Laboratory developed tests (LDTs) are usually not regulated by the Food and Drug Administration (FDA). The FDA has not enforced applicable in vitro diagnostic regulations because LDTs have been developed, validated, and offered within single laboratories, have usually been tests for rare diagnoses or conditions, and have been used by physicians within an institution and for treating their patients. LDTs were considered low-risk, adequate validation was thought not to be feasible, and the use of LDTs was geographically limited. The FDA regulation of general reagents or analyte specific reagents, which are usually components of LDTs, was intended to mitigate the existing risk.
A subgroup of LDTs, the in vitro diagnostic multivariate index assays (IVDMIAs) use a multiple variable interpretation function to determine a single patient-specific result or score intended for diagnosis (including molecular diagnostics). That score would be used to predict a disease or disease risk (e.g., genetic profiling for breast cancer prognosis).
The absence of FDA-cleared assays has resulted in widespread use of LDTs for diagnostic use, including genetic testing. Even with more widespread use, the FDA has continued to use enforcement discretion. However, in the field, there have been many issues of exaggerated claims, lack of change control, fraud, and unacceptable clinical performance. Therefore, the FDA has indicated that it believes there is a need to regulate some LDTs to ensure they are safe and effective. This has been discussed in several forums, including a U.S. Department of Health and Human Services Public Meeting on Oversight of Laboratory Developed Tests convened in July 2010.
IVDMIAs are of particular concern to the FDA for a variety of reasons, including their lack of transparency and their high-risk intended use. The result may be a derivation that cannot be verified by the end user. Performance characteristics have not been determined. Often there are testing platforms and software involved that require validation. Assays have not had validation of their clinical claim. It is not possible to clinically validate these assays, and expert physician interpretation has been removed. Because these assays emerged from research testing and were primarily laboratory developed, they may not be manufactured in compliance with the FDA Quality System. The argument has been made that validation of assays is a requirement under the Clinical Laboratory Improvement Amendments (CLIA) regulations. However, CLIA regulations are intended to ensure the quality of the laboratory that performs testing, not the quality of the actual assay or the clinical validity of the assay.
Additionally, Centers for Medicare and Medicaid Services (CMS) concerns about the quality of laboratory developed tests and the validation being performed on these assays resulted in the Agency for Healthcare Research and Quality conducting an assessment of the available scientific evidence on the quality of laboratory developed (“home brew” or “in-house”) molecular tests to (1) identify types of LDT molecular tests currently available for conditions relevant to the Medicare population; (2) identify how analytical and clinical performance of molecular tests have been determined; (3) summarize the role of federal agencies in regulating LDTs for molecular tests; and (4) identify the quality standards that have been developed for molecular tests. The intent of this assessment is to help in the decision-making process.
What does this mean to you, the laboratory? The laboratory would need to employ regulatory affairs staff who are familiar with the FDA regulations relevant to the manufacture of in vitro diagnostics (21 CFR Part 800 and possibly 21 CFR 610.44) and who are appropriately trained to successfully submit FDA marketing applications. In addition, manufacture of the assay would need to comply with the FDA Quality System regulations. Regarding reimbursement, there are FDA cleared/approved tests that do not qualify for reimbursement and LDTs that do. However, there is concern that the cost to manufacture an LDT under FDA regulation would result in a reimbursement framework that would not be feasible. That is, the total costs that would be associated with the development of such a test (particularly a test for a rare disease or diagnosis) to comply with FDA regulations would outweigh cost reimbursement.
The landscape has changed over time, and today LDTs are commonly used; they may be comprised of components that are not FDA-regulated; their offerings may be made by remote laboratories; they may be manufactured by corporations rather than hospitals or public health laboratories; and there may be lack of validation. All of these factors have contributed to FDA concern for the assurance of proper validation to demonstrate that the assays perform as they are intended. In the absence of this assurance, there is a risk of incorrect diagnosis and unnecessary or missed treatment. Laboratories should consider what their legal liability may be for such failures. How to best handle LDTs without compromising patient health is still under consideration by the FDA, and a draft guidance document from the Agency is pending
Sharyn Orton, MT(ASCP)SBB, MPSH, PhD, is Senior Consultant for Massachusetts-based MEDIcept, Inc. She has more than 30 years experience in the blood banking industry.
