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Study Shows Great Basin C. diff Test Sensitive, Specific as Established Real-Time PCR Assay

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Scientists from Great Basin Scientific and three university medical schools and hospitals have published research demonstrating that Great Basin's molecular diagnostic test for Clostridium difficile is as sensitive and specific as a competing molecular test based on real-time PCR.

Great Basin is hoping that the research will help spur uptake of its C. difficile assay, which recently won both CE IVD marking and 510(k) approval from the US Food and Drug Administration, and which the company claims has workflow and cost advantages over competing tests.

Great Basin's molecular testing platform consists of individual assay cartridges that run on an automated benchtop analyzer. The platform is true sample-to-result, can perform on-demand testing instead of batching, multiplexes up to 64 distinct targets in a single assay, and can provide test results in as little as 60 minutes, depending on the target.

The company is developing tests for several different infectious diseases, and has used a few different assay chemistries depending on the test, including helicase-dependent amplification technology licensed from BioHelix.

The C. difficile assay is the first commercial test for Great Basin's system. The test, which targets the bacterium's toxin B gene, tcdB, received 510(k) clearance from the FDA in May (PCR Insider, 5/3/2012), and also received the CE IVD mark earlier this year. The company in July began marketing its test in Europe and New Zealand through local distributors, and hired new regional business directors to support sales efforts in the US and abroad (PCR Insider, 7/11/2012).

In the study, published this month in the Journal of Clinical Microbiology, researchers from Great Basin, the University of North Carolina Hospitals, Indiana University Hospital, and the Medical College of Wisconsin tested the analytical sensitivity of the Great Basin C. diff assay by assaying different dilutions of cultured C. difficile spiked into a pooled negative stool sample at various concentrations. They determined that the assay's detection limit was about 10 colony-forming units, or CFUs, per sample.

"The analytical sensitivity [of] 10 CFU input … in the context of a stool sample … is on par with PCR amplification," CEO Ryan Ashton told PCR Insider in an e-mail this week. In comparison, the 510(k) submission for Becton Dickinson's GeneOhm Cdiff test — a real-time PCR-based test that also targets the C. difficile toxin B gene — reports a sensitivity of 4 CFU per reaction in the context of buffer. Ashton noted that the analytical sensitivity of the Great Basin test in the context of the buffer — which wasn't reported in the JCM paper — is in the range of 3 to 5 CFUs per reaction.

Then, the group tested 130 stool samples with the Great Basin C. diff assay and the BD GeneOhm Cdiff assay. Any discrepancies between test results were resolved by toxigenic culture methods. The GB assay correctly identified 31 of 32 positive samples, with one false negative and no false positives, yielding 97 percent sensitivity and 100 percent specificity.

Great Basin is attempting to differentiate its testing platform from other molecular diagnostic systems primarily on the pricing and ease-of-use fronts.

"PCR instruments used for moderately complex molecular diagnoses use microfluidics that require high manufacturing precision, precise temperature control for thermal cycling, and sophisticated optics for fluorescence detection," requirements that constrain instrument and test costs, the researchers wrote in their JCM paper.

In contrast, the Great Basin platform, which doesn't yet have a brand name, features meso-scaled fluidics, a heating element and temperature control for isothermal amplification, and a simple optical detection scheme that requires only a digital camera and not a CCD camera, as is the case with many other benchtop molecular testing platforms.

"By use of large visible features, the detection system can employ a digital camera rather than an expensive CCD imager," the researchers wrote. "Taken together, mesofluidic design, isothermal DNA amplification, and eye-visible detection enable use of off-the-shelf components for analyzer construction, driving down instrument complexity and cost while maintaining ease of use."

Ashton has previously said that the company can manufacture its platform for less than $5,000. This week, he didn't elaborate on the pricing of the system or test, but noted that Great Basin's test "provides PCR sensitivity with a less complicated and less expensive instrument."

"Workflow and specimen processing are the major advantages to our test," Ashton added. "BD GeneOhm requires batching for optimal reagent usage … [and] the hands-on time and steps required to process a specimen is much higher than our assay."

Ashton also noted that current BD GeneOhm customers, and users of real-time PCR tests in general, "love our workflow and specimen preparation," with the exception of those using Cepheid's GeneXpert C. difficile assay.

"But in the case of GeneXpert, customers are paying a premium price for convenience," he said. "Great Basin offers convenient workflow but we are priced similar to BD GeneOhm and others."

The comparison with the BD GeneOhm CDiff assay is important because it is a well-established, FDA-approved test. BD doesn't provide pricing information for the assay on its website. The assay runs on the Cepheid SmartCycler platform, but Cepheid also does not publicly disclose the cost of its system.

However, BD is beginning to phase out its GeneOhm assay in favor of a new BD-branded integrated molecular testing system, the BD MAX, which will run a variety of real-time PCR-based assays for hospital acquired infections, including C. difficile (PCR Insider, 8/9/2012).

Meantime, Great Basin does not plan to conduct further studies on its C. difficile test, as the data published in JCM was compiled prior to the company's 510(k) submission and acceptance.

However, he noted that Great Basin "is always looking for broader awareness of our progress … [and] JCM provides international exposure to clinicians who may not be watching FDA activity. In fact, the publication of this paper has already resulted in interest from new opportunities."

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