Recently, under the banner of “access”, a trade association that represents a number of biomarker testing laboratories sent a letter to two Medicare administrators expressing concerns about the administrators’ proposals for tightening coverage on precision oncology biomarker testing. The proposed updates aim to squelch reimbursement for experimental biomarker testing where the biomarker targets do not have proven value to the lives of patients. The proposed updates also aim to reduce billing fraud and patient recruitment fraud. These updates would apply to the Medicare population in a number of states in which fraudster labs, patient “brokers”, and shady doctors have run rampant. Industry, physician, and patient advocacy groups signed onto the trade association’s letter, expressing concerns that the proposed increase in paperwork for doctors and labs will have a cooling effect on precision oncology access. It’s a classic case of ‘this is why we can’t have nice things.’ But conspicuously absent from this skirmish is any acknowledgement from the various stakeholders that current laboratory credentialing is failing to protect many patients from inaccurate biomarker testing from many labs. The nearly powerless FDA has become increasingly vocal about it, the NIH is concerned about it, patient-first nonprofits are worried about it, yet the contention points in the current dust-up do not include the fact that much of what passes for precision medicine is anything but. In our view, it makes no sense to fight for broad patient access to biomarker testing without ensuring first, or at least in parallel, that biomarker results from labs are reliably accurate.

Lest you think that biomarker testing accuracy isn’t a large enough issue to prioritize in the battle for “access”, here is the top level finding from a recent study we were involved in that looked at hematologic cancer genomic biomarker test results that were uploaded into a national disease registry by treating oncologists nationwide. Because of the national reach, the biomarker test results came from different clinical laboratories across different states. “This pilot study demonstrated that limitations in the accuracy, transparency, and consistency of genetic and genomic laboratory reports make the standardization, collation, analysis, and interpretation of high-quality data across laboratories and providers impossible.” In short, biomarker test results from many labs were nonsensical to the expert eye and were sometimes blatantly in error, but in ways that oncologists were unlikely to recognize. Like most biomarker tests run in clinical labs across the USA, these tests were all laboratory developed tests. And before dismissing the study findings as biased or cherry picked, dive into the methods section in the open access publication and you’ll discover that it wasn’t. Note also that almost all of the biomarker test results were from labs that had College of American Pathologists (CAP) accreditation, and not just CLIA certification. “These findings show a need to standardize assays and reports, improve technology transparency, and increase quality control efforts dedicated to report accuracy to ensure that novel, targeted therapies are available to eligible patients.”

At the Center for Genomic Interpretation we advocate for access to *precision* medicine, but we also advocate against *imprecision* medicine. Because we lean heavily into this latter form of advocacy in our nonprofit, we sometimes draw the ire of access advocates who think we should back off from expecting clinical labs to run accurate biomarker testing for patients. Some patient advocate groups have told us that they would prefer to first secure access to biomarker testing for all appropriate patients, even if many biomarker tests are inaccurate, rather than risk giving “ammunition” to lawmakers, policy makers, and insurance payers who may be looking for reasons to deny access to and payment of biomarker testing. But can’t we advocate for both access and accuracy of biomarker testing? Shouldn’t this go hand in hand?

The fact that too many biomarker testing labs have DNA sequencing problems that regularly lead to false positive and false negative biomarker testing is a finding that CAP itself published in 2021 in their aggregate findings for proficiency testing of next generation DNA sequencing tests. Regular proficiency testing by clinical labs is required by CLIA law, and CAP is the nation’s largest commercial provider for proficiency testing. While CAP hides the ball in its publication by concluding that the vast majority of labs are reliably accurate, their own data indicates otherwise and can be easily discovered by reading past their literary puffery and looking at the data presented. By CAP’s design, which is laid out in their publication, the overwhelming majority of CAP’s proficiency test variants for genomic biomarkers are easy for both competent and incompetent labs to detect. They’re mostly single nucleotide variants (SNVs). While reliable SNV detection is important, more complex genomic variation often constitutes the majority of positive biomarker findings. Thus, as noted in the CDC’s working group report from 2019: “Commercial [proficiency testing] programs are a little bit too easy. While they may be meeting the checkbox of proficiency testing, they may not be meeting the challenge or the spirit of proficiency testing.” 

CAP’s stacking of proficiency testing with mostly “too easy” variants is in accordance with CAP’s advocacy to avoid “overburdening pathologists and laboratories”. Thankfully though, CAP sprinkles a few genuinely challenging proficiency variants into their proficiency samples. Not enough, mind you, to represent the biological reality of the biomarkers that matter most for patients, and not enough to block incompetent laboratories from passing proficiency testing, but at least CAP includes some few meaningful challenges. CAP’s 2021 publication shows that when they challenge labs with clinically important biomarkers that are challenging for some labs to detect, the competent labs are rapidly revealed from the incompetent labs. For example, when labs were challenged with something called “pseudogene interference”, slightly more than half of labs reported a false positive. CAP’s publication offers a few helpful suggestions to labs to guide them on how to fix this problem, but their publication fails to mention how catastrophic (for patients) this failing is. For context, about one third of the human genome consists of pseudogenes, a context CAP neglects to mention in their publication. So when half of labs can’t reliably report biomarker targets that could be interfered with by pseudogenes, which is extremely common, the false positive rate for such labs at the patient level is likely frighteningly high. But again, because CAP stacks the proficiency testing samples with easy SNV variants, CAP is able to pass even the incompetent labs in CLIA mandated proficiency testing. They’re also able to accurately, though disingenuously state in their 2021 publication that “while overall performance remains excellent, particularly for the detection of SNVs [single nucleotide variants], some variants are more challenging for NGS [next generation sequencing]-based methodologies.” CAP just fails to note for the reader that those “more challenging” variants are often the most important types of variants for precision medicine.

There’s an additional bug/feature of CLIA mandated proficiency testing that is harming patients. That is, for almost all clinical testing, labs need only get 80% correct on their proficiency testing challenges to be credentialed as a clinical lab. Maybe that made sense in 1988 when CLIA regulations first came to be, and when it wasn’t economically feasible to overnight courier patient samples to competent labs, but a passing threshold of 80% is much too low in the era of precision medicine when the proficiency challenges are so easy (in genetics and genomics at least). What’s more, CLIA mandated proficiency testing scores for each lab are not made available to the public, which doesn’t allow for informed decision making. With these regressive forces, and others not mentioned, precision medicine is often not what it is marketed to be once it leaves the clinical trial setting. The FDA made this statement in June 2023 regarding laboratory developed biomarker tests: “The agency has become increasingly concerned that some tests made by laboratories and not authorized by the FDA may not provide accurate and reliable test results or perform as well as FDA authorized tests. This may negatively impact treatment decisions.”

The Centers for Medicare and Medicaid Services (CMS) is where the rubber meets the road for these issues, particularly since CMS oversees CLIA. It’s a disservice to patients and their well meaning physicians for CMS to continue to ignore the evidence based concerns being expressed by the FDA and the CDC in regards to the prevalence and causes of inaccurate biomarker testing.

So in bullet point summary:

  • ACCESS & ACCURACY: We encourage access advocates to also advocate for raising the accuracy bar on laboratories. Maximizing appropriate access without the needed improvements in laboratory accuracy will result both in more people being helped by precision medicine, and more people being harmed by imprecision medicine. For patients it would be luck of the draw. It shouldn’t be left to chance. Thus we should be advocating for both access to biomarker testing, and advocating for accuracy in biomarker testing.
  • WHERE TO BEGIN IN ADVOCATING FOR ACCURACY: The best place to focus advocacy for improving laboratory test quality is to first advocate for transparency of CLIA mandated proficiency test scores. That is, the public should be able to ask and readily receive detailed proficiency test scores from each laboratory, or receive the scores for labs directly from CMS (that oversees CLIA). Such a radical change towards transparency may require another amendment to CLIA rule. Also, the appropriateness  of percentage pass rates should be evaluated in the context of how stringent proficiency testing really is, and what the patient impact of false negatives and false positives are.

In the meantime, our nonprofit will keep providing ELEVATEGENETICS BRILLIANT (advanced in silico proficiency testing for next generation sequencing tests) so insurance payers and health systems can put together smart networks of preferred laboratories, but our service wouldn’t be necessary if CLIA mandated proficiency testing was actually fulfilling its purpose.

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#FDA #CLIA #CMS #CDC #PrecisionMedicine #PrecisionOncology