NEW YORK – Rapid Biosensor Systems is targeting the clinical need for more rapid and affordable tuberculosis screening by combining breath sampling with evanescent-wave optical sensing.
The test, currently a pre-production prototype, has shown promise in detecting early-stage active TB during preliminary field trials involving 1,000 patient samples, and demonstrated both sensitivity and specificity values between 95 and 96 percent, Rapid Biosensor's CEO Dennis Camilleri said in an interview. The clinical studies were designed to evaluate the utility of the firm's pre-production prototype in low-resource, high-burden settings in Ethiopia and India. Last year, the firm published the results of its Ethiopian field testing in Biosensors and Bioelectronics Open Access.
According to the World Health Organization's Global Tuberculosis Report 2018, 10 million people fell ill with TB in 2017, and 1.6 million people died from the infection in that year. Effective diagnosis of active TB is needed to help mitigate this crisis and that requires rapid screening systems that are affordable and easy to use, David Boyle, a microbiologist and scientific director in the diagnostics program at Seattle-based PATH, said in an interview. PATH is a nonprofit global health organization once known as the Program for Appropriate Technology in Health.
While the Rapid Biosensor pre-production test is likely to encounter many challenges along a path to potential commercialization, the type of technology it employs "is appealing for this application," and its preliminary performance numbers are in the desired range for clinical applications, said Boyle, who is not involved in the development of Rapid Biosensor's technology, but is familiar with the system because of his work in identifying the landscape for emerging TB diagnostic technologies at PATH.
A breathalyzer simplifies sample collection, which is an important benefit in point-of-care testing that can enable broader access, he said. Breath tests that require no user training are easier to use at the point of care than tests that rely on a draw of blood or cerebrospinal fluid, for example, and the need for minimal training can stimulate broader adoption, Boyle said. Further, because the Rapid Biosensor system connects to an electronic reader it could become useful for surveillance, evaluating disease prevalence in specific regions, and evaluating test quality, all of which are not possible with many current point-of-care tests, he said.
The Rapid Biosensor test includes an integrated system consisting of a single-use disposable sample collection tube and a reader. A patient coughs into the collection tube and when TB bacilli are present, they react with a glass biosensor coating. The reader, using evanescent wave sensing and a laser diode, detects a reduction in fluorescence, and the unit reports a positive result.
If the system can be commercialized as a screening test, it would be able to provide health practitioners with TB test results within minutes, Camilleri said. By contrast, smear microscopy, a process involving sample culturing frequently used by clinicians to diagnose tuberculosis, can take up to six weeks to provide a result, he said.
The current Rapid Biosensor pre-production test has shown promise in the field but needs to be further developed for large-scale manufacturing, and the final product design will need to be field tested and taken through regulatory clearances prior to its commercial launch, Camilleri said, adding that he anticipates that CE marking for its noninvasive breath test, the first regulatory clearance in the firm's sights, will be "straightforward."
For that to occur, however, the firm would need to collaborate with another company or obtain funding from private investors, Camilleri said.
Camilleri, along with Elaine McCash, the firm's research and technical director, and Nicol Murray, its medical director, founded Cambridge, UK-based Rapid Biosensor in 2002 to develop patented bio-optical technology for the rapid screening and diagnosis of infectious diseases. As a result of a research and development program supported by grants from the WHO, the UK government, and £1 million ($1.3 million) in equity and loan investments, they advanced the development of the breathalyzer system.
With high placement volumes, which are possible in point-of-care TB screening, it will be possible to offer testing at a price that meets requirements of purchasing entities in low-resource, high burden settings, he said. The overall system, apart from use of a proprietary coating, uses components that are readily available. In volume production, the reader can probably be made available for less than $1,000 per system and the breathalyzer tube for less than $5 each, he said.
"Our research group consists primarily of technology inventors and medical experts," Camilleri said, adding, "Right now, the technology will do better in the hands of a corporation with all of the resources needed to scale up production and launch it as a product."
Getting a new point-of-care TB test to market can be challenging, however, Boyle noted.
From a diagnostics perspective, patients don't easily seroconvert — a process in which they undergo a change from seronegative to seropositive. TB infection grows slowly making it especially difficult to diagnose, he said, and TB's clinical symptoms manifest differently in children than in adults. The bacterium is also difficult to lyse for DMA extraction, he added.
On the business side, entrepreneurs need to be careful to accurately calculate the costs associated with taking an idea to market, Boyle noted. TB markets are price sensitive because placements often target low-resource, high-burden settings where healthcare budgets are tight, Boyle said. Further, when inventors calculate the cost of goods sold associated with new diagnostic tests, they tend to underestimate it, he said.
Inventors need to include expenses associated with establishing a production line, implementing quality systems, and building and operating sales, marketing, and regulatory teams, among other costs, Boyle said. Large diagnostic companies have an advantage over startups because they can optimally align and plan business activities, such as R&D, product development, manufacturing, regulatory oversight, and marketing and sales activities, he said.
There is already competition for TB screening systems in low-resource settings from established diagnostic companies such as Qiagen and Cepheid.
Qiagen is developing a system called QuantiFeron-TB Access for the diagnosis of latent tuberculosis infection with an aim of advancing tuberculosis control in areas with limited infrastructure, including countries in Asia, Africa, and Latin America. Its test is being developed to eliminate the need for an extensive laboratory infrastructure, the firm said. Clinical trials are being conducted this year, and commercialization is expected to begin in 2020.
Laboratory TB tests from Qiagen and its competitor Oxford Immunotec Global, both of which are based on use of interferon-gamma release assay technology, have achieved strong uptake in developed markets. Oxford Immunotec said recently that its T-spot TB diagnostic test is more readily available in the US given the recent acquisition by Quest of its US service laboratory.
Boyle noted that Danaher's Cepheid Xpert system is broadly used for rapid TB testing, and the WHO has endorsed two versions of the test for use in TB screening.
A 2017 study investigating the diagnostic accuracy of the Xpert MTB/RIF assay, published in PLOS One, reported that the sensitivity of the Xpert MTB/RIF was 85 percent and the specificity was 98 percent compared to culture.
The Cepheid system and assays present tough competition for new companies entering the field of TB diagnostics and screening, given its receipt of WHO endorsements and its availability at a current price of just less than $10 per test, Boyle said.
Still, procurement entities and donor organizations who support test implementation with funding want to see even lower pricing than is currently available, Boyle said. Affordability issues, in general, are holding back the development and adoption of tools used to diagnose tuberculosis, a disease with broad prevalence and an availability of effective drugs if the condition is detected early, he said, adding companies may need financial incentives to take on the time and costs associated with developing point-of-care tests.
In addition to Qiagen and Cepheid, UK researchers who conducted a study using a breath test being developed by Owlstone Medical said that they achieved a sensitivity of 81 percent and a specificity of 79 percent for all cases of TB. The Owlstone Medical Breath Biopsy system, which requires breath samples to be sent to a laboratory for processing, analyzes volatile organic compounds. Chris Claxton, Owlstone Medical's head of investor relations, said that the firm doesn't have plans to develop its platform for TB detection, but it has a broad number of potential applications and some of its development is led by customers.
Further, PATH, the Bill and Melinda Gates Foundation, and the US Centers for Disease Control and Prevention recently evaluated eight nucleic acid amplification technologies for potential use to detect infectious agents in low-resource settings by sending test developers blinded panels containing TB, influenza A, and Salmonella typhimurium samples.