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The regulatory landscape
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
From Pfizer’s Xalkori, targeted for non-small-lung cancer cells harboring the ALK mutation, to Genentech’s Herceptin for HER2-positive cells in breast cancer, the Food and Drug Administration (FDA) has played a central role in the development of personalized drugs and companion diagnostic tests, ensuring their safety and efficacy. However, the FDA has faced many challenges in coordinating the approval of the drug–test combination and regulating the clinical trials for drugs. The FDA has also made changes to the enforcement discretion requirement for laboratory-developed tests (LDTs). Next-generation sequencing (NGS) has also challenged the regulatory landscape, leading to new regulations concerning the intended use of genetic variants. In all these areas, the FDA is utilizing new approaches to meet innovation in drug and medical device development while still accommodating patient needs for clinical effectiveness and safety.
Preemptive antifungal therapy: Do diagnostics help?
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Vidya Jagadeesan, Margaret Powers-Fletcher, Kimberly E. Hanson
Nucleic acid amplification technologies have been increasingly applied for the detection and identification of fungal pathogens directly from clinical specimens. The majority of these assays are laboratory-developed tests (LDTs) based on polymerase chain reaction (PCR) techniques that amplify gene targets specific to a suspected pathogen or group of pathogens. Well-designed PCR assays have the potential to be highly sensitive and specific, and are amendable to preemptive surveillance strategies.
Liquid biopsy from research to clinical practice: focus on non-small cell lung cancer
Published in Expert Review of Molecular Diagnostics, 2021
Umberto Malapelle, Pasquale Pisapia, Alfredo Addeo, Oscar Arrieta, Beatriz Bellosillo, Andres F. Cardona, Massimo Cristofanilli, Diego De Miguel-Perez, Valeria Denninghoff, Ignacio Durán, Eloísa Jantus-Lewintre, Pier Vitale Nuzzo, Ken O’Byrne, Patrick Pauwels, Edward M. Pickering, Luis E. Raez, Alessandro Russo, Maria José Serrano, David R. Gandara, Giancarlo Troncone, Christian Rolfo
Finally, another crucial point is the identification of laboratory equipment. This aspect plays a pivotal role for the analysis of liquid biopsy specimens by the implementation of a robust workflow. Overall, laboratory equipment should be adopted in accordance with manufacturer instructions or following laboratory developed test (LDT) procedures. In particular, the localization and implementation of each platform should be performed according to its role in the analytical workflow. Briefly, centrifuges should be employed for the pre-analytical management of liquid biopsy specimens taking into account the characteristics of ctDNA (concentrations, stability, half-life). Subsequently, ctDNA isolation and purification may be performed manually or automatically. Finally, different analytical platforms, such as NGS or ultra-deep real-time qPCR platforms, should be adopted. A dedicated storage area with −20°C refrigerators, for the routine use of ctDNA samples (no more than three months), and −80°C freezers, for the long period storage of ctDNA samples (exceeding three months but no more than 12 months), should be implemented. In addition, analyzed data generated from experimental procedures should be stored by using back-up devices able to maintain them for at least 10 years [153].
Mass spectrometry-based metabolomics diagnostics – myth or reality?
Published in Expert Review of Proteomics, 2021
Oxana P. Trifonova, Dmitri L. Maslov, Elena E. Balashova, Petr G. Lokhov
For the development of new clinical diagnostics tests, MS-based metabolomics has potential – both as a preliminary discovery base for routine testing, and as a prototype of a multi-test, which we hope will be introduced into clinical practice in the near future. One of the possible ways to develop multi-tests is the FDA regulated type of in vitro diagnostics – laboratory-developed test (LDT). LDTs can be used to measure or detect a wide variety of analytes within a single laboratory where it was designed and manufactured. A number of these tests were developed by Metabolon in 2018 and used in the Clinical Laboratory Improvement Amendments (CLIA) certified laboratories for the diagnosis of metabolic disorders by determining up to 1,000 metabolites in blood plasma and generating a heat map of metabolite Z-scores, which can be used to identify altered metabolic pathways. In addition, the company offers a clinically confirmed Quantose Impaired Glucose Tolerance Test, which uses a proprietary algorithm to produce an ‘IGT score’ based on a combination of glucose and seven metabolites. As LDTs, these tests have not been approved by the FDA but can be used in clinics as auxiliary tests and in combination with other standard clinical diagnostic tests [60]. Thus, MS-based metabolomics diagnostics have the potential to become a reality. However, the development and introduction of protocols for standardizing the research workflow, as well as clear compliance with all procedures, are required.
Regulatory context and validation of assays for clinical mass spectrometry proteomics (cMSP) methods
Published in Critical Reviews in Clinical Laboratory Sciences, 2018
Christophe Hirtz, Pauline Bros, Cato Brede, Pierre Lescuyer, Aleksandra M. Maceski, Jerome Vialaret, Vincent Delatour, Sylvain Lehmann
The first constraint that needs to be met for cMSP methods is to comply with the regulations defined in a series of international IVD guidelines. Worldwide standardization of regulations on medical devices was the aim pursued by the Global Harmonization Task Force (GHTF) [9]. Its work ended in 2012, and its mission is now being taken over by the International Medical Device Regulators Forum (IMDRF) [10], which is an organization composed of regulatory agencies’ officials from around the world. IMDRF intends to accelerate the regulatory harmonization and convergence of international medical devices by encouraging close collaboration between regulators and stakeholders, especially between regulators and the regulated industry. Documents produced by IMDRF, which have been adopted by lawmakers around the world, provide manufacturers of MS instrumentation for use at clinical laboratories with highly relevant information such as guidelines for Unique Device Identification (UDI), requirements for Medical Device Auditing or the use of Software as a Medical Device (SaMD). In the United States (US), clinical laboratories are regulated by the Clinical Laboratory Improvement Amendments (CLIA) law passed by Congress in 1988 [11]. Laboratories must be certified by their State as well as by the Center for Medicare and Medicaid Services (CMS) before any human samples can be analyzed for diagnostic purposes [11]. The CMS issues laboratory certificates, conducts laboratory inspections and approves proficiency testing (PT) programs. In addition to the CMS, both the Food and Drug Administration (FDA) and the Center for Disease Control and Prevention (CDC) are mandated by CLIA to assure quality in clinical laboratories. The FDA regulates medical devices via the Code of Federal Regulations title 21, part 820 (21CFR820), which includes a classification system. Several manufacturers have already listed their LC–MS/MS instruments with the FDA as Class I general-purpose medical devices, while some Matrix Assisted Laser Desorption/Ionization (MALDI) MS instruments are listed as Class II medical devices intended for the identification of infectious agents. The FDA has regulated all IVDs as devices since 1976, including laboratory developed tests (LDT) which they define as a type of in vitro diagnostic test that is designed, manufactured, and used at a single laboratory. Many US laboratories are now using LDT in their daily routine, and some have developed their own cMSP methods. In 2014, the FDA started working on strengthening the regulation of LDT and plans to use a risk-based approach for the classification and approval of these tests.