What’s Holding Back Biomarker Innovation, & How Can We Solve It?

Think about it. Most rheumatology labs are stuck in the 1960s. Translational biomarker research looks excellent on paper and in theory. However, many barriers exist from the bench to the bedside. This article highlights this problem for the rheumatology community and proposes practical solutions.

Case in Point

For an example, let’s examine systemic lupus erythematosus (SLE). SLE is the 14th most common cause of death, excluding accidents and suicide, in all U.S. women aged 15–64 years old, and the fifth or sixth cause for women of color aged 15–34.¹ The average time to SLE diagnosis from symptom onset is four to six years; patients with longer delays have more severe disease and permanent organ damage.^2-4

This is no surprise. Our SLE biomarkers, henceforth called ancient biomarkers (e.g., anti-dsDNA, C3, C4, anti-Smith, anti-RNP, anti-SSA), are more than 50 years old.

Using ancient biomarkers, rheumatologists misdiagnose many SLE patients as healthy or having other disorders, only to have their SLE properly diagnosed later when they have more severe disease.⁵ We also misdiagnose non-SLE patients as having SLE, treating these patients inappropriately with high-dose glucocorticoids.⁶ The ancient biomarkers also lead to difficulty assessing disease activity, which is crucial in guiding proper management.⁷

During the past two decades, improved SLE biomarkers have become available. However, most insurance companies refuse to pay for them. This negatively impacts patients and clinicians while dissuading lab research companies and investors from pursuing biomarker research and development (R&D). Biomarkers that ultimately survive end up in the hands of the giant insurance-backed laboratories LabCorp and Quest (i.e., the duopoly), which typically do not invest in their R&D.

Medical System Failures

Consider the proprietary biomarker, the SLE-key rule-out test (by ImmunArray). This test would identify numerous autoantibody and immune system molecular patterns and indicate if a patient does not have SLE. A positive result could rule out SLE with a 94% sensitivity, 75% specificity and a 93% negative predictive value.⁸ Despite these impressive performance characteristics, ImmunArray couldn’t navigate the complicated and expensive lab approval system and the absence of insurance support that forced patients to pay for the test out of pocket. ImmunArray ultimately filed for bankruptcy, and the SLE-key test is no longer commercially available.

At other times, research biomarkers have been offered cheaply by the commercial lab duopoly of LabCorp and Quest to the financial detriment of the companies that developed such tests in the first place. Diffuse fine speckled-70 antinuclear antibody (DFS-70) helps to discriminate between the likelihood of systemic autoimmune disease in ANA-positive patients who are negative for disease-specific autoantibodies.⁹ The test was developed by a proprietary lab (Inova), which develops tests for research rather than clinical purposes. The test can now be ordered through LabCorp.

However, LabCorp runs the test for a minimal reimbursement rate.¹⁰ The problem with this route is that the level of reimbursement is not commensurate with the test’s clinical value, including recouping research and development (R&D) costs. Running the test for a low profit margin (but high volume) benefits LabCorp. However, it disincentivizes biotech companies and investigators to invest time, energy, and money into further research.

The commercial lab duopoly also seems to play an outsized role in determining if a lab test is clinically useful based on whether or not they run a specific test. Measuring hydroxychloroquine whole blood drug levels in my (Don Thomas, MD) lupus patients has transformed my lupus clinic by increasing adherence, decreasing clinic-wide disease activity, and potentially reducing the risk for retinopathy.^11,12 For several years, most insurance plans did not cover this test when performed by Exagen Diagnostics. However, after the large commercial lab duopoly (LabCorp and Quest) began offering the test, insurance covered it widely. How could a lab be determined by the insurance companies as having clinical utility only after being offered at a relatively cheap cost by the duopoly, but not when performed by Exagen?

Lost Patents

Cell-bound complement activation products (CB-CAPS) were described initially by Susan Manzi, MD et al. in 2004 and became commercially available as a proprietary lab in 2012 (Exagen).¹³

We routinely order C3 and C4 in SLE patients. Low levels can increase the pre-test probability for an SLE diagnosis and help follow disease activity and therapeutic responses. However, due to competing processes (e.g., increased hepatic production) during SLE inflammation, they are helpful in only one of five patients.⁷

During active SLE, complement consumption cleaves C4d from its parental complement. C4d binds to blood cells (i.e., cellular bound-complement activation products [CB-CAPS]) for their lifespans. CB-CAPS levels are unaffected by processes such as hepatic C4 production and are more reliable in identifying complement consumption than C4 levels. Erythrocyte cell-bound C4d (EC4d) is highly associated with SLE disease activity and can identify SLE patients with active disease who have chronically low or normal C3 and C4 levels.⁷

B cell-bound C4d (BC4d) has high SLE specificity (similar to Smith and dsDNA autoantibodies). However, BC4d has 53% sensitivity while anti-Smith and anti-dsDNA have sensitivities of only 14% and 33%. When BC4d and EC4d are used in the Lupus AVISE Test, the result significantly increases or decreases the pre-test probability for diagnosing SLE with superior sensitivity and specificity over the ancient biomarkers.

Few commercial insurance companies pay for these tests, even considering these superior statistics. I follow approximately 200 patients with SLE. The ancient biomarkers have proven unhelpful in following disease activity in many of them. Once or twice daily, I depend on EC4d to accurately identify SLE activity when anti-dsDNA, C3, and C4 do not reliably fluctuate with disease. Due to insurance non-reimbursements, many patients must pay a greatly reduced out-of-pocket fee (or for free if in a low-income bracket) courtesy of the proprietary lab. This does not cover the cost of performing these biomarker tests nor does it recuperate R&D costs.

Insurance company denial letters list many reasons for CB-CAPS testing noncoverage, including being experimental, not being proved to improve net health outcomes, not being part of SLE classification criteria and not being supported by the ACR.

We predict that CB-CAPS will become widely used and included as standard of care in clinical practice to help diagnose and manage SLE better. In 2024, the CB-CAPS patent expires. At that point, the duopoly can provide the tests on a broad scale, most likely at a much-reduced cost; they do not need to recuperate R&D expenses.

Suppose the original discoverers and producers of biomarkers continue to lose patents due to this system. This will deter others from pursuing biomarker R&D. The giant commercial lab duopoly will most benefit in the long run.

Clinical Utility

The Fryback-Thornbury Hierarchy (FTH) was developed in 1991 to demonstrate diagnostic testing validity and utility.14 CB-CAPS satisfied each FTH level: technical and diagnostic efficacy, diagnostic thinking, therapeutic and patient outcomes, and societal efficacy.^15-19

Even with so much support in peer-reviewed journals, CB-CAPS are deemed investigational by sources like UpToDate and not clinically useful by insurance companies. What objective criteria do they require?

UpToDate does not delineate their reasoning. If they were to apply similar standards to the ancient biomarkers, they would also need to label them investigational. For example, UpToDate states that CB-CAPS requires longer duration studies. This standard is not even required of new pharmaceuticals. The ancient biomarkers also lack high-quality, long-term studies other than clinical use over a half-century. Yet UpToDate recommends their use.

Unlike pharmaceutical approvals by the U.S. Food & Drug Administration (FDA), the path to FDA and Centers for Medicare & Medicaid Services (CMS) approval for biomarkers is too long, cumbersome and expensive. For example, CB-CAPS is still waiting on CMS approval even after many studies showing high sensitivity, specificity and predictive value with excellent clinical and societal utility in peer-reviewed journals.

A more realistic approach to proving clinical utility is to satisfy the FTH levels up to the Patient Outcome Efficacy level. Although the final level (Societal Efficacy) is laudable, it isn’t practical for uncommon diseases.

Another critical problem is the lack of key opinion leaders (KOLs) recommending advanced biomarkers to other rheumatologists. KOLs commonly cite the strict ACR conflict of interest (COI) requirements as reasons. The problem with this is that it is challenging to find KOLs who aren’t involved with uncommon disease biomarker R&D.

Consequences of Barriers

More accurate testing is paramount as the rheumatologist shortage worsens. Patients need to rely more on primary care providers for diagnosis and management. Better testing is critical for earlier and more accurate diagnoses and more accurate ways of accessing disease activity to better guide therapeutic decisions (personalized medicine).

Who wins in the long run with the current system? The giant lab duopoly.

Who loses in the long run? Patients who could benefit from better biomarkers, such as those who could have benefited from CB-CAPS testing over the past 11 years. The tests could have diagnosed patients more accurately and at earlier stages of SLE, helped with more accurate disease activity determinations, and reduced more severe disease and deaths.

Advanced biomarker researchers and developers also forego reaping the rewards for their hard work and innovation. There should be incentives to help drive the search for better diagnostic tools.

Proposed Solutions

To advance rheumatic disease laboratory testing, we propose the following:

• The ACR should actively support novel biomarkers shown to benefit patient care;
• The ACR should be more flexible in addressing potential COI;
• The ACR should include advanced biomarkers in diagnostic and management guidelines;
• KOLs should include advanced biomarkers when teaching healthcare providers about rheumatic disease management;
• Disease management resources (like textbooks and UpToDate) should support novel biomarkers in disease management discussions;
• Academic centers should incorporate advanced biomarkers offered by proprietary labs;
• Fellowship programs should teach the latest research regarding novel biomarkers, even if not available at their institutions;
• Community rheumatologists should use advanced biomarkers in clinical practice and not primarily rely on in-house labs;
• Insurance companies should pay for novel biomarkers that show utility in peer-reviewed journals;
• Insurance companies should reimburse proprietary labs and not favor the duopoly;
• Insurance companies must stop mistaking classification criteria for diagnostic criteria;
• Insurance companies, KOLs, and rheumatology educational platforms should adopt transparent, objective systems (such as the FTH) for evaluating all biomarkers (old and new) for clinical utility; and
• The FDA and CMS should improve laboratory test approval processes.

Act Now

Suppose the rheumatology community does not vigorously support new biomarkers. In that case, insurance companies will likely raise up major challenges in covering their costs. However, if we work diligently on the proposed solutions above, insurance companies may realize the importance of providing better care for patients.

Unless we unite to fix this system, superior biomarkers from translational research will not get through the complicated process of getting into the much-needed hands of clinicians. Many will get stuck on the bench and never reach the bedside.

Donald Thomas, MD, FACP, FACR, RhMSUS, is a rheumatologist who specializes in caring for patients with lupus and Sjögren’s disease at Arthritis and Pain Associates of P.G. County, Greenbelt, Md. He is the author of The Lupus Encyclopedia: A Comprehensive Guide for Patients and Health Care Providers. He also enjoys teaching at the Walter Reed National Military Medical Center as a clinical associate professor of medicine at the Uniformed Services University, Bethesda, Md.

Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.

Disclosures

Dr. Thomas has spoken for Exagen Diagnostics Inc. and is a scientific advisor for Progentec Diagnostics.

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