Laboratory Developed Tests in The Clinical Laboratory: Challenges for Implementation
2015; Future Science Ltd; Volume: 7; Issue: 15 Linguagem: Inglês
10.4155/bio.15.109
ISSN1757-6199
AutoresMark A. Marzinke, William Clarke,
Tópico(s)Clinical Laboratory Practices and Quality Control
ResumoBioanalysisVol. 7, No. 15 EditorialFree AccessLaboratory developed tests in the clinical laboratory: challenges for implementationMark A Marzinke & William ClarkeMark A Marzinke Department of Medicine, Johns Hopkins University School of Medicine, 1800 Orleans St. Sheikh Zayed Tower, B1020-F, Baltimore, MD 21287, USA Department of Pathology, Johns Hopkins University School of Medicine Baltimore, MD 21287, USA & William Clarke*Author for correspondence: E-mail Address: wclarke@jhmi.edu Department of Medicine, Johns Hopkins University School of Medicine, 1800 Orleans St. Sheikh Zayed Tower, B1020-F, Baltimore, MD 21287, USAPublished Online:21 Aug 2015https://doi.org/10.4155/bio.15.109AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: Clinical Laboratory Improvement Amendmentslaboratory developed testsoversightregulationUS FDAThe recent release of a draft guidance document on the regulation of laboratory developed tests (LDTs) by the US FDA has led to intense discussion by many stakeholders, including those in the public and private sectors. However, in order to fully engage in the conversation, it is imperative that one understands the definition of an LDT, the origins of oversight for clinical laboratory testing, and the potential implications to the most important stakeholder: the patient. Using the most ubiquitous terminology, an LDT is defined as an in vitro diagnostic test (IVD) that is developed, validated and utilized by the testing laboratory; of note, these assays are not commercially distributed [1]. LDTs also encompass FDA-cleared IVDs modified in their application or performance. This definition can be, and has been, interpreted differently by various stakeholders, particularly when referring to the developing laboratory. The divide between the FDA and the clinical laboratory community lies in the nature of LDTs and how they are implemented; while clinical laboratorians view LDTs as medical services provided by the testing site, the FDA views clinical laboratories producing LDTs as medical device manufacturers [2,3]. Although the interpretation seems nuanced, the implications are substantial. The Clinical Laboratory Improvement Amendments (CLIA) program, in accordance with CLIA 1988 guidelines, regulates the laboratories developing and utilizing LDTs, and focuses on the analytical quality of the testing process with the overarching goal to provide reliable and accurate test results for patient care [4,5]. Conversely, the current position of the FDA is that LDTs are IVDs manufactured by the clinical laboratory, and fall under its jurisdiction as medical devices [6]. While there is agreement that regulation of these tests is needed, deciding the 'who' and 'how' should be a thoughtful process and executed to promote healthcare advancement, as opposed to scientific stagnation.Clinical laboratory regulationsAmbiguity regarding LDTs is not new. Regulatory oversight of medical devices via the Medical Devices Amendments Act of 1976 is actually an expansion of the Federal Food, Drug and Cosmetic Act of 1938. The Medical Devices Amendments Act stratified IVDs based on patient-risk. In other words, the degree of regulatory oversight is proportional to the perceived, or potential, risk, with devices categorized as Class I (low-risk; no requirement for premarket review of approval), Class II (moderate-risk, 510(k) premarket notification) or Class III (high-risk, premarket approval) [7,8]. At that time, LDTs were developed using well-characterized analytical methodologies in hospital laboratory settings for clinical testing in the absence of a commercially available IVDs, or for the treatment or monitoring of rare diseases. Furthermore, there was a strong sense of collaboration between the provider, patient and laboratorian – the pathologist or laboratory director was directly involved in interpretation of LDT results. In this setting, the FDA exercised what it called enforcement discretion over LDTs; in other words, the position of the FDA was that it had the right to regulate these tests, but its enforcement of such regulations was not required. Over the course of the last four decades, with burgeoning interest in advanced technologies, and subsequent commercialization of these analytical platforms, guidelines were proposed to more clearly regulate components of LDTs or the tests themselves.Attempted mechanisms of providing additional oversight of LDTs included proposed regulation of assay specific reagents (ASRs) in 1997, which were subsequently modified in 2006 and 2007, as well as guidance documents regarding research or investigational use only (RUO/IUO) materials in 2011 [9]. However, these guidelines led to misinterpretation by IVD manufacturers and further complicated the regulatory landscape of LDTs. During the same period, the use of multicomponent tests with proprietary biostatistical algorithms to determine patient results in the background of various pathophysiological conditions was gaining momentum, while at the same time presenting challenges for oversight and interpretation as they could not be externally validated by clinical laboratories. The growing interest in such in vitro diagnostic multivariate index assays (IVDMIAs) led to the presentation of a draft guidance by the FDA to discuss the use and potential oversight of such tests [10]. Notably, the aforementioned guidance documents currently remain in their draft forms, as reagents, multivariate indices, and testing algorithms all fall under the umbrella of LDTs. Furthermore, the growing interest and availability of direct-to-consumer (DTC) testing providing predictive genomic risk assessments without the involvement of a physician or clinical laboratory director, as well as the increasing complexity of analytical testing has once again brought LDTs to the forefront of the healthcare arena and regulatory discussions [11]Proposed FDA regulation of LDTsThe 'FDA Notification of Medical Device Reporting for Laboratory Developed Tests (LDTs)' draft guidance document released in October 2014, which followed a notification to Congress regarding a proposed regulatory LDT framework in July of that year, clarified the intentions of the FDA with regard to LDTs, and set the stage for vigorous feedback from clinical laboratories and industry [6]. The draft guidance describes a multitier, phased-in structure for FDA oversight, in which laboratories performing LDTs would provide notification to the agency through registration and listing; based on risk-assessment, tests deemed low-risk would not require additional review but would be subject to adverse event reporting requirements. These 'traditional' LDTs would still be subject to enforcement discretion. High- and moderate-risk LDTs would undergo premarket approval or 510(k) clearance within 1 or 5–9 years postguidance approval, respectively. It is important to note that the aforementioned 'traditional' LDT enforcement discretion only applies to clinical laboratories that do not accept specimens from outside their health system. This is a clear demarcation between commercial reference laboratories and hospital laboratories, signaling the intent for the FDA to regulate LDTs offered from a commercial laboratory.The proposed framework has elicited a flurry of responses in the following months. Recent correspondence to the FDA from AdvaMedDx endorses that all tests be subject to the same risk-based regulatory processes as IVDs, with oversight managed through the FDA [12]. This shift from the previously held tenet of enforcement discretion to additional regulatory layers will have substantial ramifications within the healthcare arena, including impeding the provision of timely and accurate laboratory results to improve patient care when no FDA-cleared commercially available diagnostic test is available. Thus, the clinical community's perspective remains stalwart: LDTs are classified as high complexity tests under CLIA 1988, and as such, the analytical validity of the assay must be established with oversight by the laboratory director. Director oversight encompasses assay validation, adherence to stringent personnel, quality control and proficiency testing standards, as well as the provision of interpretative assistance to ordering providers, if needed – there is an implied evaluation of clinical utility or validity, but it is this is not explicit under CLIA oversight [2,5]. Furthermore, while the broad brushstrokes proposed by the FDA are meant to streamline and stratify LDTs, there are a number of unaddressed scenarios regarding traditional LDTs under continued enforcement discretion. These include tests that can be viewed as a traditional LDT, but also as companion diagnostics when guiding administration of a therapeutic agent (e.g. therapeutic drug monitoring), laboratory testing to support clinical trials, and the off-label use of an FDA-cleared assay (e.g., use of an FDA-cleared test for blood with an alternative matrix). How would, or should, testing with LDTs in these examples be regulated?Implications for change in regulatory oversightWhile the logistics of where and with whom oversight will lie is currently under the magnifying glass, the larger and long-term concerns revolve around the potential implications on patient care. The impetus of LDTs was to address the unmet needs of providers to assist in patient care; assays validated under trained and accredited laboratory leadership, and performed by trained and competent personnel, were efficiently provided to clinicians. The proposed guidance materials could hamper such care, leaving providers and patients alike without the testing needed to make, and benefit from, informed clinical decisions. Furthermore, reference laboratories performing LDTs, including genetic or liquid chromatographic-tandem mass spectrometric (LC–MS/MS)-based testing, will also be significantly impacted, independent of their compliance under CLIA 1988 and accreditation by deemed agencies. The proposed LDT regulatory structure may prevent reference laboratories, and potentially clinical hospital laboratories, from providing key PCR-based genetic analysis or LC–MS/MS-based therapeutic drug monitoring needed by providers to make informed clinical decisions. The impact on routine clinical care is paramount, and the long-term ramifications must be carefully weighed by all involved parties.While opinions regarding LDTs may differ widely, the consensus is that a change in paradigm is needed to ensure the sustainability of these assays in the healthcare arena. Clinical laboratories have the expertise to oversee such tests, but added layers of internal regulation may assuage public and private concerns. Potential improvements for LDT oversight under CLIA accreditation could include more formal programs for postimplementation surveillance of LDTs, standardized recommendations for proficiency testing, and a requirement for documented consultation with providers during LDT development to add an explicit evaluation of clinical utility and validity. In this structure, the analytical validity and risk assessment of LDTs still reside in the accredited laboratories developing new tests or modifying existing tests and still fall under the regulatory oversight of CMS, which assesses the laboratories performing the testing. This approach could be further extrapolated, where discrete regulation of LDTs is performed, but not under FDA, but rather through a modification or extension of CLIA. Clinical laboratory directors are currently certified to ensure and uphold the regulations outlined under CLIA 1988. Further credentialing to perform LDTs, in conjunction with the previously described additional metrics, can be the compromise we are all looking for: required oversight by appropriate parties to provide for the stakeholders with the most to lose, the patients.The recent public debate regarding LDT oversight is neither the calm before the storm nor the light at the end of the tunnel. It is a conversation worth having, and the recent FDA guidance documents serve as an important primer to help direct us toward a common ground, and ultimately, a common goal. The existing CLIA-directed regulatory infrastructure in clinical laboratories has proven to be both successful and sustainable in maintaining laboratory credibility; a more formal extension of this oversight to LDTs may be an acceptable middle ground for all stakeholders. As the discourse continues, we all must remain vigilant in our efforts to provide quality care to the patient, for merely being a passenger on the train of LDT oversight is no longer sufficient.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 American Society of Clinical Pathology Policy Statement: Regulation of Laboratory Developed Tests (LDTs); Policy Number 10–02 (2010). www.ascp.org/PDF/Advocacy/Regulation-of-laboratory-developed-tests-LDTs.aspx.Google Scholar2 Kazon PM. Chapter 6: laboratory developed tests. In: In Vitro Diagnostics, the Complete Regulatory Guide (Volume 1). Danzis SD, Flannery EJ (Eds). Food and Drug Law Institute, DC, USA (2010).Google Scholar3 Weiss RL. The long and winding laboratory road for laboratory-developed tests. Am. J. Clin. Pathol. 138(1), 20–26 (2012).Crossref, Medline, Google Scholar4 Clinical Laboratory Improvement Amendments of 1988; Final Rule. 42 CFR Part 405 et al. 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(1976).Crossref, Google Scholar8 Federal Food, Drug and Cosmetic Act of 1994 (FD&C). 21 USC §301–395 GPO, DC, USA (1994).Google Scholar9 Guidance for Industry and FDA Staff: Commercially Distributed Analyte Specific Reagents (ASRs): Frequently Asked Questions (2007). www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071269.pdf.Google Scholar10 Draft Guidance for Industry Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays (2007). www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071455.pdf.Google Scholar11 O'Leary JT. Regulating laboratory-developed tests. J. Mol. Diagn. 16(6), 595–598 (2014).Crossref, Medline, Google Scholar12 Comments to FDA on LDT Framework-AdvaMedDx. Re: Docket No. FDA-2011-D-0360; Draft Guidance for Industry, FDA Staff and Clinical Laboratories; Framework for Regulatory Oversight of Laboratory Developed Tests. (2015). http://advameddx.org/download/files/LDTFrameworkComments.pdf.Google ScholarFiguresReferencesRelatedDetailsCited ByStandardising RNA profiling based biomarker application in cancer—The need for robust control of technical variablesBiochimica et Biophysica Acta (BBA) - Reviews on Cancer, Vol. 1868, No. 1Transcriptomics in cancer diagnostics: developments in technology, clinical research and commercialization13 November 2015 | Expert Review of Molecular Diagnostics, Vol. 15, No. 12 Vol. 7, No. 15 Follow us on social media for the latest updates Metrics History Published online 21 August 2015 Published in print August 2015 Information© Future Science LtdKeywordsClinical Laboratory Improvement Amendmentslaboratory developed testsoversightregulationUS FDAFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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