In Vitro Diagnostic Devices Research Articles

Validation and verification framework and data integration of biosensors and invitro diagnostic devices: a position statement of the IFCC Committee on Mobile Health and Bioengineering in Laboratory Medicine (C-MBHLM) and the IFCC Scientific Division.

Advances in technology have transformed healthcare and laboratory medicine. Biosensors have emerged as a promising technology in healthcare, providing a way to monitor human physiological parameters in a continuous, real-time, and non-intrusive manner and offering value and benefits in a wide range of applications. This position statement aims to present the current situation around biosensors, their perspectives and importantly the need to set the framework for their validation and safe use. The development of a qualification framework for biosensors should be conceptually adopted and extended tocover digitally measured biomarkers from biosensors for advancing healthcare and achieving more individualized patient management and better patient outcome.

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.

Retrospective on molecular assay design for detecting pan-orthopox viruses and prospective on mpox laboratory preparedness and readiness

The landscape of in vitro diagnostic (IVD) devices encompasses a broad range of tests that have been used to detect and diagnose pathogens, especially tropical diseases, for decades. The COVID-19 pandemic exemplified the greater need for bringing IVDs from the laboratory directly to the consumer, and recent outbreaks such as mpox, Sudan ebolavirus, and Marburg virus further reinforce this need. The increased emergence of tropical disease outbreaks requires more agile development, higher performance, and mass production of IVD devices. Furthermore, lessons learned in previous device developments can sometimes be used to accelerate new disease diagnostic applications. As an example, we describe one case history of an earlier pan-orthopox viral assay that detected smallpox variola and vaccinia strains, and also discerned related strains including mpox. This work established the foundation for the molecular detection of orthopox viruses, which could be mobilized to address public health needs once an emergency declaration was made that opened the FDA pathway for issuing an emergency use authorization for the use of these assays. Thus, the utilization of knowledge from earlier investments was shown to enhance preparedness and readiness. Here in this retrospective, we elaborate on the processes that enable this approach, including multi-disciplinary and multisectoral collaborations to accomplish a holistic, one health world.

Ideas and Briefing about Regulatory Requirements for Laboratory Developed Tests in the US

As a special kind of in vitro diagnostic devices（IVDs）, laboratory developed tests（LDTs） are of great significance to the development of clinical laboratories. This study aims to explore the regulatory requirements ideas of LDTs. By introducing the development of LDTs and the changing of regulatory requirements in the United States, combing the current regulatory framework and discussing relevant ideas in the regulatory requirements of LDTs.

Early Dynamics of Hepatitis B Virus (HBV)-DNA and Surface Antigen (HBsAg) in Ramp-Up Phase of Viremia: Implications for Performance Evaluation of Blood Screening Assays.

The Common Specifications/EU 2017/746 regulation for market approval of class D in vitro diagnostic devices (IVDs) intended for detection of blood borne viruses requires testing of the International Standard and 10–30 seroconversion panels to demonstrate ‘state of the art’ assay performance. We examined whether these requirements for performance evaluation are reasonable for HBV-DNA and HBsAg assays. For this purpose, we quantified HBsAg and HBV-DNA (genotype A) in the ramp-up phase of five seroconversion panels and demonstrated a remarkably parallel increase in the Log concentration of both analytes over time. Testing of seroconversion panels by three nucleic acid amplification technology (NAT) methods in multiple replicates and probit analysis with sufficient critical samples from all five panels taken together showed detection limits in copies/mL that were comparable to those on a HBV-DNA genotype A standard dilution panel. This indicates that the viral doubling time in the ramp-up phase is equal above and below the quantification limit of the viral load assay. The geometric mean HBsAg (PRISM) cutoff crossing point was 20 days later than the 50% NAT (Ultrio Plus) conversion point equivalent to 1500 (range: 1100–2200) and 4.8 (CI: 3.7–6.4) HBV-DNA copies/mL, respectively. Analytical sensitivity data of different NAT assay versions obtained over a decade demonstrated that the detection limit on the International Standard is not representative of all genotyped reference samples. From our detailed mathematical analysis, we conclude that HBV-DNA and HBsAg standard dilution series are functionally equivalent to seroconversion panels. A general requirement of a 95% detection limit ≤100 HBV-DNA copies/mL for different viral genotypes would be a better-defined regulation for EU market approval of NAT blood screening assays than the testing of multiple seroconversion panels to claim ‘state of the art’ performance.

Biomarkers for Alzheimer's Disease: Context of Use, Qualification, and Roadmap for Clinical Implementation.

Background and Objectives: The US Food and Drug Administration (FDA) defines a biomarker as a characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention. Biomarkers may be used in clinical care or as drug development tools (DDTs) in clinical trials. The goal of this review and perspective is to provide insight into the regulatory guidance for the use of biomarkers in clinical trials and clinical care. Materials and Methods: We reviewed FDA guidances relevant to biomarker use in clinical trials and their transition to use in clinical care. We identified instructive examples of these biomarkers in Alzheimer’s disease (AD) drug development and their application in clinical practice. Results: For use in clinical trials, biomarkers must have a defined context of use (COU) as a risk/susceptibility, diagnostic, monitoring, predictive, prognostic, pharmacodynamic, or safety biomarker. A four-stage process defines the pathway to establish the regulatory acceptance of the COU for a biomarker including submission of a letter of intent, description of the qualification plan, submission of a full qualification package, and acceptance through a qualification recommendation. Biomarkers used in clinical care may be companion biomarkers, in vitro diagnostic devices (IVDs), or laboratory developed tests (LDTs). A five-phase biomarker development process has been proposed to structure the biomarker development process. Conclusions: Biomarkers are increasingly important in drug development and clinical care. Adherence to regulatory guidance for biomarkers used in clinical trials and patient care is required to advance these important drug development and clinical tools.

Explainability and causability for artificial intelligence-supported medical image analysis in the context of the European In Vitro Diagnostic Regulation

Artificial Intelligence (AI) for the biomedical domain is gaining significant interest and holds considerable potential for the future of healthcare, particularly also in the context of in vitro diagnostics. The European In Vitro Diagnostic Medical Device Regulation (IVDR) explicitly includes software in its requirements. This poses major challenges for In Vitro Diagnostic devices (IVDs) that involve Machine Learning (ML) algorithms for data analysis and decision support. This can increase the difficulty of applying some of the most successful ML and Deep Learning (DL) methods to the biomedical domain, just by missing the required explanatory components from the manufacturers. In this context, trustworthy AI has to empower biomedical professionals to take responsibility for their decision-making, which clearly raises the need for explainable AI methods. Explainable AI, such as layer-wise relevance propagation, can help in highlighting the relevant parts of inputs to, and representations in, a neural network that caused a result and visualize these relevant parts. In the same way that usability encompasses measurements for the quality of use, the concept of causability encompasses measurements for the quality of explanations produced by explainable AI methods. This paper describes both concepts and gives examples of how explainability and causability are essential in order to demonstrate scientific validity as well as analytical and clinical performance for future AI-based IVDs.

Postmarketing Surveillance of In-vitro Diagnostic System in the European Union

Advances in medical device technology and regulatory authorization adapt to changing requirements and market conditions. The assessment of safety and performance in the real-world scenario will help us understand clinical benefits and help in the evolution of the medical device and in-vitro diagnostic devices. The paradigm shift in the evaluation of medical devices and in vitro diagnostic devices will ensure that the device delivers intended benefits. This article discusses the new approach of the post-marketing surveillance in the context of new in vitro diagnostic regulation in the European Union.

Trends in Molecular Testing of Lung Cancer in Mainland People’s Republic of China Over the Decade 2010 to 2019

IntroductionLung cancer is the leading cause of cancer-related morbidity and mortality in the People’s Republic of China. Targeted therapies for patients with lung cancer, which depend on accurate identification of actionable genomic alteration, have improved survival compared with previously available treatments. However, data on the types of molecular testing often used in the People’s Republic of China, and how they have changed over time, are scarce. We explored the overall landscape of molecular testing of lung cancer in mainland People’s Republic of China in the past decade. MethodsWe distributed a stratified random sampling survey of molecular testing to 49 hospitals from members of the Molecular Pathology Collaboration Group of Chinese Anti-Cancer Association which was weighted by the numbers of lung cancer cases in seven different geographic regions in mainland People’s Republic of China from 2010 to 2019. The questionnaire contained four parts for all respondents. The questionnaire ascertained the use of approved in vitro diagnostic (IVD) devices published by the Center for Medical Device Evaluation, National Medical Products Administration of the People’s Republic of China. ResultsA total of 226,227 NSCLC specimens were tested from 2010 to 2019 in the selected hospitals. The annual number of initiated molecular tests increased over time (p < 0.0001), with an average annual growth rate of 31.8%. A notable increase in the number of molecular tests occurred during 2014 and 2016, which coincided with the approval of the National Medical Products Administration to IVD devices. For the diagnosis of molecular subtypes, EGFR mutation testing was first conducted in year 2007, followed by ALK translocation testing in 2010 and ROS1 in 2011. For other rare genetic variations in NSCLC, BRAF mutation testing was first launched in 2012, MET exon 14 skipping mutation in 2014, HER2 exon 20 mutations in 2017, and RET translocation in 2015. A markedly uneven distribution was also observed in the geography of leading units with the largest number of leading units located in east People’s Republic of China (34.7%, 17 of 49) and the smallest number located in northwest People’s Republic of China (6.1%, 3 of 49). The growth trends we observed illustrate the progress and increasing capability of molecular testing of lung cancer achieved in mainland People’s Republic of China in the decade from 2010. ConclusionsIn the decade 2010 to 2019, progress and increased capability of molecular testing of lung cancer were achieved in mainland People’s Republic of China. Further efforts should address the clinical application of next-generation sequencing technology, rare genomic aberrations, and the balance between novel genomic testing techniques and the approval of IVD products.

A Zika Reference Panel for Molecular-Based Diagnostic Devices as a US Food and Drug Administration Response Tool to a Public Health Emergency

In 2015, Zika virus (ZIKV) appeared as an emerging pathogen, generating a global and urgent need for accurate diagnostic devices. During this public health crisis, several nucleic acid testing (NAT)-based Zika assays were submitted to the US Food and Drug Administration (FDA) for Emergency Use Authorization. The FDA's Center for Devices and Radiological Health, in collaboration with the FDA's Center for Biologics Evaluation and Research, responded to this Zika emergency by developing and producing a reference panel (RP) for Zika RNA (Zika FDA-RP) suitable for performance assessment of ZIKV NAT-based invitro diagnostic devices. Reference panels are a fundamental tool for performance assessment of molecular tests. The panel is composed of five vials: two different heat-inactivated ZIKV strains (PRVABC59 and FSS13025) in concentrated stocks and three blinded concentrations prepared from those strains. The Zika FDA-RP was shared with developers who had devices in the final stages of validation. Invitro diagnostic developers tested the Zika FDA-RP using the FDA-provided protocol. Depending on sample type, 85% (12/14) of the NAT assays had analytical sensitivities between 500 and 5000 RNA NAT-detectable units/mL (NDUs/mL). One device showed better performance (100 NDUs/mL), and another one showed lower performance (10,000 to 30,000 NDUs/mL). Vials of the Zika FDA-RP are available on request to developers who have interacted with the FDA through the review process.

Phase I: Mapping Phase | Health Technology in South Africa: Optimising In vitro Diagnostic Device Management

Objectives: In South Africa, the introduction of the Medical and Related Substances Act R. 586 has focused more attention on the role of medical devices in health care. The objectives of this study were: a) to explore how the introduction of Health Technology Assessment (HTA) of in vitro diagnostic devices (IVD) can optimise the National Health Laboratory Service’s (NHLS’s) diagnostic test budget and b) increase test coverage to the public sector. Methods: A literature search was conducted using multiple databases to understand how the assessment and management of Health Technology (HT) is conducted in established HTA organisations. In particular key searches were in vitro diagnostic medical devices. The study was limited to HTA organisations involved with Health Technology including all those who have adopted a Health Technology Management (HTM) system for medical devices. In particular, key searches included the annotation: in vitro diagnostic medical devices. Results: The NHLS is the largest pathology service in the world. The decisions made in the diagnostic environment of NHLS can be compared to hospital based HTA. The literature review provided an overview of factors enabling the NHLS to determine whether new health technologies should be adopted. Those included, whether decision processes were appropriate, how to evaluate the methodology for IVD evaluations and how to assess factors likely to influence decisions and suggestions for current process improvement. Conclusion: Improved decision making on the acquisition of new health technologies in pathology services through the use of the HTA framework can help reduce IVD acquisition expenditure. This will help in alleviating the ongoing cost of healthcare and allow present and future substantiality to be maintained.

The Manufacturers' Perspective on World Health Organization Prequalification of In Vitro Diagnostics.

In vitro diagnostic devices (IVDs) help clinicians determine specific conditions, monitor therapeutic efficacy, and prevent drug resistance development. While stringent regulatory authorities (SRAs) regulate IVDs in most high-income countries, regulatory authorities in many low- and middle-income countries (LMICs) are nonexistent or do not enforce rigorous standards. In 2010, the World Health Organization established its Prequalification of In Vitro Diagnostics (PQDx) program to ensure "access to safe, appropriate and affordable" IVDs, especially in LMICs with little or no domestic regulatory frameworks, thereby reaching underserved populations. However, challenges in PQDx policies and procedures include an overloaded pipeline, timelines not publicly available, confusion about which products PQDx focuses on, perceived burden for documenting changes to prequalified products, overlap with SRA approvals, and uncertainty around long-term financing. PQDx can maximize its impact by considering the perspective of IVD manufacturers; similarly, IVD manufacturers should exercise adequate quality control over their submissions and associated processes.

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.

Nanotechnology-Based Surface Plasmon Resonance Affinity Biosensors for In Vitro Diagnostics.

In the last decades, in vitro diagnostic devices (IVDDs) became a very important tool in medicine for an early and correct diagnosis, a proper screening of targeted population, and also assessing the efficiency of a specific therapy. In this review, the most recent developments regarding different configurations of surface plasmon resonance affinity biosensors modified by using several nanostructured materials for in vitro diagnostics are critically discussed. Both assembly and performances of the IVDDs tested in biological samples are reported and compared.

국내 동물용 의료기기 관리실태 평가 및 개선방안 연구

(Received: April 14, 2015; Accepted: May 15, 2015)Abstract : In this study, the Korean veterinary medical devices management system was evaluated relative to systemsin the USA, EU, and Japan. Veterinary medical devices are regulated in Korea based on the Medical Appliance Actof 1997. This was initially supervised by the Ministry of Agriculture, Food and Rural Affairs and Korea Animal HealthProducts Association, and subsequently by the Animal and Plant Quarantine Agency (QIA) in 2000. These deviceswere classified approximately 1,400 categories as instruments, supplies, artificial insemination apparatus, and othercategories. Each of these devices was assigned to four regulatory grades by the QIA in 2007. The ranking systemfor veterinary medical devices was implemented in 2014 with 820 products from 162 companies registered by thatyear. However, in vitro diagnostic devices (IVDDs) for animals were managed as medical devices and biologicalmedicine. In vitro diagnostic reagents for treating infection diseases are not subjected to either a classification or gradingsystem. Veterinary medical devices are currently exempt from good manufacturing practices (GMP) and device trackingrequirements. Due to gradual growth of the domestic veterinary medical devices market since 2008, regulation of thesedevices should be improved with re-examination of IVDDs and GMP certification for the effective operating system.Keywords : medical devices, veterinary medical devices, regulatory management system

Legal basis and practice of examination of critical in vitro diagnostic devices

In vitro diagnostic devices (IVD) are categorized into different risk classes depending on the potential consequences of false test results in transfusion medicine or on the individual patient. Test systems of higher risk may be assessed and examined by a third party in addition to the manufacturer's evaluation. The preapproval examination of essential performance features can assure minimum quality features prior to marketing of the IVDs. By batch testing the variation between different batches of an IVD is determined. Comparative testing in a re-evaluation scheme can define the current state of the art. The present European IVD directive stipulates batch testing for high-risk IVDs while the draft version of the new European IVD regulation also foresees independent product testing performed by European reference laboratories.

Summary of DIA Workshop on Co-Development of Personalized Medicine and In Vitro Diagnostic Companion Devices.

The pairing of personalized medicine, including targeted drug therapy, and in vitro diagnostic (IVD) companion devices (ie, "companion diagnostics") allows treatment decisions to be tailored for each patient. However, development of companion diagnostics and personalized medicine still faces challenges in clinical development as regulatory policy tries to keep up with and accommodate this growing field. To assist industry and regulators, the DIA provided a forum for the discussion of current challenges and opportunities for progressive alignment approaches to regulating personalized medicine and IVD devices.

Point of care (POCT) testing for human immunodeficiency virus (HIV) infection in Australia: in context

The laboratory diagnosis of HIV infection is most often made by the detection of antibodies to the virus. Conventional serologi-cal tests for detection HIV antibodies are usually referred to as ‘screening or standard’ tests (the initial test) or ‘confirmatory, supplemental or reference tests’. Screening tests identify samples that contain antibodies to HIV but are usually not used to provide a presumptive diagnosis for a patient whose sample is found to be initially reactive. Only after confirmatory or reference tests have been performed can an individual conclusively be identified as being seropositive and having established HIV infection. Screening and confirmatory tests are performed in a testing strategy which has been scientifically validated for a particular population demographic to provide the most sensitive and specific result for the individual tested. For many years, point of care (PoCT, rapid or short incubation) tests for HIV have been successfully used in many developed and developing countries. In 2012, the US Food and Drug Administration (FDA) announced the approval of a home test or over-the-counter HIV PoCT that would enable individuals to perform self-testing. In many countries the use of rapid tests has overcome resource constraints where laboratory infrastructure and sample transportation logistics are limited, in remote settings and in populations where the return rate for receiving a confirmed result is poor. Recent research suggests that much HIV transmission occurs from people who have themselves only recently have become infected. Many approaches have been tried to increase the demand for testing and improve rates of testing amongst people at risk of acquiring HIV. There is a strong case of for the introduction of PoCT for HIV in Australia including the desire to improve the rates of testing for populations at risk of infection. Reducing barriers around testing through improving access and consumer experiences suggests that more convenient testing could increase the rates of testing and stimulate the demand for HIV testing in target groups. In Australia, all in vitro diagnostic devices (IVD) are regulated according to a public health risk stratification. Currently all HIV and HCV screening tests are classified in the highest category (Class 4) and undergo a high degree of scrutiny before they are approved for registration on the Australian Register of Therapeutic Goods (ARTG) and approved for sale. This ensures that tests that are available in the Australian market are of a high standard. At the time this abstract was prepared there were two PoCT tests approved on the ARTG; however, one test was approved for use as a screening test and could only be used in laboratory settings. In 2011, the National HIV Testing Policy underwent significant review and established a framework for the introduction of PoCT in Australia proposing standards around training, settings and quality assurance. This presentation will outline the current situation of point of care tests for HIV in Australia and highlight some issues around their introduction and regulation in the broad non-laboratory based context. Data will be presented on the performance of participants in the Royal College of Pathologists of Australasia (RCPA) external quality assurance program (QAP) for HIV PoCT, highlighting issues with quality in regional laboratories where PoCT are widely used.

Collaborative study to establish a proficiency panel of hepatitis B surface antigens for evaluating in vitro diagnostics

Hepatitis B virus (HBV) infection is a critical health issue. In hospitals, in vitro diagnostic devices (IVDs) are used to detect HBV infections. The Taiwan Food and Drug Administration has prepared a candidate hepatitis B surface antigen (HBsAg) proficiency panel as an analytical standard to evaluate the sensitivity of the postmarketing surveillance of HBV IVDs. The sensitivity and stability of the proficiency panel, which comprises 5 HBsAg positive sera (SN-A to E) and 1 negative serum, was determined by a collaborative study involving 8 collaboratories. The potency of the candidate proficiency panel was consistent among all collaboratories. The potencies of sera SN-A to E in semiquantitative and quantitative analyses were 2.823–0.011 and 2.229–0.009 IU/mL, respectively. The mean coefficients of variation (CV) of intra and interday precision among the collaboratories were <7%. Accelerated degradation and long-term storage tests were used as stability assays. The candidate HBsAg proficiency panel exhibited good stability under different storage conditions, while all CVs were <6%. In conclusion, this candidate HBsAg proficiency panel is credible and reliable. Therefore, it can be used for postmarketing surveillance of HBV IVDs and quality assessment by clinical researchers and IVD manufacturers.

Clinical governance: implications for point-of-care testing.

With the introduction of clinical governance in the UK during 1997 and the shift in focus from a purely financial perspective to one of quality, it has become even more important that laboratories become involved with in vitro diagnostic devices (IVDs) used outside the laboratories by non-laboratory personnel, namely, point-of-care testing (POCT). The demand for POCT is increasing and its growth will continue with advances in technology, increasing pressure to shorten patient length of stay and requirements to decrease turnaround times, alongside the national initiatives to consolidate laboratories. However, clinical governance is about practising evidence-based medicine, and both the clinical and cost-effectiveness of POCT continue to be debated. Accountability and leadership are pivotal in the implementation of clinical governance. Thus, the onus is on laboratories to take the lead for POCT and ensure that there is a robust risk management strategy to protect not only the staff, but, importantly, the patient. A rigorous POCT policy and national guidance must be adhered to. For a high quality POCT service to be delivered, fulfilling the requirements of clinical governance, a multidisciplinary local group must be established with recognized accountability, appropriate resources and, importantly, management support.