CLIA stands for Clinical Laboratory Improvement Amendments of 1988.

It is a U.S. federal law that establishes quality standards for laboratory testing performed on human specimens to ensure accurate, reliable, and timely test results, regardless of where the test is performed

• CMS (Centers for Medicare & Medicaid Services) administers the CLIA program and issues laboratory certificates.
• FDA categorizes IVD tests as Waived, Moderate Complexity, or High Complexity and reviews CLIA Waiver applications.
• CDC provides technical support and laboratory standards.

After FDA clearance or approval, an IVD test receives a CLIA complexity categorization:

To determine:

• Who can perform the test
• Where the test can be performed
• What laboratory certification is required

General performance studies demonstrate that the device works; CLIA studies demonstrate that the device still works safely and reliably when used by minimally trained users under real-world conditions. This is why general performance studies alone may not be sufficient for a CLIA Waiver application.

For example, in the General Performance Study you may show:

• 99% sensitivity
• 99% specificity
• Correct identification of HbAA, HbAS, HbSS, HbSC, etc.

This proves the device works when used according to the protocol.

FDA’s CLIA Question FDA then asks:

What happens if a nurse accidentally adds 5 drops instead of 6?

What happens if the result is read at 8 minutes instead of 10 minutes?

What happens if the user does not mix properly?

What happens if a minimally trained operator misinterprets the lines?

General performance studies usually do not answer these questions.

Dual submission is required when a manufacturer wishes to apply for both a FDA CLIA waiver application and a 510(k) submission simultaneously.

By submitting both the 510k and FDA CLIA Waiver applications at the same time, manufacturers can get their products to market faster. The FDA can review both applications together, which saves time compared to reviewing them one after the other.

Dual submission is required when a manufacturer wishes to apply for both a FDA CLIA waiver application and a 510(k) submission simultaneously.

By submitting both the 510k and FDA CLIA Waiver applications at the same time, manufacturers can get their products to market faster. The FDA can review both applications together, which saves time compared to reviewing them one after the other.

The FDA categorizes clinical laboratory tests by their complexity—from the least to the most complex:

• Waived tests (Ex: urine pregnancy test, rapid strep tests, glucometer)
• Moderate complexity test (Ex: chemistry panels, complete blood counts, PCR testing, urine dipsticks)
• High complexity test (Ex: cytology, flow cytometry, most molecular diagnostic tests, genetics tests)

When a manufacturer of in vitro diagnostic (IVD) devices believes that the device is simple enough to obtain a CLIA waiver and also initially categorized as moderate complexity but meets the criteria for the waived test can apply for a CLIA Waiver by submitting a CLIA Waiver by Application (CW) to the FDA.

When a test is categorized as waived, it allows that test to be performed by laboratories with a Certificate of Waiver (COW) or a Certificate for Provider Performed Microscopy (PPM) in addition to the other CLIA Certificate types.

Manufacturers are required to submit a Pre-submission and inform the FDA of its intention to submit a Dual 510(k) and CLIA Waiver application before making a dual submission. The FDA recommends using the Pre-Submission process to discuss intended study designs.

FDA CLIA waiver protocols and applications:

FDA determines the CLIA categorization at the time of review submission (510k or PMA). FDA create a submission tracking number for the CLIA process and notifies the sponsor of their CLIA record (CR) number in addition to the premarket number. FDA will notify sponsors of the categorization within 2 weeks of the premarket decision. FDA CLIA waiver by application should reference a cleared/approved marketing application (e.g.: 510k, PMA). In case premarket submission is reviewed by another FDA center, the other center will notify CDRH

Database for CLIA categorization of IVD devices

In a FDA CLIA waiver by application, a manufacturer must submit evidence to the FDA that their test was previously cleared or approved categorized as moderate complexity but meets CLIA waiver statutory criteria and request the FDA to categorize the test as waived.

CLIA Waivers by Application are not accepted for devices that are under premarket review at the time of submission. A Dual 510(k) and CLIA Waiver by Application should contain the complete 510(k) and waiver application in a single submission.

Study requirements:

In a dual submission, the manufacturer must include comparison and reproducibility studies. Such studies should be conducted by the intended user (i.e. untrained test operators) for a CLIA waiver and trained operators for 510(K).

An applicant may choose to conduct a single set of comparison and reproducibility studies with untrained operators to satisfy certain requirements to establish both substantial equivalence

A dual submission should contain the following information:

• A single set of comparison and reproducibility studies that are used for supporting both FDA 510k clearance and CLIA waiver.
• Description of the device that demonstrates it is simple to use
• Risk Analysis- The results of risk analysis, including the identification of potential sources of error for the device.
• Failure-Alert and Fail-Safe Mechanisms- The results of risk evaluation and control including a description of
• Implementation to mitigate the risk of errors, and
• validation and/or verification studies demonstrating the ability of failure alert, fail-safe mechanisms, and other control measures incorporated into the device to mitigate the risk of errors, even under conditions of stress.
• Flex studies – The results of flex studies demonstrate the insensitivity of the test system to environmental and usage variations under conditions of stress.
• Analytical studies- A description of the design and results of studies conducted at an internal site includes:

Analytical sensitivity (Limit of Detection (LoD) or C5-C95 for qualitative tests);

Measuring interval (Limit of Quantitation (LoQ) and Limit of Blank (LoB)/LoD, if applicable, for quantitative tests);

Analytical specificity (interferences, cross-reactivity, etc.);

Linearity (for quantitative tests);

Precision (if needed for lot-to-lot variability and/or other issues);

Carry-over (if applicable);

Reagent stability; and

Sample stability

• Comparison study- A description of the design and results of studies conducted to demonstrate that the device has an insignificant risk of erroneous results in the hands of the intended user (untrained “operator”).
• Reproduction study- A description of the design and results of studies conducted in the hands of the intended user (untrained “operator”).
• Clinical performance study- Most IVD devices do not require a clinical performance study, but some devices require either 510(K) or dual submission.
• Labeling- Proposed Labeling with instructions for uses consistent with a device that is “simple.”

In case the device is exempt from the premarket submission but CLIA categorization is needed, manufacturers submit a request to CDRH at the below address with a test package insert with instructions.

Food and Drug Administration

Centre for Devices and Radiological Health, Document Mail Center – WO66-G609, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993-0002

FDA create a submission tracking number for the CLIA process and notify the sponsor of the tracking number and categorization within 30 days of request. FDA will post the categorization in the public CLIA database concerning the CLIA Record (“CR”) number.

CLIA Database: For a list of waived tests sorted by analyte name, visit the FDA website at CLIA – Currently Waived Analytes.Tests that are categorized as waived or non-waived (i.e., moderate or high complexity), refer to the FDA CLIA Database