Achieving quality reproducible results and maintaining compliance in molecular diagnostic testing of human papillomavirus

Archives of Pathology & Laboratory Medicine,  Aug 2003  by Seabrook, Jacqueline M,  Hubbard, Roger A

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* Laboratories contemplating either the addition of new molecular tests or modifying methods approved by the Food and Drug Administration for human papillomavirus testing should be aware of a variety of procedural, performance, and regulatory issues surrounding such activity. Diagnostic medical laboratory testing in the United States is regulated by the Centers for Medicare and Medicaid Services, an agency formerly known as the Health Care Finance Administration. The regulatory vehicle of the Centers for Medicare and Medicaid Services is manifested in the Clinical Laboratory Improvement Amendments (CLIA). The CLIA program has put into place specific regulations for laboratory quality control, which includes specific recommendations for method validation. Regulations that must be followed regarding personnel, quality control, quality assurance, method validation, and proficiency testing depend on the complexity category of the individual test. All molecular diagnostic tests, including those for human papillomavirus, are considered high complexity. The Centers for Medicare and Medicaid Services retains the authority to allow private, national accreditation organizations to "deem" that a laboratory is compliant with CLIA '88 requirements. Accreditation organizations, such as the Joint Commission for Accreditation of Hospitals, the Commission on Office Laboratory Accreditation, and the College of American Pathologists (CAP), as well as several state medical laboratory-accrediting agencies, possess the authority to deem laboratories as "CLIA-approved." The CAP, through its Laboratory Accreditation Program, has promoted standards for laboratory performance and method validation. In general, guidelines set forth in the CAP Laboratory Accreditation Program checklists specify that all clinical laboratory testing must essentially meet those requirements defined for high-complexity testing under CLIA '88, including test validation standards, reportable/reference ranges, performance criteria, and proficiency testing.

The need for effective systems to assure quality and to control the molecular diagnostic laboratory has become apparent during the last decade as these techniques have become commonplace. As routine testing technologies and quality control (QC) procedures have evolved in the routine laboratory, so has the need to maintain compliance within the specialty laboratory. The molecular diagnostic testing laboratory has benefited from the growing pains and establishment of guidelines and procedures in the routine laboratory. Changes in Food and Drug Administration (FDA) requirements establishing the analyte-specific reagent ruling1 have allowed the individual laboratory to conduct in-house validations and to generate diagnostic results from these tests. This advent has led to an enormous increase in the testing capabilities of specialty reference laboratories, which prior to the analyte-specific reagent ruling were limited to reagents for in vitro diagnostic use for clinical diagnostic testing.

All medical laboratory practice (except research) performed on humans for diagnostic purposes in the United States is regulated by the Centers for Medicare and Medicaid Services. The Centers for Medicare and Medicaid Services Division of Laboratory Services, within the Survey and Certification Group under the Center for Medicaid and State Operations, has the responsibility of executing the Clinical Laboratory Improvement Act (CLIA) program. The CLIA program, with an overall objective to ensure quality laboratory testing, has implemented specific regulations for laboratory QC, which include specific recommendations for method validation.2-6

Regulations that must be followed depend on the complexity category of the individual test. These CLIA complexity categories are waived, moderate complexity, and high complexity. Each of these categories has different regulatory requirements for personnel, QC, quality assurance, method validation, and proficiency testing. All molecular diagnostic tests, including those for human papillomavirus (HPV), are considered to be in the CLIA high-complexity category. As such, all laboratories performing molecular diagnostic tests must ensure that a valid certification of accreditation is in place that covers testing of high complexity. The Clinical Laboratory Improvement Amendments of 1988 (CLIA '88) states:

The laboratory must establish and follow written QC procedures for monitoring and evaluating the quality of the analytical testing process of each method to assure the accuracy and reliability of patient test results and reports.5

CLIA '88 stipulates that a laboratory that introduces a new procedure for patient testing using a method developed in house, a modification of the manufacturer's test procedure, or a method that has not been cleared by the FDA as meeting CLIA '88 requirements for general QC must, prior to reporting patient test results, perform in-house validation for non-FDA-approved tests.