The 1976 Medical Device Amendments to the Federal Food, Drug and Cosmetic Act (FD&CA) gave the FDA authority to regulate medical devices, including in vitro diagnostic devices (IVDs). Defined as reagents, instruments, and systems intended for use in diagnosing disease or other conditions, IVDs are packaged products developed and distributed by medical device manufacturers and sold in interstate commerce. In regulating IVDs, the FDA focuses on their safety and efficacy, the manufacturer claims about clinical “intended use” of the devices, and the quality of the design and manufacturing process[i].
In contrast with IVD products, clinical laboratories perform and report laboratory tests for human patient diagnosis and management. They are regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), administered through the Centers for Medicare & Medicaid Services (CMS). CLIA focuses on the accuracy and reliability of the testing process, with attention to analytic quality control, proficiency testing, credentials of laboratory testing personnel, requirements for reporting results, and appropriate documentation of standard operating procedures.
CLIA allows clinical laboratories to modify FDA-approved tests, and, more importantly, to develop their own tests—laboratory-developed tests (LDTs)—as long as they follow the requirements to establish the performance characteristics of the LDTs.
This is demonstrated by CLIA requirements that laboratories demonstrate how well an LDT test performs using certain performance standards, including:
- Accuracy—the ability of a test to most closely measure the “true” value of a substance across the established reportable range of the test.
- Precision—the reproducibility 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[ii]
Routine, regular inspections under the auspices of CLIA are intended to ensure that these necessary steps are being followed for the LDTs offered for patient care purposes.
In the past, laboratory developed tests have also been referred to as “home brewed” tests. Often, a laboratory will choose to develop and use an LDT because a commercial test is not available. LDTs generally have not been subjected to FDA oversight because these diagnostic tests are never sold to other laboratories or hospitals. Historically, LDTs comprised a relatively small volume of tests that were relatively simple, intended for use in diagnosing rare diseases or to meet the needs of a local patient population. However, unlike traditional LDTs, modern LDTs are more complex; widely used to screen for common high-risk diseases, such as breast cancer and Alzheimer’s disease, rather than rare diseases; manufactured in high volume by large corporations with international reach and offered beyond local patient populations; manufactured with components that are not legally marketed for clinical use; and present higher risks that are similar to those of other IVDs that have undergone premarket review (e.g., used in guiding critical treatment decisions).
In light of these profound shifts in the technology and business practices with respect to the use of LDTs, the FDA currently believes that its policy of general enforcement discretion towards LDTs may no longer be appropriate. As a result, the FDA has begun to revisit its role in the regulation of LDTs. There appear to be two main factors which have caused increased concern on the part of the FDA: the use of LDTs in the exponentially growing field of molecular diagnostics, which includes tests that are used to assess high-risk conditions and supply information for critical decision-making; and the increasing number of LDTs being manufactured by corporations with far-reaching markets rather than hospitals serving local populations. These commercial companies, many with their own CLIA-certified laboratories, offer direct-to-consumer (DTC) genetic testing. The FDA has become increasingly concerned about the use of improperly clinically validated tests that may pose a public health risk. The FDA has also expressed concern that the current lab accrediting agencies are focused on test analytical validity, and not the clinical validity and use of the tests, making FDA oversight necessary[iii].
There can be several reasons why a commercial test has not been developed for a particular analyte or disease of interest. For example, many LDTs are genetic tests developed for rare diseases. These are also diseases affecting only small subset of the population, thus reducing the incentive for a manufacturer to develop a commercial version because the market for such a product would be small, without a potential decent 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 a laboratory-developed test and is subject to the regulations applied to all lab-developed tests.)[iv]
The Current Landscape
Estimates suggest that thousands of diagnostic tests, including the majority of genetic tests, are currently offered as LDTs. The list of testing which is currently being performed almost exclusively by LDTs includes newborn screening; diagnosis of genetic defects, including metabolic disorders; infectious disease testing, especially viral load testing for diseases such as HIV, CMV, EBV, and respiratory viruses; immune-histochemical stains for the diagnosis of cancers; tandem mass spectrometry, testing for a wide variety of analytes ranging from thyroid tests to immunosuppressant drugs to vitamin D; next generation gene sequencing; comparative genomic hybridization array testing; genetic variants of the Cytochrome P450 drug metabolism system and determination of appropriate individual drug dosing; and drug screening and confirmation assays, to name a few.
Direct To Consumer Testing
Commercial companies, many with their own CLIA-certified laboratories, now offer direct-to-consumer (DTC) genetic tests. Such tests give consumers information about their own genetic markers, from physical traits (such as baldness) to certain disease associations (such as prostate cancer). The identification of these “genome-wide disease associations” has become increasingly popular among consumers.
Although, many of these disease associations are weak to moderate at best, there is a growing list of companies offering this kind of information on an increasing number of conditions. The important distinction that needs to be made is that these tests offer “prediction” through statistical possibilities. They do not provide statistical certainties—a critical point that can easily be lost in translation in the marketing and consumer use of such products. Furthermore, prediction does not equal diagnosis. Because there are frequently so many other genetic and environmental factors that can determine whether a disease actually emerges, it is critical that consumers fully understand that the risk may never become reality. Similarly, the absence of a genetic risk factor (or the presence of a favorable one) may still not prevent subsequent development of disease. This context about the known association between a disease and genetic markers must be clearly communicated to the consumer through counseling—done best by medical professionals, particularly professionals trained in medical genetics.[v]
The fact that many of these DTC companies develop their own tests and testing platforms has led the FDA, as well as members of Congress, to believe that these LDTs are medical devices that must be carefully regulated so that the analytic and clinical validity and clinical usefulness are clearly understood, to protect the public safety. Accordingly, additional regulatory safeguards, provided by FDA IVD oversight to ensure the accuracy of LDTs, particularly high-risk LDTs, are under consideration to better ensure that patients do not seek unnecessary treatments, delay needed treatments or become exposed to inappropriate therapies.
In Part 2 of this blog, I will discuss the controversy regarding how FDA regulations can be applied to LDTs and the pros and cons expressed by professional organizations and industry leaders.