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US FDA Grants CLIA waiver for Roche's cobas Liat PCR System and Strep A Assay

In the wake of receiving a CLIA waiver for its rapid, point-of-care PCR testing device, Roche executives this week provided an update on the platform's infectious disease test menu pipeline.

The platform, called the Roche cobas Liat, received CLIA waiver yesterday along with a 15-minute molecular assay for group A Streptococcus.

The strep test is the first on (Lab-In-A-Tube) Liat to be CLIA waived for low-complexity healthcare settings, such as physician's offices and pharmacy clinics. The firm also has an influenza A/B assay that is FDA cleared and awaiting CLIA decision, and that assay has been the subject of recent scientific evaluations.

Roche acquired the Liat technology a year ago when it bought diagnostics developer Iquum. The acquisition included the FDA-cleared flu test, and Roche has since stated its intention to populate the system with other tests, officially launching Liat late last year.

This week, Todd Keirns, group marketing manager for microbiology at Roche Diagnostics, told GenomeWeb that Roche is currently working on a combination flu A/B plus respiratory syncytial virus test, an assay targeting both Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA), and a Clostridium difficile test.

"The MRSA/staph and C. diff tests do not have an actual timeline yet, but the flu A/B plus RSV we should be submitting this year for 510(k) approval," he said.

Liat is a relatively tiny platform, about the size of a single-serve coffee maker. The sample-in, answer-out technology also has design features that enable standard PCR thermal cycling in about 20 minutes.

Specifically, reagents for each step of PCR are crimped into bubbles of packaging partitioned from one longer string. The platform then massages the sample through each isolated segment, some of which contain magnetic beads for target capture.

CLIA waiver for low-complexity settings requires very simple handling steps, and the Liat delivers on this. "You unscrew the top [of the reagent-containing assay tube], you use the pipette that comes with [the test] to take 200 microliters of your sample, put it in, screw the top on, and then the top of the Liat opens and you put the reagents in and close it," explained John Ogden, senior scientific affairs manager at Roche Diagnostics.

Ogden said the PCR's speediness is due to the use of spatial thermal cycling. Instead of sample being heated on a block that ramps between temperatures, the assay tube is made to oscillate between two blocks, each at a constant temperature.

The 20-minute run time also includes nucleic acid isolation, Ogden pointed out, so the PCR thermal cycling is quite fast relative to other standard platforms and it does not use special polymerases to Ogden's knowledge.

"It follows traditional PCR assay design — the attempt is to make it so the performance you get out of this will be exactly the same as you get at any level of Roche product," he said.

The device is also barcode driven, with less than five minutes of hands-on time. "You just hit go, and it does the PCR cycling, and in the end it provides a readout on a screen and it can be interfaced to have a readout of electronic results into your system," Ogden said.

Six-channel multiplexing capabilities were also part of the technology while it was being developed by Iquum, as previously reported.

Scientific studies of Liat

The cobas Liat influenza A/B assay was the subject of a study published online last week in the Journal of Clinical Microbiology.

The investigator-initiated research was done at the Mayo Clinic, comparing the Liat assay with the Simplexa Flu A/B & RSV Direct assay from Focus Diagnostics.

Roche provided the researchers a cobas Liat instrument and enough reagents to do the comparison, Ogden said.

"Because it is an investigator-initiated study [the researcher] has complete control over the design of the study, the protocol, and the data," Ogden noted. "We have no input on whether or not he publishes, or what he says, [and] we rely on the third-party peer review process to determine whether or not something has scientific value."

The JCM study reported overall agreement in 196 out of 197 patient samples and a specificity of 100 percent. The sensitivity relative to Simplexa was 99.2 percent and 100 percent respectively for influenza A and B. The tests ran in less than 20 minutes, compared to about 60 minutes for the Focus test, and required less than five minutes of hands-on time

Related work assessing the test's impact on patient management was also presented in abstract form at the Clinical Virology Symposium last month.

Laboratorians at the Hennepin County Medical Center in Minneapolis, Minnesota compared the Liat flu A/B test to the GenMark respiratory viral panel.

According to the abstract, about 15 percent of a small sample of patients in the emergency department tested positive for flu by the Liat test and there was 100 percent correlation with the GenMark panel. All had influenza B.

Pre- and post-test surveys revealed rapid testing led to changes in patient management, such as initiation or discontinuation of antivirals and antibiotics.

And 20 percent of patients for whom an admission order had been initiated were subsequently discharged upon negative Liat flu testing. The study also surveyed the patients themselves, revealing 90 percent of them felt rapid testing improved their hospital visit.

Notably, two other preliminary studies presented at CVS reported on performance characteristics of the flu A/B test.

One found high sensitivity and specificity in detecting the H3N2 flu strain that was circulating this past season, compared to a Prodesse assay from Hologic and the BioFire FilmArray respiratory panel.

However, the other evaluation compared the Liat test to a lab-developed qPCR assay and found the performance of the Liat "suffers" with viral loads near the lower limit of detection, although that study also emphasized the Liat's rapid turnaround time compared to the lab test's 3.5 hours from sample to result.

There are currently only two other studies of the Liat system in the scientific literature, both describing a quantitative viral load assay for HIV-1.

These were initiated prior to Roche's acquisition of the technology and spokespersons at the firm could not confirm whether the HIV-1 work is continuing.

The first, a proof-of-principle study of the assay, was published in the Journal of Infectious Disease in 2010 and also provided background on the Liat platform in general.

The second study, by a group in Johannesburg, was published online in March in the Journal of Clinical Microbiology. It reported 30 to 35 minutes of total test time after pipetting less than 200 microliters of patient sample into the assay.

It also compared two tests, referred to as Liat HIV Quant plasma and Liat HIV Quant whole-blood, to the Roche Cap CTMv2.0 and Abbott RealTime HIV-1 PCR assays. That study concluded the Liat technology is "user-friendly and robust" and suggested it could be interchanged with existing viral load technologies in South Africa.

Whether Roche will further develop this HIV test is unknown. "Iquum may have been looking into that, but I can't confirm that the projects that Iquum had are being continued by Roche," Ogden said.

Potential competition

The Liat Strep A test is the second molecular point-of-care test ever to receive CLIA waiver for low complexity settings.

Alere's influenza assay was the first, and representatives told GenomeWeb of that firm's intent to market to physician's offices and pharmacy clinics. Alere is also populating its Alere i platform with a strep A test that has been FDA cleared and is now in the CLIA review process.

Further, that firm has a second rapid molecular platform, the Alere q, which has received CE marking for an HIV detection assay that will soon be commercialized in non-US markets, and for which Alere is developing a quantitative HIV assay. Additional menu items for the Alere i include RSV, C. difficile, and gonorrhea/chlamydia. Alere q assays in development include Ebola, tuberculosis diagnosis, TB drug resistance testing, and hepatitis C testing.

Whether and how these two platforms will now compete remains to be seen. They have different core technologies, but both enable molecular testing in the timeframe of a patient visit and report similar test menu development. Roche may have a more recognizable brand, but Alere may have inroads into in the clinical and hospital market resulting from its immunoassay business.

Roche's Ogden pointed out that the Liat platform also has advantages for "stat tests in a laboratory environment," a space in which Roche may have a natural dominance. In this respect, it may actually compete more with the Cepheid GeneXpert platform.

"There will be certain diseases where it is very important that you know immediately when someone comes into an emergency department what it is, and there are others where they don't necessarily have to be done that fast, but once they're delivered to the laboratory you would like to turn them around quickly," Ogden said, adding that the menu pipeline will "address both of those areas."

Keirns agreed. "We're not looking at it as purely a point-of-care device; this is a molecular technology that can be deployed in many different spaces in the healthcare setting," he said.

In terms of competitive advantage, Keirns also pointed out that head-to-head trials will be important in the future. He declined to say whether Roche is planning to contract with pharmacy clinics, or how it will deploy its marketing resources.

The cost of the Liat is "very competitive in the market and is based on the utilization by the customers," Keirns said, adding that this "will vary by customer based on their volume and what their needs are." The Alere i platform, by comparison, was previously reported to cost $8,500 and about $70 per assay for the influenza test, with lower prices often negotiated with users.

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