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 health care 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.