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Stakeholders Developing Toolkit to Tackle Lack of MDx Outcomes Data in Microbiology

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NEW YORK – As healthcare payors and C-suite decision makers continue to insist on clinical utility and outcomes studies to justify the use of new diagnostics in microbiology, a new collaborative spirit is growing among stakeholders.

Under the auspices of the American Society of Microbiology (ASM), industry and lab representatives have come together to outline approaches to these necessary studies, and they will soon be meeting to develop a toolkit to stimulate and guide more published outcomes research — and potentially create a pool of funds to support diagnostic agnostic trials.

The ASM Corporate Council met last year for the first time with lab representatives in an event called the Clinical Microbiology Open, resulting in a mini-review in the  Journal of Clinical Microbiology that outlined the need for more utility studies. A second Clin Micro Open is set to be kick off next week, and ASM is also strategizing a meeting next year that will ultimately lead to a toolkit on how to perform publishable clinical utility trials.

Microbiology labs are often among the earliest to see firsthand the workflow benefits of rapid molecular technology breakthroughs of the past decade. From clinical validity studies, which compare testing to gold standard methods like culture and standard PCR, the advantages of the new technologies are obvious: ease of use, faster time-to-results, and greater accuracy. Theoretically, patients who get these tests will be put on the correct treatment sooner, which should improve patient outcomes.

But payors and hospital administrators want proof. Financial gatekeepers have been pushing for clinical utility studies, often requiring health economics data from beyond just the silo of the lab to show that costlier new diagnostics actually improve care, enable quicker and more accurate treatment decisions in the real world, or lead to reduced patient morbidity, mortality, or length of stay in the hospital.

As emphasized in the JCM mini review on the subject, clinical utility studies impact guidelines, which in turn impact payor decisions on reimbursement, and hospital administrators want to see data justifying the increased cost of new testing before a new method can be adopted.

Generating this data is a tall order. A daunting number of variables contribute to healthcare economic assessments of diagnostics. Things like whether a patient was an inpatient or outpatient, or whether care was billed using CPT codes or under a DRG, how long a patient was followed, the complexity of the illness being treated, and even whether physicians are appropriately acting on diagnostic results, can all impact determination of the precise value of new diagnostic testing.

Payors and administrators have also been asking for multi-site, randomized, prospective studies incorporating different types of patient populations. These elaborate trials take huge investments of time and money, and sometimes struggle to clear the institutional review board hurdle.

For an individual company, performing an outcomes study also carries the risk that the technology may not show a clear or universal economic advantage given a particular set of variables.

Nevertheless, a clear lag in reimbursement and uptake of new molecular testing platforms has been attributed to the lack of outcomes and utility studies. For example, last year Palmetto GBA issued a finalized local coverage determination denying coverage for multiplex respiratory panels as front-line diagnostics. The payor's justification: "No clinical utility studies demonstrate that rapid, accurate highly multiplexed [nucleic acid amplification] tests decrease the use of empirical antibiotics and allow for a more targeted approach to using antivirals."

Stakeholder perspectives

Before joining Luminex as senior director of global scientific affairs, Sherry Dunbar was a clinical lab director. She has been a member of ASM for 33 years. "While running my own lab in the late 1990s, I don't recall having this high of a bar to meet to decide to bring in a new test," she said. Labs often don't make purchasing decisions on their own anymore, she said, but must first make the business case for new testing to administrators.

Companies now face a chicken and egg problem. They want to do utility and outcomes studies that customers and payors ask for, so that they can drive uptake. But, there isn’t clear criteria for study design in clinical microbiology in order to be publishable and acceptable to payors, or ultimately, to authors of practice guidelines. Without knowing in advance whether a study will be appropriate or useful to all these adjudicators, it is tough to put up the funds, "bearing in mind companies have already invested heavily in clinical trials to get US Food and Drug Administration clearance," Dunbar said.

Clinical utility studies of diagnostics pose huge challenges for labs, too. Blake Buchan, associate director for clinical microbiology and molecular diagnostics at the Medical College of Wisconsin, said in a recent interview that while new molecular tests are often faster, more comprehensive, and more sensitive, "the question then becomes, does that added benefit actually trickle down and benefit patient care and subsequently reduce overall cost of care." Individual laboratories can run clinical validity studies of their own, but they simply can't support large, randomized, controlled outcomes studies required to answer that question — either financially or in terms of staffing — and a study limited to a single center is not likely to be persuasive to payors or administrators, Buchan said.

Chris Doern, director of clinical microbiology at Virginia Commonwealth University, also said in an interview that labs are sometimes reluctant to tackle these studies, not only because of the cost and time involved, but also the effort required to get a multi-site trial design through the institutional review board. He suggested that there may ultimately need to be changes to expectations of different stakeholders as well, in order to enable this work.

For example, a multi-site, randomized, prospective study of a diagnostic test requires obtaining patient consent prior to using a test, but assessing a test with a rare target also requires a massive number of patient consents on the front end, which is time consuming and expensive. "It quickly becomes undoable," Doern said. While patient consent to scientific studies is critical, "we're now for the first time losing the ability to do diagnostic testing and serve patient populations because we haven't done the studies that are needed to show that the tests matter," he said.

Retrospective observational studies in which researchers compare a novel technology to a historical standard of care could be a reasonable alternative approach in some situations, for example, perhaps enabling a less time-sensitive consenting process. And, as noted in the JCM mini-review, the study rigor required might also hinge on the cost of testing. "High-priced tests are more likely to be held to higher evidentiary thresholds by commercial payers, who may demand larger clinical trials or randomized control trials, when at a lower price point prospective observational or retrospective trials would have been accepted," the authors wrote.

A role for ASM

Jonathan Stevens-Garcia, the new chief operating officer of ASM, said the society founded its Corporate Council a few years ago based on the belief that longer-term relationships would be beneficial both for clinical microbiologist members as well as corporate partners. 

"It really is about information, and both groups report a high level of interest in learning from one another," Stevens-Garcia said.

For ASM, bringing these groups together also allows the society to drive discussions of important topics, like the complex and growing problem of antibiotic resistance, he said.

The Corporate Council currently has about 15 industry members, according to Peggy McNult, the director of ASM's clinical and public health microbiology committee. Each are invited to the newly established Clinical Microbiology Open meeting, which focuses on sharing information between the lab and industry.

ASM's second annual Clinical Microbiology Open event will be held next week, bringing together two representatives from each Corporate Council company, 30 key leaders in microbiology, and representatives of federal agencies and ASM leadership, for an intensive networking meeting, McNult said. This year's Open will also have specific discussion of diagnostic test gaps in point-of-care, rapid AST, and emerging diagnostics, and a focus on industrial sponsored studies and collaboration, and healthcare finance and reimbursement.

While the first Open was the impetus for the JCM mini review, the stakeholders are now also planning to dive deeper into the topic of clinical utility with a separate event on the topic.

"The mini review was setting the stage that this is a great need, but the next step is, how do we get more of these studies done," said Melissa Miller, the chair of ASM's clinical and public health microbiology committee and director of the clinical molecular microbiology laboratory at University of North Carolina School of Medicine. "What we want to do … is to have a face-to-face meeting, a colloquium, if you will, to get various stakeholders in the same room to design a toolkit that will allow laboratories to work with their colleagues in their institutions to do these clinical studies," she said.

The goal is to empower laboratories and teams within institutions to perform clinical studies needed to show utility of tests, particularly the more expensive molecular tests, Miller said.

"As these [molecular tests] become the mainstay in a lot of our hospitals, we hypothesize what the benefit to the patient and the institution is," she said, "but to really be able to measure that in a meaningful, powerful way is something that a lot of clinical microbiologists aren't equipped to do. This is not really part of our training."

Clinical utility studies are very multidisciplinary, Miller also said, often involving clinical microbiologists, pharmacists, health economists, and clinical infectious disease and hospital epidemiology specialist. "Each piece is important in terms of getting to the right data to assess clinical utility or clinical impact of a molecular test," she said.

So far, Miller said, she and her colleagues have created a steering committee and identified the types of experts and stakeholders that would need to be present to develop a comprehensive toolkit aiming to bring all parties up to speed on how to run an outcomes study. And, she emphasized that the toolkit will hopefully empower stakeholders to be able to do these studies in a way that's publishable to ultimately change clinical guidelines.

The group plans to meet in the first half of 2020 at ASM headquarters, Miller said, and it is also discussing the potential of bringing in leadership from the Infectious Disease Society of America to help sponsor the meeting.

The toolkit is likely going to emphasize the need for what Miller called "diagnostic agnostic" approaches.

Rather than setting out to measure the impact of a single company's test, or even a head-to-head evaluation, the goal would be to frame outcomes studies as broadly as possible, for example by assessing rapid molecular multiplex panels for respiratory pathogens generally.

"Ideally, we want multiple types of tests that are used for the same clinical indication and multiple institutions involved, looking at doing multi-center studies so that we can generalize the data we gather from these clinical utility studies more broadly," Miller said.

Depending on whether the studies are broad enough, another idea that has repeatedly surfaced in all of the brainstorming sessions has been developing a pool of funds from industry stakeholders to support more outcomes studies.

An impartial adjudicator with the interests of both industry and researchers in mind would probably be needed for a funding pool to be successful, and ASM could potentially serve that role, VCU's Doern said.

Though it may seem far-fetched, there is precedent for commercial competitors working together, provided there is an impartial intermediary. The Antibacterial Resistance Leadership Group (ARLG) coordinated a multi-site study of more than 2,500 patients looking at extra-genital testing for commercial chlamydia and gonorrhea molecular testing, for example, and the two-year study resulted in simultaneous clearance of tests from Hologic and Cepheid for throat and rectal indications last year.

Regardless of how the outcomes studies are funded in the end, it remains clear that they are needed, and getting all the stakeholders into a room and up to speed on how to do these studies is a critical step.  

"All of the companies that are part of the Corporate Council are hoping to benefit from the opportunity to sit around the table with all the stakeholders to build relationships and help solve problems," Luminex's Dunbar said. "Even though we are competitors, something that benefits microbiology is going to benefit all of us," she said.