Regulation of laboratory-developed diagnostic assays: Where we are

Technological advancements have made diagnostic assays very powerful and valuable tools for disease diagnosis. Diagnostic assays are used for a wide range of applications: diagnosis and prognosis of disease, identification of increased risk of developing certain disorders, and monitoring response to therapy. New diagnostic techniques allow us to format personalized medicine with pharmacogenetic assays such as drug metabolism assays to avoid adverse drug effects, companion diagnostics to identify patients who will respond to a specific drug, forensic assays, and histocompatibility assays. The molecular diagnostics market has become a significant segment of the in vitro diagnostics (IVD) industry. Worldwide sales of $2.5–2.8 billion in recent years for molecular diagnostic products to clinical laboratories, plus clinical laboratory testing service revenues of ~ $3.2 billion in the US alone in 2007, make molecular diagnostics a major market. The market for molecular diagnostics is growing rapidly (1). Moreover these diagnostic assays have made detection of many diseases faster and easier, which would otherwise take a long time for detection due to slow growth or difficulty in growing cultures (2). Such assays are often created by a clinical laboratory because commercial assays for the analyte(s) of interest may not be available or the analyte may be rare; the market for such products would be too small to be profitable. Since rapid and accurate analysis of a patient’s condition is an imperative part of clinical management, these laboratory diagnostic assays become the vital part of this process. All laboratories in the US that perform clinical testing on humans—excluding clinical trials and basic science research—are regulated by the Clinical Laboratory Improvement Amendments (CLIA) of 1988, which were extensively revised in 2003 (3, 4). The 2003 final rules require that laboratories do studies for Food and Drug Administration (FDA)-approved non-waived assays to verify performance specifications established by the manufacturer. The performance characteristics that must be verified include accuracy, precision, reportable range, and reference interval. Nonetheless, laboratory developed diagnostic assays require more extensive studies: accuracy, precision, reportable range, reference interval, analytical sensitivity and specificity, validation, verification of the assays at the time of assay development (5). While most FDA-waived assays are reviewed by CLIA, CLIA regulations stipulate that it is the responsibility of clinical laboratory directors to establish performance characteristics for laboratorydeveloped diagnostic assays used in their laboratories. The fact is, laboratories face many challenges in trying to accomplish this. Although laboratories determine the type of experiments that are required, including the acceptable number and type of specimens, and choose the statistical methods to evaluate the data for the performance of tests, the technology is advancing rapidly and changing continually, making existing guidelines difficult to apply. In addition, there is no single set of comprehensive guidelines for laboratory-developed diagnostic assays that would help laboratories manage the studies for assays necessary to satisfy regulatory requirements and ensure robust performance acceptable to all accrediting organizations. Thus, laboratories are under great pressure to control costs and to pave the REGULATORY OPINION