Manufacturers seeking waived status for diagnostic tests under user-based criteria will need to perform agreement studies with at least 300 untrained users to show that those users obtain the same results as lab professionals, according to an FDA draft guidance issued Jan. 23.

"There are increased data sets," FDA Division of Clinical Laboratory Devices representative Clara Sliva explained during a Jan. 24 teleconference. "We're asking manufacturers to go out and use 300 untrained users...and use three individual tests to see if they can get the same results as laboratories."

FDA's interim guidance recommends that manufacturers of quantitative tests perform "separate studies of precision and agreement between untrained and professional users in paired samples." Manufacturers of qualitative tests "need only conduct a single untrained/ professional agreement study."

The document provides firms with an alternative path for obtaining a waiver under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).

Up until now, manufacturers seeking a waiver have had to follow the requirements established by CDC and HCFA in a September 1995 notice of proposed rulemaking. This option remains open to manufacturers and firms with reference materials may prefer to follow the old route.

FDA's Jan. 23 guidance is intended as an interim document, providing manufacturers with an alternative to the 1995 notice while the agency gathers experience with the waiver process. FDA intends to revisit the issue formally in the future by promulgating a final waiver rule.

FDA's Center for Devices and Radiological Health assumed responsibility for CLIA in January 2000. So far, CDRH has categorized 1,058 tests, 158 of which qualified for waived status, according to CDRH.

Tests categorized as being of "high" and "moderate" complexity must be performed by CLIA-certified labs. Tests receiving waived status may be performed in settings with untrained personnel, such as at point-of-care facilities or in the home.

During an August 2000 FDA CLIA workshop for stakeholders, industry reps expressed concern that no new analytes were being waived under CDC's criteria. One reason cited for the delay was FDA's demand that tests meet threshold levels of sensitivity and specificity to receive a waiver (¹ Also see "FDA CLIA Waiver Evaluation Will Focus On User Comparability" - Medtech Insight, 21 August, 2000.).

"FDA's management was committed to run the CLIA program the same way that CDC ran it.... [But] there were lots of complaints about a conservative approach," Sliva recounted during the Jan. 24 teleconference, sponsored by the American Association for Clinical Chemistry. Sliva is acting CLIA coordinator at DCLD.

According to test manufacturers, Congress intended a more user-based criteria when it approved the CLIA portions of the FDA Modernization Act of 1997 (FDAMA). This stance is suggested by the addition of the phrase "by the user" to the end of a clause stipulating that a CLIA-waived test must be "so 'simple' and 'accurate' as to render the likelihood of erroneous results negligible," industry reps say.

The interim guidance supports the claim that FDAMA revisions to CLIA eliminated the "near perfect test" criteria associated with CDC's interpretation of the proposed rule. According to the draft guidance, the definition of accuracy is "based on the legislative history and language incorporated into FDAMA."

"We interpret accurate to mean test performance (i.e., the test performs in the hands of untrained users as it does in the hands of laboratory professionals when using the device under realistic conditions)," the guidance states.

Products such as Quidel's QuickVue and ZymeTx's ZstatFlu influenza tests were waived during the fall of 2000 under the user-based criteria; such waivers suggest the criteria will expedite the approval of new analytes.

If a test conforms with the guidance's definitions of a simple and accurate test, and if it poses an insignificant risk of an erroneous result, then it meets the waiver criteria, according to the guidance.

Tests that do not meet the accuracy requirement "will not be waived unless the [HHS] secretary determines that it poses no unreasonable risk of harm to the patient if performed incorrectly, or if the test is otherwise determined to be simple with an insignificant risk of erroneous result," the document states.

Checklist-based definitions and examples are offered by the guidance. Voluntary safeguards for waived tests are also included.

Quality control is the keystone for demonstrating a test has an insignificant risk of producing an erroneous result, the guidance indicates.

"Waived tests should contain failure alert mechanisms that produce no [test] result when a test system malfunctions," the guidance says.

Further, manufacturers "should consider lockout functions that do not allow testing if QC has not been performed or if QC does not give expected results."

The guidance recommends a "two-tiered approach" in which manufacturers first conduct a hazard analysis, and then use the results for stress studies that will characterize the test's operational limits.

"FDA is now proposing that there should be an emphasis on hazard analysis," Sliva said during the AACC teleconference. "We want quality control recommendations to stress test failures and...to be based on scientific evidence."

"It's not Grandmother's way of doing QC," Sliva added, explaining that with the variety of new technologies coming to market, alternative QC methods might, in some cases, be more appropriate than "traditional QC" measures such as liquid controls. She suggested electronic QC and internal QC as two examples of alternative methods.

Sliva also noted an increase in the variety of diagnostics that CDRH is evaluating under CLIA. "I think you'll be seeing a new menu of over-the-counter tests that you didn't see before," she predicted.

Among OTC products on the rise are drugs-of-abuse tests, she indicated. However, while product diversity is growing, the volume of submissions is decreasing, she said.

The agency is preparing a brief update of CDRH's CLIA activity, as the one-year mark approaches for FDA's assumed control of the program.

Comments on the draft guidance will be due 90 days after the Federal Register notice is published.

CLIA Guidance Allows Firms To Gain Waiver Through User Comparison Studies

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