Laboratory-developed Tests (LDTs)
While most common laboratory tests are commercial tests, manufactured and marketed to multiple labs, some tests are developed, evaluated, and validated within one particular laboratory. These tests, called “laboratory-developed tests” or “LDTs” are used solely within that laboratory and are not distributed or sold to any other labs or healthcare facilities to perform on their own. Often, a lab will choose to develop and use an LDT because a commercial test is not currently available.
There can be several reasons why a commercial test has not been developed for a particular substance or disease of interest. For example, many LDTs are genetic tests that are developed for rare diseases, such as Huntington disease. These are diseases that only a small subset of the population has, reducing the incentive for a manufacturer to develop a commercial version because the market for such a product would be small and not offer much, if any, return on investment. Or, an existing test may not apply to a particular subpopulation from which the lab has patients, so modification of the test is required. (Any FDA-approved commercial test that is modified in any way by a lab is considered to be an LDT and is subject to the regulations applied to all LDTs.)
Examples of some LDTs include:
Regulation and validation
Because the LDTs are not marketed to others (they are not sold to other labs to perform testings), they currently do not require approval for marketing from the U.S. Food and Drug Administration (FDA) as do commercially developed and marketed tests. However, these types of tests must go through rigorous validation procedures and must meet several criteria before results can be used for decisions regarding patient care. Several governmental and non-governmental entities regulate and guide the development and validation of this group of tests:
- The federal government, through the Clinical Laboratory Improvement Amendments (CLIA), highly regulates the evaluation and use of laboratory tests, including lab-developed assays. CLIA states that laboratories must demonstrate how well LDTs (and commercial tests) perform using certain performance specifications. Examples include:
- Accuracy—the ability of a test to most closely measure the “true” value of a substance
- Precision—the repeatability of a test result
- Test sensitivity—the ability of a test to detect a substance especially at relatively low levels
- Test specificity—the test’s ability to correctly detect or measure only the substance of interest and exclude other substances
For a more in-depth discussion of these key concepts, see the article How Reliable is Laboratory Testing?
- In addition to the specifications required by CLIA, the FDA requires validation of a test’s clinical utility. The test should be shown to improve health outcomes — that using the test leads to health benefits, such as preventing illness or death or restoring health.
- Some state governments have requirements for validation of LDTs that are equal to or more stringent than those outlined in CLIA. If the Centers for Medicare and Medicaid Services (CMS) declares that the state standards are comparable to or more stringent than CLIA regulations, then the state is considered to be CLIA-exempt and the state requirements for evaluating a test or test system must be met. Currently, only New York and Washington are CLIA-exempt states. It is important to note that exempt status is not just based solely on the requirements to validate LDTs.
- Several professional laboratory organizations offer laboratory accreditation programs. Participating laboratories must meet certain standards and criteria set by the accrediting agency. These standards meet or exceed those set by CLIA, including standards regarding evaluation of LDTs. Accreditation is an on-going process and labs must submit to regular inspections and evaluations of their policies, procedures, and documentation. Professional organizations also seek to improve laboratory services by establishing, publishing, and promoting testing standards, including those to do with validation of LDTs.
In general, because they have not been evaluated by the FDA, LDTs should undergo a more lengthy and rigorous validation process by the individual laboratory wishing to implement the new method. The in-house procedure may involve numerous experiments, such as comparing the results from the new test method to those generated by a well-established test method.
ASRs and IVDMIAs
Although LDTs are not FDA-approved for marketing, some of the reagents, controls, and equipment used in these tests may be manufactured (and are FDA-approved). The reagents in these instances are called Analyte Specific Reagents, or ASRs. In addition, some tests are developed as proprietary tests. That is, the test is marketed to other labs and healthcare providers as a service, but samples must be sent to the lab that developed the test for analysis.
Examples of such tests include many genetic tests for various cancers. These are usually very complex tests and sometimes involve an algorithm developed by the lab used to evaluate a combination of results. These types of tests are referred to as “In Vitro Diagnostic Multivariate Index Assays” (IVDMIAs). Examples of this type of test are the gene expression tests for breast cancer.
Currently, the FDA is looking at whether it should exercise its legal right to oversee the regulation of these types of tests. In 2014, the agency informed Congress of its plans to develop a new, draft risk-based approach for overseeing moderate and high-risk LDTs that would phase in over a period of years.
FDA took steps that included posting draft guidance documents on its website and publishing notices in the Federal Register to formally announce the release of this material and asking for public comments. The agency says increased oversight of the tests is warranted, due to the potential risk some LDTs pose to consumers. In November 2015, the agency issued a report highlighting twenty case studies where LDTs may have or actually caused harm to patients.
It is the agency’s intent to release final guidance on LDT oversight later in 2016, although some industry groups and members of Congress oppose the idea of giving FDA more oversight over LDTs. Their argument is this proposal would create more administrative burdens and ultimately discourage the use of these tests.
Instead, they are calling for alternative approaches that would build upon the existing CLIA framework. As of now, the CMS is the federal agency responsible for ensuring the accuracy and quality of these tests.
It is important to note that once a laboratory has validated a test for in-house use, methods of quality assurance with regard to that test are carefully and continually followed by the laboratory. This means that laboratories must constantly monitor the test and test systems to ensure that results generated continue to be as accurate, precise, sensitive, and specific as originally validated. These processes are also regulated by federal and state governments as well as laboratory accrediting organizations and are examined on a regular basis. For more on this, see the links in Related Content below.
Sources Used in Current Review
Medicare.gov. Your Medicare Coverage. Available online at https://www.medicare.gov/coverage/clinical-lab-services.html. Accessed October 2016.
(May 24, 2016) Centers for Medicare and Medicaid Services. Regulation and Guidance, Clinical Laboratory Improvement Amendments (CLIA). Available online at https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html. Accessed October 2016.
©2016 ABIM Foundation. Choosing Wisely. Available online at http://www.choosingwisely.org/. Accessed October 2016.
©2016 AvaMedDx. Our Industry and Technology, Uses of Diagnostic Tests. Available online at http://dx.advamed.org/diagnostics-policy/our-industry-technology-0. Accessed October 2016.
(June 4, 2016) U.S. Food and Drug Administration. Humanitarian Device Exemption. Available online at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/HumanitarianDeviceExemption/default.htm. Accessed October 2016.
(August 6, 2014) U.S. Food and Drug Administration. HDE Approvals. Available online at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/HDEApprovals/default.htm. Accessed October 2016.
(June 4, 2016) U.S. Food and Drug Administration. Listing of CDRH Humanitarian Device Exemptions. Available online at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/HDEApprovals/ucm161827.htm. Accessed October 2016.
(March 17, 2014) Gaffney A. Regulatory Explainer: Making Sense of Humanitarian Use Devices. Available online at http://www.raps.org/focus-online/news/news-article-view/article/4775/. Accessed October 2016.
The Free Dictionary. Class III device. Available online at http://medical-dictionary.thefreedictionary.com/class+III+device. Accessed October 2016.
(January-February 2006) Food and Drug Administration. Medical Device and Radiological Health Regulations Come of Age. Available online at http://www.fda.gov/aboutfda/whatwedo/history/productregulation/medicaldeviceandradiologicalhealthregulationscomeofage/default.htm. Accessed October 2016.
Congress.gov. H.R.3095 – Safe Medical Devices Act of 1990. Available online at https://www.congress.gov/bill/101st-congress/house-bill/3095. Accessed October 2016.
Food and Drug Administration. December 2014 PMA Approvals. Available online at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/PMAApprovals/ucm439050.htm. Accessed October 2016.
University of California San Francisco. Information sheet for clinical laboratory testing. Available online at https://accelerate.ucsf.edu/research/clinical-laboratory-testing. Accessed October 2016.
Centers for Disease Control and Prevention. Clinical Laboratory Improvement Amendments. Available online at https://wwwn.cdc.gov/clia/Resources/TestComplexities.aspx. Accessed October 2016.
Food and Drug Administration. CLIA categorizations. Available online at http://www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm393229.htm. Accessed October 2016.
HHS, Medicare Learning Network. The Clinical Laboratory Improvement Amendments (CLIA). Available online at https://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNProducts/Downloads/CLIABrochure.pdf. Accessed October 2016.
Food and Drug Administration, PMA Monthly approvals from 6/1/2016 to 6/30/2016 http://www.fda.gov/downloads/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/PMAApprovals/UCM510219.pdf Accessed October 2016.
(November 17, 2015) Jeffrey E. Shuren M.D., J.D. Director, Center for Devices and Radiological Health, U.S. Department of Health and Human Services. Food and Drug Administration, Statement on Examining the Regulation of Diagnostic Tests and Laboratory Operations before Committee on Energy and Commerce Subcommittee on Health. Available online at http://www.hhs.gov/asl/testify/2015/11/t20151117a.html. Accessed October 2016.
(June 4, 2014) U.S. Food and Drug Administration. Learn if a Medical Device Has Been Cleared by FDA for Marketing. Available online at http://www.fda.gov/MedicalDevices/ResourcesforYou/Consumers/ucm142523.htm. Accessed October 2016.
(October 3, 2016) U.S. Food and Drug Administration. Medical Device Exemptions 510(k) and GMP Requirements. Available online at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/315.cfm. Accessed October 2016.
Encyclopedia.com. Genetic testing. Available online at http://www.encyclopedia.com/topic/Genetic_Testing.aspx. Accessed October 2016.
(April 21, 2016) CLN Stat. Who should regulate LDTs? Available online at https://www.aacc.org/publications/cln/cln-stat/2016/april/21/who-should-regulate-ldts. Accessed October 2016.
Food and Drug Administration. The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies Available online at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm472773.htm. Accessed October 2016.
Food and Drug Administration. Laboratory Developed Tests. Available online at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm407296.htm. Accessed October 2016.
National Independent Laboratory Association. Press release: Members of Congress Approve Language to Delay FDA Oversight of LDTs. Available online at http://www.nila-usa.org/nila/Members_of_Congress_Approve_Language__To_Delay_FDA.asp. Accessed October 2016.
Sources Used in Previous Reviews
The original article was written by Cathy Tokarski with additional contributions from:
Fred Lasky, PhD, formerly Director of Diagnostics Compliance for Ortho-Clinical Diagnostics, a division of Johnson & Johnson, Rochester, NY.
Robert Murray, PhD, formerly Technical Director for Midwest Diagnostic Pathology at Lutheran General Hospital, Park Ridge, IL.
Sue Evans PhD, formerly Vice President of Product Development for Caliper Technologies Corporation.
Steven Gutman, MD, formerly Director – Division of Clinical Laboratory Devices, US Food and Drug Administration.
David Sundwall, formerly President of the American Clinical Laboratory Association.
Elissa Passiment, EdM, CLS(NCA), Executive Vice President,of the American Society for Clinical Laboratory Science.
US Food and Drug Administration: Premarket Approval Applications for In Vitro Diagnostic Devices Pertaining to Hepatitis C Viruses; CDRH Consumer Information, Learn if a Medical Device Has Been Cleared by FDA for Marketing; Device Advice, Class I/II Exemptions. Available online through http://www.fda.gov.
CLIA Regulations. Subpart K, Sec. 493.1253. Available online at http://wwwn.cdc.gov/clia/regs/subpart_k.aspx#493.1250 and Subpart E available online at http://wwwn.cdc.gov/clia/regs/subpart_e.aspx. Accessed August 2009.
American Association for Clinical Chemistry Resource Library. Genetic and Laboratory-Developed Tests. Available online at http://www.aacc.org/resourcecenters/resource_topics/tests/Pages/default.aspx. Accessed August 2009.
U.S. Food and Drug Administration. Draft Guidance for Industry, Clinical Laboratories and FDA Staff. In Vitro Diagnostic Multivariate Index Assays, Issued July 26, 2007. Available online at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm079148.htm. Accessed August 2009.
College of American Pathologists. About the CAP Accreditation Program. Available online at http://www.cap.org/apps/cap.portal?_nfpb=true&_pageLabel=accreditation. Accessed August 2009.
Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Burtis CA, Ashwood ER and Bruns DE, eds. 4th ed. St. Louis, Missouri: Elsevier Saunders; 2006 Pp 353-356.
Clarke, W. and Dufour, D. R., Editors (2006). Contemporary Practice in Clinical Chemistry, AACC Press, Washington, DC, Pp 51-60.
U.S. Food and Drug Administration. Medical Devices, Device Advice: Device Regulation and Guidance, Overview (Updated August 31, 2009). Available online at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/default.htm. Accessed September 2009.
U.S. Food and Drug Administration, Center for Devices and Radiological Health (June 30, 2009 Updated). New Humanitarian Device Approval: Mesomark ™ – H060004. Available online at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm077034.htm. Accessed August 2009.
U.S. Food and Drug Administration, Center for Devices and Radiological Health Guidance for Industry and FDA Staff: Humanitarian Device Exemption (HDE) Regulation: Questions and Answers (July 18, 2006, Issued). Available online at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071473.htm. Accessed August 2009.
National Cancer Institute. Mesothelioma: Questions and Answers. Available online at http://www.cancer.gov/cancertopics/factsheet/sites-types/mesothelioma. Accessed August 2009.
Hammerschmidt, D. Humanitarian Use Devices: A Brief Guide for Clinicians, Investigators, and IRB Members (October 2002, issued). PDF available for download at http://www.research.umn.edu/irb/members/education/HUDs.pdf. Accessed August 2009.
Fujirebio Diagnostics. Managing Mesothelioma. Available online at http://www.fdi.com/mesomark/world/patients/managing_mesothelioma.html. Accessed August 2009.
Pacific Hearth & Blood Institute. Mesomark. (Dec 12, 2008). Available online at http://www.phlbi.org/phlbi/mesomark-blood-test-may-help-doctors-measure-a-patients-response-to-therapy/. Accessed August 2009.
(September 9, 2007) Clinical Trials.gov. Understanding Clinical Trials. Available online at http://www.clinicaltrials.gov/ct2/info/understand. Accessed August 2009.
Clinical Laboratory Standards Institute. About CLSI (2009), Frequently Asked Questions. Available online at http://www.clsi.org/Content/NavigationMenu/AboutCLSI/FAQ/FAQ.htm. Accessed August 2009.
US Department of Health and Human Services. Centers for Medicare and Medicaid Services. Accrediting Organizations/Exempt States. Available online at https://www.cms.hhs.gov/CLIA/13_Accreditation_Organizations_and_Exempt_States.asp#TopOfPage. Accessed September 2009.
College of American Pathologists. Accreditation and Laboratory Improvement. Available online at http://www.cap.org/apps/cap.portal?_nfpb=true&_pageLabel=accreditation. Accessed August 2009.
The Joint Commission. Accreditation, Laboratory Services. Available online at http://www.jointcommission.org/AccreditationPrograms/LaboratoryServices/HTBA/. Accessed August 2009.
National Human Genome Research Institute. Promoting Safe and Effective Genetic Testing In the United States (April 2006). Available online at http://www.genome.gov/10002393. Accessed August 2009.
US Food and Drug Administration. Medical Devices, Learn if a Medical Device Has been Cleared by the FDA for Marketing (June 18, 2009). Available online at http://www.fda.gov/MedicalDevices/ResourcesforYou/Consumers/ucm142523.htm. Accessed August 2009.