Paul Radensky

As part of product research and development, these biomarkers can be used to identify promising candidates in terms of predicted effectiveness or safety profiles, and these markers may be accepted as surrogate endpoints to allow for more rapid product approvals. In clinical practice, these biomarkers may be developed as diagnostic tests to help: (1) identify patients with a particular disorder or condition (diagnosis), (2) distinguish patients who are likely to benefit from treatment from those who are unlikely to benefit (treatment prediction), (3) identify patients who may be likely to experience serious adverse events (toxicity), (4) monitor therapy on an ongoing basis (safety and effectiveness), and (5) determine dosing.

As diagnostic tools, biomarkers can be developed for clinical use as in vitro tests, imaging procedures, or as other diagnostic modalities. Many novel biomarkers are being developed as "companion diagnostics" tied to specific therapies, with the regulatory clearance or approval of the biomarker combined with the clearance or approval of the therapeutic, and the intended use of the biomarker explained in the labeling for the product. Others are being developed as stand-alone diagnostics not tied to a specific therapeutic product. When developed in combination with the therapeutic, the scientific evidence required to support the approval of the biomarker and the timeline to approval are tied to the requirements and timeline of the therapeutic. However, when the biomarker is developed as a stand-alone diagnostic, the regulatory requirements and timelines are less clear. In addition, whether developed as a companion or as a stand alone, important questions about how these tests will be paid for must be considered. In the sections below, we discuss some of these issues in the context of biomarkers being developed and used as clinical laboratory tests.

Diagnostic tests involving the examination of human specimens for providing information for the diagnosis, prevention, or treatment of any disease or the assessment of health are clinical laboratory tests that lawfully may be performed only by certified clinical laboratories (unless they have been cleared for use by patients in their homes). Clinical laboratories must be certified to perform testing under the federal Clinical Laboratory Improvement Amendments of 1988 (CLIA) and are generally required to be licensed by individual states as well. Clinical laboratories certified under CLIA and licensed under state law must meet prescribed standards governing personnel, quality systems, and proficiency and must undergo periodic inspections to assess compliance with these standards. Some laboratories are inspected by private accreditation organizations, such as the College of American Pathologists (CAP) or the Joint Commission, whose standards are more rigorous than those specified by the CLIA program.

Clinical laboratories can follow one or both of two pathways in developing and offering novel biomarker diagnostic tests: (1) the laboratory can develop a test for its own use in testing specimens sent to the laboratory (laboratory-developed tests or LDTs) or (2) the laboratory can perform a test using a test kit cleared or approved for use by the US Food and Drug Administration (FDA).

Diagnostic tests that are developed as kits by manufacturers and shipped to laboratories for performing tests clearly fit under the definition of a medical device under the Federal Food, Drug, and Cosmetic Act (FFDCA). Similarly, reagents, equipment, and supplies used by laboratories to perform diagnostic tests generally fit under the definition of medical devices. As medical devices, these test kits or components are subject to FDA clearance or approval based on an assessment of the novelty and risk involved.

Manufacturers of the lowest-risk test kits or components generally must comply with limited regulatory requirements under the FFDCA, such as registration of the establishment with the FDA, listing of the test kit or component, maintaining complaint records, and reporting adverse events to the FDA. Compliance with the FDA's quality system regulations may be required as well.