Liquid biopsy faces educational and regulatory hurdles on the road to clinical utility

Two major themes arose during a panel discussion at the recent Precision LBx conference –  the importance of further developing clinical utility of liquid biopsy technology and the educational and regulatory hurdles facing those implementing liquid biopsy for clinical use.

The panel, hosted by Thermo Fisher Scientific, focused on opportunities and challenges facing those looking to bring liquid biopsy to the clinic.

The three-person panel was comprised of oncology experts across industries:

• Rajyalakshmi Luthra, Director of the Molecular Diagnostics Laboratory and a professor in the Division of Pathology and Laboratory Medicine at MD Anderson Cancer Center
• Gina Waller, Senior Vice President for NeoGenomics Laboratories
• Luca Quagliata, Global Head of Medical Affairs for Thermo Fisher Scientific and previous director of the Molecular Pathology Division at the University Hospital Basel in Switzerland

Clinical utility of liquid biopsy

The panelists agreed that the timely availability of tissue is a major issue with other biopsy methods and that off-site testing causes delays in patient treatment. Additionally, more traditional forms of biopsy may require larger quantities of tissue than are available.

Dr. Luthra noted that MD Anderson’s studies have shown that between 10-20% of patients with solid tumors are unable to receive genomic testing due to insufficient material. These patients could benefit greatly from the clinical use of liquid biopsy.

While both factors make liquid biopsy appealing, according to Dr. Luthra, “We have a long way to go for certain indications” and prospective studies are needed to demonstrate the clinical utility of liquid biopsy for a wide variety of tumor types.

Dr. Quagliata, who himself signed off on the very first liquid biopsy diagnostic case in Europe, agreed that demonstrating the clinical utility and validity of liquid biopsy outside of a specific indication is a big next step.

He described a previous case in which the results of a liquid biopsy indicated a certain mutation at a very low frequency. The clinician asked whether the treatment plan should be altered based on this result.

“Of course my answer was, ‘I’m not a clinician, I cannot answer. But now the point is we actually don’t know. And that’s the problem.’”

The situation highlighted the need for large prospective clinical studies that would allow clinicians to then make treatment decisions based on the test results. He added that we have a strong commitment to doing just that by engaging with MD Anderson and others in a number of studies that aim to show the clinical validity and utility of liquid biopsy across many indications.

Dr. Waller had a slightly different take on the matter. As a contract research organization (CRO) running tests for clinical trials, NeoGenomics Laboratories has a stable model performing other methods of testing. Dr. Waller noted that for organizations like hers, there are a few factors that would prompt consideration of liquid biopsy.

“We’ve always wanted to be on the leading edge of treatment,” Waller said. “There is a need for liquid biopsy clinical studies to provide evidence to show utility.” From the laboratory’s standpoint, it is important to do what is clinically relevant now and allow for what might become the status quo in the future.

Reimbursement of liquid biopsy tests

While liquid biopsy shows promise for clinical use, clinicians face many hurdles in its implementation. Among those hurdles is reimbursement.

The participants agreed that the first step in addressing the reimbursement issue was to explain why liquid biopsy was needed as an alternative to existing clinical biopsy methods. Dr. Luthra connected the current state of liquid biopsy to the early years of molecular testing.

“About 20 years ago, molecular testing was just an adjunct to histopathology. Now, we have said we do need molecular testing for our treatment decisions. We now accept tissue as the gold standard, but we are moving to liquid biopsy. One has to justify why liquid biopsy is required.”

Dr. Waller added that a diagnostic lab may more easily obtain reimbursement for a test if data are presented to support what the test is trying to accomplish, and perhaps show cost-saving associated with using it.

Recently, organizations in Switzerland and other European countries obtained reimbursement for liquid biopsy and it was expected that usage would increase. However, this did not happen.

“The point is that even if you have reimbursement in place for a certain test,” Dr. Quagliata said, “if clinicians don’t feel comfortable with it, they will not order it.”

The situation highlighted the importance of ensuring that proper reimbursement is in place but, additionally, that clinicians are confident in using the results generated with liquid biopsy to ensure they recognize the return on investment for such a test.

Educating clinicians about liquid biopsies

While reimbursement is arguably an important determinant for many labs, Dr. Quagliata thought that education was a major hurdle in clinical labs adopting liquid biopsy.

The panelists shared concerns about becoming too excited about promising developments in liquid biopsy technology and study.

“I would say we’re far, far away from the point of knowing what mutations mean and how to alter therapies,” Dr. Waller said. “When you have small changes, what does that mean clinically?”

Dr. Quagliata agreed, adding that it is important not to over-promise about the possibility of using liquid biopsy in a clinical context; we need robust clinical data to enable decision-making by clinicians.

Getting to better liquid biopsy results: GMP, the FDA and the hospital community

To build upon the progress already made in the liquid biopsy space, the experts also agree that more products developed under good manufacturing practices (GMP) would help ensure quality.

The amount of variability in interlab analysis of simple tests is astonishing, according to Dr. Waller. Product development under GMP would help solve this problem by enabling consistent results across the labs that utilize the test.

Dr. Luthra brought to light the pros and cons to tests made under GMP. “As new markers are identified, it’s very difficult to change or add. So, from a big economic institution perspective, I would think the key solution to that is good validation.”

Aside from GMP production, the panelists agreed that more FDA involvement in the space would be beneficial. An unbiased regulatory presence helps ensure standards are met. “A regulated product makes the most sense for patient care,” Dr. Luthra says.

“I also think it’s not just involving one or two institutions. You also have to have input from smaller hospital systems. It’s important to have representation from a variety of stakeholders.”

Liquid biopsy in Europe

According to Dr. Quagliata, Europe is looking to the United States’ FDA model for guidance on regulatory affairs. “In the year 2022, Europe has the goal to implement a new CEID labeling system, which will have a very similar process to the FDA approval.”

The difficulty in Europe is with the regulatory agency itself. Based in the UK, post-Brexit no one knows if there will be additional delays.

“Consequences of this might actually be quite important,” Dr. Quagliata predicts. Clinicians in large institutions may have the opportunity to outsource samples to a trusted company, however there are many that work for smaller organizations that will not be able to obtain the CEID labeled-products and they will not order the test.

“This will impact the uptake of the whole testing approach. So that’s going to be a problem,” says Dr. Quagliata.

Dr. Waller added that there could be an additional hurdle. “With community oncologists that are not connected to a big academic institution, with the uptake of something new, they’re generally the last. So, I think one of the questions to come out of this is how do we get the news on new tests, how do we get it to that reach? It’s definitely no small hurdle.”

Analytic problems and liquid biopsy tests

To wrap up the session, the panelists were asked by an audience member to summarize what they believed to be the top barriers to using liquid biopsy in a clinical environment and what could be done about these factors.

“Pre-analytical, analytical, and post-analytical variables are many, and that is one of the things we need to standardize,” said Dr. Luthra.

Showing good concordance between tissue and ctDNA across many cancer types and ensuring inter-laboratory reproducibility is of high priority.

Automation along with “stringent quality control of the assays and of the workflow in order to increase reproducibility of the results” is how we reach this goal, Dr. Luthra said.

Dr. Waller added that for someone coming from a non-academic institution, “getting oncologist and endocrinologist buy-in is probably going to be an intangible thing to measure.”

To sum it up, Dr. Quagliata added, “There are a number of pre-analytical problems: lack of standardization, lack of clinical utility, lack of reimbursement, and of course, lack of education. But, if you think about it, those problems also exist for other tests. These are not liquid biopsy problems, they are general problems with molecular testing.”