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Researchers, Clinicians See Great Future Potential for HRAM Mass Spec in Dx Market


NEW YORK (360Dx) – While triple quadrupoles currently dominate the clinical mass spec market, interest is growing among researchers and clinicians in using high-resolution accurate mass (HRAM) instruments like Orbitraps and QTOFs for clinical assays.

Better accuracy and the ability to collect discovery data while simultaneously running clinical assays give HRAM instruments significant advantages compared to triple quadrupoles, said Ravinder Singh, director of the Mayo Clinic Endrocrine Laboratory and an expert in clinical mass spec.

Currently, cost remains a major limiting factor, Singh said, but, he noted, "if money were not an issue, you would like to do all clinical assays on a [HRAM] instrument."

The Mayo Endocrine Lab has five HRAM instruments, "and they are running 24 hours a day for clinical work," Singh said.

Last month, he and colleagues at Mayo published a study in Clinical Chemistry detailing an assay using a Thermo Fisher Scientific Q Exactive Plus to quantify levels of 26 steroid metabolites in patient urine to aid in diagnoses of endocrine diseases including Cushing syndrome, adrenocortical adenoma, and adrenocortical carcinoma.

The HRAM capabilities of the Q Exactive were key to the assay's development given the structural similarities of the steroid metabolites Singh and his co-authors quantified, but he said that even for assays where triple quads are currently suitable, the higher level of confidence provided by HRAM measurements would be welcome.

"In clinical diagnostics, you don't want to take any risks," he said. "The liability is very high. [But] if this technology works in the clinical environment, even though it is more expensive, you don't want to miss out on it, because a 1 percent error on a triple quad could be very expensive for a particular patient."

Singh added that the ability of HRAM instruments to collect data on other analytes while measuring clinically relevant molecules is also attractive, particularly at a site like Mayo that does a substantial amount of clinical research.

An HRAM "machine is designed to collect information [on all the molecules present], and on clinical assays you just ignore the data that you don't need," he said. "But you could have another person from the research side then go into the same machines and start pulling out information that they could use for work on a research project. The patient sample is there, the analysis has been done, and the information is sitting in the computer."

In an ideal world, Singh said, "I would be running the instrument in a mode where I collect all the information on every sample and saving every file." More realistically, he noted, considerations around data storage and analysis will necessitate a narrower approach, where he and his colleagues would collect and store comprehensive data on clinical samples from patients relevant to a particular research project.

"Because of the cost of saving all this information and the fact that I don't have enough people to do all of the bioinformatics, [the process] is going to be a little bit more [targeted]," he said. "It will be, 'OK, in this particular patient population with this tumor, we have the potential of discovering something.'"

This sort of application of HRAM instruments for simultaneous collection of clinical and research data will be most relevant to larger reference labs with the resources and interest in developing new diagnostics and other tests, Singh suggested. He added that HRAM instrument prices would likely have to come down for the technology to broaden its clinical reach.

The Mayo Endocrine lab currently has around 80 triple quads (70 Sciex and 10 Agilent) and five Q Exactives, Singh said. US labs began adopting triple quads for clinical testing around 2000, he said, noting that uptake of these instruments has been driven by fierce competition among vendors that has pushed prices down. Currently, he said, a triple quad sells for roughly half the price of an HRAM system. And, he added, thus far, vendors have shown little inclination to position their HRAM systems for the clinic by lowering prices.

Recent releases by Thermo Fisher and Sciex suggest that those companies remain focused on triple quads as the key technology in their clinical mass spec portfolios.

In June, Thermo Fisher introduced its Cascadion SM Clinical Analyzer, a triple quad-based system that aims to combine the performance advantages of mass spectrometry with the automation, robustness, and ease of use of a conventional immunoassay-based clinical analyzer. Intended for analysis of small molecules, the instrument will allow clinical labs to run mass spec-based assays without employing staff specially trained on mass spec. The company believes it will find a market for the device both among smaller hospital labs, which would like to use mass spec but have avoided it due to the expertise traditionally required, and among larger clinical reference labs that have used mass spec for years but would like a more streamlined, turnkey option.

A month later, Sciex announced the launch of its Topaz LC-MS/MS system, a triple quad-based platform that likewise aims to streamline mass spec for the clinical lab. The company also released a US Food and Drug Administration-cleared assay for use on the instrument, its Vitamin D 200M Assay. 

The two instruments differ in the level of automation and user interaction, with the Cascadion purporting to be an essentially hands-off instrument while the Topaz retains more of the form of a conventional mass spec system and allows for operation in an "open" mode where clinicians will be able to run their own laboratory-developed tests.

Both, however, mark significant steps toward implementing simpler, more clinician-friendly versions of mass spec technology. And, as both are based on triple quad technology, their release could limit their vendors' incentive to push HRAM instruments into the clinic, which could, in theory, cut into the demand for these new clinical platforms.

Sciex declined to comment for the story. Meanwhile, Bradley Hart, market development director for Thermo Fisher's chromatography and mass spectrometry division, noted that the company's HRAM instruments are currently sold for research use only but highlighted several advantages of HRAM systems, including better accuracy and selectivity and the potential for easier assay development and less involved sample prep.

Hart also noted that while the company does not currently sell HRAM instruments for use in clinical assays, the strength of these instruments in clinical research suggest they will one day make their way to actual clinical testing.

"Mass spec could be involved in research around prevention, or screening, or early diagnosis, or diagnostic cohort differentiation, or treatment pathways, and so on," he said. "So, we expect, and we do see the Orbitrap being very, very strong in that [research] arena. And, of course, those uses are eventually going to lead to, most likely, some MD version of an Orbitrap someday."

Hart added, though, that Thermo Fisher will "wait until the market really speaks on that," to develop a clinical HRAM instrument. He noted, however, that the company anticipates growing interest in HRAM for clinical research and, ultimately, clinical assays.

"We expect movement towards HRAM, and that growth in this area will outpace triple quad growth," he said. "The interest in HRAM for doing clinical research, headed toward clinical assays someday, is clearly outgrowing what I would say the market growth is for triple quads."

He added that while the initial version of the Cascadion will be triple quad-based, Thermo Fisher currently has the technical ability to develop an HRAM version of the device.

"Technically, there's very little to impede us from having future versions of a Cascadion concept, or other medical devices that we might develop, with HRAM," he said. "You might see us, like [we did] with the triple quads, develop [HRAM] Class I medical devices first, and then depending on the demand from the market decide if it is sufficiently high to [put HRAM technology] into a clinical analyzer. We absolutely have the capability to produce an MD Orbitrap once we decide the business justification is there."

One potential driver of such a decision could be competition from large diagnostics companies that have shown an interest in moving into the clinical mass spec market with triple quad-based analyzers of their own.

Last month at the American Association of Clinical Chemistry annual meeting, Roche announced that it is developing a mass spec-based clinical analyzer featuring a triple quad produced by its partner Hitachi. Speaking to analysts at the AACC meeting, Jean-Claude Gottraux, head of Roche professional Dx, said the company plans "to take mass spectrometry from the dark corners of the research lab and put [it] into the mainstream, into the main lab."

He added that Roche expects mass specs will likely cannibalize some existing parts of its clinical business, but that "if there is going to be some kind of cannibalization of our portfolio, we prefer to be the ones who do it rather than be on the receiving end."

Roche's planned entry into the clinical mass spec market could present formidable competition for Thermo Fisher and Sciex. But, an HRAM-based clinical system, were those vendors to develop one, could prove more difficult for companies like Roche, which has limited mass spec experience.

Hart decline to comment on if or how Roche's entry into the clinical mass spec market might influence Thermo Fisher's thinking regarding clinical HRAM instrumentation, but said that he believes "the Orbitrap, especially in [a] medical device, would be highly differentiated."

This could prove more relevant as clinical mass spec moves from its current focus on the analysis of small molecules and toward measuring peptide and protein biomarkers, which are more challenging analytical targets. The Cascadion, Topaz, and proposed Roche instrument are all aimed primarily at small molecule work, but protein-based testing represents a significant part of the roughly $7 billion immunoassay market, and one that clinical mass spec has only begun to touch on.