Laboratory developed tests (LDTs) used to be referred to as “home-brew” tests or “in-house” tests. These are assays that have been developed, evaluated, and validated by the laboratory itself. In the early days of laboratory testing, home brew tests were often relatively simple, well-characterized tests that were used for low-risk diagnostics in the local population of the specific institution. In the current climate of nearly instant access to world-wide testing, the scope of testing encompassed by the category called LDTs has changed and broadened. Now, LDTs are often still considered to be tests that are developed entirely from scratch, using reagents and chemicals purchased from chemical companies. However, the reagents used in an LDT may also be manufactured by an in vitro diagnostics (IVD) company. These include such compounds as Analyte Specific Reagents (ASR) and Research Use Only (RUO) and Investigational Use Only (IUO) reagents. The category of “LDT” can even include FDA-approved IVD assays that are then adapted by laboratories for use in ways that the original IVD manufacturer did not foresee or intend. For example even something as simple as using a serum/plasma methotrexate assay to measure methotrexate in cerebrospinal fluid can be considered a Laboratory Developed Test.
The Food and Drug Administration (FDA) has always maintained that laboratory tests are medical devices, and as such are subject to FDA regulation. Until recently the FDA has exercised “enforcement discretion” in regard to LDTs and has allowed the laboratory community to police itself utilizing laboratory regulatory and accreditation agencies.
The changing landscape
In recent years, however, 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 publically traded assets and far-reaching markets rather than hospitals serving local populations. There is concern that commercial labs and biotechnology companies might use LDTs as a means of avoiding the traditional pathway of test approval through the FDA.
In addition, in the current climate, with increasing reports of faulty data analysis, exaggerated clinical claims, and unacceptable clinical performance, the FDA has become increasingly concerned about the use of improperly validated tests that may pose a public health risk, resulting in incorrect or missed diagnoses and failure to receive proper treatment. 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.
In July 2010 the FDA and the Center for Devices and Radiological Health (CDRH) held a two-day public meeting on the Oversight of Laboratory Developed Tests.1 At the meeting the FDA officially informed the medical laboratory community that the enforcement discretion days were over. The FDA will be regulating LDTs.
The FDA does realize that there are unique issues among the laboratory community which must be considered when it implements this regulatory oversight. Among those considerations are the vast number and type of LDTs that are in current use and the critical nature of some of those tests. The list of testing which is currently being performed almost exclusively by LDTs includes newborn screening; diagnosis of genetic defects, including disorders of organic acids, amino acids, and fatty acids; infectious disease testing, especially viral load testing for diseases such as HIV, CMV, EBV, and respiratory viruses; immunohistochemical 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.
Since the Clinical Laboratory Improvement Amendment of 1988 (CLIA) came into existence, it has been regulating LDTs, both in terms of their development and their continuing performance. CLIA regulation 42 CFR 493.1253(2) from the Federal Register clearly specifies the validations that must be done when performing any assay and the extra parameters that must be validated for any non-FDA-approved assay or for a non-FDA-approved use of an FDA-approved assay. Any time an assay is brought into a laboratory, even an FDA-approved assay from a manufacturer, four specific parameters must be verified before the assay can be used to test patient samples. The lab has the responsibility of proving that the test performs in the lab as advertised by the manufacturer. The four parameters include verifying the precision, accuracy, and reportable range of the test, and then verifying that the manufacturer’s reference intervals are appropriate for the patient population. For an LDT, including any laboratory adaptation of an FDA-approved test, these four parameters must be verified also, but in addition, the analytical sensitivity or lower limit of detection must be determined, the analytical specificity or any assay interferences must be determined, and often the reference interval for the population must be determined from scratch rather than transferred from a published source or previous lab assay.
Too many cooks?
Accredited laboratories already operate under a significant regulatory load, including that coming from the Center for Medicare & Medicaid Services (CMS), CLIA, the College of American Pathologists (CAP), The Joint Commission, and state agencies in specific states. CAP and CLIA accredited labs follow the CLIA guidelines and carefully evaluate and validate all tests, including LDTs, before use. In addition, LDTs are subject to the same regulatory requirements as any laboratory test in an accredited lab, including periodic proficiency testing, biannual validation of analytical measurement range, and daily quality control requirements. Additional regulatory requirements by the FDA seem redundant and in many cases unnecessary.
There is currently considerable disagreement about the regulatory roles that should be assumed by the FDA as opposed to the accrediting regulating agencies like CLIA, CMS, and CAP. CAP agrees with the FDA that more oversight of LDTs is necessary, though it does not necessarily agree about who should provide the additional oversight. CAP has generated a proposed set of guidelines for regulating LDT tests.2 Essentially, CAP proposes that a tiered approach be used for regulating LDTs based on the level of potential risk the test may have for the patient. Low-risk LDTs would require the lab’s accrediting agency to verify the assay validation performed by the laboratory and verify that the lab complies with accreditation standards as part of the normal annual inspection. Moderate-risk LDTs would require the lab offering the LDT to gain the approval of the accrediting agency before offering the test clinically. High-risk LDTs would require a full FDA review of the LDT before it could be offered clinically.
The definition of risk level is also spelled out by CAP. Low-risk LDTs include those for which an incorrect result or interpretation is unlikely to result in serious morbidity/mortality. Moderate-risk LDTs are those for which an incorrect result or interpretation may result in serious morbidity/mortality but for which the test methodology is well understood and independently verifiable. Incorrect results or interpretation of results from a high-risk LDT could result in serious morbidity/mortality, and the test method is not well understood or is not independently verifiable. Because CAP currently has accreditation oversight of so many laboratories, it may have the wherewithal to achieve LDT oversight in a more timely manner and with less disruption than the FDA can.
Valid concerns and emerging approaches
Concerns about FDA direct regulation of LDTs are myriad. The FDA is not known for its fast action, and thus submitting any test to it for approval is guaranteed to delay use of the test for an unforeseeable amount of time. Submitting tests to the FDA for approval is also an expensive proposition. Hospital laboratories and small laboratories may find these two areas so onerous and expensive that development of new tests will no longer be an option. This would in effect stifle the ability of labs to develop tests. Many labs currently operate using LDTs that have long been in existence. My own lab has an entire section devoted to metabolic disease testing that runs LDTs exclusively. The question of whether the FDA will require all those tests to be processed through its regulatory system, and at what expense in terms of both money and time, is a serious question that will have a major impact. In addition, a few of those assays were in place before my tenure. Must the lab regenerate the validation data on those assays for the FDA process, and again at what expense? It is very possible that expense will result in labs discontinuing current testing, and certainly it will result in much less future assay development.
Currently the plans for the FDA regulation of LDTs are being written. It appears that the FDA has embraced a risk-based approach to regulation, and may target LDTs it considers high-risk to begin its regulatory advance.3 At times the FDA appears to be aware that it must take a protracted and cautious approach to regulating hospital-based LDTs that are currently in use. At other times the FDA seems oblivious to the harm it can do by pushing its agenda forward. For example, the FDA has taken its first step in the direction of regulating LDTs by publishing a draft guidance on use of RUO/IUO reagents in June 2011.4 This draft guidance threatens FDA sanction against manufacturing companies that market their products as RUO/IUO and are aware that labs use them for clinical testing. The draft guidance has already resulted in manufacturers pulling reagents off the market, causing labs to stop testing or to scramble to revalidate assays using less optimal reagents. The FDA is concerned about patient safety and that RUO/IUO reagents aren’t manufactured under as stringent a set of conditions as reagents in FDA-approved test systems. Yet RUO/IUO reagents are unlikely to be manufactured by IVD companies under less stringent conditions than those used in most chemical companies. RUO/IUO reagents often work better in assays than unregulated, off-the-shelf reagents. Replacing them with chemicals from chemical companies, even if such are available, may result in suboptimal assays.
From a laboratory perspective, this draft guidance feels like the proverbial warning shot across the bow. It is a signal that the FDA will be regulating LDTs and that it’s time for laboratorians to pay attention. Change is not necessarily a bad thing. Onerous as it may be, not all regulation is bad, and some of it is necessary. The FDA is aware that sweeping regulations in this area of laboratory medicine could cripple current testing and stifle innovation. There is some hope that the FDA will move cautiously, giving due regard to the laboratories currently engaged in this testing. As laboratorians, we must be aware of the FDA’s moves and do our best to have input in the changes rather than having them imposed on us from outside.
Patricia M. Jones, PhD, DABCC, FACB, is Clinical Director of the Chemistry and Metabolic Disease Labs at Children’s Medical Center of Dallas, TX, and Professor of Pathology and Medical Laboratory Science at UT Southwestern Medical Center.
- FDA/CDRH public meeting: oversight of laboratory developed tests (LDTs). July 19-20, 2010. http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm212830.htm. Accessed August 9, 2012.
- Laboratory developed test oversight should be strengthened. CAP position statement, September 24, 2009. http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt%7BactionForm.contentReference%7D=statements%2Fldt_oversight_statement.html&_state=maximized&_pageLabel=cntvwr. Accessed August 9, 2012.
- FDA says lab-developed test regulation will take time. Clinical Laboratory News. 2011; 37:10. http://www.aacc.org/publications/cln/2011/october/Pages/LabDevelopedTestRegulation.aspx#. Accessed August 10, 2012.
- Draft Guidance for Industry and FDA Staff – Commercially Distributed In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions. http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm253307.htm. Published June 1, 2011. Accessed August 9, 2012.