In Vitro Diagnostic Medical Devices Research Articles

An improved implementation of metrological traceability concepts is needed to benefit from standardization of laboratory results.

Non-harmonization of laboratory results represents a concrete risk for patient safety. To avoid harms, it is agreed that measurements by in vitro diagnostic medical devices (IVD-MD) on clinical samples should be traceable to higher-order references and adjusted to give the same result. However, metrological traceability is not a formal claim and has to be correctly implemented, which in practice does not happen for a non-negligible number of measurands. Stakeholders, such as higher-order reference providers, IVD manufacturers, and External Quality Assessment organizers, have major responsibilities and should improve their contribution by unambiguously and rigorously applying what is described in the International Organization for Standardization 17511:2020 standard and other documents provided by the international scientific bodies, such as Joint Committee on Traceability in Laboratory Medicine and IFCC. For their part, laboratory professionals should take responsibility to abandon non-selective methods and move to IVD-MDs displaying proper selectivity, which is one of the indispensable prerequisites for the correct implementation of metrological traceability. The practicality of metrological traceability concepts is not impossible but relevant education and appropriate training of all involved stakeholders are essential to obtain the expected benefits in terms of standardization.

Assessing operational readiness: Regulatory landscape and compliance in zimbabwe for medical devices and in vitro diagnostic medical devices.

The regulation of medical devices and In Vitro Diagnostic (IVD) medical devices have lagged significantly, especially in low- and middle-income countries. Disparities in regulating medical and IVD medical devices in Africa are below the global average. This may translate to poor access to quality-assured medical and IVD devices, resulting in undesirable health outcomes. Operational readiness to regulate medical and IVD devices at the Medicines Control Authority of Zimbabwe (MCAZ) was assessed. The aim was to determine the strengths and gaps and propose an action plan that can be monitored and evaluated to assess progress over time. We used the World Health Organization (WHO) Global Benchmarking Tool for medical devices and IVDs methodology to evaluate regulatory oversight of these products. Purposive sampling was used for data collection using researcher-administered global benchmarking tool factsheets and document reviews to evaluate the implementation of the regulatory functions. The regulatory functions assessed were the National Regulatory System, Registration and Market Authorization, Vigilance, Market Surveillance and Control, Licensing Establishment, Regulatory Inspection, Laboratory Testing, and Clinical Trials Oversight. The MCAZ attained maturity level 1, with a regulatory system score of 79%, registration and market authorization 44%, vigilance 27%, market surveillance and control 40%, licensing establishment 62%, regulatory inspection 68%, laboratory testing 88%, and clinical trials 18%. Condoms and gloves were the only regulated medical devices in Zimbabwe. IVDs were not regulated by the MCAZ. This review showed that the regulatory system is not robust, fit for purpose, responsive, transparent, or proportionate to the risk classification of medical devices and IVDs. It is crucial to amend the Medicines and Allied Substance Control Act to incorporate the definition and classification of medical devices and IVDs, regulatory authority establishment, licensing and registration, quality management system, conformity assessment, post-market surveillance, labeling and instructions for use, capacity building and training, and international harmonization.

Regulation of blood-screening in vitro diagnostics in sub-Saharan African countries remains a challenge.

According to the World Health Organization, blood must be screened for major transmitted infections before transfusion to prevent the possibility of passing an infection to the recipient. For accurate detection of infectious disease pathogens in the blood of donors, in-vitro diagnostic medical devices (IVDs) of high specificity and sensitivity should be used. In mature healthcare systems, the regulatory authorities authorize the usage of devices with the highest performance capabilities, which are also controlled through active market oversight. However, in Sub-Saharan African countries, the regulation of IVDs is often poorly developed. With the lack of stringent regulatory oversight, IVDs of poor quality can be put on the market and used for blood donor screening, which, ultimately, poses a great public health threat. The BloodTrain is a humanitarian project from the Germany Federal Ministry of Health that aims to help strengthen the regulatory authorities in Sub-Saharan partner countries. Here, we present the status of IVD regulation in the partner countries and the objectives that the BloodTrain project aims to achieve in the region toward regulating IVDs.

Recommendations for Setting a Criterion and Assessing Commutability of Sample Materials Used in External Quality Assessment/Proficiency Testing Schemes.

It is important for external quality assessment materials (EQAMs) to be commutable with clinical samples; i.e., they should behave like clinical samples when measured using end-user clinical laboratory in vitro diagnostic medical devices (IVD-MDs). Using commutable EQAMs makes it possible to evaluate metrological traceability and/or equivalence of results between IVD-MDs. The criterion for assessing commutability of an EQAM between 2 IVD-MDs is that its result should be within the prediction interval limits based on the statistical distribution of the clinical sample results from the 2 IVD-MDs being compared. The width of the prediction interval is, among other things, dependent on the analytical performance characteristics of the IVD-MDs. A presupposition for using this criterion is that the differences in nonselectivity between the 2 IVD-MDs being compared are acceptable. An acceptable difference in nonselectivity should be small relative to the analytical performance specifications used in the external quality assessment scheme. The acceptable difference in nonselectivity is used to modify the prediction interval criterion for commutability assessment. The present report provides recommendations on how to establish a criterion for acceptable commutability for EQAMS, establish the difference in nonselectivity that can be accepted between IVD-MDs, and perform a commutability assessment. The report also contains examples for performing a commutability assessment of EQAMs.

A Systematic Database Approach to Identify Companion Diagnostic Testing in Clinical Trials under the New In Vitro Diagnostic Medical Devices Regulation.

The European Union In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR) introduces companion diagnostics (CDx) as a new legal term. CDx are applied in combination with a medicinal product to identify patient subgroups most likely to benefit from a treatment or who are at increased risk. This new regulation came into full effect on 26 May 2022 and represents the current development in personalized medicine. The implementation of IVDR and CDx is a regulatory challenge in the EU, requiring re-assessment of in vitro diagnostic medical devices (IVD) in terms of their CDx designation. To retrospectively identify IVD biomarker testing applied in clinical trials, a systematic search in the German PharmNet Clinical Trials database was developed. In total 3643 clinical trials conducted between 2004 and 2022 were identified. The results were analyzed in terms of medicinal products, biomarkers, and IVDs. Patient stratification based on biomarker testing mainly takes place in oncology-related trials, and the biomarkers most frequently tested are PD-L1 and HER2. Furthermore, there is a significant overlap between the collected data and non-European national authorities that have already implemented the CDx concept. This analysis could be indicatory of the medicinal products and corresponding IVD tests that could be CDx candidates under the IVDR.

Structure and content of the EU-IVDR

Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) was passed by the European Parliament and the Council of the European Union on 5 April 2017 and came into force on 26 May 2017. Anew amending regulation, which introduces aphased implementation of the IVDR with new transitional provisions for certain in vitro diagnostic medical devices (IVDs) and alater date of application of some requirements for in-house devices for healthcare facilities, was adopted on 15 December 2021. The combined use of CE-certified IVDs (CE-IVDs), in-house IVDs (IH-IVDs), and research use only (RUO) devices are acornerstone of diagnostics in pathology departments and crucial for optimal patient care. The IVDR not only regulates the manufacture and placement on the market of industrially manufactured IVDs, but also imposes conditions on the manufacture and use of IH-IVDs for internal use by healthcare facilities. Our work provides an overview of the background and structure of the IVDR and identifies core areas that need to be interpreted and fleshed out in the context of the legal framework as well as expert knowledge. The gaps and ambiguities in the IVDR crucially require the expertise of professional societies, alliances, and individual stakeholders to successfully facilitate the implementation and use of the IVDR in pathology departments and to avoid aberrant developments.

Guidance on Which Calibrators in a Metrologically Traceable Calibration Hierarchy Must Be Commutable with Clinical Samples.

Equivalent results for the same measurand in clinical samples (CSs), measured using different end-user in-vitro diagnostic medical devices (IVD-MDs), are essential for the application of clinical practice guidelines for diagnosis, treatment, monitoring, or risk assessment. The International Organization for Standardization (ISO) document 17511:2020 specifies how to establish metrological traceability to the highest available reference system component to enable equivalent results among IVD-MDs. Commutability with CSs is an essential property of a reference material used as a calibrator in a calibration hierarchy. However, not all calibrators in a calibration hierarchy are required to be commutable; different calibration hierarchies have different requirements for which calibrators must be commutable with CSs. Because assessment of commutability is a substantial effort, it is therefore important to determine which calibrators need to be commutable when implementing a calibration hierarchy. We provide guidance on which calibrators must be commutable with CSs, when a correction for any noncommutability bias is appropriate, and when commutability of a calibrator with CSs is not required for various types of calibration hierarchies described in ISO 17511:2020.

Redesigning the surveillance of in vitro diagnostic medical devices and of medical laboratory performance by quality control in the traceability era.

IVD manufacturers have total responsibility in terms of the traceability of marketed in vitro diagnostic medical devices (IVD-MD). This includes the provision of a quality control (QC) material as a part of the measuring system, suitable for traceability verification and alignment surveillance by end-users in daily practice. This material [to be used for the internal QC (IQC) component I as described in this paper] should have unbiased target values and an acceptability range corresponding to analytical performance specifications (APS) for suitable (expanded) measurement uncertainty (MU) on clinical samples. On the other hand, medical laboratories (by the IQC component II as described in this paper) should improve the IQC process and its judging criteria to establish a direct link between their performance, estimated as MU of provided results, and APS defined according to recommended models to apply corrective actions if the performance is worsening with the risk to jeopardize the clinical validity of test results. The participation to external quality assessment (EQA) programs that meet specific metrological criteria is also central to the evaluation of performance of IVD-MDs and of medical laboratories in terms of harmonization and clinical suitability of their measurements. In addition to the use of commutable materials, in this type of EQA it is necessary to assign values to them with selected reference procedures and to define and apply maximum allowable APS to substantiate the suitability of laboratory measurements in the clinical setting.

Implementing Regulation (EU) 2017/746 of 5 April 2017 on In vitro Diagnostic Medical Devices (IVDR) in Medical Laboratories, especially in Ophthalmopathology.

The European Commission revised Directive 98/79/EC on in vitro diagnostic medical devices (IVDD) to improve patient safety and take appropriate account of technical progress. With the new Regulation (EU) 2017/746 of April 5, 2017 on in vitro diagnostic medical devices (IVDR), high standards for the quality and safety of in vitro diagnostic medical devices (IVD) apply within the European Union. The IVDR is primarily aimed at manufacturers and suppliers of IVDs, but also has significant implications for medical diagnostic laboratories. Its application is mandatory as of May 26, 2022. IVD are classified into four risk classes A to D according to their intended purpose and the associated risks. For the first time, EU-wide legal requirements are formulated for products manufactured in-house. Any medical laboratory that uses "laboratory-developed tests" (LDT), or modifies or uses CE-IVD products outside the manufacturer's specifications, becomes a manufacturer itself and IVDR Article 5 (5) applies in its entirety. Production and use of LDT must then be performed within the framework of appropriate QM systems. The health care facility must comply with certain provisions (standards), in Germany the Rili-BÄK is to be mentioned here. LDT are subject to the safety and performance requirements listed in Annex 1 to the IVDR, including the requirement for validation prior to first use, while commercial CE-IVD products only require verification. Regulation (EU) 2022/112 of January 25, 2022, provides for staggered transition periods of up to six years for some of these requirements, but it is expected that many laboratories will switch from LDT to commercial CE-marked IVD products because ultimately this will be more resource-efficient for them. In this article, we describe the requirements for medical diagnostic laboratories resulting from the IVDR and offer solution concepts for their implementation in smaller, especially ophthalmopathology laboratories.

Critical Implications of IVDR for Innovation in Diagnostics: Input From the BioMed Alliance Diagnostics Task Force.

Critical Implications of IVDR for Innovation in Diagnostics: Input From the BioMed Alliance Diagnostics Task Force.

Advisory opinion of the AWMF Ad hoc Commission In-vitro Diagnostic Medical Devices regarding in-vitro diagnostic medical devices manufactured and used only within health institutions established in the Union according to Regulation (EU) 2017/746 (IVDR).

In view of the approaching application date of Regulation (EU) 2017/746 („IVDR“) and the resulting EU-wide, harmonized requirements for in-vitro diagnostic medical devices (IVD) manufactured and used within European health institutions, the Ad hoc Commission IVD of the German Association of the Scientific Medical Societies (AWMF) takes a national position on the details of the requirements and conditions related to the use of these IVD products.The Ad hoc Commission IVD emphasizes the relevance of examination procedures developed in medical laboratories, especially in the field of orphan diseases and new diagnostic markers. The IVDR sets an adequate regulatory framework for IVD manufactured and used within health institutions as long as these requirements are fulfilled with reliability and in accordance with the current state of the art in medical laboratory sciences. At the same time, the IVDR requirements have to be regarded under a pragmatic view and in accordance with the quality management systems approved within the different EU Member States. On the one hand, the mandatory requirements of the RiLiBÄK play an essential role in Germany. On the other hand, elements of voluntarily applicable international standards may support the fulfilment of product requirements for safety and performance according to Annex I of the IVDR. Both the complexity and possible solutions for the implementation of the IVDR requirements are discussed on the basis of examples such as the required documentation, performance evaluation and software validation.The Ad hoc Commission IVD recommends that, while aiming at a preferably EU-wide harmonized interpretation of the IVDR requirements, the flexibility in medical laboratory diagnostics necessary for patient care, including the use of IVD from in-house production, should be emphasized.

How the European in vitro diagnostic regulation could negatively impact the European response to the next pandemic: an urgent call for action before May 2022

Abstract The Corona Virus Disease 2019 (COVID-19) pandemic has demonstrated that the ability for laboratories to quickly set up and implement labdeveloped tests (LDTs) is essential to respond to an emerging health crisis. The Regulation on in vitro diagnostic medical devices (IVDR) could, however, profoundly impact our ability to respond to a future pandemic since the IVDR could significant restrict the use of LDTs. We address using the example of the current pandemic a number of LDT implementing issues problems which should be addressed. We conclude that the COVID-19 pandemic illustrates that commercial tests cannot cover all patient needs under any given circumstance and that sufficient degrees of freedom for laboratories to ensure their expertise to develop and implement LDTs ultimately benefit European citizens.

The end of the laboratory developed test as we know it? Recommendations from a national multidisciplinary taskforce of laboratory specialists on the interpretation of the IVDR and its complications.

The in vitro diagnostic medical devices regulation (IVDR) will take effect in May 2022. This regulation has a large impact on both the manufacturers of in vitro diagnostic medical devices (IVD) and clinical laboratories. For clinical laboratories, the IVDR poses restrictions on the use of laboratory developed tests (LDTs). To provide a uniform interpretation of the IVDR for colleagues in clinical practice, the IVDR Task Force was created by the scientific societies of laboratory specialties in the Netherlands. A guidance document with explanations and interpretations of relevant passages of the IVDR was drafted to help laboratories prepare for the impact of this new legislation. Feedback from interested parties and stakeholders was collected and used to further improve the document. Here we would like to present our approach to our European colleagues and inform them about the impact of the IVDR and, importantly we would like to present potentially useful approaches to fulfill the requirements of the IVDR for LDTs.

The EU one-stop-shop collection of publicly available information on COVID-19 in vitro diagnostic medical devices.

The JRC COVID-19 In Vitro Diagnostic Devices and Test Methods Database, aimed to collect in a single place all publicly available information on performance of CE-marked in vitro diagnostic medical devices (IVDs) as well as in house laboratory-developed devices and related test methods for COVID-19, is here presented. The database, manually curated and regularly updated, has been developed as a follow-up to the Communication from the European Commission "Guidelines on in vitro diagnostic tests and their performance" of 15 April 2020 and is freely accessible at https://covid-19-diagnostics.jrc.ec.europa.eu/.

In vitro diagnostics for screening the blood supply: the new European regulation for IVD and the WHO IVD prequalification programme.

Blood transfusion remains a routine life-saving medical procedure that helps replace blood lost due to surgery, injury or disease. The quality of transfused blood is crucial in this process as blood donors must be free of transfusion-transmissible infections and donated blood should be compatible to that of the recipient. The quality of donated blood could be affected by the quality of in vitro diagnostic medical devices (IVDs) used in the screening process. Consequently, the need for high-quality, safe and well-performing IVDs for use in transfusion medicine arises, accompanied by the need for tight regulations in this domain. In the European Union, the new IVD Regulation will replace the existing IVD Directive within a five-year transitional period. Manufacturers of IVDs are expected to fully comply with the new Regulation by 26 May 2022. In this review, we address the major differences relating to marketing authorization and testing between this new Regulation and its predecessor. We further present the main elements of the prequalification assessment introduced by the WHO for IVDs, including disease-specific IVDs for blood screening laboratories.

Electro-medical devices: Environmental regulation on hazardous substances

In this study, we summarize the drastic restrictions introduced in the last eight years within the European environmental legislation governing electro-medical devices, and highlight manufacturer's obligations to demonstrate compliance with these rules. On July 1, 2011, the recast of the Directive on the Restriction of the use of certain Hazardous Substances in electrical and electronic equipment (known as RoHS II) was published in the European Official Journal. This Directive, that within its scope, included medical devices (MDs) and in-vitro diagnostic medical devices (IVDs), aimed to limit the amount of six toxic materials released into the environment through discarded electrical and electronic equipment (EEE). MDs and IVDs had to be RoHS II compliant from July 22, 2014 and July 22, 2016 respectively. On June 4, 2015, the EU Commission published RoHS III, a new Directive that limited the content of four additional substances belonging to the phthalates group. According to RoHS III, phthalates will be subject to restriction for all EEE, starting from July 22, 2019, with the exception of MDs and monitoring and control equipment which will need another two years. RoHS II is a CE marking Directive; therefore, manufacturers must adhere to its requirements both in technical documentation and in subsequent EU declaration of conformity before affixing the “CE” mark on their finished products. RoHS III is also a CE marking Directive that medical device manufacturers will have to apply starting from July 22, 2021. Although this seems a long time, manufacturers need to start meeting the RoHS III requirements by now to avoid the risk of being out of business for that date.

ISO 15189 accreditation and competence: a new opportunity for laboratory medicine

The International Standard Organization (ISO) 15189 accreditation has raised new enthusiasm among laboratory professionals. On the one hand, it satisfies the desire to undertake a pathway attesting the high degree of quality of laboratory performance measured according to the important role of Laboratory Medicine throughout patient care. On the other hand, it allows demonstrating how the competence of each staff member produces a great impact on the level of achieved performance. However, laboratory staff must recognize that application of ISO 15189 needs great commitment in terms of both time and efforts but, before all, in terms of ability to express competence. The application of ISO 15189 is needed for collecting experiences from different laboratories and identifying the most suitable approaches to comply with requirements and oversee challenges. A close cooperation among national Scientific Societies, as expression of medical laboratories, manufacturers of in vitro diagnostic medical devices (IVD) and national Accreditation Body is needed to guarantee success of ISO 15189 Accreditation.

Performance evaluation of in vitro diagnostic medical devices: Methodology and differences compared to studies on other medical devices

The aim of this article is to summarize the rules governing Performance Evaluation on In Vitro Diagnostic Medical Devices (IVDs) and to outline the main differences compared to studies on other Medical Devices (MDs) in the European Union (EU). In fact, the term “Performance Evaluation” is exclusive to IVDs. For other MDs, the term “Clinical Evaluation” is used. However, the aim of both terms is the same: to demonstrate that a device meets the “Essential Requirements” of safety and performance. On the contrary, the methodology through performance evaluation for IVDs and clinical evaluation for other MDs are performed, is different: UNI EN ISO 14155:2011 only for MDs and EN 13612:2002 only for IVDs. This difference is due to the fact that IVDs, unlike other MDs, do not generally come into contact with patients. Therefore, it can be difficult to demonstrate direct harm to patients, unless the device itself causes deterioration in the state of health. Harm to patients is more likely to be indirect. However, in May 2017 two new regulations on MDs have been published, the first one concerning IVDs and the second one concerning other MDs. These new regulations may represent a real revolution. There will be very important changes to the requirements required to demonstrate clinical evidence. With regard to IVDs, clinical performance studies shall be carried out in the absence of clinical performance data. Moreover, performance studies should be in line with international standards, such as ISO 14155:2011, and the Declaration of Helsinki, and many others are the changes on the horizon.

Evaluation of the first Turkish in vitro diagnostic symposium

Abstract In vitro diagnostic (IVD) medical laboratory devices, tests and equipment are closely related with public health, patient safety and the safety of all who utilize these tools in laboratories. The close monitoring of the process from the production line to the end-point user is crucial so that IVD devices and tests do not pose a risk to individuals and society. Based on this background, the “First Turkish in vitro Diagnostic Symposium: Medical Laboratory Tests” was held in February, 2016. The symposium was organized by the cooperation of Turkish Biochemical Society, Izmir Branch and Dokuz Eylul University Health Sciences Institute along with the contributions of TurkLab Calibration Association. It was intended that the meeting would shed light on questions such as, ‘What is the place and importance of IVD in Turkey?’, ‘What are the responsibilities of educational institutions?’, ‘What is the role of Ministry of Health?’, with the aim that the answers would help to determine the infrastructure needed for successful production of IVD medical devices in Turkey. At the end of the symposium, feedback from participants were collected via a questionnaire. This article presents the general evaluation of the symposium based on the results of this survey.

Direct‐to‐consumer genetic testing — a regulatory nightmare?

The age of personalised medicine has seen the rapid emergence of a direct-to-consumer (DTC) genetic testing industry. While various forms of DTC testing have been available for many years, the emergence of DTC genetic testing is raising new concerns relating to the accuracy of predictions, and potential harms to consumers given there is typically no individualised genetic counselling. DTC testing also has the capacity to increase pressure on an already overstretched health care system if confused consumers seek assistance from health practitioners in interpreting test results. In Australia, a number of companies advertise genetic testing directly to consumers. While some require that a health professional orders the tests and communicates results to the consumer, others offer unmediated services. Internationally, private companies are entering the DTC genetic testing market in increasing numbers. More likely than not, Australian consumers are responding to online advertising by these companies and sending their tissue samples for analysis overseas. There is a growing body of academic commentary internationally calling for more stringent regulation of the industry. In many countries, genetic tests are already included within regimens regulating therapeutic goods, in the form of in-vitro diagnostic medical devices (IVDs). However, there is ongoing debate as to whether such regimens adequately regulate DTC testing, and a lack of consistency in regulatory approaches between countries, even within Europe. In 2003, the Australian Law Reform Commission and Australian Health Ethics Committee concluded in Essentially yours, the report of their inquiry into the protection of genetic information, that there are strong arguments for regulating the supply, directly to the public, of products used in some forms of genetic Essentially yours also canvassed the difficulties associated with regulating foreign companies offering DTC genetic testing through the internet. The Australian Therapeutic Goods Act 1989 (Cwlth) (the Act) applies to all therapeutic goods imported into, supplied in and exported from Australia. In 2002 a new regulatory framework was established for medical devices through the Therapeutic Goods (Medical Devices) Regulations 2002 (Cwlth) (the Regulations). Amendments to the Regulations in 2010 introduced an IVD regimen for genetic tests. In this article we provide a brief overview of how this new regimen regulates IVDs, and some thoughts on its likely effect on DTC genetic testing. It is not our intention to add to the extensive debate surrounding the ethical and legal implications of DTC testing, or to take a position on the appropriate regulatory response.