Final guidelines to companies developing point-of-care diagnostic tests for use in less sophisticated laboratories offer more leeway in clinical trial design than FDA initially proposed.

The device industry, however, maintains that the agency's policy is too prescriptive, and will force companies to perform studies that go beyond what Congress intended in the 1988 Clinical Laboratory Improvement Amendments.

"We were very aggressive in asking FDA to work with industry to come up with something that matched the congressional statute," said Khatereh Calleja, associate VP-technology and regulatory affairs at AdvaMed. "This approach is overly burdensome and inflexible."

AdvaMed said it appreciates FDA willingness to incorporate some industry feedback into the final guidance, "but we still have serious concerns."

The ¹ guidance on submitting applications for product waivers under CLIA, released Jan. 30, culminates years of deliberation between the Centers for Disease Control and Prevention, CMS and laboratory and industry stakeholders. FDA says it received about 40 sets of comments on the 2005 draft guidance, which had been revised from a 2001 draft (² Also see "Long-Awaited CLIA Draft Guidance Offers Some Leeway For Study Design" - Medtech Insight, 5 September, 2005. p. 7).

CLIA-waived diagnostic tests have special clearance to be sold to a broader market of labs whose facilities and personnel are subjected to the lowest level of government oversight. These labs are often based at health clinics and doctors' offices, the target customers of the rapidly growing point-of-care diagnostics market.

To obtain this status, FDA requires that a test not only get conventional premarket clearance or approval, but clear another bar supported by studies that prove an assay is sufficiently "simple" and error-proof. The guidance describes how to design these waiver studies and defines what it means for a test to be simple.

The number of specimen samples and operators needed for a CLIA waiver study may vary depending on the test, FDA says. Tests with numerical results generally require at least 360 actual patient samples from no less than three sites, obtained by at least nine operators, the guidance says. Studies for "yes"- or "no"-type tests should include 120 positive and 120 negative results from patient samples.

In a nod to complaints from stakeholders after the draft guidelines were issued, FDA doubled the number from 60 to 120 of banked or lab-contrived samples that can be substituted for actual patient samples. FDA said it sided with concerns that in some cases, particularly for rare or seasonal diseases, the actual patient sample requirement was too burdensome.

"It would be too expensive, and they would have to test for a much longer period of time to get the necessary assay range," Carol C. Benson, associate director of chemistry in FDA's Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), said in an interview. "Now we'll allow up to a third of the samples to be banked."

Final Guidance, Same Problems - AdvaMed

When the draft guidance was issued in 2005, industry warned that it would make it financially and logistically difficult to design trials for certain diseases, even common but seasonal conditions such as the flu. AdvaMed asserted in written comments that the draft "could increase hurdles to access to point-of-care tests."

"We asked that they pull back the guidance and actually start over," Calleja told "The Gray Sheet." "To now get a guidance that is similar to the 2005 guidance is disappointing."

The increased flexibility on patient samples was helpful, the trade group says, but requiring a minimum number of 360 patient samples seems arbitrary. Firms should be allowed to determine the appropriate number of patient samples on a case-by-case basis, AdvaMed says (³ Also see "AdvaMed, CMS Take Conflicting Views On FDA Lab Test Waiver Requirements" - Medtech Insight, 19 December, 2005., p. 5).

"The purpose of the waiver study should be to establish the user's ability to operate the test using directions from the manufacturers," Calleja said.

But James Nichols, Ph.D., director of clinical chemistry at Baystate Health in Springfield, Mass., who works with the American Association for Clinical Chemistry's point-of-care committee and sits on the CDC's Clinical Laboratory Improvement Advisory Committee board, says the recommended waiver trial design is feasible. A danger of using too many banked or "spiked" samples, Nichols explained, is that they may give test developers a "false sense of positive predictive value."

"With real world specimens, the performance that you're really getting on the device is typical of the type of performance you'll see" outside of a trial setting, he said. FDA also mentions that this is not the only way that companies can proceed, Nichols added. "The manufacturer can develop its own protocol, and the guidance says just to call the [FDA] office."

FDA's Benson also stressed that point. "If you have another kind of approach, or a special case, we're encouraging people to contact us before they go and do some studies, and we're encouraging them to use the pre-IDE process."

The guidance also recommends conducting waiver studies in at least three different "intended use" sites, with the type of operators who would likely use the device in a real world setting. It further urges firms to "enroll operators with the least amount of training that might be encountered at the types of sites for which this device is intended."

The final document also clarifies the types of comparative methods that waiver studies should use to evaluate test results against results obtained in a laboratory setting by laboratory professionals.

"We have narrowed the comparator methods to make it simpler," Benson said. Study results can be compared to a thoroughly investigated "reference method" or a "traceable method" that traces back to certain accepted standards, FDA explains.

"But the basic principle of testing real samples over time is still the underlying theme, performed by people you would typically find in waived settings," Benson concluded.

With the final guidance issued, OIVD can presumably now launch a pilot program agreed to in the 2007 user fee reauthorization to evaluate whether the 510(k)-review and CLIA-waiver review processes can be performed in parallel, rather than one after the other (⁴ Also see "FDA User Fee Commitments Drive Diagnostics Office Priorities In 2008" - Medtech Insight, 21 January, 2008., p. 3).

- Jessica Bylander (j.bylander@elsevier.com)

FDA Says Final CLIA Waiver Guidance Eases Burdens; Industry Isn’t Satisfied

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