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FDA Clearances of Three GenMark BCID Panels Paves Way for Customizable Approach to Sepsis MDx

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NEW YORK (GenomeWeb) – GenMark recently announced that the last of three planned multiplex molecular diagnostic assays to detect blood stream infection pathogens has been cleared by the US Food and Drug Administration. The firm has been offering two multiplex panels — one for gram-positive bacteria and one for fungi — for about four months, but the addition of a third panel for gram-negative bacteria completes a suite for identifying pathogens in blood cultures, which is anticipated to now bring in new business.

Multiplex molecular diagnostic testing for blood culture identification, or BCID, is a relatively new technology, but it has shown some ability to reduce cost and enhance patient care. In one oft-cited 2017 meta-analysis, for example, rapid molecular diagnostic testing resulted in decreased length of hospital stay and lower costs, as well as decreased mortality if testing was paired with antimicrobial stewardship interventions.

Unlike some BCID multiplex test developers, GenMark had chosen to create three separate large panels rather than have a single panel.

The GenMark gram-positive panel (BCID-GP) contains 20 bacterial targets and 4 resistance markers, while its fungal panel (BCID-FP) includes 15 fungal pathogens, including 11 different species of Candida. The BCID-GP and BCID-FP were each cleared by the FDA late last year.

The gram-negative panel (BCID-GN) detects 21 bacterial targets and 6 resistance makers, and was cleared earlier this month.

The rationale for splitting BCID into three panels involved customer input as well as assessment of the market and reasoning about incidence and trends in infectious diseases, according to James McNally, the senior vice president of marketing and business development at the Carlsbad, California-based company.

When a patient is suspected of having a blood stream infection, clinicians will usually order a variety of blood tests. These will frequently include a blood culture, which is typically run in bottles containing certain kinds of media to see if pathogen can be grown from their blood samples. Many labs also use automated systems for blood cultures, so technicians will be alerted if the instrument detects pathogen growth.

If a blood culture bottle "rings positive," the standard of care always includes a gram stain, McNally said.

Indeed, Thomas Grys, the director of microbiology at the Mayo Clinic's campus in Phoenix, said in an interview while there are no guidelines from infectious disease groups or lab oversight agencies specifically instructing labs to do a gram stain on a positive blood culture, there are guidelines for how long it should take to report the results of a gram stain. So, essentially it is assumed that a gram stain will be done because it is an ingrained standard of care.

This is because the gram stain has been unchanged for more that 100 years and "it is among the most rapid and helpful things that we can do," Grys said. By classifying organisms on these grounds, "we can often predict the most effective emperic therapy," and allow clinicians to quickly de-escalate inappropriate therapies. 

That said, "The organisms are all different isolates, and sometimes they don't read the book about how they're supposed to look," Grys joked. In particular, "If they are under-colorized, the gram-negative might appear positive, which is always the concern."

However, each of the three GenMark BCID panels includes a "pan" target that is supposed to detect the targets covered in the other two panels. For instance, the gram-negative panel has a "pan gram-positive" and "pan-fungal" target. Grys noted that a BCID system from Luminex has also adopted this strategy.

So far, his lab has not done a comprehensive clinical utility evaluation of the BCID-GN, although it recently published this sort of an assessment for the BioFire BCID panel. The lab has so far run about 20 clinical samples on the GenMark system, and "thrown some curveballs at it," Grys said. In terms of usability, he said the lab technicians using the GenMark system have told him it was "intuitive and easy to use." He added that if techs are going to be able to interact with a system easily and quickly, that is valuable for the whole lab.

Other recent evaluations of the system have been positive as well, albeit with small sample sizes. For example, researchers from St. James Hospital in Dublin, Ireland, presented early data from a study of the BCID system earlier this month at the European Congress of Clinical Microbiology & Infectious Diseases.

They evaluated 21 blood cultures comparing the GenMark ePlex workflow to the standard of care in the lab, which included culture, MALDI-TOF, and a technology called EUCAST AST.

They found the ePlex BCID reduced the time it took to identify pathogens by an average of about 26 hours, and reduced the time it took to determine drug resistance of the pathogens by almost 58 hours. And, in one case, the panel detected a fungus in a patient's blood associated with the skin surface called Malassezia furfur that had failed to grow in the lab. It required ID and AST at the UK Mycology Reference Laboratory, with the final report delivered 38 days after the blood culture was found to be positive for a fungus using the GenMark panel, according to the ECCMID poster.

McNally also highlighted a few other differentiating characteristics of the GenMark system, such as inclusion of other common skin flora targets that can help tell a lab that a sample may have been contaminated. The system also provides customers a way to configure the software for local clinical practice guidelines and rules, providing what is known as a templated comment to support stewardship that is delivered along with the diagnostic results of the testing.

Breadth of menu is important to drive adoption of diagnostic systems, and McNally said that GenMark sees a large number of customers who are using its ePlex system for respiratory testing that are now interested in bringing on the BCID suite, as well as ones who didn't require respiratory testing but have adopted the initial BCID tests. There is also a wave of new customers who had been holding off on adopting the system until the all three BCID tests were cleared, he said.

The molecular BCID market

For molecular BCID, there are a handful of vendors of multiplex tests competing for an estimated $500 million market opportunity.

BioMérieux sells the BioFire FilmArray BCID, which has been commercially available since 2013 and detects eight gram positive and 11 gram-negative bacterial targets, five fungal targets, and three resistance markers, from blood cultures in a single panel. Clinical utility of the BioFire BCID panel has been shown in a number of studies, including in a pediatric population.

Nanosphere developed the Verigene system and launched a gram-positive BCID panel in 2012, followed by a gram-negative BCID panel in 2014. The company was subsequently acquired by Luminex in 2016. It's gram-positive blood culture panel was found to speed up testing and reduce costs in a 2013 study, as well as in a more recent evaluation.

And, T2 Biosystems makes small multiplexed panels that have the advantage of testing directly from a patient's blood sample. It has a CE-marked and FDA-cleared five-target bacterial test and an FDA-cleared yeast pathogen panel, and recently received Breakthrough Device Designation from the FDA for a panel to detect 13 resistance genes from both gram-positive and gram-negative pathogens.

Also in terms of direct-from-blood testing, BioMérieux has partnered with Qvella, a Canada-based developer of a point-of-care bloodstream infection test that uses whole blood samples, and this could to have the potential to someday change the competitive landscape as well.

There are also a number of multiplex tests in development or submitted to the FDA for multiplex detection of bloodstream infections, and overall, competition seems to be intensifying as labs seek out testing solutions with both speed as well as accuracy.

Financial analysts have been bullish on the potential for the GenMark BCID suite. Before the gram-negative panel was cleared, analysts had said that clearance of all three panels could drive growth for the company, as previously reported.

Now, the suite is complete. When the BCID-GN clearance was announced, Doug Schenkel at Cowen, suggested in a research note that the ePlex system is now likely to be installed in more than 350 customer sites by the end of 2019, and Mark Massaro at Canaccord Genuity said in a separate note that the panels could add revenue of between about $7 million and $11 million for 2019.

Brian Weinstein at William Blair noted in a research note that "the BCID market is likely large enough for multiple players and technologies to coexist," and given the size of GenMark, his team thinks even a modest penetration into this market can be meaningful to its growth profile.

For the labs kicking the tires on bloodstream infection multiplex molecular test solutions, peer-reviewed prospective studies of GenMark's three-panel workflow — particularly clinical utility studies that speak to potential cost savings and health consequences for patients — might ultimately be the most compelling.

McNally said the three clinical trial studies for each of the three panels are being written up and going through the peer-review process currently. And, a clinical trial in Grenoble, France is scheduled to begin recruiting patients this month to evaluate the clinical utility as well as the economic impact of GenMark's three-panel solution.

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