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Roche, BioMerieux Get New FDA Clearances for PCT Assays to Help Assess Sepsis Risk


NEW YORK (GenomeWeb) – Sepsis, the body’s severe inflammatory response to an infection, contributes to more than 1.6 million hospital visits annually in the US, and it is the most common cause of death in the intensive care unit (ICU). Diagnostic tools and techniques have their limitations, and depend largely on culture-based pathogen detection and non-specific physiological criteria.

The need for greater diagnostic certainty and less time to effective treatment has led multiple companies to pursue better diagnostic tools. Many of these newer tools use molecular approaches to, for instance, directly identify sepsis-causing organisms in the blood or measure host gene expression in response to sepsis.

However, some diagnostics firms are still betting on a more well-established approach to diagnosing sepsis — measuring patient levels of procalcitonin, a peptide precursor of the hormone calcitonin. Namely, in the past two weeks the US Food and Drug Administration has granted 510(k) clearances to PCT assays from Roche and BioMérieux to test for the risk of severe sepsis or septic shock.

"What our FDA label permits us to say is that we can project 28-day mortality risk to sepsis-like symptoms," Alan Wright, chief medical officer at Roche Diagnostics, North America, told GenomeWeb. "FDA clearance enables us to put procalcitonin on our large central analyzers — including our Cobas solution…It’s a well-known and well-defined technology, and we have repurposed that technology to measure procalcitonin levels in the blood."

Roche’s Elecsys BRAHMS PCT is an electrochemiluminescence immunoassay for the determination of procalcitonin in human serum or plasma on the automated Roche Elecsys, Modular, and Cobas e immunoassay analyzers. The assay is designed to provide full automation, which means no reagent preparation or hands-on testing is required. It provides same-day results with an incubation time of 18 minutes, and it has a measuring range of 0.02 to 100 ng/mL, extending to 400 ng/mL with a recommended 1:4 dilution.

"The assay itself has been around for a while,” Wright said. “It has been available in the United States on a low-volume analytic device that made it difficult to use in a high-volume setting where many procalcitonin tests were being ordered. If you had a large intensive care unit, it was difficult to get many [pro]calcitonin tests.”

The availability of procalcitonin with the Cobas series of analyzers is a new market for Roche, Wright said. "The use of this is a step forward in the management of critically ill patients. And it's not as much the use as the broader availability that has Roche very excited about this assay."

If unchecked, sepsis can rapidly progress leading to organ dysfunction and if not managed properly, may lead to death of the patient. Clinical manifestations of sepsis can be vague and may progress undetected by signs and symptoms to a severe condition, Roche said in a statement.

The Roche procalcitonin assay assesses risk when somebody presents with sepsis-related symptoms. Procalcitonin levels return to normal when the presumptive sepsis causing agent is treated, and the procalcitonin level can enter into the physician's decision to manage antibiotic therapy, Wright said.

"If you have someone in intensive care and you are treating them with antibiotics, and you get a procalcitonin level that’s normal, then that data point enters into a clinician’s decision whether to continue or discontinue antibiotics," he said. "The patient may still be critically ill and for other reasons require intravenous feeding and be on ventilation, but one of the main points in managing these patients is deciding whether to continue or discontinue use of antibiotics."

BioMérieux, in the week following Roche’s clearance, announced on Friday that it has received FDA 510(k) clearance for the expanded use of its Vidas BRAHMS PCT assay for managing sepsis patients with elevated risk of mortality.

The test was originally approved for use in patients in the first day following admission to an intensive care unit. Now, it is cleared for monitoring PCT levels over 96 hours to help physicians make treatment decisions for high-risk sepsis patients.

The assay, which runs on BioMérieux's fully automated Vidas instrument, is designed to measure changes in blood levels of procalcitonin to differentiate bacterial infections from viral ones.

"In many patients, it can be very difficult to diagnose sepsis up until the moment of obvious shock," Devendra Amin, medical director of critical care services at Morton Plant Hospital in Clearwater, Florida, said in a statement. "The expanded indication for PCT will allow us to obtain vital information prior to the admission to the ICU and will give us vital information about the patient’s prognosis, risk of mortality, response to treatment, and likelihood of survival."

BioMérieux said that as part of a filing for the expanded approval, it provided the FDA with equivalence data of Thermo Fisher Scientific’s Procalcitonin Monitoring Sepsis Study — or MOSES — which tracked PCT levels of patients with severe sepsis or septic shock.

The same study also supported FDA clearance of Roche's Elecsys BRAHMS PCT assay. The trial design of the study leveraged patient samples to enable a universal analysis-based approach to demonstrate substantial equivalence to the FDA resulting in the clearance of the assay, Roche said in a statement.

"The MOSES study identified the risk prognosis attributes of procalcitonin," Wright said. "It featured in our FDA submittal and it featured in the approval of procalcitonin use in the United States."

The study investigated the relationship between the decrease in procalcitonin levels over the first four days in the hospital, and outcomes in patients diagnosed with severe sepsis or septic shock, according to Thermo Fisher. It followed 858 adult patients, across 13 sites, who were diagnosed with severe sepsis or septic shock in an ICU, emergency department, or medical ward, prior to admission to the ICU.

The MOSES study found that patients showing a decrease in PCT less than or equal to 80 percent during the first four days following diagnosis of severe sepsis or septic shock had a twofold increased risk of death when compared to those who experienced a more than 80 percent decrease in PCT, Thermo Fisher said in a statement. The study also found that a baseline PCT measurement greater than 2.0 ng/mL is an additional mortality risk factor when evaluating PCT measurements on subsequent days.

In March, Thermo Fisher Scientific announced it had received clearance from FDA that expanded the clinical claims of its procalcitonin biomarker assay for sepsis risk assessment.

The new clearance added to the existing use of the BRAHMS PCT, cleared by the FDA in 2006, to help assess risk for progression to severe sepsis and septic shock of critically ill patients on their first day of being admitted to the intensive care unit. As a result of the clearance, Thermo Fisher's PCT test can be used to obtain measurements in emergency departments and hospital wards prior to admission to the intensive care unit.

Clinicians can use BRAHMS PCT to help assess the response of septic patients to treatment by comparing a baseline PCT measurement with a PCT value taken on day four. The change in PCT over time, in conjunction with other laboratory findings and clinical assessments, aids in assessing the cumulative 28-day risk of mortality for patients with severe sepsis or septic shock who are admitted to the intensive care unit, Thermo Fisher scientific said in a statement.

A number of noteworthy developments have begun to emerge involving alternative molecular approaches to sepsis diagnosis.

Even while BioMerieux continues to expand the market for its PCT assay, one of its subsidiaries, BioFire Diagnostics, is pursuing a newer molecular approach to diagnosing sepsis. Among BioMerieux’s test solutions for sepsis are its FilmArray Blood Culture Identification Panel for multiplex PCR systems that, according to the company’s Website, enables automated detection of pathogens and antibiotic resistance genes associated with bloodstream infections. The panel tests for a list of 24 pathogens and 3 antibiotic resistance genes associated with bloodstream infections. With one test you can identify pathogens in 9 out of 10 positive blood cultures in about an hour with only 2 minutes of hands-on time. The panel is designed for the BioMerieux FilmArray system, a multiplex PCR system that integrates sample preparation, amplification, detection and analysis.

In April, Spanish clinical diagnostics firm Stat-Diagnostica closed €25 million ($27.8 million) in Series C financing to prepare for the 2017 launch of its DiagCore near-patient testing system.

According to the company's website, its Stat-Immuno cartridge is designed to automate high-sensitivity immunoassays for critical care markers such as procalcitonin for sepsis.

Earlier, in January, a Duke University-led research team reported that its classifiers, which were part of a gene expression-based model, fared better than procalcitonin and three published gene expression classifiers at distinguishing bacterial and viral infections. The team has developed a microarray-based approach to determine whether a patient's respiratory disease is due to a bacterial or viral infection, both, or neither.

Towards the end of 2015, scientists from molecular diagnostics firm Immunexpress and collaborators in Australia and The Netherlands published new research describing the development and clinical validation of SeptiCyte, the firm's flagship RT-qPCR host-response assay for sepsis diagnosis.

The potential value of such an assay is that it would be much faster than relatively accurate culture methods, which can take a few days; and more accurate than the array of parameters currently used by critical care doctors to quickly diagnose sepsis, including molecular tests for specific organisms or measuring levels of certain patient-response markers like procalcitonin or C-reactive protein.

In June, T2 Biosystems announced that data presented at ASM Microbe 2016 confirmed the capability of its T2Candida Panel to quickly and accurately diagnose sepsis and, according to T2 Biosystems, strengthen the growing body of evidence supporting the integration of rapid diagnostic testing in hospitals and clinical settings. Researchers from Lee Memorial Health System, presenting key findings from a 182-patient study, reported that T2Candida enabled reducing "time to appropriate antifungal therapy by 34 hours."

In a research note released in June, analysts at investment bank Leerink Swann wrote that the T2 platform offers many advantages over blood culture, including reduced time to appropriate therapy, avoiding unnecessary drug use, and reduced length of stay. The T2 Biosystems proprietary magnetic resonance technology is one of the leading candidates to address the need for non-culture based diagnostic assays with better sensitivity and improved time to diagnosis and species identification, wrote Dan Leonard, managing director life science tools and diagnostics at Leerink. "Other technologies showing promise include next-gen sequencing and polymerase chain reaction-mass spec (PCR-MS) combo (i.e. Abbott’s Iridica)."