The gaps between the new EU legislation on in vitro diagnostics and the on-the-ground reality.

The background to this debate is now well-known: an EU policy decision to tighten controls on the devices and diagnostics sector led to the adoption of a regulation in 2017 with a schedule for implementation over coming years - a timetable extended still further by last-minute legislation in early 2022, to provide the sector and regulators with more time to adapt to the changes. Discussions among experts organised in April by the European Alliance for Personalized Medicine (EAPM) exposed continuing challenges that cannot be fully resolved by the recent deferral of implementation deadlines. One salient problem is that there is little awareness of the In Vitro Diagnostic Regulation (IVDR) across Europe, and only limited awareness of the different structures of national systems involved in implementing IVDR, with consequent risks for patient and consumer access to in vitro diagnostics (IVDs). The tentative conclusion from these consultations is that despite a will across the sector to seek workable solutions, the obstacles remain formidable, and the potential solutions so far proposed remain more a matter of aspirations than of clear pathways.

Recommendations for validation testing of home pregnancy tests (HPTs) in Europe.

Home pregnancy tests (HPTs) available in Europe include accuracy and other performance claims listed on their packaging. Due to the lack of guidance on the standardisation of such products, it is often difficult to replicate these claims when tested on a clinical sample, whether in a laboratory setting or by lay users. The In Vitro Diagnostic Regulation is a set of requirements that mandate comprehensive validation data on human pregnancy tests and other in vitro devices. It is due to replace the current European Directive (98/79/EC) and fully implemented in Europe by 2022. In June 2019, a panel of seven experts convened to discuss the validation studies required to provide the information needed to meet the new regulation for HPTs in Europe and proposed 15 recommendations for best practice. Defining best practice at all stages of validation of these important tests may ensure that tests marketed in Europe are fit for purpose, enabling lay users to be confident of the high quality of the HPT results they obtain. The panelists believe that the recommendations proposed here for the validation of HPTs may constructively contribute to improved standardisation of validation procedures in Europe.

The new IVD Regulation 2017/746: a case study at a large university hospital laboratory in Belgium demonstrates the need for clarification on the degrees of freedom laboratories have to use lab-developed tests to improve patient care.

Objectives: The new European In Vitro Diagnostic (IVD) Regulation 2017/746 (IVDR) restricts the use of lab-developed tests (LDT) after 26th May 2022. There are no data on the impact of the IVDR on laboratories in the European Union. Methods: Laboratory tests performed in UZ Leuven were divided in four groups: core laboratory, immunology, special chemistry, and molecular microbiology testing. Each test was classified as Conformité Européenne (CE)-IVD, modified/off-label CE-IVD, commercial Research Use Only (RUO) or LDT. Each matrix was considered a separate test. Results: We found that 97.6% of the more than 11.5 million results/year were generated with a CE-IVD method. Of the 922 different laboratory tests, however, only 41.8% were CE-IVD, 10.8% modified/off-label CE-IVD, 0.3% RUO, and 47.1% LDT. Off-label CE-IVD was mainly used to test alternative matrices not covered by the claim of the manufacturer (e.g., pleural or peritoneal fluid). LDTs were mainly used for special chemistry, flow cytometry, and molecular testing. Excluding flow cytometry, the main reasons for the use of 377 LDTs were lack of a CE-IVD method (71.9%), analytical requirements (14.3%), and the fact the LDT was in use before CE-IVD available (11.9%). Conclusions: While the large majority of results (97.6%) were generated with a CE-IVD method, only 41.8% of laboratory tests were CE-IVD. There is currently no alternative on the market for 71.5% of the 537 LDTs performed in our laboratory which do not fall within the scope of the current IVD directive (IVDD). Compliance with the IVDR will require a major investment of time and effort.

Semi-automated serum steroid profiling with tandem mass spectrometry.

Objectives: Highly selective and sensitive multi-analyte methods for the analysis of steroids are attractive for the diagnosis of endocrine diseases. Commercially available kits are increasingly used for this purpose. These methods involve laborious solid phase extraction, and the respective panels of target analytes are incomplete. We wanted to investigate whether an improvement of kit solutions is possible by introducing automated on-line solid phase extraction (SPE) and combining originally separate analyte panels. Methods: Sample preparation was performed using automated on-line SPE on a high-pressure stable extraction column. Chromatographic separation, including isobaric compounds, was achieved using a 0.25 mM ammonium fluoride-methanol gradient on a small particle size biphenyl column. Standard compounds and internal standard mixtures of two panels of a commercially available kit were combined to achieve an optimized and straightforward detection of 15 endogenous steroids. Validation was performed according to the European Medicines Agency (EMA) guidelines with slight modifications. Results: Validation was successfully performed for all steroids over a clinically relevant calibration range. Deviations of intra- and inter-assay accuracy and precision results passed the criteria and no relevant matrix effects were detected due to highly effective sample preparation. External quality assessment samples showed the applicability as a routine diagnostic method, which was affirmed by the analyses of anonymized clinical samples. Conclusions: It was found possible to complement a commercially available kit for quantitative serum steroid profiling based on isotope dilution LC-MS/MS by implementing automated on-line SPE, thereby improving the practicality and robustness of the measurement procedure.

D-dimer Testing in Pulmonary Embolism with a Focus on Potential Pitfalls: A Narrative Review.

D-dimer is a multifaceted biomarker of concomitant activation of coagulation and fibrinolysis, which is routinely used for ruling out pulmonary embolism (PE) and/or deep vein thrombosis (DVT) combined with a clinical pretest probability assessment. The intended use of the tests depends largely on the assay used, and local guidance should be applied. D-dimer testing may suffer from diagnostic errors occurring throughout the pre-analytical, analytical, and post-analytical phases of the testing process. This review aims to provide an overview of D-dimer testing and its value in diagnosing PE and discusses the variables that may impact the quality of its laboratory assessment.

Pre-analytical processes in medical diagnostics: New regulatory requirements and standards.

In May 2017, the European In Vitro Diagnostic Regulation (IVDR) entered into force and will apply to in vitro diagnostics from May 26th, 2022. This will have a major impact on the in vitro diagnostics (IVD) industry as all devices falling under the scope of the IVDR will require new or re-certification. It will also affect health institutions developing and using in-house devices. The IVDR also has implications with respect to product performance validation and verification including the pre-analytics of biological samples used by IVD developers and diagnostic service providers. In parallel to the IVDR, a series of standards on pre-analytical sample processing has been published by the International Organization for Standardization (ISO) and the European Committee for Standardization (CEN). These standards describe pre-analytical requirements for various types of analyses in various types of biospecimens. They are of relevance for IVD product developers in the context of (re)certification under the IVDR and to some extent also to devices manufactured and used only within health institutions. This review highlights the background and the rational for the pre-analytical standards. It describes the procedure that leads to these standards, the major implications of the standards and the requirements on pre-analytical workflows. In addition, it discusses the relationship between the standards and the IVDR.