Screening for Colorectal Cancer-Non-Invasive Biomarker Tests

Dear Dr. Li:

The American Society for Gastrointestinal Endoscopy (ASGE) appreciates the opportunity to comment on CMS’s consideration of coverage for ColoSense, a multitarget stool RNA (mt-sRNA) test for colorectal cancer (CRC) screening. ASGE is a 17,000-member professional medical society whose mission is to advance patient care and digestive health by promoting excellence in gastrointestinal endoscopy.

The declining incidence and mortality rates of CRC in the United States are a public health success story. This progress is due largely to the widespread adoption of screening colonoscopy, the only screening modality that detects and removes precancerous polyps. ASGE applauds CMS for the critical role it has played in supporting access to high-quality screening options for Medicare beneficiaries.

Despite these gains, CRC continues to be a leading cause of cancer-related death. In 2025, an estimated 52,900 Americans will die from colon and rectal cancers, with over 154,000 new cases expected. CRC will represent 7.6% of all new cancer cases and 8.6% of all cancer-related deaths this year. Many of these deaths are preventable through early detection and treatment, although just 61.4% of adults aged 45 to 75 are up to date with CRC screening. This falls below the Healthy People 2030 target of 72.8%. While screening has contributed to a decline in the incidence and mortality of CRC over the past two decades, these numbers underscore the continued need for effective, evidence-based screening strategies.

ASGE supports innovation in CRC screening that expands access and improves outcomes. However, we believe coverage decisions must be guided by rigorous evidence, particularly for the Medicare population. As CMS evaluates non-invasive biomarker screening tests, including their sensitivity and specificity, we urge the Agency not to rely on performance thresholds established a decade ago. As technology advances, the standards by which these tests are evaluated must also advance, as illustrated by quality metrics in colonoscopy.

Furthermore, ASGE believes that requirements should be applied consistently across all non-invasive biomarker screening tests, whether stool-based or blood-based. For example, precancerous lesion sensitivity is not currently considered in the evaluation of blood-based tests, despite its clinical importance. It is also worth emphasizing that as technology advances every CRC screening test should demonstrate adequate performance across all relevant lesion types, especially serrated polyp lesions, which are more likely to progress to cancer and are often more difficult to detect.

In response to Geneoscopy’s request for Medicare coverage of ColoSense and based on the available data from the CRC-PREVENT trial and the FDA’s approval documentation, ASGE urges CMS to carefully consider the following evidence and policy recommendations.

Clinical Effectiveness
In the CRC-PREVENT trail, ColoSense demonstrated a specificity of 87.5% (95% CI: 86.7%–88.3%) in individuals with no lesions on colonoscopy. The FDA determined that the pivotal study demonstrated that ColoSense met the primary performance point estimate measures for sensitivity and specificity. However, due to the low number of CRC cases, Geneoscopy is required to perform a post-approval study. The FDA noted the following in the Summary of Safety and Effectiveness Data (SSED) based on the current clinical validation data: “Due to the small number of CRCs in the study (27), there is a chance that as many as 24.3% of CRC cases could be missed by this device, which represents a major source of uncertainty regarding device performance.” To address this risk, the Agency required warnings and precautions to be added to the clinical brochure. ASGE urges CMS to consider the downstream implications of this potentially high false negative rate, such as delayed diagnosis, missed opportunities for early intervention, and ultimately poorer patient outcomes.

Medicare Population Representation
The pivotal CRC-PREVENT trial included 1,081 Medicare beneficiaries that represented just 12.1% of the study population. Among these, only three CRC cases were identified. This limited representation makes it difficult to assess the test’s performance in the population most at risk for CRC. ASGE urges CMS to require stronger evidence of effectiveness in the Medicare population.

Policy Considerations
As CMS evaluates its coverage for ColoSense and other non-invasive biomarker screening tests, it is essential that patients are educated about both the benefits and limitations of each screening option. Patients must understand that every positive or abnormal non-invasive screening test result requires a completion colonoscopy. Equally important, as it relates to ColoSense, patients should be aware that based on current validated data, nearly 25% of negative test results may be false negatives, meaning the test could even miss existing CRC, in addition to limited sensitivity for precancerous lesions. This risk underscores the need for clear communication about the limitations of some non-invasive screening technologies and the importance of continued vigilance in follow-up care, including completion colonoscopy.

If CMS chooses to move forward with Medicare coverage for ColoSense, ASGE anticipates that the recommended screening interval will align with existing guidance for other multitarget stool-based tests, such as Cologuard. We encourage CMS to apply consistent standards across similar technologies while continuing to monitor real-world performance data.

Conclusion
ASGE supports providing patients with multiple CRC screening options, including colonoscopy, FIT, and emerging technologies like ColoSense. However, it is essential to underscore the fact that colonoscopy remains the gold standard for CRC screening due to its unmatched sensitivity and ability to prevent cancer through polyp removal. CMS’ coverage decisions for new technologies must be grounded in robust evidence and reflect the needs of the Medicare population.

ASGE appreciates CMS’s commitment to evidence-based colorectal cancer prevention and welcomes continued dialogue to ensure that Medicare beneficiaries have access to safe, effective, and reliable screening options that support early detection and reduce mortality.

Should you need additional information, please contact Lakitia Mayo, Chief Policy and Member Engagement Officer, ASGE, at lmayo@asge.org or 630-570-5641.

Sincerely,

Amitabh Chak, MD, MASGE
ASGE President

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October 10. 2025
VIA Electronic Submission to cms.gov
Joanna Baldwin
Acting Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850
RE: Screening for Colorectal Cancer – Non-Invasive Biomarker Tests (CAG-00440R)

Dear Ms. Baldwin:

The Coalition for 21st Century Medicine (C21) appreciates the opportunity to provide comments in response to the initiation of the above-captioned national coverage analysis (NCA).

C21 comprises many of the world’s most innovative diagnostic technology companies, clinical laboratories, physicians, venture capital companies, and patient advocacy groups. C21’s mission is to improve the quality of health care by encouraging research, development, and commercialization of innovative diagnostic technologies that will personalize patient care, improve patient outcomes, and reduce health care costs. C21 has a keen interest in this specific NCA, as multiple C21 members furnish non-invasive colorectal cancer (CRC) screening tests. Individual members will be submitting their own comments under separate cover.

Consistent with C21’s historical position, C21 strongly supports the inclusion of language in the National Coverage Determination (NCD) that allows CMS to add CRC screening tests for coverage as soon as prespecified coverage criteria have been met. Streamlining the ability of the agency to add coverage for new services will eliminate staff burden for CMS to implement a full NCD re-opening process each time a new high-quality colorectal cancer screening test becomes available. This will also enhance transparency and predictability for patients, clinicians, test developers, and payers. Implementing this flexible approach will help ensure Medicare beneficiaries have timely access to life-saving, standard of care CRC screening services.

Additionally, C21 requests that CMS remove language imposing specific ordering clinician requirements. The existing requirement that a “treating physician” or “attending physician” order certain CRC screening test does not align with the purpose of non-invasive CRC screening tests, which are intended for asymptomatic individuals at average-risk for CRC. These individuals do not present with symptoms or an existing medical condition to treat. This “treating physician” requirement can limit access to screening modalities that have the potential to close CRC screening gaps, particularly among beneficiaries that are less likely to have a primary care doctor.

C21 thanks CMS for the opportunity to comment on evaluating non-invasive CRC screening tests for Medicare coverage, and looks forward to working with the agency to ensure access to new screening and diagnostic technologies.

Thank you for considering our comments. Please contact me should you have any questions or if we can provide you with further information.

Sincerely,

Dan Todd
Dan@toddstrategy.com
Executive Director, Coalition for 21st Century Medicine
Principal, Todd Strategy Group

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October 10, 2025

Centers for Medicare & Medicaid Services
Coverage and Analysis Group
Attention: NCA Tracking Sheet for Colorectal Cancer Screening Biomarker Tests (CAG-00440R)
7500 Security Boulevard
Baltimore, MD 21244
Re: National Coverage Analysis (CAG-00440R)
Request for Public Comment on Coverage of Colorectal Cancer Non-Invasive Biomarker Screening Tests

The National Center for Health Research (NCHR) appreciates the opportunity to provide comments in response to the Centers for Medicare & Medicaid Services (CMS) request for input on the coverage of colorectal cancer (CRC) non-invasive biomarker screening tests, including multi-target stool RNA (mt-sRNA) assays, and on the review of sensitivity and specificity cut points.
NCHR is a nonprofit think tank committed to bridging the gap between scientific evidence and public policy with the goal of improving the health and safety of patients and consumers. Our mission is to ensure that medical products and technologies are not sold in the U.S. unless they are proven safe and effective based on rigorous, independent evidence, with particular attention to how benefits and risks differ across diverse patient populations, including older adults who make up the majority of Medicare beneficiaries.

We recognize the need for more convenient CRC screening. However, FDA approval of the multi-target stool RNA (mt-sRNA) screening test ColoSense does not in itself establish clinical effectiveness in Medicare populations. The FDA’s Summary of Safety and Effectiveness Data (P230001) for ColoSense noted uncertainty regarding the test’s sensitivity, requiring a post-market study of 12,500 participants to confirm accuracy. We agree on the need for such a study, but it should be completed and analyzed prior to Medicare making a coverage decision. We describe the research evidence and shortcomings below.

Background and Context
ColoSense, the multi-target stool RNA (mt-sRNA) test, was assessed in the pivotal CRC-PREVENT trial (Barnell et al., 2023) of 8,289 participants, demonstrating analytical validity and 94% sensitivity for colorectal cancer (CRC). However, the FDA’s Summary of Safety and Effectiveness Data (SSED; PMA P230001) identified several limitations in the study design and performance interpretation. According to the SSED, “there is a chance that as many as 24.3% of patients with colorectal cancer may be missed by this test” based on the lower bound of the 95% confidence interval. The FDA therefore required Geneoscopy to conduct a post-approval study of 12,500 participants to confirm real-world sensitivity and specificity. The protocol for this post-market study was originally accepted on May 3, 2024, and the current protocol was accepted on September 9, 2024, but the study appears to have not begun according to fda.gov and there is no NCT registration number for the post-market study posted to ClinicalTrials.gov.

This lack of an active or publicly registered required post-approval study raises substantial concerns about transparency, regulatory compliance, and readiness for coverage in the Medicare population. A study of 12,500 patients followed for 2 years will take years to complete, and yet the company hasn’t even started the research yet. Without post-market validation data, CMS cannot reasonably determine whether ColoSense performs as well as existing CMS-covered tests such as Colorguard, the multi-target stool DNA test.

Furthermore, ColoSense’s existing data reported a specificity of 85.6%, which is substantially lower than that of Cologuard Plus (91%), suggesting it would result in an increased false-positive burden and downstream colonoscopy demand (Exact Sciences, 2025). These unresolved issues reinforce the need for the FDA’s required post-market study to be appropriately completed before any national coverage determination is made.

The Role of Stool-Based RNA Colorectal Cancer Screening Tests
Stool-based RNA colorectal cancer screening tests expand early-detection options beyond colonoscopy and traditional fecal tests. These assays analyze RNA biomarkers shed by cancer cells into stool, identifying colorectal cancers and precancerous lesions through simple at-home sample collection (Barnell et al., 2023; Barnell et al., 2025). Unlike other stool-based tests, the mt-sRNA test, ColoSense, eliminates the need for patients to swab or scrape their stool. Instead, the patient deposits a sample into a container and mails it to a lab for technician-handled analysis (Barnell 2025). This could potentially increase adherence among patients who are uncomfortable with other stool-based tests and unwilling or unable to undergo colonoscopy. However, the potential for increased adherence is valuable only if verified with real-world data.

Sensitivity and Specificity of Current Non-Invasive CRC Screening Tests
There are several FDA-approved stool-based CRC screening tests that are covered by Medicare. The goal of stool-based CRC screening tests is to be non-invasive and more convenient than colonoscopies, with the understanding that positive results will require additional testing with a colonoscopy. They therefore must balance high sensitivity to detect early cancers and advanced adenomas, as well as adequate specificity to prevent unnecessary colonoscopies and associated risks.

The fecal immunochemical test (FIT) is the most widely used stool-based screening tool. It detects hidden (occult) blood in stool by identifying human hemoglobin proteins using specific antibodies. FIT is simple, inexpensive, and can be done annually at home. However, while it is highly specific (~94%), its sensitivity for early cancers (~74%) and advanced adenomas (~23%) is lower than that of multi-target molecular stool tests, leading to more missed precancerous lesions (Imperiale et al., 2014; Lin et al., 2016; Knudsen et al., 2021; US Preventive Services Task Force (JAMA 2021).

The currently approved multi-target stool DNA (mt-sDNA) test, marketed as Cologuard, combines molecular DNA markers with a fecal immunochemical test (FIT) to detect occult blood and DNA mutations associated with colorectal cancer (CRC) and advanced adenomas. In the DeeP-C trial (Imperiale et al., 2014), Cologuard achieved 92.3% sensitivity for CRC, 42.4% for advanced adenomas, and 86.6–89.8% specificity, outperforming FIT alone (73.8% CRC sensitivity, 23.8% advanced adenoma sensitivity, 94% specificity) (Eckmann et al., 2020).

In contrast, ColoSense, a multi-target stool RNA (mt-sRNA) test, uses RNA rather than DNA biomarkers. However, the ColoSense test is not based solely on RNA biomarkers; it combines three components, which are a fecal immunochemical test (FIT) that detects hidden blood in stool, a panel of RNA transcripts shed by tumor or precancerous cells, and a patient factor (smoking status) to generate an overall test score. This means that the mt-sRNA assay, ColoSense, builds upon, rather than replaces, the traditional FIT methodology. However, the FDA’s performance audit identified several limitations in the CRC-PREVENT trial of ColoSense, so the agency required a post-market study to provide real-world accuracy and safety (FDA, 2023; P230001C).

It is important to note that when the RNA portion of the ColoSense test was analyzed separately, it performed only slightly better than random chance with an Area Under the Receiver Operating Characteristic (AUROC) value of 0.58–0.62 (An AUROC of 0.5 indicates no diagnostic value, while 1.0 indicates perfect accuracy.). This indicates that most of the test’s diagnostic power likely comes from the FIT component rather than the RNA markers themselves. This raises clear questions about the added clinical value of the RNA component and reinforces the importance of continued evidence development before granting full Medicare coverage (Barnell et al., JAMA 2023; Supplement 3, eFigure 3).

Taken together, these data indicate that while ColoSense is promising, it has not demonstrated that it as effective or superior to the existing CMS-covered mt-sDNA (Cologuard) or FIT tests.

Patient-Centered Considerations
Expanding coverage for non-invasive colorectal cancer screening options has been found to improve participation among older adults and those with comorbidities who face challenges with colonoscopy preparation, sedation, or access to endoscopy facilities (Cooper et al., 2013; Lin, 2014; Kwok et al., 2023). These at-home stool tests, including the fecal immunochemical test (FIT), multi-target stool DNA (mt-sDNA; Cologuard), and multi-target stool RNA (mt-sRNA; ColoSense) can reduce logistical and procedural barriers to screening. For rural, minority, and socioeconomically disadvantaged populations, mail-based stool tests may help overcome transportation and access barriers (Sepassi et al., 2024; CDC, 2025; Redwood et al., 2023). However, these tests complement, rather than replace colonoscopy, which remains the diagnostic gold standard for detecting and removing precancerous lesions.

Risks, Limitations, Concerns, and Data Gaps

1. Disproportionate inclusion of smokers may bias the results.
   The ColoSense CRC-PREVENT trial incorporated smoking status as a variable in its composite scoring algorithm, alongside the fecal immunochemical test (FIT) and RNA biomarkers. The FDA’s Summary of Safety and Effectiveness Data (PMA P230001, 2024) reported that 34.3% of participants were classified as current or former smokers, a prevalence nearly three times higher than the U.S. adult current smoking rate average of approximately 12% (CDC, 2024). Because smoking is a known risk factor for colorectal neoplasia, this overrepresentation may have artificially inflated test sensitivity in a high-risk cohort. Moreover, the company does not explain why their study sample included so many smokers, and whether the study participants may not be representative of the general population or of the Medicare population in other ways as well. In addition, since smoking behavior was self-reported and some participants declined to disclose their status, the accuracy of this variable is uncertain and the proportion of smokers may have been even higher.
2. False positives increase the downstream burden of colonoscopy.
   While stool-based screening tests aim to reduce unnecessary colonoscopies, their value depends on whether they perform at least as well as existing noninvasive options. ColoSense (mt-sRNA) demonstrated a specificity of 85.6% in the CRC-PREVENT trial, lower than the FDA-approved and CMS-covered Cologuard (mt-sDNA) test, which achieved about 91% specificity and 92% sensitivity for colorectal cancer in the DeeP-C study (Imperiale et al., 2014). Since ColoSense (mt-sRNA) data do not indicate that this RNA-based approach is at least as accurate or that it meaningfully improves real-world adherence, it may not be as beneficial as the ColoGuard test. Moreover, higher false positives increase downstream colonoscopy burden, so any new stool test with more false positives must demonstrate substantial added value to justify coverage.
3. Trial performance may not reflect real-world Medicare outcomes.
   Adherence and follow-up rates observed in clinical trials are likely to be substantially higher than those seen in community or Medicare populations. Consequently, real world evidence of ColoSense compared to Cologuard would provide important information that is currently lacking. Continuous monitoring providing real world evidence of adherence, false-positive rates, and follow-up colonoscopy completion is essential to validate test performance.

For all the reasons specified in #1-3, the composite model’s performance may not reflect the accuracy of the test for a representative sample of patients of any age or health status, and certainly not those in the Medicare population. CMS should therefore interpret ColoSense’s published accuracy metrics with caution and require independent validation of the model without the smoking variable before considering coverage.

1. FDA-Mandated post-approval study is pending; CMS should wait.
   The FDA mandated a post-approval study to confirm the safety and effectiveness of ColoSense, enrolling 12,500 participants to assess performance across diverse populations (FDA PMA P230001C, 2024). Although the protocol was accepted on September 9, 2024, the FDA database currently lists the study as “Study pending” with no posted study information and no NCT number assigned on clinicaltrials.gov. The reporting schedule on the FDA website notes that progress reports have been submitted on time, but no links or public summaries of these reports are available. At present, the only registered clinical trial related to ColoSense is the pivotal CRC-PREVENT study (NCT04739722).

This FDA requirement of a post-approval study for ColoSense and the lack of evidence that the company has started recruited patients adds to the concerns about ColoSense’s trial findings and limits CMS’s ability to assess its performance in Medicare-age populations to make an evidence-based coverage determination. Given ColoSense’s commercial availability, the timely initiation and completion of the required post-approval study may not be a high priority. A NCD could inadvertently reduce the incentive to generate the evidence necessary for regulatory and clinical validation. We strongly encourage CMS to refrain from granting coverage until the required post-market data are available and reviewed by the FDA and/or CMS.

Recommendations

Based on results and concerns about the current research and the lack of any useful information about the required post-market study, CMS should not grant coverage for ColoSense, the only multi-target stool RNA (mt-sRNA) test on the market, at this time. As noted above, the FDA mandated a post-approval study enrolling 12,500 participants to confirm the accuracy, safety, and effectiveness of ColoSense (FDA PMA P230001C, 2024). Although the protocol was accepted on September 9, 2024, the FDA database currently lists the study as “pending,” with no NCT registration number and no publicly available results or progress reports. Without completion and publication of this required post-market study, there is insufficient evidence to determine whether ColoSense is as beneficial to Medicare patients as currently covered non-invasive screening options. CMS should therefore withhold national coverage until the FDA-mandated study has been completed on a representative sample and its findings peer-reviewed. This cautious approach ensures scientific integrity, regulatory consistency, and prudence before providing a national Medicare NCD “seal of approval” to a test whose effectiveness and specificity remain unproven outside a potentially biased pivotal trial due to its very large proportion of smokers.

Given that CMS already provides coverage for several convenient non-invasive stool-based tests, CMA should determine if future coverage for these or other stool-based CRC screening tests meet clear, evidence-based performance thresholds validated in Medicare-relevant populations.
These thresholds should include:

• CRC sensitivity: ≥ 90% preferred, ≥ 70% minimum (Imperiale et al., 2014; 2024; Barnell et al., 2023).
• Advanced adenoma sensitivity: ≥ 40% minimum, ≥ 50–55% preferred.
• Specificity: ≥ 85% minimum; ≥ 90% preferred.

However, analytical accuracy alone should not justify coverage. CMS should require demonstration of adherence, follow-up completion, and cancer detection stage shifts prior to any future coverage determination.

Prior to making a coverage determination, CMS should require Geneoscopy and other mt-sRNA screening test companies to make all FDA post-approval study protocols, enrollment progress, and data publicly available. Public dashboards or FDA-linked updates should include adherence rates, positivity rates, specificity, and follow-up colonoscopy completion, stratified by demographics. Such transparency will prevent premature coverage of unproven technologies and support equitable, evidence-based policy.

Conclusions

While multi-target stool RNA (mt sRNA) testing represents a potentially useful approach to colorectal cancer screening, the current evidence is insufficient to support Medicare coverage at this time. The CRC PREVENT trial demonstrates analytical validity but lacks direct comparison with existing stool-based tests such as FIT or mt-sDNA, shows only marginal incremental value of RNA biomarkers beyond FIT, and includes population and methodological biases. Moreover, the FDA’s Summary of Safety and Effectiveness Data (P230001) acknowledges that the test (ColoSense) can miss up to 24 percent of colorectal cancers and mandated a post-approval study of 12,500 participants to confirm real world accuracy and safety. As of October 2025, this study has not been initiated, assigned a ClinicalTrials.gov (NCT) number, or publicly reported.

For Medicare coverage, new tests are reasonable and necessary if they either demonstrate significantly higher sensitivity, specificity, or adherence, or show that they are equally effective and more accessible than existing options. The current data for ColoSense show that the test may be less accurate, especially in a representative Medicare population, and there is no evidence that it meaningfully improves screening uptake.

Given these substantial evidence gaps, CMS should defer national coverage until the FDA mandated post-approval study is completed, independently verified, and vetted by FDA or CMS. Only when it is demonstrated to be at least as beneficial as the mt-sDNA test should CMS reconsider coverage. Taking this cautious, evidence driven approach will uphold CMS’s mission to ensure that coverage determinations are scientifically justified and protective of patient safety and public resources.

Respectfully submitted,
National Center for Health Research

Citations:

1. Barnell EK, Kruse K, Wurtzler EM, Scott MC, Barnell AR, Duncavage EJ. Analytical validation of a scrape-free multitarget stool RNA test for colorectal cancer screening. Pract Lab Med. 2025 Sep 3;47:e00502. doi: 10.1016/j.plabm.2025.e00502. PMID: 40994831; PMCID: PMC12454295.
2. PMA P230001: FDA Summary of Safety and Effectiveness Data. Accessed October 2025: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf
3. FDA, 2023; P230001C Summary of Safety and Effectiveness Data. Accessed October 2025 : https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001C.pdf
4. Post-Approval Studies (PAS) Database. Accessed October 2025: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma_pas.cfm?t_id=783383&c_id=7964 5. Exact Sciences. (2025). Cologuard HCP FAQ. Accessed October 2025. https://www.cologuardhcp.com/resources/faq
6. Santos DAR, Eiras M, Gonzalez-Santos M, Santos M, Pereira C, Santos LL, Dinis-Ribeiro M, Lima L. A preliminary assessment of a stool-based microRNA profile for early colorectal cancer screening. Sci Rep. 2025 Aug 5;15(1):28597. doi: 10.1038/s41598-025-14485-z. PMID: 40764826; PMCID: PMC12325799.
7. Liu H, Hansen L, Song C, Lin H, Chen D, Chen Z, Zhou H, Yang X, Pan W, Du J. Bioinformatic screen with clinical validation for the identification of novel stool based mRNA biomarkers for the detection of colorectal lesions including advanced adenoma. Sci Rep. 2025 Aug 11;15(1):29397. doi: 10.1038/s41598-025-13074-4. PMID: 40789879; PMCID: PMC12339692.
8. Barnell EK, Wurtzler EM, La Rocca J, et al. Multitarget Stool RNA Test for Colorectal Cancer Screening. JAMA. 2023;330(18):1760–1768. doi:10.1001/jama.2023.22231
9. Lin JS, Perdue LA, Henrikson NB, Bean SI, Blasi PR. Screening for Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2021;325(19):1978–1998. doi:10.1001/jama.2021.4417
10. Le, Q. A., Greene, M., Gohil, S., Ozbay, A. B., Dore, M., Fendrick, A. M., & Limburg, P. (2025). Adherence to multi-target stool DNA testing for colorectal cancer screening in the United States. International journal of colorectal disease, 40(1), 16. https://doi.org/10.1007/s00384-025-04805-0
11. Cooper GS, Kou TD, Rex DK. Complications Following Colonoscopy With Anesthesia Assistance: A Population-Based Analysis. JAMA Intern Med. 2013;173(7):551–556. doi:10.1001/jamainternmed.2013.2908
12. Lin O. S. (2014). Performing colonoscopy in elderly and very elderly patients: Risks, costs and benefits. World journal of gastrointestinal endoscopy, 6(6), 220–226. https://doi.org/10.4253/wjge.v6.i6.220
13. Kwok, K., Levin, T. R., Dominitz, J. A., Panganamamula, K., Feld, A. D., Bardall, B., ... & Day, L. W. (2023). Transportation barriers and endoscopic procedures: barriers, legal challenges, and strategies for GI endoscopy units. Gastrointestinal Endoscopy, 98(4), 475-481.
14. Eckmann, J. D., Ebner, D. W., & Kisiel, J. B. (2020). Multi-target stool DNA testing for colorectal cancer screening: emerging learning on real-world performance. Current treatment options in gastroenterology, 18(1), 109-119.
15. Imperiale, T. F., Ransohoff, D. F., Itzkowitz, S. H., Levin, T. R., Lavin, P., Lidgard, G. P., ... & Berger, B. M. (2014). Multitarget stool DNA testing for colorectal-cancer screening. New England Journal of Medicine, 370(14), 1287-1297.
16. Imperiale, T. F., Porter, K., Zella, J., Gagrat, Z. D., Olson, M. C., Statz, S., ... & Limburg, P. J. (2024). Next-generation multitarget stool DNA test for colorectal cancer screening. New England Journal of Medicine, 390(11), 984-993.
17. https://www.cms.gov/medicare/coverage/evidence
18. Sepassi, A., Li, M., Zell, J. A., Chan, A., Saunders, I. M., & Mukamel, D. B. (2024). Rural-Urban Disparities in Colorectal Cancer Screening, Diagnosis, Treatment, and Survivorship Care: A Systematic Review and Meta-Analysis. The oncologist, 29(4), e431–e446. https://doi.org/10.1093/oncolo/oyad347
19. https://www.cdc.gov/pcd/issues/2025/25_0025.htm
20. Redwood D, Toffolon M, Flanagan C, Kisiel J, Kaur JS, Jeffries L, Zenku M, Lent J, Bachtold J. Provider- and System-Level Barriers and Facilitators to Colonoscopy and Multi-Target Stool DNA for Colorectal Cancer Screening in Rural/Remote Alaska Native Communities. International Journal of Environmental Research and Public Health. 2023; 20(22):7030. https://doi.org/10.3390/ijerph20227030
21. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=281

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As a practicing Gastroenterologist, I see first hand the significant value in enhancing uptake of screening for colon cancer. The online social media recruitment platform used in the CRC-PREVENT study of mt-sRNA suggests a model that could improve outcomes for populations that would not otherwise seek care.

Ideally, though, the innovative approach would be paired with a validated technology such as next generation mt-sDNA, which has a better specificity (86.9 for mt-sRNA vs 92.7 for the next gen mt-sDNA).

Particularly if more patients are considering colonoscopy on the basis of a stool based assay, it makes sense to use an apparently superior and stand alone test to maximize yield given the limitations on access for colonoscopy.

Before approving coverage for a test which was studied in a cohort with very high percentage of tobacco users and included a subset of non average risk participants per protocol, it would seem most reasonable to require a head to head comparison.

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1301 Pennsylvania Avenue, NW
Suite 400
Washington, D.C. 20004

October 10, 2025

JoAnna Baldwin
Acting Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Analysis (NCA) for Colorectal Cancer Screening (CAG-00454N)

Dear Ms. Baldwin,

On behalf of the MedTech Association (AdvaMed), we appreciate the opportunity to submit comments on the National Coverage Analysis (NCA) for colorectal cancer (CRC) screening (CAG-00454N). AdvaMed and CMS share a common goal – ensuring timely access for Medicare beneficiaries to preventive services, based on scientifically sound clinical evidence with appropriate safeguards.

AdvaMed member companies develop and produce a wide range of medical devices, diagnostic tests, and digital health solutions that transform care through earlier detection, less invasive approaches, and more effective disease management. Our members, large and small, are united in their commitment to improving patient outcomes and ensuring that Medicare beneficiaries have access to lifesaving and life-enhancing technologies.

CRC is the second leading cause of cancer death in the U.S., and screening remains underutilized, particularly among underserved and rural populations. Section 1861(pp) of the Social Security Act defines colorectal cancer screening tests and gives CMS authority to include “other tests or procedures” the Secretary deems appropriate. This provision was designed to let coverage policy evolve with science and innovation. Ensuring up-to-date CRC national coverage policies supports the national goal of increasing CRC screening to at least 80% in every community. Broad coverage of high-quality screening options fosters patient choice, supports adherence, and strengthens equity in preventive care. In that vein, we support a thorough NCA process and CMS’ commitment to upholding evidence standards, including relevance to the Medicare population, to ensure timely access to innovative tests that are as good, ideally better than, what is available today [1]. We also applaud CMS for striving to provide more clarity around what standards and cut points are necessary for testing to meet coverage criteria.

Since its creation almost 20 years ago, this NCD has been updated numerous times to incorporate new testing modalities. As CMS works to update this NCD again, we ask CMS to ensure that there are no unintentional variations across colorectal cancer (CRC) screening modalities with comparable performance profiles, which may create unnecessary administrative complexity consistency across screening approaches. An operative NCD framework that promotes equitable coverage of screening tests meeting established standards would work towards advancing the shared goal of increasing CRC screening among Medicare beneficiaries, and minimize the likelihood CMS would need to update the NCD again in the future.

NCD Reconsideration Requests

While AdvaMed appreciates the NCD dashboard that CMS issues periodically, we have concerns about the length of time that some requests have waited to be addressed [2]. Some NCDs have been on the waitlist for years, such as Infusion Pumps - Continuous subcutaneous insulin infusion (CSII). We encourage CMS to review and modernize its process for managing the NCD reconsideration request waitlist to support more timely and efficient policy updates. In many instances, requested changes may not require a full national coverage analysis but could be addressed through targeted revisions informed by new evidence or updated clinical standards.

A recent Government Accountability Office (GAO) report found challenges related to varied frequencies of CMS’s communication to stakeholders about the status of their NCD request and a lack of transparency about the criteria the agency uses to prioritize such requests [3]. Establishing clearer prioritization criteria for NCD requests would enhance transparency and help stakeholders understand how CMS allocates resources across competing policy needs. Additionally, improving the timeliness of updates would help to reduce administrative burden on both CMS and stakeholders while ensuring that Medicare beneficiaries gain timely access to clinically appropriate and innovative technologies. We welcome the opportunity to work collaboratively with CMS on identifying and implementing these process enhancements to strengthen the NCD framework and support timely, evidence-based coverage decisions.

The request that initiated this NCA was sent to CMS in May 2024 and while the statute defining CRC screening was designed to let coverage policy evolve with science and innovation, that intent only works if Medicare acts promptly to review new evidence as innovative screening technologies emerge. AdvaMed encourages CMS to work quickly in issuing a Proposed Decision Memo, following the close of this comment period, and subsequently a final decision memo.

We look forward to continuing to work with CMS. If you have any questions regarding these comments or require additional information, please contact me at tburke@advamed.org.

Sincerely,
Tara L. Burke, PhD
VP, Payment & Healthcare Delivery Policy
AdvaMed

References

1. CMS National Coverage Analysis Evidence Review, Guidance Document (Aug. 7, 2024), available at: https://www.cms.gov/files/document/cms-evidence-review2024pdf.pdf.
2. National Coverage Determination Dashboard. Centers for Medicare & Medicaid. September 2025 https://www.cms.gov/files/document/ncddashboard2025.pdf (Accessed October 9, 2025)
3. “Medicare: National Coverage Determinations Are Generally Timely, but Improvements Are Needed.” Medicare: | U.S. GAO, September 9, 2025. https://www.gao.gov/products/gao-25-107623.

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The National Comprehensive Cancer Network® (NCCN®) appreciates the opportunity to comment on the Screening for Colorectal Cancer-Non-Invasive Biomarker Tests National Coverage Analysis (NCA) as it relates to NCCN’s mission of defining and advancing quality, effective, equitable, and accessible cancer care and prevention so all people can live better lives. NCCN will focus our comments on ways NCCN content can be used as a resource to inform coverage analyses, keep coverage determinations evergreen as the science evolves, and ensure Medicare beneficiaries have access to the highest standard of care possible.

NCCN Background
As an alliance of 33 leading academic cancer centers in the United States (US) that treat hundreds of thousands of patients with cancer annually, NCCN® is a developer of authoritative information regarding cancer prevention, screening, diagnosis, treatment, survivorship care, palliative care, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97 percent of cancers affecting patients in the US.

NCCN Guidelines® and Library of Compendia products help ensure access to appropriate care, clinical decision-making, and assessment of quality improvement initiatives. The NCCN Drugs & Biologics Compendium has been recognized by CMS and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications.

NCCN Guidelines® and Biomarker Compendium®
NCCN develops authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Guidelines are a comprehensive set of 88 guidelines detailing the sequential management decisions and interventions across 228 algorithms that currently apply to 97 percent of cancers affecting patients in the United States. More than 1,950 panel members participate in guideline development. In 2024, there were 16 million downloads of NCCN Guidelines across web-based and mobile applications. The guidelines are developed by multidisciplinary expert panels from NCCN Member Institutions in an evidence-based process integrated with expert consensus. The NCCN Guidelines are updated at least annually, but quite often are updated more frequently, with 241 total version updates across all guidelines in 2024.

The NCCN Guidelines are considered the standard for clinical care and policy in oncology in the United States. The NCCN Guidelines are the most thorough and most frequently updated clinical practice guidelines in any area of medicine, are the most frequently referenced clinical practice guideline in oncology, and are widely available free of charge for non-commercial use. Our guidelines are also available through a multitude of health information technology vendors, used by payers representing more than 85% of covered lives in the United States, and form the basis for insurance coverage policy and quality evaluation.

To further support evidence-based decision making, NCCN also offers companion resources such as the NCCN Biomarkers Compendium®. NCCN Biomarkers Compendium® serves as a resource for payers, providers, and health care entities navigating the rapidly changing evidence-base for medically necessary biomarker testing in oncology. It contains information derived directly from the NCCN Guidelines to support clinical decision-making around the use of biomarker testing in patients with cancer. The Biomarker Compendium is updated continuously in conjunction with the NCCN Guidelines to stay evergreen. Included in the Biomarkers Compendium are testing methodologies to measure changes in genes or gene products and used for the purposes of diagnosis, screening, monitoring, surveillance, treatment planning, prediction, and prognostication. The NCCN Biomarker Compendium focuses largely on the biology or abnormality being measured rather than on commercially available tests or test kits.

Importantly, NCCN imposes strict policies to shield the guidelines development processes from external influences. The “firewall” surrounding the NCCN Guidelines processes includes: financial support policies; panel participation and communication policies; guidelines disclosure policies; and policies regarding relationships to NCCN’s other business development activities. The guidelines development is supported exclusively by the Member Institutions’ dues and does not accept any form of industry or other external financial support for the guidelines development program.

Guideline Adherence as a Tool to Improve Outcomes, Reduce Costs, and Keep Coverage Evergreen
Numerous independent studies have found adherence to NCCN Guidelines improve care delivery and outcomes for patients with cancer. Improved health outcomes proven through concordance with NCCN Guidelines include improved rates of survival for colon cancer, ovarian cancer, gastric cancer, nasopharyngeal cancer, and pancreatic cancer; decreased locoregional recurrence of melanoma; and improved pain control. (1,2,3,4,5,6)

Guideline adherent care has also been shown to decrease costs to both the payer and the patient. A peer-reviewed, published study by United, eviCore, and NCCN entitled “Transforming Prior Authorization to Decision Support” demonstrated mandatory adherence to NCCN Guidelines and NCCN Compendium® using a real-time Clinical Decision Support Mechanism by United Healthcare significantly reduced total and episodic costs of care by 20% compared to trend while also reducing denials and increasing access to guideline-concordant care. (7) A 2019 study "Guideline Discordance and Patient Cost Responsibility in Medicare Beneficiaries With Metastatic Breast Cancer" by Williams, et.al found median cost for metastatic breast cancer patients receiving guideline-discordant treatment was $7,421 versus $5,171 for those receiving guideline-concordant care. (8) This study found an additional $1,841 in out-of-pocket cost savings for patients receiving guideline concordant care versus patients who received care that did not adhere to guidelines. These cost savings have also been found in studies evaluating the Medicare population. At the 2022 ASCO Annual Meeting, CVS Health also presented two abstracts looking at total costs of care beginning with the first treatment and for the subsequent 180 days for breast and colon cancer patients in relation to adherence to NCCN Guidelines. (9,10) In both studies, there was a significant reduction in total cost of care with concordance with NCCN Guidelines. In the colon cancer study, this was most prominent and significant in the Medicare population. In the breast cancer study, significant reductions were observed across both commercially insured and Medicare patients, with the greatest reductions again seen in the Medicare population. Recognizing the value of guidelines that are continuously updated and proven to reduce costs while improving outcomes, NCCN recommends that CMS consider utilizing nationally recognized guidelines to inform the Screening for Colorectal Cancer (CRC)-Non-Invasive Biomarker Tests NCA in order to ensure coverage decisions remain current and offer beneficiaries optimal, evidence-based care.

Usage of NCCN CRC Guidelines to Inform the NCA
NCCN commends CMS for initiating this NCA to better understand the role of multi-target stool RNA (mt-sRNA) CRC screening tests and to inform coverage decisions. NCCN appreciates the opportunity to provide further insight into the current NCCN Guidelines recommendations in relation to CRC screening tests.

In the United States, CRC is the third most commonly diagnosed cancer and the second most common cause of cancer death. (11) Approximately 154,270 new cases of CRC, AND 52,900 related deaths are estimated for 2025. (12) Screening individuals for CRC can play a critical role in reducing CRC mortality by detecting cancer at earlier, more treatable stages, and decreasing incidence by detecting and removing precancerous polyps.

The NCCN Guidelines for CRC Screening outlines multiple evidence-based colorectal screening modalities and recommends screening schedules for patients at average or increased risk of developing CRC. (13) Within these guidelines, the CRC Screening Panel recommends the inclusion of mt-sRNA-based testing as one of the stool-based screening options for individuals at average risk. Other stool-based screening options recommended for individuals of average risk include fecal immunochemical test (FIT), guaiac-based testing, and multi-target stool DNA (mt-sDNA) based testing. For individuals of average risk, the choice of a particular screening modality should follow an informed discussion between the patient and their healthcare provider to determine the most appropriate option based on patient preference and availability. NCCN values access to effective evidence-based testing modalities that contribute to increased adherence to screening recommendations, thus improving prevention and early detection efforts. As such, NCCN supports the coverage of mt-sRNA-based testing as one of the available screening modalities for CRC in alignment with nationally recognized evidence-based guidelines.

NCCN again appreciates the opportunity to comment on the Screening for Colorectal Cancer-Non-Invasive Biomarker Tests NCA. NCCN is happy to serve as a resource and looks forward to working together to ensure Medicare beneficiary access to optimal cancer care.

Sincerely,

Crystal S. Denlinger, MD, FACP
Chief Executive Officer
National Comprehensive Cancer Network

Sources
1. Erickson Foster J, Velasco JM, Hieken TJ. Adverse outcomes associated with noncompliance with melanoma treatment guidelines. Annals of Surgical Oncology. 2008;15(9):2395-2402. doi:10.1245/s10434-008-0021-0
2. Visser BC, Ma Y, Zak Y, Poultsides GA, Norton JA, Rhoads KF. Failure to comply with NCCN guidelines for the management of pancreatic cancer compromises outcomes. HPB. 2012;14(8):539-547. doi:10.1111/j.1477-2574.2012.00496.x
3. Bristow RE, Powell MA, Al-Hammadi N, et al. Disparities in ovarian cancer care quality and survival according to race and socioeconomic status. JNCI Journal of the National Cancer Institute. 2013;105(11):823-832. doi:10.1093/jnci/djt065
4. Bristow RE, Chang J, Ziogas A, Randall LM, Anton-Culver H. High-volume ovarian cancer care: Survival impact and disparities in access for advanced-stage disease. Gynecologic Oncology. 2014;132(2):403-410. doi:10.1016/j.ygyno.2013.12.017
5. Mearis M, Shega JW, Knoebel RW. Does adherence to National Comprehensive Cancer Network guidelines improve pain-related outcomes? An Evaluation of Inpatient Cancer Pain Management at an Academic Medical Center. Journal of Pain and Symptom Management. 2014;48(3):451-458. doi:10.1016/j.jpainsymman.2013.09.016
6. Schwam ZG, Sosa JA, Roman S, Judson BL. Receipt of care discordant with practice guidelines is associated with compromised overall survival in nasopharyngeal carcinoma. Clinical oncology (Royal College of Radiologists (Great Britain)). https://www.ncbi.nlm.nih.gov/pubmed/26868285. Published June 2016.
7. Newcomer LN, Weininger R, Carlson RW. Transforming prior authorization to decision support. Journal of Oncology Practice. 2017;13(1). doi:10.1200/jop.2016.015198
8. Williams CP, Azuero A, Kenzik KM, et al. Guideline discordance and patient cost responsibility in medicare beneficiaries with metastatic breast cancer. Journal of the National Comprehensive Cancer Network. 2019;17(10):1221-1228. doi:10.6004/jnccn.2019.7316
9. Sapkota U, Cavers W, Reddy S, Avalos-Reyes E, Johnson KA. Total cost of care differences in National Comprehensive Cancer Center (NCCN) concordant and non-concordant breast cancer patients. JCO. 2022;40(16_suppl):e18833-e18833. doi:10.1200/JCO.2022.40.16_suppl.e18833
10. Sapkota U, Cavers W, Reddy S, Avalos-Reyes E, Johnson KA. Total cost of care differences in National Comprehensive Cancer Center (NCCN) concordant and non-concordant patients with colon cancer. JCO. 2022;40(16_suppl):3624-3624. doi:10.1200/JCO.2022.40.16_suppl.3624
11. Colorectal cancer statistics: How common is colorectal cancer?. American Cancer Society. (2025, April). https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html
12. Cancer Stat Facts: Colorectal Cancer. National Cancer Institute SEER. (n.d.). https://seer.cancer.gov/statfacts/html/colorect.html
13. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Colorectal Cancer Screening. National Comprehensive Cancer Network. (2025f, June 24). https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf

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Joanna Baldwin
Acting Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop # S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: National Coverage Analysis (NCA) Tracking Sheet for Screening for Colorectal Cancer – Non-Invasive Biomarkers Tests (CAG-00440R)

Dear Ms. Baldwin:

On behalf of Guardant Health, I would like to submit our comments related to the National Tracking Sheet for Colorectal Cancer (CRC) screening – Non-Invasive Biomarkers Tests. Guardant Health is a leading precision oncology company dedicated to helping patients at all stages of cancer live longer and healthier lives through the power of blood tests and the data they unlock— from informing better treatment in patients with advanced cancer, to new ways of monitoring recurrence in cancer survivors, and screening to find cancer at its earliest and most treatable stage in the general population. Guardant360® CDx was the first FDA-approved liquid biopsy for comprehensive genomic profiling (CGP) in advanced cancer patients across all solid cancers. Following our initial tests in advanced cancer, we have released and gained Medicare coverage for two different MRD Minimum Residual Disease (MRD) tests. Finally, in 2024, Shield™ became the first blood-based test approved by the FDA as a primary screening option for CRC.

Guardant would like to express our support for CMS creating a national coverage policy that comprehensively covers Non-Invasive Biomarker Tests when they meet the appropriate criteria. CMS underwent extensive evidence review in 2020 related to the appropriate sensitivity and specificity cut points for blood-based testing. The outcome of that review was determined that the sensitivity cut point should be that of FIT which was 74% and the specificity of Cologuard which was 89.8%, rounded to 90% in the coverage language. This analysis was finalized in the decision memo for CAG-00454N.

Since this decision, several companies, including Guardant Health, have optimized their blood-based test performance to meet the specificity requirement listed in the NCD. The FDA has also recognized this specificity as relevant for colorectal blood-based testing by approving Shield as a primary screening option for CRC. Shield’s performance was targeted to get the maximum sensitivity while preserving the 90% specificity requirement. The Shield sensitivity performance, as demonstrated in the ECLIPSE study published in the New England Journal of Medicine(1) and approved by the FDA, is 83% at the 90% specificity cut point. Freenome additionally published evidence demonstrating that they would meet the historic criteria with performance of 79% sensitivity and 91.5% specificity in JAMA(2).

Now that there are two blood-based tests with performance data it is reasonable to use the minimum of their sensitivity performance as the sensitivity cutpoint for services that have >=90% specificity.

In response to CMS’s request for input on alternative, reasonable performance cut points under NCD 210.3, we propose a pathway that allows slightly lower colorectal cancer (CRC) specificity when a test demonstrates high sensitivity. In CAG-00454N, CMS relied on the original Cologuard performance reported in Imperiale 2014 to establish a reasonable benchmark. A similar approach could be extended to other non-invasive technologies.

Specifically, CMS could establish coverage for services that either (a) achieve sensitivity at or above Cologuard’s 92.3% while maintaining reasonable specificity, or (b) meet a balanced threshold consistent with sensitivity performance from the blood-based screening tests. Operationalized, this yields two coverage cut points for non-invasive CRC screening tests:

Coverage cut point (non-invasive tests):	Sensitivity	Specificity
Cut Point #1	>=92%#	>=87%*
Cut Point #2	>=79%^	>=90%$

#Rounded sensitivity from the Deep-C clinical study
* Rounded specificity from the performance in CRC-PREVENT clinical study(3) based on No findings on Colonoscopy.
^Rounded sensitivity from the PREEMPT CRC clinical study
$ Rounded specificity from the Deep-C clinical study based on No findings on Colonoscopy.

We are pleased that CMS chose to redetermine the NCD since we believe that there should be consistency in the ordering requirements for non-invasive tests, which is currently not the case. Fecal Occult Blood Tests (FOBT) require that the test is ordered by an attending physician, Cologuard has no ordering physician requirement, and blood-based tests must be ordered by a treating physician. The differing ordering requirements between these tests do not appear to be based on any clinical requirements for differential decision making as all these tests are noninvasive and have similar intended purposes and safety profiles.

CMS Transmittal 94 states that the treating physician is a physician “who furnishes a consultation or treats a beneficiary for a specific medical problem, and who uses the results of a diagnostic test in the management of the beneficiary’s specific medical problem.” This definition does not align with the purpose of non-invasive CRC screening tests, which are intended for asymptomatic individuals at average-risk for CRC. These individuals do not present with symptoms or an existing medical condition to treat. Linking the above definition of and requirement for a treating physician to Blood-based Biomarker Tests in NCD 210.3 can lead to a narrower interpretation of the types of providers who can order blood-based CRC screening compared to the other covered screening modalities in NCD 210.3. Such inconsistency among providers eligible to order covered CRC screening tests can lead to confusion and limit access to screening modalities that have the potential to close CRC screening gaps. Blood-based biomarkers tests for CRC screening serve the same purpose as the other noninvasive screening modalities and should be equally available to order.

A publication from 2023 reviewing primary care visits between 2013 and 2019 demonstrated that 25% of all primary care visits were performed by a nurse practitioner or a physician assistant(4). Enabling all provider types that are allowed by the Social Security Act to order preventive services for Medicare Beneficiaries to order all Medicare-covered non-invasive CRC screening tests will help address the chronic under screened population, particularly among beneficiaries that are less likely to have a primary care doctor.

Today, 1 in 3 people in the U.S. eligible for screening are not being screened for CRC, and there are significant geographical differences in CRC screening rates, incidence, and outcomes, with higher incidence and mortality in parts of the South, Midwest, and Appalachia(5). Blood-based testing can overcome many of the access barriers associated with current methods by incorporating CRC screening into routine medical care. Furthermore, evidence suggests that offering Shield alongside other screening modalities increases screening adherence overall. A randomized study from Kaiser Permanente demonstrated that when Shield was offered as an additional choice to stool testing and colonoscopy, 2.4 times as many individuals were screened(6). In a separate study in two Appalachian primary care clinics, integration of Shield alongside other modalities increased the overall screening completion rate from 45% to 90%, where 69% of those individuals who completed screening had never been screened(7).

As a result, we request that the treating physician ordering requirement is not explicitly written into the coverage criteria of the NCD for all non-invasive screening tests, similar to the current Cologuard requirements. This will ensure that any provider type that can order preventive services for Medicare beneficiaries per statute and regulation can equally offer all non-invasive CRC screening tests and help close screening gaps.

Sincerely,
AmirAli Talasaz PhD,
Co-CEO
Guardant Health

(1) https://www.nejm.org/doi/full/10.1056/NEJMoa2304714
(2) Shaukat A, Burke CA, Chan AT, et al. Clinical Validation of a Circulating Tumor DNA–Based Blood Test to Screen for Colorectal Cancer. JAMA. 2025;334(1):56–63. doi:10.1001/jama.2025.7515
(3) Barnell EK, Wurtzler EM, La Rocca J, Fitzgerald T, Petrone J, Hao Y, Kang Y, Holmes FL, Lieberman DA. Multitarget Stool RNA Test for Colorectal Cancer Screening. JAMA. 2023 Nov 14;330(18):1760-1768. doi: 10.1001/jama.2023.22231. Erratum in: JAMA. 2024 Mar 12;331(10):888. doi: 10.1001/jama.2024.1637. PMID: 37870871; PMCID: PMC10594178.
(4) https://pmc.ncbi.nlm.nih.gov/articles/PMC10498453/
(5) ibid.
(6) Coronado GD, Jenkins CL, Shuster E, et al. Blood-based colorectal cancer screening in an integrated health system: a randomized trial of patient adherence. Gut.2024;73(4):622-628. doi:10.1136/gut jnl-2023-330980.
(7) Haynes, et al. 2024. Blood-based Colorectal Cancer Screening: Implementation into Two Appalachian Primary Care Clinics. Am J of Preventive Medicine.

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(Additional comments)
EASIER PATIENT ACCESS to testing and
REMOVAL OF BARRIERS TO PATIENTS
are ESSENTIAL POINTS for understanding this need.

Item 1. The sensitivity/specificity cut-off points for blood-based testing that were established by CMS in 2020 are appropriate and should remain the same. These cut-off points are working. Keeping them ensures patients have CONTINUED ACCESS to this important and innovative testing.

Item 2. Suggesting that the treating physician requirements related to blood-based biomarker tests should be modified to ensure consistency with other non-invasive tests. CMS should remove the “treating provider” language from the NCD to make ordering requirements consistent across all non-invasive CRC screening tests. These tests have similar purposes and safety profiles, yet ordering rules vary — creating unnecessary barriers, especially for individuals without primary care providers.

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The American Cancer Society Cancer Action Network (ACS CAN) appreciates the opportunity to comment on the National Coverage Analysis (NCA) for non-invasive biomarker tests for screening for colorectal cancer. ACS CAN is making cancer a top priority for public officials and candidates at the federal, state, and local levels. ACS CAN empowers advocates across the country to make their voices heard and influence evidence-based public policy change, as well as legislative and regulatory solutions that will reduce the cancer burden. As the American Cancer Society’s (ACS) nonprofit, nonpartisan advocacy affiliate, ACS CAN is more determined than ever to end cancer as we know it, for everyone.

More than 2 million Americans will be diagnosed with cancer this year and more than 18 million Americans living today have a history of cancer.(1) In 2025, an estimated 107,320 cases of colon cancer will be diagnosed in the United States, a majority of which will be diagnosed in individuals aged 45 and older.(2) An estimated 52,900 people will die from the disease this year.(3) Colorectal cancer remains one of the deadliest forms of cancer.(4)

Colorectal cancer screening is the most effective way of preventing cancer before it starts and finding it early when it’s most treatable. Cancers that are found at an early stage can be treated more easily, and lead to greater survival. Despite the benefits of screening, only 65 percent of people aged 45 years and older report being screened for colorectal cancer.(5) Colorectal cancer screening must reach more eligible people to save more lives from cancer.

We are unaware of any completed systematic review of the evidence related to the mt-sRNA test, apart from the FDA review, and other than the National Comprehensive Cancer Network (NCCN)(6) , we are not aware of any other guideline/recommendation-issuing organization that has reached a determination regarding including the mt-sRNA test among the options for CRC screening.

At this time, ACS is not able to advise CMS on whether to provide coverage for ColoSense, an FDA-approved multi-target stool RNA (mt-sRNA) colorectal cancer (CRC) screening test, because it and several other newer CRC screening tests are currently under review by the ACS Guideline Development Group.

(1) American Cancer Society. Cancer Facts & Figures 2025. Atlanta: American Cancer Society; 2025.
(2) Id.
(3) Id.
(4) Siegal RL, Miller KD, Fuchs HE Jemal A. Cancer statistics, 2021. Cancer. 2021; 71:7-33, doi 10.3322/caac.21654.
(5) American Cancer Society. Cancer Prevention & Early Detection Facts & Figures 2025-2026.
(6) National Comprehensive Cancer Network (NCCN). Colorectal Cancer Screening guidelines version 2.2025. Available from https://www.nccn.org/guidelines/guidelines-detail?category=2&id=1429.

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Issue 1: Reinforcing that the current sensitivity and specificity cut-off points for blood-based biomarker tests should remain

The sensitivity/specificity cut-off points for blood-based testing that were established by CMS in 2020 after an extensive evidence review are appropriate and should remain the same. New tests were specifically designed and developed to meet these performance standards, and one has since been FDA-approved. These cut-off points are working. Keeping them ensures patients have continued access to this important and innovative screening method.

Issue 2: Suggesting that the treating physician requirements related to blood-based biomarker tests should be modified to ensure consistency with other non-invasive tests

CMS should remove the “treating provider” language from the NCD to make ordering requirements consistent across all non-invasive CRC screening tests. These tests have similar purposes and safety profiles, yet ordering rules vary — creating unnecessary barriers, especially for individuals without primary care providers.

Blood-based tests are intended for average-risk, asymptomatic people who do not present with a condition to treat, so requiring a “treating physician” is not necessary. Expanding ordering privileges to all provider types allowed to order preventive services will increase access to this modality and improve screening rates, particularly in underserved regions where screening rates remain low.

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October 10, 2025

Carl Li, M.D.
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Screening for Colorectal Cancer – Non-Invasive Biomarkers Tests (CAG-00440R)

Dr. Li,

On behalf of the Prevent Cancer Foundation®, thank you for the opportunity to provide comments on the proposed National Coverage Determination (NCD) for Screening for Colorectal Cancer – Non-Invasive Biomarkers Tests.

The Prevent Cancer Foundation is the only U.S.-based nonprofit organization solely dedicated to cancer prevention and early detection. Through research, education, outreach and advocacy, we have helped countless people avoid a cancer diagnosis or detect their cancer early enough to be successfully treated. We are driven by a vision of a world where cancer is preventable, detectable and beatable for all.

More than two million Americans are expected to be diagnosed with cancer in 2025, making widespread, equitable screening more urgent than ever to reduce late-stage diagnosis. The Prevent Cancer Foundation’s 2025 Early Detection Survey revealed alarming declines in the rate of routine medical visits and screening for cancer among adults in the United States. Colorectal cancer is highly preventable when detected early, yet too many Americans remain unscreened. Major obstacles to accessing care stem from a knowledge gap about the benefits of routine screening, cost concerns, fear of the possibility of a cancer diagnosis, and skepticism of the health care system.

We support the inclusion of stool RNA tests in the NCD for colorectal cancer screening. Increasing the number of accessible and affordable screening options—including noninvasive stool-based tests—can help remove barriers and encourage more individuals to get screened.

Additionally, we urge CMS to modify the treating physician requirements related to blood-based biomarker tests to ensure consistency across all non-invasive colorectal cancer screening modalities. These tests share similar purposes and safety profiles, yet current ordering requirements vary—creating unnecessary barriers, particularly for individuals without a primary care provider. Blood-based biomarker tests are designed for average-risk, asymptomatic individuals who do not present with a condition to treat, making the “treating physician” requirement unnecessary. Expanding ordering privileges to all provider types authorized to order preventive services will increase access to this screening modality and improve overall screening rates, especially in underserved regions where colorectal cancer screening remains low.

Providing patients and providers with a broader range of effective, accessible screening tools will improve early detection, reduce disparities, and ultimately save lives. Including stool RNA testing as a covered option—and ensuring consistent ordering requirements across all non-invasive tests—aligns with CMS’s commitment to advancing equitable, evidence-based care and directly supports our shared goal of preventing cancer before it starts.

We urge CMS to finalize the NCD with the inclusion of stool RNA testing and to revise ordering provisions for blood-based tests to promote consistency, accessibility, and patient-centered care. Together, these steps will help more individuals take proactive measures to protect their health and prevent cancer.

Sincerely,
Jody Hoyos
Chief Executive Officer

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I am writing to express my strong support for key aspects of the Medicare National Coverage Determination (NCD) 210.3 regarding colorectal cancer screening, and to encourage consideration of refinements that will further strengthen patient access and alignment with clinical practice.

First, I want to emphasize the importance of maintaining the current sensitivity and specificity cut-off points for blood-based biomarker tests. The sensitivity/specificity cut-off points for blood-based testing that were established by CMS in 2020 after an extensive evidence review are appropriate and should remain the same. New tests were specifically designed and developed to meet these performance standards, and one has since been FDA-approved. These cut-off points are working. Keeping them ensures patients have continued access to this important and innovative screening method. Preserving these standards is critical for patient safety, clinical confidence, and maintaining the integrity of non-invasive screening alternatives. Lowering these thresholds could increase the risk of false positives or false negatives, ultimately undermining trust in these important tools.

Second, I urge modification of the treating physician requirements related to blood-based biomarker tests. CMS should remove the “treating provider” language from the NCD to make ordering requirements consistent across all non-invasive CRC screening tests. Aligning these requirements with other non-invasive tests, such as stool-based screening, would ensure consistency, reduce confusion, and streamline the process for patients and providers alike. These tests have similar purposes and safety profiles, yet ordering rules vary — creating unnecessary barriers, especially for individuals without primary care providers.

Blood-based tests are intended for average-risk, asymptomatic people who do not present with a condition to treat, so requiring a “treating physician” is not necessary. Expanding ordering privileges to all provider types allowed to order preventive services will increase access to this modality and improve screening rates, particularly in underserved regions where screening rates remain low.”

Together, these steps, maintaining evidence-based sensitivity and specificity cutoffs and adjusting treating physician requirements for consistency, will help ensure that Medicare beneficiaries have equitable, timely, and reliable access to life-saving colorectal cancer screening. The National Cancer Institute reported in 2024 that of the 940,000 colorectal cancer deaths averted from 1975 to 2020, 79% were due to screening and removal of precancerous polyps. Colorectal cancer screening saves lives.

Thank you for your leadership in protecting patient access to high-quality cancer screening. I respectfully urge you to support these considerations as NCD 210.3 is implemented and evaluated.

Sincerely,

Andrew R. Spiegel, Esq.
Chief Executive Officer
Global Colon Cancer Association
andrew@globalcca.org|www.globalcca.org

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JoAnna Baldwin, Acting Director
Kimberly Long, Lead Analyst
Olivia Harbison, Lead Analyst
Carl Li, M.D., Lead Medical Officer
Coverage and Analysis Group (CAG)
Centers for Medicare & Medicaid Services (CMS)
7500 Security Boulevard
Baltimore, MD 21244

Executive Summary
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Exact Sciences Corporation welcomes the opportunity to comment on the CMS National Coverage Analysis (NCA) for Screening for Colorectal Cancer (CRC) – Non-Invasive Biomarker Tests (CAG-00440R). This NCA represents a critical moment to reaffirm CMS’ dedication to evidence-based coverage that guarantees Medicare beneficiaries access to safe, effective, and rigorously validated screening technologies. As stated by CMS in the last NCA related to CRC screening, these technologies should be “as good as, or ideally better than, the current screening test[s] to continue the progress achieved in colorectal cancer survival over the past 20 years [1].” Lowering standards risks reversing progress and will result in missed opportunities for CRC prevention and early detection, unnecessary follow-up procedures, and poorer overall outcomes. The following recommendations align with CMS precedent and NCA guidance, stressing methodological rigor and applicability to Medicare. Maintaining these standards guarantees that CRC screening is grounded in strong science, ensuring beneficiaries get effective, equitable care.

CMS pioneered the framework to support current coverage for non-invasive CRC screening tests outlined in CAG-00440N. Through the parallel review pathway with CMS and the FDA, Exact Sciences facilitated the design and execution of the pivotal DeeP-C trial (NCT01397747) which established a precedent for evaluating non-invasive CRC screening tests for both FDA approval and CMS coverage. Between 2013 and 2023, CRC screening rates in a Medicare aged population 65-75 years old increased from 69.4% [2] to 82.7% [3]. During a similar period, Cologuard® has been used to screen for CRC more than 20 million times, resulting in detection estimates of over 114,000 CRCs (80% at an early-stage) and 640,000 advanced precancerous lesions (APLs) [4].

Building upon this progress, Exact Sciences remains committed to continued innovation for improving patient care. Cologuard Plus®—validated in the pivotal BLUE-C trial (NCT04144738) — now offers Medicare beneficiaries a non-invasive molecular test for CRC screening with 95% CRC sensitivity and 93% specificity (category 6). These foundational studies, along with the FDA Summary of Safety and Effectiveness Data (SSED), have established new benchmarks for sensitivity, specificity, and detection of CRCs and APLs. A revised National Coverage Determination (NCD) should promote rigorous standards and definitions that will serve as the foundation for non-invasive biomarker tests for CRC screening.

With the above in mind, we strongly recommend that CMS revise NCD 210.3 for advanced stool-based non-invasive molecular tests to read as follows:

“Non-invasive, advanced stool-based molecular colorectal cancer screening tests are covered once every three years for Medicare beneficiaries if the test has received unconditional FDA market authorization for detection of both colorectal cancer and advanced precancerous lesions, and has met all of the following criteria as published in the FDA SSED for the indicated population:

• Sensitivity for colorectal cancer: ≥ 95%
• Specificity (category 6): ≥ 93%
• Sensitivity for advanced precancerous lesions: ≥ 43%

Tests that do not meet these criteria, or that require post-approval studies to confirm performance, will not be covered until robust, generalizable, and FDA-validated data are available.”

These recommendations are firmly rooted in CMS precedent and the agency’s 2024 National Coverage Analysis Evidence Review guidance document which states the importance of methodological rigor, precision, and generalizability to the Medicare population [5]. In addition to recommending operative NCD language for advanced stool-based molecular CRC tests, Exact Sciences also believes blood-based CRC screening tests can play an important role in reaching the estimated 60 million Americans who remain unscreened [6]. In response to the request for comments regarding cut points for non-invasive biomarker screening tests, generally, we believe it is appropriate for CMS to reevaluate the criteria set for blood-based testing five years ago, given more recently available data and the importance of evaluating consistent test characteristics and maintaining rigorous data quality standards for all non-invasive biomarker tests for CRC screening.

1. Establishment of Cut Points for Advanced Molecular Stool-Based Tests using CMS Precedent

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1.1. CRC Sensitivity and Specificity Cut Points Should Not Reverse Progress

We support CMS’ goal of establishing clear test criteria, including performance cut points to facilitate coverage of future non-invasive CRC screening tests without having to reconsider the NCD. As a condition for coverage, CMS should require all advanced molecular stool-based tests for CRC screening meet or exceed CRC sensitivity and specificity cut points of 95% and 93%, respectively, based on the FDA SSED. The precedent-based approach is consistent with CMS statements that new tests should be at least as good as, and ideally better than, currently covered tests [1]. Because of the clinical differences between specimen modalities, it is imperative to establish distinct cut points by specimen type (i.e., stool and blood) rather than generalize the cut points in a manner where the lowest performance metrics are used for minimum cut points across all non-invasive modalities. By setting these rigorous performance standards, CMS will ensure that only high-performing tests, clinically validated in the indicated population are accessible to Medicare beneficiaries, continuing the substantial progress in CRC screening and survival achieved over recent decades.

Colorectal neoplasms shed DNA, RNA, and other cellular debris directly into the lumen of the colon, making stool the most proximate and biologically relevant specimen source for detecting early-stage CRCs and APLs. This direct shedding allows stool-based tests to capture tumor-derived material with high fidelity, even before vascular invasion occurs. In contrast, blood-based tests rely on the presence of circulating tumor DNA (ctDNA) or methylated fragments that enter the bloodstream only after tumors breach their normal tissue barriers. This biological limitation inherently reduces the sensitivity of blood-based tests for early-stage disease and precancerous lesions [7].

Historically, due to limited available data for blood-based CRC screening, CMS used its experience with Cologuard and the 11-year old DeeP-C study data to set blood-based cut points using the lowest performance values from two different stool-based tests: fecal immunochemical test (FIT) sensitivity (74%) and Cologuard category 6 specificity (90%) [1]. However, given the biological differences and the quality of data available, setting minimum cut points across modalities is not appropriate. A sensitivity cut point for CRC should be much higher for an advanced stool-based molecular screening test, as achieved by Cologuard, in a head-to-head comparison to FIT in the DeeP-C study [8]. Moreover, as of March 31, 2025, Medicare Part B beneficiaries only have access to Cologuard Plus (observed sensitivity and specificity of 95% and 93%, respectively [9]), which has surpassed the historical performance characteristics that laid the foundation for this NCD in 2014.

1.2. Establishing APL Sensitivity Cut Point is Critical to Early Detection of CRC

Setting cut points for non-invasive CRC screening biomarker tests cannot simply start and end with CRC sensitivity and specificity. As a condition for coverage, CMS should require all advanced molecular stool-based tests for CRC screening meet or exceed an APL sensitivity cut point of 43%, based on the FDA SSED. APLs such as advanced adenomas and sessile serrated lesions are the precursors to invasive colorectal cancer. Detecting and removing these lesions can prevent cancer from developing, which is the primary goal of CRC screening. Regulation 42 CFR 410.37 [10] outlines the conditions for and limitations on coverage for CRC screening tests and asserts “procedures [are] furnished to an individual for the purpose of early detection of colorectal cancer.” Detecting precursors to CRC is critical to realizing the full benefits of broadly applied CRC screening. Identifying and removing precancerous lesions places cancer prevention at the forefront of public health, effectively reducing the risk of CRC before it can develop.

In its 2021 CRC screening decision memo on blood-based biomarker screening, CMS stated, “we did not propose a sensitivity threshold for advanced precancerous lesions for blood-based biomarker tests because, at the time of our proposed decision, there was insufficient evidence to establish an appropriate minimum threshold [1].” Today, there are multiple clinical validation studies of both blood- and stool-based non-invasive CRC screening tests that have enrolled tens of thousands of participants, providing ample, more recently available performance data related to APL detection. Numerous studies and the World Endoscopy Organization (WEO) CRC screening committee consensus guidelines affirm that identifying and removing APLs interrupts the progression to invasive cancer, thereby reducing both CRC incidence and mortality [11]. Modeling analyses estimate that precancer detection results in 83% of the life-years gained (LYG) from mt-sDNA and 64-67% of the LYG from blood-based CRC screening [12]. Although limited evidence may have been available in 2021, we support CMS for “acknowledg[ing] the utility and potential clinical benefit of screening for advanced adenomas [1].”

2. Data Quality Standards are Critical in Establishment of Cut Points

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2.1 The Source of Data for Cut Points Should be Standardized and Unbiased

The importance of establishing minimum cut points for CRC sensitivity, APL sensitivity, and specificity for all non-invasive biomarker tests for CRC screening is clear. However, how studies are conducted and data are evaluated is even more critical. As a condition for coverage, CMS should require all advanced molecular stool-based tests for CRC screening have unconditional FDA market authorization for detection of both colorectal cancer and advanced precancerous lesions, meet performance criteria as published in the FDA SSED for the indicated population, and ensure no required post-approval studies have yet to be completed to confirm performance. The CMS NCA Evidence Review guidance document outlines the methodological principles and robust framework used by CMS when evaluating high quality evidence. NCDs concerning whether a particular item or service is reasonable and necessary under section 1862(a)(1)(A) of the Act are based on information including clinical experience, and medical, technical, and scientific evidence [5].

When applying this guidance to non-invasive CRC screening, it is evident that test effectiveness should be evaluated against the FDA approval dataset, as it accurately reflects real-world, on-label performance in the intended population, including Medicare beneficiaries. CMS established a framework for assessing Medicare coverage for non-invasive CRC screening tests with Cologuard during the parallel review pathway with FDA. The SSED published by the FDA for CRC screening tests offer an impartial basis for verifying point estimates and confidence intervals regarding CRC sensitivity, APL sensitivity, and specificity, using a standardized approach to relevant screening endpoints. Table 1 below presents data referent to the currently available FDA-approved, USPSTF-endorsed, and Medicare-covered advanced stool-based molecular test for CRC screening. As of March 31, 2025, Cologuard Plus is the only advanced stool-based molecular test covered and utilized for screening Medicare beneficiaries. A comparison between published data and the FDA SSED for Cologuard Plus demonstrates marked consistency across key performance metrics.

Table 1: Cologuard Plus pivotal trial data and FDA approval SSED

	BLUE-C Trial Publication [13]	FDA Approval SSED [9]
Subjects evaluated	20,176	18,911
Medicare aged (≥ 65) CRC cases	53	47
Total CRC cases	98	85
Medicare aged (≥ 65) CRC sensitivity (95% CI)	94 (84-99)	93 (83-98)
Overall CRC sensitivity (95% CI)	94 (87-98)	95 (88-99)
APL sensitivity (95% CI)	43 (41-46)	43 (41-46)
Specificity (category 6) (95% CI)	93 (92-93)	93 (92-93)

Note: BLUE-C supplemental data combined from 65-69, 70-75, and =76 age groups used to calculate both the Medicare aged CRC sensitivity and CI. FDA approval SSED data combined from 65-69, 70-74, and =75 age groups used to calculate both the Medicare aged CRC sensitivity and CI.

While clinical trials can be structured to target specific point estimates, their results may not always accurately represent broader populations or predict real-world performance. Variations in each trial—such as differing endpoint definitions, adjustments based on age, and APL categorizations—are used to achieve these estimates, making it important to avoid “overfitting” simply to satisfy coverage criteria. Table 2 below presents mt-sRNA published data and the FDA SSED under consideration for coverage.

Table 2: ColoSense® pivotal trial data and FDA approval SSED

	CRC-PREVENT Publication [14]	FDA Approval SSED [15]
Subjects evaluated	8,920	7,763
Medicare aged (≥ 65) CRC cases	8	3*
Total CRC cases	36	27*
Medicare aged (≥ 65) CRC sensitivity (95% CI)	88 (53-98)	67 (21-94)
Overall CRC sensitivity (95% CI)	94 (81-99)	93 (76-99)
APL sensitivity (95% CI)	46 (42-50)	43 (41-46)
Specificity (category 6) (95% CI)	88 (87-89)	87 (86-88)

Note: CRC-PREVENT supplemental data used to calculate both the Medicare aged CRC sensitivity and CI for trial publication. FDA approval Medicare aged CRC sensitivity CI and specificity (category 6) CI calculated using available data in SSED.
*Per FDA, Geneoscopy Inc. must conduct a prospective validation study to expand the total number of CRC cases evaluated by ColoSense. Data from the original CRC-PREVENT trial will be pooled with the FDA required post-approval study to assess primary endpoints.

FDA-approved CRC screening tests reveal significant differences between pivotal trial results and SSED data which reflect real-world, on-label performance in the intended population. These variations can greatly influence projections of screening benefits, burdens, and efficiency. According to the CMS NCA Evidence Review guidance document, “precision is typically judged based on the width of the confidence interval . . . A wide confidence interval does not permit a confident conclusion regarding the effects of treatment [5].” The FDA SSED for ColoSense notes that “because of the lower number of CRC cases the acceptance criteria for the lower bound of 2-sided 95% CI did not meet pre-specified 2-sided 95% CI LB of 80%, achieving 2-sided 95% CI LB of 76%. Therefore, Geneoscopy will perform [a] post-approval study to enroll an additional 12,500 participants to achieve 33 additional patients with CRC [15].” As shown in Table 2, the number of CRC cases included in the Medicare aged population affects the associated level of confidence in the sensitivity point estimate (with n=3 cases, the lower bound of the 95% CI is 21%).

Establishing cut points is an important part of enabling coverage to move with the speed of technology. To protect beneficiaries and ensure the integrity of those cut points, Exact Sciences believes the FDA SSED is the most objective source of that information for future CRC screening tests. Guideline bodies are important, but do not set cut points, and the timing of their recommendations may lag. For example, the United States Preventive Services Task Force (USPSTF), United States Multi-Society Task Force (MSTF), and individual professional gastrointestinal (GI) societies have yet to evaluate mt-sRNA technology. More importantly, the FDA SSED represents a thorough evaluation of the test performance and associated risks. Currently, the SSED Benefit-Risk Determination for ColoSense notes that “. . . due to the small number of CRCs in this study (27), there is a chance that as many as 24.3% of CRC cases could be missed by this device, which represents a major source of uncertainty regarding device performance” and “the consequences of false negatives could be quite serious, such as progression of disease, such as CRC to a more advanced, and less treatable stage [15].” Because of this uncertainty, FDA states “additional investigation in the form of post-approval studies are required to confirm the performance of this device for CRC detection [15].” When critical concerns are present in the FDA SSED, they should be thoughtfully evaluated and resolved to inform a national coverage decision.

2.2 The Source of Data Should Demonstrate Efficacy in a Medicare Population

CMS NCA guidance further states “even well-designed and well-conducted trials may not supply evidence relevant for CMS if study results do not apply to the Medicare beneficiary population,” and the “generalizability of findings from relevant studies to the Medicare beneficiary population” is one of the key factors in conducting NCAs for an item or service under the reasonable and necessary statute [5]. Coverage should be confined to tests with unconditional FDA approval, robust Medicare population representation, and demonstrated effectiveness in the intended population.

Tables 1 and 2 above show both the number of CRCs in the trial publication and FDA SSED in the Medicare aged population for Cologuard Plus and ColoSense, respectively. The FDA SSED for ColoSense indicates only 3 CRCs, one of which was not detected, were used to estimate CRC sensitivity in the 65 and older age group. It is difficult, if not impossible, to confidently assess test performance in the Medicare aged population based on a sample size of 3 cases. Cologuard and Cologuard Plus are the only advanced stool-based molecular tests to receive Medicare coverage since 2014 and did so by demonstrating generalizability in a Medicare aged population with an average of over 50 CRC cases (54 and 47, respectively), supporting the precision of both tests in the Medicare aged population.

CMS has stressed the importance of generalizability when demonstrating reasonable and necessary requirements, however, without explicit guidance on generalizability, there is always risk associated with manufacturers falling short with limited data in the indicated population. There is even more risk when developing foundational NCD criteria that will essentially provide automatic coverage for any new tests meeting the established cut points. CMS should strongly consider how it anticipates clearly articulating generalizability criteria within the NCD for future tests in the non-invasive CRC screening space. CRC sensitivity, APL sensitivity, and overall specificity alone cannot determine whether a new test is as good, or better than existing services available to Medicare beneficiaries.

3. Considerations for Blood-Based Biomarker Test Cut Points

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Blood-based CRC screening tests can play an important role in reaching the estimated 60 million Americans who remain unscreened [6]. Evaluating consistent test characteristics and maintaining rigorous data quality standards across specimen types is necessary to ensure Medicare beneficiaries have options for non-invasive CRC screening that are equally effective and continuously improving over time. Similar to stool-based testing, setting cut points for non-invasive CRC screening biomarker tests cannot simply start and end with CRC sensitivity and specificity.

Again, in 2021, CMS stated “we did not propose a sensitivity threshold for advanced precancerous lesions for blood-based biomarker tests because, at the time of our proposed decision, there was insufficient evidence to establish an appropriate minimum threshold. The available studies did not consistently report sensitivity for advanced precancerous lesions, and the clinical significance of detecting these lesions with blood-based tests remains unclear. Therefore, we are not finalizing a sensitivity cut point for advanced precancerous lesions for blood-based CRC screening tests at this time [1].” CMS went on to further state that, “While we acknowledge the utility and potential clinical benefit of screening for advanced adenomas, there is very limited available evidence on the accuracy of blood-based tests to detect advanced adenomas and the sensitivity of FIT for advanced adenoma is low. Thus, we did not include point sensitivity or specificity to screen for advanced adenoma [1].” As previously noted, APLs are the precursors to invasive colorectal cancer. Detecting and removing these lesions prevent cancer from developing, which is the primary goal of CRC screening [11].

Available evidence on blood-based biomarker testing demonstrates limited precancer and early-stage cancer detection [16]. Current National Comprehensive Cancer Network (NCCN) guidelines state that, “given its modest performance, particularly among advanced precancerous lesions, [blood-based testing] is only recommended for individuals who would not be willing to undergo screening through another modality [17].” In addition, the American Gastroenterology Association (AGA) CRC Workshop Panel calls for rigorous evaluation of liquid biopsy tests because they are predicted to be less effective and more costly than currently established screening programs. Authors state liquid biopsy is not recommended to replace established effective screening methods [18]. Furthermore, the AGA Clinical Practice Update states, “Patients and doctors should understand that although novel blood tests may improve participation in CRC screening, use of the novel tests could result in net harm if they are substituted for more effective screening tests. For patients who decline any other form of CRC screening, blood tests are an acceptable option [19].”

With additional data now available and current professional society practice guidelines positioning blood-based testing as second line, CMS should not only reevaluate the NCD parameters for blood-based testing to ensure effectiveness in detecting APLs and preventing and detecting CRC at the appropriate interval or frequency, but also consider the importance of shared decision making to ensure appropriate use.

4. Recommendation for Advanced Molecular Stool-Based Test NCD Language

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CMS’ own standards and recent peer-reviewed evidence all highlight the necessity of maintaining rigorous, evidence-based thresholds for non-invasive CRC screening tests. We strongly urge CMS to continue upholding its longstanding standard that new CRC screening tests must be as good as, or ideally better than, those already covered. Only by adhering to rigorous, evidence-based standards can we ensure that this standard is met in early detection and outcomes for CRC.

Again, we urge CMS revise NCD 210.3 for advanced stool-based non-invasive molecular tests to read as follows:

References

—————— [1] "Screening for Colorectal Cancer - Blood-Based Biomarker Tests," 19 January 2021. [Online]. Available: https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&ncaid=299. [Accessed 1 October 2025].
[2] "CDC Morbidity and Mortality Weekly Report (MMWR)," 2015. [Online]. Available: https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6417a4.htm. [Accessed 1 October 2025].
[3] "Use of Cancer Screening Tests, United States, 2023," 14 August 2025. [Online]. Available: https://www.cdc.gov/pcd/issues/2025/25_0139.htm. [Accessed 1 October 2025].
[4] Data on File and D. M. O. A. e. a. Estes C, "Clinical, social and economic impacts of colorectal cancer screening with the multi-target stool-DNA test: 10-year experience – a simulated study.," MedRxiv, no. Updated based on new screening data, 2024.
[5] CMS Coverage and Analysis Group, "CMS National Coverage Analysis Evidence Review Guidance Document," 2024.
[6] K. J. F. A. e. a. Ebner DW, "Estimated Average-Risk Colorectal Cancer Screening–Eligible Population in the US," JAMA Network Open, vol. 7, no. 3, 2024.
[7] A. Shaukat, C. Burke, A. Chan and e. al., "Clinical Validation of a Circulating Tumor DNA–Based Blood Test to Screen for Colorectal Cancer," JAMA, vol. 334, no. 1, pp. 56-63, 2025.
[8] T. Imperiale, D. Ransohoff, S. Itzkowitz, T. Levin, P. Lavin, G. Lidgard, D. Ahlquist and B. Berger, "Multitarget Stool DNA Testing for Colorectal-Cancer Screening," New England Journal of Medicine, vol. 370, no. 14, pp. 1287-1297, 2014.
[9] FDA Summary of Safety and Effectiveness Data, "PMA P230043," 3 October 2024. [Online]. Available: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230043B.pdf. [Accessed 1 October 2025].
[10] N. Archives, "Code of Federal Regulations," [Online]. Available: https://www.ecfr.gov/current/title-42/chapter-IV/subchapter-B/part-410/subpart-B/section-410.37. [Accessed 1 October 2025].
[11] S. C. Y. G. e. a. Bresalier RS, "An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles," Gut, vol. 72, no. 10, pp. 1904-1918, 2023.
[12] F. A. E. D. e. a. Kisiel JB, "Estimated impact and value of blood-based colorectal cancer screening at varied adherence compared with stool-based screening," J Med Econ, vol. 27, no. 1, pp. 746-753, 2024.
[13] T. Imperiale, K. Porter, J. Zella and e. al., "Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening," New England Journal of Medicine, vol. 390, no. 11, pp. 984-993, 2024.
[14] E. K. e. a. Barnell, "Multitarget Stool RNA Test for Colorectal Cancer Screening," JAMA, vol. 330, no. 18, pp. 1760-1768, 2023.
[15] FDA Summary of Safety and Effectiveness Data, "PMA P230001," 3 May 2024. [Online]. Available: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf. [Accessed 1 October 2025].
[16] D. e. a. Chung, "A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening," New England Journal of Medicine, vol. 390, no. 11, pp. 973-983, 2024.
[17] N. C. C. Network, "NCCN Guidelines Colorectal Cancer Screening 2.2025," 2025. [Online]. Available: https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. [Accessed 1 October 2025].
[18] D. Lieberman, A. Shaukat, F. May and e. al., "Commentary: Liquid Biopsy for Average-Risk Colorectal Cancer Screening," Clinical Gastroenterology and Hepatology, vol. 22, no. 6, pp. 1160-1164, 2024.
[19] A. e. a. Shaukat, "AGA Clinical Practice Update on Current Role of Blood Tests for Colorectal Cancer Screening: Commentary," Clinical Gastroenterology and Hepatology, vol. 23, no. 9, pp. 1486-1491, 2025.

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JoAnna Baldwin, MS
Acting Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard Baltimore, MD 21244

Re: National Coverage Analysis for Screening for Colorectal Cancer-Non-Invasive Biomarker Tests [CAG-00440R]

Dear Ms. Baldwin,

On behalf of Freenome Holdings, Inc., we appreciate the opportunity to provide feedback on the current National Coverage Determination (NCD) for CRC non-invasive biomarker screening tests (210.3) and the newly opened National Coverage Analysis (NCA) [CAG-00440R]. Freenome’s mission is to detect cancer in its earliest, most treatable stages, and to make screening easy and accessible for everyone. We developed a multimodal discovery platform that leverages state-of-the-art computational biology and machine learning approaches to evaluate multiple biomarker classes and identify the earliest biological signals of disease.

This platform enabled the creation of a qualitative colorectal cancer (CRC) screening blood test, SimpleScreen™ CRC, that detects DNA methylation patterns associated with advanced colorectal neoplasia using circulating cell-free DNA from the plasma of peripheral whole blood. The performance of SimpleScreen CRC was recently validated in a prospective, multicenter, observational study (PREEMPT CRC®) and exceeded the accuracy targets for blood-based CRC testing set by the Centers for Medicare & Medicaid Services (CMS) (1).

CRC remains a significant public health challenge, and non-invasive options, particularly blood-based tests, could provide a convenient, accessible alternative to conventional testing. We commend CMS for establishing a foundational policy that has successfully encouraged innovation and the development of new screening tests. As the manufacturer of a CRC screening blood test, we wanted to identify opportunities to improve the current NCD language and comment on criteria related to blood-based biomarker testing.

We offer the following recommendations for your consideration:

1. Expand the description of blood-based testing to include tests that incorporate biomarker classes beyond DNA.
2. Broaden the language related to the healthcare professionals ordering the blood-based test to avoid unnecessary screening barriers for eligible adults.
3. Maintain the current sensitivity and specificity thresholds for blood-based testing.

1. Expand the description of blood-based testing to include tests that incorporate biomarker classes beyond DNA.

We recommend that CMS consider broadening its description of blood-based testing to accommodate the potential for future innovation and test development to include biomarker classes beyond conventional DNA. The current description in the NCD under blood-based biomarker testing is: “Blood-based DNA testing detects molecular markers of altered DNA that are contained in the cells shed into the blood by colorectal cancer and pre-malignant colorectal epithelial neoplasia.” This language, while representative of the CRC screening blood test currently available, could inadvertently stifle the development of new, high-performing multiomics tests that incorporate other informative biomarker classes such as RNA and protein.

We suggest modifying the description in favor of more inclusive language such as “biomarkers” or “analytes” to ensure that future blood-based tests that meet the pre-determined performance standards can be considered for coverage, regardless of their underlying molecular detection technology.

2. Broaden the language related to the healthcare professionals ordering the blood-based test to avoid unnecessary screening barriers for eligible adults.

Currently, the NCD states that blood-based biomarker testing is covered “...when ordered by a treating physician…,” which, as defined in 42 CFR § 426.110, is “the physician who is the beneficiary’s primary clinician with responsibility for overseeing the beneficiary’s care and either approving or providing the service at issue”. Sections 1861(s)(2)(R) and 1861(pp) of the Social Security Act authorize coverage for CRC screening tests under Medicare Part B without reference to the term “treating physician.” Adding a requirement that blood-based CRC screening tests be ordered by a treating physician could be interpreted as significantly narrowing the coverage authorized under the Act.

Unfortunately, the term “treating physician” can be restrictive for CRC screening. First, that descriptor is not harmonized across CRC screening tests in the NCD for Colorectal Cancer Screening Tests (210.3). For example, under the Indications and Limitations of Coverage, FOBT requires a written order from an “attending physician”, while no category of healthcare professional is specified to recommend the multitarget sDNA test (Cologuard). Second, that descriptor does not include other qualified healthcare professionals who oversee preventive care and recommend screening tests. Recently published data on an existing non-invasive CRC screening test showed that nurse practitioners and physician assistants, who are considered "treating practitioners" as defined by the Social Security Act § 1861(aa)(5)(A), account for a substantial percentage (28%) of tests ordered for individuals (2). The current, narrower language may therefore create a potential administrative barrier to screening access by excluding qualified practitioners.

We recommend either striking the phrase “when ordered by a treating physician,” or amending the term “treating physician” so that qualified healthcare professionals other than a treating physician can order the test, in order to resolve this discrepancy and ensure the NCD unambiguously supports broad, equitable access to approved CRC screening tests.

3. Maintain the current sensitivity and specificity thresholds for blood-based testing.

Finally, in response to the NCA request for input on performance standards for non-invasive CRC screening tests, we believe the current sensitivity and specificity thresholds for blood-based biomarker tests are appropriate and should be maintained. These standards are consistent with the performance of the only FDA-approved CRC screening blood test, and they provide a clear, effective benchmark for evaluating the performance of future tests under development. Maintaining this minimum performance threshold will ensure that patients and providers can benefit from the convenience of blood-based biomarker testing without sacrificing test sensitivity or specificity.

Conclusions

We believe these targeted recommendations will enhance the NCD for blood-based biomarker testing by promoting innovation, reducing potential administrative barriers to care, and ensuring high standards for test performance.

Thank you for considering our comments. Please do not hesitate to reach out if you have any questions regarding these comments or require additional information.

Sincerely,

Aaron Elliott, PhD
Chief Executive Officer
Freenome Holdings, Inc.

* * * * *

References

1. Shaukat A, Burke CA, Chan AT, Grady WM, Gupta S, Katona BW, et al. Clinical Validation of a Circulating Tumor DNA–Based Blood Test to Screen for Colorectal Cancer. JAMA. 2025 July 1;334(1):56–63.
2. Le QA, Greene M, Gohil S, Ozbay AB, Dore M, Fendrick AM, et al. Adherence to multi-target stool DNA testing for colorectal cancer screening in the United States. Int J Colorectal Dis. 2025 Jan 17;40(1):16.

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My name is Dr. Jennifer M. Weiss, and I am a Professor of Medicine and Gastroenterologist at the University of Wisconsin School of Medicine and Public Health, where I specialize in colorectal cancer prevention, screening, and population health. My research and clinical practice focus on improving screening uptake and adherence through evidence-based, patient-centered strategies. Over the course of my career, I have worked extensively with national organizations and health systems to advance guideline-concordant colorectal cancer screening and to evaluate emerging technologies that have the potential to reduce disparities and improve outcomes across diverse patient populations.

Cutoffs define a test’s operating point on the receiver operating characteristic (ROC) curve and directly determine clinical sensitivity, specificity, positive predictive value, and negative predictive value. Historically, these thresholds have varied widely across covered screening modalities, reflecting fundamental differences in biology, methodology, and clinical intent. For example:

• Fecal Immunochemical Test (FIT; =20 µg Hb/g stool [range 10–50]) – Sensitivity CRC: 73–88%; Sensitivity AA: 20–25%; Specificity: 90–96% [1]
• Multi-target Stool DNA (Cologuard and Cologuard Plus) – Sensitivity CRC: 92–94%; Sensitivity AA: 42–43%; Specificity: 90–93% [2-3]
• Mammography – Sensitivity: 77–91%; Specificity: 88–91% [4]
• PSA Testing – Sensitivity: 20–44%; Specificity: 85–91% [5]
• HPV Testing – Sensitivity: 55–70%; Specificity: 75–96% [6-7]

Given the meaningful reductions in cancer incidence and mortality achieved across these programs despite differing analytic thresholds, a single universal sensitivity or specificity cutoff is neither biologically justified nor policy-appropriate. It is well known that providing physicians with numerous valuable screening alternatives and allowing them to choose the test that best fits the individual preferences and needs of each patient increases screening adherence and improves health outcomes. Tests that deliver comparable real-world benefits, achieving similar reductions in cancer incidence and mortality through distinct analytic approaches, should be considered clinically equivalent for coverage purposes.

Moreover, test performance in isolation is insufficient to determine clinical value. A test with slightly lower analytical sensitivity but 30–40% higher adherence may ultimately produce superior population-level outcomes. Improvements achieved by ColoSense, particularly its design to minimize patient burden, have the potential to drive significantly higher adherence compared to stool-based tests that require handling of stool. Increased participation directly translates to earlier detection, improved survival, and a greater public health impact. CMS should offer a framework that covers ColoSense and ensures future tests that deliver comparable effects on cancer incidence and mortality, as determined through rigorous clinical studies, are covered without an NCD reconsideration.

Sincerely,
Dr. Weiss

Citations
[1] Imperiale TF, Gruber RN, Stump TE, Emmett TW, Monahan PO. Performance Characteristics of Fecal Immunochemical Tests for Colorectal Cancer and Advanced Adenomatous Polyps: A Systematic Review and Meta-analysis. Ann Intern Med. 2019 Mar 5;170(5):319-329. doi: 10.7326/M18-2390. Epub 2019 Feb 26. PMID: 30802902.
[2] Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014 Apr 3;370(14):1287-97. doi: 10.1056/NEJMoa1311194. Epub 2014 Mar 19. PMID: 24645800.
[3] Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014 Apr 3;370(14):1287-97. doi: 10.1056/NEJMoa1311194. Epub 2014 Mar 19. PMID: 24645800.
[4] Ohuchi N, Suzuki A, Sobue T, Kawai M, Yamamoto S, Zheng YF, Shiono YN, Saito H, Kuriyama S, Tohno E, Endo T, Fukao A, Tsuji I, Yamaguchi T, Ohashi Y, Fukuda M, Ishida T; J-START investigator groups. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial. Lancet. 2016 Jan 23;387(10016):341-348. doi: 10.1016/S0140-6736(15)00774-6. Epub 2015 Nov 5. PMID: 26547101.
[5] Ankerst DP, Thompson IM. Sensitivity and specificity of prostate-specific antigen for prostate cancer detection with high rates of biopsy verification. Arch Ital Urol Androl. 2006 Dec;78(4):125-9. PMID: 17269614.
[6] Castanon A, Landy R, Michalopoulos D, Bhudia R, Leaver H, Qiao YL, Zhao F, Sasieni P. Systematic Review and Meta-Analysis of Individual Patient Data to Assess the Sensitivity of Cervical Cytology for Diagnosis of Cervical Cancer in Low- and Middle-Income Countries. J Glob Oncol. 2017 Mar 1;3(5):524-538. doi: 10.1200/JGO.2016.008011. PMID: 29094092; PMCID: PMC5646897.
[7] Almonte M, Murillo R, Sánchez GI, González P, Ferrera A, Picconi MA, Wiesner C, Cruz-Valdez A, Lazcano-Ponce E, Jerónimo J, Ferreccio C, Kasamatsu E, Mendoza L, Rodríguez G, Calderón A, Venegas G, Villagra V, Tatti S, Fleider L, Terán C, Baena A, Hernández ML, Rol ML, Lucas E, Barbier S, Ramírez AT, Arrossi S, Rodríguez MI, González E, Celis M, Martínez S, Salgado Y, Ortega M, Beracochea AV, Pérez N, Rodríguez de la Peña M, Ramón M, Hernández-Nevarez P, Arboleda-Naranjo M, Cabrera Y, Salgado B, García L, Retana MA, Colucci MC, Arias-Stella J, Bellido-Fuentes Y, Bobadilla ML, Olmedo G, Brito-García I, Méndez-Herrera A, Cardinal L, Flores B, Peñaranda J, Martínez-Better J, Soilán A, Figueroa J, Caserta B, Sosa C, Moreno A, Mural J, Doimi F, Giménez D, Rodríguez H, Lora O, Luciani S, Broutet N, Darragh T, Herrero R. Multicentric study of cervical cancer screening with human papillomavirus testing and assessment of triage methods in Latin America: the ESTAMPA screening study protocol. BMJ Open. 2020 May 24;10(5):e035796. doi: 10.1136/bmjopen-2019-035796. PMID: 32448795; PMCID: PMC7252979.

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Labcorp supports coverage for multi-target stool RNA (mt-sRNA) colorectal cancer screening tests under National Coverage Determination 210.3. Labcorp is a global leader of innovative and comprehensive laboratory services headquartered in Burlington, North Carolina. With nearly 70,000 employees, Labcorp supports clients in approximately 100 countries, providing a wide range of diagnostic and drug development services. The company performs over 700 million tests annually.

Labcorp is deeply embedded in the U.S. healthcare system, offering digital solutions, test ordering platforms, and clinical decision support tools tailored for primary care. Labcorp's extensive network includes over 2,200 patient service centers. Through its Diagnostics Laboratories and Biopharma Laboratory Services segments, Labcorp delivers comprehensive laboratory services that aid in healthcare decisions and advance scientific research globally.

Labcorp has publicly announced a strategic collaboration through which it intends to make available to providers and patients the first FDA-approved non-invasive multi-target stool RNA test for colorectal cancer, ColoSense, which is performed on a sample collected by patients using a simplified, FDA-approved stool collection method.

Colon cancer is the second leading cause of cancer deaths in individuals ages 65 and over. CRC screening remains a significant challenge for Medicare. Approximately 88% of the 69 million Medicare beneficiaries enrolled in Hospital/Medical benefits are between the ages of 45 and 85 and are eligible for CRC screening under NCD 210.3.(1,2) The American Cancer Society National Colorectal Cancer Roundtable reports that more than 1 in 3 adults ages 45+ are not screened as recommended.(3) This is supported by analysis of the data from both the 2022 Behavioral Risk Factor Surveillance System (BRFSS) and the 2023 National Health Interview Survey.(4,5)

One major barrier to higher CRC screening compliance remains access and ease of ordering. Upon launch, ColoSense will be immediately available through Labcorp’s infrastructure for physicians who want to order the test for their patients. Labcorp data feeds and connectivity have bidirectional interfaces with >700 EMR, PMS, and LIS systems nationwide. This provides more clinicians with more choices for CRC screening and provides an easy-to-use option for patients, particularly in underserved areas and health deserts and who may be reluctant or unable to access more traditional and invasive methods of CRC screening. By introducing a new innovative, FDA-approved stool-based screening test, delivered via Labcorp’s nationwide infrastructure, we can significantly increase access to life-saving screenings, particularly for unscreened Medicare beneficiaries.

In the CRC-PREVENT clinical trial, a total of 8,920 subjects completed all study requirements. A subset of 7,763 subjects were determined by the FDA to be average-risk for CRC. The Average-risk Cohort (n = 7,763) served as the primary effectiveness cohort for the PMA review. In the Average-risk Cohort, ColoSense demonstrated 93% sensitivity for CRC and 45% sensitivity for Advanced Adenomas. It was further stated by the Agency that, “ColoSense additionally demonstrated benefit over FIT, identifying 4 of 6 (67%) CRC cases that were not identified by FIT. Similarly, for AA detection, ColoSense identified 52 of 335 (16%) AA cases that were not identified by FIT.”(6)

The ColoSense test has also demonstrated excellent performance in the population of participants in Medicare and Medicaid. Across all 8,920 subjects in the CRC-PREVENT clinical trial, 1,360 (15.2%) were 65 years or older, 781 were Medicaid beneficiaries (8.8%), 1,081 (12.1%) were Medicare beneficiaries, and 687 (7.7%) were Medicare Advantage enrollees. When looking at subjects in the CRC-PREVENT study who are eligible for health coverage under CMS (Medicare/Medicaid) (n = 2,549), ColoSense showed 95% sensitivity for detecting Colorectal Cancer (n = 19) and 56% sensitivity for detecting advanced adenomas (n = 242).(7) This is particularly important for the Medicare-aged population, as an American Cancer Society report estimated that individuals ages 65 and older would account for 56% of colorectal cancer cases and 68% of colorectal cancer deaths in 2023.(8)

ColoSense is a reasonable and necessary screening test for the detection of colorectal neoplasia in Medicare beneficiaries. Expanding the current NCD to cover stool RNA technologies, when FDA approved and meeting designated thresholds of performance, will assist CMS in meeting the needs of patients.

Sincerely,
Jim Almas, M.D.
VP & National Medical Director for Clinical Effectiveness
Labcorp

1. https://www.kff.org/medicare/state-indicator/medicare-beneficiaries-by-age/
2. https://data.cms.gov/tools/medicare-enrollment-dashboard
3. https://nccrt.org/our-impact/data-and-progress/
4.https://www.cdc.gov/pcd/issues/2025/25_0139.htm#:~:text=In%202023%2C%20%20estimated%20percentages%20of,vs%2073.4%25%2C%20P%20%3C%20
5. https://www.cdc.gov/pcd/issues/2025/25_0175.htm#:~:text=The%20overall%20response%20rate%20for,69.4%20million%20people%20(Table)
6. https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf
7. https://www.cms.gov/files/document/id319.pdf
8. American Cancer Society. Colorectal Cancer Facts & Figures 2023-2025. Atlanta: American Cancer Society; 2023.

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Mercy’s Precision Medicine program has adopted and deployed Colosense into the current suite of CRC primary care screening methodologies due to several key attributes related to the test parameters and characteristics. As such, we’ve been able to accumulate practical and pragmatic experience that leads us to fully support the expansion of the National Coverage Determination to be inclusive of Colosense and mt-stool RNA detection methodologies.
The current sensitivity and specificity cutpoints in the National Coverage Determination (NCD) for blood-based colorectal cancer screening tests (74% sensitivity for CRC and 90% specificity for no lesions) fail to account for a test such as ColoSense that has much higher as well as diversified sensitivity (94% for CRC, 46% for advanced adenomas). There is ample evidence in the literature [1] that a test with much higher colorectal cancer and advanced adenoma sensitivity, at a slightly lower specificity, would be expected to reduce CRC incidence and mortality more substantially than meeting the blood-based threshold without sensitivity for precancerous lesions. We have seen this public health promise demonstrated firsthand - previously screen reluctant patients who’ve agreed to Colosense testing are positive with subsequent advanced adenomas removed during colonoscopy. This type of narrative has been potent as we develop internal clinical champions – clinicians who previously were skeptical of other home-based options due to limited ability to find precursor lesions.
We are also in favor of and would advocate for CMS adding supplemental coverage criteria supporting coverage for tests with higher CRC sensitivity and meaningful advanced adenoma sensitivity. For example, setting the CRC threshold at 83% (based on Guardant Shield [2]) and the advanced adenoma threshold at 24% (based on FIT [3]), while modestly lowering the specificity threshold below 88% (Based on ColoSense [4]) for no lesions. I would amplify a salient point made by another commentor in this space that the specificity for version 1 of this novel stool RNA screening product is approximately the same as the specificity of the original Cologuard test version as it entered the commercial screening marketplace. We are in full agreement with the statement made that all non-invasive tests that provide superior advanced adenoma detection rates (including traditional serrated adenomas or other advanced serrated lesions), thus preventing more cases of CRC, should be prioritized and promoted over tests that only provide early detection.
While one might reasonably conclude that reduced specificity means higher false positive rates, leading to more unnecessary colonoscopies, a practical and targeted approach in a diverse community utilizing the full complement of screening technologies as well as appropriate risk stratification helps mitigate this type of concern. Notable as well and related to the above point, in CRC-PREVENT Colosense was demonstrated to have consistent performance across age groups, with no degradation in sensitivity among younger participants. This is particularly important when considering that, according to the January 2024 Dual Eligible Data Book, 19% of Medicare beneficiaries are under age 65 and dually eligible for Medicare and Medicaid. These individuals often live with complex comorbidities or disabilities that limit access to in-person care and contribute to disproportionately high healthcare costs. Offering a non-invasive, highly sensitive screening test like ColoSense (starting at age 45) provides a convenient and accessible option for this vulnerable population.
Additionally, ColoSense's novel collection methodology makes it easier for patients to complete, particularly for older individuals and those with limited dexterity. Improved compliance for stool-based testing will be a critical driver of reducing morbidity and mortality, and ColoSense is uniquely positioned in the market to achieve that goal. In summary, ColoSense elegantly addresses two major challenges in CRC screening: making screening accessible and ensuring patients complete the process. By providing a high fidelity, noninvasive test paired with navigation options to facilitate positive patients to colonoscopy, ColoSense can help bridge persistent gaps in early detection. With CMS’s support for innovative screening methods, there is an opportunity to promote greater equity by reaching more people, boosting follow-through, and ultimately saving more lives - especially in our most challenged and disadvantaged communities.

1. Ladabaum U, Church TR, Feng Z, Ransohoff DF, Schoen RE. Counting Advanced Precancerous Lesions as True Positives When Determining Colorectal Cancer Screening Test Specificity. J Natl Cancer Inst. 2022 Jul 11;114(7):1040-1043. doi: 10.1093/jnci/djac027. PMID: 35134969; PMCID: PMC9275773.
2. Chung DC, Gray DM 2nd, Singh H, Issaka RB, Raymond VM, Eagle C, Hu S, Chudova DI, Talasaz A, Greenson JK, Sinicrope FA, Gupta S, Grady WM. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening. N Engl J Med. 2024 Mar 14;390(11):973-983. doi: 10.1056/NEJMoa2304714. PMID: 38477985.
3. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014 Apr 3;370(14):1287-97. doi: 10.1056/NEJMoa1311194. Epub 2014 Mar 19. PMID: 24645800.
4. Barnell EK, Wurtzler EM, La Rocca J, Fitzgerald T, Petrone J, Hao Y, Kang Y, Holmes FL, Lieberman DA. Multitarget Stool RNA Test for Colorectal Cancer Screening. JAMA. 2023 Nov 14;330(18):1760-1768. doi: 10.1001/jama.2023.22231. Erratum in: JAMA. 2024 Mar 12;331(10):888. doi: 10.1001/jama.2024.1637. PMID: 37870871; PMCID: PMC10594178.

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Early detection dramatically improves outcomes for colorectal cancer (CRC). Catching CRC early makes a life-changing difference for patients and families. Innovative, non-invasive, and at-home screening options expand choice and convenience, making it far more likely that people will complete their recommended screenings. These newer tests can also identify cancer at earlier stages or detect precancerous lesions before symptoms appear—when treatment is most effective and survival rates are highest. Medicare policy should ensure equitable access to CRC screening. CMS has an important role to play in achieving the goal of 80% screening in every community.

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Geneoscopy is pleased to note the opening of the NCA to reconsider NCD 210.3, and we write today to emphasize the benefit of adding multi-target stool RNA (mt-sRNA) tests to broaden screening alternatives covered for Medicare beneficiaries in Section 210.3 of the National Coverage Determinations (NCD) Manual.

CMS has covered one multi-target Stool DNA (sDNA) test under the stool-based colorectal cancer screening section of the NCD since October 9, 2014. While the agency has made limited updates to this section—most notably lowering the recommended screening age—January 19, 2021 marked the first time CMS expanded coverage of biomarker screening tests for CRC under NCD 210.3, establishing performance criteria specific to blood biomarker tests and facilitating coverage for new blood biomarker tests following FDA approval. Based on the strong test performance characteristics of ColoSense, as provided in the pivotal trial that formed the basis of FDA approval, it is appropriate for the agency to update the NCD to cover stool RNA tests with similar analytical and clinical validity for sensitivity and specificity that CMS considered in its 2014 coverage decision.

I. Background & Clinical Evidence in Support of Medicare Coverage

Geneoscopy’s CAP/CLIA-certified laboratory, located in St. Louis, Missouri, developed and will perform the ColoSense multi-target sRNA CRC screening test. The FDA granted ColoSense a Breakthrough Device Designation on January 10, 2020. Geneoscopy submitted a PMA application for ColoSense to the FDA on January 19, 2023. ColoSense was approved by the FDA on May 3, 2024.

ColoSense is intended for the qualitative detection of colorectal neoplasia-associated RNA markers and for the presence of occult hemoglobin in human stool for the purpose of aiding in the detection of colorectal cancer (CRC), advanced adenomas (AA), and serrated precancerous lesions (SPL). A positive ColoSense result may indicate the presence of CRC, AA, and/or SPL and should be followed by a diagnostic colonoscopy. ColoSense involves a proprietary RNA extraction method that amplifies the human signal and degrades bacterial noise in stool, allowing for sensitive extraction of human sRNA.

ColoSense underwent clinical validation through the CRC-PREVENT clinical trial (NCT04739722) [1]. This study evaluated 8,920 subjects who completed ColoSense and a subsequent colonoscopy. Across all 8,920 subjects, 1,360 (15.2%) were 65 years or older, 781 were Medicaid beneficiaries (8.8%), 1,081 (12.1%) were traditional Medicare beneficiaries, and 687 (7.7%) were Medicare Advantage enrollees. Results from CRC-PREVENT became available in December 2022 and were published in the Journal of the American Medical Association in October 2023 [2].

Across all eligible subjects (n = 8,920), a total of 36 subjects were found to have colorectal cancer on colonoscopy (prevalence of 0.4%), and a total of 606 subjects were found to have advanced adenoma on colonoscopy (prevalence of 6.8%). ColoSense detected 34 of 36 subjects with colorectal cancer (94% sensitivity). ColoSense detected 278 of 606 subjects with advanced adenomas (46% sensitivity). Importantly, ColoSense demonstrated 100% sensitivity for Stage I CRC (n = 14 / 14).

Among all 8,920 subjects, 7,763 were considered average-risk for CRC and were eligible for the primary effectiveness analysis performed by the FDA. In the average-risk cohort, ColoSense demonstrated 93% sensitivity for CRC, 45% sensitivity for AA, 22% sensitivity for SPL, and 86% sensitivity for all other findings, with 88% specificity for no findings on colonoscopy. It was further stated by the Agency that, “ColoSense additionally demonstrated benefit over FIT, identifying 4 of 6 (67%) CRC cases that were not identified by FIT. Similarly, for AA detection, ColoSense identified 52 of 335 (16%) AA cases that were not identified by FIT. For SPL detection, ColoSense identified 12 of 88 (14%) SPL cases that were not identified by FIT.”

II. CMS Precedent Supports ColoSense Coverage

The clinical utility of non-invasive, stool-based CRC screening tests has been well established, and CMS has stated its position on the clinical utility of stool-based biomarker testing and the need for innovations to improve uptake of screening. In October 2014, CMS expanded the CRC screening benefit to include coverage of Cologuard. In the Decision Memo for Cologuard, CMS reasoned that “[p]rimary prevention, early detection and early treatment have contributed to the observed reduction in mortality” in CRC. CMS noted that “Medicare currently covers several CRC screening tests, yet utilization rates are suboptimal. The Cologuard test is a technologically advanced, non-invasive CRC screening test, with test performance that has been shown to be significantly better in detecting advanced adenomas and cancers than current fecal immunochemical tests.” The agency found that “[b]ased on a systematic review of the evidence…colorectal cancer screening in Medicare beneficiaries using the Cologuard test is appropriate for the prevention or early detection of illness or disability.”

ColoSense’s clinical pattern of use as a CRC screening test mirrors that of Cologuard, but uses sRNA biomarkers rather than sDNA biomarkers. The agency’s 2014 determination that Cologuard is appropriate for the prevention or early detection of illness or disability applies equally to ColoSense. In the 2014 determination, CMS affirmed that a multi-target stool nucleic acid test could serve as a CRC screening test by providing higher sensitivity for colorectal neoplasia at multiple stages, given a specificity tradeoff, versus FIT. The ColoSense clinical data on which the FDA based its approval demonstrate comparable sensitivity and specificity test benchmarks as those underlying CMS’s 2014 coverage determination, with a similar modest tradeoff in specificity. These clinical data for ColoSense should lead CMS to the same conclusion that ColoSense qualifies as reasonable and necessary for the prevention or early detection of CRC in Medicare beneficiaries.

III. Precancerous Adenoma Sensitivity Supports ColoSense Coverage

The early identification and removal of precancerous lesions has long been viewed as a critical attribute of screening, and CMS has acknowledged that CRC-related survival can be improved through prioritizing early-stage detection of adenomas and malignant lesions. In the 2021 NCD related to Blood-Based Biomarker Tests, CMS concluded, “The ability of a CRC screening test to detect advanced adenomas is essential to prevent cancer by removing the adenoma before it progresses and is one advantage to direct visualization tests like screening colonoscopy. Of the non-invasive tests, the stool DNA test (Cologuard®) had a sensitivity of 42.4% for advanced adenomas (Imperiale, 2014) and FIT had a sensitivity of 27% for advanced adenomas (Niedermaier, 2017).”

Advanced adenomas can now be detected with increased sensitivity, a development that accompanies the evolution of non-visualization laboratory tests for colorectal neoplasia. This corresponding improvement in advanced adenoma sensitivity can result in improved prevention of CRC, thereby reducing CRC morbidity and mortality. Continued improvement in advanced adenoma sensitivity would be a significant contributor to improved patient health. In this context, ColoSense, a noninvasive biomarker test that demonstrated 46% sensitivity for advanced adenomas (n = 606, CI: 42%-50%), in addition to the 100% sensitivity for Stage I cancer (n = 14, CI: 79%-100%), would be anticipated to confer incremental clinical utility when compared to a test with lower sensitivity for early-stage cancer and precancerous adenomas.

IV. Published HEOR Modeling Data Supports ColoSense Coverage

In prior coverage decisions, CMS has acknowledged the absence of direct or indirect mortality data. Instead of relying on clinical utility data, CMS has used clinical validity (i.e., sensitivity and specificity) to assess the capabilities of various tests to detect colorectal cancer and precancerous lesions in patients. In this National Coverage Analysis, CMS will likely take a similar approach, but in doing so, must consider that different sensitivity / specificity combinations can achieve comparable results in terms of mitigating CRC morbidity and mortality.

In an article titled, “Projected Impact and Cost-Effectiveness of Novel Molecular Blood-Based or Stool-Based Screening Tests for Colorectal Cancer” [3], leading experts in analytic modeling studies assessed numerous tests, including three nucleic-acid, stool-based tests (Cologuard, Cologuard Plus, and ColoSense). Researchers concluded that all three tests yielded “similar results” in terms of CRC incidence and mortality reductions. Specifically, relative to no screening, the model estimated that Cologuard, Cologuard Plus, and ColoSense would reduce CRC cases by 68%, 67%, and 68% respectively. This similar outcome was despite different specificity profiles of the various tests, with Cologuard, Cologuard Plus, and ColoSense being assumed to have a specificity of 90%, 93%, and 87%, respectively.

First, this analysis suggests that ColoSense should be covered, based on the expectation that its sensitivity and specificity lead to similar clinical utility to two tests already covered under the existing NCD 210.3 (B) (2). Second, it suggests Medicare should establish multiple sets of coverage criteria (i.e., sensitivity and specificity cutpoints) to ensure tests with varying cutpoints, but similar expected outcomes, are eligible for coverage.

V. Innovation & Ease of Use Supports ColoSense Coverage

The addition of a novel multi-target, stool-based screening test into the market will stimulate innovation in test performance, characteristics, and features, which will ensure physicians have ample, and ever-improving, alternatives to support patient care. In the 18 months since ColoSense was approved, this incremental innovation is already apparent.

In over a decade since Medicare covered the first multi-target nucleic acid-based test, Geneoscopy is not aware of any significant product change made to improve the patient experience and streamline collection. Geneoscopy designed the ColoSense sample collection process with the patient experience in mind, recognizing the evidence that at-home stool collection has been perceived as unpleasant and is a significant barrier to improving compliance [4]. These researchers state that, “Concerns [with fecal swabs] identified by patients and providers included the possibility of false positives with the FIT which could be caused by test contamination or failing to perform the test properly. Patients also described feelings of disgust toward performing the FIT and difficulties in following the instructions.” Geneoscopy’s simple, low-contact process has demonstrated excellent patient acceptance, low rates of collection errors, and low frequency of invalid samples. Reductions in missed screenings can be achieved through patient acceptance, and persistent adherence has been shown to improve the efficacy of cancer screening, with an overall impact on population health. Competition drives innovation, a vital characteristic of a functioning market for patients and providers.

While CMS has indicated in prior decisions that adherence or compliance with CRC screening guidelines should not be considered a test performance characteristic of a screening test, it is nevertheless a critical driver of clinical outcomes. An accurate screening test that is not completed, or completed incorrectly, will not detect colorectal cancer or precancerous adenomas. Geneoscopy’s innovation to streamline the stool collection process while maintaining clinical performance is a critical differentiator for Medicare beneficiaries, particularly for older individuals, individuals with reduced health literacy, and those with limited dexterity.

VI. Clinical Guideline Inclusion Supports ColoSense Coverage

On May 30, 2025, the National Comprehensive Cancer Network (NCCN) updated its Colorectal Cancer Screening guidelines to include ColoSense as a first-line test for colorectal cancer screening in average-risk patients [5]. The NCCN guidelines are comprehensive, evidence-based recommendations to support the prevention, diagnosis, and treatment of more than 97% of cancers affecting patients in the United States. They are regularly updated to reflect the latest scientific evidence and improve the quality and consistency of cancer care.

In the guidelines, multi-target stool RNA-based testing was recommended as an equivalent screening modality with the same screening interval (i.e., every 3 years) as multi-target stool DNA testing. Inclusion of ColoSense in clinical guidelines affirms that leading experts support its use in practice and recognize it as consistent with accepted standards of medical care, reinforcing that the test is reasonable and necessary for Medicare beneficiaries.

VII. Commercial Medical Policy Inclusion Supports ColoSense Coverage

Since FDA Approval, ColoSense has been covered by numerous commercial insurance plans, including Blue Cross and Blue Shield's Federal Employee Program, Blue Cross Blue Shield of Michigan, Blue Cross Blue Shield of Massachusetts, Louisiana Blue, Blue Cross and Blue Shield of Kansas, Blue Cross Blue Shield of Rhode Island, and the Community Health Plan of Washington. These plans reviewed the evidence associated with ColoSense, and subsequently issued a policy statement deeming it medically necessary as a screening technique for colorectal cancer and advanced adenomas. The summary of evidence in several policies states the following, “Clinical utility of FIT-RNA is based on the similar performance characteristics of FIT-RNA compared to FIT-DNA so that FIT-DNA modeling studies are also of relevance for FIT-RNA. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome”.

Commercial coverage serves as a strong indicator of lab test acceptance in the broader medical community, and can serve as a proxy for appropriateness and utility. This real-world context on how ColoSense is being adopted by commercial payors after FDA approval and how the test is valued outside of the Medicare system further supports the conclusion that the ColoSense test is reasonable and necessary for the Medicare population.

VIII. Update to NCD 210.3 Warranted for Multi-target Stool RNA

Evidence supports modifications to NCD 210.3 to provide coverage of sRNA stool testing and create opportunities for further innovation in colorectal cancer screening using novel biomarkers. The NCD is over ten (10) years old, with subsections B.2 and C(1) specifically limiting coverage to a single commercial brand, the Cologuard sDNA test. In the context of advancing science and innovation, the test-specific coverage restriction is out of alignment with the significant advances in sRNA CRC screening technology over the past several years.

Geneoscopy is pleased to have this opportunity to comment and inform the NCD process. We are gratified to see the widespread support for adding ColoSense as a covered benefit for Medicare beneficiaries, as reflected in the public comments.

Sincerely,
Dr. Erica K. Barnell, MD PhD
Chief Medical and Science Officer
Geneoscopy Inc.

Citations

[1] ClinicalTrials.gov. ColoSense – Study of ColoSense in Diagnosing Colorectal Conditions. ClinicalTrials.gov Identifier: NCT04739722. Accessed October 9, 2025. https://www.clinicaltrials.gov/study/NCT04739722?term=colosense&rank=1
[2] Barnell EK, Wurtzler EM, La Rocca J, Fitzgerald T, Petrone J, Hao Y, Kang Y, Holmes FL, Lieberman DA. Multitarget Stool RNA Test for Colorectal Cancer Screening. JAMA. 2023 Nov 14;330(18):1760-1768. doi: 10.1001/jama.2023.22231.
[3] Ladabaum U, Mannalithara A, Schoen RE, Dominitz JA, Lieberman D. Projected Impact and Cost-Effectiveness of Novel Molecular Blood-Based or Stool-Based Screening Tests for Colorectal Cancer. Ann Intern Med. 2024 Dec;177(12):1610-1620. doi: 10.7326/ANNALS-24-00910. Epub 2024 Oct 29. PMID: 39467291; PMCID: PMC12302969.
[4] Luque JS, Wallace K, Blankenship BF, Roos LG, Berger FG, LaPelle NR, Melvin CL. Formative Research on Knowledge and Preferences for Stool-based Tests compared to Colonoscopy: What Patients and Providers Think. J Community Health. 2018 Dec;43(6):1085-1092. doi: 10.1007/s10900-018-0525-x. Erratum in: J Community Health. 2018 Dec;43(6):1093. doi: 10.1007/s10900-018-0534-9. PMID: 29767821; PMCID: PMC6239994.
[5] National Comprehensive Cancer Network. Colorectal screening. NCCN. Accessed October 9, 2025. https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf

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I am a gastroenterologist and outcomes researcher at the Northwestern University Feinberg School of Medicine, where I serve as the Director of Precision Medicine for the Gastroenterology Division. My research focuses on advancing precision medicine and clinical trial development in inflammatory bowel disease and colorectal cancer prevention. I have been involved in numerous phase 2 and 3 clinical trial programs and evidence generation for colon cancer screening/surveillance and chemoprevention which has been used for guideline developments as well as national screening recommendations.

As a result of my research and thought leadership, there is a broad recognition that the most meaningful way to reduce colorectal cancer (CRC) incidence and mortality is through the detection and removal of advanced adenomas (AAs), precancerous lesions that have a high likelihood of progressing to cancer if left untreated. The CRC-PREVENT trial demonstrated that ColoSense, an RNA-based stool test, detected 278 of 606 subjects with advanced adenomas, representing a 46% sensitivity (CI95% 42%-50%).¹ This class of lesions included serrated precancerous lesions with dysplasia and traditional serrated adenomas, which, among serrated lesions, carry the highest propensity for malignant transformation.²

This level of precancer detection is critical. Many other noninvasive screening options that are currently covered by CMS, including FIT and emerging blood-based tests, show limited sensitivity for AAs and can include FDA-required labeling that explicitly warns of their poor performance in detecting these lesions or early-stage CRCs. While detecting late-stage cancer is important, it is not enough. True cancer prevention requires identifying disease at the precancerous stage, before it has the opportunity to become life-threatening.

ColoSense’s high sensitivity for AA is compounded by its simplified at-home collection method. While other at-home stool tests require stool sample manipulation, or the separation of a stool sample into multiple containers, ColoSense has removed any touching or scraping of the sample from its process.³ We know from many years of experience with stool based tests, and my own research related to implementation of stool based tests for inflammatory bowel disease, that confusion and undesirable aspects of the at-home collection, are big barriers to compliance. ColoSense overcomes these challenges.

This matters because the uptake and completion of a test are among the most critical determinants of a screening strategy’s real-world effectiveness. A screening test with excellent sensitivity and specificity is of limited value if patients do not complete the testing process or fail to follow through with diagnostic colonoscopy after a positive result. Multiple studies have highlighted this reality: adherence to the entire screening continuum (including initial participation, proper sample collection, return of the kit, and follow-up on abnormal findings), is what drives reductions in colorectal cancer incidence and mortality.^4-5 In fact, comparative modeling groups have shown that the benefit of any given modality cannot be evaluated in isolation of its uptake, as differences in participation rates and follow-up adherence often outweigh differences in test accuracy.⁶ ColoSense differentiates itself by excelling in both domains: strong clinical performance and high patient acceptability, coupled with system-level support that closes gaps across the screening continuum.

Expanding access to noninvasive tests like ColoSense that can detect AAs while alleviating the burden on the patient to comply with screening recommendations, offers a path toward meaningful cancer prevention, not just late-stage diagnosis. This distinction has important implications for both patient outcomes and long-term healthcare costs, and I support expanding Medicare coverage to this category of innovative and high sensitivity tests by creating coverage criteria that accommodates ColoSense’s specificity of 88% for no lesions on a colonoscopy, a modest reduction from the current 90% threshold for blood-based tests.

Parambir S. Dulai, MD
Associate Professor of Medicine, Division of Gastroenterology & Hepatology
Director, Precision Medicine
Northwestern University Feinberg School of Medicine

1. Barnell EK, Wurtzler EM, La Rocca J, Fitzgerald T, Petrone J, Hao Y, Kang Y, Holmes FL, Lieberman DA. Multitarget Stool RNA Test for Colorectal Cancer Screening. JAMA. 2023 Nov 14;330(18):1760-1768. doi: 10.1001/jama.2023.22231. Erratum in: JAMA. 2024 Mar 12;331(10):888. doi: 10.1001/jama.2024.1637. PMID: 37870871; PMCID: PMC10594178.
2. Yang F, Ma D. Sessile Serrated Lesion Pursuit: FITness and Benchmark. Gastroenterology. 2024 Nov;167(6):1246-1247. doi: 10.1053/j.gastro.2024.04.010. Epub 2024 Apr 22. PMID: 38657778.
3. Barnell EK, Kruse K, Wurtzler EM, Scott MC, Barnell AR, Duncavage EJ. Analytical validation of a scrape-free multitarget stool RNA test for colorectal cancer screening. Pract Lab Med. 2025 Sep 3;47:e00502. doi: 10.1016/j.plabm.2025.e00502. PMID: 40994831; PMCID: PMC12454295.
4. Zauber AG, Winawer SJ, O'Brien MJ, Lansdorp-Vogelaar I, van Ballegooijen M, Hankey BF, Shi W, Bond JH, Schapiro M, Panish JF, Stewart ET, Waye JD. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med. 2012 Feb 23;366(8):687-96. doi: 10.1056/NEJMoa1100370. PMID: 22356322; PMCID: PMC3322371.
5. Knudsen AB, Zauber AG, Rutter CM, Naber SK, Doria-Rose VP, Pabiniak C, Johanson C, Fischer SE, Lansdorp-Vogelaar I, Kuntz KM. Estimation of Benefits, Burden, and Harms of Colorectal Cancer Screening Strategies: Modeling Study for the US Preventive Services Task Force. JAMA. 2016 Jun 21;315(23):2595-609. doi: 10.1001/jama.2016.6828. PMID: 27305518; PMCID: PMC5493310.
6. Ladabaum U, Mannalithara A. Comparative Effectiveness and Cost Effectiveness of a Multitarget Stool DNA Test to Screen for Colorectal Neoplasia. Gastroenterology. 2016 Sep;151(3):427-439.e6. doi: 10.1053/j.gastro.2016.06.003. Epub 2016 Jun 14. PMID: 27311556.

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On behalf of the members of the American Gastroenterological Association (AGA), we appreciate the opportunity to provide input on CMS’s consideration of the addition of ColoSense, an FDA-approved multi-target stool RNA (mt-sRNA) colorectal cancer (CRC) screening test, from Geneoscopy to the National Coverage Decision (NCD) Colorectal Cancer Screening Tests, Publication Number 100-3, Manual Section Number 210.3. The AGA is the trusted voice of the GI community, advancing the science and practice of gastroenterology. Our organization includes over 16,000 members from around the globe engaged in all aspects of the science, clinical practice, and advancement of gastroenterology. The AGA supports CMS’s proposed expansion of coverage to FDA-approved mt-sRNA CRC screening tests.

A recent study by Barnell et al. (JAMA, 2024) evaluated the clinical performance of the mt-sRNA test in an average-risk U.S. population. The results demonstrated that sensitivity and specificity for CRC, and sensitivity for advanced precursor lesions, are comparable to the performance of currently covered stool-based tests such as FIT and Cologuard (mt-sDNA).

The Geneoscopy mt-sRNA test demonstrates operating characteristics, including sensitivity and specificity for CRC and advanced adenomas, that are comparable to Cologuard, which CMS has already approved. Published decision-modeling (Gastroenterology 2024, Annals of Internal Medicine 2024, Clin Gastroenterol Hepatol 2025) shows that the mt-sRNA test would prevent a similar number of CRC cases and deaths as as other fecal test-based strategies. These results further justify coverage expansion.

Expanding coverage to include mt-sRNA testing would increase the number of evidence-based, non-invasive screening options available to Medicare beneficiaries. Greater availability of screening tests can improve access, reduce barriers, and drive competition that benefits patients, payers, and society.

Given the strong clinical evidence, favorable test characteristics, and potential to improve outcomes, AGA supports CMS’s proposal to add FDA-approved, stool-based mt-sRNA CRC screening tests to the NCD on Colorectal Cancer Screening Tests.

References
Barnell EK, Wurtzler EM, La Rocca J, et al. Multitarget Stool RNA Test for Colorectal Cancer Screening. JAMA. 2023;330(18):1760–1768. doi:10.1001/jama.2023.22231. Error in Results. JAMA. 2024;331(10):888. doi:10.1001/jama.2024.1637
Ladabaum U, Mannalithara A, Weng Y, et al. Comparative Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With Blood-Based Biomarkers (Liquid Biopsy) vs Fecal Tests or Colonoscopy. Gastroenterology 2024;167:378-391.
Ladabaum U, Mannalithara A, Schoen RE, et al. Projected Impact and Cost-Effectiveness of Novel Molecular Blood-Based or Stool-Based Screening Tests for Colorectal Cancer. Ann Intern Med 2024;177:1610-1620.

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As molecular genetic pathologist and director of the Division of Genomic and Molecular Pathology at Washington University I have developed multiple assays to better diagnose patients with cancer over the last 20 years. Most of this work involves the detection of acquired somatic mutations present within the genomes of individuals with cancer and detectable via changes in a patient's DNA or RNA. As part of this work as well as work with professional organizations including the College of American Pathologists (CAP), the Association for Molecular Pathology (AMP), and the American Medical Association (AMA) I have evaluated hundreds of molecular oncology assays and am deeply committed to ensuring that emerging diagnostic technologies undergo rigorous and transparent analytical validation and have significant clinical validity.

Molecular testing continues to transform the field of cancer screening including for colorectal cancer (CRC). Manufacturers of stool-based (CRC) screening tests should be expected to provide rigorous validation data including receiver operating characteristic (ROC) analyses that detail how test cutoffs were derived and validated across representative populations, along with transparent justification for balancing the sensitivity and specificity of test cut-offs. The ColoSense assay uniquely discloses this analytical data. By contrast, the molecular performance of other stool-based tests must be inferred indirectly, by subtracting the area under the curve (AUC) of a comparator fecal immunochemical test (FIT) component from the composite test’s AUC.

When comparing the contribution of the molecular components (DNA or RNA) to ROC AUC for CRC, advanced adenomas (AA) or advanced neoplasia (CRC+AA) across independent, non-head-to-head studies, ColoSense offers a similar or improved contribution as summarized below:
ColoSense [1]: +0.12 (CRC) / +0.08 (AA)
Cologuard [2]: +0.05 (CRC) / +0.06 (advanced neoplasia (CRC+AA))
CologuardPlus [3]: +0.13 (CRC) / +0.11 (advanced neoplasia (CRC+AA))

The ColoSense RNA component contributes a quantifiable and additive classification signal, improving sensitivity without an unacceptable reduction in specificity. This performance transparency underscores ColoSense’s analytic rigor and shows that its molecular contribution equals or exceeds that of other FDA-approved multi-target stool tests.

In making coverage decisions , CMS should evaluate the “total clinical value”, as determined by the aggregate analytical and clinical performance of the assay as a whole and not attempt parse out the potential value of individual elements of the complex algorithms that power such tests. The performance of the aggregate assay, which results in either a positive or negative result, combined with patient adherence, is what determines patient outcomes. Doing so ensures that innovative technologies like ColoSense, which meaningfully expand access and adherence while maintaining robust clinical performance, receive equitable consideration within national coverage determinations.

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One Cancer Place

Subject: Public Comment on NCD CAG-00440R – Empowering the Patient

To: The Centers for Medicare & Medicaid Services (CMS)

On behalf of One Cancer Place, a patient-led organization committed to empowering patients and caregivers to navigate the complex cancer landscape, we strongly support the inclusion of stool RNA tests in the National Coverage Determination (NCD) for colorectal cancer screening.

Our mission is to turn a fragmented healthcare system into a landscape of survival. Screening is the first, most crucial point of navigation for patients. The addition of a non-invasive, home-based stool RNA test significantly reduces the major logistical and psychological barriers that prevent millions of eligible Americans from getting screened.

This test offers a simplified, patient-friendly pathway:

It eliminates the need for extensive bowel prep or sedation, easing the emotional and physical burden associated with colonoscopy.

It allows for easy, scrape-free at-home collection, removing major barriers for those with mobility issues or poor access to transportation.

By adopting this NCD, CMS is directly investing in patient empowerment and early detection. We urge CMS to finalize this determination promptly to ensure that this patient-friendly tool is widely accessible to all Medicare beneficiaries, helping to save lives and simplify the journey through cancer prevention.

Thank you.

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Given the limited capacity and acceptance of screening colonoscopy in the U.S., the only way to increase the uptake of and adherence to colorectal cancer (CRC) screening is with good non-invasive tests, where “good” includes rigorously developed and tested test characteristics of high sensitivity (> 90%) for curable-stage CRC, at least some signal for the most advanced of the advanced precancerous lesions, and a false positive risk no more than 10% +/- 2%. Screening with tests less than “good” and well-quantified test characteristics risks harming patients and contributing to increases in CRC incidence and mortality (1). For example, if people previously screened with the fecal immunochemical test (FIT) annually, the multi-target stool DNA (mt-sDNA) test every 3 years, or colonoscopy decide to get screened with one of the blood tests for CRC screening, the inferior detection rates for CRC and especially advanced precancerous lesions will result in less protection from CRC (2).

Such may be the case for the multitarget stool RNA (mt-sRNA) test. While the test may be a “good” test, there are several issues with mt-sRNA that require clarification.

1. From the FDA’s Summary of Safety and Effectiveness Data (SSED) (3), the overall CRC sensitivity of 92.6% was based on 27 cases, with only 3 CRCs among persons aged 65 years and older, the age group with the highest CRC risk. How “confident” could anyone be regarding CRC sensitivity with such a small number of cancers, especially the most important-to-detect early stage (AJCC stages I and II; n=19) CRCs? For a baseball player who starts the season with 12 hits after the first 27 at-bats (a batting average of .444), no person in their right mind would bet on that player winning the batting title at the end of the season. There needs to be greater “confidence” in the sensitivity point estimates for mt-sRNA, which requires evaluating the test in more persons with screen-detected CRCs, particularly among seniors.

2. Also based on the FDA’s SSED, the mt-sRNA test has a suboptimal specificity of 85.6%. Recall that version 1 of the mt-sDNA test had a specificity of 86.6%, a value that was consistently criticized by providers. This (legitimate) criticism was the primary reason for the development and evaluation of the next generation mt-sDNA, which has a specificity of 90.7%, an improvement of more than 30%. The high false-positive rate of mt-sRNA is also concerning for whether some of the “sensitivity” for advanced precancerous lesions may be due to serendipity from the low specificity (4).

3. Importantly, the value added of each of the 3 test components – mRNAs, FIT, and smoking history – requires clarification. It appears possible that FIT + cigarette smoking account for most or all of mt-sRNA’s discrimination. A figure that plots the area under the curve of FIT + smoking status would help understand quantitatively the contribution of the 3 test components. Further, based on Figure 2 and Supplement eFigure 3 of the mt-sRNA pivotal study (5), FIT alone may have better discrimination than the complete mt-sRNA test.

One advantage of the mt-sRNA test is that the FIT component of the test does not require separate collection by the patient. A recent study by Barnell and colleagues (6) showed analytical validation of in-lab FIT, which would preclude the need for home-collection by patients and could eliminate one of the barriers to stool-based screening tests. As acknowledged by the authors, the in-lab approach requires data on clinical validity and real-world feasibility.

The U.S. needs non-invasive CRC screening tests with good and rigorously established CRC test characteristics and minimal user burden, with a clear understanding of how the test works. The mt-sRNA test has not yet clearly achieved these criteria.

References:

1. Dominitz JA, et al. JAMA. 2025. PMID: 40455619
2. Ladabaum, et al. Ann Intern Med 2024; Dec;177(12):1610-1620
3. https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf
4. Lang CA, Ransohoff DF. JAMA 1994 April 6;271(13):1011-3.
5. Barnell EK, et al. JAMA. 2023 Nov 14;330(18):1760-1768. doi: 10.1001/jama.2023.22231.
6. Barnell EK et al. Pract Lab Med. 2025 Sep 3:47:e00502

Disclosure: Dr. Imperiale has received grant support provided to Indiana University School of Medicine for collaborative research with Exact Sciences Corp.

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I am a Professor of Medicine at Washington University School of Medicine in St. Louis. As a gastroenterologist and physician-scientist, my work spans both clinical practice and translational research with the goal of improving prevention, early detection, and treatment of gastrointestinal diseases. I have a particular interest in advancing approaches to colorectal cancer screening and surveillance, as well as understanding how mucosal biology and the gut microbiome contribute to gastrointestinal health and disease. Through these efforts, I strive to enhance patient outcomes by bringing innovative science into everyday clinical care.

As a gastroenterologist and researcher, I have long supported the use of the fecal immunochemical test (FIT) as a proven and effective tool for colorectal cancer (CRC) screening. Within integrated healthcare systems, FIT has demonstrated strong utility in improving screening rates and detecting early-stage disease. However, in broader practice outside of such coordinated systems, sustaining high adherence to annual FIT screening remains a significant challenge, underscoring the need for additional strategies and innovations to close gaps in CRC prevention.

Improving adherence in more fragmented healthcare settings will require expanding the toolbox of screening options. RNA-based stool tests like ColoSense offer a promising path forward. As noted by the FDA, “ColoSense additionally demonstrated benefit over FIT, identifying 4 of 6 (67%) colorectal cancer cases that were not identified by FIT. Similarly, for advanced adenoma detection, ColoSense identified 52 of 335 (16%) advanced adenoma cases that were not identified by FIT.” The higher sensitivity for both colorectal cancer and advanced adenomas is achieved with a modest reduction in specificity, which is expected given the tradeoff between these two metrics.

In its 2014 decision, CMS concluded that, “The Cologuard™ test had a significantly higher sensitivity for colorectal cancer and advanced precancerous lesions compared to FIT; while specificity was significantly lower (more false positive results; Imperiale, 2014)” and that Cologuard would serve as a “a suitable screening test likely to lead to improvements in health outcomes”. The CMS framework established in the coverage of Cologuard should apply to ColoSense, and I would recommend establishing formal cut-points and coverage criteria specific to tests that have high sensitivity for colorectal cancer, and more importantly, advanced adenomas.

Expanding coverage to include additional options like ColoSense is an important step toward improving population-wide CRC screening adherence and outcomes.

Sincerely,
Matthew A. Ciorba, MD
Professor of Medicine
Division of Gastroenterology
Director, Inflammatory Bowel Disease Center
Washington University School of Medicine in St. Louis

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Working at one of the nation’s largest Federally Qualified Health Centers, I have seen how ensuring access to a wide range of covered colorectal cancer screening options is essential. Colorectal cancer screening has further evolved into a shared decision-making process, where personalized choices empower patients to engage in their care. Expanding options—such as advanced stool-based tests that incorporate RNA or emerging blood-based tests—helps meet patients where they are and honors individual preferences. Ensuring CMS coverage for these options is particularly vital in underserved communities, where addressing disparities in colorectal cancer screening can lead to earlier detection and improved outcomes.

I am an employee of AltaMed Health Services, the views expressed here are my own.

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Big Mike's Bottom Line is a non-profit organization committed to empowering people to speak freely about colorectal health, learn the signs/symptoms of colorectal cancer, and understand the importance of prevention and early detection so we can eliminate the threat of lives lost to this disease. Having options and clear education is our quest. We appreciate you taking the time to review our comments and appreciate your consideration as we learn more, improve technologies, and share the options, all intended to save lives.

1: Maintain the Current Sensitivity and Specificity Cut-Points for Blood-Based Testing

At Big Mike’s Bottom Line, we support maintaining the current sensitivity and specificity cut-points for blood-based CRC screening tests as established by CMS in the 2020 evidence review. These thresholds were determined through a rigorous process that balanced accuracy, feasibility, and access. Since that review, multiple blood-based CRC screening tests have been developed to meet these specific performance standards, and the FDA has now approved one of these tests as a primary screening option. This approval further validates that the current cut-points are both appropriate and achievable.

Maintaining these evidence-based standards ensures continued patient access to non-invasive, blood-based screening options—particularly for individuals who are hesitant to complete stool-based testing or colonoscopy. This flexibility supports increased screening rates, earlier detection, and improved outcomes—key goals that align directly with BMBL’s mission to save lives through awareness and prevention.

As such, we strongly support keeping the current cut-points for blood-based CRC screening tests to maintain access to this important screening modality.

2: Remove “Treating Provider” Language to Improve Access and Consistency Across Non-Invasive Tests

We also urge CMS to remove the “treating provider” language from the National Coverage Determination (NCD) to harmonize ordering requirements across all non-invasive CRC screening tests. Currently, the NCD contains inconsistent provider requirements for different CRC screening modalities:

-Fecal Occult Blood Tests (FOBT) must be ordered by an attending physician;
-Cologuard has no ordering physician requirement; and
-Blood-based tests must be ordered by a treating physician.

These inconsistencies create confusion and restrict access, especially given that non-invasive CRC screening tests are preventive, not diagnostic. They are intended for average-risk, asymptomatic individuals, many of whom do not have an established primary care provider. Requiring a “treating physician” to order a preventive blood-based screening test places an unnecessary administrative barrier in front of the very populations that could most benefit from a simple, accessible screening option.

As a result, we request that a “treating physician” requirement not be explicitly written into the NCD, consistent with how the Cologuard requirements were written in 2014. Doing so would ensure that any provider type authorized by statute or regulation to order preventive services for Medicare beneficiaries can equally offer all non-invasive CRC screening tests.

This alignment would help close existing screening gaps, improve equitable access, and support CMS’s broader goal of increasing CRC screening participation across diverse populations—helping more people get screened! Every screening can potentially save a life.

Thank you for your time.

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Compared to what is already on the market, including the new, updated stool DNA test and FIT tests, the stool RNA test has a considerably lower specificity at 86%. This will lead to more false positives and unnecessary colonoscopies in already strained system. The stool RNA test also has a relatively low serrated lesion detection rate at 22.4% and as outlined by the SSED, based on the CRC sensitivity and lower bound of the CI, there is a chance that as many as 24% of individuals with colorectal cancer may be missed with the test. More data are needed at this time as evidenced by the requirement for an additional post-approval study.

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As an academic gastroenterologist with 41 years of clinical experience, and over 30 years investigating colorectal cancer biology and screening tests, I wish to raise several issues about the ColoSense test for CMS to consider when making its coverage decision. My comments place this test into perspective with the multi-target stool DNA test that has been used clinically for the past decade, and in my opinion, serves as the standard for molecular stool-based tests. My comments are based on my understanding of CRC screening test design and performance, and reflect my own opinion and not those of my institution or any organization or member of industry.

Although the CRC-PREVENT Trial met its primary endpoints for sensitivity and specificity, careful review of the details provided in the ColoSense Summary of Safety and Effectiveness Data (SSED) deserve further scrutiny (1). Regarding sensitivity of the test for CRC among individuals >65 yrs or older (Medicare population), the limited total number of cancers (n=27) in the analysis set resulted in a total of 3 patients being of Medicare age, only 2 (67%) of whom had a positive ColoSense result (ColoSense SSED, Table 19). By contrast, the BLUE-C study found that among a total of 85 cancers, 44/47 (94%) cancers in the Medicare age set were Cologuard Plus positive (Cologuard Plus SSED, Table 21) (2).

This limitation in sensitivity raises important questions about the factors that contribute to the sensitivity of the ColoSense test. For one thing, it is not clear how much the RNA analysis contributes to the performance of the test, over and above the FIT component. ROC curves for FIT are not provided, and the AUC for the RNA-only component is only 0.62 for CRC and 0.58 for advanced adenomas – metrics that seem to hardly justify adopting a test that is technically complex and expensive.

Of greater concern is the rather unusual inclusion of an environmental factor, namely smoking, into the algorithm of a molecular diagnostic test. Why was this factor included over others such as chronic alcohol use or high BMI that increase CRC risk? The Centers for Disease Control and Food and Drug Administration estimate that only 18.7% of U.S. adults currently use any tobacco product (3). The fact that 33% of subjects in the CRC-PREVENT Trial were smokers suggests that the studied population was higher than average risk, biasing in favor of finding more colorectal neoplasia. Indeed, this seems to be the case: while 30.7% of individuals with a negative colonoscopy were smokers, smokers accounted for 37.0%, 49.8%, and 37.8% of those with CRC, advanced adenomas, and serrated polypoid lesions, respectively (ColoSense SSED, Table 12). Thus, the sensitivity of the assay may be inflated in these pathological subgroups. The embedding of smoking status into the algorithm raises questions as to how the assay would perform without the inclusion of this factor. Also, it seems that the test relies on accurate and honest reporting by patients about their smoking status, something that in clinical practice (outside of a clinical trial) is quite subjective and cannot be confidently measured or validated. In real world settings, patients may be reluctant, or feel embarrassed, to report that they are smokers. So, if those people are entered as “non-smokers”, will the test performance suffer? It is also not clear whether “positive smoking status” reflects current versus former smokers.

With respect to specificity, a very important concern among clinicians, and patients, is the false-positive rate of a molecular stool-based test. For the past decade, the medical community learned to accept the approximate 13% false-positive rate of Cologuard (4). However, advances in stool DNA technology have resulted in the current commercially available Cologuard-Plus test having an overall false-positive rate that is reduced almost by half (7.3%; specificity 92.7%; SSED Cologuard Plus, Table 17). Granted, Cologuard Plus has a 11.6% false positive rate (88.4% specificity) in the Medicare population. But this is still better than the overall false-positive rate for ColoSense of 14.5% (85.6% specificity; ColoSense SSED, Table 15) and 16% (83.9% specificity, Colosense SSED, Table 19) among the Medicare population. A higher false-positive rate for ColoSense represents a setback from what is currently available, and will result in many unnecessary colonoscopies with their attendant costs and risks, particularly in the elderly.

I am all in favor of any colorectal cancer screening test that has performance metrics that improve upon existing tests of similar use. And I realize that stool-based molecular assays can be refined and improved over time. However, in its current iteration, the ColoSense test has many issues that, in my opinion, greatly limit its intended effectiveness.

1. https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf
2. https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230043B.pdf
3. DOI: 10.15585/mmwr.mm7218a1
4. DOI: 10.1056/NEJMc1405215.

Disclosures: I have received consulting fees from Exact Sciences Corporation and Geneoscopy, and research support from Exact Sciences Corporation and Freenome.

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Re: National Coverage Analysis (CAG-00440R)
Request for Public Comment on Coverage of Colorectal Cancer Non-Invasive Biomarker Screening Tests

Dr. Rachel Weintraub appreciates the opportunity to provide comments to the Centers for Medicare & Medicaid Services (CMS) on the coverage of colorectal cancer (CRC) non-invasive biomarker screening tests. Dr. Weintraub is an independent health policy researcher and advocate with FDA regulatory experience in medical devices and a PhD in Organic Chemistry. Dr. Weintraub’s mission is to ensure that the competing interests of protecting the public health and ensuring access to critical medical products and technologies are balanced in a way that provides the greatest net benefit to patients overall.

Acronyms:
? FIT: Fecal Immunochemical Test
? mt-sRNA: Multitarget Stool RNA
? gFOBT: Guaiac-based Fecal Occult Blood Test
? CRC: Colorectal Cancer
? AA: Advanced Adenoma

1. Role and Advantages of Stool-Based RNA Colorectal Cancer (CRC) Screening Tests:

Unlike other stool-based tests, the ColoSense eliminates the need for the patient to swab and scrape the stool. Rather, the patient deposits the sample into the container and mails it to a lab where a technician handles the sample preparation and analysis. This makes the test less aversive and will help with patient adherence (Barnell et al. 2025; Barnell et al. 2023).

Given the less aversive nature and superior performance of the ColoSense relative to other stool-based screening tests, the ColoSense appears to be a good option for patients, particularly those experiencing barriers to accessing colonoscopies. The RNA screening tests are also expected to be less expensive than colonoscopies as they do not require the use of expensive scopes and anesthesia, nor are highly trained and paid physicians needed to analyze and report the results. See below for an in-depth discussion of the performance of RNA CRC screening tests.

While it is not clear that stool-based colorectal cancer screening tests like the ColoSense should completely replace routine screenings via colonoscopy for all patients, they appear to be helpful adjuncts that will facilitate earlier detection and may ultimately be used to reduce the frequency of colonoscopy screenings in asymptomatic patients.

The list price for ColoSense, which was established by CMS, is $508.87, whereas the list price for Cologuard can be as high as $600-681, and the list price for Cologuard Plus is $790 (Ref. 6-10). Thus, ColoSense is typically less expensive out-of-pocket than Cologuard and Cologuard plus. Therefore, extending coverage to ColoSense would be a cost-effective way for CMS to ensure that seniors have access to accurate, noninvasive colorectal screening tests.

2. Performance of Stool-Based RNA Colorectal Cancer (CRC) Screening Tests (Ref. 4-5):

ColoSense has a higher specificity for no lesions than colonoscopy (i.e., fewer false positives; 88% vs 86%, respectively) and is very close in sensitivity for colorectal cancer (i.e., similar false negatives; 94 vs 95%).

While the ColoSense and other FIT-mt-sRNA tests may have significantly lower sensitivities for advanced adenomas than colonoscopies (95%), their sensitivities (about 46%) are slightly higher than FIT-DNA tests (about 42%) and significantly higher than FIT and gFOBT tests (23.8% and 23.9%, respectively). Modeling shows that the number of colorectal cancer deaths averted per 1000 healthy 40-year-olds that undergo screenings from ages 50-75 with 100% adherence, follow-up, and surveillance is similar between the colonoscopy (22-24), FIT (20-23), FIT-DNA (21-24), and gFOBT methods (20-23), with the FIT-DNA being almost identical to colonoscopy. Given the strong similarities between the sensitivity and specificity profiles for FIT-DNA and FIT-RNA, it is anticipated that these methods will perform similarly in terms of their ability to prevent colorectal cancer deaths.

Since the lower performance of the FIT and gFOBT in terms of sensitivity for colorectal cancer, advanced adenomas, and smaller adenomas, relative to the other methods, does not appear to translate to a significant difference in the number of deaths averted, the performance of these methods can be used to establish minimum acceptable sensitivity levels for stool-based tests. For example, a minimum sensitivity of 70% for colorectal cancer and 23.8% for advanced adenomas may be appropriate.

Similarly, 85% may be an appropriate minimum acceptable specificity for stool-based tests. This will give a similar rate of false positives for colonoscopy and will allow for the coverage of the FIT-RNA tests, which appear to have slightly improved performance overall relative to the FIT-DNA methods and comparable rates of deaths averted to colonoscopy, the gold standard for colorectal cancer detection.

3. References:
1. Barnell EK, Kruse K, Wurtzler EM, Scott MC, Barnell AR, Duncavage EJ. Analytical validation of a scrape-free multitarget stool RNA test for colorectal cancer screening. Pract Lab Med. 2025 Sep 3;47:e00502. doi: 10.1016/j.plabm.2025.e00502. PMID: 40994831; PMCID: PMC12454295.
2. Santos DAR, Eiras M, Gonzalez-Santos M, Santos M, Pereira C, Santos LL, Dinis-Ribeiro M, Lima L. A preliminary assessment of a stool-based microRNA profile for early colorectal cancer screening. Sci Rep. 2025 Aug 5;15(1):28597. doi: 10.1038/s41598-025-14485-z. PMID: 40764826; PMCID: PMC12325799.
3. Liu H, Hansen L, Song C, Lin H, Chen D, Chen Z, Zhou H, Yang X, Pan W, Du J. Bioinformatic screen with clinical validation for the identification of novel stool based mRNA biomarkers for the detection of colorectal lesions including advanced adenoma. Sci Rep. 2025 Aug 11;15(1):29397. doi: 10.1038/s41598-025-13074-4. PMID: 40789879; PMCID: PMC12339692.
4. Barnell EK, Wurtzler EM, La Rocca J, et al. Multitarget Stool RNA Test for Colorectal Cancer Screening. JAMA. 2023;330(18):1760–1768. doi:10.1001/jama.2023.22231
5. https://www.uptodate.com/contents/image?imageKey=PC%2F116366. Sources for UptoDate figure data: A) Zauber A, Knudsen A, Rutter CM, et al. Evaluating the Benefits and Harms of Colorectal Cancer Screening Strategies: A Collaborative Modeling Approach. AHRQ Publication No. 14-05203-EF-2. Rockville, MD: Agency for Healthcare Research and Quality; October 2015. B) Knudsen AB, Zauber AG, Rutter CM, et al. Estimation of Benefits, Burden, and Harms of Colorectal Cancer Screening Strategies: Modeling Study for the US Preventive Services Task Force. JAMA 2016; 315:2595.
6. https://www.forbes.com/sites/adairalandry/2025/09/27/colon-cancer-rising-in-adults-colosense-offers-noninvasive-screening-tool/
7. https://www.cologuard.com/insurance
8. https://www.premera.com/wa/provider/news/pharmacy/cologuard-fit-kits/
9. https://www.jackson.org/partners/issues/partners-magazine-fall-2022/the-truth-about-cologuard-tests/
10. https://www.goodrx.com/conditions/colon-cancer/at-home-colon-cancer-test?srsltid=AfmBOor8Tuci_7SkS5xfwIH70Qz1firnzgGHhIUmUOaKkek2BsU8Z4hF

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On behalf of Fight Colorectal Cancer (Fight CRC), the nation’s leading colorectal cancer patient advocacy organization, we appreciate the opportunity to comment on the National Coverage Decision (NCD) regarding Screening for Colorectal Cancer - Non-Invasive Biomarker Tests.
Colorectal cancer is the second leading of cancer death in the U.S., even though screening can prevent or detect disease early. Innovation in screening methods, particularly those that demonstrate high sensitivity and specificity, plays a vital role in reaching unscreened populations and improving overall health outcomes. The evidence shows that when patients can choose the test that best fits their individual needs and preferences, screening uptake is higher. Access to a variety of quality screening options is crucial for meeting the needs of our population, enabling timely and effective CRC detection and treatment.
While Fight CRC does not endorse specific tests, we wholeheartedly support increased access to quality screening tools that can provide reliable, convenient options for individuals nationwide. Our commitment to increasing CRC screening rates reflects our broader advocacy priorities to enhance patient care and outcomes. For these reasons we are supportive of CMS efforts to expand colorectal cancer screening coverage to additional screening modalities when they are proven to be safe and effective and meet established sensitivity and specificity thresholds.
CMS beneficiaries are fortunate to have access to many options when choosing between covered colorectal cancer screening tests, including non-invasive options. We encourage CMS to ensure that coverage of any new modalities applies to average-risk beneficiaries aged 45 and over, in accordance with national guidelines. These non-invasive tests play a vital role in expanding access to CRC screening, particularly in communities with limited access to colonoscopies. If a positive non-invasive test is not followed by colonoscopy however, the benefit of the screening test cannot be realized, and a non-invasive test alone is not enough to confirm a diagnosis. It is medically necessary for patients who receive an abnormal result on a non-invasive test to complete a follow-up colonoscopy in order for screening to be achieved.
Individuals who did not receive a follow-up colonoscopy after an abnormal non-invasive screening result were found to have a risk of death from colorectal cancer that was twice as high as those who did. 42 CFR § 410.37(k) ensured that effective January 1, 2025, colorectal cancer screening tests include a follow-on screening colonoscopy after a Medicare covered non-invasive stool-based colorectal cancer screening test or blood-based biomarker colorectal cancer screening test returns a positive result at no cost to CMS beneficiaries. We strongly encourage CMS to ensure uniform application of comprehensive, cost-free coverage for follow-up colonoscopies for any new non-invasive colorectal cancer screening modalities added for CMS beneficiaries. Patients must not face surprise out-of-pocket costs at that critical step, or else the prevention promise of screening is undermined.
We appreciate the opportunity to comment and hope CMS considers these remarks as they make their final coverage decisions.

Sincerely,

Anjee Davis, MPPA
Chief Executive Officer
Fight Colorectal Cancer

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Title: Gastroenterologist, Metropolitan Gastroenterology Associates

Organization: GI Alliance

I am a board-certified gastroenterologist with Metropolitan Gastroenterology Associates, part of GI Alliance, where I specialize in the prevention, diagnosis, and treatment of gastrointestinal disorders including trying to prevent colon cancer through screening mechanisms. Unfortunately I've had more patients than I can count develop colon cancer due to lack of screening & I've seen first hand how this not only has lifelong mental & physical stressors on individuals & families. Additionally colon cancer is economically harmful through increased costs to the medical community including private insures & medicare. Throughout my 20+ year career, I have been dedicated to advancing digestive health through both patient care and clinical research. I have participated at various levels in research and understand the critical importance of noninvasive testing in improving adherence to colorectal cancer screening. In addition, I recognize the role that health economic modeling plays in demonstrating the value of these tests, both in improving patient outcomes and in reducing the overall burden on the healthcare system.

CMS specifically solicited public comment on sensitivity and specificity cut points for noninvasive tests indicated for the detection of colorectal cancer and advanced colon adenomas. I wanted to highlight a recent manuscript published by Dr. Uri Ladabaum [1], a leading authority in cost-effectiveness modeling for colorectal cancer screening, in which two hypothetical tests were compared:

Hypothetical Test 1: A test that satisfies the CMS thresholds exactly (i.e., 74% sensitivity for CRC, 90% specificity for no lesions), while not detecting advanced precancerous lesions beyond chance. This test would be predicted to reduce CRC incidence and mortality by 16% and 32% in individuals aged 65 years, and by 30% and 48% in those aged 45 years.

Hypothetical Test 2: A similar test that also detects advanced precancerous lesions with 30% sensitivity. As a result of the higher sensitivity for additional precancerous lesions, the CRC specificity decreases to 88%. This test would be predicted to reduce incidence and mortality more substantially (30% and 43% in those aged 65 years; 45% and 58% in those aged 45 years).

This example highlights the tradeoff between sensitivity and specificity, and the corresponding impact on expected outcomes. The ColoSense mt-sRNA test performs similarly to Hypothetical Test 2, where sensitivity for CRC and advanced adenomas is increased (94% and 46%, respectively) versus the current CMS blood-based threshold, with a modest reduction in specificity (88% specificity for no lesions). As such, ColoSense would be expected to reduce CRC incidence and mortality more substantially than would tests without its enhanced sensitivity for precancerous lesions.

The current sensitivity and specificity cut points in the National Coverage Determination (NCD) for blood-based colorectal cancer (CRC) screening tests fail to account for a test that has meaningful advanced adenoma detection beyond chance. The reconsideration of the NCD creates an opportunity for CMS to address advances in early detection capabilities and establish coverage parameters that recognize sensitivity/specificity tradeoffs [2]. As CMS considers coverage criteria for biomarker tests that screen for CRC, it should recognize an important principle: assays falling within an efficiency threshold, balancing gains in early detection against modest decreases in specificity, should be considered for coverage.¹

A careful and deliberate framework is necessary to ensure that innovation in CRC screening (including assays like ColoSense) can be properly evaluated, fairly compared, and effectively deployed to reduce the burden of this disease. I recommend adding supplemental coverage criteria supporting coverage for tests with meaningful advanced adenoma sensitivity. Setting the colorectal cancer sensitivity to 83% (based on Guardant Shield) [3] with an advanced adenoma threshold of 24% (based on FIT) [4], while modestly lowering the specificity threshold to 85% for no lesions, would achieve these aims.

Mark J. Wegmann, MD

Gastroenterologist

Metropolitan Gastroenterology Associates / GI Alliance

Metairie, Louisiana

1. Ladabaum U, Church TR, Feng Z, Ransohoff DF, Schoen RE. Counting Advanced Precancerous Lesions as True Positives When Determining Colorectal Cancer Screening Test Specificity. J Natl Cancer Inst. 2022 Jul 11;114(7):1040-1043. doi: 10.1093/jnci/djac027. PMID: 35134969; PMCID: PMC9275773.

2. van den Puttelaar R, Nascimento de Lima P, Knudsen AB, Rutter CM, Kuntz KM, de Jonge L, Escudero FA, Lieberman D, Zauber AG, Hahn AI, Inadomi JM, Lansdorp-Vogelaar I. Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With a Blood Test That Meets the Centers for Medicare & Medicaid Services Coverage Decision. Gastroenterology. 2024 Jul;167(2):368-377. doi: 10.1053/j.gastro.2024.02.012. Epub 2024 Mar 26. PMID: 38552671; PMCID: PMC11193618.

3. Chung DC, Gray DM 2nd, Singh H, Issaka RB, Raymond VM, Eagle C, Hu S, Chudova DI, Talasaz A, Greenson JK, Sinicrope FA, Gupta S, Grady WM. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening. N Engl J Med. 2024 Mar 14;390(11):973-983. doi: 10.1056/NEJMoa2304714. PMID: 38477985.

4. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014 Apr 3;370(14):1287-97. doi: 10.1056/NEJMoa1311194. Epub 2014 Mar 19. PMID: 24645800

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Title: Gastroenterologist, Metropolitan Gastroenterology Associates

Organization: GI Alliance

I am a board-certified gastroenterologist and serve as the Medical Director of the New Orleans Research Institute, GI Alliance. Over the course of my career, I have combined clinical practice with a deep commitment to research, as a principal investigator for numerous clinical trials designed to improve the diagnosis and treatment of gastrointestinal disease. I have had the privilege of contributing to studies that helped bring new therapies to patients, presenting findings that have shaped clinical practice. I take pride in leading patient-centered research initiatives, mentoring colleagues, and advancing innovation in gastroenterology.

In the colorectal cancer screening National Coverage Determination, sensitivity and specificity cut points are being used as a proxy for a test’s ability to reduce CRC morbidity and mortality. While this is appropriate in the absence of longitudinal clinical outcomes data, it’s important to remember that the key drivers of better outcomes are colorectal cancer sensitivity and advanced adenoma sensitivity.

While several comments have focused on specificity. A false positive due to slightly lower specificity results in a potentially unnecessary colonoscopy, but colonoscopy is an extremely safe procedure, and remains the gold standard for colorectal cancer screening, while also allowing for the removal of colonic lesions. Modeling studies based on well-established assumptions arising from literature on detection rates and clinical outcomes have consistently supported that the sensitivity and specificity of ColoSense is expected to yield favorable outcomes ^1,2,3

While modeling studies have their limitations, these modeling studies are not theoretical but instead lean on the key assumptions that CMS is weighing in its evaluation of non-invasive biomarker colorectal cancer screening tests; sensitivity and specificity cut points. In the past, the Coverage and Analysis Group has used similar information to justify decisions and should do so again. In the instance of colorectal cancer screening, it’s clear that coverage criteria (i.e., sensitivity and specificity cut points) should be added to cover ColoSense, and facilitate future category-based coverage for additional tests that show similar capabilities for the reduction of CRC morbidity and mortality.

George E. Catinis, MD FACG

Medical Director, New Orleans Research Institute
Gastroenterologist, GI Alliance
New Orleans, Louisiana

1. Shaukat A, Levin TR, Liang PS, Weiss JM, Smare C, Boller E, Venkatachalam M, Barnell EK. Cost-effectiveness of Novel Noninvasive Screening Tests for Colorectal Neoplasia. Clin Gastroenterol Hepatol. 2025 Jun 23:S1542-3565(25)00525-7. doi: 10.1016/j.cgh.2025.06.006. Epub ahead of print. PMID: 40562290.

2. Ladabaum U, Mannalithara A, Schoen RE, Dominitz JA, Lieberman D. Projected Impact and Cost-Effectiveness of Novel Molecular Blood-Based or Stool-Based Screening Tests for Colorectal Cancer. Ann Intern Med. 2024 Dec;177(12):1610-1620. doi: 10.7326/ANNALS-24-00910. Epub 2024 Oct 29. PMID: 39467291; PMCID: PMC12302969.

3. Rui M, Wang Y, You JH. Novel non-invasive tests for colorectal cancer screening – a cost-effectiveness analysis. Cancer Epidemiol Biomarkers Prev. 2025;OF1–OF11. doi:10.1158/1055-9965.EPI-24-1549.

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Colorectal cancer screening can reduce cancer incidence and mortality. However, colorectal cancer risks are rising in people born 1960 and later, and screening is underutilized. Increasing options for non-invasive screening tests, such as fecal based tests has the potential to increase screening uptake and improve outcomes. The CRC-PREVENT trial examined the performance of a novel fecal screening test that measures RNA markers and human hemoglobin for detection of colorectal neoplasia. This large, prospective trial used colonoscopy as the reference standard, and found that the novel test had sensitivity of 94% for colorectal cancer and 46% for advanced polyps. Importantly, 64% of enrolled participants had never been screened for colorectal cancer. Taken together, the results suggest that a favorable coverage decision will expand the range of options for effective colorectal cancer screening available to the Medicare population, and have potential to improve rates of screening participation.

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As a practicing medical oncologist with a focus in gastrointestinal malignancies its with grave concern i write with regards to the potential CMS coverage of an inferior, unproven RNA stool based screening test for colon cancer.
I have been involved with the promise of Methylated DNA screening tests for colon cancer since my medical oncology fellowship in 2001 when i was helping capture plasma of patients with colon cancer and seeing if we could detect this aberrantly methylated DNA in patients serum. The ability to detect Colon cancer in a stool based assay was always a promise but the fear was that the gold standard colonoscopy would be ignored but the general public and their clinicians. Over the ensuing decade however the development of a highly sensitive and specific stool based screening assay for colon cancer has been transformative. While a screening colonoscopy is still the gold standard, the convenience of the test has dramatically increased the numbers of patients willing to undergo screening tests for colon cancer. As an oncologist I now see more cases of colon cancer originally diagnosed from cologuard rather than a colonoscopy. I can only assume that many of these patients would never had a screening test given the invasive and involved nature of a colonoscopy.
While the RNA based Colosense seems to be an exciting technology, based on the published data available it appears to be inferior to the cologuard in terms of sensitivity and specificity of both colon cancer and advanced adenomas. Their own publications issue a warning to patients that it may miss as many as 24.3% of colorectal cancers. The high false positive rate of this test will necessitate follow up colonoscopies which will stress a system already struggling to get patients access to colonoscopies in an expedient fashion.
The fact that the FDA required additional testing should not be ignored. RNA based testing seems promising. I wonder why this testing couldn't be combined with existing technologies to increase the sensitivity and specificity of established screening tests?
Please do not pay for an inferior test and give patients the false sense of security that they are being effectively screened for this deadly disease until we are absolutely certain its the best stool based test available

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I encourage caution while interpreting the CRC-PREVENT trial where the performance of multitarget stool RNA (mt-sRNA) has been described. I am a practicing gastroenterologist specialized in gastrointestinal neoplasia and my research has focused on colorectal cancer prevention, economics, and outcomes research.

Stool based colorectal cancer screening has been shown to be effective through detection of hemoglobin as well as exfoliated tumor markers. FIT testing is the primary screening modality for colorectal cancer across the world. With emerging stool-based tests, such as multitarget stool DNA (mt-sDNA), test performance was directly compared to an independent FIT. Namely, patients completed both mt-sDNA and a separate FIT test. In doing so test performance can be directly compared (1, 2, 3). This methodology was also utilized with the next-generation mt-sDNA test (4). Without this head-to-head comparison, test performance cannot be accurately compared. With colorectal neoplasia incidence drift, comparisons to other cohorts are limited. In the CRC-PREVENT trial, an independent FIT was not utilized, rather the mt-sRNA FIT result was compared to the entire mt-sRNA panel (FIT plus RNA plus smoking status). As such, mt-sRNA test performance is being reported in isolation, and it is uncertain as to whether the observed test performance is non-inferior to FIT. Particularly as the mt-sRNA FIT seems to outperform the mt-sRNA panel as reflected in Figure 2 and Supplement 3 eFigure 3 (5).

The mt-sRNA test also utilizes smoking status in generation of the mt-sRNA test score. The number of trial participants labeled as a smoker (34.3%, supplemental 3, eTable 4) is significantly higher than the incidence of tobacco uses in the United States (6). Some trial participants preferred to not answer their smoking status (supplemental 3, eFigure 1). With the weight of smoking status on the generation of the test score and the enriched smoking population in the trial it is difficult to discern whether the FIT and categorical smoking variable rendered the test result positive. This suspicion is raised when considering the positive predictive values (PPV) for colorectal cancer or advanced adenomas with mt-sRNA (20.6%) compared to the PPV for advanced neoplasia alone (37.7%) with next-generation mt-sDNA. While these two tests are from different cohorts (a limitation as noted above), next-generation mt-sDNA only factors in exfoliated tumor markers and hemoglobin, the degree in which sRNA enhances neoplasia detection beyond FIT and smoking status is unclear.

Colorectal cancer screening effectiveness rests on test accuracy and patient participation. Patient participation has increased through the ability to choose among various screening modalities and new and emerging screening tests hope to increase participation in colorectal cancer screening. However, as the number of available tests increases, it is important to compare test performance. There is concern that patients may not fully realize the differences in test performance across the available strategies and with the available information it is uncertain where mt-sRNA is positioned.

1. https://doi.org/10.1056/NEJMoa1311194
2. https://doi.org/10.1016/j.mayocp.2015.10.008
3. https://doi.org/10.14309/ajg.0000000000000445
4. Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening | New England Journal of Medicine
5. Multitarget Stool RNA Test for Colorectal Cancer Screening - PubMed
6. https://odphp.health.gov/healthypeople/objectives-and-data/browse-objectives/tobacco-use/reduce-current-cigarette-smoking-adults-tu-02/infographic?utm_source=chatgpt.com

I am an employee of Mayo Clinic; the views are my own. I also have a professional service agreement with Exact Sciences serving as an independent contractor to provide guidance on study design and analysis, paid to the Mayo Clinic.

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The promise of new screening technologies to detect colorectal cancer earlier and save lives is always exciting and worth careful evaluation. I am sharing my analysis of the ColoSense test from a statistical perspective to clarify some of the metrics provided and offer insights that may help stakeholders consider this technology more thoroughly for future decision-making.

Sensitivity and Specificity Trade-off Analysis
The published results show high sensitivity (94%) but notably lower specificity (86.9%) compared to standard FIT (95.4%) and next-generation mt-sDNA (92.7%). This sensitivity-specificity trade-off, inadequately justified in the publication, has significant clinical implications: the reduced specificity means higher false positive rates, leading to more unnecessary colonoscopies, invasive, costly procedures with inherent risks that strain already limited colonoscopy resources and healthcare capacity. Additionally, the confidence intervals for sensitivity are relatively wide (81%-99%), reflecting limited sample sizes specially for the Medicare groups, which affects the precision of estimates.

Limited RNA Component Contribution
eFigure 3 shows the RNA only component has modest performance (AUC = 0.62 for CRC, 0.58 for advanced adenomas). The publication does not clearly delineate what proportion of detection capability comes from FIT versus the RNA markers. The data suggests that FIT provides the majority of detection power, while the RNA component adds minimal incremental value despite adding substantial cost and complexity to the test.

Evidence for Simpler Alternatives
A recent JAMA publication (Niedermaier et al., 2024; doi: 10.1001/jama.2024.9289) demonstrates that comparable sensitivity (94.9%) and specificity to ColoSense can be achieved simply by lowering the standard FIT threshold from 17 µg/g to 8.8 µg/g without any RNA testing or additional biomarkers. This finding strongly suggests that the added cost and complexity of RNA analysis may not be justified when threshold optimization of existing tests can achieve equivalent performance.

Disclosure: I have over 10 years of experience in simulation modeling across different fields and have previously collaborated on projects with Exact Sciences.

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09/24/25

As an organization focused on women’s preventive health, the Alliance for Women’s Health and Prevention (AWHP) is deeply committed to both the prevention and early detection of cancer. Given the concerning rise in rates of colorectal cancer among younger adults, access to and coverage of comprehensive prevention and screening options — including colonoscopies, stool tests, and blood-based tests — is more critical than ever. As such, we urge you to consider the positive health impacts of innovative screenings for colorectal cancer and the importance of broad access by approving Medicare coverage of ColoSense.

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Dear Dr. Li,

The American College of Radiology (ACR), a professional medical specialty society representing over 41,000 physicians practicing diagnostic radiology, interventional radiology, radiation oncology, and nuclear medicine as well as medical physicists, appreciates the opportunity to submit comments to the Centers for Medicare & Medicaid Services (CMS) on the National Coverage Determination (NCD) for Colorectal Cancer Screening Tests.

CMS recently updated the NCD dashboard to reflect changes to NCD 210.3 – Colorectal Cancer Screening Tests¹, a topic that had been on the waitlist for several months. While we appreciate the progress, we are requesting that the NCD be comprehensively revised to reflect the important expansion of coverage for screening computed tomographic colonography (CTC), as finalized in the 2025 Medicare Physician Fee Schedule final rule, effective January 1, 2025.

CMS issued Change Request (CR) 13939 / Transmittal 13097², instructing Medicare Administrative Contractors (MACs) to begin covering CPT code 74263 for screening CTC, with an implementation date of July 1, 2025. This guidance also specifies that coinsurance and deductible should be waived for this service.

However, the current language in NCD 210.3 still includes the following nationally non-covered indication:

(2) Screening computed tomographic colonography (CTC), effective May 12, 2009.

Additionally, the original non-coverage decision (CAG-00396N: Screening Computed Tomography Colonography (CTC) for Colorectal Cancer)³ remains publicly available in the Medicare Coverage Database.

To avoid confusion among providers and beneficiaries, we respectfully request that:

1. NCD 210.3 be updated to reflect the expanded coverage for CTC as outlined in CR 13939.
2. CAG-00396N be retired or removed to align with the current CMS policy and ensure clarity for stakeholders.

We believe these updates are essential to support appropriate access to colorectal cancer screening and to ensure consistency across CMS policy documents. Thank you for your attention to this matter. If you have any questions or comments on this letter or any other issues with respect to radiology, please contact Alicia Blakey, MS, Principal Economic Policy Analyst at ablakey@acr.org.

References

1. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=281
2. https://www.cms.gov/files/document/r13097otn.pdf
3. https://www.cms.gov/medicare-coverage-database/view/nca.aspx?ncaid=220

Sincerely,

Dana Smetherman, MD, MPH, MBA, FACR, FSBI
Chief Executive Officer
American College of Radiology

Cc:
JoAnna Baldwin, CMS/CCSQ
Kimberly Long, CMS/CCSQ
Kevin J. Chang, MD, FACR, FSAR, ACR
Judy Yee, MD, FACR, ACR
Katie Keysor, ACR
Alicia Blakey, ACR

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With 15+ years’ experience in cancer biomarker discovery & development, including the design and conduct of clinical trials for submission to FDA and Medicare coverage, I comment as a member of a community with a unified goal to save lives. I implore CMS and other commentators to read the mt-sRNA (ColoSense) FDA label and critically appraise the CRC-PREVENT trial. An evidence-based lens will show:
1) FDA’s confidence in mt-sRNA cancer sensitivity seems low. Their summary of safety and effectiveness audit of primary study data from CRC-PREVENT excluded 9 of 36 (25%) cancer events due to ineligibility or non-intended use, leaving only 2/3 Medicare-age cancer events detected, and warned that mt-sRNA might miss as many as 24% of colorectal cancers. FDA has mandated a post-market study of an additional 12,500 participants “to provide more certainty in the test performance.”
2) Low specificity may lead to unnecessary colonoscopies. The specificity of mt-sRNA of 85.6% falls well below that set by CMS-covered mt-sDNA (Cologuard Plus) of 90.7%. If studied in the same population, mt-sRNA might increase false positive results by 55%* relative to mt-sDNA.
3) Mt-sRNA has not been directly compared to other tests and may not do better than FIT: CRC-PREVENT was neither designed nor executed to show that mt-sRNA is better than or as good as any other molecular test. FDA specifically cautions on this point. Figure 2 of CRC-PREVENT shows FIT and mt-sRNA points on the same ROC curve; this questions whether a different FIT cut-off could have produced the same result, without RNA. Supplement 3, eFigure 3 shows the performance of RNA alone (AUROC values of 0.62-0.58) but provides no demonstration that stool RNA markers by themselves out-perform the flip of a coin (AUROC 0.50). Mt-sRNA has never been studied head-to-head against mt-sDNA (Cologuard or Cologuard Plus) in the same patients; assertion that mt-sRNA is comparable to mt-sDNA is completely unsupported.
For these reasons, the mt-sRNA test misses key evidence and performance thresholds to meet or exceed existing CMS standards and portends a clinical step backwards.

https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001C.pdf
https://pubmed.ncbi.nlm.nih.gov/37870871/);
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma_pas.cfm?t_id=783383&c_id=7964
*(90.7-85.6)/(100-90.7) = 0.548

I am an inventor of Mayo Clinic intellectual property in the field of colorectal cancer screening, licensed to Exact Sciences (Madison WI), and have received grant support and royalties from Exact Sciences, paid to Mayo Clinic.

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Challenging the performance of Colosense regarding a lower specificity (vs Cologuard Plus) is valid. Yet, the specificity for version 1 of this novel stool RNA screening product is approximately the same as the specificity of the original Cologuard test version as it entered the commercial screening marketplace.

All genomic-driven testing is eventually optimized per the algorithm. This will undoubtedly happen with Colosense and others in the space.

Given that FIT, with its poor real-world performance in the United States, particularly in the underserved (Medicaid, Community Health Centers,FQHCs) locations, remains an option, Colosense and its embedded navigation services will likely have similar outcomes (except for more specificity-related false positives) to existing MT-stool DNA products in all populations, including the underserved.

The more critical issue is that increased competition in the stool-free Multi-Omic space (DNA, RNA, Proteomics) will drive down costs, incentivize innovation, and improve access to and completion of the two-step testing paradigm. Embedded navigation also appears to be a crucial factor in non-invasive screening processes. Colosense includes this.

All non-invasive tests that provide superior advanced adenoma detection rates ( including sessile serrated adenomas), thus preventing more cases of CRC, should be prioritized and promoted over tests that only provide early detection. Stool-free Multi-Omics, rather than stand-alone FIT, are the future of average-risk CRC screening.

Respectfully submitted.

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As the former Chief Medical Officer of a large medical group and recent President of a clinically integrated network, I am a strong proponent of alternatives to colonoscopy for colorectal cancer (CRC) screening. I applaud the proposed test’s strong sensitivity; however, I have concerns about its specificity falling below 90%.

While a few percentage points may seem minor, in population-level screening those differences translate into large numbers of false positives. In a cohort of 10,000 average-risk patients, a sub-90% specificity rate could mean a thousand people being told they may have an pre-cancerous adenoma or cancer when they do not. Each of those individuals will need to undergo an unnecessary colonoscopy—an invasive procedure that brings real cost, capacity strain, and avoidable anxiety. Gastroenterologists also report the professional and emotional burden of explaining to patients why their screening test was “wrong.”

No screening test will ever achieve perfect specificity, but CMS should carefully weigh whether this test meaningfully advances CRC detection compared with currently available non-invasive options, or whether the trade-off risks adding cost, patient confusion, and stress to an already stretched system.

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As a physician-scientist and gastroenterologist who has studied colorectal (CRC) pathogenesis and prevention for over 30 years, I have dedicated my career to uncovering the biological mechanisms of gastrointestinal cancers and championing equitable access to screening and care. Through both academic research and national policy efforts, I’ve seen firsthand how delayed or missed screening disproportionately affects underserved populations and how urgently we need solutions that meet patients where they are.

Many of these challenges were made worse by the COVID-19 pandemic. During the initial months of the pandemic (March to June 2020), there was a 90% drop in colorectal cancer screening particularly by colonoscopy relative to the same period in 2019. This is estimated to have resulted in 1.7 million missed colonoscopies and 18,000 missed or delayed CRC diagnoses. Altogether, delays in CRC screening during the COVID-19 pandemic are projected to result in a 12% increase in cancer deaths over the next several years. Improving the availability of well-validated, non-invasive CRC screening tests may help mitigate the number of missed CRCs and preventable deaths. This has been shown in a Kaiser study with navigation through non-invasive screening for CRC.

RNA-based stool testing represents a powerful new tool in our fight to expand access to overcome health disparities that the pandemic has worsened. The CRC-PREVENT clinical trial demonstrated that ColoSense offers high sensitivity for colorectal neoplasia, including early-stage cancers and advanced adenomas. Equally important, the trial showed that an at-home, easy-to-use test can engage individuals who have historically remained unscreened and help guide them through the full diagnostic process. The CRC-PREVENT study data shows that the sensitivity for CRC is higher than other non-invasive tests on the market and at least on par or better than other DNA-based CRC screening tests using the new RNA detection technology.

ColoSense addresses two of the most persistent barriers in CRC screening: accessibility and follow-through. By offering a high-performing, noninvasive test paired with patient navigation to colonoscopy, ColoSense has the potential to close longstanding gaps in early detection. CMS now has an opportunity to accelerate progress toward equity by covering innovative screening tools that extend reach, improve adherence, and ultimately save lives—especially in the communities that need it most.

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To whom it may concern,

I am a gastroenterologist, health equity researcher, and Associate Professor of Medicine at UCLA. I serve as Director of the Melvin and Bren Simon Gastroenterology Quality Improvement Program and Associate Director of the UCLA Kaiser Permanente Center for Health Equity. My clinical and research work focuses on improving colorectal cancer prevention and addressing disparities in care delivery. Through the May Lab, I lead initiatives aimed at advancing health equity, particularly in underserved communities, by improving screening access, care quality, and patient outcomes across diverse healthcare settings.

The ColoSense test, evaluated in the CRC-PREVENT trial, represents a meaningful step forward in efforts to deliver equitable CRC screening. The study was uniquely designed to reach individuals outside of traditional healthcare systems—leveraging digital outreach and decentralized enrollment to engage over 14,000 participants across 49 states. Of those, 8,920 completed both stool testing and colonoscopy, including populations that have long been underrepresented in clinical research and underserved in preventive care.

The trial cohort was uniquely representative in its diversity including 11% Black, 4% Asian, and 1% Native American/Alaskan. The trial included 5% of subjects in rural areas, 37% of subjects with low income (<$30,000 annual income) and 20% Medicare beneficiaries. A majority of participants had never been screened before (64%), and 68% did not have a colonoscopy scheduled at the time of enrollment. These statistics speak to the trial’s success in reaching patients who face structural and systemic barriers to preventive services.

By combining a high-performing RNA-based test with a decentralized, patient-centered approach, CRC-PREVENT demonstrated how innovation can drive inclusion. CMS coverage of ColoSense would support not only access to a clinically validated test, but also a delivery model capable of addressing long-standing disparities in colorectal cancer screening. It’s time to expand our definition of innovation to include not just new technologies—but also new ways of reaching the people who need them most.

Warmly,

Folasade P. May, MD, PhD, MPhil
Associate Professor of Medicine
Director, Melvin and Bren Simon GI Quality Improvement Program
Associate Director, UCLA Kaiser Permanente Center for Health Equity
UCLA Health and David Geffen School of Medicine at UCLA

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