Cepheid's CLIA-Waived Multi-Module System Ups Competition in POC MDx; Barriers to Uptake Linger

NEW YORK (GenomeWeb) – Cepheid's new CLIA-waived influenza test and multi-module instrument are intended for use at the point of care, putting them in competition with a handful of other systems in the rapid molecular diagnostic test space for flu. 

The new CLIA-waived system and test provide certain advantages in number of gene targets and number of tests that can be run simultaneously, and Cepheid has also described an expanded menu. However, there remain barriers to uptake of point-of-care molecular testing in general, and cost-effectiveness studies are sorely needed, according to one expert.

Cepheid's new system resembles the moderately complex GeneXpert platform but has a few hardware and software changes to make it CLIA waivable by the US Food and Drug Administration, David Persing, the firm's chief medical and technology officer, said in a recent interview.

Previously Cepheid had obtained FDA clearance of its Xpress flu and flu/RSV tests to run on its GeneXpert platform, and CLIA waiver for a single-module Xpress system along with its Flu+RSV Xpress test, Persing explained. 

The new clearance and waiver is for an enhanced version of the Xpress flu test as well as a new instrument that can process more than one test at a time. This test, which delivers results in 30 minutes but can provide positive results in as little as 15 minutes, will replace the previously waived one-hour test and instrument. 

The instrument is available as a two- or four-module system, the GeneXpert Xpress II or GeneXpert Xpress IV, respectively, and features a touch screen computer tablet, a barcode scanner, and a quality control lockout. A two-module system could potentially run 32 tests per 8-hour shift, while the four-module system could run 64 tests.

This throughput is important because, "In a clinic during a busy flu season it provides surge capacity to handle multiple patient samples at one time, [which is] an operational advantage during the course of a busy season," Persing said.

Flu tests are also at the mercy of seasonal drift, and can become less sensitive as viruses mutate. Persing described the Xpress Flu A/B assay as "future proofed" because it can detect three different targets for flu A and two for flu B. This is "unprecedented for a CLIA-waived test," he said.

There is also an avian influenza target in the test which covers the strains known to infect humans, including H5N1, H7N9 and other less common avian strains, Persing said. In total, the test uses 14 primers and five probes for flu A/B plus a separate reagent set for the avian targets. 

The redundancy provided by multiple targets has contributed to the test having a high sensitivity and specificity, Persing said. Compared to a gold standard lab-based RT-PCR test, the Xpress flu assay had 98 percent and 99 percent sensitivity and specificity, respectively. Negative and positive predictive values were around 98 percent for the viruses, with an even higher PPV for flu B, Persing said.

The Xpress test cartridges have modifications that allow for faster specimen processing in the cartridge as well as more rapid cycling parameters using high concentrations of enzymes. 

Cepheid plans to add Flu/RSV and Group A Strep to the CLIA-waived Xpress system sometime in the middle of this year, and a chlamydia and gonorrhea test as well as a multiplex vaginal panel for bacterial vaginosis, candida, and trichomonas over the next two years.

"Having a multi-module system allows customers to be able to expand and adapt as the menu grows," Persing said, given that a four-module platform can run four different tests at the same time. He added that he believes labs doing CLIA-waived testing are experiencing backlogs because of limitations on the instruments and workflows. 

The timing of the clearance of the new system precludes widespread adoption at this point, Persing said, since the current flu season is already well under way.

"Our customers are using the moderate complexity flu/RSV test for this season, but we expect new opportunities will arise to place the Xpress technology for the next year, and at that time we will have an expanded menu," he said.

Persing asserted that RT-PCR-based point-of-care tests – Cepheid's GeneXpert and Xpress tests and Roche Liat assays — are more sensitive than tests based on other amplification methods, and Cepheid's additional modules and nasal swab claim could give it a leg up over the Roche Liat.

'Is the juice worth the squeeze'

In general, CLIA-waived point-of-care molecular diagnostics have not been the game changers initially anticipated, in part because they have a higher cost and there have not been thorough cost-effectiveness studies to justify a switch from other technologies, Frederick Nolte, director of clinical laboratories and a professor of pathology at the Medical University of South Carolina, said in an interview.

In a presentation at the Association of Molecular Pathology annual conference in November, Nolte described opportunities and challenges in molecular point-of-care testing, highlighting the flu space in particular and thoroughly comparing the Roche Cobas Liat and Alere i flu A/B tests. Nolte has also published a head-to-head comparison of the Roche and Alere flu A/B test performance.

Overall, the point-of-care influenza testing niche has been dominated by inexpensive immunoassays. Molecular tests tend to have much higher sensitivity and specificity, but lab-based nucleic acid amplification tests were historically slower and required more expertise to run. Now, point-of-care molecular tests are "essentially 100 percent sensitive," Nolte said, as opposed to around 80 percent sensitivity for a lateral flow test.

"But that comes at a cost that is four times as much, so the question is, is the juice worth the squeeze," he said.

His lab has decided, for now, that it is not. "But I continue to consider it, because I'm a laboratory guy and I think this is cool technology and there ought to be a way to demonstrate its cost effectiveness," Nolte said.

When Alere received CLIA waiver on the first ever rapid molecular flu test two years ago, Alberto Gutierrez, then the US Food and Drug Administration's director of the Office of In Vitro Diagnostics at the Center for Devices and Radiological Health, said the agency expected "many other simple and accurate tests using nucleic acid-based technology to be developed in the near future," and added that, "such tests can allow healthcare professionals to receive test results more quickly to inform further diagnostic and treatment decisions."

Roche followed soon after with CLIA waiver for the Cobas Liat flu test, and both Roche and Alere have now expanded menus that include a respiratory syncytial virus target in the flu test, as well as Group A Strep testing.

The Roche and Alere systems are similar in that they have very small footprints, while the Cepheid system is substantially larger. Tests on the Alere i platform take 15 minutes and use an isothermal amplification technique. Tests on the Roche Liat take 20 minutes, but, like the Cepheid system, have fewer workflow steps overall than the Alere test. 

Alere's test is waived for nasal swabs while Roche's is waived for nasopharyngeal swabs. Cepheid's test is waived for both nasopharyngeal and nasal swabs, with the latter being a more convenient specimen and less painful to collect, particularly for pediatric patients, Persing said.

Taking a step back, the overall importance of flu testing in and of itself also remains to be seen, Nolte believes. Flu A and B are the only respiratory viruses for which there is a drug. "The therapy piece drives the diagnostic piece … but in reality, only one in three patients with a positive test for flu are candidates" for Tamiflu treatment, Nolte said.

Multiplex panels are a more attractive option, in his opinion. At any time in the winter months when flu is circulating other respiratory viruses are more common than influenza, even in the peak of flu season, he said, and a panel test to detect all respiratory viruses costs him $120 dollars while a point-of-care test to detect flu A or B costs around $40.

His hospital system uses BD Veritor digital immunoassays at the point of care for flu testing, and then the only other option offered for respiratory virus testing is the BioFire respiratory panel in the lab. BioFire also has a CLIA-waived version of its FilmArray respiratory panel that detects 11 targets rather than 21 in the lab-based test, but Nolte uses the lab test, which has a two-hour turnaround time compared to about one hour for the CLIA version, which doesn't provide any benefits in terms of throughput or test time.

A 30-minute POC test could possibly make a difference in some specific cases, Nolte said, such as distal clinics in the hospital system or physician's offices.

But while enhanced sensitivity and throughput and multiple targets are nice features, even with a very bad flu season, Nolte said he does not anticipate a dramatic uptake for molecular until there are published studies demonstrating cost effectiveness. Unfortunately, these kinds of studies are quite challenging to undertake because they require standardizing physician behavior and getting very detailed local cost information.

"I would like to see some evidence that I can use to convince myself and others that [adopting POC molecular] is something we need to do," Nolte said. "I'm just not there yet."

Meanwhile, Danaher, which recently acquired Cepheid, announced yesterday at the JP Morgan Healthcare conference that the Cepheid Omni point-of-care molecular system is expected to launch later this year. The instrument will run Xpress tests and boasts a lower cost than others in the space as well as enhanced "ruggedization" to enable use in low-resource settings.