not know for certain if an asset will ever become a licensed drug, and likewise if an assay will require to be an approved IVD providing critical data for decision making in disease diagnosis, monitoring, and treatment in phase III or post-filing patient management. It does not serve the patient to bring such early assays into the full glare of the IVDR when it unnecessarily delays drug development without bringing any value to the patient.