FDA-approved, Nonwaived Laboratory Tests: Method Validation, Performance Standards, and Biological Variations

INTRODUCTION

In the United States of America, laboratories must be licensed by the department of health to process patient samples. The federal government established a federal code of conduct to manage and monitor clinical laboratories. The Clinical Laboratory Improvement Amendments (CLIA) are a group of rules that were established in 1988 to help regulate clinical laboratories, provide guidelines to the scope of testing, and protect consumer rights. CLIA divides laboratory testing into waived and non-waived tests based on the complexity of the analysis (Figure 1).

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Figure 1.

Test complexity determined by CLIA and the FDA.

Waived tests require minimal technical competency and they yield low risk in the event of an erroneous result. Any individual can perform a waived test in a physician office or their home and no educational or professional training is required. If the test is performed in a physician’s office, the office must apply for a CLIA certificate and the facility that performs the test must comply with all the manufacturer recommendations. CLIA doesn’t demand any other regulations for waived tests.

Non-waived tests are defined as either moderate or high complexity. Unique educational and professional experience are required to perform non-waived tests. CLIA and the Food and Drug Administration (FDA) determine the complexity of the test, using specific criteria.¹ Health care facilities that perform non-waived tests must obtain a CLIA certificate and abide by CLIA regulations. In addition, the facility must be inspected periodically and provide proof that they comply with the CLIA quality requirements. All laboratory developed tests and non-FDA approved tests are classified as high complexity tests, and CLIA requirements are more rigorous for these kinds of tests.¹

Laboratory assays are developed based on the need to test for a specific substance, to monitor a particular process, or for a faster and more accurate methodology.² In the past few years, clinical research determined that Vitamin D deficiency contributed to many diseases and conditions. The discernment led to the need for an assay to monitor Vitamin D levels. Likewise, the need to improve the turnaround time for microbial culturing methods contributed to the development of Polymerase Chain Reaction techniques that determine the presence or absence of specific microorganisms in patient specimens. Polymerase Chain Reaction techniques can identify mircoorganisms within two hours with high accuracy, while cultures require 48 to 72 hours.

METHOD VALIDATION

The details of a method validation are described in this focus series in, “Eight Steps to Method Validation in a Clinical Diagnostic Laboratory.” Briefly, precision, accuracy, and linearity, as described below, are considered part of the method validation process. To adopt a new clinical laboratory test, it is important to determine what values for precision and accuracy are acceptable. Total error, random error (RE), and systematic error should be calculated for the new test and compared to the total allowable error range published by CLIA. Furthermore, as detailed in “Performance Standards for Quality Control Systems,” the quality of an assay must be monitored by quality control (QC). Setting and using quality goals allows laboratories to design an efficient QC system and select error detection limits specific to the quality level of each analyte. Generally, the error for any of these values must be less than or equal to the CLIA requirements and follow the acceptable published biological variation data for the measured analyte.⁵

CONCLUSION

The process of implementing a new laboratory test, while time consuming, is a crucial one. A well-executed validation study results in good outcomes. Rushing through the process can impact the quality of the test results which, as a result, can impact patient care.