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The article deals with the legal requirements and liability issues related to the use of Research-Use-Only (RUO) products in the field of In-House In-Vitro Diagnostics (IVD). RUO products are exclusively intended for research purposes and must not be used for diagnostic procedures in humans. The article examines the legal permissibility of this use and the associated liability issues. It is noted that RUO products are subject to lower regulatory requirements than products for clinical use and must meet certain quality standards. Manufacturers of RUO products are obliged to label their products accordingly, but there is no obligation for market surveillance regarding the intended use of these products. The article also describes the definition and use of "In-House IVD" (In-House In-Vitro Diagnostics) in clinical laboratories. In-House IVD refers to diagnostic tests developed and used by clinical laboratories to diagnose, monitor, or predict certain diseases or conditions. The requirements and liability for the use of Research-Use-Only (RUO) products for diagnostic purposes are also discussed. [Extracted from the article]

BackgroundThe VALID Act is a legislative effort that, if enacted, would alter the regulatory requirements of laboratory developed tests (LDTs) used for clinical testing in the United States. Benzodiazepines, which are primarily excreted into urine as glucuronidated metabolites such as lorazepam, cross-react poorly with FDA-cleared immunoassays, leading to false-negatives. This shortfall can be addressed with LDTs created by adding glucuronidase to the immunoassay reagents producing "high sensitivity" assays that detect glucuronidated metabolites.MethodsPrecision and stability of two high-sensitivity (HS) benzodiazepine immunoassays from Roche and Thermo Scientific were evaluated using manufacturer-supplied quality control (QC) material and glucuronidated QC material. The immunoassays were directly compared to an LC-MS/MS LDT benzodiazepine assay to determine clinical sensitivity/specificity using urine specimens (n = 82 for Thermo Scientific; n = 265 for Roche). The clinical impact of the HS LDT immunoassay was determined by analyzing clinical testing results 60 days before and after its implementation.ResultsThe precision and clinical sensitivity/specificity of the HS-Thermo Scientific and HS-Roche benzodiazepine assays were acceptable. The reagent stability of the HS-Thermo Scientific immunoassay was poor, whereas the HS-Roche immunoassay was stable. After implementation of the HS-Roche benzodiazepine immunoassay as an LDT, there was a 30-fold increase (p-value: < 0.00001) in the percentage of lorazepam confirmations.ConclusionsWe demonstrate the development and validation of an immunoassay LDT with improved sensitivity for glucuronidated benzodiazepines. This LDT can detect glucuronidated benzodiazepines in clinical urine specimens and is stable for 60 days. Importantly, we were able to validate the immunoassay as an LDT by utilizing an LC-MS/MS LDT.

Background: The VALID Act is a legislative effort that, if enacted, would alter the regulatory requirements of laboratory developed tests (LDTs) used for clinical testing in the United States. Benzodiazepines, which are primarily excreted into urine as glucuronidated metabolites such as lorazepam, cross-react poorly with FDA-cleared immunoassays, leading to false-negatives. This shortfall can be addressed with LDTs created by adding glucuronidase to the immunoassay reagents producing “high sensitivity” assays that detect glucuronidated metabolites. Methods: Precision and stability of two high-sensitivity (HS) benzodiazepine immunoassays from Roche and Thermo Scientific were evaluated using manufacturer-supplied quality control (QC) material and glucuronidated QC material. The immunoassays were directly compared to an LC-MS/MS LDT benzodiazepine assay to determine clinical sensitivity/specificity using urine specimens (n = 82 for Thermo Scientific; n = 265 for Roche). The clinical impact of the HS LDT immunoassay was determined by analyzing clinical testing results 60 days before and after its implementation. Results: The precision and clinical sensitivity/specificity of the HS-Thermo Scientific and HS-Roche benzodiazepine assays were acceptable. The reagent stability of the HS-Thermo Scientific immunoassay was poor, whereas the HS-Roche immunoassay was stable. After implementation of the HS-Roche benzodiazepine immunoassay as an LDT, there was a 30-fold increase (p-value: < 0.00001) in the percentage of lorazepam confirmations. Conclusions: We demonstrate the development and validation of an immunoassay LDT with improved sensitivity for glucuronidated benzodiazepines. This LDT can detect glucuronidated benzodiazepines in clinical urine specimens and is stable for 60 days. Importantly, we were able to validate the immunoassay as an LDT by utilizing an LC-MS/MS LDT.

Exosomes are membrane-defined extracellular vesicles (EVs) approximately 40–160 ​nm in diameter that are found in all body fluids including blood, urine, and saliva. They act as important vehicles for intercellular communication between both local and distant cells and can serve as circulating biomarkers for disease diagnosis and prognosis. Exosomes play a key role in tumor metastasis, are abundant in biofluids, and stabilize biomarkers they carry, and thus can improve cancer detection, treatment monitoring, and cancer staging/prognosis. Despite their clinical potential, lack of sensitive/specific biomarkers and sensitive isolation/enrichment and analytical technologies has posed a barrier to clinical translation of exosomes. This review presents a critical overview of technologies now being used to detect tumor-derived exosome (TDE) biomarkers in clinical specimens that have potential for clinical translation.

Companion diagnostics (CDx) hail promise of improving the drug development process and precision medicine. However, there are various challenges involved in the clinical development and regulation of CDx, which are considered high-risk in vitro diagnostic medical devices given the role they play in therapeutic decision-making and the complications they may introduce with respect to their sensitivity and specificity. The European Union (E.U.) is currently in the process of bringing into effect in vitro Diagnostic Medical Devices Regulation (IVDR). The new Regulation is introducing a wide range of stringent requirements for scientific validity, analytical and clinical performance, as well as on post-market surveillance activities throughout the lifetime of in vitro diagnostics (IVD). Compliance with General Safety and Performance Requirements (GSPRs) adopts a risk-based approach, which is also the case for the new classification system. This changing regulatory framework has an impact on all stakeholders involved in the IVD Industry, including Authorized Representatives, Distributors, Importers, Notified Bodies, and Reference Laboratories and is expected to have a significant effect on the development of new CDx. [ABSTRACT FROM AUTHOR]

Rapid development and deployment of diagnostic testing for COVID-19 have been a key component of the public health response to the pandemic. Out of necessity, academic and other clinical laboratories developed laboratory testing innovations for COVID-19 to meet clinical testing demands. In addition to constraints on local testing supplies and equipment, a rapidly changing regulatory framework created challenges for translational scientists. Illustrative examples of approaches used to develop laboratory tests during the early stages of the COVID-19 pandemic demonstrate effective team science approaches to this challenging clinical care and public health emergency. These experiences and the associated lessons learned are relevant to the development of public health response plans for future pandemics. [ABSTRACT FROM AUTHOR]

Rapid development and deployment of diagnostic testing for COVID-19 have been a key component of the public health response to the pandemic. Out of necessity, academic and other clinical laboratories developed laboratory testing innovations for COVID-19 to meet clinical testing demands. In addition to constraints on local testing supplies and equipment, a rapidly changing regulatory framework created challenges for translational scientists. Illustrative examples of approaches used to develop laboratory tests during the early stages of the COVID-19 pandemic demonstrate effective team science approaches to this challenging clinical care and public health emergency. These experiences and the associated lessons learned are relevant to the development of public health response plans for future pandemics.

Regulatory compliance in the direct-to-consumer genetic testing market is highly sophisticated as there are numerous federal, state, and ethical barriers to entry. In 2010, amid an underregulated market, 23andMe sought to do what few companies in the medical industry had attempted before--disregard the guidance and requests of the US Food and Drug Administration. This regulatory strategy effectively destined the company's Personal Genome Service for failure; however, the company changed course and has been granted several regulatory clearances. This exemplifies the importance of a healthy relationship with regulatory agencies, although challenges remain. The DTC industry continues to have a perplexing regulatory framework at both the federal and state level. There are also ethical concerns with the monetization of deidentified genetic health information, as genetic data have an inherent level of identifiability and are not fully protected by the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule in these scenarios. Although some DTC tests are now cleared in the United States, the concern that a learned intermediary is needed for interpretation of results remains. The regulatory oversight of this market will need to continue to develop to ensure the protection of consumer health and privacy. [ABSTRACT FROM AUTHOR]

Objectives: We introduce regulatory terms, definitions, and the Quality System Regulation as proposed by the US Food and Drug Administration in the 2014 draft guidance entitled Framework for Regulatory Oversight of Laboratory Developed Tests and explore medical device requirements applicable to a laboratory environment to design, develop, and validate laboratory developed tests (LDTs). Methods: We performed nine interviews with laboratory professionals to explore concerns and challenges regarding the draft, translated the results into operational factors, and surveyed professionals to test the factors that would comprise a regulatory quality management system framework. Results: Nine interviewees and 35 survey respondents shared concerns of risk classification, process validation, patient safety, and general ambiguity regarding the proposed requirements for development of LDTs. Conclusions: Respondents agree that a regulatory quality management system is needed in laboratories that develop LDTs, but the translation and method for design control to a clinical laboratory do not exist. As a result, laboratories are taking the wait-and-see approach. [ABSTRACT FROM AUTHOR]

Targeted genomic profiling (TGP) using massively parallel DNA sequencing is becoming the standard methodology in clinical laboratories for detecting somatic variants in solid tumors. The variety of methodologies and sequencing platforms in the marketplace for TGP has resulted in a variety of clinical TGP laboratory developed tests (LDT). The variability of LDTs is a challenge for test-to-test and laboratory-to-laboratory reliability. At the University of Vermont Medical Center (UVMMC), we validated a TGP assay for solid tumors which utilizes DNA hybridization capture and complete exon and selected intron sequencing of 29 clinically actionable genes. The validation samples were run on the Illumina MiSeq platform. Clinical specificity and sensitivity were evaluated by testing samples harboring genomic variants previously identified in CLIA-approved, CAP accredited laboratories with clinically validated molecular assays. The Molecular Laboratory at Dartmouth Hitchcock Medical Center (DHMC) provided 11 FFPE specimens that had been analyzed on AmpliSeq Cancer Hotspot Panel version 2 (CHPv2) and run on the Ion Torrent PGM. A Venn diagram of the gene lists from the two institutions is shown. This provided an excellent opportunity to compare the inter-laboratory reliability using two different target sequencing methods and sequencing platforms. Our data demonstrated an exceptionally high level of concordance with respect to the sensitivity and specificity of the analyses. All clinically-actionable SNV and InDel variant calls in genes covered by both panels (n = 17) were identified by both laboratories. This data supports the proposal that distinct gene panel designs and sequencing workflows are capable of making consistent variant calls in solid tumor FFPE-derived samples. [ABSTRACT FROM AUTHOR]

In the last decade, there has been a flood of new technology in the sequencing arena. The onset of next-generation sequencing (NGS) technology has resulted in the vast increase in genetic diagnostic testing available to the ordering physician. Whole exome sequencing (WES) has become available as a diagnostic test performed in certified clinical laboratories. This has led to increased presence in the diagnostic marketplace, increased consumer awareness, and the question has been raised by various stakeholders to whether there is sufficient stringent regulation of WES and other NGS-based tests. We discuss the various WES services currently available in the marketplace, current regulation of WES as a laboratory developed test, the proposed FDA involvement in its oversight as well as the response of various laboratory groups that provide these diagnostic services. Overall, a rigorous process oversight and assessment of inter-lab reproducibility is strongly warranted for WES as it is used as a diagnostic test, but regulation should be mindful of the excessive administrative burden on academic and smaller diagnostic laboratories. [ABSTRACT FROM AUTHOR]

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.

Summary: On April 30, 2008, the Secretary''s Advisory Committee on Genetics, Health, and Society released its Report, “US System of oversight of genetic testing: a response to the charge of the Secretary of HHS.” Positive features of this Report include recommendations for increased funding for the development and characterization of reference materials and methods; enhanced support for the growth and improvement of public reference sequence databases; encouragement for the implementation of electronic medical records; promotion of the efforts of clinical utility-oriented study groups such as the Evaluation of Genomic Applications in Practice and Prevention Working Group; and enforcement of the prohibitions against clinical testing by laboratories that lack Clinical Laboratory Improvement Amendments certification. The Committee reaffirmed recommendations set forth in its publication, “Coverage and reimbursement of genetic tests and services,” that would expand Medicare coverage and increase payment rates for appropriately performed genetic tests. However, in its Report, the Secretary''s Advisory Committee on Genetics, Health, and Society used an overly broad definition of genetic testing that is neither scientifically sound nor practically workable. This definition led to the Committee''s inability to distinguish genetic tests from other complex laboratory assays. The Report has fallen short by unnecessarily advocating for Food and Drug Administration review of all laboratory developed tests and proposing the creation of a mandatory registry for all clinical laboratory tests. [Copyright &y& Elsevier]

Lung cancer is the leading cause of cancer death worldwide with low response rates to conventional chemotherapy. New promising therapies have emerged based on programmed cell death protein 1 (PD-1) immunity checkpoint inhibitors (ICI), including anti-PD-1, such as nivolumab and pembrolizumab, or programmed death ligand 1 (PD-L1) inhibitors, such as atezolizumab, durvalumab, and avelumab. The prescription of pembrolizumab has been approved by FDA and EMA for advanced stages non-small cell lung carcinoma (NSCLC), restricted for first-line setting to patients whose tumor presents ≥50% of PD-L1 positive tumor cells (TC), and ≥1% for second-line and beyond, leading to consider PD-L1 assay as a companion diagnostic tool for pembrolizumab. Very recently, the EMA has approved durvalumab for the treatment of patients with unresectable stage III NSCLC not progressing after chemoradiotherapy and whose tumors express PD-L1 on ≥1% of TC. Four standardized PD-L1 immunohistochemistry assays have been used in clinical trials; 22C3 and 28-8 PharmDx assays on Dako/Agilent platforms, and SP142 and SP263 assays on Ventana platforms, each test having been developed initially for a specific ICI. They differ in terms of primary monoclonal antibody, platform, detection system and scoring methods with different thresholds of positivity validated in clinical trials. Several studies have shown a close analytical performance of the 22C3, 28-8 and SP263 assays regarding TC staining in NSCLC, with poor concordance with SP142 assay and for immune cells. However, as dedicated platforms are not available in all pathology laboratories and because of the high cost of these assays, laboratory developed tests are widely used in many countries. Their validation must guarantee the same sensitivities and specificities as compared to standardized assays. Overall, PD-L1 test is of great help to select patients who could benefit for ICI and most pathologists have included this test in their daily practice for advanced stages NSCLC, besides ALK and ROS1 IHC., Competing Interests: Conflicts of Interest: S Lantuejoul declares consultancy and/or honoraria (speaker) for AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Ventana; J Adam declares consultancy and/or honoraria (speaker) for AstraZeneca, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme; V Hofman declares no conflict of interest; D Damotte declares consultancy and/or honoraria (speaker) Bristol-Myers Squibb, AstraZeneca, Merck Sharp & Dohme, and Roche.

Today, many LC-high-resolution MS instruments have become affordable, easy-to-use, sensitive and quantitative. Meanwhile, there is an increased need for more comprehensive approaches. However, omics analyses are still restricted to specialists whereas, in hospitals, routine analyses are targeted and quantitative and represent the main and heavy tasks. But the availability of fully automated LC-MS instruments that can handle independently from sample extraction to result reporting, as well as the increasing biomedical interest for global approaches, clinical analytical workflow should be reorganized. Bioanalysts are now in the position to develop/implement clinical metabolomics or proteomics as routine analyses. In this article, this coming evolution and the reasons to implement global/omics determinations as routine analysis, is described.