Standards have been determined by regulatory agencies for the verification and validation of molecular assays. In 1988, the US Congress passed the Clinical Laboratory Improvement Amendments (CLIA '88) to establish quality standards for all laboratory testing. The standards were designed to ensure the accuracy and reliability of human patient testing results regardless of where the test was performed. CLIA regulations are based on the complexity of the test performed. Laboratory testing is divided into simple or "waived" tests, tests of moderate complexity, and tests of high complexity. All molecular tests fall within the "high-complexity" category as defined by CLIA '88 (1).
The College of American Pathologists (CAP) has established the Laboratory Accreditation Program to improve the quality of clinical laboratory services through voluntary compliance to established performance standards. CAP also has mandated that specific parameters must be verified for each assay before that assay is implemented into use in the laboratory (2). Before CAP issues accreditation to a laboratory, the laboratory must show that it has defined the required verification parameters for the assays the lab performs.
As shown in Table 1, CLIA and CAP differ to some extent in their requirements for assay verification. CLIA differentiates assays into two groups: (1) FDA-approved tests and (2) non-FDA- cleared tests. The latter group would include commercial
Research Use Only (RUO) tests, commercial kit components, and in-house developed assays. For FDA-cleared tests, CLIA requires that the performance specifications for accuracy, precision, and reportable range be determined or confirmed and that these performance specifications be comparable to those established by the manufacturer. The verification requirements for non-FDA-cleared tests are more extensive and include reference range, analytical sensitivity, and analytical specificity. The CAP requirements for verification do not differentiate among different types of assay, regardless of their FDA clearance status. CAP requires the more extensive verification process that CLIA requires for non-FDA-cleared tests.
Various professional organizations have published perspectives or guidelines concerning the verification of molecular assays. The National Committee for Clinical Laboratory Standards (NCCLS) has completed guidelines that address various types of molecular diagnostic assay (3-9), as well as guidelines that address the evaluation of specific assay performance characteristics (10-12). The American Society for Microbiology and the Association for Molecular Pathology have also published perspectives on the verification and use of molecular assays (13,14).
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