FDA CLIA Waiver Application Guidance

01 What the document says

Under CLIA, a test can be waived from most laboratory requirements only if it is simple and has an insignificant risk of an erroneous result. This guidance describes how a manufacturer that already holds, or is seeking, FDA clearance or approval can assemble a CLIA Waiver by Application to show the test meets both criteria. It replaced the 2008 version of the same guidance.

The document is organized around three kinds of evidence. First, a description of the device and its labeling showing that it is simple: fully automated or otherwise easy to perform, with unprocessed or minimally processed specimens, no operator intervention in the measurement, and clear, unambiguous results. Second, a risk analysis that identifies potential sources of error across the whole testing process and shows how the device design and labeling control them, supported by flex studies that stress the test under plausible environmental and usage variations such as temperature, timing, lighting, or sample volume. Third, clinical performance studies showing that the test is accurate in the hands of its intended operators.

The 2020 revision implements section 3057 of the 21st Century Cures Act. Accuracy can now be demonstrated in more than one way, including a comparison of results obtained by untrained operators in waived-type settings against results obtained by trained operators in a moderately complex laboratory, in addition to the older approach of comparing untrained-operator results to a traceable reference method. The clinical study is expected to enroll the intended-use population prospectively, span the measuring range or decision thresholds, and be run at several sites representative of the waived environment, with the untrained operators relying only on the labeling.

02 What it means when you plan a study

• Operators must be genuinely untrained: personnel with no prior experience on the device, no training beyond the package insert and quick reference instructions, and no coaching from the sponsor or study staff during testing.
• Sites must look like the places a waived test will actually be used, such as physician offices, urgent care clinics, or pharmacies, not hospital laboratories; a site network that already holds Certificates of Waiver shortens startup.
• Enrollment is driven by the number of positive and negative results needed in each decision category and by the need to cover the full range of expected values, so a prevalence-dependent target is usually set before the first subject.
• A comparator plan has to be fixed before the study: either a traceable reference method or a trained-operator arm running the same device in a moderately complex laboratory, each with its own specimen handling and stability constraints.
• Flex studies and the risk analysis are bench work that typically precedes the clinical study and often reveals labeling changes; locking labeling before field testing avoids repeating the clinical arm.

03 Pathways it applies to

• CLIA Waiver Studies
• Dual Submission Studies

Source document: Recommendations for Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices (fda.gov).