Screening for Colorectal Cancer-Non-Invasive Biomarker Tests

While it appears to be well-detailed and scientifically rigorous, the proposed Decision Memo, “Screening for Colorectal Cancer – Non-invasive Biomarker Tests” (CAG-00440R) has an undertone of salutary neglect that favors the less well-established tests, as it skirts several issues, all of which were raised by other commenters. These include: 1) clarification of the proposed dual criteria for test characteristics (assuming these are sensitivity for colorectal cancer [CRC] and specificity for lesions less advanced than advanced precancerous polyps). Why are both a minimal number of CRCs and at least a lower 95% confidence limit not included? 2) if agreement on what constitutes an advanced precancerous lesion is not achievable, then there should be specificity measures for each non-invasive test that includes and omits sessile serrated lesions 1 cm or greater. Gastroenterologists treat these large sessile lesions as adenoma equivalents, as they should, since indirect evidence links them to an alternative pathway to CRC. 3) consideration of minimal test characteristics (primarily, sensitivity) for advanced precancerous lesions, as their detection contributes significantly to the effectiveness of CRC screening. How could these lesions be ignored by the memo? 4) a more careful and deliberate consideration of test characteristics of the included non-invasive tests in the Medicare population – both point estimates and confidence limits – with the understanding that 95% CIs for CRC may be wide. Why would CMS ever consider paying for any of these newer non-invasive tests without having some idea about test performance in the Medicare population?

A more objective and rigorous review process is needed to finish the job started by the decision memo. I recommend that Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) complete the process and require data that addresses each of the aforementioned issues. Greater detail as specified above, consensus around non-invasive test performance, and a clearer understanding of the limitations of each test are required to move forward in a rigorous and sensible way. To make any decisions about coverage without doing so may be considered negligent.

Less

In public health, the most dangerous mistakes are not the ones made with bad intentions. They are the ones made with good intentions and insufficient evidence. As someone who has spent a career at the intersection of medicine, policy, and public service, I have seen how well-meaning decisions can produce outcomes that nobody wanted. I am concerned that CMS is on that path with its proposed coverage framework for colorectal cancer screening tests.

Let me be clear about what I am not saying. I am not saying that innovation in cancer screening is unwelcome. The development of new testing technologies represents exactly the kind of scientific progress that can transform outcomes for patients over time. Expanding access to screening is a worthy goal, and any tool that brings more Americans into the screening tent deserves serious consideration.

What I am saying is that the proposed coverage standard does not adequately account for what the science tells us about how colorectal cancer screening actually saves lives. The evidence is compelling and consistent: the majority of the long-term mortality benefit from colorectal cancer screening comes from detecting and removing precancerous lesions before they develop into cancer. A coverage framework built primarily around cancer detection thresholds, without meaningful requirements for precancerous lesion sensitivity, is a framework that is not fully aligned with that evidence.

This is not a fringe position. It is the conclusion reached by multiple peer-reviewed analyses, modeling studies, and leading gastroenterology societies. When the science points this clearly in one direction, coverage policy should follow.

So what should CMS do? I want to offer a pragmatic suggestion rather than simply a critique.

CMS should convene a Medicare Evidence Development and Coverage Advisory Committee, commonly known as a MedCAC, to conduct a formal, independent review of the evidence before this proposed rule is finalized. A MedCAC brings together clinical experts, researchers, patient advocates, and methodologists to evaluate the evidence base for coverage decisions in a structured, transparent, and public process. It is precisely the kind of rigorous, deliberate review that a decision of this magnitude deserves.

The stakes are high enough to warrant that level of care. Colorectal cancer is the second leading cause of cancer death in the United States. Screening works. But screening only delivers its full benefit when the tests being covered are held to standards that reflect the complete picture of what effective screening requires. Getting this wrong does not just cost money. It costs lives.

A MedCAC review would accomplish several things. It would give CMS the benefit of independent expert judgment on the question of precancerous lesion detection and its role in long-term outcomes. It would create a transparent public record of the evidence and the reasoning behind the final coverage decision. And it would signal that CMS is committed to evidence-based policymaking, not just meeting the minimum threshold for approving what is new and convenient.

I have served in uniform, in operating rooms, and in the highest levels of public health leadership. In every one of those roles, the lesson was the same: when the decision is consequential and the evidence is complex, you do not cut corners on the process. You bring in the best minds, you evaluate the evidence carefully, and you make the call that the science supports.

CMS has the tools to do this right. A MedCAC review is the appropriate next step, and I urge the agency to pursue it before issuing a final rule. The seniors who depend on Medicare deserve nothing less than a coverage standard built on the full weight of the evidence. That is not too much to ask. It is exactly what good public health demands.

Sincerely,
Richard Carmona, MD, MPH, FACS
17th Surgeon General of the United States

Less

At the Colon Cancer Coalition, we are dedicated to increasing screening rates and saving lives by expanding access and increasing the number of people who get screened for colorectal cancer. Our primary goal is to reduce the incidence of this disease through widespread screening and public awareness. One of our primary focuses is increasing screening rates for all average-risk adults aged 45 and older.

We know that colorectal cancer, when detected early, is highly treatable, boasting a 5-year survival rate of 91%. Access to a noninvasive test with high sensitivity for advanced adenomas (precancerous polyps) can provide a higher rate of detection before cancer even has a chance to develop.

We strongly support CMS adopting the proposed NCD to ensure that Medicare beneficiaries have access to new and innovative evidence-based colorectal cancer screening options that can improve early detection and patient outcomes.

Ensuring coverage for current and future evidence-based screening options that meet the thresholds outlined in the proposed language will allow patients the widest variety of screening options. Allowing health care providers and their patients to choose the method that best suits each individual’s needs and preferences will directly impact patient willingness to screen for colorectal cancer.

By supporting the inclusion of mt-sRNA testing in the NCD, and future innovative biomarker screening in the future, we can empower more individuals to take control of their health and get screened for colorectal cancer while enhancing early detection of neoplasia. This will help all of us in our mission to end the disease.

Sincerely,

Chris Evans
President
Colon Cancer Coalition

Less

CellMax Life appreciates the opportunity to comment on the proposed decision memo on screening for colorectal cancer-non-invasive biomarker tests (CAG-00440R) for NCD 210.3. Though preventable colorectal cancer (CRC) continues to be the second largest cancer killer in the United States. Only timely and effective screening to detect advanced adenomas (AA) and Stage-I Colorectal cancer (CRC) will meaningfully impact both incidence and mortality. We appreciate the time and consideration by the Centers for Medicare & Medicaid Services (CMS) to expand the coverage of colorectal cancer (CRC) screening for Medicare beneficiaries. We support modifications to the NCD final decision that are reasonable and necessary based on published scientific evidence in the best interests of patient safety and public resources.

Beyond our general support of the proposed decision memo, we provide the below recommendations and specific changes in Appendix A to the coverage criteria for CMS to consider in the final decision memo.

Background on CellMax and FirstSight

CellMax Life is developing blood tests for cancer screening informed by both cellular and molecular markers. Our FirstSight™ assay is a blood-test for preventive CRC screening that has received Breakthrough Device Designation from the FDA for advanced neoplasia (AA+CRC).

The FirstSight™ blood test has higher accuracy for the detection of advanced adenomas than current non-invasive tests, while also maintaining high accuracy for colorectal cancer. The test is designed to detect circulating advanced adenoma and cancer cells that are shed in the blood early in cancer development.¹

These rare and fragile cells are isolated using a proprietary platform that comprises multiple proprietary innovations: microfluidic chip, antibodies specific to the colon and rectum, and gentle air-foam release to isolate the captured cells. An algorithm combines these results along with molecular DNA markers, which is then reported as "positive" or "negative".

Colonoscopy has high sensitivity for the detection of adenomas. Unfortunately, compliance with colonoscopy is less than 40%. There are non-invasive testing options, both stool- and blood-based. Stool-tests detect AAs but suffer from poor compliance and, first generation blood-tests are unable to effectively detect AAs, the bridge between precancer and cancer malignancy, with decades of evidence including National Polyp Study² indicating marked increase risk for progression to cancer. As a result, 60% of colorectal cancer is diagnosed too late — after it is no longer localized when survival rates are low.

Support For Finalizing Expanded CRC Coverage

CMS is a recognized pioneer in ensuring their beneficiaries have access and reimbursement for screening for optimized healthcare for CRC. The proposed decision memo importantly highlights that separate from perceived inconveniences such as scheduling, work time constraints, transportation needs for colonoscopy and continued uncertainty of reimbursement, regardless of results of a non-invasive test, these barriers may result in beneficiaries being screened or not. The approximately 35% of beneficiaries who are not compliant to professional society guidelines are expected to be most of the 158,840 of those expected to be diagnosed with CRC, and 55,230 of those who will die due to CRC in 2026.³ A truly consequential result for a preventable cancer, second overall cancer for mortality and the leading cause of cancer death for those under 50 years old.

We strongly support several of the changes of the proposed decision memo as important expansions of the current NCD coverage criteria. Specifically, we support: 1) the change in ordering provider to ensure greater access; 2) the new range of screening age range (45-85); 3) a transition from test-by-test decision to a coverage based on a performance framework; and 4) the need for follow up studies recommended by FDA before coverage is considered.

The Importance of Early Detection of Adenoma-Carcinoma in Improved Mortality

The new understanding of CRC natural history recognizes the adenoma-carcinoma development as a continuum of what appears to be discrete stages.^4-7 Nearly three decades ago, the wealth of evidence, including the National Polyp Study (NPS) leading Winawer et al⁸ to state that,

In this regard, adjacent apparent stages serve as proxies of performance for adjoining classifications. Most notable in this regard is the sensitivity of AA being a proxy of Stage I disease: specifically, the higher the AA sensitivity, the higher the sensitivity for Stage I cancer.

Niedemaier et al (2020)⁹ reported in a large study that Stage I cancer, the curable stage of cancer with longest life years gained, was found to have lower sensitivities than later stages (II-IV) with non-invasive screening tests. High sensitivity for Stage I and AA is critical to reduce incidence and provide detection of the cancer at the curable and most treatable stage. CMS appropriately includes statements of support in the proposed decision to recognize the critical value of AA and stage I detection. The proposed decision memo correctly notes that:

Equally important the proposed decision memo underscores the critical role in the detection of adenomas with mortality. CMS states that:

CMS notes that specificity and AA are reported in different ways. Just as CMS clarified a specificity definition in the proposed decision memo, CMS should clarify in the final decision memo the definition for AA. The AA definition, though at times using different words, is common for the FDA, ACS, USMSTF, USPSTF and ACG.

We recommend CMS use the definition of Advanced Adenoma of the US Multitask Force Guideline¹⁰ as set out below:

CMS should establish a minimal performance criteria for AA and Stage I detection.^11-14 These are the two most impactful ‘stages’ for prevention and cure, impacting respectively incidence and mortality. For example for first generation blood tests, by aggregating the sensitivity for Stages I-IV, the sensitivity for Stage I, the least sensitive and most curable stage is masked resulting in perceived ambiguous performance for HCP and those undergoing screening. AA detection provides prevention and Stage I detection permits cancer cure after colonoscopy. We recommend CMS require a threshold of 79% for both overall and Stage I sensitivity.

See table below that summarizes key clinical implications of CRC screening detection.

CRC Continuum	Intervention Mechanism	5 Year Surviival w trt	Clinical Impact	Life-Years Gained
Colonoscopy (polypectomy)	Cancer prevention	100%	Prevented	10-20+ years
Stage I	Curative surgery	~90-92%	Near-curative with surgery	10-15+ years
Stage II	Curative ± chemo	~70-87%	Partly curable	8-12 years
Stage III	Surgery + chemo	~50- 72%	Curable only in a subset with chemo	5-10 years
Stage IV	Systemic therapy	~ 11-15%	Rarely curable, only life-prolonging	1-3 years

Recommendations For The Final Decision

CMS should continue to reimburse previously covered CRC screening tests to avoid disruption while stimulating innovation with the updated proposal. Support for this position includes real world evidence of performance and impact on incidence and/or mortality, separate from a designated clinical trial. The proposal decision memo notes that “FIT testing is not being reconsidered.” We recommend language in Appendix A that CMS include in the final decision memo specific language to indicate “Tests approved under V1 of this policy are not being reconsidered.”

We also note that the non-overlapping bins of sensitivity and specificity metrics leads to case wherein a potentially superior test fulfills the performance metric in between the bins, so better performing than either, but would be rejected by the approach outlined in the proposal as drafted. In addition, this recommended language will encourage future innovation because technology for CRC detection is rapidly developing.^15-16

Between the FDA approved stool- and blood- tests the NCD encompasses two distinct intended uses, with vastly different implications: 1) an advanced neoplasia (advanced adenoma and cancer) screening and 2) CRC screening test. As noted by CMS, the tests have different FDA intended uses.

We recommend the NCD final decision memo should recognize this critical and markedly different clinical implication of the different stages of CRC and require a minimal performance of FIT. Coverage criteria should clearly recognize that current FDA approved Blood-Test(s) have the label for CRC screening only and the label has a warning for low performance of Stage-I as well, making it decidedly inferior to stool-tests: having no impact on incidence and comparatively limited impact on mortality, while the stool-tests are for AA & CRC (Advanced Neoplasia). For example, the intended use for the Exact Sciences Cologuard test is to screen for colorectal cancer (CRC) and high-risk adenoma lesions (AA) in adults aged 45 or older who are at average risk.

This feature of screening is clearly seen in first-generation blood-based tests that have compromised sensitivity of both AA and Stage I. It is a qualitative, in vitro test that detects CRC-derived DNA in the blood to detect cancer, with positive results requiring follow-up colonoscopy. The first-generation blood-based tests have limited detection (55%-65%) of Stage I colorectal cancer and only detects AA at 13%. The NCD encompasses two discrete intended uses: an advanced neoplasia (advanced adenoma and cancer) surveillance and CRC surveillance test.

As noted earlier, the higher the AA sensitivity, the higher the sensitivity for Stage I cancer. This feature of screening is clearly seen in first-generation blood-based tests that have compromised sensitivity of both AA and Stage I.

An additional clinical implication of AA detection are guidelines that recommend first degree relatives of those with AAs detected to be identified at increased risk. These first degree relatives may themselves be CMS beneficiaries and benefit from this knowledge.¹⁷

Fendrik et al.(2023)¹⁸ reported a modeling study that even a non-invasive test with 100% adherence (an impractical expectation), would require 30% AA sensitivity to reach the Life Years Gained of the mt-sDNA test.

CMS set the interval of non-invasive testing at 3 years but the proposed decision memo does not identify the evidence to support a 3 year interval for tests that have AA and Stage I detection performance reported for first-generation blood-based tests separate from being the same as previously covered tests. A major medical concern is that the transition time from AA to Stage I and time from Stage I to Stage III which are both 2-4 years, and the current blood-test(s) are unable to detect AAs and detect Stage-I with high sensitivity.

SEER and CISNET natural history studies and modeling indicate 8-12% of AA would transition to Stage I and 30-70% of Stage I would progress to Stage III – given that the prevalance of AAs is ~8-10% with of CRC at ~0.35% and Stage I at ~0.1% , lack of ability to detect AAs will lead to increase in mortality vis-à-vis stool-tests. The observation that only 50% of those with a positive non-invasive test may have colonoscopies further compounds the issue of progression. In brief, the 3 year interval for blood-tests would lead to notable progression to cancer and to non-curable cancer. CMS should re-evaluate the recommended time interval for tests with performance metrics of present blood-based tests. The time interval should be evidence-based.^19-20

CMS clearly recognizes that nucleic acid is only one of the potential analytes for screening and should draft a proposal that permits other analytes to be used; it is clear that other analytes are needed to meaningfully detect AA & Stage-I CRC.

CellMax Life, as an example, has reported high sensitivity at high specificity using a multi-modla test, FirstSight, that includes cfDNA mutations, methylation and circulating AA cells. Recent studies reported release of cells from adenoma lesions much earlier than previously thought.

Conclusion

CMS has the responsibility to ensure policy decisions do not cause erosion of the present successes. CMS must ensure new tests are disruptive, not a disruption of past success.²² Thank you for your consideration and we welcome the opportunity to meet with CMS should any of these recommendations require further clarification.

Sincerely,

Atul Sharan
Chief Executive Officer

APPENDIX A – RECOMMENDED REDLINES TO NCD 210.3

(CHANGES IN CAPS)

FIT AND PRIOR V1 PROPOSAL COVERAGE DECISION ARE NOT BEING RECONSIDERED.

The Centers for Medicare & Medicaid Services (CMS) proposes changes to NCD (210.3) colorectal cancer screening tests according to the provisions in sections I.B. and I.C. below.

B. Coverage Criteria

We propose that non-invasive biomarker colorectal cancer screening tests are covered once every three years for Medicare beneficiaries when ordered by the physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient and when all the following conditions are met:

a. Patient Criteria

1. Age 45 to 85 years, and,
2. Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test (gFOBT) or fecal immunochemical test (FIT)), and,
3. At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or adenomatous polyps, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

b. Test Criteria

1. The test must be Food and Drug Administration (FDA) market authorized and indicated for colorectal cancer screening; and,
2. The test must achieve the requirements of the FDA-required post-approval study as specified in the Safety and Effectiveness Data (SSED) to continue coverage; and
3. The test must be processed in a CLIA certified laboratory; and,
4. PERFORMANCE THRESHOLDS

   	Test Performance Criteria 1	Test Performance Criteria 2
   CANCER
   Sensitivity*	≥ 90%	≥ 79%
   Specificity	≥ 87%	≥= 90%
   ADVANCED ADENOMA
   SENSITIVITY	≥40%	≥30%
   SPECIFICITY	≥87%	≥90%
   *MERGED AND STAGE I ALONE

   THE DEFINITION OF ADVANCED ADENOMAS IS THE US MULTITASK FORCE GUIDELINE OF ADENOMATOUS LESIONS WITH CANONICAL COMPONENTS OF SIZE >10mm, VILLOUS/TUBULOVILLOUS HISTOLOGY OR HIIGH-GRADE DYSPLASIA WITH FDA EXPANDED NONCANONICAL COMPONENETS IN INTENDED USES INCLUDING BUT NOT EXCLUSIVELY SERRATED LESIONS >10MM.

   THE TWO INTENDED USES INCLUDE ADVANCED NEOPLASIA AND COLORECTAL CANCER

   FOR CRITERIA 1, A CANCER SENSITIVITY OF GREATER THAN OR EQUAL TO 90% OVERALL AND FOR STAGE I ALONE AND A SPECIFICTY OF GREATER THAN OR EQUAL TO 87% IN THE DTECETION OF COLORECTAL CANCER COMPARED TO THE RECOGNIZED STANDARD (ACCEPTED AS COLONOSCOPY AT THIS TIME), BASED ON THE FDA LABELING. FOR ADVANCED ADENOMA, A SENSITIVITY OF GREATER THAN OR EQUAL TO 40% ANDS A SPECIFICITY OF GREATER THAN OR EQUAL TO 87% IN THE DETECTION OF ADVANCED ADENOMA COMPAED TO THE RECOGNIZED STANDARD (ACDCEPTED AS COLONOSCOPY AT THIS TIME), BASED ON THE FDA LABELING.

   FOR CRITERIA 2, A CANCER SENSITIVITY OF GREATER THAN OR EQUAL TO 79% OVERALL AND FOR STAGE I ALONE AND A SPECIFICTY OF GREATER THAN OR EQUAL TO 90% IN THE DTECETION OF COLORECTAL CANCER COMPARED TO THE RECOGNIZED STANDARD (ACCEPTED AS COLONOSCOPY AT THIS TIME), BASED ON FDA LABELING. FOR ADVANCED ADENOMA, A SENSITIVITY OF GREATER THAN OR EQUAL TO 30% ANDS A SPECIFICITY OF GREATER THAN OR EQUAL TO 87% IN THE DETECTION OF ADVANCED ADENOMA COMPAED TO THE RECOGNIZED STANDARD (ACDCEPTED AS COLONOSCOPY AT THIS TIME), BASED ON THE FDA LABELING.

   C. Other Uses of Colorectal Cancer Screening Biomarker Tests

   All other indications for colorectal cancer screening not otherwise specified in the Act and regulations, or otherwise specified above, remain nationally non-covered.

   Citations

   1. Friedland, S, Watson, D., Pan, J, et al. Development and Clinical Validation of a Blood Test for Early Detection of Colorectal Adenomas and Cancer for Screening and Postpolypectomy Surveillance Gastro Hep Advances 2022, 1(2), 223-230. doi.org/10.1016/j.gastha.2021.11.004
   2. Winawer SJ, Zauber AG, O’Brien MJ, et all. The National Polyp Study at 40: challenges then and now. Gastrointestinal Endoscopy 93, No. 3: 2021. doi.org/10.1016/j.gie.2020.09.044
   3. Siegel R, Kratzer TB, Wagle NS, et al, Cancer statistics, 2026 CA Cancer J Clin. 2026;e70043. doi.org/10.3322/caac.70043
   4. Becker, W.R., Nevins, S.A., Chen, D.C. et al. Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer Nature Genetics 2022, 54 (7), 985–995. doi: 10.1038/s41588-022-01088-x
   5. Hu, Z., Li, Z., Ma, Z., et al. Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases. Nature Genetics, 2019; 52(7), 701–708. doi.org/10.1038/s41588-020-0628-z
   6. Van Egeren , D., Schenck, R.O., Khan, A. et al. Polyclonal origins of human premalignant colorectal lesions Nature 2026; 650(8103):1017-1024. doi.org/10.1038/s41586-025-09930-y
   7. Klein, C. A. Cancer progression and the invisible phase of metastatic colonization. Nature Reviews Cancer, 2020; 20(10), 573–586. doi.org/10.1038/s41568-020-00300-6
   8. Winawer, S. J., & Zauber, A. G. The advanced adenoma as the primary target of screening. Gastrointestinal Endoscopy Clinics of North America 2002; 12(1), 1–.doi.org/10.1016/S1052-5157(02)00001-1
   9. Niedermaier, T, Balavarca, Y, Brenner, H. Stage-Specific Sensitivity of Fecal Immunochemical Tests for Detecting Colorectal Cancer: Systematic Review and Meta-Analysis. The American Journal of Gastroenterology 2020; 115(1), 56–69. doi.org/10.14309/ajg.0000000000000465
   10. Patel, S. G., May, F. P., Anderson, J. C., et al. Updates on Age to Start and Stop Colorectal Cancer Screening: Recommendations From the U.S. Multi-Society Task Force on Colorectal Cancer. The American Journal of Gastroenterology 117(1), 57–69. doi.org/10.14309/ajg.0000000000001548
   11. Ladabaum U, Church TR, Feng Z, et al. Counting Advanced Precancerous Lesions as True Positives When Determining Colorectal Cancer Screening Test Specificity. Oxford JNCI J Natl Cancer Inst 2022, 114(7): 1-14. doi.org/10.1053/j.gastro.2024.03.011
   12. Shaukat A, Ladabaum U, Kanth P, Lieberman D. AGA Clinical Practice Update on Current Role of Blood Tests for Colorectal Cancer Screening: Commentary. Clin Gastroenterol Hepatol. 2025; 23:1486–1491. doi.org/10.1016/j.cgh.2025.04.003
   13. Coronado GD, Hoffman RM, Llavona-Ortiz J, et al. The Centers for Medicare and Medicaid Services and others misunderstand stool testing for colorectal cancer JNCI: Journal of the National Cancer Institute, 2026, 118(3), 386–391. doi.org/10.1093/jnci/djaf341
   14. Lieberman D, Centers for Medicare and Medicaid and colorectal cancer screening test standards: time for a change. JNCI: Journal of the National Cancer Institute, 2026, 118(3), 371–372. doi.org/10.1093/jnci/djaf367
   15. https://www.discoveriesinhealthpolicy.com/2026/03/mapping-colorectal-cancerscreening.html?m=1
   16. https://www.discoveriesinhealthpolicy.com/2026/03/cms-posts-new-idea-forcolorectal.html?m=
   17. Kolb, JM, Molmenti, CL, Patel, SG, et al. Increased Risk of Colorectal Cancer Tied to Advanced Colorectal Polyps: An Untapped Opportunity to Screen First-Degree Relatives and Decrease Cancer Burden. American Journal of Gastroenterology 2020, 115(7), 980–988. doi.org/10.14309/ajg.000000000000063
   18. Fendrick, A. M., Vahdat, V., Chen, J. V., et al. Comparison of Simulated Outcomes Between Stool-and Blood-Based Colorectal Cancer Screening Tests. Population Health Management 2023; 26(4). doi: 10.1089/pop.2023.0037
   19. Heisser T, Sergeev D, Hoffmeister M, et al. Contributions of early detection and cancer prevention to colorectal cancer mortality reduction by screening colonoscopy: a validated modeling study. 2024 Gastrointestinal Endoscopy. 2024, 100 (4), 710-716. doi.org/10.1016/j.gie.2024.03.010
   20. Rutter, C.M. and Savarino, E. An Evidence-Based Microsimulation Model for Colorectal Cancer: Validation and Application Cancer Epidemiol Biomarkers Prev. 2010; 19(8): 1992– 2002. doi:10.1158/1055-9965.
   21. Brenner H, Hoffmeister M, Stegmaier C, et al. Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840,149 screening colonoscopies. Gut. 2007;56(10):1585–1589. doi:10.1136/gut.2007.122739
   22. Parikh, R.B. and Prasad, V. Blood-Based Screening for Colon Cancer A Disruptive Innovation or Simply a Disruption? JAMA 2016; 315(23), 2519-2520. doi.org/10.1001/jama.2016.7914

   Less

I am a practicing gastroenterologist and Assistant Professor of Medicine at the Johns Hopkins Hospital, Medical Director at the Center for Bioengineering Innovation and Design in the JHU Biomedical Engineering department, and adjunct faculty at the JHU Carey Business School. I also serve on the Johns Hopkins Technology Value Analysis Committee, where we evaluate the integration and adoption of new technologies into clinical care. I applaud CMS for proposing coverage for non-invasive CRC screening biomarker tests and for establishing a technology-agnostic framework that will streamline access and encourage innovation. The decision to cover follow-up colonoscopy regardless of test result is critical, as colonoscopy remains the gold standard to which all screening modalities are compared. I am acutely aware of the importance of providing acceptable screening approaches not only for the overall average-risk population but also for addressing disparities in screening uptake. My colleagues and I recently published a study (Sequeira et al., Cancers (2025)) analyzing over 85,000 subjects due for CRC screening in a large Baltimore outpatient network. In our age-stratified analysis, younger patients had significantly lower rates of up-to-date screening and a significantly higher proportion electing non-invasive modalities—underscoring that the performance standards we apply to these tests must be rigorous enough to justify the trust patients place in them.

However, I respectfully urge CMS to reconsider its decision not to include performance benchmarks for detecting advanced adenomas (AAs) and early-stage CRC. The proposed decision memo itself states that early detection and removal of large precancerous adenomas prevents progression to cancer and improves mortality, and yet the coverage criteria set thresholds only for CRC detection, not for the precursor lesions whose removal is the very mechanism by which screening prevents cancer. This omission is consequential: AA sensitivity varies dramatically across covered modalities, ranging from approximately 13% for the blood-based cfDNA test to 43–46% for stool-based alternatives. Similarly, Stage I CRC sensitivity is only 65% with the blood-based test, compared with 93–95% with stool-based tests. A blanket coverage framework that does not differentiate on these metrics risks incentivizing the adoption of tests that detect cancer at later stages while missing the precursor lesions and early cancers where intervention is most impactful. Over a three-year screening interval, a false-negative for an advanced adenoma or Stage I cancer can mean the difference between a curative polypectomy and a diagnosis of advanced-stage disease. I would encourage CMS to consider, at a minimum, a threshold for pre-cancer sensitivity that at least matches the approximately 24% sensitivity of FIT for advanced adenomas, and to require stage-specific CRC sensitivity reporting on the FDA label. If a single threshold is not feasible, CMS should consider tiered or differentiated coverage consistent with the NCCN’s 2025 recommendation that blood-based testing be reserved for individuals unwilling to undergo screening through another modality.

I am excited and optimistic about the new multimodal technologies reported in the literature. Non-invasive screening and early detection are vital to addressing the CRC burden in the United States. But coverage policy should be nuanced enough to ensure that Medicare beneficiaries receive not just any non-invasive test, but one that provides comprehensive protection - detecting cancer early and identifying the advanced adenomas that are the very targets of screening. I commend CMS for this important initiative and welcome the opportunity to engage further.

Less

Re: Blood-Based Colorectal Cancer Screening Coverage

I am the Founder and CEO of Big Mike’s Bottom Line, a community-based organization focused on increasing awareness, reducing stigma, and promoting early detection of colorectal cancer—particularly among individuals under age 50, where incidence is rising at alarming rates.

Colorectal cancer remains the second leading cause of cancer-related deaths in the United States, yet nearly one in three eligible individuals are not up to date with recommended screening. In our work, this gap reflects not only access barriers, but also fear, stigma, and lack of engagement with screening options that feel acceptable to patients.

Big Mike’s Bottom Line strongly supports policies that prioritize patient choice in colorectal cancer screening. Consistent with the American Cancer Society, expanding access to a range of non-invasive screening options—including blood-based tests—can significantly improve screening uptake. When individuals understand they have options, they are more willing to engage in conversations about colorectal cancer and take the first step toward screening.

Importantly, offering choice also increases patient understanding. When individuals engage in selecting a screening method, we find they become more receptive to learning about colorectal cancer, including the signs and symptoms that warrant medical attention. This is critical because no screening test is perfect. However, when patients are informed about symptoms—such as changes in bowel habits, blood in stool, unexplained weight loss, or persistent abdominal discomfort—they are more likely to seek care and initiate timely conversations with providers. Screening should be positioned as one component of a broader, informed approach to early detection.

At the same time, expanded access must be paired with strong and consistent standards. The current sensitivity and specificity thresholds established by CMS should remain intact, as they have already supported the development and FDA approval of high-quality blood-based screening tests. Maintaining these thresholds ensures access to reliable tools while avoiding unnecessary barriers or uncertainty.

CMS should also maintain transparent and consistent evidentiary standards across screening modalities, providing clarity for developers and confidence for clinicians and patients, while ensuring timely access to qualifying tests.

To improve access in real-world settings, CMS should allow a broader range of qualified healthcare providers to order screening tests. This reflects how patients actually interact with the healthcare system and helps reduce missed opportunities for early detection.

Finally, coverage policy should remain adaptive to evolving science and care delivery, ensuring sustained patient access to innovative screening options without unnecessary delay.

From a community-based perspective, the greatest challenge is not awareness alone—it is helping individuals take action. Expanding access to non-invasive screening options, while emphasizing patient education and maintaining high standards, represents a critical opportunity to reach individuals who would otherwise remain unscreened.

Thank you for the opportunity to provide comment. We appreciate CMS’s commitment to advancing equitable, evidence-based colorectal cancer screening.

Less

April 09, 2026

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

RE: Proposed Decision Memo for Screening for Colorectal Cancer—Non-Invasive Biomarker Tests (CAG-00440R)

Dear Ms. Baldwin,

The American Clinical Laboratory Association (ACLA) appreciates the opportunity to provide comments on the Proposed Decision Memo for Screening for Colorectal Cancer—Non-Invasive Biomarker Tests (CAG-00440R). We applaud CMS for promoting timely beneficiary access to preventive services that are supported by sound clinical evidence, while also preserving patient safety and the integrity of the Medicare coverage framework.

ACLA is the national trade association representing leading laboratories that deliver essential diagnostic health information to patients and providers by advocating for policies that expand access to the highest quality clinical laboratory services, improve patient outcomes, and advance the next generation of personalized care.

ACLA appreciates that the Proposed Decision Memo represents meaningful progress and is encouraged by the direction CMS has taken. Specifically, ACLA supports CMS’s focus on strong, evidence based coverage standards; its recognition of the need for timely Medicare beneficiary access to non invasive, biomarker based colorectal cancer (CRC) screening tests; and its proposal to apply consistent ordering requirements across CRC screening modalities. ACLA respectfully requests that CMS carefully consider these comments as it moves toward finalizing the decision memorandum.

ACLA supports CMS’s emphasis on robust, evidence-driven coverage policies. Coverage for non-invasive biomarker tests used in colorectal cancer (CRC) screening should be based on strong, high-quality clinical evidence that is relevant to the Medicare population and demonstrates reliable clinical performance. CRC remains the second leading cause of cancer-related mortality in the United States, and Medicare beneficiaries experience a disproportionate impact. This population includes a higher percentage of individuals who are underserved, have multiple chronic conditions, and encounter clinical and logistical barriers to preventive screening. These factors create distinct risks that must be considered in coverage decisions.

Coverage policies that account for the specific characteristics and needs of the Medicare population are more likely to result in meaningful reductions in CRC-related morbidity and mortality. Clearly articulated and consistently applied evidentiary requirements across screening technologies offer laboratories predictable guidance and reinforce confidence among clinicians and patients that covered tests meet appropriate standards for effectiveness and clinical value for Medicare beneficiaries.

CMS recognizes the importance of ensuring timely access to non-invasive, biomarker-based CRC screening tests for Medicare beneficiaries, and ACLA agrees. A coverage pathway that moves smoothly and efficiently from evidence assessment to coverage decision would facilitate timely access for patients and supports the broader public health goal of increasing colorectal cancer screening across the country. ACLA looks forward to a final decision memorandum that maintains high evidentiary standards while allowing screening tests that meet those requirements to be available to Medicare beneficiaries.

ACLA supports CMS’s proposal in the decision memorandum to establish consistent ordering requirements across all colorectal cancer (CRC) screening test modalities. Applying uniform requirements across modalities allows clinicians to present patients with the complete range of screening options and supports shared decision making, enabling providers and beneficiaries to choose the option the patient is most likely to complete.

ACLA also supports CMS’s proposal to expand eligible ordering providers to include physicians, physician assistants, nurse practitioners, and clinical nurse specialists who incorporate test results into patient management. This proposal appropriately reflects contemporary care delivery models, in which preventive screening is commonly directed by a multidisciplinary group of qualified healthcare professionals.

To promote long term stability of the National Coverage Determination (NCD) and avoid the need for future revisions based solely on evolving provider scope of practice standards, ACLA recommends that CMS further align the ordering provider language with the federal regulatory definition of “non physician practitioners.” Referencing these regulations would allow the NCD to automatically include additional provider types recognized under the Social Security Act whose scope of practice encompasses ordering preventive services. This forward looking approach would help ensure the coverage policy remains current as care delivery models evolve, without requiring additional administrative updates.

We thank you for your consideration of ACLA’s comments on the Proposed Decision Memo for Screening for Colorectal Cancer—Non-Invasive Biomarker Tests (CAG-00440R). Please contact me at 202-637-9705 or jkegerize@acla.com with any questions.

Sincerely,

Joan Kegerize, JD
Vice President, Reimbursement and Scientific Affairs
American Clinical Laboratory Association

Less

April 9, 2026

Via Electronic Submission

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

RE: National Coverage Determination (NCD) 210.3 – Colorectal Cancer Screening (CAG-00440R)

Dear Ms. Baldwin,

On behalf of the Medical Device Manufacturers Association (MDMA), which represents manufacturers of innovative diagnostic technologies and medical devices, we appreciate the opportunity to comment on CMS's proposed changes to NCD 210.3 governing colorectal cancer (CRC) screening tests. MDMA's mission is to ensure patients have timely access to safe, effective medical technologies that improve health outcomes.

MDMA supports CMS's continued emphasis on evidence-based coverage for non-invasive biomarker CRC screening tests. It is especially important that coverage criteria reflect the characteristics of the Medicare population, which faces higher disease burden, complex comorbidities, and structural barriers to screening. Rigorous yet population-relevant evidence standards will support earlier detection when intervention is most effective. We also appreciate CMS's effort to define objective performance thresholds, which provide predictability for developers and support informed decision-making by clinicians and patients. Coverage criteria should be aligned to the clinical capability of the screening modality, with differentiated thresholds based on each modality’s ability to detect colorectal cancer and/or precancerous lesions.

We strongly support CMS's goal of expanding access to high-quality, non-invasive screening options. Participation rates remain well below the national target of 80% [1], particularly in underserved communities, and a coverage framework that enables efficient transition from evidence generation to coverage is critical to closing persistent screening gaps. Offering a range of clinically validated options better aligns with patient preferences, a key driver of adherence, and advances health equity across diverse populations.

MDMA also supports CMS's proposed approach of permitting coverage for tests subject to an post-approval study (PAS) required by the Food and Drug Administration (FDA), rather than requiring study completion prior to coverage. This pragmatic balance serves timely patient access while maintaining accountability for post-market performance. In the final decision memo, CMS should clarify that achievement of FDA-specified PAS results is a condition for continued coverage only to the extent that results affect the test characteristics required under the NCD. CMS should also provide guidance on coordination with FDA regarding PAS oversight.

Finally, MDMA appreciates CMS's updated ordering provider language recognizing physicians, nurse practitioners, physician assistants, and clinical nurse specialists. To ensure this provision remains durable over time, we encourage CMS to adopt a forward-looking approach that extends eligibility to additional provider types as recognized under the Social Security Act, avoiding the need for future policy revision as care models evolve.

Sincerely,

Daniel Waldmann
EVP, Health Policy & Reimbursement
Medical Device Manufacturers Association

Footnotes:
[1] See, e.g., Inadomi, J. et al. What Multi-Level Interventions Do We Need to Increase the Colrectal Screening Rate to 80%? Clin Gastroenterol Hepatol. 2019 Dec 27;19(4):633–645. doi: 10.1016/j.cgh.2019.12.016; Dalton, M. Study Reveals Demographic Disparities in Uptake of Colorectal Screenings. Yale News, Oct. 28, 2025. https://news.yale.edu/2025/10/28/study-reveals-demographic-disparities-uptake-colorectal-cancer-screenings.

Less

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

RE: Proposed Decision Memo for Screening for Colorectal Cancer—Non-Invasive Biomarker Tests (CAG-00440R)

I. Executive Summary

Abbott is a global healthcare leader that helps people live more fully at all stages of life. Our portfolio of life-changing technologies spans the spectrum of healthcare, with leading businesses and products in diagnostics, medical devices, nutritionals, and branded generic medicines. Our 122,000 colleagues serve people in more than 160 countries. On March 23, 2026, Abbott completed its acquisition of Exact Sciences, establishing Abbott as a leader in cancer screening and diagnostics.

Abbott appreciates the opportunity to comment on the CMS proposed decision memorandum (PDM) from the National Coverage Analysis (NCA) for Screening for Colorectal Cancer (CRC) – Non-Invasive Biomarker Tests (CAG-00440R). CMS should not depart from its past commitment to evidence-based review of new CRC screening tests, but rather reaffirm its dedication to evidence-based coverage that guarantees Medicare beneficiaries access to safe, effective, and rigorously validated screening technologies that improve health outcomes.

Abbott respectfully submits CMS maintain that new stool-based testing innovations continue to meet or exceed the established standards that were reviewed in the original consideration of this national coverage determination (NCD) over a decade ago with 92% CRC sensitivity, 90% specificity, and 42% advanced precancerous lesions (APL) sensitivity. Lowering standards in the evaluation of stool-based CRC screening tests can have unintended consequences and further burden an already backlogged healthcare system while increasing costs. CMS should also require that new innovations complete any FDA post-approval study requirements needed to ensure that products with insufficient evidence related to proposed NCD test performance criteria, complete rigorous analyses that meet FDA and CMS statistical standards, prior to being eligible for coverage under an NCD.

The central issue with the PDM is its conflation of stool-based and blood-based CRC screening tests into a single “non-invasive biomarker” coverage decision. These are biologically, clinically, and regulatorily distinct modalities with meaningfully different profiles—particularly with respect to the detection of APL, which is the primary mechanism through which screening prevents CRC. Abbott believes that both stool-based and blood-based CRC screening tests can play an important role and should be evaluated for coverage with distinct NCD criteria based on their unique characteristics. Setting distinct test performance criteria for stool-based tests should not lower existing stool-based testing standards and doing so risks reversing the significant progress made in the reduction in CRC mortality.

Collapsing these different tests into a single framework obscures their important differences and contravenes CMS’s history of regulation, the statutory definition of an NCD, and the agency’s stated commitment to prevention, quality, and safety. Abbott requests that CMS maintain distinct, modality-specific coverage criteria for stool-based and blood-based CRC screening tests that include APL sensitivity criteria for each test type and supports CMS setting this criterion by consulting with appropriate professional societies or convening a Medicare Evidence Development and Coverage Advisory Committee (MEDCAC).

II. Lowering established stool-based performance standards will have unintended consequences to the healthcare system.

CMS has historically emphasized the importance of new screening tests being “at least as good as” current screening tests “to maintain and, ideally, to continue the reduction in CRC mortality seen over the past 20 years [1].” In the original 2014 consideration of this NCD, CMS undertook an evidence-based review of clinical data that included CRC sensitivity, specificity, and APL sensitivity of 92%, 90%, and 42%, respectively, and set a standard by pioneering a coverage framework for Cologuard® (mt-sDNA). For over a decade individuals in the United States, including Medicare beneficiaries, have had access to this, United States Preventive Services Task Force (USPSTF) guideline-endorsed, stool-based non-invasive test which 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 APLs [2].

Exact Sciences (now Abbott) continued commitment to innovation and improved patient care led to investing in the development of Cologuard Plus® which for the past year has been offering Medicare beneficiaries an advancement in non-invasive molecular stool-based CRC screening with new benchmarks for CRC sensitivity, specificity, and APL sensitivity of 95%, 93%, and 43%, respectively [3]. Cologuard Plus detects CRC and APL with even greater sensitivity than Cologuard while reducing false positives by more than 30%.

CMS has consistently recognized the necessity of maintaining stringent standards for CRC screening tests. Reversing this progress can negatively impact Medicare beneficiaries and public health. Coverage pathways for stool-based tests with specificity below the current standards can unnecessarily lead to more false positive results and follow-up colonoscopies. Innovation and competition are crucial for continued advancement in the fight against CRC, however lowering standards to promote competition is counterproductive to improving public health.

According to modeling data, if 10% of Medicare beneficiaries were to use a stool-based test with a specificity of 87%, instead of the currently available stool-based tests with 93% specificity over a three-year screening interval, the projected increase in unnecessary follow-up colonoscopies would exceed 36,000 [4].

Furthermore, assuming sensitivities and adherence for two stool-based CRC screening options are the same, if all Medicare beneficiaries were to utilize a test with a 6% drop in specificity (93% to 87%)—corresponding to an increase in the false positivity rate from 7% to 13%—this would result in approximately 360,000 additional follow-up colonoscopies per 6 million patients screened [4]. Assuming an estimated $1,500 screening colonoscopy total cost, this translates to approximately $540M in additional, unnecessary healthcare spending, without any reasonable expectation of added clinical benefit. This type of regression would further burden an already backlogged healthcare system and increase costs while offering no meaningful improvement in outcomes.

A recent modeling study found that Cologuard Plus was the only non-invasive screening option shown to be efficient at guideline-endorsed intervals and across recommended screening age range [5]. The study used the validated CRC-AIM microsimulation platform, the same modeling approach developed by the Cancer Intervention and Surveillance Monitoring Network (CISNET) and used to inform the USPSTF 2021 colorectal cancer screening guidelines. The USPSTF defines an “efficient” screening strategy [6] as one that delivers the greatest number of life-years gained for the fewest colonoscopies. This benefit-to-burden ratio is driven largely by test performance where higher sensitivity increases early stage and precancer detection, leading to more life years gained, while higher specificity reduces unnecessary colonoscopies driven by false-positive results. Cologuard Plus was the only non-invasive test to reach efficiency at guideline-recommended intervals and ages. ColoSense® (mt-sRNA) test strategy was not efficient or near-efficient for primary screening.

The findings underscore Cologuard Plus as an important tool to improve CRC outcomes while helping preserve limited colonoscopy capacity. Several pressures are affecting access to colonoscopy, including expanded screening age guidelines [7], increased cases of early-onset CRC [8], and a declining number of practicing gastroenterologists [9].

CMS has historically recognized the importance of maintaining high specificity in CRC screening tests as evidenced by establishment of a 90% specificity threshold (taken from the standard set by CMS coverage of Cologuard) in the existing Screening for Colorectal Cancer - Blood-Based Biomarkers NCD (CAG-00454N) [1]. There is a linear relationship between test specificity and the number of unnecessary follow-up procedures: for every 1-percentage point decrease in specificity, unnecessary colonoscopies increase by roughly 14%. Therefore, a reduction in specificity by 6 percentage points results in an estimated 84% rise in unnecessary colonoscopies [4]. This sharp escalation underscores the critical role of specificity in minimizing avoidable interventions, patient burden, and system strain.

Lowering standards in the evaluation of stool-based CRC screening tests will have unintended consequences on the healthcare system. As such, new stool-based testing innovations should continue to meet the minimum established standards that have supported coverage for over a decade — 92% CRC sensitivity, 90% specificity, and 42% APL sensitivity — ensuring Medicare beneficiaries retain access to tests that are as good as, or ideally better than, those available today.

CMS recently stated through the Center for Clinical Standards and Quality (CCSQ) that improving quality and protecting beneficiary safety is one of the strategic goals for the agency, emphasizing that coverage policy must promote high-quality care, minimize avoidable harm, and ensure that Medicare beneficiaries are not exposed to unnecessary clinical risk [10]. In the context of population-based screening, quality and safety are inseparable from test performance certainty, transparency around known limitations, and safeguards against downstream harms triggered by false negative and false positive results.

CMS’s own NCA guidance document 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 [11].

The FDA Summary of Safety and Effectiveness Data (SSED) for ColoSense indicates only three (3) CRCs, one of which was not detected, were used to estimate CRC sensitivity in the 65 and older age group [12]. It is difficult, if not impossible, to confidently assess test performance in the Medicare-aged population based on a sample size of three 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 [3]. In the PDM, CMS states that “[they] expect the results of new non-invasive CRC screening tests to be generalizable to the Medicare population.” When making a proposed coverage decision for ColoSense, CMS reviewed the pivotal studies from three FDA-cleared screening tests and broadly stated that “Considering the many clinical sites, large sample sizes, and lack of restrictive exclusion criteria, the study findings are likely to be applicable to a Medicare population.” Large sample sizes may apply to the overall study populations, but such a broad generalization assumes the number of CRC cases across different tests is similar and this is not in line with the FDA SSED for ColoSense.

CMS should account for explicit FDA-identified limitations and unresolved safety concerns. FDA findings, approved indications, and labeling requirements are not meaningfully incorporated into CMS’s evidence review or reflected in the proposed coverage criteria in the PDM. Currently, the SSED Benefit-Risk Determination for ColoSense explicitly warns 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 [12].” Because of this uncertainty, FDA states “additional investigation in the form of post-approval studies [to enroll additional 12,500 participants to achieve 33 additional patients with CRC] are required to confirm the performance of this device for CRC detection [12].” These statements are not discretionary commentary; they are FDA mandated risk disclosures tied to residual uncertainty at the time of authorization. The label also indicates “non-inferiority or superiority of ColoSense programmatic sensitivity as compared to other recommended screening methods for colorectal cancer, advanced adenomas, or serrated precancerous lesions has not been established [12].”

This FDA-mandated warning directly implicates patient safety in a screening context, where false negative results could delay colonoscopy and diagnosis, allowing disease progression to a more advanced and higher-risk stage. A core quality and safety concern arises from CMS’s decision to automatically provide coverage for tests that still need to confirm performance, per FDA requirement, on the very criteria (i.e., CRC sensitivity) CMS requires to evaluate coverage. In this instance for mt-sRNA, FDA reliance on post-approval studies reflects an acknowledgment that performance uncertainty remains at the time of authorization. CMS’s proposed framework, however, would allow immediate national coverage—potentially at scale—before those uncertainties are resolved, effectively shifting the consequences of performance shortfalls onto Medicare beneficiaries and the Medicare program.

Given the number of covered, high-quality and widely available methods to screen for CRC, there is simply no need for CMS to sacrifice quality and safety to accelerate coverage for new tests prior to confirming performance characteristics that are sufficiently robust for generalizability to the Medicare population. Where key test performance criteria (i.e., sensitivity or specificity) or safety questions remain unresolved at the time of FDA authorization, CMS should require that any CRC screening test complete all studies, inclusive of any FDA post-approval study requirements needed to ensure that products with insufficient evidence related to CMS coverage criteria, complete rigorous analyses that meet FDA and CMS statistical standards, prior to being eligible for coverage under an NCD.

Primary prevention, early detection, and early treatment have contributed to declining overall mortality rates for CRC over the past decade. Between 2013 and 2023, CRC screening rates in a Medicare-aged population 65-75 years old increased from 69.4% [13] to 82.7% [14]. Lowering standards will reverse the progress achieved and can have a negative impact on Medicare beneficiaries and public health.

III. The PDM’s conflation of blood-based and stool-based tests in a single NCD exceeds statutory authority.

The PDM’s express purpose of outlining common coverage criteria across a series of distinct types of tests does not align with the Social Security Act. The Act’s section 1869(f)(1)(B) defines an NCD as “a determination by the Secretary with respect to whether or not a particular item or service is covered nationally.” (Social Security Act § 1869(f)(1)(B)). The PDM proposed that this NCD, in contrast, would “outline coverage criteria for any current or future noninvasive biomarker FDA approved/cleared screening tests” and is “not test specific but rather [applies] across noninvasive biomarker tests” to avoid reconsideration as new tests come to market. As drafted, the PDM collapses multiple biologically and clinically distinct services, including stool-based screening and blood-based screening, into a single category with the same coverage criteria. Abbott believes stool-based and blood-based non-invasive CRC screening tests have historically been evaluated under separate NCDs. This review and PDM also explicitly excludes FIT, another non-invasive stool-based CRC screening test covered under a separate NCD. The proposal thus operates as a substantive rule that should not be implemented through an NCD and requires notice and comment rulemaking. CMS’s policy rationale—administrative efficiency and “futureproofing”—may be unintentionally overriding the statutory requirement that an NCD apply to a particular item or service.

A determination regarding an open-ended series of different tests that have widely divergent performance characteristics and serve different patient needs and preferences is not a determination with respect to a particular item or service. CMS’s regulatory framework confirms that stool-based and blood-based CRC screening tests are distinct. For example, 42 C.F.R. § 410.37 references “noninvasive stool-based colorectal cancer screening” and “blood-based biomarker colorectal cancer screening” as separate tests. (eCFR, 2026).

Abbott respectfully urges CMS to maintain distinct, modality-specific coverage criteria for stool-based and blood-based CRC screening tests in order to appropriately establish and evaluate coverage criteria and protect patient care. Without these guardrails, the proposed policy exceeds the statutory bounds of an NCD.

IV. The PDM’s conflation of blood-based and stool-based tests could unintentionally roll back progress in the reduction of CRC mortality.

The goal of population-based CRC screening is to detect CRC, and its biological precursors, at the earliest possible opportunity. When CRC is detected at early stages, it is more treatable, which is clinically beneficial. When the process of carcinogenesis is interrupted at the precancer stage, however, it is preventable, which is clinically optimal.

Stool-based CRC screening is biologically better suited to detect APL than blood-based CRC screening because it directly samples exfoliated cells and biomarkers shed from or through the colonic mucosa into the intestinal lumen where precancerous adenomas and serrated lesions originate and reside. Precancerous lesions frequently shed abnormal molecular markers (i.e., methylated DNA) and intermittently leak blood-derived markers (i.e., hemoglobin) into stool long before they breach normal anatomic boundaries and invade deeply enough to release detectable circulating tumor DNA (ctDNA) into the bloodstream. As a result, stool is a proximal and biologically enriched substrate for early lesion detection.

In contrast, current blood-based assays rely on detecting ctDNA, which is released primarily by more advanced, higher-burden tumors, and therefore ctDNA is demonstrably low or absent in asymptomatic and early-stage disease, including APL, due to limited vascular access and low tumor shedding. Clinical evidence reflects this biological constraint: large prospective studies of blood-based CRC screening tests show that while capable of identifying established or advanced cancers, they are limited at identifying APL and early-stage cancer. In contrast, stool-based tests (including FIT, which is explicitly excluded from this PDM) demonstrate substantially higher detection of APL because they capture localized molecular and blood-derived signals before malignant invasion.

This fundamental difference explains why professional societies and evidence reviews conclude that stool-based screening is more effective for CRC prevention. Stool-based tests enable detection and removal of precancerous lesions, while blood-based screening is inherently constrained by biology with respect to intercepting disease at a more favorable, pre-invasive stage in the process of carcinogenesis.

CCSQ has recently stated that prevention is the organizing principle for its work. CCSQ’s strategic roadmap “starts with a simple idea: healthcare begins with prevention,” and emphasizes that when people have early access to the right services, including screening, health outcomes meaningfully improve [10]. The PDM acknowledges this prevention mechanism multiple times, grounding clinical utility (mortality reduction) in “the detection of large adenomas and early-stage cancer where treatments have been shown to be more effective.” It also recognizes that “early detection and removal of large pre-cancerous adenomas helps prevent” progression to cancer. Despite CMS’s recognition that precancer detection is the primary mechanism through which prevention is possible, the PDM rejects the inclusion of minimum performance criteria for APL sensitivity, contradicting administration goals.

The PDM purports to rationalize this omission of precancer detection in a passage that simultaneously (a) recognizes the clinical value of advanced adenoma (AA) detection and (b) declines to set minimum criteria: “While we acknowledge the utility and potential clinical benefit of screening for AAs, there continues to be limited available evidence on the accuracy of non-invasive screening tests to detect AAs and the sensitivity for detecting AA is low (Imperiale, 2019). We did not include point sensitivity or specificity to AA in the proposed test performance criteria.”

This language is not new. In fact, CMS used strikingly similar language in the NCA - Screening for Colorectal Cancer - Blood-Based Biomarker Tests (CAG-00454N) over five years ago, before multiple new pivotal studies were published that included AA sensitivity: “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 (Imperiale, 2019). Thus, we did not include point sensitivity or specificity to screen for advanced adenoma in the decision [1].” In both 2021 and 2026, the citation is referring to a systematic review and meta-analysis on “Performance Characteristics of Fecal Immunochemical Tests for Colorectal Cancer and Advanced Adenomatous Polyps.” The 2019 publication [15] is being taken out of context and is commenting on the heterogeneity of various FIT products at different positivity thresholds and the conclusion cannot be extrapolated to other molecular non-invasive tests.

The PDM asserts that “the sensitivity for detecting AAs remains around 40% to 43% … [and] there continues to be limited available evidence on the accuracy of non-invasive screening tests to detect AAs.” This statement is demonstrably inconsistent with the current evidence base and does not recognize the established, greater than 3-fold difference in APL detection with molecular stool-based versus blood-based screening tests. The precancer sensitivities reported for blood-based screening tests in the PDM are markedly different at 13.2% and 12.5% in Table 1 and Table 11, respectively.

CMS also combines stool-based and blood-based evidence to broadly conclude that “the published evidence demonstrates that the available mt-sDNA test, the mt-sRNA test, and the BBB [blood-based biomarker] screening test will identify CRC biomarkers sufficiently early to perform interventions to prevent progression of AAs to cancer . . .” However, the FDA SSED for the BBB test contradicts this conclusion and states that the following precaution must be prominently displayed in the test’s labeling and advertising: “Precaution: Based on data from clinical studies, Shield® has limited detection (55%-65%) of Stage I colorectal cancer and does not detect 87% of precancerous lesions. One out of 10 patients with a negative Shield result may have a precancer that would have been detected by a screening colonoscopy [16].” The FDA label goes further indicating that “due to the performance for AA, the indication for this device does not include the detection of AA.”

The FDA labeling for stool-based tests differs significantly than the labeling for the blood-based test. The SSED for Cologuard Plus® states: “Data from the BLUE-C clinical study supports the effectiveness of Cologuard Plus to screen for the presence of CRC or APL . . . [3].” The SSED for ColoSense states: “Data from the CRC-PREVENT clinical trial support the effectiveness of ColoSense to screen for the presence of colorectal cancer, advanced adenoma or serrated precancerous lesions . . . [12].”

The PDM’s statements are also inconsistent with the 2021 NCD for Blood-Based Biomarker Tests, where CMS recognized that the preventative benefit of screening is at risk when a test does not detect large polyps well. CMS noted that a lower performing blood-based test “does not prevent cancer as well as the stool DNA test, since this test does not prevent cancer by detecting large polyps that can lead to cancer; thus, missing the opportunity to remove these pre-cancerous polyps during therapeutic colonoscopy [1].”

Another reason CMS offered for declining to incorporate APL coverage criteria in the PDM was “there appears to be an inconsistent use of definitions for AAs” and that CMS “could not find a standardized uniform methodology or a consensus statement for reporting AAs.” FDA has standardized definitions for precancer categorization that are outlined in the SSED that CMS can and should rely upon as part of the review process since coverage of CRC screening tests requires FDA approval. Furthermore, with respect to specificity, CMS reached a different conclusion despite invoking the same concern. CMS acknowledged that “there is no standardized uniform method for reporting specificity,” but nonetheless defined specificity for purposes of the NCD as a negative colonoscopy (no findings), noting that this definition may not consistently map to numeric categories across studies and that no consensus methodology exists. Thus, CMS relied on inconsistent definitions to exclude AAs from coverage criteria while simultaneously adopting an operational definition of specificity resulting in two divergent outcomes based on the same underlying rationale.

The PDM further obscures the precancer detection differences in stool-based and blood-based testing by assigning a three-year coverage frequency to all modalities without requiring any level of precancer detection. Applying the same screening intervals to all tests, without regard to each modality’s ability to detect precancer, increases the risk that there may be delayed diagnosis and missed prevention opportunities—particularly in a Medicare-aged population.

The omission of APL sensitivity criteria is the result of treating fundamentally unequal preventive capabilities as equivalent for coverage purposes. Considering different CRC screening modalities as equivalent on “prevention” even when their preventive capability is markedly different is methodologically flawed and is misaligned with CMS priorities.

There are no professional society guidelines or evidence-based guidelines that recommend blood-based CRC screening as a first-line screening option, and that is largely due to the inability of blood-based tests to identify precancerous lesions. The following are examples of how experts incorporate precancerous lesion detection into their evaluation of CRC screening tests:

• The PDM recognizes that while the National Comprehensive Cancer Network® (NCCN) includes blood-based cell-free DNA screening every three years in its guidelines, NCCN only recommends it “for individuals who are not willing to undergo colon cancer screening through another modality [17].” However, CMS does not acknowledge that NCCN recommends blood-based testing only as a second-line option because of “. . . its modest performance, particularly among advanced precancerous lesions. . .”
• The American Society for Gastrointestinal Endoscopy put forth a position statement in 2025, stating that “blood-based tests are inferior to established screening options (i.e., colonoscopy and stool-based tests) especially concerning APL detection,” and “the scientific evidence does not support its use as a first line screening tool [18].”
• The 2024 American Gastroenterological Association CRC Workshop Panel published a paper on the role of blood-based testing, with the experts concluding that “the models also show the insufficiency of focusing on sensitivity to detect CRC alone, showing that effective and cost-effective tests also must detect AAs. In fact, modeling shows that increasing AA sensitivity modestly likely would provide more benefit than improving CRC sensitivity up to 95%. The panel concluded that, based on modeling, LB [liquid biopsy] should not be recommended to replace current existing tests because it is neither as effective or cost effective, and would worsen outcomes [19].”
• The USPSTF commissioned the CISNET Colorectal Cancer Working Group to conduct comparative modeling to estimate life-years gained, CRC cases averted, and CRC deaths averted for various screening strategies (i.e., CRC sensitivity, specificity, and AA sensitivity). The PDM has no mention of CISNET and references no modeling evidence inconsistent with CMS’s prior NCD on blood-based CRC screening from 2021.

Under 42 C.F.R. § 410.37, Medicare’s regulation governing CRC screening tests, subsection (a)(1)(v) states that CMS should determine coverage “in consultation with appropriate organizations.” Unlike past NCD PDMs, this PDM does not identify any consultation with appropriate professional organizations and CMS chose not to convene a MEDCAC for expert consultation. To align the final NCD with CCSQ’s prevention strategy and the available evidence today, CMS should consider final national coverage on meeting an expert-informed, minimum APL sensitivity criterion for both stool-based and blood-based CRC screening (in separate NCDs) in addition to CRC sensitivity and specificity. Given the divergence of the PDM from CMS prevention goals, biological differences between stool-based and blood-based screening with the evidence to support, CMS would benefit from gathering expert opinion on CRC screening to finalize appropriate performance criteria for each modality.

As professional medical societies and evidence-based guidelines have established, stool-based screening tests and blood-based screening tests serve different roles and have substantially different abilities to detect precancerous lesions. These stark differences necessitate that CMS evaluate these tests separately for coverage. Failing to do so could cause providers and patients to assume that stool-based and blood-based tests are interchangeable from a safety and performance standpoint when that is not the conclusion that professional medical societies and evidence-based guideline organizations have reached.

V. Summary and requested modifications to the NCD.

Abbott supports CMS’s efforts to modernize coverage pathways, accelerate beneficiary access to innovation, and align national policy with CCSQ’s strategic priorities. However, to ensure that the final NCD advances prevention, quality and safety, and durable clinical utility—rather than unintentionally rolling back the significant progress that has been made over the years in CRC screening—CMS should revise the proposed framework in several critical ways.

First, Abbott agrees that innovation is crucial in continued advancement in the fight against CRC and that a level playing field is appropriate to promote competition to improve public health. However, lowering standards in the evaluation of stool-based CRC screening tests will have unintended consequences on the healthcare system. CMS should maintain that new stool-based testing innovations continue to meet or exceed the established standards that were reviewed in the original consideration of this NCD over a decade ago — 92% CRC sensitivity, 90% specificity, and 42% APL sensitivity — ensuring Medicare beneficiaries retain access to tests that are as good as, or ideally better than, those available today.

Next, where key test performance criteria (i.e., sensitivity or specificity) or safety questions remain unresolved at the time of FDA authorization, CMS should require that any CRC screening test complete all studies, inclusive of any FDA post-approval study requirements needed to ensure that products with insufficient evidence related to NCD test performance criteria, complete rigorous analyses that meet FDA and CMS statistical standards, prior to obtaining Medicare coverage. These changes will allow CMS to achieve its strategic quality and safety goals while ensuring that national CRC screening policy continues to save lives, prevent cancer, and steward Medicare resources responsibly.

Additionally, CMS should maintain distinct coverage criteria for stool-based and blood-based CRC screening tests. Collapsing these biologically and clinically distinct modalities into a single “non-invasive biomarker” category is inconsistent with the statutory concept of a “particular item or service,” CMS’s history of past modality-specific CRC NCDs, and the pivotal clinical evidence base, and could inadvertently negatively impact public health. Robust, modality-specific data exist for both stool-based and blood-based screening tests. Treating these technologies as interchangeable obscures meaningful differences in cancer detection, precancer detection, safety, and downstream outcomes—and risks allowing tests to qualify for coverage under a generalized framework that lacks appropriate guardrails.

Finally, to ensure that CMS’s final coverage policy aligns with its prevention goals and supports clinical utility, it is critical that APL sensitivity be included as an explicit coverage criterion alongside CRC sensitivity and specificity in separate NCDs for stool-based and blood-based tests. Making prevention operational within the coverage criteria will help distinguish the preventive capabilities of different screening modalities and avoid treating unequal technologies as interchangeable. CMS should actively consult with relevant professional organizations or convene a MEDCAC to gather expert opinions and ensure that the NCDs reflect the best available evidence and expert guidance. While Abbott believes that both stool-based and blood-based CRC screening tests can play an important role, CMS should evaluate these test modalities separately and consult experts in its evaluation.

* * * * *

We thank you for your consideration of Abbott’s comments on the Proposed Decision Memo for Screening for Colorectal Cancer—Non-Invasive Biomarker Tests (CAG-00440R). Please contact me at mkemeter@exactsciences.com with any questions.

Sincerely,
Mike Kemeter

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 7 April 2026].
[2] Data on file; Estes C, Dehghani M, Ozbay A, et al., "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.
[3] FDA SSED Data, "PMA P230043," 3 October 2024. [Online]. Available: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230043B.pdf. [Accessed 7 April 2026].
[4] Exact Sciences Corporation, Modeling data on file.
[5] D. Ebner, M. Fendrick, J. Kisiel and et al., "Evaluating benefit-to-burden ratios of the established and emerging colorectal cancer screening strategies," JNCI: Journal of the National Cancer Institute, 2025.
[6] Knudsen AB, Rutter CM, Peterse EFP, et al., "Colorectal Cancer Screening: An Updated Decision Analysis for the U.S. Preventive Services Task Force. AHRQ Technical Report No. 20-05271-EF-2," Agency for Healthcare Research and Quality, May 2021. [Online]. Available: https://www.ncbi.nlm.nih.gov/books/NBK570833/pdf/Bookshelf_NBK570833.pdf. [Accessed 7 April 2026].
[7] Vespa J, Medina L, Armstrong DM, "Demographic Turning Points for the United States: Population Projections for 2020 to 2060. Current Population Reports, P25-1144. Washington, DC: U.S. Census Bureau," February 2020. [Online]. Available: https://www.census.gov/library/publication. [Accessed 8 April 2026].
[8] American Cancer Society, "Colorectal Cancer Facts & Figures 2023–2025," 2023. [Online]. Available: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/colorectal-cancer-facts-and-figures/colorectal-cancer-fact. [Accessed 8 April 2026].
[9] Association of American Medical Colleges, "U.S. Physician Workforce Data Dashboard. Association of American Medical Colleges," 2023. [Online]. Available: https://www.aamc.org/data-reports/report/us-physician-workforce-data-dashboard . [Accessed 8 April 2026].
[10] "Centers for Medicare & Medicaid Services Newsroom," 11 March 2026. [Online]. Available: https://www.cms.gov/newsroom/blog/optimal-health-all-within-nations-health-long-term-care-systems-ccsq-fy2025-2028-strategic-roadmap. [Accessed 7 April 2026].
[11] CMS Coverage and Analysis Group, "CMS National Coverage Analysis Evidence Review Guidance Document," 2024.
[12] FDA SSED Data, "PMA P230001," 3 May 2024. [Online]. Available: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf. [Accessed 7 April 2026].
[13] "CDC Morbidity and Mortality Weekly Report (MMWR)," 2015. [Online]. Available: https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6417a4.htm. [Accessed 1 October 2025].
[14] "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].
[15] T. F. Imperiale, R. N. Gruber and T. E. Stump, "Performance Characteristics of Fecal Immunochemical Tests for Colorectal Cancer and Advanced Adenomatous Polyps: A Systematic Review and Meta-analysis," Annals of Internal Medicine, vol. 170, no. 5, pp. 319-329, 2019.
[16] FDA SSED Data, "PMA 230009," 26 July 2024. [Online]. Available: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230009B.pdf. [Accessed 7 April 2026].
[17] National Comprehensive Cancer Network, "NCCN Guidelines Colorectal Cancer Screening 2.2025," 2025. [Online]. Available: https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. [Accessed 7 April 2026].
[18] American Society for Gastrointestinal Endoscopy, "ASGE Position of Blood-Based Colorectal Cancer Screening," 25 August 2025. [Online]. Available: https://www.asge.org/docs/default-source/advocacy/08-25-2025-asge-crc-blood-tests-position-paper.pdf. [Accessed 7 April 2026].
[19] D. Lieberman, "AGA CRC Workshop Panel. Commentary: Liquid Biopsy for Average-Risk Colorectal Cancer Screening," Clin Gastroenterol Hepatol, vol. 22, no. 6, pp. 1160-1164, 2024.

Less

Re: Proposed Decision Memo – Screening for Colorectal Cancer: Non-Invasive Biomarker Tests (CAG 00440R)

Dear Administrator and CMS Leadership,

The Colorectal Cancer Alliance is the nation’s leading nonprofit organization dedicated to the awareness, prevention, and treatment of colorectal cancer. The Alliance appreciates the opportunity to provide public comment on the Centers for Medicare & Medicaid Services (CMS) proposed decision memo regarding coverage of non-invasive biomarker colorectal cancer screening tests.

As a patient advocacy organization, we strongly support efforts to expand access to evidence-based, person-centered screening options for Medicare beneficiaries at average risk. Early detection and prevention of colorectal cancer save lives. At the same time, expanding access must not come at the expense of clinical clarity, nor should it introduce confusion about how emerging screening modalities compare to well-established strategies already in practice.

From a patient perspective, colorectal cancer screening is not a one-time event. It is a longitudinal surveillance and prevention strategy. Patients and providers rely on clear, evidence-based guidance to understand which test is appropriate, how often to screen, and what follow-up and outcomes to expect. For this reason, coverage policy must accurately reflect the distinct performance characteristics, evidence base, and intended use of each specific modality.

The Alliance respectfully urges CMS to revise the proposed policy to ensure that screening intervals, performance expectations, and clinical positioning are explicitly tied to individual test modalities, their supporting evidence, and their FDA-authorized labeling, which is not applied broadly across a heterogeneous category of tests.

CMS’s proposed application of a uniform three-year screening interval across non-invasive biomarker tests risks obscuring important differences among modalities. CMS’s own evidence review, as well as existing clinical guidelines, consistently demonstrate that screening intervals are modality-specific, reflecting differences in test design, sensitivity, and intended clinical use.

For example, the United States Preventive Services Task Force (USPSTF) recommends annual fecal immunochemical testing (FIT) and multitarget stool DNA (mt-sDNA) testing every one to three years for average-risk adults aged 45 to 75. Similarly, the American Cancer Society (ACS) recommends stool-based screening beginning at age 45 with modality-specific intervals. At present, USPSTF does not include serum-based tests in its colorectal cancer screening recommendations, underscoring the importance of maintaining clear distinctions between modalities. CMS should ensure that the final National Coverage Determination is grounded in and consistent with the specific language of FDA-authorized indications for each modality, including mRNA-based tests, prior to establishing coverage parameters.

While we appreciate CMS’s effort to establish a practical framework for emerging technologies, the proposed approach relies heavily on one-time colorectal cancer sensitivity and specificity thresholds. Patients, however, experience screening in real-world settings over time. The central question is not simply whether a test meets a minimum detection threshold at a single point, but whether it performs appropriately relative to established screening strategies, including annual FIT and periodic mt-sDNA testing, and whether it contributes meaningfully to cancer prevention through detection of advanced precancerous lesions.

Colorectal cancer screening serves two distinct but related purposes:
? Early cancer detection, and
? Prevention through identification and removal of advanced precancerous lesions (APL)

These are not interchangeable goals. A test that primarily detects existing cancer differs fundamentally from one that effectively identifies precancerous lesions and thereby prevents cancer from developing. This distinction is critically important to patients and should be clearly reflected in coverage policy.

The Alliance recommends:
? Ensure screening frequency is explicitly stated for each specific modality, its supporting clinical evidence, and its FDA-authorized label, rather than applying a uniform interval across all non-invasive biomarker tests. This will ensure that coverage aligns with how each test is designed, validated, and intended to be used in clinical practice.
? Ensure accurate and forward-looking representation of guideline alignment for emerging modalities. While current USPSTF recommendations do not include serum-based tests, the policy should clearly acknowledge that guideline support remains modality-specific while also recognizing the potential for future inclusion of blood-based and mRNA-based screening technologies as evidence evolves. CMS should avoid overstating current alignment while allowing room for innovation grounded in robust clinical validation.
? Both coverage criteria and policy language should reflect the distinction between a test that functions primarily as a cancer detection tool and one that serves as a preventive screening modality. Advanced precancerous lesion (APL) detection is central to this distinction and has meaningful implications for patient outcomes.
? Reinforce the necessity of a timely follow-up colonoscopy after any abnormal non-colonoscopy screening result. Screening improves outcomes only when abnormal findings are followed by appropriate diagnostic evaluation without delay.

CMS’s final policy should expand access while preserving clinical accuracy, transparency, and patient understanding.
Without additional clarification, the proposed framework risks blurring meaningful differences between established stool-based screening options and newer biomarker tests with distinct performance profiles and evidence bases.
In addition to revising the National Coverage Determination, we encourage CMS to issue sub-regulatory guidance—such as an implementation FAQ—that clearly:
? Distinguishes this policy from existing FIT coverage
? Explains screening intervals by modality
? Reinforces the importance of follow-up colonoscopy
? Identifies key evidence gaps, including interval performance, real-world adherence, APL detection, and outcomes in the Medicare population

Patients depend on CMS to ensure that coverage decisions are both innovative and grounded in evidence, supporting access while preserving the integrity of colorectal cancer screening as a preventive continuum of care.

Thank you for the opportunity to provide public comment and for your continued commitment to improving patient outcomes.

The Colorectal Cancer Alliance

Less

1301 Pennsylvania Avenue, NW
Suite 400
Washington, D.C. 20004
P :: 202.783.8700
F :: 202.783.8750
W :: AdvaMed.org

April 9, 2026

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

Re: Proposed Decision Memo for Screening for Colorectal Cancer—Non-Invasive Biomarker Tests (CAG-00440R)

Dear Ms. Baldwin,

On behalf of the MedTech Association (AdvaMed), we thank the Centers for Medicare & Medicaid Services (CMS) for the substantial work reflected in the Proposed Decision Memo for Screening for Colorectal Cancer—Non-Invasive Biomarker Tests (CAG-00440R). We appreciate the opportunity to submit comments and commend CMS for moving promptly from the close of the initial comment period to a proposed decision. AdvaMed and CMS share a common goal—ensuring timely access for Medicare beneficiaries to preventive services grounded in scientifically sound clinical evidence, with appropriate safeguards that protect patients and preserve the integrity of the coverage process.

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 are united in their commitment to improving patient outcomes and ensuring that Medicare beneficiaries have access to lifesaving and life-enhancing technologies. In that spirit, we write to express AdvaMed’s areas of agreement with the proposed NCD framework and to offer recommendations for CMS’s consideration as it works toward a final decision.

1. Commitment to Evidence Standards and Relevance to the Medicare Population

AdvaMed strongly supports CMS’s commitment to rigorous, evidence-based coverage standards. We agree that coverage of non-invasive biomarker colorectal cancer (CRC) screening tests should be grounded in high-quality clinical evidence, including evidence that is directly relevant to the Medicare beneficiary population. CRC is the second leading cause of cancer death in the United States, and the Medicare population includes a disproportionate share of underserved individuals, and carries higher rates of comorbidities and thus faces unique risks and barriers to screening. Coverage policy that reflects the clinical realities of this population will be most effective in achieving meaningful reductions in CRC mortality. AdvaMed thanks CMS for the transparency it has brought to this process, including its efforts to articulate the criteria against which non-invasive biomarker tests will be evaluated. Transparent, well-defined evidentiary thresholds provide manufacturers with meaningful guidance, and give clinicians and patients confidence in covered tests.

2. Support for Timely Access to Screening Technologies

AdvaMed agrees with CMS that Medicare beneficiaries should have timely access to non-invasive biomarker CRC screening tests. Screening remains underutilized, particularly among underserved and rural populations. Expanding access to high-quality screening options that align with patient preferences can foster adherence and advance health equity. A coverage framework that moves efficiently from evidence review to coverage determination, without unnecessary delay, serves both individual patients and the broader public health goal of increasing CRC screening rates in every community. We look forward to a final decision memo that preserves CMS’s commitment to evidence while ensuring that tests meeting the rigorous coverage criteria can reach Medicare beneficiaries without unnecessary delay.

3. Support for Alignment with FDA Labeling

AdvaMed supports the proposed decision’s approach of tying coverage eligibility to FDA-approved or authorized labeling. Grounding coverage criteria in the FDA label, which itself reflects a rigorous evaluation of safety, effectiveness, and intended use, is a sound and principled approach that reduces duplicative review, and provides manufacturers with a clear and predictable pathway to coverage. This alignment also helps ensure that tests are used in the population and clinical context for which they have been validated, including safety limitations, which protects both patients and the integrity of the screening benefit. We encourage CMS to maintain this alignment in the final decision memo and to consider how its framework can continue to accommodate future FDA-authorized tests efficiently as the field of non-invasive CRC screening continues to advance.

4. Post-Approval Study Requirements Balance Timely Access and Post-market Accountability

AdvaMed agrees with the principle that coverage should be conditioned on demonstrated test performance. We recognize that CMS’s proposed approach, which allows coverage for tests that have an FDA-required post-approval study to demonstrate performance endpoints, rather than requiring completion of such studies prior to any coverage, reflects a pragmatic balance between evidence generation and timely access. In the final decision memo, CMS should also clarify that achieving the FDA-specified results of the post-approval study is only a requirement for continued coverage of a test under the NCD if the results would impact tests characteristics that are required for coverage. This approach acknowledges the real-world constraints on pre-market evidence generation for CRC screening tests while preserving meaningful accountability for post-market performance.

AdvaMed recommends that CMS provide additional guidance on how FDA and CMS will coordinate oversight of post-approval studies, including a formal mechanism for manufacturers to report study updates, such as FDA-approved changes to enrollment or reporting timelines, and study outcomes directly to CMS.

5. Recommendations to Ensure the Durability of Ordering Provider Criteria

AdvaMed welcomes CMS's decision within the proposed decision memo to make the ordering requirements consistent across test modalities. Doing so ensures that providers can offer the full range of CRC screening options to their patients, allowing shared decision-making between the provider and beneficiary to select the test they are most likely to complete. Similarly, AdvaMed appreciates CMS’s decision to broaden the ordering provider language to include physicians, physician assistants, nurse practitioners, and clinical nurse specialists who will use the results in the management of the patient. This update appropriately reflects the realities of modern care delivery, where a range of qualified providers play central roles in preventive screening. To ensure the NCD remains durable and does not require reopening solely due to future changes in provider scope, we recommend that CMS modify the language to directly reference the federal regulations defining “non-physician providers.” This would allow for the inclusion of any additional provider types subsequently recognized under the Social Security Act when ordering preventive services would fall within their scope of practice.(see redline below). Such forward-looking language would allow the NCD to keep pace with the evolving healthcare landscape without necessitating future administrative action.

AdvaMed respectfully requests that CMS delete the phrase 'in the management of the patient' from the ordering provider criterion entirely. As currently drafted, this language creates a risk in circumstances where a screening or diagnostic test returns a negative or normal result, situations in which there is, by definition, nothing to actively manage. Auditors applying this standard could reasonably expect documentation of patient management activity that does not exist and need not exist, creating administrative burden for providers and potential exposure for ordering clinicians who have acted entirely appropriately. Removing the phrase would eliminate this ambiguity without limiting CMS's ability to ensure that tests are ordered in a clinically appropriate context.

Should CMS be unwilling to delete the phrase in its entirety, AdvaMed urges CMS to consider a more targeted revision: replacing “in the management of the patient” to “for the management of the patient” to better reflect the role of the ordering provider in the screening process. Currently, when a provider orders a non-invasive test and it is positive, regardless of the nature of the relationship between the provider and patient, the follow up action is referral to colonoscopy; the provider who orders the screening test is not typically the specialist that will perform the colonoscopy. As such, a change from “in” to “for” is consistent with the current role of the ordering provider in the screening process. The management of the patient that is needed following a positive test result is referral to colonoscopy, and additional management of the patient may appropriately fall to another provider.

Suggested targeted revision:
From (existing language in proposed decision memo):
We propose that non-invasive biomarker colorectal cancer screening tests are covered once every three years for Medicare beneficiaries when ordered by the physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient and when all the following conditions are met

To:
We propose that non-invasive biomarker colorectal cancer screening tests are covered once every three years for Medicare beneficiaries when ordered by the physician, physician assistant, nurse practitioner, clinical nurse specialist or other nonphysician practitioner practicing within the scope of their statutory authority in section 1861 [1] who will use the results for the management of the patient and when all the following conditions are met

AdvaMed again thanks CMS for its diligent work on this proposed decision memo and for the thoughtful approach reflected throughout. We appreciate the opportunity to engage in this process and look forward to a final decision that advances timely access to evidence-based CRC screening for Medicare beneficiaries. If you have any questions regarding these comments or require additional information, please contact me at tburke@advamed.org.

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

References:
1. Social Security Act § 1861, codified at 42 U.S.C. § 1395x, which defines medical and other health services and the practitioner types recognized under the Medicare program.

Less

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, pragmatic experience that enables us to fully support the expansion of the National Coverage Determination to include ColoSense and mt-stool RNA detection methodologies.

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.

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 existing blood-based sensitivity and specificity threshold. We have seen this public health promise demonstrated firsthand - previously screen-reluctant patients who’ve agreed to ColoSense testing have been 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.

Further, I anticipate improved compliance with stool-based testing with the addition of ColoSense, given its novel collection methodology. The novel test design makes it easier for patients to complete, particularly for older individuals and those with limited dexterity. Improved compliance with 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. Beyond compliance, there are indications that ColoSense’s modified collection approach could improve performance, with the reported method-adjusted specificity approaching 90%. [2]

The proposed reconsideration appropriately recognizes that advances in biomarker-based screening technologies can expand the range of effective colorectal cancer screening options available to Medicare beneficiaries. By establishing clear performance expectations, including adding a coverage pathway for high-sensitivity tests, and acknowledging evidence from prospective clinical studies, CMS has created a framework that allows innovative screening approaches to be evaluated in an objective, modality-neutral, and specimen-agnostic manner. 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.

It is also important to highlight that 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 CMS did not establish performance criteria for advanced adenomas, as suggested in our comment on the tracking sheet, we appreciated CMS's acknowledgment of the utility and potential clinical benefit of screening for advanced adenomas.

Finalizing the proposed decision will help ensure that screening programs continue to evolve to improve early detection, expand access, and ultimately benefit patients across diverse and medically complex populations.

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. Barnell EK, Levin TR, Gupta S, Carethers JM, Shaukat A, Kruse K, Ghannam R, Lieberman DA. Clinical Validation of a Simplified, Scrape-Free Collection Method for Multitarget Stool RNA Testing in Colorectal Cancer Screening. J Clin Gastroenterol. 2026 Jan 19. doi: 10.1097/MCG.0000000000002336. Epub ahead of print. PMID: 41549820.

Less

April 9, 2026

The Honorable Mehmet Oz, MD
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Comments on Proposed National Coverage Analysis, Centers for Medicare & Medicaid Services, “Screening for Colorectal Cancer – Blood-Based Biomarker Tests” (NCA ID: 319)

Dear Administrator Oz:

Thank you for the opportunity to submit these comments on the proposed decision memorandum issued by the Centers for Medicare & Medicaid Services (CMS) regarding Medicare coverage for blood-based biomarker tests for colorectal cancer (CRC) screening. We appreciate your agency’s continued commitment to expanding access to preventive services for Medicare beneficiaries and its leadership in shaping evidence-based national coverage policy.

My name is Christopher Sheeron, and I am the founder and president of Action for Health.(1) Action for Health is a national nonprofit advocacy organization working to ensure fair outcomes for critical healthcare issues. We educate policymakers, the media, and concerned citizens about policies, laws, and regulations that are important to patients.

The comments below provide an analytical assessment of the clinical, epidemiological, and systemic implications of expanding Medicare coverage to include blood-based CRC screening tests that, at present, demonstrate lower sensitivity and specificity compared to established screening modalities.

Introduction

Colorectal cancer remains a significant public health challenge nationwide. According to data from the American Cancer Society, CRC is the third most diagnosed cancer and the second leading cause of cancer-related mortality among men and women combined.(2) In 2024 alone, it is estimated that more than 150,000 new cases of CRC will be diagnosed and over 50,000 deaths will occur nationwide.(3)

The burden of CRC is particularly relevant for the Medicare population, as incidence increases substantially with age.(4) Individuals aged 65 and older account for approximately 60% of new CRC diagnoses and 70% of CRC deaths, making the efficacy of the primary screening tool a critical determinant of Medicare program outcomes.(5) Early detection through effective screening has been shown to reduce both CRC incidence and mortality, primarily through the identification and removal of precancerous polyps and early-stage malignancies.(6)

Established Screening Modalities and Clinical Effectiveness

Current guideline-recommended CRC screening options include colonoscopy, fecal immunochemical testing (FIT), and stool DNA testing.(7) Colonoscopy remains the gold standard due to its dual diagnostic and therapeutic capability, allowing for both detection and removal of adenomatous polyps in a single procedure.(8) Non-invasive tests such as FIT and stool DNA tests have also demonstrated strong performance characteristics. For example, FIT tests typically achieve sensitivities for CRC detection in the range of 70–80%, while stool DNA tests may exceed 90% sensitivity for detecting established cancers.(9)

By contrast, emerging blood-based biomarker tests – while promising from an accessibility and adherence standpoint – have demonstrated comparatively lower sensitivity, particularly for detecting advanced adenomas and early-stage cancers.(10) In recent pivotal trials, blood-based cfDNA tests demonstrated a sensitivity for advanced neoplasia of only 13%, compared to 94% for colonoscopy and 43% for multi-target stool DNA (mt-sDNA) testing.(11) This significant "prevention gap" suggests that blood-based tests may fail to detect nearly 9 out of 10 precancerous lesions that a colonoscopy would identify making the distinction of care essential to conversations around coverage and impact.

Implications of Blood-Based Testing on Preventive Care

The proposed expansion of Medicare coverage to include blood-based CRC screening tests raises important concerns regarding a potential shift from preventive to reactive care. Unlike colonoscopy and, to a lesser extent, stool-based tests, blood-based assays are generally not capable of detecting and enabling removal of precancerous polyps.(12) As such, reliance on these tests may result in:

• Lower rates of adenoma detection;
• Delayed diagnosis of early-stage CRC; and
• Increased detection of cancers at more advanced stages.(13)

Modeling data suggests that if patients switch from more sensitive tests to blood-based biomarkers, the lifetime risk of developing CRC could increase. Current projections indicate that a screening strategy with low AA sensitivity could result in a 15–20% higher incidence of cancer compared to high-sensitivity stool DNA or colonoscopy-based strategies.(14)

Medicare’s Role in Shaping Clinical Practice

Coverage determinations by CMS extend far beyond the Medicare population. As the largest payer in the country, Medicare policy often establishes benchmarks that are subsequently adopted by commercial insurers, Medicaid programs, and integrated health systems.(15) Thus, expanding coverage for lower-sensitivity screening modalities may have system-wide consequences, including:

• Shifts in provider practice patterns toward less effective screening tools;
• Changes in patient perception of screening adequacy; and
• Potential erosion of adherence to higher-value screening strategies.

Economic considerations are also relevant as blood-based tests may offer lower upfront costs and improved patient compliance, however these potential advantages must be weighed against the downstream costs associated with later-stage cancer diagnosis and treatment.(16) The cost of treating Stage IV CRC is estimated to be more than 300% higher than the cost of treating Stage I CRC, often exceeding $200,000 per patient in the first year of management.(17) Broadening coverage for a test with lower preventive efficacy could inadvertently increase long-term Medicare expenditures by shifting the burden from inexpensive screening to intensive oncology care.

Patient Adherence and Equity Considerations

Proponents of blood-based screening emphasize improved patient adherence, particularly among populations reluctant to undergo colonoscopy or stool-based testing.(18) This is a meaningful consideration, as screening uptake remains suboptimal in certain demographic groups. However, the trade-off between increased participation and reduced diagnostic accuracy must be carefully evaluated. A screening test that is more acceptable but less effective may still result in worse overall population outcomes if it fails to detect disease at a curable stage.

A more balanced approach may involve positioning blood-based tests as secondary options for patients who decline recommended first-line screening modalities, rather than as equivalent alternatives. Data from the PREEMPT CRC study indicates that while blood-based tests can reach underserved populations, the clinical benefit is only realized if positive results are followed by a "reflex" colonoscopy; currently, follow-up rates for positive non-invasive tests in some Medicare populations remain as low as 50–60%.(19)

Recommendations

In light of the above considerations, Action for Health respectfully offers the following recommendations:

1. Maintain Hierarchical Positioning of Screening Modalities: Blood-based CRC screening tests should not be positioned as equivalent to colonoscopy or high-performing stool-based tests in coverage policy or clinical guidance.
2. Require Robust Evidence Thresholds: Coverage should be contingent upon demonstration of clinically meaningful sensitivity for both CRC and advanced adenomas, consistent with established screening standards.
3. Implement Guardrails in Coverage Policy: CMS should consider limiting coverage of blood-based tests to individuals who are unable or unwilling to undergo recommended screening modalities.
4. Monitor Real-World Outcomes: CMS should establish mechanisms to track the impact of blood-based testing on CRC stage at diagnosis, incidence rates, and mortality within the Medicare population.
5. Preserve the Preventive Care Framework: Policy decisions should prioritize screening strategies that demonstrably reduce cancer incidence, not solely those that increase detection rates.

Conclusion

We commend CMS for its continued efforts to expand access to cancer screening and improve beneficiary outcomes. However, the proposed expansion of coverage to include blood-based CRC screening tests raises substantial clinical and policy concerns.

Absent stronger evidence of comparable effectiveness, broad adoption of these tests risks shifting the healthcare system away from prevention and toward later-stage disease management. Given Medicare’s central role in shaping national healthcare delivery, such a shift would have far-reaching consequences.

We appreciate your consideration of these comments and would welcome the opportunity to provide additional information or analysis. If we can be of any help to you or your staff, please do not hesitate to contact me directly at (202) 823-2333.

Sincerely,
Christopher G. Sheeron
President
Action for Health

(1) Action for Health, www.action4health.org.
(2) American Cancer Society, Cancer Facts & Figures 2024, https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures.html.
(3) American Cancer Society, Cancer Facts & Figures 2024, https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures.html; National Cancer Institute, Surveillance, Epidemiology, and End Results (SEER) Program: Colorectal Cancer Statistics, https://seer.cancer.gov/statfacts/html/colorect.html.
(4) National Cancer Institute, Surveillance, Epidemiology, and End Results (SEER) Program: Colorectal Cancer Statistics, https://seer.cancer.gov/statfacts/html/colorect.html.
(5) Siegel, R. L., et al. "Colorectal Cancer Statistics, 2023," CA: A Cancer Journal for Clinicians (2023), https://pubmed.ncbi.nlm.nih.gov/36856579.
(6) U.S. Preventive Services Task Force, “Screening for Colorectal Cancer: Recommendation Statement,” JAMA (2021), https://jamanetwork.com/journals/jama/fullarticle/2779985; American College of Gastroenterology, “ACG Clinical Guidelines: Colorectal Cancer Screening 2021,” https://journals.lww.com/ajg/fulltext/2021/03000/acg_clinical_guidelines__colorectal_cancer.14.aspx.
(7) Ibid.
(8) American College of Gastroenterology, “ACG Clinical Guidelines: Colorectal Cancer Screening 2021,” https://journals.lww.com/ajg/fulltext/2021/03000/acg_clinical_guidelines__colorectal_cancer.14.aspx.
(9) Lee, J. K., et al., “Accuracy of Fecal Immunochemical Tests for Colorectal Cancer,” Annals of Internal Medicine (2014), https://www.acpjournals.org/doi/10.7326/M13-1484; Imperiale, T. F., et al., “Multitarget Stool DNA Testing for Colorectal-Cancer Screening,” New England Journal of Medicine (2014), https://www.nejm.org/doi/full/10.1056/NEJMoa1311194.
(10) U.S. Food and Drug Administration, Summary of Safety and Effectiveness Data (SSED): Blood-Based CRC Screening Test, https://www.fda.gov/medical-devices; Klein, E. A., et al., “Performance of a Cell-Free DNA Blood-Based Test for Colorectal Cancer Screening,” Journal of Clinical Oncology (2023), https://ascopubs.org/journal/jco.
(11) Chung, Daniel et al. "A Cell-Free DNA Blood-Based Test for Colorectal Cancer Screening (ECLIPSE Study)," New England Journal of Medicine (2024), https://pubmed.ncbi.nlm.nih.gov/38477985.
(12) Ibid.
(13) Zauber, A. G., et al., “Evaluating Test Strategies for Colorectal Cancer Screening,” Annals of Internal Medicine (2008), https://www.acpjournals.org/doi/10.7326/0003-4819-149-9-200811040-00004.
(14) Provenzale, D., et al. "Comparative Effectiveness of Colorectal Cancer Screening Strategies," Annals of Internal Medicine (2022).
(15) Kaiser Family Foundation, Medicare’s Role in the U.S. Health Care System, https://www.kff.org/medicare/.
(16) Mariotto, A. B., et al., “Projections of the Cost of Cancer Care in the United States,” Journal of the National Cancer Institute (2021), https://academic.oup.com/jnci/article/113/11/1501/6275201.
(17) National Cancer Institute. "Financial Burden of Cancer Care," Cancer Control and Population Sciences (2023 update), https://progressreport.cancer.gov/after/economic_burden.
(18) Ladabaum, U., et al., “Colorectal Cancer Screening and Surveillance,” Gastroenterology (2020), https://www.gastrojournal.org/article/S0016-5085(19)41349-3/fulltext.
(19) Inadomi, J. M., et al. "Adherence to Colorectal Cancer Screening: A Randomized Clinical Trial," JAMA Network Open (2021), https://www.sciencedirect.com/science/article/abs/pii/S1542356519314958.

Less

To the Centers for Medicare & Medicaid Services:
As a Federally Qualified Health Center (FQHC) dedicated to serving underserve population, and to provide quality and accessible primary health care services through community-responsive approaches that address financial, geographic, and other barriers to care, we strongly support the expansion of coverage for non-invasive colorectal cancer (CRC) screening biomarkers. In the safety-net setting, the most effective screening tool is the one that patients can realistically access and complete.

CMS has a stated priority of reducing health disparities, particularly in CRC where mortality rates remain disproportionately high for minority and rural populations. For our patients, traditional colonoscopies present significant socio-economic hurdles, including unpaid time off work, lack of reliable transportation, and the complexity of bowel preparation in unstable housing environments.
By providing coverage for high-sensitivity, non-invasive biomarker tests, CMS directly addresses these social drivers of health (SDOH). Transitioning to a "patient-centered" screening model allows us to improve clinical utility by meeting patients where they are, whether through a simple blood draw during a routine visit or a stool-based kit used at home.

CRC is a "family-altering" disease. When a primary caregiver or breadwinner in an underserved community is diagnosed with late-stage cancer, the resulting economic instability and trauma can impact a family for generations.
Focus on Precancerous Lesions: We urge CMS to prioritize coverage for tests with proven sensitivity for advanced adenomas. Detecting and removing these precancers is the "gold standard" of prevention.

Normalizing Preventive Care: Lowering the barrier to entry for screening helps normalize preventive health within families, shifting the community's perception of CRC from a "silent fate" to a manageable and preventable condition.

From an operational standpoint, expanded coverage for non-invasive tests allows our FQHC to optimize limited specialist resources. By using these biomarkers as a primary screening layer, we can more effectively triage our highest-risk patients for diagnostic colonoscopies. This ensures that our over-burdened gastroenterology referral pipelines are reserved for those with the greatest clinical need, thereby improving the efficiency and cost-effectiveness of the entire local healthcare ecosystem.

We recommend that CMS finalize a test-agnostic policy that maintains rigorous standards for precancer detection. This approach ensures that FQHCs have the flexibility to offer the most innovative and effective technology available. Expanding access to these non-invasive options is a critical step toward closing the health equity gap and protecting the long-term health of the families we serve and reduce the health care cost.
Sincerely,

Less

To CMS:

[PHI Redacted]

CMS has proposed updates to its coverage framework for non-invasive colorectal cancer screening tests under National Coverage Determination (NCD) 210.3. As a physician and former Surgeon General, I am concerned that the current proposal may not fully align with the established science on what makes screening most effective at preventing colorectal cancer.

The science is clear: the greatest long-term reduction in colorectal cancer mortality - more than 80% of the benefit - comes from detecting and removing precancerous lesions (such as advanced adenomas) before they develop into cancer. My own experience underscores this reality. Screening is most powerful when it interrupts the disease process early, not just when it identifies cancer after it has formed.

The proposed framework emphasizes performance thresholds focused primarily on cancer detection. While that is important, it risks underweighting the need for strong sensitivity to precancerous lesions. A standard that prioritizes convenience and cancer detection alone, without robust requirements for detecting advanced precancerous changes, may miss the full preventive potential of screening. It's akin to a smoke detector that alerts only after flames are visible, rather than when smoke first appears.

I commend this administration's commitment to improving healthcare efficiency, reducing waste in Medicare, and expanding access to innovative tools. Administrator Oz has brought valuable energy and a fresh perspective to CMS, challenging longstanding approaches in ways that can benefit patients and taxpayers. Innovation is essential - but so is ensuring that covered tests meet evidence-based standards that truly advance prevention.

Preventing cancer is far more cost-effective than treating it. A coverage approach that guides patients toward tests strong in convenience but weaker in detecting precancerous lesions could ultimately increase long-term costs to Medicare, in both financial and human terms.

CMS has an opportunity here to set a strong, technology-neutral standard: require that any covered non-invasive screening test demonstrate meaningful sensitivity to advanced precancerous lesions - not just to cancer itself. This would encourage the development of better tools while protecting patients.

To help ensure the final decision reflects the best available evidence, I encourage CMS to convene a Medicare Evidence Development and Coverage Advisory Committee (MedCAC). Bringing together clinical experts, researchers, and patient advocates for a rigorous, transparent review would be a responsible step for a decision of this importance.

During my time as Surgeon General, I consistently urged Americans to get screened for colorectal cancer. I know from both professional and personal experience why that message is vital. CMS now has the chance to reinforce prevention with a coverage framework that fully supports it. I hope they will seize this opportunity to prioritize the science of early intervention and save lives.

Thank you for the opportunity to comment.

Sincerely,
Jerome Adams, MD, MPH
20th Surgeon General of the United States

Less

On behalf of the American College of Gastroenterology (ACG), we appreciate the opportunity to provide comment on the Centers for Medicare and Medicaid Services’ (CMS) proposed Medicare coverage decision (NCD 210.3) on non-invasive colorectal cancer prevention and screening tests.

Background

CMS proposes that non-invasive biomarker colorectal cancer screening tests are covered once every three years for Medicare beneficiaries when ordered by the physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient and when all the following conditions are met:

Patient Criteria

Age 45 to 85 years, and,

Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test (gFOBT) or fecal immunochemical test (FIT)), and,

At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or adenomatous polyps, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

Test Criteria

The test must be Food and Drug Administration (FDA) market authorized and indicated for colorectal cancer screening; and,

The test must achieve the requirements of the FDA-required post-approval study as specified in the Safety and Effectiveness Data (SSED)?to continue coverage; and

The test must be processed in a CLIA certified laboratory; and,

The test must demonstrate performance characteristics that meet?EITHER?Criteria?1,?a sensitivity of greater than or equal to 90% and a specificity greater than or equal to 87%,?OR Criteria 2,?a sensitivity of greater than or equal to 79% and a specificity of greater than or equal to 90% in the detection of colorectal cancer compared to the recognized standard (accepted as colonoscopy at this time), based on the FDA labeling.

ACG Comments

We organize our comments by the “evidence questions” guiding the agency’s analysis and review. These questions include:

Question 1:?Is the evidence sufficient to determine that screening for colorectal cancer with non-invasive biomarker tests is reasonable and necessary for the prevention or early detection of illness or disability?

ACG Comments to Question 1:

We appreciate that CMS has recognized colorectal cancer prevention as well as early detection. The goal of colorectal cancer screening is best directed towards prevention. However, the proposed sensitivity/specificity criteria are for colorectal cancer detection. The criteria do not appear to include non-advanced or advanced adenomas, and do not contain any performance thresholds for precancer or advanced precancerous lesion (APL) sensitivity. CMS should acknowledge that APLs, such as advanced adenomas and adenoma with high grade dysplasia, are important targets for noninvasive tests. Thus, CMS should deem non-invasive tests of higher value if detection of APL is better for a certain test. CMS should also strongly consider adding thresholds for adenoma with high grade dysplasia, as these lesions are closest to colorectal cancer. There must be a focus on cancer prevention. Without such focus, test developers and manufacturers have no incentive for improving APL detection if these tests receive automatic Medicare coverage under proposed criteria. These criteria, as proposed, are not “reasonable and necessary” for colorectal cancer prevention under this question.

Question 2: Is the evidence sufficient to determine that screening for colorectal cancer with non-invasive biomarker tests is appropriate for Medicare beneficiaries?

ACG Comments to Question 2:

It is unclear whether this proposal includes guidance on including Medicare-age beneficiaries in any post-market study requirement. Without such data, it is difficult to answer this question. ACG also urges CMS to provide data supporting the three-year interval between tests for Medicare beneficiaries. While ACG does not oppose the three-year interval per se, the correct interval should be based on the characteristics of each specific test. CMS should at least acknowledge the need for more data and more studies on this interval period.

Other ACG Comments:

ACG recommends including patients without iron deficiency or amenia in the patient criteria for “average-risk.”

ACG urges CMS to convene a Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) for additional expert input on the evidence and analysis in the proposed coverage decision.

Less

April 9, 2026

Dr. Mehmet Oz
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Administrator Oz,

I am writing to express concerns around Medicare’s proposed expansion of colorectal cancer screening tests to include less effective blood-based tests. As a former Member of Congress and having served on the Veterans’ Affairs Subcommittee on Hospitals and Healthcare, I understand the importance of ensuring that federal health programs deliver both strong clinical outcomes and are a responsible use of taxpayer dollars.

In the United States, colorectal cancer (CRC) is the third most commonly diagnosed cancer and, unfortunately, the second-most leading cause of cancer-related deaths. Promisingly, older Americans have seen a yearly 2.5% decrease in CRC and a 2% decrease in CRC-related deaths due to the development of effective screening tests. These tests allow precancerous polyps to be found and removed earlier than ever before thus catching the devastating disease before it can form. This makes the adoption of effective colorectal cancer screening tests that much more vital to prevention and early-stage detection. Although the proposal to expand CRC screening tests to include new blood-based tests is valiant in theory, in practice, it expands coverage to a test that is less effective at detecting cancer signals, threatening the progress made in this field.

Colonoscopy and stool-based tests are the standard colorectal cancer screening devices. Colonoscopies have a greater than 90% sensitivity for detecting precancerous lesions while stool-based tests, like Cologuard, catch precancerous lesions 42-43% of the time. Medicare’s proposed expansion would cover a test that only catches advanced precancerous lesions 13% of the time.

Innovation in this field must be embraced, but lowering the standards of efficacy risks undermining patient outcomes and reversing the progress already achieved. Expanding coverage to include a test that detects only 13% of precancerous lesions does not advance innovation – it diverts finite resources away from the development and adoption of more accurate, clinically meaningful screening tools. By directing funding and attention toward less effective options, Medicare may inadvertently slow the pursuit if higher-performing technologies that could deliver greater benefits to American patients.

Additionally, American patients deserve their Medicare dollars to be directed at tests that will help protect them and keep them healthy. The new blood-based test costs around $1,500 opposed to $500 for standard stool-based tests. This means that there are more taxpayer dollars being spent on less effective tests.

Covering ineffective tests – and more expensive tests at that – could ultimately lead to worse health outcomes for Americans over time. While CRC rates have declined among Americans 65 and older, early-onset CRC continues to rise in younger populations, underscoring the need for the most effective screening strategies available. Coverage decisions also shape provider behavior. When Medicare reimburses a test, it signals clinical legitimacy and encourages use in practice. As a result, covering less effective blood-based screening tests may steer providers toward options that are less likely to detect disease early, creating a downstream impact on patient care and outcomes.

This is why CMS should take a more measured approach to its proposed expansion of Medicare coverage to include blood-based colorectal screening tests. Because a simple blood draw at the doctor’s office without the laborious preparation of a stool sample is an appetizing alternative, the proposed tests may hold clear appeal for veterans and other patients in need of colorectal cancer screening. However, if these tests should be considered as part of the screening toolkit, that consideration must be grounded in evidence of success. Convenience alone cannot justify adoption if it comes at the expense of effectiveness. This is why CMS should ensure that any screening option, blood-based or otherwise, meets a meaningful standard for detecting precancerous growths and demonstrates real potential to prevent disease.

In time, a simple blood test may meet this standard but, for now, it is not the type of screening that will meet the high standards of the CMS.

Sincerely,
Michael Patrick Flanagan, former U.S. Representative for Illinois’s 5th District

Less

I appreciate CMS's commitment to expanding access to innovative colorectal cancer (CRC) screening technologies. The development of new stool-based testing modalities, including multi-target stool RNA (mt-sRNA) assays, represents meaningful progress in the field, and I recognize their potential to broaden screening options for patients.

In case CMS is interested in viewing this from an engineering and statistical perspective, I would like to share the following observations. In collaborative with Exact Sciences, we conducted an uncertainty analysis of the next-generation multi-target stool DNA (mt-sDNA) and multi-target stool RNA (mt-sRNA) tests using their validated CRC simulation model. The analysis drew directly from the confidence intervals reported in each test's FDA Summary of Safety and Effectiveness Data (SSED). Using 500 Monte Carlo simulations with random draws from these parameter distributions, we observed the following:

mt-sRNA-based screening produces approximately 3-fold greater variance in projected life-years gained compared with mt-sDNA, reflecting substantial uncertainty in expected outcomes.
mt-sRNA-based screening requires approximately 1.2 times more colonoscopies than mt-sDNA due to lower specificity, increasing burden on patients and the healthcare system, while also exhibiting approximately 2.6-fold higher variance in colonoscopy-related outcomes.
CRC deaths averted by colonoscopy were at least 13% lower for mt-sRNA compared with mt-sDNA, even when comparing the most favorable mt-sRNA scenario against the least favorable mt-sDNA scenario.
In the Medicare-relevant population, only 3 CRC cases were observed in the mt-sRNA pivotal study, yielding an estimated sensitivity of approximately 66%, which introduces significant uncertainty for the population most relevant to CMS coverage decisions.

From a decision engineering standpoint, screening tools deployed at the population level must demonstrate stable, reproducible, and generalizable performance. When confidence intervals are wide, the risk of inconsistent clinical outcomes and inequitable screening effectiveness increases across diverse patient populations and clinical settings.

I respectfully recommend that CMS consider requiring post-market performance monitoring and transparent reporting as a condition of coverage for mt-sRNA testing. This approach would preserve patient access to emerging screening options while ensuring that real-world performance data, particularly in the Medicare population, are systematically collected and evaluated over time.

Disclosure: I have served as a consultant for Exact Sciences in the past.

Less

I have over thirty years of experience in the diagnostics industry, holding leadership positions in both large (Roche, Becton Dickinson, and Cepheid/Danaher) and small companies. While working in industry, I have maintained ties with academia, serving as a volunteer mentor at the University of California, San Francisco (UCSF) Catalyst Program for more than 20 years, focusing on translating novel technologies into healthcare markets to deliver better outcomes for all.

As a physician, I have treated patients with CRC, including admitting them for complications post-colonoscopy. Highly sensitive, easy-to-use, and broadly available noninvasive screening tests are critical to overcome the challenges and health disparities associated with CRC. ColoSense demonstrated high sensitivity for CRC in its pivotal study (94% for colorectal cancer and 46% for advanced adenomas) and has developed a novel collection approach to minimize patient burden. These two characteristics, the strong performance and easier sample collection, have the potential to drive significantly higher adherence than other tests that require handling stool; translating to earlier detection, improved survival, and a greater public health impact. But a great test is nothing without access, and I commend CMS on issuing a proposed coverage policy that would establish coverage for ColoSense.

On the topic of access, to bridge the gap between regulatory approval and sustained patient access, CMS should establish a formal notification mechanism that clarifies how the ultimate completion of FDA post-approval studies triggers the final validation of long-term coverage requirements. This structural alignment would ensure that test developers have a transparent pathway to maintain continuity of care while upholding the rigorous safety and performance standards established by both agencies.

Regarding performance, the final coverage determination should clearly indicate the medically precise specificity rate for mt-sRNA testing as 87.9% to ensure the administrative record aligns with the most appropriate and comparable definition of a “negative” colonoscopy. A true negative on a colonoscopy is when no suspicious/precancerous lesions are removed. While histopathological classifications are constantly evolving and lesion definitions vary across studies, a situation in which a GI does not identify any lesions to remove is objective and consistently measurable. CMS should clarify the definition of specificity to be a colonoscopy in which no lesions are removed. As noted, ColoSense’s 87.9% specificity meets this bar and would be covered under the NCD.

As I have learned over many years, physicians need a range of approaches and options available. We need to keep studying and learning. CMS takes this approach with the Colorectal Cancer Screening NCD, and I support it in this instance and as a framework for future coverage decisions.

Less

As a 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 detecting acquired somatic mutations in the genomes of individuals with cancer, 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. I’m writing today to provide comments on the proposed NCD for Screening for Colorectal Cancer - Non-Invasive Biomarker Tests, including addressing a misstatement in one of the public comment letters.

I believe the proposed decision memo appropriately focuses coverage considerations on the overall clinical performance of non-invasive biomarker-based screening tests. By creating performance characteristics based on validated sensitivity and specificity thresholds derived from prospective clinical studies, CMS has adopted an evaluation framework that reflects how complex molecular diagnostics are designed, validated, and used in clinical practice. Maintaining this approach in the final decision will help ensure that screening technologies with strong analytical validation and demonstrated clinical performance can be incorporated into colorectal cancer screening programs in a manner that ultimately benefits Medicare beneficiaries.

I did want to highlight that in the Assessment of Evidence section for RNA-based stool tests, the proposed memo cites a specificity of 86.9% for the mt-sRNA test. This appears to be a misapplication of the data published in JAMA. The 86.9% figure includes "findings" such as hyperplastic polyps, which does not align with the definition of specificity CMS has established for this NCD: "negative colonoscopy (no findings on a colonoscopy)."

To remain consistent with CMS’s definition, the specificity for the mt-sRNA test should be cited as 87.9% (as reported for "no lesions on colonoscopy" in the Barnell et al. 2023 study).

Further, I believe it’s also important to note the similarity between the specificity as published in JAMA and in the FDA’s SSED. In the SSED, the FDA identifies the specificity for no lesions on a colonoscopy as 87.5%. Leveraging either data set for ColoSense, the performance bar for specificity is met.

Finally, I’d like to address a public comment, which states, “First, the single clinical trial sensitivity and specificity estimates for several new tests (specifically mt-sRNA, and blood-based cfDNA (from Geneoscopy, Guardant, and Freenome)) are compared to historical values for fecal immunochemical testing (FIT) and not within-study FIT comparisons to an independent laboratory test.”

Addressing ColoSense, I concur that it was not compared to an independent FIT test, but it was, in fact, held to an even higher standard. As I noted in my comment on the tracking sheet, manufacturers of stool-based colorectal cancer (CRC) screening tests should be expected to provide receiver operating characteristic (ROC) analyses that detail how test cutoffs were derived and validated across representative populations, along with transparent justification for balancing sensitivity and specificity. ColoSense uniquely discloses this analytical data.

With respect to ColoSense and the FIT component of its assay, the FDA concluded, “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.”

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 the strong contribution of the assay’s molecular component.

Less

Geneoscopy agrees that the coverage of Colorectal Cancer-Non-Invasive Biomarker Tests should be conditioned on demonstrated test performance, including as modified or determined in post-market studies. This approach acknowledges the real-world constraints on pre-market evidence generation, while preserving rigorous evidence standards and meaningful accountability for post-market performance. As our team reviewed the NCD language, we found areas where further clarification may be warranted to align implementation with intent and ensure coordination between CMS and the FDA. The following are three excerpts from different sections of the NCA:

Geneoscopy would like to comment on the above passages, in hopes of further clarifying the NCD as it becomes finalized in the coming weeks:

1. Post-approval study (PAS) requirements are not always uniformly focused on the performance characteristics that supported the original approval. Some tests may not meet all PAS requirements, yet retain FDA approval for their indication for use, and continue to satisfy the performance thresholds outlined in the approval letter and codified by the NCD. Additionally, PAS studies may include primary or secondary endpoints unrelated to performance characteristics in the NCD; failure to meet one or more of these endpoints may not affect FDA approval or compliance with performance thresholds established by CMS. Accordingly, we pose the following questions:
   1. How may manufacturers collaborate with the FDA and CMS post-FDA review of the PAS to ensure alignment on study completion and interpret
   ation of outcomes, in an effort to support continued CMS coverage after FDA affirms satisfactory PAS completion?
   2. More specifically, does CMS intend to rely on a binary determination from the FDA (i.e., completed vs. not completed) in assessing continued CMS coverage, potentially informed by resulting updates to product labeling?
      1. If not, what additional criteria or benchmarks will CMS apply post-FDA review to evaluate ongoing coverage, and how will these be operationalized relative to FDA determinations and study outcomes?
2. The FDA Approval Letter and SSED often include operational requirements, such as interim assessments, reporting requirements, and enrollment timelines. The FDA Approval Letter and SSED represent a snapshot in time, but post-approval, we have seen FDA and manufacturers collaborate through revised milestones, updated reporting expectations, and other similar qualitative changes.
   1. We are seeking clarity on how CMS will account for the fluid relationship and process by which manufacturers and the FDA may engage with one another through PAS revisions. Will manufacturers be responsible for communicating amongst the Agencies, or is there an independent process by which manufacturers may stay abreast of what the Agencies discuss regarding PAS developments?

Geneoscopy believes it's important for manufacturers to have clarity on process expectations and hopes that CMS and FDA can collaborate to ensure a clear, defined path to continued coverage. During our review, we have respectfully developed potential clarifying language that may be directionally appropriate in addressing some of the lingering questions we have. Our clarifying language, as it relates to the three excerpts shared earlier, is as follows:

Making the proposed changes may help ensure tests that continue to meet the standard of reasonable and necessary for Medicare beneficiaries maintain coverage under the NCD. Providing additional guidance to manufacturers on oversight and reporting will ensure coordination and timely implementation of post-approval study requirements.

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.

Less

I appreciate the opportunity to comment on the proposal for CMS coverage of additional non-invasive colorectal cancer screening tests.

As a practicing Gastroenterologist in Idaho, serving a largely rural and under-screened population, I can certainly appreciate the desire to expand access for this very relevant cancer screening need. Tests that are widely available and convenient are going to be paramount in the fight against colorectal cancer and the increasing prevalence in younger patients who are still working, raising families, etc. At that same time though it is absolutely key that governing bodies support tests that are effective. Blood based testing to this point has not proven to have sufficient sensitivity for those advanced pre-cancerous lesions that are key to identify and remove for colon cancer prevention, nor have blood-based tests proven to be highly sensitive for early-stage CRC (stage I & II). To expand access or support for blood-based testing without tiering or qualifying goals of screening tests, like the 90% sensitivity threshold for stage I CRC by the AGA, the wrong message is being sent to screen eligible patients and providers regarding currently available options, likely resulting in harm and missed opportunities to prevent CRC or diagnose early cancers. We need tests that patients will do and have access to, but first and foremost we need tests that work, and in their current state, blood-based CRC screening tests do not have the sensitivity for early-stage cancers to advanced pre-cancers to justify their use as a primary screening option.

Less

Dr. Mehmet Oz
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Screening for Colorectal Cancer-Non-Invasive Biomarker Tests

Dear CMS and Administrator Oz,

I am writing to provide comment on the National Coverage Analysis regarding Screening for Colorectal Cancer-Non-Invasive Biomarker Tests. Nearly twenty years ago, I had the privilege of working alongside lawmakers, health experts, and patient advocates to help pass one of the most consequential reforms to Medicare in its history: the Medicare Prescription Drug, Improvement, and Modernization Act of 2003. (1) That law was built on the simple, but powerful, principle that Medicare should empower seniors to access the best available care, not settle for less.

I am proud of that work, which is why I am deeply concerned about what CMS is proposing today.

The recently announced coverage framework for colorectal cancer screening tests, while well-intentioned, sets the bar in the wrong place. (2) The proposed performance thresholds focus primarily on whether a test can detect cancer after it has already developed. What they fail to meaningfully account for is whether a test can find the precancerous polyps that cause cancer in the first place. That is where the real opportunity to save lives lies.

This distinction matters enormously. The evidence proves that the long-term mortality benefit from colorectal cancer screening comes not from catching cancer early, but from finding and removing precancerous lesions before they ever become cancer.(3) A coverage standard that ignores this reality is a coverage standard that accepts more cancer deaths among Medicare beneficiaries. That should be unacceptable to everyone.

Consider a simple analogy. Imagine two smoke detectors, one alerts you when your house is already engulfed in flames, and the other which detects the first wisp of smoke before the fire starts. While both technically detect fire, only one saves your home. CMS is proposing to cover both detectors equally, even though one gives seniors a fighting chance and the other may simply confirm that the damage is already done.

I have spent decades fighting for Medicare to work better for the seniors who depend on it. I have seen firsthand how coverage decisions made in Washington ripple out to affect real people managing serious diagnoses, navigating complex treatment decisions, and counting on their government to point them toward the most effective care available. This proposed rule does not do that.

I am also a strong supporter of the Trump administration's commitment to rooting out waste and inefficiency in Medicare. (4) Under Administrator Oz, there has been real leadership in pushing CMS to think more critically about what it covers and why.(5) But covering screening tests that are largely blind to precancer, while equivalent or superior alternatives exist, is not a path to greater efficiency. It is a path to worse patient outcomes down the road, when cancers that could have been prevented must instead be treated. Medicare must invest in prevention today, not advanced cancer treatment for America’s seniors tomorrow.

The good news is that CMS can get this right. The fix is straightforward: coverage standards should require that any screening test, regardless of the underlying technology, demonstrate it can detect advanced precancerous lesions, not just cancer. This is a technology-neutral standard that rewards genuine performance and ensures Medicare dollars are directed toward tests that deliver the greatest preventive benefit for seniors.

The stakes here are clear. Medicare's promise to seniors is not just to find disease, it is to help prevent it. CMS has an opportunity to honor that promise by setting coverage standards that reflect the full body of scientific evidence and demand the highest level of preventive performance from every test seeking Medicare reimbursement. I helped build this program to protect seniors. I hope CMS will rise to that standard.

I urge CMS to reconsider this proposed coverage expansion until the tests meet efficacy standards that will help prevent millions of Americans from cancer. Thank you for your consideration.

Respectfully,
Jim Martin
Founder and Chairman of the 60 Plus Association, the American Association of Senior Citizens.

1. Medicare Prescription Drug, Improvement, and Modernization Act of 2003, H.R. 1, 108th Cong. (2003), https://www.congress.gov/bill/108th-congress/house-bill/1.
2. Centers for Medicare & Medicaid Services, “Proposed Decision Memo for Screening for Colorectal Cancer - Blood-Based Biomarker Tests (NCA 100.11),” CMS.gov, https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=319.
3. Centers for Disease Control and Prevention, “Colorectal Cancer Priorities,” National Center for Chronic Disease Prevention and Health Promotion, https://www.cdc.gov/nccdphp/priorities/colorectal-cancer.html.
4. Keiser Family Foundation, “Medicare Program Integrity and Efforts to Root Out Improper Payments: Fraud, Waste, and Abuse,” June 11, 2024, https://www.kff.org/medicare/medicare-program-integrity-and-efforts-to-root-out-improper-payments-fraud-waste-and-abuse/.
5. Centers for Medicare & Medicaid Services, “Dr. Mehmet Oz Shares Vision for CMS,” CMS.gov Newsroom, February 11, 2025, https://www.cms.gov/newsroom/press-releases/dr-mehmet-oz-shares-vision-cms.

Less

April 9, 2026

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
Proposed Decision Memo (CAG-00440R)

Dear Ms. Baldwin:

The Coalition for 21st Century Medicine (C21) appreciates the opportunity to provide comments in response to the above-captioned proposed decision memo.

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 specific interest in this proposed National Coverage Determination (NCD), 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 proposed 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 revision 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 welcomes the proposed revision to allow a “physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient” to order any non-invasive CRC screening test. We recommend that CMS modify this language to:

(1) To ensure the NCD does not require reopening solely due to future changes in provider scope, we recommend that CMS modify the language to allow ordering by “any other nonphysician practitioners authorized under 42 U.S.C. 1395x(s).” Such forward-looking language would allow the NCD to keep pace with the evolving healthcare (and regulatory) landscape without necessitating future revisions.

(2) Delete the language requiring that the ordering provider “will use the results in the management of the patient” OR if CMS will not delete “will use results in the management of the patient,” clarify that the results be used “for the management of the patient.” If the patient has a negative result, the ordering provider’s “use” of such results may be limited to reviewing the results. Similarly, if the patient has a positive result, the ordering clinician’s “use” of such result will in most cases be a referral to a specialist provider (e.g. a gastroenterologist) trained to provide a screening colonoscopy. The gastroenterologist may not have been involved in the patient’s care prior to the abnormal result, and by referring the patient, the ordering provider will have provided appropriate management for that patient.

* * * *

C21 thanks CMS for the opportunity to comment on the proposed NCD, 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
Acting Executive Director, Coalition for 21st Century Medicine
Principal, Todd Strategy Group

Less

Geneoscopy commends CMS on the proposed National Coverage Determination, which would allow coverage of FDA-approved colorectal cancer screening tests meeting certain coverage criteria in a modality-neutral, specimen-agnostic manner. If finalized, this coverage policy will increase beneficiary access to clinically validated, FDA-approved screening options recommended by their healthcare providers. I also applaud CMS for establishing flexible test performance characteristics to encourage innovation and preserve the patient-provider relationship to choose the appropriate test from a panel of options that meet predetermined sensitivities and specificities across varied proposed cut points.

The framework is sound, and in finalizing the NCD, CMS should ensure that no uncertainty remains regarding the performance criteria and the definitions of sensitivity and specificity that determine whether current and/or future tests are covered. My comment proposes clarifying modifications to mitigate ambiguity and address contradictory language in the proposed decision memo regarding the definition of specificity.

#1) In the proposed decision memo, CMS states, “Given that there is no standardized uniform method for reporting specificity, we clarify specificity for the purposes of this NCD as negative colonoscopy (no findings on a colonoscopy)”. We believe CMS’s intent in this definition is a colonoscopy where no lesions are removed. We understand some publications refer to this as “no findings on a colonoscopy”, but this definition could cause confusion, given ColoSense’s JAMA publication has a category referred to as “No Findings” that includes hyperplastic polyps. It may eliminate ambiguity to modify the parenthetical at the end of the sentence from “no findings on a colonoscopy” to “no lesions removed during colonoscopy.” Given CMS explicitly states in the Specificity Criteria that the 86.9% specificity for ColoSense was excluded from consideration because it represented “no findings,” the use of “no findings on a colonoscopy” as the definition of specificity is contradictory and leaves uncertainty as to whether CMS intended to define specificity as “no lesions removed during colonoscopy.” We respectfully request that CMS clarify its intent regarding the definition of specificity.

#2) Under the Assessment of Evidence for RNA-Based Stool Tests, the analysis states, “The mt-sRNA test specificity for no findings on a colonoscopy was 86.9%, and 95.4% (95% confidence interval [CI]: 95 to 96) for the FIT test”. These numbers represent what Geneoscopy referred to in its JAMA publication as no findings (which includes hyperplastic polyps). As we highlighted above, given that CMS is excluding the 86.9% metric, we believe the intent here is to reference the specificity for no lesions on a colonoscopy. If so, the statement should be revised to state, “The mt-sRNA test specificity for no lesions on a colonoscopy was 87.9%, and 95.7% (95% confidence interval [CI]: 95 to 96) for the FIT test.”

#3) Under Specificity Criteria 1, we believe that the inclusion of metrics in this paragraph that are not applicable to the specificity definition could create confusion. For example, the 86.6% specificity for the original mt-sDNA test includes hyperplastic polyps and small adenomas. Further, the 86.9% specificity for the mt-sRNA test includes hyperplastic polyps. The inclusion of these statements could introduce ambiguity regarding coverage of current and future tests. The removal of these two statistics, combined with the modification suggested above, in which the definition of specificity was clarified to be “negative colonoscopy (no lesions removed during colonoscopy)”, would ensure that Specificity Criterion 1 is clear.

#4) Finally, in reviewing Table 2, a small typo was identified where it states, “No lesions on colonography”. We believe this should state, “No lesions removed during colonoscopy.”

Our impression based on our reading of the analysis is that CMS intended for the definition of specificity to be “no lesions on colonoscopy.” Clarification of CMS’s intent regarding the definition of specificity in the final decision would eliminate ambiguity and ensure that the interpretation of the NCD for currently FDA-approved tests is clear, while providing clarity for manufacturers developing the next generations of CRC screening tests.

Separately, Geneoscopy echoes the views of commenters who have noted that non-invasive biomarker colorectal cancer screening tests should be covered for Medicare beneficiaries when ordered by a physician or nonphysician practitioner within the scope of their authority in 42 CFR 410.32(a)(2) who will use the results for the management of the patient.

Less

April 9, 2026

Labcorp Comments on Screening for Colorectal Cancer – Non-Invasive Biomarker Tests Proposed Decision Memo (CAG-00440R)

I am writing on behalf of Laboratory Corporation of America® Holdings (Labcorp) to comment on the changes to National Coverage Decision (NCD) 210.3 proposed by the Centers for Medicare and Medicaid Services (CMS) in its proposed decision memo, Screening for Colorectal Cancer – Non-Invasive Biomarker Tests (Proposed Decision Memo). Labcorp is a global leader of innovative and comprehensive laboratory services that helps doctors, hospitals, pharmaceutical companies, researchers and patients make clear and confident decisions. We provide insights and advance science to improve health and improve lives through our unparalleled diagnostics and drug development laboratory capabilities. Labcorp has publicly announced that it intends to serve as a distribution channel for the first FDA-approved Multi-target Stool RNA test (sRNA), ColoSense, and therefore Labcorp would be directly affected by finalization of the Proposed Decision Memo. Consideration of the following issues in advance of finalization of the Proposed Decision Memo can help ensure that its content will be in the best interest of Medicare beneficiaries.

While one of the most preventable cancers, colorectal cancer (CRC) remains the second leading cause of cancer death in the United States, and Medicare beneficiaries disproportionately include individuals with higher disease burden, greater medical complexity, and longstanding barriers to screening. Non invasive screening options play a critical role in addressing these disparities. They reduce barriers related to transportation, mobility, cost, and procedural risk, all of which disproportionately affect older adults and individuals with chronic conditions. Coverage policies that account for these realities are essential to achieving meaningful reductions in CRC incidence and mortality.

Labcorp strongly supports CMS’s commitment to maintaining rigorous, evidence based standards for coverage determinations. We agree that Medicare coverage of non invasive biomarker CRC screening tests must be anchored in high quality clinical evidence—particularly evidence that reflects the characteristics, comorbidities, and clinical outcomes relevant to the Medicare population.

Below, we offer our recommendations for improvement of the Proposed Decision Memo with respect to the following topics:

• Clarification of the definition of specificity
• Ordering provider criteria
• Post-Approval Study Requirements
• Technical corrections

A. Clarification of the definition of specificity

Labcorp supports CMS’s framework for establishing evidence based sensitivity and specificity cut-points for non invasive CRC screening tests. Clear, clinically relevant performance thresholds help ensure that covered tests meaningfully detect CRC while maintaining appropriate specificity to avoid unnecessary follow up procedures. We agree that a consistent, transparent approach to defining these cut-points provides manufacturers with predictable expectations for evidence development and strengthens clinician and patient confidence in the reliability of covered screening options.

While we agree with CMS’ clarification of specificity as it has been applied in the NCD, we believe further clarification would avoid uncertainty about whether a non-invasive CRC screening test meets the stated criteria. We request that CMS consider the following modifications to avoid any uncertainty in determining whether the reported specificity for any current or future test meets the criteria established in the NCD.

In the Proposed Decision Memo, CMS states, “Given that there is no standardized uniform method for reporting specificity, we clarify specificity for the purposes of this NCD as negative colonoscopy (no findings on a colonoscopy).” Based on CMS’ detailed Coverage Analysis, “no findings on a colonoscopy” would not be represented by a reported specificity metric that includes hyperplastic polyps, as is the case for the “no findings” specificity category in Barnell et al., 2023 (CRC-PREVENT Trial). To further clarify CMS’ intent we request that CMS modify the parenthetical in the statement to correlate with the FDA histopathological category that is commonly used in Summary of Safety and Effectiveness Data (SSED) documents, 6.2 No lesions on colonoscopy as follows: “(no findings on a colonoscopy – i.e., when no lesions are removed during the colonoscopy).”

We also request that CMS update the following statement in the Evidence for RNA-Based Stool Tests section: “The mt-sRNA test specificity for no findings on a colonoscopy was 86.9%, and 95.4% (95% confidence interval [CI]: 95 to 96) for the FIT test”. The “no findings” metric reported for specificity from the Barnell 2023 JAMA publication does not align with the proposed definition for specificity in the NCD, as the reported specificity metric for “no findings” includes hyperplastic polyps. We request that the statement be modified to reflect the JAMA publication numbers for “no lesions on a colonoscopy,” consistent with CMS’s proposed definition of specificity for the performance criteria. This statement should therefore be revised to read, “The mt-sRNA test specificity for no lesions on a colonoscopy was 87.9%, and 95.7% (95% confidence interval [CI]: 95 to 96) for the FIT test.”

In addition to amending the above statement, Under Specificity Criteria 1, we request that CMS modify the paragraph as follows to reduce any uncertainty regarding the criteria for specificity:

“We are using a different approach for selecting the proposed specificity minimum for Criteria 1. We selected the lowest point from across the range of estimates for specificity, which we define as no findings on a colonoscopy – i.e., when no lesions are removed during the colonoscopy. In Table 5 above, the lowest specificity among the recent key pivotal studies was for the mt-sRNA test published in the Barnell (2023) study, which reported a specificity for no lesions on colonoscopy of 87.9%. The SSED reported specificity for the mt-sRNA assay is 87.5%. Therefore, the proposed specificity is 87%, which we propose is an acceptable bound when coverage is driven by a high sensitivity (Criteria 1 sensitivity =90%).”

B. Ordering provider criteria

Labcorp supports CMS’ proposed language to expand the ordering provider language to include physicians, physician assistants, nurse practitioners, and clinical nurse specialists who will use the results in the management of the patient. This update appropriately reflects the realities of modern care delivery, where a range of qualified providers play central roles in preventive screening. We recommend CMS consider the following modification to allow for inclusion of additional provider types that may be recognized under the Social Security Act when ordering preventive services would fall under their scope of practice:

“We propose that non-invasive biomarker colorectal cancer screening tests are covered once every three years for Medicare beneficiaries when ordered by the physician, physician assistant, nurse practitioner, clinical nurse specialist, or other nonphysician practitioner within the scope of their authority in 42 CFR 410.32(a)(2) who will use the results in the management of the patient and when all the following conditions are met.”

C. Post-Approval Study Requirements

Labcorp supports CMS’ proposal to cover non-invasive CRC tests that have an FDA-required post-approval study to demonstrate performance endpoints, rather than requiring completion of such studies prior to any coverage. We request that CMS clarify that continued coverage of a test under the NCD upon completion of the FDA-required post-approval study is based on the FDA’s continuation of the test’s market authorization with an indication for CRC screening, and the test continuing to meet performance characteristics as specified in the final NCD.

D. Technical Corrections

In Appendix B, we note two items for which technical corrections are needed.

In Table 8, which seeks to represent Table 2 from the Barnell (2023) publication on CRC-PREVENT which examined the Sensitivity and Specificity of the Multitarget Stool RNA (mt-sRNA) Test and Fecal Immunochemical Test (FIT), the last line of the table is incorrectly labeled as, “No lesions on colonography”. While minor, this is the metric that corresponds to the performance criteria, so to eliminate confusion, we recommend it be corrected to read, “No lesions on colonoscopy.”

Additionally, we note that Table 5 is missing from Appendix B.

E. Conclusion

Expanding Medicare coverage for non-invasive CRC screening tests will meaningfully improve early detection and help close long standing gaps in care. These tests offer a safe, accessible, and patient centered alternative for individuals who may be unwilling or unable to undergo colonoscopy as an initial screening method. By recognizing the value of non-invasive modalities, CMS can empower more beneficiaries to participate in routine screening—ultimately reducing late stage diagnoses, improving outcomes, and lowering long term healthcare costs.

The proposed updates to NCD 210.3 represent an important step toward aligning Medicare policy with current clinical evidence and real world patient needs. Thank you for your thoughtful consideration of Labcorp’s comments and for your continued leadership in strengthening preventive health services for the Medicare population.

Sincerely,

Donald E. Horton, Jr.
Senior Vice President
Global Government Relations & Public Policy

Less

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. Throughout my career, I have been dedicated to advancing digestive health through both patient care and clinical research. I 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 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 this Hypothetical Test 2, whereby 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.

Regards,

Mark J. Wegmann, MD
Gastroenterologist

Metropolitan Gastroenterology Associates / GI Alliance
New Orleans, 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.

Less

I am a diagnostics consultant and strategic advisor with over 30 years of experience driving innovation in the In Vitro Diagnostics (IVD) and life sciences sectors. I hold a PhD in Human Genetics and was one of the first postdoctoral researchers on the Human Genome Project and was in the first group of molecular geneticists to be medically boarded in "clinical molecular genetics". I help companies bridge the gap between complex clinical science and commercial viability, specializing in navigating the intricacies of product development, regulatory pathways, and market entry/access strategies.

Bridging the “valley of death” that life sciences start-ups often face between FDA approval and insurance coverage is crucial to ensuring patients have access to the diagnostics they need. I commend CMS on drafting a forward-looking NCD that provides innovators a clear path to coverage once FDA approval is achieved. This will support innovation and drive investment in diagnostic innovation.

As a point of further clarification, I believe innovators would benefit from CMS clarifying in the final NCD the mechanism by which innovators should follow up with CMS after the FDA has completed its review of the post-approval study. This clarification will be a critical component of ensuring continuity of coverage once the post-approval study requirement is met. The current process is both onerous and expensive for companies that have met the very highest safety and efficacy standards of pre market approval (PMA).

Disclosure: I served as a consultant to Geneoscopy from 2018 to 2021 during the development of ColoSense through FDA approval.

Less

Thank you for the distinguished opportunity to comment on the proposed CMS update regarding coverage for non-invasive, colorectal cancer, bio markers test. When considering a disease such as colorectal cancer and its significant impact on the lives of the people that it affects and their loved ones, I believe it’s very important to assure that we are continuing to make progress in the overall eradication of this disease. We’ve made great strides since the 1990s when screening colonoscopy was first instituted as a preventative measure. There have been many advances in diagnostic testing for colorectal cancer, especially highlighting the stool based tests that have shown significant evidence in approaching the sensitivity of the gold standard, colonoscopy.

That one fact, EVIDENCE, is why I would like to express concern that including blood based tests in a category where the evidence is not there to support them being included, could lead practitioners into a false sense of security when administering these tests. It may behoove us to have a category for these blood based test that is not to be confused with the other evidence based modalities that currently exist. If the desire going forward is to add a blood category I would encourage that CMS considers a minimum threshold for pre-cancer sensitivity. Pre-cancer detection is critical to cancer prevention and detection. At a minimum, I would encourage CMS to consider the pre-cancer detection for FIT which is about 24%. The current proposal has no threshold and could result in regression of stage presentation, hence shifting cancer detection backwards.

One final point that I would want CMS to consider is that introducing a test like this may disproportionately affect a particular group of patients more than others as it relates to missed cancers or false negative results. This could lead to further disparities in this disease that we would like to avoid.

Less

I appreciate the opportunity to comment on the CMS coverage proposal for non-invasive testing for colorectal cancer screening. I am a gastroenterologist, professor of medicine at Stanford University and lead principal investigator on Zenith, a U.S. clinical study testing the efficacy of the CellMax Life blood test for the detection of colorectal cancer and advanced adenomatous polyps.

Colonoscopy is the gold standard in detection of colon cancer as well as in prevention of cancer through removal of precancerous polyps. However, because colonoscopy is inconvenient and invasive, it is essential to offer patients effective alternatives to improve compliance with screening. Although there are noninvasive stool tests that detect early stage cancer effectively, and also detect a significant proportion of advanced polyps, a well performing blood test has the potential to dramatically increase patient compliance by virtue of convenience. However, it is critical that any blood based screening test not decrease our ability to detect the most curable cancers- stage 1 cancers- or advanced polyps that can be removed to prevent cancer from forming.

Less

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

Re: Second Comment on 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 additional opportunity to provide feedback on the proposed changes to the National Coverage Determination (NCD) for CRC non-invasive biomarker screening tests (210.3). As the manufacturer of SimpleScreen™ CRC, a colorectal cancer (CRC) screening blood test, we believe that non-invasive and minimally invasive screening options, particularly blood-based tests, provide a convenient, accessible alternative to conventional testing.

We commend the Centers for Medicare & Medicaid Services (CMS) for its thoughtful review of recent publications related to CRC screening when drafting the NCD. Overall, we agree with the proposed revisions, which maintain rigorous performance standards for non-invasive tests while permitting high-quality innovation to better improve CRC screening rates and reduce patient mortality.

We would like to highlight several components in the current NCD version that we believe warrant further refinement:

1. Reconsider Fixed Coverage Interval for Blood-Based Testing

In the current NCD draft, CMS proposes a coverage interval of once every three years for all non-invasive CRC screening tests. This position is built upon two primary justifications: (1) a one- to three-year interval is currently recommended by three major guideline organizations for FIT-DNA testing; and (2) National Comprehensive Cancer Network (NCCN) guidelines [3] recommend blood-based testing at that same frequency. In the Blood-Based Biomarker Tests NCD [1], CMS also covers blood-based tests once every three years, but regarding future adjustments to the testing interval for blood-based tests, CMS has expressed a willingness “to consult with relevant professional society guideline or peer reviewed consensus statements and USPSTF recommendations and will adjust the frequency as appropriate in an expedited NCD for frequency only if evidence supports.”

The coverage interval for a non-invasive screening test is a complicated interplay between economic cost, test performance, manufacturer recommendation, and clinical utility and implementation. The primary justification for the three-year coverage interval recommended in the current NCD is based on the experience of FIT-DNA. While CMS covers FIT-DNA testing once every three years, the United States Preventive Services Task Force (USPSTF) guidelines suggest a one- to three-year interval is supported by clinical evidence [4,5].

Notably, for the three-year testing frequency of FIT-DNA, the USPSTF defers to the manufacturer’s recommendations in their Recommendation Statement. Specifically, in the characteristics table (Table 1), the USPSTF added a footnote of “as stated by the manufacturer” next to the “3” in the “every 1 to 3 y” description and wrote under the Evidence of Efficacy that “modeling suggests that that screening [with FIT-DNA] every 3 y does not provide a favorable (ie, efficient) balance of benefits and harms compared with other stool-based screening options (ie, annual FIT or [FIT-DNA] every 1 or 2 y)”.

We are not proposing to adjust the coverage interval for FIT-DNA. Rather, we recommend that the approach used to determine the coverage interval for FIT-DNA be applied to all non-invasive CRC screening tests, which includes a consideration of each test’s unique performance characteristics, clinical evidence, and manufacturer recommendations. In addition, for blood-based testing, we believe it is premature to permanently and preemptively anchor the covered screening interval before major guidelines have published their first recommendations, let alone before they are updated as new evidence becomes available. FIT-DNA and blood-based testing are fundamentally different in their methodology and performance, and alongside FIT-DNA, other covered non-invasive tests like fecal immunochemical test (FIT) and guaiac fecal occult blood test (gFOBT) are recommended every one to three years. By anchoring the interval strictly to NCCN guidelines, CMS risks a scenario in which coverage could be denied even if other major organizations eventually suggest only an annual or biennial frequency, a result that would be counterproductive to screening goals.

We recommend flexible language for the screening interval, consistent with current recommendations for FIT-DNA, that would allow a determination based on multiple factors, economic cost, test performance, manufacturer recommendation, and clinical utility and implementation. In addition, for blood-based testing, we recommend prioritizing formal guideline updates from major organizations — eg, American College of Gastroenterology (ACG), American Cancer Society (ACS), and USPSTF — rather than relying solely on NCCN guidelines. Given the potential for delays in the USPSTF screening update process, we propose that CMS enable broader coverage for existing tests to ensure sufficient access until a broader clinical consensus is reached.

We propose the following revised language: “CMS covers non-invasive CRC screening tests at intervals that align with the specific performance characteristics, clinical evidence, and manufacturer recommendations for each technology. For non-invasive CRC screening tests, the screening interval shall be three years, but CMS will engage with test manufacturers and consult with relevant professional society guideline or peer reviewed consensus statements recommendations (including but not limited to USPSTF, ACS, and ACG) and will adjust the frequency as appropriate in an expedited NCD for frequency only if evidence supports.”

2. Ordering Physician Language

We strongly support the expansion of the ordering clinician language and commend CMS for including physician assistants, nurse practitioners, and clinical nurse specialists in the current NCD draft. We wholeheartedly agree with the rationale that there is no evidentiary reason to limit the ordering of non-invasive CRC screening tests to physicians. However, to ensure equitable access to CRC screening for all eligible adults, we recommend moving away from an exhaustive list of professional titles in favor of a broader, licensure-based standard that reflects modern clinical workflows.

The current NCD language of “ordering practitioner,” in which the ordering provider is also required to use the test results “in the management of the patient”, could restrict access in telehealth and population health models where centralized providers authorize screenings at scale while separate clinical teams manage the follow-up care. This is a vital distinction for health systems using “bulk” ordering or registry-based outreach to close screening gaps.

We recommend that CMS define the eligible ordering clinician as “any physician or non-physician practitioner authorized to order diagnostic laboratory tests under the laws of the State in which the services are furnished” or something similar. This standard, which adopts similar language to that used in the Medicare Benefit Policy Manual[6], provides unambiguous coverage for all qualified providers under the current definition while accommodating potential future categories recognized by State law.

3. Refining Patient and Test Criteria

The current patient and test coverage criteria are inconsistent with existing summaries of safety and effectiveness data (SSEDs) for non-invasive CRC screening tests, which creates a disconnect that could meaningfully restrict access for eligible populations. To ensure clinical relevance and patient safety, these criteria should be updated to align with the contraindications of recently approved tests and the latest evidence-based clinical guidelines.

3.1. Patient Criterion #2: Expand to Include All Non-Invasive Screening Tests

The second patient criterion in the current NCD draft is: “Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test (gFOBT) or fecal immunochemical test (FIT))”.

We suggest that this criterion is updated to include all non-invasive modalities and their respective intervals. The draft NCD is limited to gFOBT and FIT. A more comprehensive definition would account for patients who have had a positive test within a specific window or those who have already been screened using another method — such as FIT-DNA, FIT-RNA, or blood-based testing — within that test's recommended screening interval, ensuring that these coverage criteria avoid permitting unnecessary or redundant testing. A summary of prior test history contraindications in FDA labeling is provided in 3.1.1.

3.1.1. Prior Test History Contraindication

We propose the following revised language: “Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive result from any CRC screening test within the last six months; no FDA-approved screening tests completed within the test’s current guideline-recommended interval).”

3.2. Patient Criterion #3: Adjust Definition of Family History and Hereditary Syndromes

3.2.1. Align “Family History of CRC” with Current Guidelines/Clinical Practice

Under Patient Criterion #3, the current NCD draft includes “no family history of colorectal cancers” as a qualification to exclude people at higher risk of developing CRC. We believe that this blanket exclusion of any family history of CRC is overly restrictive and inconsistent with major clinical guidelines.

Major professional organizations, including the American Academy of Family Physicians (AAFP) [10] and the ACG [11], recommend that individuals with a first-degree relative diagnosed with CRC after the age of 60 continue to be screened for CRC at the same intervals as average-risk individuals. This position is bolstered by the ACS 2018 guidelines, which defines high-risk family history as a first-degree relative diagnosed before the age of 60 [12].

Moreover, an increased risk profile does not — and should not — categorically preclude the use of non-invasive CRC screening tests. The ACS explicitly noted [13] that while “people at increased or high risk might need to start CRC screening before age 45, be screened more often, and/or get specific tests”, the presence of a risk factor does not necessarily invalidate the use of specific screening technologies at recommended intervals. These patients do not require the “more focused, intensive approach for screening,” to borrow language from the current NCD draft, reserved for high-risk syndromes.

To ensure maximum screening adherence and beneficiary access, we recommend that individuals with a first-degree relative diagnosed with CRC after the age of 60 remain eligible for coverage at average-risk screening intervals.

3.2.2. Remove “Adenomatous Polyps” from Family History

Under Patient Criterion #3, the current NCD draft includes the following item in its parenthetical list defining average-risk individuals: “no family history of colorectal cancers or adenomatous polyps”. We believe that including a family history of “adenomatous polyps” as a disqualifying factor for average-risk coverage is inconsistent with clinical evidence and existing family history categorizations (see 3.2.2.1 and 3.2.2.2).

3.2.2.1. Family History Contraindication

3.2.2.2. Guideline Definition of “High-Risk” for CRC

Because hereditary conditions related to adenomas are already separately defined and managed under high-risk protocols, including adenomatous polyps here without an age limitation could create an unnecessary and restrictive barrier to care. Since adenomatous describes any adenoma regardless of size or histology, we believe using that description in this context is too broad.

Modeling data suggests that the lifetime risk of developing one or more adenomas of any kind ranges from 40% to 75%, and implementing an age limitation for family history before the age of 60 only lowers the modeled lifetime risk of developing adenomas from between 30% and 35% [15,16]. If this criterion is maintained, a substantial portion of the Medicare population — potentially up to three-quarters of all beneficiaries — could be inadvertently disqualified from non-invasive screening coverage. By revising the language to “advanced polyps or lesions,” it aligns better with the ACS, ACG, and NCCN guidelines (the USPSTF guidelines do not specify family history of adenomas).

We propose the following revised language: “...no first-degree relatives with CRC or advanced polyps or lesions diagnosed before the age of 60….”

3.2.3. Standardize the Heritable CRC Syndromes Description

Under Patient Criterion #3, the current NCD draft includes “no family history of…familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer”. This language is inconsistent with clinical evidence and SSEDs for recently approved non-invasive CRC screening tests (see 3.2.3.1 and 3.2.3.2).

3.2.3.1. Heritable CRC Syndrome Contraindication

3.2.3.2. Guideline Language on Hereditary CRC Syndromes

We propose the following revised language: “At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no first-degree relatives with CRC or advanced polyps or lesions diagnosed before the age of 60; no personal history of relevant hereditary cancer syndromes including but not limited to familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).”

3.3. Test Criteria #2: Post-Approval Study Requirements

Currently, the NCD Decision Summary states that “[t]he test must achieve the requirements of the FDA-required post-approval study as specified in the Safety and Effectiveness Data (SSED) to continue coverage.” Further explanation is provided under the Rationale for Test Criteria explanation: “Non-invasive CRC screening tests often include the requirement for a post-approval study in the FDA approval documentation and labeling. Since this means that the manufacturer must continue to collect and submit data on the test’s performance post-market to ensure its continued safety and effectiveness, we propose this as a requirement for continued reasonable and necessary coverage. The test must complete the post-approval study, and the FDA specified results must be achieved.”

Since a PAS involves an ongoing, iterative conversation between the test manufacturer and the FDA, its existence does not necessarily mean that the manufacturer is re-evaluating test performance. These studies can focus on non-performance-related elements such as real-world patient adherence, the feasibility of unsupervised self-collection, and the optimization of long-term screening intervals. Indeed, the current NCD draft references the PAS for FIT-DNA [5], which assessed the impact of repeat testing at three years in average-risk patients. Although the study was underpowered to establish a definitive screening interval [5], the FDA determined the data were sufficient to maintain the test's approval status and subsequent CMS coverage — a conclusion we support.

Because a PAS must be conducted primarily to ensure a test retains its FDA approval status, the mandate that “the FDA specified results must be achieved” is vague and difficult to interpret. Ultimately, we believe the regulatory emphasis for a PAS should remain on the test’s continued status as a validated, FDA-approved product, rather than on achieving specific study endpoints that may not be material to its clinical validity.

We propose two changes to the current NCD language to allow for greater flexibility and relevance for PASs:

4. Census-Adjusted Test Performance for SimpleScreen CRC

A detailed description and explanation of the census-adjusted performance estimates for SimpleScreen CRC are provided in the corresponding publication [2]. Briefly, enrollment challenges exist for clinical validation studies of CRC screening tests, and how much a study population represents the intended-use population depends heavily on enrollment criteria and sampling strategies. To assess the accuracy and representativeness of the observed performance in the intended-use population, an adjustment analysis should be considered after a study is completed. Such an adjustment analysis is suggested by the FDA during its regulatory review [17], and census-adjusted performance has been reported in the SSEDs of other FDA-approved, non-invasive CRC screening tests [18,8].

Results from our prespecified adjustment analysis, including the methodology and the census-adjusted performance by stage, advanced precancerous lesion (APL) subtype, and index lesion size and location, were recently published [2] and were included in our SSED submission to the FDA. Census-adjusted performance values should be considered to be added to the Evidence Review and Referenced Materials sections of the NCD to enable a thorough and comprehensive description of SimpleScreen CRC performance.

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 additional comments and please do not hesitate to reach out with any questions or requests for additional information.

Sincerely,

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

* * * * *

References

1. Centers for Medicare & Medicaid Services. Screening for Colorectal Cancer - Blood-Based Biomarker Tests (CAG-00454N) [Internet]. 2021. National Coverage Determination for Screening for Colorectal Cancer-Blood-Based Biomarker Tests. Available from: https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&NCAId=299
2. Shaukat A, Meng Z, Kutnik K, Sun CK, Edwards V DK, Piscitello A, Deciu C, Lee LC, Levin TR. Age- and sex-adjusted performance of a colorectal cancer screening test using US census distribution. JNCI J Natl Cancer Inst. 2026 Jan 9;djag007. doi:10.1093/jnci/djag007 PubMed PMID: 41512291.
3. National Comprehensive Cancer Network. Colorectal Cancer Screening, Version 2.2025 [Internet]. 2025 Jun. (NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®)). Available from: https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf
4. US Preventive Services Task Force, Davidson KW, Barry MJ, Mangione CM, Cabana M, Caughey AB, Davis EM, Donahue KE, Doubeni CA, Krist AH, Kubik M, Li L, Ogedegbe G, Owens DK, Pbert L, Silverstein M, Stevermer J, Tseng CW, Wong JB. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2021 May 18;325(19):1965–77. doi:10.1001/jama.2021.6238 PubMed PMID: 34003218.
5. Imperiale TF, Lavin PT, Marti TN, Jakubowski D, Itzkowitz SH, May FP, Limburg PJ, Sweetser S, Daghestani A, Berger BM. Three-Year Interval for the Multi-Target Stool DNA Test for Colorectal Cancer Screening: A Longitudinal Study. Cancer Prev Res (Phila Pa). 2023 Feb 6;16(2):89–97. doi:10.1158/1940-6207.CAPR-22-0238
6. Centers for Medicare & Medicaid Services. Medicare Benefit Policy Manual: Chapter 15 – Covered Medical and Other Health Services [Internet]. 2025. Available from: https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/bp102c15.pdf
7. U.S. Food & Drug Administration. Summary of safety and effectiveness data [Cologuard Plus] [Internet]. 2024 [cited 2025 Jul 16]. Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230043B.pdf
8. U.S. Food & Drug Administration. Summary of safety and effectiveness data [Shield] [Internet]. 2024 [cited 2025 Aug 1]. Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230009B.pdf
9. U.S. Food & Drug Administration. Summary of safety and effectiveness data [ColoSense] [Internet]. 2024 [cited 2024 Sep 17]. Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf
10. American Academy of Family Physicians. Clinical Preventive Service Recommendation: Colorectal Cancer Screening, Adults [Internet]. 2021. Available from: https://www.aafp.org/family-physician/patient-care/clinical-recommendations/all-clinical-recommendations/colorectal-cancer-adults.html
11. Shaukat A, Kahi CJ, Burke CA, Rabeneck L, Sauer BG, Rex DK. ACG clinical guidelines: colorectal cancer screening 2021. Am J Gastroenterol. 2021 Mar;116(3):458–79. doi:10.14309/ajg.0000000000001122
12. Wolf AMD, Fontham ETH, Church TR, Flowers CR, Guerra CE, LaMonte SJ, Etzioni R, McKenna MT, Oeffinger KC, Shih YT, Walter LC, Andrews KS, Brawley OW, Brooks D, Fedewa SA, Manassaram-Baptiste D, Siegel RL, Wender RC, Smith RA. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018 Jul;68(4):250–81. doi:10.3322/caac.21457
13. American Cancer Society. American Cancer Society Guideline for Colorectal Cancer Screening [Internet]. 2024. Available from: https://www.cancer.org/cancer/types/colon-rectal-cancer/detection-diagnosis-staging/acs-recommendations.html
14. US Preventive Services Task Force, Davidson KW, Barry MJ, Mangione CM, Cabana M, Caughey AB, Davis EM, Donahue KE, Doubeni CA, Krist AH, Kubik M, Li L, Ogedegbe G, Owens DK, Pbert L, Silverstein M, Stevermer J, Tseng CW, Wong JB. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2021 May 18;325(19):1965. doi:10.1001/jama.2021.6238
15. Meester RGS, van Herk MMAGC, Lansdorp-Vogelaar I, Ladabaum U. Prevalence and Clinical Features of Sessile Serrated Polyps: A Systematic Review. Gastroenterology. 2020 Jul;159(1):105-118.e25. doi:10.1053/j.gastro.2020.03.025 PubMed PMID: 32199884.
16. Knudsen AB, Rutter CM, Peterse EFP, Lietz AP, Seguin CL, Meester RGS, Perdue LA, Lin JS, Siegel RL, Doria-Rose VP, Feuer EJ, Zauber AG, Kuntz KM, Lansdorp-Vogelaar I. Colorectal Cancer Screening: An Updated Modeling Study for the US Preventive Services Task Force. AHRQ Publication No. 20-05271-EF-2. Rockville (MD): Agency for Healthcare Research and Quality (US); 2021 May. Report nos.: 20-05271-EF-2. PubMed PMID: 34003219; PubMed Central PMCID: PMC8409520.
17. U.S. Food and Drug Administration. Guidance for Industry: E9 Statistical Principles for Clinical Trials [Internet]. 1998 Sep [cited 2025 May 30]. Available from: https://www.fda.gov/media/71336/download
18. U.S. Food & Drug Administration. FDA Executive Summary: Cologuard [Internet]. 2014 [cited 2025 Aug 1]. Available from: https://wayback.archive-it.org/7993/20170114045719/http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/MolecularandClinicalGeneticsPanel/UCM390220.pdf

Less

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

Dear Ms. Baldwin:

On behalf of Guardant Health, we thank the Centers for Medicare & Medicaid Services (CMS) for the thoughtful coverage policy described in the Proposed Decision Memo for NCD 210.3 Screening for Colorectal Cancer (CRC) Non-Invasive Screening Tests and we appreciate the opportunity to submit comments.

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 stages in the general population, Guardant Health’s molecular test portfolio provides invaluable insights to over 100,000 Medicare patients and their care teams each year. Guardant360® CDx was the first FDA-approved liquid biopsy for comprehensive genomic profiling (CGP) in advanced cancer patients across all solid cancers. To date, Guardant360 has been clinically validated with more than 500 publications and is trusted by more than 15,000 oncologists with over 750,000 patient test results delivered. Leveraging our established oncology diagnostic infrastructure and scientific learnings from the hundreds of thousands of blood samples tested, in July 2024, Shield™ became the first blood-based test approved by the FDA as a primary screening option for CRC.

Guardant Health would like to express our support for CMS’s decision to create a national policy that comprehensively covers non-invasive biomarker tests when they meet appropriate criteria.
We applaud CMS for covering tests in a technology-agnostic manner that is both forward thinking and inclusive of all non-invasive modalities that are currently FDA-approved and for services with comparable performance in major published validation studies. CMS proposes a two-criteria system for performance metrics that allows flexibility for test developers to prioritize higher specificity at the expense of some sensitivity or vice versa. We believe this is a reasonable and appropriate approach and thank CMS for taking public comments into consideration when devising this strategy. Transparent, well-defined evidentiary thresholds that are consistent across modalities provide test developers with clear guidance, gives clinicians and patients confidence in covered tests, and ensures patients can access tests that meet the coverage criteria without delay.

Overall, by enabling patient access to more non-invasive options, this coverage policy can help to increase CRC screening rates, which remain suboptimal. CRC is now the second leading cause of cancer deaths in the U.S. and 1 in 3 people in the U.S. that are eligible for screening are not being screened for CRC (1). More options increase the likelihood that a patient will be able to select a screening method that they will complete. Blood-based screening has the potential to overcome adherence barriers associated with traditional screening methods by incorporating CRC screening into routine medical care. Real-world clinical experience demonstrates over 90 percent test completion rates for blood-based testing and clinical studies have shown that integrating blood-based CRC screening alongside other modalities increases both CRC screening acceptance and completion (2,3). As one example, in a study in two Appalachian primary care clinics, integration of blood-based testing alongside other CRC screening modalities increased the overall screening completion rate from 45% to 90%, where 69% of those individuals who completed screening had never been (4).

Guardant Health strongly supports CMS's proposal to make ordering requirements consistent across test modalities. Doing so ensures that providers can offer the full range of CRC screening options to their patients, allowing shared decision-making between the provider and beneficiary to select the most appropriate test for the patient. Similarly, Guardant Health appreciates CMS’s decision to broaden the ordering provider language to include physicians, physician assistants, nurse practitioners, and clinical nurse specialists. This update reflects the realities of preventive medicine where there are a range of appropriate providers who may order a screening test for a beneficiary. Allowing additional provider types to order non-invasive screening tests can be especially impactful in rural communities with more limited access to care, which is especially important given the significant geographical differences in CRC screening rates, incidence, and outcomes (5). In expanding the provider types eligible to order non-invasive screening tests, CMS is helping to ensure more patients have access to appropriate screening.

In the decision rationale, CMS states that “we do not believe there is an evidentiary reason to limit the ordering of non-invasive CRC screening test to physicians.” To ensure the NCD does not require reopening solely due to future changes in provider scope, we recommend that CMS modify the language to directly reference the statute that underlies the federal regulations defining “non-physician providers.” This would preserve CMS’ intent while allowing for the inclusion of any additional provider types subsequently recognized under the Social Security Act when ordering preventive services would fall within their scope of practice. (See suggested language below). Such forward-looking language would allow the NCD to keep pace with the evolving healthcare landscape without necessitating future revisions.

We further suggest a change from “in the management of the patient” to “for the management of the patient” to better reflect the role of the ordering provider in the screening process. The most common provider types that currently order non-invasive tests are Primary Care Physicians (PCPs), and the non-physician practitioners listed in the proposed decision memo. Following an abnormal result, these providers refer the patient to a gastroenterologist for a screening colonoscopy and would rarely if ever perform the procedure themselves. Gastroenterologists are also less likely to be the ordering provider for a non-invasive screening test given the eligibility criteria that the patient be asymptomatic and of average risk. As such, a change from “in” to “for” is consistent with the current role of the ordering provider in the screening process. The management of the patient that is needed following an abnormal test result is referral to colonoscopy. Additional management of the patient appropriately falls to a specialty provider that may not be involved in the patient’s care prior to the abnormal result.

Original language:

We propose that non-invasive biomarker colorectal cancer screening tests are covered once every three years for Medicare beneficiaries when ordered by the physician, physician assistant, nurse practitioner, clinical nurse specialist who will use the results in the management of the patient and when all the following conditions are met

Suggested version:

We propose that non-invasive biomarker colorectal cancer screening tests are covered once every three years for Medicare beneficiaries when ordered by the physician, physician assistant, nurse practitioner, clinical nurse specialist , or other nonphysician practitioner authorized under 42 U.S.C. 1395x(s) who will use the results for the management of the patient and when all the following conditions are met

We again thank CMS for this thoughtful proposed decision memo and for considering stakeholder feedback in drafting this coverage framework. We appreciate the opportunity to engage in this process and look forward to finalization of this coverage policy and the meaningful impact it will have on improving patient access to CRC screening technologies that can help close screening gaps.

Sincerely,
AmirAli Talasaz PhD,
Co-CEO
Guardant Health

References:
1: American Cancer Society. Colorectal Cancer Facts & Figures 2023-2025. Atlanta: American Cancer Society; 2023.
2: Coronado GD, Jenkins CL, Shuster E, et al. Blood-based colorectal cancer screening in an integrated health system: a randomised trial of patient adherence. Gut 2024; 73 :622-628. DOI: 10.1136/gutjnl-2023-330980
3: Graham-Adderton, C., Guerra, C. E., Ngo-Metzger, Q., Hoang, T., & Raymond, V. M. (2025). Implementation of blood-based colorectal cancer screening: real-world adherence and outcomes. Current medical research and opinion, 41(10), 1915–1920. DOI: 10.1080/03007995.2025.2582257
4: Haynes, et al. 2024. Blood-based Colorectal Cancer Screening: Implementation into Two Appalachian Primary Care Clinics. Am J of Preventive Medicine. DOI: 10.1016/j.amepre.2025.04.006
5: American Cancer Society. Colorectal Cancer Facts & Figures 2023-2025. Atlanta: American Cancer Society; 2023.

Less

The American Cancer Society (ACS) and the American Cancer Society Cancer Action Network (ACS CAN) appreciate the opportunity to comment on the proposed decision memo for changes to the existing National Coverage Decision (NCD) 210.3 related to screening for colorectal cancer (CRC) using non-invasive biomarker tests. The ACS mission is to improve the lives of people with cancer and their families through advocacy, research, and patient support, to ensure everyone has an opportunity to prevent, detect, treat, and survive cancer. ACS, operating throughout the United States (US), is the largest voluntary health organization in the country. ACS CAN is making cancer a top priority for public officials and candidates at the federal, state, and local levels. ACS CAN is the nonprofit, nonpartisan advocacy affiliate of ACS, advocating for evidence-based public policies to reduce the cancer burden for everyone. 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.

ACS has estimated that in 2026, 108,860 cases of colon cancer would be diagnosed in the United States and an estimated 55,230 people would die from the disease.¹ Colorectal cancer remains one of the deadliest forms of cancer.² Colorectal cancer is the third most commonly diagnosed cancer and the third most common cause of cancer-related death in both men and women in the United States.³ Almost half (45%) of new diagnosis are in individuals under age 65, up from 27% in 1995.⁴

Regular screening is the most effective way of detecting precancerous growths and early colorectal cancer. Removal of precancerous lesions can prevent colorectal cancer, and cancers found at an early stage can be treated more easily, and lead to greater survival.⁵ For colorectal cancer, the five-year survival rate is 91% when the cancer is discovered and treated early.⁶ In contrast, individuals aged 65 and older whose colorectal cancer is found at a later stage, after the cancer has metastasized, have a 10% five-year survival rate.⁷

We are pleased to see the reconsideration given the updated scientific evidence and clinical recommendations available. We have the following comments:

II. CLINICAL REVIEW

A. Background

The proposed decision memo states that colorectal cancer is the fourth most common cancer and the second leading cause of cancer deaths in the U.S., citing Siegel, et al. 2024. We recommend that the decision memo qualify this statistic as follows: Colorectal cancer is the third most common cancer in both women and men, and the second leading cause of cancer death in the United States.

We would also like to bring to the attention of the Centers for Medicare & Medicaid Services (CMS) that estimates of new cancer cases are derived by the ACS each year – not, as noted in the proposed decision memo, by the National Cancer Institute (NCI). In fact, the NCI cites the ACS estimates on the SEER website. We ask that when the decision memo is finalized that CMS properly attribute the source of these yearly annual estimates of expected new cases and deaths to ACS. The methodology for deriving the estimates can be found in ACS’ annual publication of our Cancer Facts and Figures.⁸ We also urge CMS to use the most current data, 2026, in its final decision memo. These can be found in the ACS Facts and Figures 2026⁹, or preferably the annual cancer statistics in the CA: A Cancer Journal for Clinicians.¹⁰

At the end of paragraph two in this section, the proposed decision memo states: “Colonoscopy is the gold standard for CRC screening.” Most organizations, and especially those that issue clinical guidelines and recommendations, have stopped claiming that colonoscopy is a gold standard. Instead, collectively these organizations all say the best test is the one that individuals will undertake. All colorectal cancer tests produce lifetime benefits similar to colonoscopy when colorectal cancer screening with any recommended test is done regularly over the period that screening is recommended. Since many individuals do not wish to undergo an invasive screening test but are willing to be screened with beneficial noninvasive tests, we urge CMS to not diminish the value of other recommended tests by placing colonoscopy in an exalted position.

E. Assessment of the Evidence

Bullet 8 cites the lack of long-term follow-up to measure morbidity and mortality. Given that the natural history of colorectal cancer is well established, as is the efficacy of screening based on multiple randomized clinical trials utilizing different colorectal cancer screening tests, there is broad consensus that new screening technology only needs to demonstrate the detection of surrogate indicators (advanced neoplasia in the form of precursor lesions and cancer) with an established comparison test, with both followed up with colonoscopy as the reference test. New tests would remain in limbo for a decade or more if a mortality endpoint were required. It is unreasonable to expect these studies to follow up to mortality because it is unnecessary. As for morbidity, there is next to no morbidity associated with a noninvasive screening test. Any morbidity that occurs associated with the volume of follow-up colonoscopy can be estimated based on established data, but the morbidity occurs with the follow-up test, not from collecting stool or a blood draw. We therefore recommend that this bullet also be deleted from the final decision memo.

The proposed decision memo states in the first bullet of the list of limitations, “All studies of commercially available CRC tests (Cologuard®, ColoSense®, Shield™) were supported by the companies that developed the tests.” Although this limitation is commonly listed in systematic reviews when including industry sponsored research, it is a risk of bias without substantiation, and it signals to readers that the reviewers carried this sense of anticipated bias when reviewing the literature. Scientific research must be entirely judged on the basis of the quality of the research, without a cloud of suspicion based on who sponsored the research. We note, compared with the following limitations, there is no citation to support that an industry sponsored study is inherently biased. We also note that industry commonly recruits academic leaders to run their studies, knowing that scientists with unimpeachable reputations will add credibility to the investigation. These studies tend to be published in leading high impact journals and always have undergone peer review. It is for these reasons that we recommend deleting this bullet from the final decision memo.

Most guidelines/recommendations have an allowance for screening past age 75, based on estimated longevity and shared decision making. All recommendations and guidelines also stress as a condition of undergoing screening, regardless of age, that individuals should be in good health and not suffer from life-limiting co-morbid conditions. In the final version of the decision memo, we urge CMS to make note that guidelines organizations do not adhere to a strict maximum age for screening before the age of 80 or 85.

IV. CMS COVERAGE ANALYSIS

B. CMS Analysis for Coverage of CRC screening

In previous comments to CMS, we have expressed concerns about test criteria thresholds, specifically the combination of sensitivity/specificity performance characteristics for the detection of invasive colorectal cancer that must be met for coverage. We question why these thresholds are only set for cancer, without also including criteria for advanced precursor lesions (APLs). It has recently been estimated that we are reducing more colorectal cancer mortality by interrupting the natural history of disease when we detect and remove APLs. All recommended CRC tests have better sensitivity for cancer compared with APLs, but we want to see that these tests have at least respectable performance for detecting APLs. Given the variability of definitions of APLs in the literature, CMS might just focus on high grade dysplasia. Specificity should be defined as the absence of advanced colorectal neoplasia. Second, most of the sensitivity and specificity statistics are based on the performance of a single test. Tests with shorter screening intervals are expected to have better performance over comparable time periods (3 yrs., 5 yrs., 10 yrs.). We recommend that CMS consider adding test criteria for the detection of cancer and APLs adjusted for comparable periods of regular screening.

With respect to sensitivity and specificity criteria, the proposed NCD claims that there is an inverse relationship between sensitivity and specificity. At the upper limits this is true, but with quality improvement, screening tests, particularly those that involve some degree of operator dependence, can see simultaneous improvements in both sensitivity and specificity. The assumption that there is an “iron law” of the inverse relationship between sensitivity and specificity further complicates the statement that: “If the test manufacturer decided to increase screening test sensitivity, then it is likely that specificity would decrease for the screening test. If the test manufacturer decided to increase screening test specificity, then it is likely that sensitivity would decrease.” We see the following problems with these thresholds:

• All thresholds are expressed as “equal to or greater than.”
• Criteria 1 and 2 have uneven differences between sensitivity and specificity: 3 percentage points for Criteria 1, and 11% points for Criteria 2
• For Criteria 1, an improvement in sensitivity from 90% to 94% that led to a half point decline in specificity 86.5% would disqualify the test compared with only met minimum criteria.
• We wonder why CMS is prepared to accept a screening test that is only done every 3 years, but with a sensitivity of 79% would miss 21% of invasive cancers.

In general, missing the thresholds by small numbers could mean that new tests that outperform the point sensitivity and specificity of many tests in the recommended categories, specifically gFOBT and FIT that are cleared by the Food and Drug Administration (FDA) and widely used today, would be disqualified.¹¹

We concur with the ordering requirements including physician assistants, nurse practitioners, or clinical nurse specialists who will use the results in the management of the patient.

We are surprised that there is no mention of the comparatively poor performance of blood-based tests in the detection of precursor lesions. The one blood-based test that is currently available for CRC screening includes cautionary language that their test has low sensitivity to detect precursor lesions compared with other colorectal cancer screening tests. Given that modeling data show that a substantial fraction of reduced incidence and mortality derives from detecting and removing precursor lesions, patients should know the limitations of these tests compared with other recommended tests that have better performance for detecting precursor lesions. On the other hand, attention should be given to the possibility that these tests may be acceptable to individuals who are repeatedly non-adherent to recommendations for colorectal cancer screening, or who state that they are not willing to undergo any of the currently recommended tests.

With respect to the answers to evidence questions 1 and 2, we concur with CMS’ decision to include these tests in coverage for Medicare beneficiaries.

A copy of our comment letter with citations is available at https://www.fightcancer.org/policy-resources/acs-and-acs-can-comments-medicare-ncd.

1American Cancer Society. Cancer Facts & Figures 2026. Atlanta: American Cancer Society; 2026.
2Siegal RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. Cancer. 2021; 71:7-33. doi 10.3322/caac.21654.
3American Cancer Society. Colorectal Cancer Facts & Figures 2023-2025. Atlanta: American Cancer Society; 2024.
4Siegel RL, Wagle NS, Star J, Kratzer, Smith RA, Jemal A. Colorectal cancer statistics, 2026. CA Cancer J Clin. 2026; 76(2)(e70067). doi:10.322/caac.70067.
5American Cancer Society. Cancer Prevention & Early Detection Facts & Figures 2023-2024. Atlanta: American Cancer Society; 2024.
6Colorectal Cancer Facts & Figures 2023-2025.
7Id.
8See Cancer Facts & Figures 2026 at page 41.
9Id.
10 Colorectal cancer statistics, 2026.
11 See, Levy BT, Xu Y, Daly JM, Hoffman RM, et al. Comparative Performance of Common Fecal Immunochemical Tests : A Cross-Sectional Study. Ann Intern Med. Oct 2024;177(10):1350–1360. doi:10.7326/M24-0080.

Less

Fight Colorectal Cancer (Fight CRC) appreciates the opportunity to comment on the Centers for Medicare & Medicaid Services (CMS) proposed decision memo for coverage of non-invasive biomarker colorectal cancer screening tests. We support efforts to expand access to evidence-based, patient-centered screening options for Medicare beneficiaries at average risk. Expanding access, however, should not come at the expense of clinical clarity or create confusion about how newer tests compare with established screening strategies already used in practice.

Fight CRC urges CMS to revise the final policy to make clear that the screening interval must be test specific, not category wide. The proposed memo applies a frequency of once every three years to non-invasive biomarker colorectal cancer screening tests as a category. That approach risks misrepresenting clinically important differences among screening modalities and could create downstream confusion in coverage interpretation, patient counseling, and care delivery. CMS’s own review of the evidence and guideline recommendations reflects that screening intervals are modality specific, not interchangeable across all non-invasive tests.

The United States Preventive Services Task Force (USPSTF) recommends that average risk adults ages 45 to 75 receive a fecal immunochemical test (FIT) every year and a multitarget stool DNA test (mt-sDNA) every one to three years. USPSTF does not currently include serum tests in its colorectal cancer screening recommendation. The American Cancer Society (ACS) similarly recommends stool-based screening options for average risk adults beginning at age 45 at modality-specified intervals, including annual FIT and mt-sDNA testing every three years.

Fight CRC appreciates CMS’s effort to establish a practical coverage framework for emerging non-invasive biomarker colorectal cancer screening tests. However, the proposed framework is built primarily around one-time colorectal cancer sensitivity and specificity thresholds, while patients experience screening as a longitudinal prevention strategy. From the patient perspective, the relevant question is not simply whether a test clears a minimum threshold for cancer detection at a single point in time. The relevant question is whether that test performs appropriately relative to established screening pathways already in use, particularly annual FIT and mt-sDNA screening every three years, and whether it meaningfully detects advanced precancerous lesions. Because the purpose of colorectal cancer screening is not only early detection, but also prevention, CMS should not imply that minimum colorectal cancer detection thresholds alone establish parity with existing screening strategies.

Accordingly, Fight CRC urges CMS to:

1. Revise the final National Coverage Determination (NCD) so screening frequency is tied to the specific covered modality, the supporting evidence base, and FDA authorized labeling, rather than imposing a single three year interval across the non-invasive biomarker colorectal cancer screening category.

2. State explicitly that this proposal does not alter or narrow existing annual FIT coverage. CMS has indicated that it does not intend to review longstanding FIT coverage. The final policy should remove any ambiguity on this point.

3. Avoid overstating alignment with national guidelines for blood-based tests. While CMS may establish Medicare coverage standards for certain biomarker tests, final policy language should accurately reflect that USPSTF does not currently include serum tests in its colorectal cancer screening recommendation and that guideline support remains modality specific.

4. Clarify that the proposed sensitivity and specificity thresholds are minimum coverage criteria, not evidence of equivalence to established screening strategies. If CMS finalizes these thresholds, it should make clear that they do not by themselves demonstrate parity with annual FIT or mt-sDNA screening in real world clinical practice.

5. Explicitly account for advanced precancerous lesion detection, because a screening policy that focuses too narrowly on existing cancer detection does not fully serve patients’ interest in prevention.

6. Reinforce the need for timely follow-up colonoscopy after any abnormal non-colonoscopy screening test. Access to screening improves outcomes only when abnormal results are followed by appropriate diagnostic evaluation.

7. Reflect the need for individualized screening decisions for adults ages 76 to 85, consistent with broader clinical guidance and the realities of health status, screening history, life expectancy, and patient preference.

CMS’s final policy must expand access without sacrificing clinical accuracy, patient understanding, or alignment with established screening practices. Without additional clarification, the proposed approach risks blurring important distinctions between annual FIT, stool-based screening options used at longer intervals, and newer biomarker tests whose performance characteristics and evidence base differ in meaningful ways.

In addition to revising the final NCD language, CMS should issue a brief implementation FAQ or other sub regulatory guidance that clearly distinguishes this policy from existing annual FIT coverage, explains screening interval by modality, and reinforces the need for timely colonoscopy after an abnormal non-colonoscopy screening test. CMS should also identify key evidence gaps for future review, including interval performance, real world adherence, advanced precancerous lesion detection, and outcomes in the Medicare population.

Thank you for the opportunity to comment.

Less

The American Society for Gastrointestinal Endoscopy (ASGE), representing more than 17,000 gastrointestinal endoscopists worldwide, is dedicated to advancing patient care and digestive health through excellence in endoscopy. We appreciate the opportunity to comment on the proposed changes to National Coverage Determination (NCD) 210.3, “Screening for Colorectal Cancer – Non-Invasive Biomarker Tests.”

ASGE supports broad, evidence-based colorectal cancer (CRC) screening with multiple high-quality options to increase participation and reduce CRC incidence and mortality. ^1,2,3

Colonoscopy remains the gold standard for colorectal cancer screening, as it is the only modality that both detects and prevents cancer through the identification and removal of precancerous lesions. ^4,5

We also support continued innovation in screening technologies. However, coverage policy must ensure that innovation advances clinical outcomes and does not inadvertently compromise cancer prevention.

ASGE respectfully offers the following concerns regarding the current proposed determination.

Prioritizing Cancer Prevention
We are deeply concerned that the proposed decision does not include performance thresholds for advanced precancerous lesions (APLs), despite well-established evidence. Landmark studies and current clinical guidelines support, that the life-saving benefit of CRC screening is derived from the detection and removal of precancerous lesions.^4,2 Tests with limited APL sensitivity do not provide the same prevention benefit as colonoscopy or established stool-based tests.^6,7 Recent evidence further demonstrates that while blood-based screening tests may detect some cancers, they have substantially lower sensitivity for advanced precancerous lesions, limiting their ability to prevent colorectal cancer compared to established screening modalities.¹³ Expanding coverage without incorporating APL detection risks shifting screening toward modalities that detect cancer later rather than preventing it.

Performance Threshold Framework
The proposed dual-threshold framework (=90%/87% or =79%/90% sensitivity/specificity) raises important scientific concerns.⁷ This approach treats sensitivity and specificity as interchangeable tradeoffs, when in the context of cancer screening, they are not clinically equivalent.^1,2 Lower sensitivity increases the risk of missed cancers and missed opportunities for early intervention. Allowing tests with substantially lower sensitivity to meet coverage criteria may introduce screening options that provide inferior clinical outcomes.

Grouping of Distinct Modalities
ASGE is also concerned with the proposal to collapse all non-invasive biomarker tests into a single category. Stool-based and blood-based tests differ significantly in their ability to detect both colorectal cancer and advanced precancerous lesions.^6,7 Evidence also indicates that blood-based screening tests have lower sensitivity for both advanced precancerous lesions and early-stage colorectal cancer, reinforcing that these modalities are not clinically equivalent.¹⁴ Treating these modalities as equivalent for coverage purposes risks creating a false equivalency and may lower the performance expectations for all tests within the category.

Innovation and Public Health
CMS coverage policy plays a critical role in shaping the direction of innovation.⁸ Establishing lower or non-differentiated performance standards may unintentionally incentivize the development and adoption of tests that are easier to deploy but less effective at preventing cancer. Evidence also suggests that while blood-based tests may improve screening participation, this benefit must be carefully weighed against their lower sensitivity for advanced precancerous lesions and early-stage disease.¹⁵ At a time when CRC screening rates have improved and mortality has declined substantially due to effective screening,^9,10 it is critical that new policies build upon—not erode—these gains.

Legal and Process Considerations
Finally, ASGE notes that the proposed consolidation of screening modalities into a single biomarker category represents a departure from CMS’s longstanding approach to NCD 210.3, in which individual screening tests have been evaluated and added based on their specific evidence base. This approach aligns with the statutory requirement that NCDs address a “particular item or service” under federal law.^11,12 Moving to a broad category-based framework raises concerns regarding both statutory alignment and the rigor of evidence evaluation.

Recommendations
ASGE respectfully recommends that CMS:

• Incorporate explicit performance thresholds for APL detection for all non-invasive screening tests.
• Reconsider the dual-threshold framework to ensure that sensitivity remains appropriately prioritized.
• Maintain distinct evaluation pathways for different screening modalities.
• Ensure that new screening options are positioned within a structured shared decision-making framework, and consistent with NCCN guidance used for patients who decline established, higher-performing screening options after appropriate counseling on tradeoffs.¹⁶
• Convene a Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) to provide independent expert input on the role of APLs given the complexity and impact of this decision.

Conclusion
ASGE shares CMS’s commitment to increasing CRC screening and reducing cancer burden. However, expanding coverage must not come at the expense of clinical effectiveness. Policies that fail to prioritize prevention risk undermining decades of progress in reducing CRC incidence and mortality.

We appreciate CMS’s thoughtful consideration of these issues and stand ready to support the Agency in ensuring that coverage decisions reflect the highest standards of evidence and patient care. Should you need additional information, please contact Lakitia Mayo, Chief Policy and Member Engagement Officer at lmayo@asge.org.

FOOTNOTES
1. U.S. Preventive Services Task Force. Screening for Colorectal Cancer: Recommendation Statement. JAMA. 2021;325(19):1965–1977.
2. Shaukat A, et al. ACG Clinical Guidelines: Colorectal Cancer Screening 2021. Am J Gastroenterol. 2021;116:458–479.
3. American Cancer Society. Colorectal Cancer Screening Guideline. CA Cancer J Clin. 2018;68(4):250–281.
4. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic Polypectomy and Long-Term Prevention of Colorectal-Cancer Deaths. N Engl J Med. 2012;366:687–696.
5. Nishihara R, et al. Long-term CRC Incidence and Mortality after Lower Endoscopy. N Engl J Med. 2013; 369:1095–1105.
6. Imperiale TF, et al. Multitarget Stool DNA Testing for CRC Screening. N Engl J Med. 2014; 370:1287–1297.
7. Centers for Medicare & Medicaid Services. Proposed Decision Memo (CAG-00440R).
8. Medicare Payment Advisory Commission (MedPAC). Report to Congress: Medicare Payment Policy.
9. Centers for Disease Control and Prevention. Colorectal Cancer Statistics.
10. National Cancer Institute. SEER Cancer Statistics Review.
11. Social Security Act §1869(f)(1)(B), 42 U.S.C. §1395ff(f)(1)(B).
12. Social Security Act §1861(pp)(1)(D), 42 U.S.C. §1395x(pp)(1)(D).
13. 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;177(12):1610-1620.
14. 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(2):378-391.
15. Ladabaum U, Dominitz JA, Lieberman D, Schoen RE. Can molecular cancer signals circulating in blood help us prevent cancer-related deaths?. Lancet. Published online January 6, 2025.
16. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. Version [most recent]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf

Less

I wish to reiterate and stand by my comment from fall 2025:
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, yet 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 publication's issue a warning to patients that it may miss as many as 24.3% of colorectal cancers. In addition, 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 as i am fearful it will put additional stress on a system struggling to keep up with patients needs.

Less

As a practicing Gastroenterologist, I appreciate the tabular presentation of the data for these colon cancer prevention and screening options. I agree that standardization of endpoints would help considerably. While comparison of test performance characteristics to FIT provides a useful frame of reference, it also seems to set a low bar which allows entry of products with test performance characteristics that are inferior to established and easily available options. Some key differences in the testing options deserve to be highlighted.

Though long term mortality is difficult to study, it should be possible to intentionally stratify the importance of various screening goals and develop standardized endpoints to aim for these targets. Ideally, colon cancer prevention should be given significantly more weight compared to colon cancer detection. Similarly, detection of early colon cancer (stage I) should be prioritized over detection of later stage cancers which are not as treatable, involving significantly higher morbidity, mortality, and cost of care.

If we view detection of neoplasia globally along a timeline of disease progression, several timepoints for intervention are critically important to our patients and the healthcare system in general. Two of the most important are the transition from precancerous to invasive cancer and the transition from early stage to late stage cancer. Screening tests with low sensitivity for advanced precancerous lesions (APLs) and stage I colon cancer move the detection time-point further down the disease progression timeline. Advanced disease at detection is exchanged for a small increase in adherence. Perhaps more concerning, though, is the false sense of security in a subset of patients who have already self-selected into a population less likely to be compliant with healthcare treatment and follow up, which can be considerable in late stage colon cancer.

For example, if a patient with an APL agrees to a blood based cf DNA test and has a negative result, they will be less likely to agree to another screening test, and coverage for another test will only be available in 3 years. The sensitivity of this blood based cf DNA test for APLs is 13.2%, The next generation mt sDNA test for this patient has a sensitivity of 43.4% for APLs. That is an almost three-fold difference in detection at a defined timepoint between prevention of colon cancer and a diagnosis of invasive neoplasia.

A similar trend is seen for stage I adenocarcinoma with the blood based test missing around half of the cases (sensitivity 55-65%) versus next generation mt sDNA sensitivity 88%. If we then retest at 3 years, how far will this patient, who was offered the blood based test, have progressed across pivotal timepoints?

Prevention of colon cancer should be the ultimate endpoint for these tests. If a patient is unfortunate enough to develop colon cancer, an early stage diagnosis is significantly better compared to advanced disease. I routinely see serial negative annual FIT testing, followed by a better screening test (mt sDNA) from a primary care physician that returns positive. The first question I get after the index colonoscopy at age 75 shows cancer is "Why were all those tests negative". Our patients trust us to offer the most state of the art screening tests. Anything less will lead to worse long term outcomes and perhaps even more distrust for healthcare.

Less

The Global Healthy Living Foundation (GHLF) appreciates the opportunity to comment on CMS’s proposed decision regarding coverage of non-invasive colorectal cancer (CRC) screening tests.

GHLF supports CMS’s efforts to expand coverage of non-invasive CRC screening options when they meet appropriate clinical and performance criteria. Ensuring that Medicare beneficiaries have access to FDA-approved screening modalities, including blood-based tests that demonstrate performance comparable to other non-invasive options, represents an important step toward modernizing CRC screening and improving patient outcomes.

From a patient perspective, access to a broader range of screening options is critical. Despite longstanding clinical guidelines recommending routine CRC screening, adherence remains suboptimal, particularly among populations facing structural and practical barriers to care. Many patients encounter challenges related to transportation, time away from work, caregiving responsibilities, or discomfort with existing screening modalities. As a result, a significant number of individuals who are eligible for screening remain unscreened or underscreened.

For these patients, the availability of additional non-invasive screening options, including blood-based tests, can be the difference between participating in screening and forgoing it altogether. Real-world evidence and clinical experience increasingly demonstrate that offering a wider range of screening modalities improves patient acceptance and completion of screening. Expanding access to blood-based testing therefore has the potential to meaningfully increase screening uptake, particularly among historically underserved and hard-to-reach populations.

Improving screening rates is not an abstract goal. Colorectal cancer remains a leading cause of cancer-related death in the United States, despite being highly preventable and treatable when detected early. Delayed or missed screening can lead to later-stage diagnoses, more intensive treatment, and worse outcomes for patients. Policies that expand access to screening are directly tied to earlier detection and improved survival.

At the same time, it is important to recognize that screening is part of a continuum of care. A positive result from any non-invasive screening modality must be followed by timely diagnostic colonoscopy to achieve the full benefit of screening. Coverage policy should therefore support not only access to initial screening, but also the broader goal of ensuring that patients complete the screening process.

As CMS finalizes its coverage framework, GHLF encourages the agency to adopt an approach that is flexible and forward-looking, allowing for the inclusion of FDA-approved, Medicare-eligible non-invasive screening tests as the evidence base continues to evolve. A framework that reflects both clinical performance and real-world patient behavior will better serve Medicare beneficiaries and help close persistent gaps in cancer screening.

We appreciate CMS’s commitment to improving preventive care and stand ready to support efforts that expand access to effective, patient-centered colorectal cancer screening.

Less

On behalf of The Blue Hat Foundation, I am writing to provide a balanced perspective on the proposed expansion of Medicare coverage for blood-based colorectal cancer (CRC) screening. Our organization serves minority and medically underserved communities nationwide—populations that bear a disproportionate burden of CRC mortality.

We believe that while blood-based biomarkers represent a breakthrough in patient adherence, the policy must be implemented with careful attention to both its potential and its limitations.

1. The Case for Access: Overcoming Adherence Barriers
The primary appeal of a blood-based test like Guardant Shield is its ability to reach the "unscreened." In the communities we serve, cultural stigmas, medical mistrust, and logistical hurdles often lead patients to decline invasive or stool-based tests.

The Benefit: A simple blood draw during a routine wellness visit "meets the patient where they are." We support a policy that offers this choice as a way to normalize screening and improve the current 1-in-3 non-completion rate in the U.S.

2. Addressing Technical Concerns: Sensitivity and Specificity
We recognize the concerns raised by CMS regarding the performance thresholds of blood-based tests compared to stool-based options.

Detection vs. Prevention: We acknowledge that current blood-based tests have lower sensitivity for advanced adenomas (precancerous polyps) compared to Cologuard or colonoscopy. It is vital that CMS and providers clearly communicate that this is a cancer detection tool, not a prevention tool.

Maintaining Standards: We support the 74% sensitivity and 90% specificity thresholds. Underserved communities deserve innovation that is accurate; lowering these standards could lead to a high rate of false negatives (missing cancer) or false positives (causing unnecessary anxiety and procedures).

3. The "Financial Trap" of Follow-up Care
The most significant concern for our community is the financial burden of a positive test.

The Burden: Currently, if a non-invasive screening returns a positive result, the follow-up colonoscopy is often billed as a "diagnostic" procedure. For the low-income and working-class populations we serve, an unexpected out-of-pocket cost is a barrier that stops the screening journey entirely.

Our Request: We strongly urge CMS to ensure that all follow-up colonoscopies after a positive blood-based test are covered as preventive services with $0 cost-sharing.

4. Empowering Community Health Providers
In many "screening deserts," specialized gastrointestinal care is scarce. We advocate for allowing a broader range of qualified providers (including PCPs and community clinics) to order these tests. Access should not be restricted by a patient's proximity to a specialist.

Conclusion
The Blue Hat Foundation supports the inclusion of blood-based biomarkers in NCD 210.3, provided that coverage is paired with clear patient education on test limitations and the total removal of financial barriers for follow-up care.

Sincerely,

Candace Henley
Founder, The Blue Hat Foundation

Less

I am a physician and oncologist who served as the 24th Commissioner of the Food and Drug Administration (FDA) from December 2019 to January 2021. I previously served in high-level leadership roles at the University of Texas MD Anderson Cancer Center, where I served as Chief Medical Executive, and at the University of Pennsylvania’s Perelman School of Medicine. During my tenure at the FDA, I oversaw the agency's response to the COVID-19 pandemic, the emergency use authorizations for the first vaccines and treatments.

Upon reviewing the NCD, I commend CMS on its proposal to collaborate closely with FDA to ensure the continued safety and efficacy of tests and to keep them reasonable and necessary for the Medicare population. Given my experience at the FDA, I would emphasize the importance of preserving the FDA's statutory authority and independence in its oversight of post-approval studies. I would encourage CMS to develop a mechanism such that the FDA can inform CMS of completed post-approval studies, and also, at the FDA's discretion, inform CMS when post-approval studies have not been completed. For the NCD for Screening for Colorectal Cancer-Non-Invasive Biomarker Tests, once CMS is notified that a post-approval study is completed, CMS could confirm that the revised product labeling continues to meet the performance characteristics.

This would strengthen collaboration between the two agencies, maintain clarity on roles and responsibilities, and enable both agencies to provide oversight while supporting innovation.

Less

Dear Administrator Oz,

On the surface, this proposal to cover blood-based colorectal cancer screening tests sounds like progress: more options, more innovation, more access for seniors and people with disabilities.[1] Upon closer inspection, it appears to be a shift toward a test that is simply worse at detecting cancer where it matters most.

There is a simple way to think about cancer screening: the goal is not just to find cancer but to stop it before it starts. That distinction is what separates truly preventive care from care that reacts after the fact. When it comes to colon cancers, colonoscopies work by finding and removing precancerous polyps before they become dangerous.[2] Stool-based tests, though less comprehensive, still detect a meaningful share of those early warning signs and therefore are meaningful preventative tests.[3]

In contrast, the newer blood-based tests are primarily designed to detect cancer once it already exists. Their clinical efficacy in identifying the precancerous changes that make screening valuable is notably lower, with one test catching advanced precancerous polyps just 13% of the time.[4] This shifts the system away from prevention and toward later detection in a way that is difficult to justify as an improvement.

Coverage decisions shape behavior in predictable ways, as doctors tend to recommend what is easiest for patients to complete and patients tend to choose what is most convenient. When Medicare elevates a test that is convenient but demonstrates lower efficacy in early-stage prevention, it does not merely sit alongside existing options, it begins to displace them.

This dynamic reflects an unfortunate pattern in Washington where policies are framed as improving efficiency while quietly weakening incentives for high-quality results. What ultimately matters is not how many options are technically available, but the clinical performance of those options and whether they lead to better health results.

Colorectal cancer remains one of the clearest examples of a disease where prevention works when the system is aligned properly, and catching and removing polyps early can increase the odds of preventing cancer entirely.[5] The performance gap between different screening methods is not a minor technicality; it is a central question of whether we prioritize the most effective tools available. Missing early warning signs leaves patients facing a disease that could have been avoided.

An approach aligned with the "Make America Healthy Again" (MAHA) agenda should be grounded in the idea that new technologies must earn their place through demonstrated results. Prevention should take priority over convenience when the two are in tension. This proposal moves in the opposite direction by lowering the bar for coverage in a way that risks normalizing a lower standard of efficacy.

There is a straightforward alternative that does not reject innovation but instead insists on evidence. Blood-based screening tests will likely play a major role in preventive care if they can demonstrate an ability to reliably detect precancerous disease at rates comparable to current standards. However, covering them before that standard is met does not accelerate progress; it risks locking in weaker outcomes across the system.

Healthcare policy often revolves around abstractions such as coverage categories and reimbursement structures, but the measure that ultimately matters is whether more disease is being prevented or less. If a policy prioritizes a less effective test, resulting in fewer precancerous conditions being addressed early, then it is not making the country healthier.

What is needed is not a longer list of covered options but a clearer focus on outcomes. In cancer screening, the difference between prevention and delayed detection is not theoretical and it is not marginal. Policy decisions that blur that distinction risk producing exactly the kind of results that a prevention-focused healthcare agenda is supposed to avoid.

Respectfully,

Jerry Rogers
RealClearPolicy and RealClearHealth

References

1. Centers for Medicare & Medicaid Services. Proposed Decision Memo for Screening for Colorectal Cancer-Non-Invasive Biomarker Tests (CAG-00440R). Medicare Coverage Database. Published March 10, 2026. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=319
2. Colon Cancer Coalition. All About Polyps. Published 2024. https://coloncancercoalition.org/all-about-polyps/
3. Gómez-Molina R, Suárez M, Martínez R, Chilet M, Bauça JM, Mateo J. Utility of Stool-Based Tests for Colorectal Cancer Detection: A Comprehensive Review. Healthcare (Basel). 2024;12(16):1645. doi:10.3390/healthcare12161645
4. Voss A. Colorectal Cancer Screening: Where Does the Shield Liquid Biopsy Fit In? Cancer Currents Blog. National Cancer Institute. Published October 11, 2024. https://www.cancer.gov/news-events/cancer-currents-blog/2024/shield-blood-test-colorectal-cancer-screening
5. Dartmouth Cancer Center. Making sense of colorectal cancer screening. News & Stories. Published March 22, 2024. https://cancer.dartmouth.edu/stories/article/making-sense-colorectal-cancer-screening

Less

April 8, 2026

Dr. Mehmet Oz
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: National Coverage Analysis and Proposed Decision Memo Regarding Screening for Colorectal Cancer-Non-Invasive Biomarker Tests

Dear Administrator Oz,

The American Academy of Physician Associates (AAPA), on behalf of the over 190,000 PAs (physician associates/physician assistants) throughout the United States, would like to provide comments to the proposed decision memo titled “Screening for Colorectal Cancer-Non-Invasive Biomarker Tests.” In the proposed update to National Coverage Determination (NCD) 210.3, CMS seeks to increase access to colorectal cancer screenings, in part by authorizing coverage for non-invasive biomarker colorectal cancer screening tests once every three years when ordered by a PA, physician, nurse practitioner, or clinical nurse specialist.

AAPA broadly approves of efforts to increase access to screenings that might provide early detection of treatable illnesses and applauds the agency’s actions to date. The importance of regular screenings to detect colon cancer is well documented. We note that CMS has proposed many provisions in recent Physician Fee Schedule rules that have sought to expand coverage for colorectal screenings. However, AAPA suggests that there remain other barriers to colorectal cancer screenings that, when removed, would further increase access to these critical services.

Expanded Authorizations Under the NCD

AAPA is pleased that CMS is seeking to expand access to essential colorectal screening services by authorizing qualified health professionals, who are currently prohibited from doing so, to order them. Current policy under NCD 210.3 re: Colorectal Cancer Screening Tests, includes physician-centric language regarding blood-based biomarker tests. The proposed authorization in this decision memo would modify the NCD to expand who may order RNA-based stool tests, DNA-based stool tests, and DNA-based blood tests to include other non-physician health professionals such as PAs.

This expanded authorization will improve screening and detection of colorectal cancer by allowing patients treated by PAs to obtain authorization in a more timely manner, promote disease prevention by opening the opportunity for screening to beneficiaries seen exclusively by PAs, reduce the administrative burden of requiring an otherwise unnecessary physician order for patients cared for by PAs, and could improve program integrity by reducing waste if patients do not have to have a separate encounter with a physician to obtain an order that their treating PA could otherwise provide. Such additional visits with a physician to order the screening may be costly to the beneficiary through an additional co-pay requirement, to the Medicare program through an additional unnecessary encounter, and to the physician and PA through reduced efficiency and effectiveness of team-based care delivery.

Remaining Restrictive Policy Regarding Ordering of Cancer Screenings

While AAPA applauds and supports CMS’s proposed authorization for PAs to order non-invasive colorectal cancer screening tests, we note that such an authorization is not extended to fecal occult blood tests (FOBT). Language in the NCD being revised, NCD 210.3 re: Colorectal Cancer Screening Tests, continues to use physician-centric language regarding the ordering of FOBT. AAPA notes that FOBT is also non-invasive and thus should receive similar authorization.

Further, the physician-centric language regarding FOBT in NCD 210.3 remains in direct contradiction to sections of the CFR. Specifically, 42 CFR §410.37(b) authorizes payment of FOBT ordered by PAs, stating: “Condition for coverage of screening fecal-occult blood tests. Medicare Part B pays for a screening fecal-occult blood test if it is ordered in writing by the beneficiary's attending physician, physician assistant, nurse practitioner, or clinical nurse specialist.” In addition, 42 CFR §410.32(a)(2) authorizes payment generally for diagnostic laboratory tests ordered by PAs.

Moreover, CMS has acknowledged in NCD 210.3 that there is no evidentiary basis for limiting the ordering of non-invasive colorectal cancer screening tests to physicians. That rationale applies equally to FOBT. FOBT is a long-standing, non-invasive, low risk screening tool routinely incorporated into primary care workflows – settings in which PAs play a critical role in delivering preventive services to Medicare beneficiaries. PAs are extensively trained and fully qualified to assess colorectal cancer screening eligibility, counsel patients, and order appropriate screening tests. Allowing PAs to order FOBT would promote regulatory consistency, improve access to timely colorectal cancer screening, and advance CMS’s stated goals of expanding preventive care and early cancer detection without compromising patient safety or quality.

For these reasons, AAPA encourages that CMS update NCD 210.3 to authorize PAs to order RNA-based stool tests, DNA-based stool tests, and DNA-based blood tests (as proposed) and to revise the language to clarify that PAs are also authorized to order FOBT to conform with regulatory authority and agency goals.

Continued Regulatory Restrictions on Colonoscopies

While not under the purview of this NCD update, AAPA wishes to note that there remain other federal regulatory policies that limit access to appropriate colorectal cancer screenings. AAPA believes CMS should further increase access to colorectal cancer screening procedures by authorizing PAs to perform colonoscopies. This could be achieved by modifying current policy at 42 CFR § 410.37(f) that payment for colonoscopies only be made when performed by a doctor of medicine or osteopathy.

PAs have demonstrated the competency to perform colonoscopies, including biopsies when medically necessary, comparable to gastroenterologists in technical performance and quality metrics. Specifically, a study demonstrated that there were no significant differences in cecal intubation time or success, adenoma detection rate, or adverse reactions reported related to the endoscopic procedure up to 30 days post-colonoscopy for PAs compared to gastroenterologists. The researchers, who included five allopathic physicians, concluded that the findings support the use of trained PAs to perform average-risk screening colonoscopies, and that “this approach may be particularly relevant to underserved populations and resource-poor areas where access to and cost of colonoscopy limits the optimization of colorectal cancer screening strategies.”

The planned lowering and eventual removal of patient coinsurance for associated procedures , along with an increased demand from patients eligible for the procedure due to the initiation of these screenings earlier in life (from age 50 to 45), will place a serious strain on the availability of colonoscopy services. Accordingly, PAs represent a trained, ready, and available workforce poised to help meet the growing demand for these critical, life-saving colorectal cancer screening procedures.

Consequently, AAPA recommends that CMS modify 42 CFR § 410.37(f) to authorize PAs to perform colonoscopies.

Thank you for the opportunity to provide comments regarding the colorectal cancer screening NCD. AAPA welcomes further discussion with CMS regarding these important issues. For any questions you may have please do not hesitate to contact Sondra DePalma, AAPA Vice President of Reimbursement & Professional Practice, at sdepalma@aapa.org.

Sincerely,
Sondra M. DePalma, DHSc, PA-C, DFAAPA
Vice President, Reimbursement and Professional Practice
American Academy of Physician Associates

References:
1. U.S. Food and Drug Administration. Colorectal Cancer: What You Should Know About Screening. March 28, 2024. https://www.fda.gov/consumers/consumer-updates/colorectal-cancer-what-you-should-know-about-screening
2. U.S. Preventive Services Task Force. Colorectal Cancer: Screening. May 18, 2021. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/colorectal-cancer-screening
3. Fejleh, M. Phillip MD; Shen, Ching-Chieh MD; Chen, Jacqueline MD; Bushong, Joseph A. PA-C; Dieckgraefe, Brian K. MD, PhD; Sayuk, Gregory S. MD, MPH. Quality metrics of screening colonoscopies performed by PAs. Journal of the American Academy of Physician Assistants 33(4):p 43-48, April 2020. | DOI: 10.1097/01.JAA.0000657192.96190.ab https://journals.lww.com/jaapa/Fulltext/2020/04000/Quality_metrics_of_screening_colonoscopies.8.aspx

Less

Thank you for sharing your work and asking for public comment.

Colon cancer is the quintessential example of a common cancer disease that is *preventable*, not just identifiable early.
In our busy endoscopy unit, every day we find advanced adenomas (AAs), remove them, and prevent a potential cancer.

The data shared overlooks the great importance providers and patients place on prevention.
I argue that the point sensitivity for AAs (and also low risk adenomas) must be included in grid format, beside the data for colon cancer, for each of the commercially-available stool-based tests, blood-based test(s), and optical colonoscopy.

Without this information, the healthcare community is likely to miss the key data that would help them make their best choice for screening *and* prevention.

Patients want prevention every 10 years, not early detection.
Including the data on AAs will aid in well-informed decision making between patients and their doctors.

Thank you for taking the time to review my comment.
Brian Levitt, MD

Less

Thank you for the opportunity to comment on the CMS update regarding coverage for non-invasive colorectal cancer (CRC) biomarker tests.

Having advocated for timely screening and effective testing for over 20 years, I have seen both the benefits of medical advancement and the tragic consequences of diagnostic/screening confusion. The primary goal of CRC screening is to identify and remove precancerous polyps, leading to prevention or stage-one detection, where the cure rate is 90%.

Currently, blood-based tests do not meet the performance threshold for effective precancer detection. My concern is that if these tests are offered under the current guidelines recommended tests, patients may opt for the most convenient method without understanding its limitations. This could result in missed diagnoses and an increase in Stage 4 cases.

While blood-based tests have a role for patients who refuse all other options, they must not be categorized alongside more effective screening tools. It is vital that we are transparent about what these tests miss and avoid overstating the capabilities of technology that is not yet fully realized. I look forward to the day blood-based test can do it all.

Thank you for your time and consideration.

Sincerely,

Anita Isler

Less

As a physician I frequently read in the medical literature that colon cancer is being diagnosed more frequently especially in younger adults. Furthermore I am aware of the hesitancy of this group to agree to undergo a colonoscopy to look for evidence of early cancer. To me Colosense makes perfect sense as an alternative for early cancer screening. The ease of utilizing this test provides a favorable option to individuals and its RNA basis provides more accurate results than the current stool tests on the market.
Furthermore the cost of a stool test such as Colosense is far less than a colonoscopy as an initial screening procedure.

Less

Colorectal cancer (CRC) screening should prioritize the detection of advanced precancerous lesions (advanced adenomas and advanced serrated lesions, including villous histology and high-grade dysplasia), as these are the principal targets for colonoscopic identification and removal and the basis of CRC prevention. Screening metrics should elevate sensitivity for these high-risk lesions alongside CRC sensitivity, as cancer detection alone does not reflect preventive impact. In two-step screening, advanced adenoma lesion detection should serve as a core metric to guide referrals to colonoscopy and overall program effectiveness.
Blood-based screening tests are an important and promising option, but their use and labeling should reflect current performance. Current data demonstrate substantially lower sensitivity for advanced precancerous lesions (~10–13%) compared with FIT (~20–30%) and multitarget stool DNA testing (~40–45%), limiting their effectiveness as prevention tools. By analogy, a cervical cancer strategy that detects cancer but not precancerous lesions would not achieve its preventive potential. Accordingly, blood-based tests are best positioned and labeled as third-tier noninvasive options for individuals unwilling to undergo structural or stool-based genomic screening. National guidelines should prioritize CRC prevention over detection, while maintaining access to blood-based testing as an emerging option and continuing to evaluate it through real-world evidence.
A shift away from established two-step screening strategies toward primary reliance on blood-based testing risks diminishing the preventive impact of CRC screening at a time when the ability to detect and remove precancerous lesions, thus preventing CRC, is greater than ever.

Less

I submit this comment as a regulatory attorney (and a program beneficiary). 2026 will mark my 50th anniversary representing clients regulated by FDA, CMS and other federal and state healthcare agencies. My interest in non-invasive CRC screening diagnostics can be found in the end note.*

Comment

In evaluating the NCD for ColoSense CMS must apply the “reasonable and necessary” standard for Medicare beneficiaries. (Social Security Act, Section 1862(a)(1)(A)) There are two criteria of this standard that merit consideration by CMS in its deliberations:

1. PMA Approval.

While FDA approval is not a prerequisite to be eligible for an NCD, the findings of FDA in the PMA process deserve scrutiny, specifically related to the areas of sensitivity and specificity for which CMS requested input. To that end, the Summary of Safety and Effectiveness for ColoSense) (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P230001) should be carefully reviewed with a particular focus on two of FDA’s conclusions that CMS must consider in its review:

a. “[D]ue to the small number of CRCs in [the ColoSense] 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.”

b. “Due to the uncertainty regarding the CRC sensitivity of this device, additional investigation in the form of post-approval studies are required to confirm the performance of this device for CRC detection….”

There are differing standards between FDA approval of PMAs and CMS’s determining that a device is eligible for an NCD. FDA determines whether a device is safe and effective, without a statutory requirement to consider comparative effectiveness to existing modalities. Unlike FDA, the review standard of CMS, discussed below, includes comparative safety and efficacy.

2. “At Least as Beneficial as an Existing and Available Medically Appropriate Alternative” — CMS Reasonable and Necessary Standard

To authorize an NCD for ColoSense, CMS must find that the diagnostic is “reasonable and necessary.” One of the long-recognized factors in that determination by CMS is a required finding that ColoSense is “at least as beneficial as an existing and available medically appropriate alternative.” (Medicare Program Integrity Manual (Pub. 100-08, Chapter 13, Section 13.5.4) Inasmuch as ColoSense is a stool-based CRC diagnostic, the appropriate “alternative” comparators for the “at least as beneficial” test are Cologuard and Cologuard Plus.

FDA’s PMA approval history includes the agency a) concluding that up to 24.3% of CRC cases could be missed by ColoSense, and b) expressing uncertainty regarding the CRC sensitivity of ColoSense. FDA’s concerns led the Agency to require the following Precaution in the PMA approved labeling for ColoSense (https://colosense.com/risk-information/ and https://colosense.com/ifu/ (both accessed 10/12/2025)):

"Precaution: No colorectal cancer screening test is perfect. ColoSense may produce false negative or false positive results. Based on the clinical validation data for ColoSense, with 25/27 colorectal cancers from typical average-risk patients identified (92.6%) and with a 95% two-sided confidence interval lower bound of 75.7%, there is a chance that as many as 24.3% of patients with colorectal cancer may be missed by this test, given the current data available."

Based on its sister agency’s findings, to which CMS should afford deference, there is simply no way that CMS can make the determination that Colosense is at least as effective or beneficial as the “available medically appropriate [stool-based] alternatives”: Cologuard or Cologuard Plus.

:

Closing References

In closing, I also include by reference

• the comments on the sensitivity and specificity of ColoSense in this docket filed by John Kisiel, Professor of Medicine at the Mayo Clinic.
• A 10/1/25 publication in the Journal of the National Cancer Institute entitled “Evaluating benefit-to-burden ratios of the established and emerging colorectal cancer screening strategies” (https://academic.oup.com/jnci/article/117/12/2653/8269297) describing a modeling approach for CRC non-invasive diagnostics consistent with the US Preventive Services Task Force (USPSTF) methodology. (CMS should consider incorporating benefit-to-burden ratios in its consideration of this NCD).

Respectfully submitted,

Richard O. Wood
rowood@woodburditt.com

* End Note — Disclosure of Interest: As stated above, I am a Founding Member and now Of Counsel with the Wood Burditt Group, a firm concentrating its practice in regulatory law, including FDA, CMS and other health regulatory agencies. Neither I, nor other members of the firm, have performed legal/regulatory work for Exact Sciences, Guardant Health, or to our knowledge, any firm involved with non-invasive CRC diagnostics.

My interest in CRC screening generally, and non-invasive methods specifically, stems from personal experience. I have lost three close friends in recent years to CRC; and I have had two close friends experience perforations during colonoscopies.

I am also a member of the Chicago Investors Society (CIS), a Chicago-based investment club for which I am responsible for recommending/following drug/medical device stocks. Both I personally and CIS owned shares in Exact Sciences prior to its recent purchase by Abbott. At times I have personally owned shares in Guardant Health.

4

5 https://doi.org/10.1093/jnci/djaf209 ; https://doi.org/10.1093/jnci/djaf266 (Relevant Correspondence)

Less

I appreciate CMS’s efforts to update coverage for CRC non-invasive biomarkers tests. This is an important decision that could have a large impact on CRC screening, incidence and mortality.

First, the decision does not address detection of advanced precancerous polyps, thereby framing screening tests as cancer detection tools rather than preventive screening tests. Detection of advanced adenomas is central to CRC prevention. Absent such standards, clinicians—particularly those less familiar with test performance differences—may preferentially order blood-based tests due to convenience, potentially undermining prevention, and increasing risk of CRC incidence and mortality. Further, The American Gastroenterological Association (AGA) and the American Society of Gastrointestinal Endoscopy both recommend against the routine use of blood-based screening tests in CRC screening. The AGA Colorectal Cancer Screening Working Group concluded, “A new liquid biopsy test that is not as effective as current screening tests, should not be recommended to screen-eligible individuals as a replacement for current screening tests.” This should be included in the recommendations from professional societies and in the CMS coverage decision.

Second, screening intervals must be considered when evaluating test performance. An annual test with moderate sensitivity is not comparable to a test with low sensitivity performed every three years. Longer intervals for tests that primarily detect later-stage cancers and do not identify precancerous lesions will increase the risk of interval cancers. CMS should consider screening intervals in their decision.

Less

CMS has historically prioritized evaluation of emerging screening tests against established comparators. In the setting of noninvasive colorectal cancer screening, FIT has served as the benchmark that new tests are expected to meet or exceed. Importantly, comparisons between emerging tests and FIT should be conducted within the same patient sample, because it is well established that test performance can vary across different study populations, thereby limiting generalizability. With the exception of mt-sDNA and next-generation mt-sDNA, as noted in other comments, emerging noninvasive biomarker tests have not directly compared their performance with FIT in the same patient cohort. This makes it exceedingly difficult to accurately assess relative performance, justify coverage decisions, and provide patients with well-informed guidance.

In reviewing the criteria currently being considered for emerging noninvasive test performance, I am concerned that there is no requirement for comparative performance against an established noninvasive screening test. Equally concerning is that the proposed criteria appear to focus only on sensitivity and specificity thresholds for colorectal cancer. Given that coverage for these proposed noninvasive biomarker screening tests would be limited to once every three years, failing to consider sensitivity and specificity for advanced colorectal neoplasia could place patients at significant risk. There is substantial evidence showing that delays in colonoscopy after a positive FIT are associated with higher colorectal cancer mortality and more advanced stage at diagnosis (1). In contrast, screening tests with higher sensitivity for advanced precancerous lesions, such as mt-sDNA and next-generation mt-sDNA, offer greater potential for cancer prevention, earlier detection, and cost savings because of their superior test performance (2). This was further supported by our microsimulation modeling, which compared the performance of FIT, next-generation mt-sDNA, blood-based testing, and multitarget stool RNA strategies (3). In our simulation blood-based and multitarget stool RNA strategies were not efficient for primary screening

In summary, emerging noninvasive screening tests should be required to demonstrate direct comparative performance against established noninvasive screening options. In addition, test performance criteria should include not only sensitivity and specificity thresholds for colorectal cancer, but also thresholds for advanced precancerous lesions.

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC8096663/
2. https://pubmed.ncbi.nlm.nih.gov/41517291/
3. https://pubmed.ncbi.nlm.nih.gov/41027593/

Less

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

RE: Proposed Decision Memo for Screening for Colorectal Cancer-Non-Invasive Biomarker Tests CAG-00440R.

Dear Ms. JoAnna Baldwin,

On behalf of the Association for Molecular Pathology (AMP), we thank you for the opportunity to comment on the proposed decision memo: Screening for Colorectal Cancer-Non-Invasive Biomarker Tests CAG-00440R.

AMP is an international medical and professional association representing approximately 3,100 physicians, doctoral scientists, and medical laboratory scientists (technologists) who perform or are involved with laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Membership includes professionals from academic medicine, hospital-based and private clinical laboratories, the government, and the in vitro diagnostics industry.

AMP appreciates that CMS recognizes the value of non-invasive biomarker tests in screening for colorectal cancer. We do have some concerns regarding the proposed coverage policy. As such, AMP would like to provide comments on the following proposed coverage criteria:

The test must demonstrate performance characteristics that meet EITHER Criteria 1, a sensitivity of greater than or equal to 90% and a specificity greater than or equal to 87%, OR Criteria 2, a sensitivity of greater than or equal to 79% and a specificity of greater than or equal to 90% in the detection of colorectal cancer compared to the recognized standard (accepted as colonoscopy at this time), based on the FDA labeling.
AMP has significant concerns with CMS dictating sensitivity and specificity requirements in any coverage policy and believes it is not the role of the Coverage and Analysis Group at CMS to evaluate tests’ sensitivity and specificity requirements in order to determine a test’s medical usefulness. Diagnostic performance, such as test sensitivity and specificity, should be determined by FDA in the event the test is an in vitro diagnostic test kit, or under the CLIA program if the test is a laboratory developed testing procedure. The Coverage and Analysis Group dictating performance standards is outside its mandate to evaluate the clinical utility of a service and even more concerning, staff lack the scientific expertise to establish performance characteristics. This should be left to agencies and divisions with those oversight authorities, i.e. FDA and the CLIA Program.
If CMS insists upon including the specificity and sensitivity within the coverage document, AMP insists upon using the positive predictive value (PPV) and the negative predictive value (NPV) in its stead. The PPV and NPV include the prevalence of a disease within its calculations and therefore is more meaningful for screening due to the context of real-world performance.
FDA market authorization with an indication of colorectal cancer screening

Requiring FDA market authorization unreasonably narrows patient access to clinically useful blood-based colorectal cancer screening tests, and as drafted, this policy eliminates any possible path for tests without FDA authorization; it states that “All other indications for colorectal cancer screening not otherwise specified in the Act and regulations, or otherwise specified above, remain nationally non-covered.” Non-invasive biomarker screening tests are a growing and dynamic type of testing. To ensure that clinically and analytically-validated colorectal screening tests are recognized by Medicare as a viable, covered service for beneficiaries, CMS should provide coverage pathways within the NCD for other tests, such as those performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.

The CMS Coverage and Analysis Group has existing policies that support coverage pathways for laboratory developed testing procedures and clarification that such tests do not require FDA authorization. Specifically, the National Coverage Determination (NCD) for Next Generation Sequencing (NGS) (90.2) provides coverage pathways for both FDA-approved or –cleared tests as well as laboratory developed testing procedures, the latter via promulgation by Medicare Administrative Contractors (MACs)1.We ask that the NCD add the language below to include coverage available via MACs:

Medicare Administrative Contractors (MACs) may determine coverage of Non-invasive Biomarker Tests as a diagnostic laboratory test for patients every one- to – three years when the test is performed in a CLIA-certified laboratory, meeting test performance criteria in b.4. when ordered by the physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient, and when the patient meets the Patient Criteria in Section B.a.

Thank you again for the opportunity to review and provide comments on this proposed decision memo. AMP appreciates CMS’ efforts to ensure access to medically necessary testing and provide coverage for testing more broadly. We welcome the opportunity to work with you and should you have any questions or require additional information, please direct your correspondence to Samantha Pettersen, AMP Manager of Public Policy and Advocacy, at spettersen@amp.org.

Sincerely,
Jay Patel, MD MBA
Chair of Economic Affairs Committee,
Association for Molecular Pathology

Less

Dear CMS,

As the founder of Cheeky Charity, an organization dedicated to colorectal and anal cancer advocacy with a focus on the LGBTQ+ community, I write in strong support of the proposed National Coverage Determination to expand Medicare coverage of non-invasive biomarker screening tests for colorectal cancer. We urge CMS to finalize this NCD without delay.

CRC remains the second leading cause of cancer death in the United States and the number one cause of cancer death for people under 50. Despite effective screening tools, roughly one in three eligible adults remain unscreened. Among LGBTQ+ individuals, screening rates are even lower due to stigma, discrimination in healthcare settings, discomfort with invasive procedures, and a lack of culturally competent provider recommendations.

This is why expanding coverage for validated non-invasive tests matters so much. Stool-based screening technologies - including multi-target stool tests that meet appropriate sensitivity and specificity thresholds - give patients and providers more tools to match the right test to the right patient. For communities that face real barriers to colonoscopy, including LGBTQ+ individuals, rural populations, and communities of color, these are not second-best options. They are often the difference between getting screened and not getting screened at all.

We support the proposed performance criteria and offer the following points for CMS's consideration as it finalizes this NCD:

1. Patient-centered test selection saves lives. Different patients face different barriers. Non-invasive options that can be completed at home reduce obstacles for patients who avoid or delay colonoscopy due to discomfort, transportation challenges, time off work, or distrust of the healthcare system. The more high-quality options available, the more people we reach.

2. The 80% goal demands new approaches. The National Colorectal Cancer Roundtable's "80% in Every Community" goal will not be achieved through colonoscopy alone. Medicare coverage of validated non-invasive tests is essential to closing the screening gap, particularly in underserved communities where colonoscopy access is most limited.

3. Equity must be central to coverage decisions. LGBTQ+ patients, racial and ethnic minorities, rural populations, and low-income communities are disproportionately underscreened. Expanding the menu of covered, accessible screening options is itself an equity intervention.

4. Performance standards should reflect the full value of screening. CRC screening's unique power lies not just in detecting cancer but in finding and removing precancerous polyps before they become cancer. As CMS considers the broader landscape of non-invasive test coverage - particularly for emerging blood-based biomarker tests - we encourage the establishment of meaningful performance benchmarks for advanced adenoma detection.

We appreciate CMS's work to modernize coverage and expand access to effective screening. Finalizing this NCD will help ensure that Medicare beneficiaries have access to the range of validated tools needed to drive screening rates up and cancer deaths down.

Thank you for the opportunity to comment.

David Russo (he/him)
Executive Director, Cheeky Charity

Less

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) Proposed Decision Memo (CAG-00440R) 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 91 guidelines detailing the sequential management decisions and interventions across 237 algorithms that currently apply to 97 percent of cancers affecting patients in the United States. More than 2,000 panel members participate in guideline development. In 2025, there were more than 18.4 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 248 total version updates across all guidelines in 2025.

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 incorporating NCCN Guidelines or nationally recognized clinical practice guidelines, as a coverage mechanism within the policy. Incorporating such guidelines would help ensure that coverage policies remain current and adaptable over time as the evidence supporting colorectal cancer incidence and optimal screening evolves, while supporting access to optimal current evidence-based care for beneficiaries.

Usage of NCCN CRC Guidelines to Inform the NCA
NCCN thanks CMS for referencing NCCN Guidelines throughout the Screening for Colorectal Cancer-Non-Invasive Biomarker Tests NCA Proposed Decision Memo. NCCN appreciates the opportunity to provide further insight into the current NCCN Guidelines recommendations in relation to CRC screening tests. NCCN will organize our comments across each section of the decision memo in relation to NCCN content.

Evidence- Based Guidelines
Within the proposed decision memo, CMS states:
“In 2025, the NCCN published an update (Version 2.2025 – June 24, 2025) to their 2024 CRC screening guidelines and added mt-sRNA and bb-cfDNA tests as recommended stool-based and blood-based, respectively, colorectal cancer screening strategies, in addition to the currently NCCN recommended mt-sDNA-based testing, for average risk individuals (NCCN, 2025).”

NCCN appreciates CMS’s accurate reference to the NCCN Guidelines for Colorectal Screening. The Panel recognizes mt-sRNA as an emerging option for CRC screening and supports its inclusion as a potential screening modality in individuals at average risk. However, the Panel cautions that data to help determine adherence to/participation rates of screening, as well as how mt-sDNA testing may fit into an overall screening program are limited. The Panel also acknowledges the inclusion of bb-cfDNA as an additional screening modality for individuals who are not willing to undergo colon cancer screening through another modality.

CMS Coverage Analysis
Within the proposed decision memo, CMS states:
“The 2025 NCCN Guidelines recommend screening for individuals age 45 years to 75 years (NCCN, 2025). They further recommend that the decision to screen between ages 76–85 years should be individualized and include a discussion of the risks and benefits based on comorbidity status and estimated life expectancy (NCCN, 2025).”

NCCN thanks CMS for once again accurately referencing NCCN Guidelines, which outline the Panel’s current age-based screening recommendations.

Within the proposed decision memo, CMS also states:
“In the NCCN Colorectal Cancer Screening Clinical Practice Guidelines (NCCN, 2025), how specificity was defined depended on how it was reported in each test’s publication. For instance, “the specificity for nonneoplastic findings with next-generation mt-sDNA” was reported (NCCN, 2025). However, for the mt-sRNA test, “the specificity for no lesions on colonoscopy” was reported (NCCN, 2025).

NCCN respectfully provides the following clarification. The reported specificity values on the Screening Modality and Schedule table (CSCR-A 2 of 7) in NCCN Guidelines are from respective publications. However, for mt-sRNA, the specificity for advanced adenoma is reported. For mt-sDNA test, specificity for both advanced neoplasia and advanced adenoma are reported based on the New England Journal of Medicine article, Multitarget stool DNA Testing for Colorectal-Cancer by Imperiale TF, et al. rather than the next-generation mt-sDNA study.

Additional references to NCCN Guidelines regarding definitions include:
“The NCCN CRC Screening Clinical Practice Guidelines glossary (NCCN, 2025), defined advanced precancerous lesion as AA or sessile serrated polyp (SSP) / SSL = 1 cm and / or containing dysplasia.”

This statement accurately reflects the definition provided in the NCCN Guidelines glossary.

Lastly, within this section CMS states:
“In 2025, the National Comprehensive Cancer Network (NCCN) published an update (as Colorectal Cancer Screening, Version 2.2025 – June 24, 2025, NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines]) to their 2024 colorectal cancer screening guidelines and added mt-sRNA and bb-cfDNA tests as recommended stool-based and blood-based, respectively, CRC screening strategies, in addition to the currently NCCN recommended mt-sDNA-based testing, for average risk individuals (NCCN, 2025). For mt-sDNA and mt-sRNA testing, the recommended frequency is for every three years for average risk for CRC individuals (NCCN, 2025). For bb-cfDNA-based testing (or BBB test for this proposed decision memo), the recommended frequency is testing every three years for average risk individuals, but the NCCN only recommends this test for individuals who are not willing to undergo colon cancer screening through another modality (NCCN, 2025).”

As previously noted, the updated NCCN Guidelines include mt-sRNA and bb-cfDNA tests as recommended stool-based and blood-based screening modalities. A rescreening interval of every 3 years has been suggested for both. NCCN further reiterates that bb-cfDNA- based testing is only recommended for individuals who are not willing to undergo colon cancer screening through another modality. Screening decisions should be individualized and include a discussion with patients about the risks and benefits of each modality.

Appendices
In “Table 3. Professional guidelines for CRC screening in asymptomatic average-risk adults,” in the NCCN section, CMS includes flexible sigmoidoscopy in the “Screening/Rescreening timeline if negative or no polyps (with any modality)” column with a recommended interval of 5-10 years. The most recent NCCN Guidelines (Version 2.2025) include only a 5-year interval. There are alternative strategies that have been recommended with flexible sigmoidoscopy, including flexible sigmoidoscopy every 10 years combined with annual FIT.

NCCN thanks CMS for preparing the Screening for Colorectal Cancer-Non-Invasive Biomarker Tests NCA proposed decision memo. 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. In the United States, CRC is the third most commonly diagnosed cancer and the second most common cause of cancer death. Approximately 158,850 new cases of CRC, and 55,230 related deaths are estimated for 2026. (11)

NCCN supports efforts that increase access to evidence-based comprehensive care, including appropriate screening. We appreciate the opportunity to comment on the Screening for Colorectal Cancer-Non-Invasive Biomarker Tests NCA proposed decision memo (CAG-00440R). NCCN is happy to serve as a resource and looks forward to working together to ensure Medicare beneficiaries have 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. Siegel, R. L., Wagle, N. S., Star, J., Kratzer, T. B., Smith, R. A., & Jemal, A. (2026). Colorectal cancer statistics, 2026. CA: A Cancer Journal for Clinicians, 76(2). https://doi.org/10.3322/caac.70067

Less

I am on Medicare since last several years and 'have subjected myself to traditional Colonoscopy to screen for any colon abnormalities, including cancer. I find this traditional procedure harsh, especially the prep to rinse the colon [PHI Redacted]. Second, traditional procedure is expensive for a payer and even a patient's copay is not a small change. When the proven science is advancing by leaps and bounce and non-invasive Biomarker Tests for screening Colorectal Cancer is a product of such advancement, I highly endorse this inexpensive test both as a scientist and Medicare beneficiary.

Less

To Whom It May Concern at the Centers for Medicare & Medicaid Services:

I am submitting this comment in support of ensuring that any revised coverage criteria for colorectal cancer (CRC) screening explicitly address the detection of precancerous lesions.

I write [PHI Redacted] as someone who understands the clinical stakes of this policy question. [PHI Redacted] That is not a hypothetical benefit. That is the documented, primary mechanism by which CRC screening saves lives.

The proposed changes to CMS coverage criteria concern me for a specific and evidence-based reason: they do not establish any performance standards for the detection of precancers or precancerous lesions. This is a critical omission.

Approximately 80% of the life-saving benefit of colorectal cancer screening comes not from detecting cancer that has already formed, but from detecting and removing the polyps that would have become cancer. Screening criteria that focus exclusively on cancer detection — while ignoring precancer detection — are therefore measuring the wrong outcome. They evaluate tools based on their ability to find a disease that screening should, ideally, prevent.

"The current generation of blood-based CRC screening tests, while valuable for expanding access to those who might otherwise decline screening, demonstrate a critical and well-documented limitation: they cannot meaningfully detect precancerous lesions. Guardant Health's Shield test — currently the only FDA-approved blood-based CRC screening test — has a clinically confirmed advanced adenoma sensitivity of just 13%, meaning it misses 87 out of every 100 precancerous lesions that a colonoscopy would find. This is not a disputed claim; it appears in the test's own FDA-approved labeling as a stated precaution. By contrast, stool-based tests like Cologuard detect both cancer and precancerous polyps. Placing these two categories of tests under the same coverage framework — without any precancer detection standard — creates a misleading equivalence that could leave patients with a false sense of protection."

Furthermore, blood-based tests currently carry the highest cost among non-invasive CRC screening options — making them the least beneficial option at the greatest expense to Medicare and its beneficiaries.

I urge CMS to:
1. Require that coverage criteria for non-invasive CRC screening tests include minimum performance thresholds for the detection of advanced adenomas and precancerous polyps — not only invasive cancer.
2. Ensure that beneficiaries and their physicians are clearly informed of meaningful differences in precancer detection rates across available screening modalities.
3. Avoid creating a policy framework in which cost and convenience are inadvertently rewarded over clinical effectiveness.

[PHI Redacted] I would ask CMS to ensure that the coverage criteria it establishes reflect the full scope of what screening is meant to accomplish: not just finding cancer, but preventing it.

Thank you for considering this comment.
Erika Hanson Brown, CEO
ONE CANCER PLACE
Denver, CO 80203

Less

Support Colorectal Cancer Non Invasive Bio Marker tests , stress the importance of data providing evidence based information with trials, systematic reviews clinical guidelines, with real world evidence to provide appropriate screening and testing of patients. Especially current release of data indicating lower age group 20-40 with colon cancer leading cause of death, need appropriate screening for earlier diagnosis and treatment, as well as education to patients for risk reduction , to promote better outcomes. Biomarker testing with sensitivity and specificity thresholds meeting current standards with appropriate FDA and CLIA certification.

Less

The American Gastroenterological Association (AGA) appreciates the opportunity to comment on the proposed changes by the Centers for Medicare and Medicaid Services (CMS) to National Coverage Decision (NCD) 210.3, “Screening for Colorectal Cancer-Non-Invasive Biomarker Tests,” (CAG-00440R). 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.

We recognize the importance of informed choice by patients and healthcare providers regarding colorectal cancer (CRC) screening test options, and we commend CMS for their efforts to devise a unified approach for the evaluation of all CRC non-invasive biomarker tests.

The AGA is deeply concerned about expanding coverage to current blood-based CRC screening tests as CMS lacks the ability to handle these tests as a second-line option. We understand the challenges involved in assessing test sensitivity for advanced precancerous lesions, and the lack of uniformity in the literature, as laid out in CAG-00440R. But we believe that this critical parameter cannot be ignored in a coverage determination.

CMS recognizes this critical issue by stating in CAG-00440R, Section IVB, Coverage Analysis: “In a scenario where a test does not detect large adenomas or early cancer as well as currently covered tests, there may be detriments to patients since the opportunity for cancer prevention may have been missed or cancer treatments may be initiated at a later stage when health outcomes may be reduced.” Despite recognizing this critical dimension, CMS does not account for it in the coverage determination in CAG-00440R.

The goal by CMS to define a single approach towards the evaluation of all non-invasive biomarker tests for CRC (stool-based, blood-based, or other) is laudable. However, we believe that approach must consider explicitly the detection of advanced precancerous lesions. Specifically:
1) The current generation of blood-based CRC screening tests has poor sensitivity for Stage I colorectal cancer and for advanced precancerous lesions. Substituting these tests for the alternatives is expected to worsen colorectal cancer incidence and mortality rates.
2) As an informative illustration, suppose a new stool test matches the sensitivity and specificity for colorectal cancer of current fecal immunochemical test (FIT) or FIT-DNA or FIT-RNA, but does not detect advanced precancerous lesions at a rate above chance. Under CAG-00440R, such a test would be covered. It would not make sense to offer such a test as an alternative to existing tests.

We urge CMS to reconsider how it incorporates into its coverage determination what is known about the importance of advanced precancerous lesion detection.

We understand that beneficiaries may specifically request a blood-based test and could refuse all other CRC screening test options. We note that CMS does incorporate shared decision-making that includes the patient in some of its NCDs; ideally, that approach could be incorporated into this coverage decision. We understand that this is an unconventional application of the way CMS incorporates shared decision-making in NCDs, but we believe it is important that patients are provided with education to support selection of a high-quality, covered screening test and completion of the full screening process.

If CMS expands coverage to blood-based tests, it should only do so, in the context of shared decision-making, for beneficiaries who have been informed about the available screening tests and the inferiority of current blood-based tests; who decline colonoscopy or current FIT, FIT-DNA or FIT-RNA options; and who express an understanding that a follow-up colonoscopy is indicated if a blood-based CRC screening test returns an abnormal result. If future generations of blood-based CRC screening tests have sensitivity for advanced precancerous lesions that is comparable to that of existing non-invasive tests, then such a second-line designation should no longer apply.

We understand this is a difficult and complex decision. We urge CMS to use all available tools, including the incorporation of shared decision-making, to keep Medicare beneficiaries healthy and not compromise their safety.

Less

I appreciate the effort that CMS has taken to issue this updated coverage decision. I have a few suggestions and questions that may help to clarify the decision memo:
1. A limitation of offering only two discrete performance criteria is that this approach may exclude future tests with clinically favorable tradeoffs that do not exactly satisfy either Criterion 1 or Criterion 2. For example, a test with 88% sensitivity and 89% specificity could represent a reasonable balance of benefits and harms, yet fail both proposed thresholds. To better support innovation, CMS could consider an additional continuous sensitivity-specificity tradeoff criterion, or a defined range of acceptable paired thresholds, rather than only two fixed cut points.
2. Section E indicates that future studies should include comparison to FIT. However, the blood-based tests cited in the proposal do not appear to include direct head-to-head comparisons with FIT. Please clarify whether CMS intends to require direct within-study comparisons to FIT, or whether indirect comparisons to published FIT performance would be considered sufficient
3. In the justification for Criteria 1, I am concerned that the phrase ‘minimum upper bound’ could be misread as referring to a confidence-bound criterion for sensitivity performance, such as the upper or lower limit of a 95% confidence interval. In this section, however, the proposed 90% value is derived from averaging point estimates, not from interval estimation. I suggest revising this terminology to ‘higher sensitivity threshold’ or ‘minimum sensitivity requirement in Criterion 1, and clarifying that this refers to a point estimate for performance, if that is the intent.
4. The decision memo could be strengthened by more explicitly reinforcing the two-step nature of non-invasive colorectal cancer screening tests. Specifically, non-invasive tests should be presented to patients as requiring repeat testing at recommended intervals following a normal result, and diagnostic colonoscopy following any abnormal result. In addition, CMS may wish to encourage clinicians and health systems to monitor and optimize colonoscopy completion after abnormal non-invasive tests, given the importance of timely follow-up for achieving screening benefit. Finally, clarifying appropriate patient selection—for example, avoiding use of non-invasive tests among individuals who are up to date with colonoscopy-based screening or who have a history of precancerous polyps—would help reduce inappropriate screening and align with existing guideline recommendations
5. The decision memo provides limited information on how non-invasive test performance may vary by age. Although available data are often based on relatively small sample sizes, age-stratified performance estimates from pivotal studies of tests such as Cologuard Plus, ColoSense, Shield, and SimpleScreen could be summarized where available. In particular, providing information on potential variation in specificity by age would help clinicians better understand the likelihood of false-positive results and support more informed screening decisions.

Less

While I firmly believe in offering patients more choices in screening for colon cancer, the First Reconsideration on Screening for Colorectal Cancer-Non-Invasive Biomarker Tests (CAG-00440R) poses several issues that must be considered further.

First, the single clinical trial sensitivity and specificity estimates for several new tests (specifically mt-sRNA, and blood-based cfDNA (from Geneoscopy, Guardant, and Freenome)) are compared to historical values for fecal immunochemical testing (FIT) and not within-study FIT comparisons to an independent laboratory test. This design aspect directly led the FDA to state on Colosense and Shield (Summary of Safety and Effectiveness Data) that neither of these tests have shown superiority nor non-inferiority to FIT. Only Cologuard and Cologuard Plus have met this evidentiary standard.

Second, the NCD performance metrics do not emphasize the key preventive benefit from finding and removing screen relevant advanced pre-cancerous lesions (APL). This crucial principle has been shown as the major driver of clinical effectiveness by both observational (Winawer NEJM 1993) and microsimulation (eg., Ladabaum Gastroenterology 2024) studies. Blood-based CRC tests have not shown meaningful pre-cancer detection. Gastroenterology 2024;167:378–391 effectively demonstrates that blood-based CRC screening tests NEITHER at CMS thresholds, NOR Guardant Shield, meet the performance of current USPSTF-endorsed screening tests (Colonoscopy, FIT, Cologuard) in terms of CRC cases prevented or CRC deaths averted.

Accordingly, the AGA CRC Workshop panel (Lieberman Clin Gastroenterol Hepatol 2024) concluded that liquid biopsy CRC tests will “harm patient outcomes” if not meeting the performance of, and drawing participants away from, use of current screening tests. This issue has also drawn the attention of the National Comprehensive Cancer Network (NCCN Guidelines Version 2.2025 Colorectal Cancer Screening) who advise that blood-based cfDNA testing (eg. Shield) be recommended for individuals who would not be willing to undergo screening through another modality. CAG-00440R currently makes no such distinction.

In aggregate, these issues and many others are a sufficiently compelling indication to seek the input of a Medicare Evidence Development & Coverage Advisory Committee in the effort to bring a stronger consideration of the potential benefits and harms to the Medicare covered population and help ensure that we are moving forward, not regressing.

Less

I commend the forward-looking approach CMS has taken in this proposed decision. By clarifying coverage for non-invasive biomarker-based colorectal cancer screening tests and establishing transparent performance criteria, CMS is creating a policy framework that encourages both scientific innovation and broader patient access. Importantly, the inclusion of two performance criteria appropriately recognizes that different technological platforms may achieve high clinical value through distinct strengths in sensitivity and specificity. This balanced approach provides physicians with additional validated screening options while ensuring that future innovations can be evaluated through a clear and evidence-based pathway. I wrote a recent review on comparing these non-invasive tests (https://www.annualreviews.org/content/journals/10.1146/annurev-med-043024-032619).

Equally important, expanding coverage to include additional stool-based screening options has the potential to improve access for underserved populations who face practical barriers to completing existing tests. Some stool tests require patients to complete a fecal swab sampling step, which can present challenges for individuals with limited dexterity, physical disability, low health literacy, or other barriers that make multi-step collection procedures difficult to complete. The RNA (ColoSense) test does not require a fecal swab as part of the sampling process, which may make the test easier for some patients to successfully complete. Prior to this expansion, only a single molecular stool-based screening option was covered nationally, limiting flexibility for clinicians seeking approaches that best fit the needs of diverse patient populations. By recognizing additional validated technologies such as ColoSense, CMS is helping address practical access barriers and supporting screening strategies that can better reach populations historically underrepresented in colorectal cancer prevention. I strongly support CMS finalizing the proposed national coverage determination as written.

Less

I am a board-certified gastroenterologist and serve as the Medical Director of the New Orleans Research Institute within GI Alliance. Throughout my career, I have combined clinical practice with research as a principal investigator on numerous clinical trials aimed at improving the diagnosis and treatment of gastrointestinal diseases. My work has focused on advancing patient-centered research and helping translate emerging innovations into meaningful improvements in clinical care.

Within the proposed colorectal cancer screening National Coverage Determination, sensitivity and specificity thresholds are being used as practical indicators of a test’s expected ability to reduce colorectal cancer morbidity and mortality. In the absence of long-term outcomes data, which can take decades to accrue, this is a reasonable and widely accepted approach for evaluating emerging screening technologies.

While the national coverage analysis emphasizes differences in specificity among screening tests, it is important to recognize that a false positive primarily results in a diagnostic colonoscopy. Colonoscopy is not only a safe procedure but remains the gold standard for colorectal cancer detection and allows for immediate removal of precancerous lesions when present. Accordingly, the most critical drivers of improved colorectal cancer outcomes when screening with non-invasive tests are sensitivity for early-stage colorectal cancers and the ability to detect advanced adenomas. Highly sensitive noninvasive tests help navigate patients who need it most to diagnostic colonoscopy.

Several modeling studies based on established assumptions from the colorectal cancer screening literature have evaluated the expected clinical and economic impact of emerging biomarker-based screening tests. These analyses consistently demonstrate that tests with the performance characteristics observed in studies such as CRC-PREVENT (i.e., RNA-based stool tests like ColoSense) are projected to generate favorable outcomes in terms of colorectal cancer prevention, life-years gained, and cost-effectiveness. [1-3]

While modeling studies have inherent limitations, these analyses rely on the same fundamental parameters that CMS is appropriately considering in its evaluation, namely sensitivity and specificity thresholds for colorectal cancer detection. In my prior comment, I indicated that the Coverage and Analysis Group had historically incorporated similar modeling evidence when evaluating screening technologies, and doing so again would be consistent with prior policy decisions.

I believe the proposed policy appropriately reflects the conclusions of these modeling studies, creating a pragmatic and evidence-based approach to evaluating emerging colorectal cancer screening technologies. By defining performance thresholds grounded in established screening principles, CMS is ensuring that coverage decisions remain closely tied to expected population health impact.

From a health economics perspective, stool-based molecular screening tests have consistently demonstrated strong economic value compared with other molecular screening modalities. These tests can be deployed broadly, require minimal clinical infrastructure, and have the potential to reach individuals who might otherwise remain unscreened.

Expanding coverage to include additional stool-based technologies such as ColoSense may further improve the efficiency of colorectal cancer screening programs. ColoSense is offered at a lower cost than many existing molecular screening options, supporting broader access while maintaining strong clinical performance.

George E. Catinis, MD FACG

Medical Director, New Orleans Research Institute
Gastroenterologist, GI Alliance
Director, Department of Education, GI Alliance.
Adjunct Clinical Professor, William Carey University College of Osteopathic Medicine
Chairman, Board of Directors, GIANT LEAP Foundation.

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.

Less

CMS evidence review of the 8,920-patient pivotal study found that ColoSense showed high sensitivity for colorectal cancer, detecting 100% of Stage I cancers and demonstrating strong performance for advanced adenomas. The test’s overall metrics support proposed coverage, highlighting its potential role as an effective noninvasive screening option. Colorectal cancer remains a major public health issue, with screening gaps contributing significantly to mortality, particularly among adults under 50. Expanding access to patient-friendly screening tools like ColoSense is viewed as essential to reducing both incidence and death rates, and the test has gained recognition in clinical guideline frameworks. I especially think this will be important for patients that do not seek out more invasive care for colorectal cancer i.e. colonoscopy. It is a much cheaper and, of course, less invasive screening tool that a large segment of the population would agree to versus colonoscopy.

Less

Colosense has demonstrated high sensitivity for CRC detection, especially at Stage1.
Screening for CRC remains a top public health initiative. It is important that in addition to being patient friendly, the screening tool must also be highly sensitive. Colosense checks both of those boxes. Expanding access to a screening test like Colosense, makes the most sense for our Medicare population. The data supports it, patients have endorsed it, and now the commercial payors have as well. Colosense is the best available stool based test for detecting cancers at the earliest stage, and best indicator of needed follow up studies, thus resulting in more efficiency for the patient, and appropriate utilization for our clinicians.

Less

To Whom It May Concern,

I am writing to express strong support for the timely approval and reimbursement pathway for ColoSense as a noninvasive colorectal cancer screening modality.

As a practicing gastroenterologist, I am deeply invested in improving both screening adherence and early detection of colorectal neoplasia, particularly at the adenoma stage where intervention has the greatest impact on cancer prevention. In this regard, ColoSense represents a meaningful advancement over currently available stool-based screening options.

Key Clinical Considerations

1. Improved Adenoma Detection – A Critical Advantage
The most compelling differentiator for ColoSense is its enhanced sensitivity for advanced adenomas compared to existing stool-based tests such as Cologuard. While cancer detection is essential, the true value of screening lies in identifying and removing precancerous lesions before malignant transformation occurs.

Higher adenoma detection directly translates into:

• Reduced colorectal cancer incidence
• Fewer interval cancers
• Lower long-term healthcare costs

This represents a preventive advantage, not merely a diagnostic one.

2. Comparable Performance for Colorectal Cancer Detection
Equally important, ColoSense demonstrates consistent and comparable sensitivity for colorectal cancer detection relative to established tests like Cologuard. This ensures that adoption of ColoSense does not come at the expense of missing clinically significant malignancies.

Maintaining high cancer detection while improving adenoma detection is a clinically meaningful and rare combination that should be strongly prioritized.

3. Potential to Improve Screening Uptake
Noninvasive, stool-based testing remains a cornerstone for reaching patients who are unwilling or unable to undergo colonoscopy. Expanding the pool of effective screening options—particularly those with improved performance characteristics—will:

• Increase patient participation
• Reduce disparities in screening
• Enhance population-level outcomes

Public Health Impact

Colorectal cancer remains a leading cause of cancer-related mortality despite being highly preventable. Technologies that improve early detection and prevention simultaneously should be accelerated, not delayed.

Delays in approval and reimbursement risk:

• Slowing adoption of a superior screening modality
• Missing opportunities for early adenoma detection
• Ultimately contributing to preventable cancer cases

Conclusion

ColoSense offers a compelling advancement in colorectal cancer screening by combining:

• Improved adenoma detection
• Equivalent cancer detection performance
• A noninvasive, patient-friendly approach

Given these attributes, I strongly encourage the FDA to support timely approval and facilitate reimbursement pathways that allow patients access to this important innovation.

Thank you for your consideration and continued commitment to advancing colorectal cancer prevention.

Less

I support the proposed NCD to extend coverage of CRC screening to blood based assays with a suggested modification.

It is essential that CMS considers the role of congressionally mandated guideline bodies in coverage decisions. While granting initial coverage helps set the policy, continued coverage should be based on approval by inclusion in guideline such as the USPSTF. This aligns with proposed NCD language related to FDA's role and also ensures that rigorous or additional evidentiary standards are applied to assess net benefit of ongoing coverage.

Additionally, for new tests that are approved based on single studies, comparative studies of performance characteristics and/or limited evidence (such as blood-based assays) a provision should be included for review the NCD based on post-marketing studies as a condition for long-term coverage. This is particularly important for tests approved on the basis of comparative studies with colonoscopy. It is well documented that colonoscopy quality varies widely and industry sponsored studies have the potential to introduce additional biases.

CMS made the critical change to the definition of CRC screening to include follow-up colonoscopy. Adding language on the need for colonoscopy is critical. I recommend adding language such as "Non-invasive tests should only be performed in patients willing or able to undergo colonoscopy when positive or abnormal." This will connect this NCD more appropriately to potential NCQA metric on follow-up colonoscopy (Doubeni CA, et al. Am Fam Physician. 2025. PMID: 40961298)

Appreciate the opportunity to comment on this proposed changed to CRC screening

Less

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

Less

While colonoscopy remains the gold standard in colorectal cancer detection, offering multiple covered modalities will improve adherence to current quality reporting standards. By shifting the onus from the patient to the clinician to complete the test, completion of screening rates will also improve. Patients tend to fail to return stool testing kits, such as Cologuard or FOBT or do not collect specimens appropriately. With a blood-based test that can be collected in a clinical setting, we are likely to see improved rates of screening and early intervention. Additionally, patients who have comorbidities that inhibit utilizing colonoscopy as a screening modality would benefit from another option that is less invasive. We understand that the large majority of patients this will affect are not Medicare beneficiaries, however, commercial payors have historically followed suit when CMS determines coverage for certain tests and procedures. It would be in the best interest of Medicare beneficiaries nationwide for this test to fall as a covered service and also for the Quality Payment Program to recognize this as meeting the measure for Colorectal Cancer Screening.

Less

CMS currently covers non-invasive colorectal cancer (CRC) biomarker screening tests if they meet a performance threshold roughly equivalent to =74% sensitivity and =90% specificity for detecting colorectal cancer when compared with colonoscopy. In simple terms, the test must detect most cancers (few false negatives) while keeping the false-positive rate low enough that colonoscopies are not overused. Because any diagnostic test has a tunable threshold that shifts the balance between sensitivity (catching more cancers) and specificity (avoiding unnecessary colonoscopies), developers can move along a tradeoff curve: improving one usually worsens the other.

Nature of the tradeoff.

This relationship is the familiar receiver-operating characteristic (ROC) tradeoff. If a test is tuned to be very sensitive, it will capture more cancers but also send more patients to colonoscopy unnecessarily. If tuned to be very specific, it will avoid colonoscopies but miss more cancers. The acceptable balance depends on the clinical context of screening. For CRC screening, CMS is attempting to strike a balance between the harms of missed cancers (false negatives) and the harms and costs of unnecessary follow-up colonoscopies (false positives).

CMS proposal: two “bins.” (Uh-oh)

In the current proposed framework, CMS offers two acceptable combinations of sensitivity and specificity. A test qualifies if it satisfies either:

Criterion 1: sensitivity =90% and specificity =87%

Criterion 2: specificity =90% and sensitivity =79%

The intent is to allow some flexibility: one test might emphasize sensitivity, another specificity. However, mathematically these rules simply define two discrete points on the ROC plane. A test must land inside one of the two boxes to qualify.

Why a continuous equivalence frontier makes more sense.

In reality, diagnostic performance lies along a continuous tradeoff frontier, not two discrete bins. The two CMS criteria implicitly define the endpoints of that frontier. The acceptable combinations between them can be described with a simple linear relationship—essentially the line connecting those two CMS points:

Specificity = 1.115 - 0.273*(Sensitivity)
That's not an equation that should blow up anyone's brain.

This equation simply expresses the same tradeoff CMS already recognizes: as sensitivity increases, some decrease in specificity is acceptable, and vice versa. The mathematics involved is no more complicated than high-school algebra.

Using a continuous equivalence frontier would better reflect the underlying biology and statistics of screening tests. Developers designing a test typically target a particular operating point on the ROC curve, but the final result in a large, expensive pivotal trial may fall slightly above or below the intended sensitivity or specificity threshold due to sampling variation. Under a two-bin rule, a test could fail coverage because it lands between the bins—even if its overall diagnostic accuracy lies squarely between, and possibly above, the performance of tests that CMS approves. For example, a test with intermediate sensitivity and specificity might fall just outside both bins yet still lie well within the reasonable tradeoff frontier implied by the CMS endpoints.

Adopting an equivalence frontier would therefore provide a fairer and more scientifically coherent standard. It would preserve CMS’s intended balance between missed cancers and unnecessary colonoscopies while avoiding arbitrary exclusions of tests whose overall performance is comparable—or even superior—to those that happen to fall inside one of the discrete bins.

Less