FDA-Cleared versus Laboratory-Developed Tests: Why Start from Scratch When Kits Are Available?

One of the most common questions facing laboratories when bringing up new clinical tests is deciding which specific assay best suits the needs of the lab, its patients, and its providers. At first glance, assays cleared by the Food and Drug Administration (FDA)² for use in clinical testing would seem to have some obvious advantages: the validation requirements are less onerous than for laboratory-developed tests (LDTs) (1), and much of the legwork, e.g., sensitivity and specificity testing, is done by the manufacturer rather than falling on the laboratory.

Certainly, there are situations where an FDA-cleared test is the obvious choice over bringing up an LDT, particularly for well-established analytes that have high-quality assays readily available. There are a number of challenges associated with LDTs, including the difficulty of standardization or harmonization with other testing platforms, in addition to the increased validation and quality assurance requirements. The ongoing discussion regarding tighter regulation of LDTs by the FDA has added another layer of complexity to the decision as well (2), particularly for laboratories that currently have few or no LDTs but are considering adding them. However, there are often good reasons why laboratories might opt for LDTs over FDA-cleared tests.

One of the most important reasons why laboratories might choose to bring up LDTs is the quality of the available FDA-cleared tests. FDA clearance does not guarantee that an assay is free of interferences or problems; it simply mandates that manufacturers evaluate and report susceptibility to some common interferences. A common scenario where laboratories frequently choose LDTs is therapeutic drug monitoring for immunosuppressant drugs such as tacrolimus, cyclosporine, sirolimus, and everolimus. Many of the available commercial immunoassays for these drugs have cross-reactivity with metabolites, which can lead to uncertain quantification of the active parent drug, particularly in patients with atypical pharmacokinetics such as impaired clearance (3). Although there is potentially some clinical benefit to using assays that incorporate biologically active metabolites, mass spectrometry provides a mechanism for accurately quantifying the drug of interest without active or inactive metabolites. Before FDA clearance of mass spectrometry “kits” for some immunosuppressants, LDTs were the only option for laboratories seeking to avoid metabolite cross-reactivity.

Similar concerns lead laboratories to modify FDA-cleared kits when they fail to meet clinical needs. Common examples include extending the analytical measurement range or establishing different criteria for sample rejection due to interferences such as hemolysis or lipemia. Although these modifications are less extreme than moving to a fully lab-developed assay, they do come with the burden of additional validation and demonstration that the modified test meets quality requirements for use in the clinical laboratory.

Another common reason why laboratories validate LDTs is to meet clinical needs in areas where tests are changing rapidly. An excellent example is genetic testing, particularly for highly polymorphic genes where new variants are continually being described. FDA clearance is a long and expensive process, which makes it difficult for assay manufacturers to keep up with an ever-expanding list of clinically relevant variants. Laboratories focused on cutting-edge diagnostics might not have the luxury of waiting for FDA-cleared assays to become available for novel analytes. The need for flexibility to incorporate newly described variants or emerging biomarkers into a clinical laboratory practice can make LDTs preferable over waiting for new assays or test updates to clear the FDA pipeline.

Finally, there are some very practical reasons why laboratories might opt for LDTs, which include the cost of FDA-cleared kits and the instrumentation required. Newly marketed tests and single-vendor tests are often relatively expensive, which can make LDTs a cost-effective option despite the additional regulatory burden. If a laboratory would be required to purchase new instrumentation to run an FDA-cleared kit, modifying the test for an available platform or developing an LDT might be more economical options.

So, which test should you choose? There is no single best answer: these considerations have to be weighed according to the specific situation of each lab, including available resources, patient population, and clinical need. For many laboratories, the additional burden of more extensive validation and quality assurance can make LDTs less desirable, while laboratories with greater resources and technical expertise might have more flexibility. Although there are a number of logistical practicalities that must be weighed, ultimately the question comes down to whether an LDT or a cleared assay is better able to serve the laboratory in providing the best possible patient care.

2 Nonstandard abbreviations

 
• FDA

  Food and Drug Administration

 
• LDT

  laboratory-developed test.

Author Contributions:  All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors' Disclosures or Potential Conflicts of Interest:  No authors declared any potential conflicts of interest.