New accreditation program checklist section: Imaging mass spec scores its own quality standards

“One of the powers of the IMS technology is that there is no chemical labeling requirement, so we don’t have any antibody we have to link to, we don’t have a specific probe we use, and we detect molecules in their native state. This makes it universal, in that any tissue type can go into the instrument and be analyzed,” Dr. Norris points out.

He believes Frontier will enter the market with its first IMS assay within a year, and he hopes it will be the first company to do so. “I think we’ll have a laboratory-developed test for which the clinical utility studies are completed and we can provide evidence that it’s effective for solving a problem, and we will be selling the test to clinical labs.”

When the IMS checklist project was initiated, John D. Pfeifer, MD, PhD, professor of pathology and immunology and vice chair for clinical affairs at Washington University School of Medicine, was chair of the CAP Personalized Health Care Committee. In that role, he helped bring Drs. Caprioli and Norris in to speak to the committee two years ago about the potential uses for the technology.

The same committee had followed a similar process when developing the in vivo microscopy checklist, Dr. Pfeifer says. “That technology matured to the point that there is an IVM committee now. And we realized that IMS was at about the same stage in its development, and that labs that do it would welcome guidance to make sure they have a quality operation. Given my experience with the process for IVM, I was comfortable helping to lead it again for IMS.”

Dr. Caprioli demonstrated to the committee that IMS technology had a technical piece and an informatics analysis piece that could be used to discover information from tissue sections that could not be obtained from the tissue slides by conventional microscopy or histochemistry, Dr. Pfeifer says. “Through IMS, there were reproducible patterns of molecules—they could be lipids, small metabolites, proteins, a number of things—that were characteristic of specific normal tissues or disease states. He also showed that with appropriate validation you could build a test that would have clinical utility around that.”

IMS is still in a category of boutique testing, Dr. Pfeifer says. “It still requires a specialized instrument to perform, and platform manufacturers have only recently become interested in the space. It’s one of those things that only specialized centers have been able to do because the necessary equipment has been expensive and you needed a certain infrastructure.” Now, a number of manufacturers are developing, or already have, instruments that are cheaper and have the required functionality, he says. “I think now we’re in a situation where the technology is poised for growth.”

As with any other test, he says, “there are a few labs that do the hard work to show it is reproducible and has utility. Then, based on the work of those labs, commercial entities that manufacture the platforms, the mass spectrometers, develop something you can buy and put in your lab. They’re starting to do that, which will, of course, engender more widespread use of the technology.” Dr. Pfeifer is not aware of any applications pending at the FDA at this time.

IMS’ impact could be significant, he says. “We all know that routine immunohistochemical stains are powerful tools for diagnosis and prediction. But we’re also aware there’s other information in tissues that you can’t discover by light microscopy. IMS is another tool in the kit.”

Migration from research to clinical use is taking place already, Dr. Pfeifer says. “It’s become clear that IMS is almost certain to have clinical utility in some settings, and the labs that are doing it are looking for guidance to know what sort of testing would meet high-quality criteria.”

Although it’s early in IMS’ career as a clinical test, Dr. Pfeifer says “that’s the point at which the CAP should be getting involved in these things”—just as the CAP did some five years ago with in vivo microscopy. “If it’s coming out of a research environment, a lot of the people there are creative, brilliant people. But they’re not pathologists, so they’re uncertain about what it looks like to develop a quality test from a regulatory perspective. So the first goal is to help them. The second goal is to make sure it’s done right.”

Potentially, Dr. Pfeifer says, some other group could develop a checklist and offer accreditation that isn’t at the same standard as what the CAP offers. In fact, “The CAP explored the boundary of being too late with NGS sequencing. Labs were already using these checklists from molecular testing that were generally correct but did not reflect the intricacies or unique aspects of NGS.”

“The good news,” he adds, “is the field didn’t suffer.” The CAP “moved in and embraced NGS” as a new technology. “And for in vivo microscopy, the CAP was right there where it needed to be, with a checklist.”

The committee was able to draw on earlier checklists to assemble the IMS checklist, Dr. Pfeifer notes. Those included, for example, the mass spectrometry checklist for toxicology or clinical chemistry, and the telepathology checklist. Also helpful were experts who use mass spectrometry in toxicology, clinical chemistry, and microbiology and who use telepathology, as well as those who understand the computational components (bioinformatics) of NGS.

The new checklist addresses the analytical data analysis procedure in requirement CHM.21445, which calls for “a written procedure that describes and identifies the algorithms and steps that make up the data analysis process used to analyze, interpret, and report test results.” The committee might pay even more attention to data analysis in future editions of the checklist, Dr. Pfeifer says. “Everybody is talking about computer-assisted diagnostics, image analysis, artificial intelligence, machine learning, and so on. People are developing algorithms that will soon be in routine use. So we’re getting close to the point that the CAP might want a checklist for validating those types of algorithms.” Although it’s still too early for that checklist, he says, it will have some of the same themes as NGS and IMS. “Operationally, the IMS checklist is just the latest example of the evolution of computationally intensive processes to help get better diagnoses.”

Optimizing patient care is always the No. 1 purpose, Dr. Pfeifer says. “Pathologists are, after all, laboratory physicians. One of the CAP’s primary missions is to support pathologists in that role by providing guidance to perform high-quality testing. In my view, if the CAP ever stops doing that for emerging technologies, its reputation and relevance as an organization will come into question.”

The usefulness of IMS technology in coming years, Dr. Lehman says, depends on how quickly any laboratory develops its own test for that purpose. “This is a new and interesting area and we don’t yet know what contribution it will make to the diagnosis or prognosis of disease. It’s at a very early stage. And I think the College is being very proactive in getting some initial checklist items prepared for the first couple of labs that have an LDT or for a manufacturer that wants to offer an FDA-approved test.”

Anne Paxton is a writer and attorney in Seattle.