Screening for Colorectal Cancer-Non-Invasive Biomarker Tests

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.

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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 either at CMS thresholds, or 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.

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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.

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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.

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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.

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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.

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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.

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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

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

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

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

However, the current language in NCD 210.3 still includes the following nationally non-covered indication:
(2) Screening computed tomographic colonography (CTC), effective May 12, 2009.
Additionally, the original non-coverage decision (CAG-00396N: Screening Computed Tomography Colonography (CTC) for Colorectal Cancer)³ remains publicly available in the Medicare Coverage Database.

To avoid confusion among providers and beneficiaries, we respectfully request that:
1. NCD 210.3 be updated to reflect the expanded coverage for CTC as outlined in CR 13939.
2. CAG-00396N be retired or removed to align with the current CMS policy and ensure clarity for stakeholders.

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

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

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

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

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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.

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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.

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