Screening for Colorectal Cancer-Non-Invasive Biomarker Tests

Non-invasive biomarker tests for colorectal cancer screening are covered according to the provisions in sections I.B. and I.C. below.

Non-invasive biomarker colorectal cancer screening tests are covered once every three years when all the following criteria are met:

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

See Appendix A for Medicare National Coverage Determinations Manual language.

June 8, 2026

1. Decision
   1. Decision
   2. Coverage Criteria
      1. Ordering Criteria
      2. Patient Criteria
      3. Test Criteria
   3. Other Uses of Colorectal Cancer Screening Biomarker Tests
2. Clinical Review
   1. Background
   2. Food and Drug Administration Status
3. Evidence
   1. Evidence Questions
   2. Technology Assessments
   3. Medicare Evidence Development and Coverage Advisory Committee (MEDCAC)
   4. Clinical Literature Search
      1. Summary of Evidence
   5. Assessment of the Evidence
      1. RNA-based stool tests
      2. DNA-based stool tests
      3. DNA-based blood-based tests
      4. Limitations
      5. Relevance and generalizability to Medicare beneficiaries
      6. Evidence from systematic reviews and meta-analyses
   6. Evidence-Based Guidelines
   7. Professional Society Recommendations / Consensus Statements / Other Expert Opinion
   8. Appropriate Use Criteria
   9. Public Comments
4. CMS Coverage Authority
   1. CMS Coverage Authority
   2. CMS Analysis for Coverage of CRC screening
      1. Rationale for Coverage Requirements for CRC screening
      2. Evidence Questions – Answered
   3. Benefit Category
5. History of Medicare Coverage
   1. Current National Coverage Request
   2. Timeline of NCA Milestones
6. Appendices
   Appendix A: Proposed Medicare National Coverage Determinations Manual Language
   Appendix B: Referenced Materials
Bibliography

Abbreviations used throughout the Decision Memorandum for Colorectal Cancer Screening Non-Invasive Biomarker Tests

AA – Advanced adenoma
ACG – American College of Gastroenterology
ACS – American Cancer Society
BBB – Blood-based biomarker
bb-cf DNA - Blood-based cell-free DNA
cfDNA – Cell-free DNA (deoxyribonucleic acid)
CI – Confidence interval
CMS – Centers for Medicare and Medicaid Services
CRC – Colorectal cancer
CTC – CT colonography
ct-DNA – Circulating tumor DNA
DNA – Deoxyribonucleic acid
fDNA – Fecal deoxyribonucleic acid
FOBT – Fecal occult blood test
FDA – United States Food & Drug Administration
FIT – Fecal immunoassay test or Fecal immunochemical test; also known as iFOBT (Immunochemical Fecal Occult Blood Test)
gFOBT – Guaiac fecal occult blood test
HGD - High-grade dysplasia
iFOBT – Fecal immunochemical test or Immunochemical Fecal Occult Blood Test, also known as FIT (Fecal Immunochemical Test)
mt-sDNA – Multi-target stool DNA (deoxyribonucleic acid)
mt-sRNA – Multi-target stool RNA (ribonucleic acid)
NCI – National Cancer Institute
NPV – Negative predictive value
PPV – Positive predictive value
RCT – Randomized control trial
RNA – Ribonucleic acid
sDNA – Stool deoxyribonucleic acid
SEER – Surveillance, Epidemiology, and End Results
SSA – Sessile serrated adenoma
SSED – Summary of Safety and Effectiveness Data
SSP – Sessile serrated polyps
USPSTF – United States Preventive Services Task Force

I.                 Decision

Non-invasive biomarker tests for colorectal cancer screening are covered according to the provisions in sections I.B. and I.C. below.

Non-invasive biomarker colorectal cancer screening tests are covered once every three years when all the following criteria are met:

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

See Appendix A for Medicare National Coverage Determinations Manual language.

II.              Clinical Review

Colorectal cancer (CRC) is the third most common cancer in both women and men and the second leading cause of cancer deaths in the United States (Siegel et al., 2026). The American Cancer Society (ACS) estimated that, in 2026, there will be 158,850 new cases of CRC, and 55,230 people will die from these cancers (ACS, 2026). In 2025, the highest percentage of colorectal cancer cases (25.8%) was in ages 65 to 74 years and had a median age at diagnosis of 66 years (NCI/SEER, 2025). Primary prevention, early detection and early treatment have contributed to declining overall mortality rates for CRC over the past decade. However, CRC was estimated to account for over 52,000 deaths in 2025, with a median age at death of 72 years (NCI/SEER, 2025).

Early detection and removal of large pre-cancerous adenomas helps prevent the progression of these noncancerous tumors to cancerous tissue (carcinoma), reducing the incidence of colorectal cancer and improving mortality (American Cancer Society, 2024). If cancerous cells spread beyond where they started (localized versus regional or distant), it can negatively affect a person’s survival (NCI/SEER, 2025). While the screening rate of CRC has increased, there are still missed opportunities as the screening rate in adults aged 45-75 years (63%) remains below the Healthy People 2030 goal of 72.8% (US HHS, 2024). Colonoscopy is the gold standard for CRC screening.

Constant colorectal epithelial tissue renewal occurs in the colon epithelium, in which cells migrate to surface levels and then undergo apoptosis (normal programmed cell death) and are shed into the colon lumen. Normal systems that regulate DNA repair and healthy cell proliferation (e.g., suppressor genes, oncogenes, DNA repair genes) become damaged by cellular mutations as adenomas form (Nguyen et al., 2020). Sequential alterations in growth regulatory genes and progressive cellular tissue changes can occur via multiple pathways, but specific gene mutations must occur for these cells to become malignant (Nguyen et al., 2020). Testing of stool for fecal DNA or RNA aims to detect molecular biomarkers of altered genetic material that are contained in the cells shed by CRC and pre-malignant colorectal epithelial neoplasia into the lumen of the large bowel (Gómez-Molina et al., 2024).

Genetic biomarkers are released regularly and continuously, due to the constant sloughing of the colorectal epithelial cells lining the bowel lumen and end up in the stool stream. Using selective enrichment and amplification techniques, multitarget stool DNA (mt-sDNA) and multitarget stool RNA (mt-sRNA) tests are designed to detect very small amounts of genetic biomarkers to identify pre-malignant colorectal neoplasia (including advanced adenomas [AAs]) and CRC.

Altered genetic material shed by cancerous cells can also be released into the bloodstream and potentially be identified with “liquid biopsies” or blood serum samples, including tests that examine non-genetic cell-free DNA (cfDNA) biomarkers (Mannucci & Goel, 2024). Multitarget blood-based tests are designed to detect the presence of cancer-derived signals based on different profiles and combinations of the circulating cfDNA.

On August 11, 2014, the FDA approved the Cologuard® premarket approval (PMA) application (P130017). Cologuard® is intended for the qualitative detection of colorectal neoplasia associated with DNA markers and for the presence of occult hemoglobin in human stool and is indicated as a screening test for adults, 45 years or older, who are at typical average-risk for CRC.

The Summary of Safety and Effectiveness Data (SSED) can be accessed at: https://www.accessdata.fda.gov/cdrh_docs/pdf13/p130017b.pdf.

The Cologuard® post-approval study (PAS) was a prospective longitudinal study to assess the impact of repeat Cologuard® testing at 3 years in average risk patients.

On May 3, 2024, the FDA approved the ColoSense® PMA application (P230001).  ColoSense® is intended for the qualitative detection of colorectal neoplasia associated RNA markers and for the presence of occult hemoglobin in human stool and is indicated as a screening test for adults, 45 years of age or older, who are at typical average-risk for developing CRC.

The SSED can be accessed at: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf.

The ColoSense® PAS is a prospective study. The primary objective is to continue to evaluate the clinical effectiveness of ColoSense® by obtaining at least 23 CRC cases (23 cases in addition to the 27 obtained in CRC-PREVENT for a total of 50 CRC cases) to have an adequate number of CRC subjects that are part of the intended use population (average risk) to provide more certainty in the test performance. The secondary objective of this PAS is to further define sensitivity for CRC, AAs, and serrated precancerous lesions and specificity for negative findings on a colonoscopy for Geneoscopy’s mt-sRNA test (ColoSense®), using colonoscopy as the reference method.

On July 26, 2024, the FDA approved the Shield™ PMA application (P230009). Shield™ is a qualitative, in vitro diagnostic test intended to detect colorectal cancer derived alterations in cfDNA from blood collected in the Guardant Shield Blood Collection Kit and is intended for screening in individuals at average risk of the disease, age 45 years or older.

The SSED can be accessed at: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230009B.pdf.

The Shield™ PAS is a prospective, longitudinal study supplemented with Real World Evidence (RWE) to evaluate the longitudinal performance of Shield™ in an average risk population at a second round of testing for individuals between the ages of 45 and 81 at average risk of CRC using colonoscopy as the reference method.

On October 3, 2024, the FDA approved the Cologuard Plus™ PMA application (P230043). Cologuard Plus™ is a qualitative in vitro diagnostic test intended for the detection of colorectal neoplasia associated DNA markers and for the presence of occult hemoglobin in human stool and is indicated to screen adults 45 years or older, who are at average risk for CRC.

The SSED can be accessed at: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230043B.pdf.

The FDA PAS Database can be accessed at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma_pas.cfm.

III.           Evidence

This section provides a summary of the evidence considered during this review.  The evidence presented here includes the pertinent published clinical research on CRC screening. This NCD addresses CRC screening biomarker tests. It does not address the long-standing policy on fecal occult blood tests (FOBT).

A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature can be found in the CMS National Coverage Analysis Evidence Review Guidance Document, published August 7, 2024.

The following questions guide our review and analysis of the evidence on the clinical utility of CRC non-invasive biomarker screening tests:

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?

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

CMS did not request an external technology assessment on this topic.

A MEDCAC meeting was not convened on this topic.

A systematic literature review was undertaken to address the evidence questions defined above. Literature searches were conducted in PubMed and Embase focusing on non-invasive biomarker CRC screening tests. The database searches were conducted using structured vocabulary terms and included key words centered on non-invasive CRC screening multi-targeted stool RNA or DNA and blood-based tests (molecular biomarkers). The review included published English language literature from 2021 to present. The literature search excluded abstracts from presentations at meetings and animal studies.

A supplementary search was conducted specifically targeting blood-based CRC screening tests. The original database searches included the term “non-invasive” and would potentially exclude tests utilizing a patient peripheral venous blood draw.

The literature searches were originally conducted on December 19, 2024. Additional literature was submitted during the initial 30-day comment period and included in the evidence review.

This review identified 9 studies that met the inclusion criteria, only one of which was a randomized controlled trial. Five studies were observational prospective cohort designs including two stool RNA, two stool DNA, and one blood-based DNA study. One study was a retrospective cohort study of a stool-based DNA test in hemorrhoid patients, one study used a retrospective comparison design to compare a stool-based DNA test to CT colonography (CTC), and one study was a prospective comparative trial of two new stool-based DNA tests versus a FIT test.

Table 2 (Appendix B) provides an overview of studies included in this systematic review.

Table 3 (Appendix B) outlines the CRC specificity & sensitivity primary outcomes for each study included in the report.

Barnell et al., 2021 assessed the ability for the stool-based RNA-FIT test to detect advanced neoplasias (CRC and AA), examining sensitivity for highly aggressive precancerous adenomas (AAs with high-grade dysplasia (HGD), carcinoma in situ, or villous/tubulovillous architecture). One thousand three hundred five (1,305) participants were split into a 939-patient screening model development training set, and then the model was used on a 366-patient hold out testing set, with 22 samples also obtained from patients after diagnosis of CRC or AA. The RNA-FIT assay demonstrated 95% sensitivity for CRC detection and 85% specificity for no findings on a colonoscopy in a geographically diverse, predominantly White participant sample. Along with high sensitivity, the test was able to detect 62% of all AAs and 25% of other non-advanced adenomas (non-AA). The authors speculate that the RNA-FIT assay reduction in specificity relative to existing screening alternatives may have been partially attributable to missed adenomas on colonoscopy considering this increased test sensitivity for both AA and non-AA. Overall, the authors concluded that the RNA-FIT test was able to demonstrate clinically relevant detection by the RNA-FIT screening test of all grades of colorectal neoplasia, including carcinomas, AAs, and other non-AAs (ONAs).

Barnell et al., 2023 was a phase III pivotal clinical trial (CRC-PREVENT) to evaluate the sensitivity and specificity of a noninvasive, mt-sRNA test (ColoSense®) compared with results from a colonoscopy. The study sample was also geographically diverse across the US, although only 4.7% of participants were enrolled in rural settings and participants were predominantly White, recruited from an online social media platform through a decentralized recruitment effort. The mt-sRNA test demonstrated 94.4% sensitivity for CRC detection and 45.9% for AA. The mt-sRNA test sensitivity for CRC detection (94.4% vs 77.8%; McNemar p = .01) and AA detection (45.9% vs 28.9%; McNemar p < .001) was significantly higher when compared to the FIT test. 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. The FIT test specificity for no lesions on colonoscopy was also higher than the mt-sRNA test (95.7% vs 87.9%; p < .001). When examining test performance by age group, results indicated a sensitivity of 87.5% (n=7/8) for CRC and 49.6% (n=61/123) for AA in adults 65 years of age or older. Specificity in this age group for no findings was 85.2% (n=588/690). FIT test performance in this age group was not reported.

Imperiale et al., 2021 sought to quantify the specificity and sensitivity of a mt-sDNA test for CRC and advanced precancerous lesions (APL) in average-risk 45–49-year-olds who were interested in having a screening colonoscopy. No participants had CRC or HGD, and the large sample size required to estimate sensitivity in a low prevalence population precluded the feasibility of estimating mt-sDNA test sensitivity. The mt-sDNA test sensitivity for APL detection was 32.7%, but there was a lack of HGD identified in the participants. The specificity for no findings (either nonadvanced neoplasia or negative findings) was 95.2% and 96.3% for only negative findings. The authors noted that the higher specificity likely reflects the expected lower prevalence of any colorectal neoplasia, lesions that cause bleeding, and lower background methylation in stool samples in a younger age group.

Imperiale et al., 2024 conducted a large prospective pivotal study (BLUE-C trial) on a new mt-sDNA screening test, identified as a 2.0 next-generation test being developed by Exact Sciences, that used the same principle of operation as the prior FDA-approved Cologuard® test. However, the new version includes an optimized methylation marker panel, a newly formulated hemoglobin sample stability buffer, and removes the KRAS mutation detection (Imperiale et al., 2024). The researchers indicated these changes were aimed at increasing test specificity and increasing the time between collection and testing, while maintaining or increasing the CRC and AA sensitivity. The FDA approved this test as “Cologuard Plus™” in October 2024, and became publicly available in 2025, based upon the results of this trial. The study recruited participants aged 40 and above, though only 59 of the 20,176 enrolled, evaluable participants were 40 to 44 years of age. Only 60.1% of participants identified as White (not Hispanic or Latino) in the study conducted at 186 sites across the US. The test sensitivity for CRC detection was 93.9% and sensitivity for APL was 43.4%. The specificity for nonneoplastic findings or negative colonoscopy was 92.7% and the specificity for AA was 90.6%.

Deiss-Yehiely et al., 2022 compared noninvasive screening detection of high-risk Sessile Serrated Lesions (SSLs) between the mt-sDNA test and CTC in separate electronic medical record cohorts at one large institution. Participants selected for the study with a negative test result would not have typically followed up with a colonoscopy, preventing the researchers from determining a sensitivity and specificity for detection of high-risk SSLs. Unlike mt-sDNA and other stool-based tests that yield binary results (e.g., positive, negative), CTC provides information on polyp size and morphology and can be stratified by size thresholds for test positivity (e.g., small polyps: 6–9 mm, large polyps: ≥ 10 mm, or frank masses concerning for CRC) and diagnostic confidence. Results indicated that CTC at both thresholds had significantly higher yield (6-mm= 1.7%; 10-mm: 1.6%) for high-risk SSLs compared with mt-sDNA (0.7%) detection rate (p<0.001). Similarly, there were significant differences (p<0.001) for the positive predictive value (PPV) of mt-sDNA for high-risk SSLs (5.5%) compared with CTC at the 6-mm threshold (14.4%) and CTC with the 10-mm threshold (25.9%). Age (63.8 vs. 56.2 years) and gender (females: 64% vs 54%; males: 36% vs 46%) were significantly different in this retrospective cohort study between the mt-sDNA and CTC groups (both p <0.001).

Ebner et al., 2023 conducted a retrospective study of participants from the DeeP-C Trial (Original study: Imperiale et al., 2014) to evaluate the effect of hemorrhoids on noninvasive mt-sDNA stool test performance for CRC screening. The DeeP-C study took place from 2011 to 2013 and was the trial to support the safety and effectiveness of the mt-sDNA Cologuard® test as a screening device for the detection of markers associated with the presence of CRC and AA. The mt-sDNA specificity for the detection of advanced neoplasia was 86.4% in patients without hemorrhoids versus 86.7% in those with hemorrhoids (p=67). The mt-sDNA sensitivity for CRC detection was 92.9% in patients with hemorrhoids and 91.9% in those without. Overall, the authors reported that none of the mt-sDNA test characteristics differed significantly on the basis of hemorrhoid status.

Jin et al., 2022 tested two new stool-based DNA tests against a FIT test for CRC screening to estimate the sensitivity and specificity of the tests to detect CRC. The tests were developed and offered to outpatient adults because the mt-sDNA Cologuard® test was not available in China. The specificities for a negative colonoscopy result for the stool DNA test-I (91.4%) and test-II (93.3%) were significantly lower (both p < 0.001 by McNemar test) than the FIT (96.8%). The sensitivity for CRC detection for stool-based DNA test-I (90.5%) was not significantly different from a FIT test (88.1%) adjusted to match the specificity of the DNA test. Likewise, the test-II (92.9%) sensitivity did not differ from an adjusted FIT test (88.1%). Although the two types of stool-based DNA tests demonstrated adequate sensitivity and specificity for CRC screening, there was no significant advantage compared with FIT.

Coronado et al., 2024 was the only RCT identified and examined whether adherence to CRC screening recommendations in an organized FIT screening program could be improved by integrating a blood-based testing option opportunistically as part of standard health encounters. The primary outcome was receipt of any CRC screening test (blood draw or FIT or FIT-DNA or flexible sigmoidoscopy or colonoscopy) within 3 months of eligibility determination. Participants were randomly assigned to receive either the Guardant Health cfDNA blood test or standard of care, which included point-of-care reminders to complete FIT testing. A total of 30.5% underwent CRC screening blood test, FIT, or colonoscopy and 13% of the usual care group completed a FIT or colonoscopy. Further, 10.4% had abnormal results with the blood test, leading to a follow-up colonoscopy in 50% of cases. In comparison to cfDNA blood test, 4.7% had abnormal results on FIT test and 70% of these had a follow-up colonoscopy. The authors reported an increase in CRC screening of 17.5% when adding the option of a blood test. Hence, adding cfDNA as an additional screening tool with FIT for CRC screening might increase CRC screening among an average risk population.

Chung et al., 2024 conducted the ECLIPSE Study (Evaluation of the ctDNA [circulating tumor DNA] LUNAR Test in an Average Patient Screening Episode) to assess the performance characteristics of a cfDNA blood-based test in a population eligible for CRC screening. All patients underwent cfDNA testing followed by colonoscopy.  The cfDNA test demonstrated a sensitivity of 83.1% for detecting CRC, with varying sensitivities by different stages (Stage I: 65%, Stage II: 100%, Stage III: 100% and Stage IV: 100%). The specificity for no neoplasia was 89.9%, with a false positive rate of 10.1%. Exploratory analyses examined PPV and negative predictive value (NPV) for several lesions. Overall, PPV (CRC) was 3.2%, PPV (advanced cancerous lesions) was 12.9% and NPV (no CRC) was 99.9%. The study further reports sensitivity across tumor sizes, tumor grade, as well as histopathology diagnosis and demographic characteristics including age, race, gender, and tobacco use. The authors reported that there were no unanticipated adverse device events observed across the 22,877 enrolled subjects. Of the 43 reported adverse events, 30 (70%) were minor related to phlebotomy and 13 (30%) were unrelated to the study intervention, including the two reported serious adverse events. Key possible adverse events related to the device/ screening technique included bruising and swelling at the site of blood collection, dizziness, syncope, emesis, fainting, hematoma, nausea and vomiting, and vasovagal episode. The study suggested the potential utility of the cfDNA blood test as a non-invasive screening tool to increase adherence for CRC detection in the average risk population.

The reviewed evidence had several limitations. 

• All studies of commercially available CRC tests (Cologuard®, ColoSense®, Shield™) were supported by the companies that developed the tests.
• While utilizing multiple recruitment sites may potentially benefit the generalizability of the study findings, it also may lead to differing standard colonoscopy protocols (e.g., scheduling, bowel preparation, reporting practices, pathology reports) and practitioners with varying experience and skill levels. The variability in both aspects of the study may affect colonoscopy withdrawal times and adenoma detection rates, potentially increasing the variability of results and the false-positive and false-negative result rate of the mt-sRNA, mt-sDNA, and blood-based biomarker (BBB) tests (Barnell et al., 2021; Barnell et al., 2023; Chung et al., 2024; Imperiale et al., 2024).
• Non-randomly selected or non-randomly assigned study designs have the potential for participant self-selection bias, which are open to confounding factors that may be controlled with randomization strategies.
• The retrospective study designs have inherent weaknesses, such as the potential for confounding and bias, leading to limits to the study’s internal validity (Deiss-Yehiely et al., 2022; Ebner et al., 2023).
• The comparative mt-sDNA vs CTC study conducted by Deiss-Yehiely et al., 2022 did not match participants by age, sex, or propensity score and reported a significant difference in age and sex between the groups. Differential health behavior, CRC risk and prevalence associated with age and gender may impact study findings.
• Ebner et al., 2023 retrospectively studied the effect of hemorrhoids on a mt-sDNA test from study data that was not collected for this purpose and did not control for other non-neoplastic factors (e.g., angioectasias, diverticulum) that may have potentially influenced the result of the mt-sDNA test.
• Imperiale et al., 2021 studied a mt-sDNA test in an average-risk screening population of 45- to 49-year-olds; however, none of the study participants were found to have CRC or HGD, potentially inhibiting performance for CRC detection and limiting the interpretation of the APL sensitivity.
• Furthermore, cross-sectional designs and randomized trials with short follow-up duration preclude accurate assessment of long-term benefits in clinical outcomes. No study reported adverse events, except for Chung et al. (2024), or morbidity or mortality-related outcomes.
• Study cohorts reported enrollment of predominantly White participants; the majority of participants in all studies were female.

Although CRC screening is recommended to begin for adults well below the age of most Medicare beneficiaries, guidelines recommend screening continue until at least age 75 years. The risk of CRC increases with age and continues in older adult populations, with the number of colon cancer cases increasing from 34.3–62.5 per 100,000 between ages of 50–64 years to 92.6–212.2 per 100,000 between 65–85 years (Mattiuzzi et al., 2019). CRC incidence rates increase by approximately 80% to 100% with each 5-year age group until 50 years of age and then by 20% to 30% from ages 55-59 years upward (ACS, 2023). Routine screening for CRC continues to be an important part of health and wellness, and disease prevention in the Medicare population.

In terms of applicability of study findings, consideration of multiple study design and participant sample characteristics help determine whether the findings from these studies are applicable to other populations (i.e., Medicare beneficiaries). The studies reviewed for this report had few exclusion criteria, other than exclusion criteria for a history of colorectal neoplasia, digestive cancer, or inflammatory bowel disease, indicators of a high-risk population. The studies recruited and enrolled asymptomatic, average-risk participants. The studies varied in the reporting of other demographic information (e.g., income, health, body mass index [BMI], geographic location, colonoscopy testing setting).

All but two reviewed studies (Deiss-Yehiely et al., 2022; Imperiale et al., 2021) reported age groups for participant samples in order to identify the number of older adults enrolled. One study only enrolled participants 45-49 years old (Imperiale et al., 2021) and only approximately 4% of participants in the mt-sRNA test study by Barnell et al. (2021) were adults over 65 years of age. All other studies reporting age groups reported older adult (greater than age 60 or 65) enrollment of 25-50% of the studied sample. Three studies reported CRC test performance results by age group, specifically in adults 60 or 65 years or older (Barnell et al., 2023; Chung et al., 2024; Imperiale et al., 2024). These three studies covered the three FDA-cleared screening tests (mt-sRNA, mt-sDNA, mt-cfDNA).

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. However, there was a general lack of diversity in racial and ethnic participant characteristics, potentially limiting the applicability of study results to some population subgroups.

The systematic reviews and meta-analyses captured by the searches conducted for this report were closely reviewed for any potential studies that may meet the report’s inclusion criteria and did not yield additional qualifying studies. Some of the key ongoing and emerging research summarized in the reviews are outlined below.

Biomarkers associated with methylation processes are a common focus of research, including methylated circulating tumor DNA (ctDNA), white blood cell DNA, and panels of methylated genes (Khabbazpour et al., 2024). As a biochemical epigenetic process, methylation occurs when a methyl group is added to a protein, DNA, or another molecule, signaling a potential alteration in gene expression (Ferrari et al., 2021; Goyal et al., 2023; Khabbazpour et al., 2024). Genetic alterations can also be detected in RNA, micro-RNA (miRNA), and Piwi-Interacting RNA (piRNA) that serve important regulatory functions related to cell differentiation, development, and growth (Ferrari et al., 2021; Goyal et al., 2023; Zakari et al., 2024; Zhao et al., 2021). The FDA-cleared available stool and blood-based tests include processes to identify methylated genes, and more work is being conducted to identify other potential genetic biomarkers or panels of these biomarkers that may have increased sensitivity and specificity for CRC. Alterations in circulating blood lipids and elevated levels of various panels of proteins (e.g., carcinoembryonic antigen, carbohydrate antigen 19-9) are also being studied as blood-based biomarkers to detect CRC (Ferrari et al., 2021). Many of the potential protein CRC biomarkers can also be present or elevated with inflammatory processes present in other non-cancerous conditions, confounding progress for this work.

In a recent novel approach, researchers sponsored by Freenome Holdings have developed and tested a blood-based CRC screening test that combines multiple technologies, such as computational biology, machine learning, and multiple data types (RNA, DNA, proteins). The company has utilized multi-omics (i.e., using data from different research areas such as genomics, epigenomics, transcriptomics, proteomics, metabolomics) as the basis for developing the CRC screening test and has conducted a large prospective cohort clinical trial (PREEMPT CRC) in average-risk, asymptomatic adults aged 45-85 years (Shaukat et al., 2025). The trial enrolled 48,995 participants (27,010 were evaluated) across more than 200 research sites, using virtual and traditional recruitment methods to reach underserved communities and ensure a representative population (Shaukat et al., 2025). The study found that the blood-based CRC screening method demonstrated a CRC sensitivity in detecting colorectal cancer of 79.2% (Stage I: 57.1%, Stage II: 100%, Stage III: 82.4%, Stage IV: 100%) and a 91.5% specificity for non-advanced colorectal neoplasia (Shaukat et al., 2025). The company has indicated that it will continue to optimize the testing method for CRC sensitivity and AA detection.

Along with altered RNA and DNA, other potential stool-based biomarkers include an isoenzyme (M2-PK) and differential gut microbiota have been identified in some CRC patients (Ferrari et al., 2021; Song et al., 2023). Recent reviews of the potential use of gut microbiota as a CRC screening modality concluded that there were conflicting results related to a high level of heterogeneity in inclusion criteria and study methodology, and no consensus on common markers among the studies (Lișcu et al., 2024; Zwezerijnen-Jiwa et al., 2023).

Overall, ten systematic reviews were screened for applicable noninvasive CRC stool or blood-based screening tests. As noted, a large body of work exists for emerging CRC screening biomarkers, though the consensus from these reviews suggests limited reliability and generalizability despite advances in CRC biomarker research. Specifically, the studies lack standardized protocols for biomarker detection and quantification methods, resulting in high variability of results across studies, as well as a lack of sufficient validation in large, diverse patient populations (Goyal et al., 2023; Laugsand et al., 2021; Mannucci & Goel, 2024; Zakari et al., 2024). As with studies of existing FDA-cleared CRC screening tests, trials will need to conduct direct performance comparisons FIT tests that use colonoscopy as the gold standard comparator and evaluate their combined use for advanced pre-cancerous lesion screening (Goyal et al., 2023).

We identified five evidence-based professional society guidelines (ACG, ACP, NCCN, ASGE, ACS) relevant to CRC screening. A complete summary of these guidelines is included in Table 4 (Appendix B).

We identified one evidence-based professional society recommendation (USPSTF) relevant to CRC screening. A complete summary of this recommendation is included in Table 4 (Appendix B).

There are no relevant, published appropriate use criteria.

CMS uses the initial public comments to inform its proposed decision. Public comments that cite published clinical evidence give CMS useful information.  Public comments that contain information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination.

First Comment Period: 9/10/2025-10/10/2025

During the first 30-day public comment period CMS received 47 comments. Some commenters expressed support for mt-sRNA screening tests and recommended they be covered, while other commenters expressed concerns about the evidentiary base for mt-sRNA screening tests. A few commenters recommended removing or lessening ordering requirements. Some commenters noted that colonoscopy is the gold standard of colorectal cancer screening. All comments that were submitted during the comment period without personal health information may be viewed by using the following link https://www.cms.gov/medicare-coverage-database/view/ncacal-public-comments.aspx?ncaid=319.

The majority of comments were provided by professional societies and advocacy groups, as well as many physicians and professors. There were also comments by healthcare systems and test manufacturers, including the requestor, Geneoscopy. Six comments were provided by national associations/professional organizations; the National Comprehensive Cancer Network (NCCN), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE), American Cancer Society Cancer Action Network (ACS CAN), the American College of Radiology (ACR), and the National Center for Health Research (NCHR).

Numerous commenters provided references for our deliberation of this NCA. We appreciate this information. All such references were assessed for inclusion in our evidence review.

Second Comment Period: 3/10/2026-4/9/2026

During the second 30-day public comment period CMS received 95 comments. The majority of commenters supported efforts to modernize the coverage pathway and expand access to CRC screening to increase adherence. Commenters supported the expansion of the ordering requirements. While most commenters supported adding stool-based RNA screening tests as an additional screening option, some commenters believe it is an inferior test to current stool DNA tests. Many commenters noted concern for blood-based screening tests. Even though they have been a Medicare coverable test since 2021, many commenters requested test sensitivity criteria be included for detecting advanced adenomas and designate blood-based screening tests as a second line screening option. Many commenters supported the FDA post approval study requirement. All comments submitted during the comment period without personal health information may be viewed at: https://www.cms.gov/medicare-coverage-database/view/ncacal-public-comments.aspx?ncaid=319&ncacaldoctype=all&status=all&sortBy=status&bc=17.

The majority of comments were provided by physicians and other health care professionals. Comments were also received by five test manufacturers, including Abbott (previously Exact Sciences), CellMax Life, Freenome, Geneoscopy, and Guardant Health. Eleven comments were provided by national associations/professional organizations including the Advanced Medical Technology Association (AdvaMed), American Academy of Physician Associates (AAPA), the American Cancer Society and the Cancer Action Network (ACS CAN),  the American Clinical Laboratory Association (ACLA), the American College of Gastroenterology (ACG), the American College of Radiology (ACR), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE), Association for Molecular Pathology (AMP), Medical Device Manufacturers Association (MDMA), and the National Comprehensive Cancer Network (NCCN). Fourteen comments were provided by advocacy organizations/coalitions including 60Plus Association, Action for Health, Alliance for Aging Research, Big Mike’s Bottom Line, the Blue Hat Foundation, Cheeky Charity, Coalition for 21^st Century Medicine (C21), Colon Cancer Coalition, Colon Cancer Prevention Project, Colon Cancer Stars, Colorectal Cancer Alliance, Fight CRC, Global Healthy Living Foundation, and One Cancer Place.  Other comments were provided by professors, healthcare systems, a former Member of Congress, consultants, a regulatory quality coordinator, a regulatory attorney, and Medicare beneficiaries. Five comments did not provide their titles and/or organizations.

Numerous commenters provided references for our deliberation of this NCA. All such references were assessed for inclusion in the evidence review. 

Screening Strategy

Comment: The majority of commenters expressed support for broader Medicare coverage of non-invasive biomarker colorectal cancer screening tests. Many commenters stated that expanding access to additional screening options could improve screening uptake, facilitate earlier detection, and reduce colorectal cancer morbidity and mortality. Some commenters noted that broader access could help address barriers such as reluctance to undergo colonoscopy, difficulty with stool collection, transportation challenges, time away from work, and other practical concerns. Some commenters also believed broader access could improve screening participation in underserved populations and beneficiaries facing logistical, financial, or other barriers to care.

Response: We thank commenters for highlighting these issues in support of the proposed NCD.

Comment: Several commenters supported maintaining distinct coverage pathways for stool-based and blood-based CRC screening tests based on their differences in ability to detect colorectal cancer and advanced precancerous lesions. Some commenters believe this coverage approach does not align with the statutory requirement that NCDs address a “particular item or service” under § 1869(f)(1)(B) of the Social Security Act (the Act).  They also cite 42 C.F.R. § 410.37 (k) for referencing “noninvasive stool-based colorectal cancer screening” and “blood-based biomarker colorectal cancer screening” as separate tests.

Response: As noted in the Analysis under ‘Consistent CRC Detection Test Criteria for Stool-based and Blood-based Tests,’ the test performance coverage criteria for colorectal cancer detection for the stool-based tests and the blood-based tests are not separated. This approach standardizes coverage by applying consistent criteria across the testing modalities (e.g. stool-based, blood-based).

We do not agree that this screening strategy for non-invasive biomarker CRC screening tests does not align with the statutory requirement that NCDs address a “particular item or service” under § 1869(f)(1)(B) of the Act. These class of tests are used for the same purpose of cancer detection and all use biomarkers.  Test performance criteria were determined appropriate based on current FDA approved screening tests and currently covered Medicare screening tests; new tests within the space of non-invasive biomarker screening to detect colon cancer must meet the criteria to be eligible for coverage. This coverage approach, rather than test-specific, is also used in NCD 90.2 Next Generation Sequencing.

42 C.F.R. 410.37(k) defines a complete colorectal cancer screening to include a follow-on screening colonoscopy after a Medicare covered non-invasive stool-based CRC screening test or blood-based biomarker CRC screening test returns a positive result. Thank you for this comment as in the future we will consider making a conforming change to the regulatory language for consistency. 

Comment: A commenter suggested allowing Medicare Administrative Contractors (MAC) discretion for tests without FDA authorization.

Response:  MACs do not have authority to make Medicare coverage determinations with respect to expanding coverage for new colorectal cancer screening tests under § 1861(pp)(1)(D) of the Act.

Screening Interval

Comment: Some commenters stated that the rescreening interval should be test-specific and based on the evidence and FDA-authorized labeling for each modality, rather than applying a uniform three-year interval across all non-invasive biomarker tests.

Response: As noted in the Analysis under ‘Frequency of testing’, the NCD is aligned with the most consistent screening frequency interval recommended across the NCCN, ACG, ACS, and USPSTF.  The indications for use in the three SSEDs (mt-sDNA, Cologuard Plus, 2024; mt-sRNA, ColoSense, 2024; BBB, Shield, 2024) do not report a screening interval.

Ordering Criteria

Comment: Commenters supported expanding the list of clinicians who may order non-invasive colorectal cancer screening tests to include physician assistants, nurse practitioners, and clinical nurse specialists and consistency among all non-invasive screening tests. Some commenters recommended further broadening the language to include other nonphysician practitioners recognized under Medicare law or regulation, such as § 1861(s) of the Act or 42 CFR 410.32(a)(2).

Response: We appreciate the suggestion to broaden the non-physician providers even further however, this expansion is in alignment with the ordering requirements for screening FOBT in 42 CFR §410.37(b).

Comment: Some commenters recommended either deleting or revising the requirement that the ordering practitioner use the results “for” the management of the patient, rather than “in” the management of the patient to better define the role of the ordering provider in the screening process. The management of the patient that is needed following a positive result is referral to colonoscopy, and therefore the management falls to another provider.

Response:  The health care provider who orders the screening test is the person who receives the results of the screening test and who then recommends next steps in the management of the patient, which can include referral to another health care provider if the test is positive or a discussion with the patient of when the next screening test will occur if the test is negative.  We consider these steps as described to be for the management of the patient.  We are finalizing as proposed.

Comment: While this NCA does not include a review of the long-standing coverage for fecal occult blood tests (FOBT), a commenter indicated that the ordering requirements for FOBT in NCD 210.3 are not in alignment with the colorectal cancer screening section 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.”

Response: We appreciate the commenter bringing this to our attention. We will make a conforming change to the ordering requirements for FOBT in NCD 210.3 for consistency with the regulatory language in 42 CFR §410.37(b).

Patient Criteria

Comment: Two commenters noted the need for individualized screening decisions for adults ages 76 to 85, based on health status, prior screening history, life expectancy, and patient preference.

Response: Consistent with current existing professional organization recommendations and coverage of other CRC screening tests, we are finalizing the age range of 45-85 years. The USPSTF currently recommends the decision to screen for colorectal cancer in adults aged 76 to 85 years should be an individual one, taking into account the patient’s overall health and prior screening history, and we agree this is appropriate.  We further anticipate that ordering CRC screening tests may stem from a beneficiary’s Annual Wellness Visit and personalized prevention plan which should take into account the concerns identified by the commenter. 

Comment: One commenter suggested updating the “asymptomatic” and “average risk” patient criteria to align with the contraindications of recently approved tests and clinical guidelines. The longstanding definition for colorectal cancer screening defines asymptomatic as ‘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).”

Response: Thank you for the comment. We agree that this should be expanded to include any positive non-invasive biomarker tests to align with new FDA market authorized non-invasive biomarker CRC screening tests that have come to market, including the mt-sDNA test, mt-sRNA test, and BBB test. It was an oversight that this was not updated to include mt-sDNA when BBB tests were added to the NCD in 2021. The final NCD reflects this change.

The average risk definition is derived from 42 CFR §410.37(a)(3). It defines an individual at high risk for colorectal cancer to mean an individual with a close relative (sibling, parent, or child) who has had colorectal cancer or an adenomatous polyp; a family history of familial adenomatous polyposis; a family history of hereditary nonpolyposis colorectal cancer; a personal history of adenomatous polyps; a personal history of colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease, and ulcerative colitis. Average risk defines an individual that does not meet the high-risk criteria. We are finalizing as proposed.

Comment: Many commenters expressed the need for shared decision-making. They suggest that patients need to be educated about the available screening tests, their test performance and the completion of the full screening process if the test provides a positive result. While commenters support non-invasive screening tests they acknowledge there are performance differences between stool-based and blood-based tests and patients need to be educated to select the most appropriate test.

Response: We appreciate and share in the concern for the patient to know the risks and benefits based on the test performance and the importance of a follow-on colonoscopy if the test returns a positive result. We are concerned that a formal, required shared decision-making requirement could be overburdensome, so the final NCD includes criteria that the patient is provided with information about test performance and the importance of a follow-on colonoscopy, if the test returns a positive result.  We anticipate this will offer an appropriate balance for policy though we encourage beneficiaries and their practitioners take the opportunity to discuss non-invasive CRC screening tests such as during the Annual Wellness Visit.

Comment: Many commenters emphasized that the value of any non-invasive colorectal cancer screening test depends on timely follow-on colonoscopy after an abnormal result. Some commenters also recommended that non-invasive screening be described as part of a two-step screening process and that patients should be counseled regarding repeat screening intervals, follow-on colonoscopy after positive results, and the differing strengths and limitations of available screening options.

Response: We appreciate and echo the importance of the screening continuum. While screening colonoscopy is currently the standard for colorectal cancer detection and allows for immediate removal of precancerous lesions, non-invasive biomarkers provide additional options for those unwilling to undergo a screening colonoscopy. It is important for the patient to understand that a follow-on colonoscopy is necessary if the non-invasive screening test provides a positive test result. The follow-on colonoscopy after a positive non-invasive stool-based or blood-based CRC screening test is considered a complete CRC screening as set forth in 42 C.F.R. § 410.37(k). As part of the complete CRC screening, the follow-on colonoscopy is not subject to cost sharing. The final NCD includes criteria that the patient is provided with information about test performance and the importance of a follow-on colonoscopy, if the test returns a positive result.

Test Criteria

Comment: Many commenters expressed concern that the proposed framework does not give sufficient weight to the detection of advanced precancerous lesions and early-stage colorectal cancer. These commenters stated that colorectal cancer screening should prioritize prevention through detection of precursor lesions, not only detection of existing cancer.

Response: CMS did not include sensitivity criteria for detecting advanced adenomas because the detection rates are low across all the non-invasive tests. While stool-based tests have a higher detection rate than blood-based, the rates are still below 50%, meaning over half of the test results will be erroneous. In comparison, screening colonoscopy has a detection rate of 89%-95% (USPSTF, 2021). We encourage innovators to continue to improve the accuracy of screening tests for identifying advanced adenomas and look forward to practice guidelines and prevention recommendations reviewing and recommending tests based on this ability.

Comment: Many commenters expressed concern that currently available blood-based colorectal cancer screening tests have lower sensitivity for advanced precancerous lesions and early-stage colorectal cancer than stool-based tests and colonoscopy. Some commenters recommended that blood-based tests should be positioned only as an option for beneficiaries who decline colonoscopy or stool-based screening, rather than being treated as equivalent alternatives to established screening modalities.

Response: Comparing stool-based screening tests to blood-based tests in this decision, we acknowledge the technological differences in the testing platforms and the differences in the physiological and biochemical pathways in how the biomarkers reach the test devices.   However, sensitivity for both types of tests for colorectal cancer detection fall within a range (79% to 95%), as does specificity (87% to 93%), which we can consider appropriate given the role of the ordering practitioner to order the test most appropriate for the patient. In the Analysis under ‘Second Line Test Designation’, we further discuss the issues with designating screening tests as second line tests.  We are not separating the test performance coverage criteria for colorectal cancer detection for the stool-based tests and the blood-based tests. We are finalizing as proposed.

Comment: Many commenters addressed the proposed sensitivity and specificity thresholds. Some supported the proposed thresholds as written, while others recommended revisions to better reflect prevention, tradeoffs between sensitivity and specificity, and differences across screening modalities. Some commenters also recommended that CMS maintain or exceed prior stool-based performance standards, require stronger evidence of performance in the Medicare population, evaluate stool-based and blood-based tests separately, or seek additional expert review.

Response: As noted in the Analysis under ‘Sensitivity and specificity criteria: Parameters of Test Criteria’, our framework for specifying two sets of test performance criteria for both sensitivity and specificity uses an evidence-based approach and covers a range of tests (across non-invasive biomarker) so the patient and their practitioner can select the test that is most appropriate and that the patient is willing to complete. This also offers innovators more flexibility to improve the overall performance of CRC screening tests. We also believe this allows for a balance of the false positive rate against the false negative rate.  The test performance criteria will yield the most reasonable balance of the benefits and harms of the non-invasive CRC screening tests based on the evidence available.  In the final NCD, the test performance coverage criteria for colorectal cancer detection for the stool-based tests and the blood-based tests are not separated.

Comment: One commenter suggested the use of a continuous equivalence frontier based on the receiver operating characteristic (ROC) curve for the sensitivity and specificity minimum thresholds, rather than using two distinct cut points.

Response: We acknowledge the advantages of defining sensitivity and specificity cut points using a continuous equivalence frontier based on receiver operating characteristic (ROC) curve. However, trial results are not typically presented as ROC curves in the pivotal study publications or in the summary of safety and effectiveness data (SSED) documents.  Due to the likely lack of published ROC curve trial data, we believe it would be difficult to determine the appropriate ROC curve that best represents the appropriate continuous cut points for the coverage test criteria and it would be more burdensome for the sponsors to determine if their screening test meets our screening test performance criteria.

Comment: Several commenters requested that CMS delay posting of this final decision memorandum in order to hold a MEDCAC on this topic.

Response: The NCD process is described in sections 1862(l) and 1869(f) of the Social Security Act. If a MEDCAC meeting is convened it would occur during the internal review following the initial public comment period and adds an additional 3 months for the posting of the proposed NCD. The final NCD is statutorily due 60 days following the posting of the proposed NCD. A MEDCAC is not convened at other times in the NCD process. The NCD Process Notice can be viewed at:  https://www.cms.gov/medicare/coverage/determinationprocess/downloads/fr08072013.pdf.

Comment: Several commenters supported aligning coverage with FDA market authorization and FDA-authorized labeling and noted that the stool and blood-based tests have different intended uses.

Response: Thank you for the supportive comment. The current FDA authorized blood-based test is intended to detect CRC while the current FDA authorized stool-based tests are intended to detect advanced adenomas and CRC. Please see the above Section II.B. Food and Drug Administration Status, which contains detailed FDA test information.

Comment: Some commenters specifically supported adding stool RNA screening tests to the available Medicare CRC screening tests, while others expressed concern that this testing is inferior to existing stool-based tests. Some commenters noted FDA required a post-approval study (PAS) for ColoSense.

Response: We recognize that current non-invasive CRC screening tests have different sensitivity and specificity for detecting colorectal cancer and are inferior to a screening colonoscopy. While ColoSense has the most recent PAS, they were also required by FDA for the other CRC screening tests. Please see the above Section II.B. Food and Drug Administraion Status, which provides a brief summary of the PAS for each test.

Comment: Some commenters noted concerns that the mt-sRNA test is not generalizable to the Medicare population based on the clinical validation study submitted for FDA authorization.

Response: For the mt-sRNA test, we acknowledge that the pivotal trial included three colorectal cancer cases who were aged 65 years or older.  The PAS for the mt-sRNA test requires that the sponsor add at least 23 more CRC cases in addition to the 27 CRC cases already obtained in the pivotal trial for a total of 50 CRC cases.  The rationale for the increase in the number of CRC cases is to have an adequate number of CRC subjects that are part of the intended use population (average risk) to provide more certainty in the test performance characteristics (SSED, ColoSense. 2024).  The FDA PAS Database can be accessed at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma_pas.cfm.

Comment: Some commenters expressed concern that non-invasive CRC screening tests are not required to be directly compared to FIT, thus complicating the assessment of relative performance. One commenter requested clarification on whether CMS intends to require direct within-study comparisons to FIT, or whether indirect comparisons to published FIT performance would be considered sufficient for future studies.

Response: CMS acknowledges that the strongest evidence for effectiveness of a non-invasive CRC screening test is a direct within study head-to-head comparison with FIT in a pivotal study. However, we also acknowledge that the sponsor, in collaboration with the FDA, has purview over the design of the pivotal study. 

Comment: One commenter noted that the use of minimum upper ‘bound’ in the justification for test performance criteria 1 could be misread as referring to a confidence-bound criterion for sensitivity performance.

Response: Thank you for the comment and we did not intend to confuse terms. We use the terminology “point estimate” everywhere else in the Analysis to show that Criteria 1 and Criteria 2 are point estimates and not confidence intervals. We removed the word “bound” in the final decision to avoid confusion.

Post-Approval Studies

Comment: The majority of commenters supported the test requirement that the test must achieve the requirements of the FDA-required post-approval study (PAS) as specified in the SSED to continue coverage. A few commenters requested the PAS study be completed prior to obtaining Medicare coverage.

Response: We appreciate support for the requirement of achieving the FDA specified results.  We believe that a test’s performance characteristics can be demonstrated in the SSED upon device authorization but, for a test to maintain coverage, it is appropriate that the test achieve the requirements of the FDA-required PAS. Successfully achieving the study objectives and endpoints as specified in the SSED will provide further support for the earlier demonstrated performance characteristics. Tests can be removed from coverage if those objectives and endpoints are not successfully met.

Comment: Some commenters requested clarification regarding how CMS will determine continued coverage after FDA-required post-approval studies are completed and how CMS and FDA will coordinate oversight of those studies.

Response: The FDA’s PAS database is updated according to the report schedule for each study. The website can be accessed at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma_pas.cfm. If a test does not achieve the requirements of the PAS as specified in the SSED, CMS can remove that proprietary laboratory analyses (PLA) code from the coding spreadsheet through the Change Request process.

Clarifications

Comment: NCCN noted that CMS accurately referenced the updated 2025 NCCN Guidelines including stool-RNA and BBB test as recommended screening modalities once every three years but requested some clarifications.

Response: The final decision memorandum includes that NCCN recommends BBB tests as a screening modality for individuals who are not willing to undergo CRC screening through another modality and that the data to help determine adherence to screening as well as how mt-sRNA testing may fit into an overall screening program are limited. The NCCN clarified for us that the reported specificity values on the Screening Modality and Schedule table in the 2025 NCCN guidelines was updated to reflect that multitarget stool DNA testing for colorectal cancer by Imperiale TF, et al, rather than the next-generation mt-sDNA study. The Screening Modality and Schedule table in the 2025 NCCN guidelines also reports, for mt-sRNA, the specificity for advanced adenoma based on the Barnell (2023) publication. The clarifications have been made to the Analysis and Table 4.

Comment: One commenter noted that the yearly annual estimates of new cancer cases derived by the American Cancer Society (ACS) did not represent the most current 2026 data and incorrectly referenced the National Cancer Institute (NCI) as the source of the cancer statistics.

Response: Thank you for bringing this to our attention. We updated the cancer statistics and correctly referenced the source as ACS.

Comment: One commenter noted that it is common practice to report the source of funding in the publication for a clinical trial. Because all studies of commercially available CRC tests are supported by companies that develop the tests, they recommended deleting Bullet 1 listed under ‘Study Limitations’ in Section III.E.4. Assessment of the Evidence as opposed to listing it as a limitation.

Response:While all studies were funded by the test developers, we still find it appropriate to note manufacturer funded studies as they would be considered a generally accepted limitation. The first bullet remains a limitation in the final.

Comment: One commenter recommended deleting Bullet 8 listed under Limitations in Section III.E.4 Assessment of the Evidence. It cites the lack of long-term follow-up to measure morbidity and mortality, and the commenter believes it is unnecessary and unreasonable for these studies to follow up mortality and morbidity. The commenter notes there is broad consensus that new screening technology only needs to demonstrate the detection of surrogate indicators with an established comparison test, with both followed up with colonoscopy as the reference test.

Response: In the Analysis, we acknowledge that mortality is direct evidence of the net health outcome of the CRC screening test. Sensitivity and specificity do not provide direct evidence on net health outcomes.  There is no direct evidence on outcomes such as mortality for newer stool-based or BBB tests used in screening for CRC. USPSTF notes that “newer screening tests with similar sensitivity may result in CRC mortality reductions similar to reductions shown in existing trials. If sensitivity is better, without a trade-off in specificity (e.g., various FITs), mortality reductions could be greater” (USPSTF, 2021). Therefore, we assessed whether there was supporting indirect evidence from studies that used FOBT or FIT as comparators to establish a link to the screening test under consideration. By comparing the test performance characteristics, defined as sensitivity and specificity, of new screening tests to FOBT or FIT, we can assess whether other, newer stool-based and blood-based tests might translate into similar reductions in disease mortality for Medicare beneficiaries. Thus, if the sensitivity and specificity of the new screening tests are as good as or better than the sensitivity and specificity of FOBT or FIT, then we have indirect evidence, based on the intermediate outcomes of sensitivity and specificity, suggesting that the new stool-based or BBB tests may reduce CRC mortality.  In the Analysis, we discuss morbidity as harms related to the non-invasive CRC screening tests.  Bullet 8 remains a limitation in the final because, while not included as direct evidence in any recent study, it should still be noted as an observed limitation of the literature.

Comment: Several commenters were concerned with the definition of specificity as “no lesions removed during colonoscopy.” They believe hyperplastic polyps should be included in the definition of specificity for “no findings.”

Response: We acknowledge that negative colonoscopy (no findings on a colonoscopy) may or may not necessarily crosswalk to numeric categories as the definitions and terminology may differ across studies and SSEDs.  The SSED for the mt-sDNA test defines Category 6.2 as “no lesions on colonoscopy” (SSED for mt-sDNA test, Cologuard Plus, 2024).  The SSED for the mt-sRNA test under the category of Negative Findings (NEG) defines Category 6.2 as “No lesions on colonoscopy” (SSED for mt-sRNA test, Colosense, 2024).  The SSED for the BBB test does not have a Category 6.2 but does define Category 6 as “Negative, or other findings” (SSED for BBB test, Shield, 2024).  In the Barnell (2023) study, under specificity, “No findings” contains two distinct categories: “Hyperplastic polyps < 10 mm or other negative lesions” and “No lesions on colonoscopy”.  In the SSEDs for Category 6.2, hyperplastic polyps and “no lesions removed during colonoscopy” are not part of the definition for Category 6.2.  We acknowledge the distinction between hyperplastic polyps and “no lesions removed during colonoscopy”.  We used the definition of “negative colonoscopy (no findings on a colonoscopy)” for specificity in the final NCD so that we could maximize the consistency of the comparative analysis of specificity across all of the studies that encompasses the results from all of the pivotal trials and incorporates all of the relevant SSEDs.  Links to the SSEDs for each test were added to Section B. ‘FDA Status’ in the final decision memorandum.

Comment: Several commenters requested we update the specificity for the RNA-Based Stool Test to 87.9% for no lesions on colonoscopy under Section III.E. Assessment of the Evidence. The PDM states, “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”. Commenters noted that based on the Barnell (2023) publication, this statement should 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.”

Response: We updated the specificity for the RNA-Based Stool Tests to 87.9% for no lesions on colonoscopy under Section E. Assessment of the Evidence in the final decision memorandum based on the 2023 publication. Please note that the appropriate specificity of 87.9% was used in the calculation of the specificity for Criteria 1.  We did not include the results from the SSED in the calculation of the specificity for Criteria 1. 

Comment: One commenter submitted a publication that included census-adjusted performance estimates for the SimpleScreen blood test and requested the estimates be included in the Evidence Review. SimpleScreen is not FDA market authorized or indicated for CRC screening.

Response: Our evidence review is based on comparing the results that use similar definitions for the outcomes of interest.  We acknowledge the importance of census-adjusted test performance results, but other studies did not report census-adjusted test performance results.  We want to ensure consistency in comparing outcomes across the studies in the comparative analysis.

Comment: One commenter noted that the recommended screening interval for flexible sigmoidoscopy is listed incorrectly as 5-10 years for the 2025 NCCN Guidelines in Table 3 “Professional guidelines for CRC screening in asymptomatic average-risk adults”.

Response: The recommended 2025 NCCN Guidelines screening interval included in Table 3 for flexible sigmoidoscopy has been updated in the final decision memorandum to state a 5-year interval. Please note that Tables 1 through 5 have been renumbered in the final based on public comments. Table 3 is now labeled as Table 4.

Comment: Two commenters noted that the American Society for Gastrointestinal Endoscopy (ASGE) 2025 position statement and the 2024 American Gastroenterological Association (AGA) CRC Workshop Panel publication were not included in the proposed DM.

Response: Thank you for informing us of these publications. The ASGE 2025 position statement is included in Table 4 in Appendix B in the final. We did not include the 2024 American Gastroenterological Association CRC Workshop Panel publication in the Evidence-Based Guidelines because this appears to be an expert consensus statement published as a commentary  based on modeling data and cost effectiveness data, and not clinical trial evidence.

Comment: One commenter noted that Table 5 is missing in the Appendix.

Response: We apologize for the confusion. Table 5 (Sensitivity and Specificity by Test from Key Pivotal Studies and SSED) is embedded in the Decision Memorandum (DM). We renumbered Tables 1 through 5 in the final to be in chronological order and lessen the confusion. Table 5 is now numbered Table 1. Tables 6 through 11 in Appendix B remain the same.

Comment: One commenter identified a typo in Table 8 (Barnell (2023) publication on CRC-PREVENT which examined the multitarget stool RNA (mt-SRNA) test (Table 2) Sensitivity and Specificity of mt-SRNA and FIT) which reads, “No lesions on colonography.” It should read colonoscopy.

Response: We appreciate the feedback. The correction is reflected in the final.

Comment: One commenter noted 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.

Response: Table 1 (Chung 2024) reports the sensitivity for advanced precancerous lesions of 13.2% for the Shield test. Table 11 shows that the Shaukat 2025 study on the SimpleScreen test using circulating tumor-DNA (ct-DNA) reports a sensitivity for advanced precancerous lesions of 12.5%. The reported sensitivities come from different BBB tests. Please note that Tables 1 through 5 have been renumbered in the final based on public comments. Table 1 is now labeled as Table 2.

Comment: One commenter noted that the PDM had no mention of CISNET and references no modeling evidence inconsistent with CMS’s prior NCD on blood-based CRC screening from 2021.

Response: In the 2021 Blood-Based Biomarker CRC screening decision memo, we did not include CISNET modeling studies in our internal technology systematic review of the published primary evidence.

Comment: Some commenters requested that CMS explicitly preserve existing FIT coverage and clarify that this proposal does not alter current FIT policy.

Response: The final NCD does not alter the current FIT policy.

Additional Comments

Comment: One commenter suggested that CMS authorize physician associates/assistants (PAs) to perform colonoscopies by modifying 42 CFR § 410.37(f) that payment for colonoscopies only be made when performed by a Doctor of Medicine or Osteopathy.

Response: Changes to 42 CFR § 410.37(f), which governs Medicare coverage for colorectal cancer screening tests, occur through the federal rulemaking process and is not under the purview of this NCD reconsideration.

Comment: A few commenters cited modeling data to estimate cost associated with unnecessary colonoscopies and the cost differences among the non-invasive screening tests.

Response: We appreciate the comments regarding cost effectiveness however, the focus of this NCA is whether non-invasive biomarker CRC screening tests detect CRC. While colonoscopy is the gold standard, non-invasive screening tests provide individuals not willing or able to undergo a colonoscopy, an alternative. A risk of using a non-invasive screening test is the risk of  a false positive. The final NCD includes criteria that the patient is provided with information about the test performance and the importance of a follow-on colonoscopy if the test returns a positive result.

IV.         CMS Coverage Authority

National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally by Medicare (§ 1869(f)(1)(B) of the Act).  In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B and must not be otherwise excluded from coverage.  Moreover, with limited exceptions, items or services must be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member (§ 1862(a)(1)(A) of the Act).  Congress has specifically authorized coverage of certain screening tests under Part B of the Medicare program. CRC screening tests have a benefit category under §1832, §1861(s)(2)(R) and §1861(pp) of the Act. Specifically, we are using the NCD authority under section 1861(pp)(1)(D) (and implementing regulations at 42 CFR 410.37(a)(1)(v)) to determine whether the scope of the CRC screening benefit should be expanded.

This section includes CMS’ analysis of the evidence related to the use of non-invasive biomarker tests for CRC screening. Relevant details from studies listed in Tables 1 and 2 (Appendix B) are provided in context when key study findings or limitations are discussed with respect to coverage.

The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that the specific assessment questions raised in a National Coverage Analysis (NCA) can be answered conclusively. When conducting NCAs for an item or service under the reasonable and necessary statute, CMS generally makes three kinds of assessments: (1) The quality of relevant individual studies; (2) What conclusions can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential harms and benefits; and (3) The generalizability of findings from relevant studies to the Medicare beneficiary population.  (See CMS’ Evidence Review Guidance Document).

CMS covers non-invasive biomarker CRC screening according to the provisions in Section I.B. Coverage Criteria under the Decision section of this document, which are explained below.

A.    Ordering Criteria:

Rationale for ordering practitioner:

We do not believe there is an evidentiary reason to limit the ordering of non-invasive CRC screening test to physicians and are proposing to allow physicians, physician assistants, nurse practitioners, or clinical nurse specialists who will use the results in the management of the patient to order these tests. 

We encourage a discussion between the patient and their practitioner to include the balance of benefits and harms of CRC screening, along with the patient’s health status, including life expectancy and comorbid conditions; prior screening status; family history; and individual patient preferences. Clinicians and patients may consider a variety of factors in deciding which screening test may be best for each individual. For example, each test requires different frequencies of screening, location of screening (home or office), methods of screening (stool-based or blood-based, or direct visualization), preprocedural bowel preparation, anesthesia or sedation, and follow-up for abnormal findings (USPSTF, 2021). We believe the consultation should also include a discussion of the importance of adherence to non-invasive CRC screening frequency guidelines, the impact of comorbidities, and ability or willingness to undergo follow-on colonoscopy for diagnosis and treatment, since these concepts are an integral and important component of the benefit and harm discussion around non-invasive CRC screening and a positive screening test should result in a timely follow-on colonoscopy. Discussion of these considerations with a patient may help better identify CRC screening tests that are more likely to be completed by a given individual.

B.    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 non-invasive biomarker colorectal cancer screening test); and,
3. At average risk of developing CRC (no personal history of adenomatous polyps, CRC, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of CRCs or adenomatous polyps, familial adenomatous polyposis, or hereditary nonpolyposis CRC); and,
4. Provided with information about the test performance and the importance of a follow-on colonoscopy if the test returns a positive result.

Rationale for patient criteria:
Age Range (45 to 85 years): A number of professional societies and organizations have developed guidelines for CRC screening using non-invasive CRC screening tests.  The American Cancer Society (ACS) recommends screening at age 45 years to age 85 years (Wolf, 2026). The American College of Gastroenterology (ACG) recommends CRC screening at 45 years to 75 years old (Shaukat, 2021). The 2021 USPSTF recommends CRC screening at 45 years to 85 years (Davidson, 2021). 

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).

Since the methodology and analytic approach for CRC screening tests have been used consistently for past considerations, we determined that the age range for screening will remain as 45 years to 85 years for non-invasive CRC screening tests. 

Asymptomatic: Preventive services are generally for individuals without symptoms of the disease being screened. We are updating the positive gFOBT or FIT test language to align with new FDA market authorized non-invasive biomarker CRC screening tests that have come to market, including the mt-sDNA test, mt-sRNA test, and BBB test. We are expanding the definition of asymptomatic to include any positive test result for non-invasive biomarker tests. 

At average risk of developing colorectal cancer: Preventive services help prevent illness, detect health conditions early when they are most treatable, and manage disease to avoid complications.  Individuals at high risk require a more focused, intensive approach for screening.

Provided with information about the test performance and the importance of a follow-on colonoscopy if the test returns a positive result: It is important for the patient to know the risks and benefits based on the test performance and the importance of a follow-on colonoscopy if the test returns a positive result. NCCN recommends for individuals at average risk, the choice of a particular screening modality should include a conversation with the patient concerning their preference and availability. (p. CSCR-1, NCCN, 2025). The final NCD includes criteria that the patient is provided with information about test performance and the importance of a follow-on colonoscopy if the test returns a positive result.

C.     Test Criteria

1. The test must be FDA market authorized and indicated for CRC screening; and,
2. The test must achieve the requirements of the FDA-required post-approval study as specified in the SSED to continue coverage; and
3. The test must be processed in a CLIA certified laboratory; and,
4. 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.
   
   

   	Test Performance Criteria 1	Test Performance Criteria 2
   Sensitivity for CRC	≥ 90%	≥ 79%
   Specificity for CRC	≥ 87%	≥ 90%

Rationale for test criteria:
FDA market authorized and indicated: The non-invasive CRC screening test must follow the FDA-approved label indication for colorectal cancer screening.

FDA-required post-approval study: 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 require this for continued reasonable and necessary coverage. The test must complete the post-approval study, and the FDA specified results must be achieved. 

CLIA certified laboratory: The non-invasive CRC screening test must be performed in a CLIA certified laboratory to ensure the accuracy, reliability, and timeliness of the patient test results.

Sensitivity and specificity criteria: Parameters of Test Criteria

Our framework for specifying two sets (Criteria 1 or Criteria 2) of cut points for both sensitivity and specificity uses an evidence-based approach, provides continuity of coverage for tests currently covered by Medicare, provides coverage predictability for tests coming onto the market and covers a range of tests (across non-invasive biomarker) so the patient and their practitioner can select the test that is most appropriate for the patient and that the patient is willing to complete. This proposal also offers innovators more flexibility to improve the overall performance of CRC screening tests. Given the inverse relationship between sensitivity and specificity, we believe that having the “or” statement could allow for innovation in the development of non-invasive CRC screening tests. 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.

The non-invasive CRC screening test must fulfill ONE of the test performance criteria to meet the test criteria for coverage.

Test performance criteria 1:

If the test has a sensitivity that is greater than or equal to 90%, then the specificity must be greater than or equal to 87%.

Test performance criteria 2:

If the test has a specificity that is greater than or equal to 90%, then the sensitivity must be greater than or equal to 79%.

The cut points allow for a balance of the false positive rate against the false negative rate. We were concerned about the tradeoff relationship between low sensitivity and high false negative rate, leading to incorrectly informing a patient that they do not have cancer resulting in missing individuals with CRC. Additionally, we acknowledge the tradeoff between low specificity and a high false positive rate, leading to incorrectly telling a patient that they have cancer when they do not, resulting in unnecessary follow up procedures (colonoscopy) and emotional stress. It is important to note that colonoscopy is the gold standard for diagnosing CRC. While we are interested in decreasing the false positive rate, having a highly sensitive test decreases the false negative rate.  We have a focus on improving the false negative rate out of concern over minimizing the possibility of incorrectly telling a patient that they do not have CRC and reducing the opportunity of missing cases of CRC. The test performance criteria will yield the most reasonable balance of the benefits and harms of the non-invasive CRC screening test based on the evidence available.

Test performance characteristics that allow some flexibility could encourage innovation and promote competition to develop better tests and will encourage manufacturers to develop screening tests with sensitivities and specificities above the cut points.

This approach will also allow sponsors to develop non-invasive screening tests with higher sensitivity and specificity for AA. While we acknowledge the utility and potential clinical benefit of screening for AAs, there is very limited available evidence on the accuracy of non-invasive screening tests to detect AAs and the sensitivity of FIT for AA is low (Imperiale, 2019), which we further discuss in the section on AA. Thus, we do not include point sensitivity or specificity to screen for AA in the decision.

This NCD outlines coverage criteria for any current or future noninvasive biomarker FDA approved/cleared screening tests. We believe non-invasive stool-based and blood-based screening tests and potential future non-invasive biomarker screening tests should be considered using the same methodology. Further, published evidence demonstrates that non-invasive CRC screening tests that meet these criteria would improve health outcomes for Medicare patients. Therefore, by establishing criteria in the NCD that is not test-specific but rather across non-invasive biomarker tests, the NCD will not require reconsideration as new tests come to market.

In past NCDs on screening FIT, stool DNA tests (Cologuard®), and BBB tests, we determined test performance criteria that would improve health outcomes (early diagnosis, reduced mortality).  The methodology in this NCD builds upon prior work and better serves beneficiaries by eliminating delays to coverage as new tests meet the CMS criteria.    

The following table reviews the sensitivity and specificity of CRC screening tests currently on the market. 

Table 1. Sensitivity and Specificity by Test from Key Pivotal Studies and SSED

* Because the SSED and the publication of the results of the pivotal trial occur at different times, the sensitivity shown in the SSED might be somewhat different from the sensitivity shown in the published Imperiale (2024) pivotal trial results, as seen in Table 1.  For example, in the study of Cologuard Plus™, the analysis in the Imperiale (2024) study had a slightly larger study population and had 98 CRC cases which is 13 more CRC cases when compared to the Cologuard Plus™ SSED which had 85 CRC cases.

To reduce the burden on providers and to streamline implementation of the NCD, we are clarifying the parameters of the test criteria for the analytic comparison.  It will be necessary to demonstrate at least equivalent test performance of a new stool-based or blood-based CRC screening test. In the BBB screening test NCD, we established the specific threshold relative to FIT since it has been shown to prevent CRC and improve health outcomes for patients with early-stage CRC. We recognize the importance of test performance and note that there may be harms associated with utilizing a screening test with lower performance. As noted in the background, there has been a steady decline in CRC mortality due in large part to cancer prevention (removal of large or AAs before large adenomas progress to cancer) and detection of cancer at an early stage where treatments are most effective in improving survival.  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.  For the parameters of the test criteria, we selected minimum upper and minimum lower cut points that are point estimates for specificity and sensitivity. 

Specificity

Specificity Criteria 1

We used a different approach for selecting the specificity for Criteria 1. We selected the lowest point from across the range of estimates for specificity. In Table 1 above, the lowest specificity among the recent key pivotal studies is 87.9% (we excluded the specificity (86.6%) for the original mt-sDNA test since that test has been replaced by a newer generation). The results of the pivotal study for the mt-sRNA test published in the Barnell (2023) study reported a specificity of 87.9%, which was the lowest specificity for no lesions on colonoscopy. The specificity of 86.9% was excluded because this was the specificity for no findings. Therefore, the specificity is 87% which is an acceptable point estimate when coverage is driven by a high sensitivity (Criteria 1 sensitivity ≥90%). 

Specificity Criteria 2

We base the specificity on the BBB test cut point (established in a prior NCD) at 90%.  CMS did not identify a compelling reason to change this cut point when test characteristics are driven by higher specificity. 

Specificity Definitions

The use of specificity was inconsistent across publications. Table 6 (Appendix B) provides the test result histopathological classification system shown in the SSED for the mt-sRNA test (ColoSense®). As seen in Table 6, specificity can be defined as test results with negative findings which include categories 3.1 to 6.2.  Other definitions for specificity include non-advanced precancerous lesions (NAPL) defined as category 3 to 5. Alternatively, specificity can be defined as negative (NEG) findings consisting of category 6 which includes category 6.1 and 6.2, as shown in the Imperiale (2024) study. 

Table 7 (Appendix B) from the SSED for ColoSense® is based on the specificity test result histopathological classification system, NAPL (category 3 to 5) and NEG findings (category 6).

In Table 8 (Appendix B) from the Barnell (2023) publication on CRC-PREVENT which examined the mt-sRNA test, specificity was defined in several ways including medium-risk adenomas, low risk adenomas, and no findings, with each category including several subcategories. The specificity reported in the SSED is different from the specificity reported in the Barnell (2023) publication on CRC-PREVENT which examined the same mt-sRNA test but used different definitions for specificity, such as medium-risk adenoma, low-risk adenoma, and no findings. 

In Table 9 (Appendix B) from the Imperiale (2024) study on the next-generation Cologuard Plus™ test, the authors reported on three definitions of specificity based on the specificity test result histopathological classification system which were categories 3 through 6, category 6 (6.1 or 6.2), and category 6.2.

The sensitivity and specificity for the mt-sDNA, mt-sRNA, and the BBB (bb-cf-DNA) tests are shown in Table 10 (Appendix B) from the NCCN 2025 guidelines.  For the mt-sRNA test, the sensitivity for colon cancer is reported to be 94% but no specificity for colon cancer is shown.

A pivotal study on the circulating tumor DNA-based blood-based (ct-DNA) test SimpleScreen™ was recently published (Shaukat, 2025). Table 11 (Appendix B) reported the specificity for a ct-DNA-based blood-based test which was defined in several different ways including no findings (category 4.4) with category 4.4 defined as “no findings on colonoscopy, no histopathological review” (Shaukat, 2025). The definition of specificity used in the ct-DNA-based blood-based test clinical trial appears to be different from how specificity was defined in the specificity test result histopathological classification system used in the SSED for ColoSense® (mt-sRNA).

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.  NCCN provided 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."

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) which may (but does not necessarily) crosswalk to numeric categories as they may differ across studies. Further, we could not find any consensus statement on how to report specificity using a uniform methodology.

Sensitivity

Sensitivity Criteria 1

Instead of selecting from across the range of estimates of point threshold levels for sensitivity, since many of the point estimates clustered above 90%, we averaged the point levels for sensitivity to come up with an arithmetic mean sensitivity that can be used as a sensitivity cut point. We used the sensitivity for the next-generation mt-sDNA test published in the Imperiale (2024) study because it is the updated version of the mt-sDNA test that was published in the earlier Imperiale (2014) study. The arithmetic mean sensitivity among the key pivotal studies in Table 1 above is (94.4% [mt-sRNA]+ 93.9% [only next generation mt-sDNA] + 83.1% [BBB] / 3) 90.46%.  The sensitivity upper point estimate is 90%.

Sensitivity Criteria 2

The lowest overall sensitivity among the publications in the table of key pivotal studies in Table 1 above is 79.2% which is the sensitivity of the ct-DNA blood test. The sensitivity lower point estimate is 79%.  This appropriately will allow continuity of coverage of a blood-based screening test and pairs this sensitivity with a high specificity of ≥ 90%.

Advanced Adenomas

While we acknowledge the utility and potential clinical benefit of screening for AAs, the definitions for AAs have been used inconsistently. 

In the SSED for ColoSense®, AA was defined in three different categories (Table 6-Appendix B) as Category 2.1 High-grade dysplasia (HGD) or ≥ 10 adenomas, any size; Category 2.2 Tubulovillous adenoma (TVA), any size; or Category 2.3 Tubular adenoma, > 10 millimeters (mm).  In addition, a positive test result was defined as a Serrated Precancerous Lesions (SPL) (Category 2.4).

In the Barnell (2023) study on the mt-sRNA test, lesions within the AAs category were defined as at least 10 adenomas of any size or lesions with HGD, tubulovillous adenomas (TVA); any size, or traditional serrated adenomas (TSA) or tubular adenomas (TA); ≥10 mm. 

In the Imperiale (2024) study on the next-generation mt-sDNA test, the authors reported on advanced precancerous lesions (APLs) defined as adenomas and sessile serrated lesions (SSL) (including large, hyperplastic polyps) that were at least one (1) centimeter (cm) in the longest dimension, lesions with villous histologic features, or HGD.

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.

The general term “polyp” is an abnormal growth of tissue that protrudes from the surface of an organ, like the large intestines of the gastrointestinal (GI) tract.  The term “polyp” in the practice guidelines refers to both polyps (polypoid lesions) and nonpolypoid (flat) lesions.  The guidelines define polypoid lesion as a lesion protruding from the surface of the GI mucosa into the lumen that is ≥ 2.5 millimeters (mm).

The term “adenomas” is used synonymously with “adenomatous polyps”, which are most often found to be tubular. Adenoma is defined as noninvasive neoplastic lesion of the columnar epithelium. AA is defined as an adenoma that is ≥ 1 cm or has villous or tubulovillous histology, or HGD. TVAs are comprised mostly of tubular glands and have <25% villous features. Villous adenomas have high risk features such as a polyp/adenoma with > 75% villous structures (long finger-like or leaf-like projections on the surface). TVAs have high risk features such as a polyp/adenoma with 25%-75% villous histology.  HGD has high risk features and refers to the distribution of nuclei within the cells.

The three main subtypes of serrated polyps (SPs), another precursor lesion of colorectal cancer, are SSP / SSLs, traditional serrated adenomas (TSAs), and hyperplastic polyps. It is noted that the classification systems for serrated lesions continue to evolve. 

In the 2021 USPSTF CRC screening recommendation statement, in four studies on Cologuard® (n = 12,424) reporting the accuracy of sDNA- FIT (now designated as mt-sDNA in this decision memo), pooled sensitivity for CRC detection was 0.93 (95% confidence interval [CI], 0.87-1.0) and pooled specificity was 0.84 (95% CI, 0.84-0.86), with a lower pooled sensitivity for detecting AAs (0.43 [95% CI, 0.40-0.46]) but higher pooled specificity (0.89 [95% CI, 0.86-0.92]).  It appears that in these studies of sDNA-FIT, the pooled sensitivity for detecting AAs was 43%.

There appears to be an inconsistent use of definitions for AAs. We could not find a standardized uniform methodology or a consensus statement for reporting AAs. The sensitivity for detecting AAs remains around 40% to 43%. 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 screen for AA in the test performance criteria. 

Advanced Adenoma Detection Rates

The benefits of early detection of advanced adenomas have been well demonstrated.  Examining the evidence for advanced adenomas, the advanced adenoma detection rates are low across all the non-invasive tests with blood-based tests being the lowest.  The sensitivity of the mt-sRNA test for advanced adenoma was 46% (ColoSense, Geneoscopy; Barnell, 2023), the highest sensitivity for advanced adenomas.  If a screening test has a sensitivity of 46%, then over half (54%) of the test results will be erroneous (false negative test result).  The sensitivity of the next generation mt-sDNA test for advanced adenomas (advanced precancerous lesions in the publication) was 43% (Cologuard Plus, EXACT Sciences; Imperiale, 2024).  Other pooled sensitivities for detecting advanced adenomas are lower (earlier versions of mt-sDNA test, 43%; USPSTF, 2021; fecal immunochemical test [FIT], 23%; USPSTF, 2021) giving rise to even more incorrect test results.  The sensitivity of a blood-based biomarker (BBB) test for advanced precancerous lesions (advanced precancerous lesions include advanced adenomas and sessile serrated lesions at least 10 mm in the largest dimension) was 13% (Shield, Guardant Health; Chung, 2024).

Hypothetically, if a cut point based on sensitivity for advanced adenomas was selected, as coverage test criteria or for designating a second line CRC screening test, this cut point would be a minimum cutpoint.  If a sensitivity cut point for advanced adenomas was selected as 43%, as suggested by some public comments, then blood-based tests would become non-covered, because of a sensitivity (13%) far below the cut point (43%), even though they have been coverable by Medicare since 2021 and the first covered test came to market in 2025.

The benefits of screening for early detection of precancerous lesions have been well demonstrated. However, if a screening test has a sensitivity of 43%, then over half (57%) of the test results will be erroneous. The sensitivity for detection of adenomas by colonoscopy ranged from 89% to 95% (USPSTF, 2021). We look forward to innovators continuing to improve the accuracy of identifying precancerous lesions and look forward to practice guidelines and prevention recommendations reviewing and recommending tests based on this ability.  

While stool-based tests have a higher detection rate than blood-based, the rates are still below 50%, meaning over half of the test results will be erroneous.  The final NCD maintains the test performance criteria to detect CRC only and does not include a criterion to detect advanced adenoma. The final NCD includes criteria that the patient is provided information about the test performance so that the most appropriate test is selected and the patient is aware of the importance of a follow-on colonoscopy if the test returns a positive result.

Consistent CRC Detection Test Criteria for Stool-based and Blood-based Tests

Comparing stool-based screening tests to blood-based tests in this decision, we acknowledge the technological differences in the testing platforms and the differences in the physiological and biochemical pathways in how the colorectal cancer molecular biomarkers involved in abnormal cell growth, cancer development, and other cancer-derived signals reach the test devices.   However, sensitivity for colorectal cancer detection for stool-based and blood-based tests used in this decision memo falls within a narrow range (79% to 95%), as does specificity for colorectal cancer for both types of tests (87% to 93%).  In the final NCD, the test performance coverage criteria for colorectal cancer detection for the stool-based tests and the blood-based tests are not separated.  This approach standardizes coverage by applying consistent criteria across the testing modalities (e.g. stool-based, blood-based).

Second Line Test Designation

In 2025, the National Comprehensive Cancer Network (NCCN) for bb-cfDNA-based tests, called in this NCD as BBB tests, stated that “given its modest performance, particularly among advanced precancerous lesions, this test is only recommended for individuals who would not be willing to undergo screening through another modality” (NCCN, 2025). The USPSTF has not evaluated BBB tests as a colorectal cancer screening test.  However, in the Safety and Effectiveness Data (SSED) for the BBB test, the Indications for Use label does not designate using the BBB test as a second line test or recommending this test for individuals who refuse or are unwilling to use another screening modality nor is it mentioned as a Precaution (SSED-BBB Shield test, 2024).  The final decision language provides coverage for Food and Drug Administration (FDA) market authorized tests that are used according to label.  

The American Cancer Society stated in their 2026 guideline update for colorectal cancer screening that “[b]lood‐based screening tests are not preferred screening options at this time; they should be recommended only to individuals who decline or have not completed one of the preferred colorectal cancer screening tests.  Blood‐based tests should not be ordered without prior discussion with the patient.  Patients who choose a blood‐based test should be informed that: Blood‐based tests have lower sensitivity than high‐sensitivity stool‐based tests and direct visual examinations in detecting advanced precancerous lesions and stage I colorectal cancers, limiting their effectiveness for reducing colorectal cancer incidence and mortality relative to the preferred options. . . . If their blood‐based test is positive, patients will need to undergo a follow‐up colonoscopy to complete the screening process.” (Wolf, 2026).

Given that the sensitivity for colorectal cancer detection for stool-based and blood-based tests used in this decision falls within a narrow range (79% to 95%), as does specificity for colorectal cancer for both types of tests (87% to 93%), which we can consider appropriate given the role of the ordering practitioner to order the test most appropriate for the patient, it is not possible to separate out second line tests from first line tests based on the test performance for colorectal cancer detection for both types of tests.  

Given that the FDA indications for stool and blood tests are for colorectal cancer screening and do not designate first or second line test, we are emphasizing the importance of the health care provider discussing with the patient the issues about the effectiveness of non-invasive colorectal cancer screening tests in improving health outcomes and the importance of a follow-on colonoscopy to confirm the diagnosis of colorectal cancer.  In the final decision language under patient criteria for coverage, we have outlined the general components of what should be discussed with the patient. The most appropriate test for the patient is based on knowledge of test performance, understanding of a follow-on colonoscopy if a positive non-invasive test result and patient preferences.  In response to public comments, the final NCD includes language for a patient criterion so that the patient is provided with information about test performance and the importance of a follow-on colonoscopy if the non-invasive screening test returns a positive result.

Implementation of Threshold Test Performance Criteria

In determining the performance characteristics for any test, we suggest using the sensitivity and specificity data published in the FDA label. Because the FDA label includes the results from the pivotal study, the sensitivity and specificity of the new screening test can be compared to CMS’ Criteria 1 and Criteria 2 cut points.  The analysis of sensitivity and specificity will be valid as long as the pivotal study incorporates colonoscopy as the gold standard comparator to the new CRC screening test.  If the pivotal study does not estimate the sensitivity and specificity of the new non-invasive CRC screening test, then the test performance characteristics may come from another published comparative clinical study that has colonoscopy as the gold standard comparator. We expect the results of new non-invasive CRC screening tests to be generalizable to the Medicare population.

To further demonstrate clinical utility of this type of screening test, if applicable, the non-invasive CRC screening test must achieve the requirements of the FDA-required PAS as specified in the SSED to continue coverage. In the PAS, the screening test must achieve the study objectives and the study endpoints as specified in the SSED.  Failure to comply with post-approval requirements as stated in the FDA approval letter will result in noncoverage. 

Frequency of testing

Non-invasive biomarker CRC screening tests are covered once every three years.

Rationale for testing frequency
A number of professional societies and organizations have developed guidelines for CRC screening using non-invasive CRC screening tests. The ACG recommends the mts-DNA test every three years (Shaukat, 2021), the ACS recommends the mt-sDNA test every three years (Wolf, 2026), and the USPSTF in 2021 recommends the mt-sDNA every one to three years (Davidson, 2021).

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 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). 

NCCN provided the following comments for clarification.

“The NCCN 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-sRNA] 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.”

“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.”

This approach is consistent with the past NCDs on both stool-based and blood-based non-invasive CRC screening tests.

Our review of the evidence on the clinical utility of CRC screening for Medicare beneficiaries was guided by two general questions.

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?

Yes - The evidence demonstrates that screening in Medicare beneficiaries using a non-invasive CRC screening test is suitable for prevention or early detection of CRC. The published evidence shows that the tests we reviewed that met either Category 1 or Category 2 criteria improve health outcomes for Medicare beneficiaries. 

The key pivotal studies for the mt-sDNA test, the mt-sRNA test, and the BBB test provided the evidence for the analysis of sensitivity. The sensitivity for the FIT test is used as a comparator, since there is a large evidence base that was available on the accuracy of FIT. In the USPSTF CRC screening recommendation for FIT, the pooled sensitivity for detection of CRC was 74% and pooled specificity was 94% (USPSTF, 2021). Among the key pivotal studies, sensitivity is higher than 74% for the BBB test (83.1%; Chung, 2024), the next-generation mt-sDNA test (93.9%; Imperiale, 2024), and the mt-sRNA test (94.4%; Barnell, 2023). With the ct-DNA-based blood-based test included in the analysis, the sensitivity (79.2%; Shaukat, 2025) is also greater than the sensitivity for FIT. 

The key pivotal studies for the mt-sDNA test, the mt-sRNA test, and the BBB test provide the evidence for the analysis of specificity. The comparator for specificity of 90% is used which was the test performance criterion for the specificity cut point from the Screening for Colorectal Cancer - Blood-Based Biomarker Tests (CAG-00454N) decision memo (CMS, 2021). Among the key pivotal studies, specificity was found to be higher than 90% for the next-generation mt-sDNA test (93.4%; Imperiale, 2024). The specificity for the ct-DNA blood-based test (91.5%; Shaukat, 2025) is also greater than the specificity of 90%.

As noted in the Screening for Colorectal Cancer - Stool DNA Testing (CAG-00440N) decision memo (CMS, 2014), like other non-invasive, stool-based CRC screening tests (FOBT, FIT), the harms from the mt-sDNA, and, for this decision memo, the mt-sRNA test are likely to be small. The associated harms lie in the downstream risks from diagnostic and therapeutic colonoscopy after a positive mt-sDNA test or positive mt-sRNA test. The harms from colonoscopy have been well documented and are generally considered low.

The primary harms from stool-based screening tests are thought to come from false-positive and false-negative results and from harms of workup of positive non-invasive screening test results, such as colonoscopy. Serious harms from colonoscopy to follow-up positive screening results are estimated to be 17.5 serious bleeding events and 5.4 perforations per 10,000 colonoscopies (USPSTF, 2021). Rates of serious bleeding events and perforations are lower with screening colonoscopy than with colonoscopy performed following positive stool-based screening test results (presumably because of fewer biopsies and adenoma removals), with 14.6 major bleeding events per 10,000 colonoscopies and 3.1 perforations per 10,000 colonoscopies (USPSTF, 2021).

If sedation is used during colonoscopy, cardiopulmonary events may rarely occur, although the precise frequency of occurrence is not known. Other serious reported harms include infection and other gastrointestinal events (besides bleeding and perforation). Bowel preparation for colonoscopy may lead to dehydration or electrolyte imbalances, particularly in older adults or persons with comorbid conditions, but accurate estimates of the rates of these events were not available (USPSTF, 2021).

Overall, the mt-sDNA test, the mt-sRNA test, and the BBB test are suitable screening tests for CRC with a higher sensitivity compared to another currently covered stool-based screening test, FIT. For the mt-sDNA test, this is consistent with the ACG (Shaukat, 2021), the 2021 USPSTF (Davidson, 2021), the ACS (Wolf, 2026), and the 2025 NCCN (NCCN, 2025) recommendations for the mt-sDNA test as a suitable test for CRC screening. For the mt-sRNA test, the 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 CRC screening guidelines and added mt-sRNA as a recommended stool-based CRC screening strategy (NCCN, 2025). The ACS 2026 guideline update for colorectal cancer screening includes the mt-sRNA test among the preferred stool-based test options (Wolf, 2026).  As noted in the previous BBB NCD (CAG-00454N; CMS, 2021), the BBB test is suitable for CRC screening. Relevant to this decision, the NCCN includes the BBB test (bb-cf-DNA) as a suitable modality for CRC screening (Chung, 2024; in NCCN, 2025). The ACS 2026 guideline update states that BBB tests are not preferred screening options at this time; they should be recommended only to individuals who decline or have not completed one of the preferred colorectal cancer screening tests (Wolf, 2026). 

The benefits outweigh the harms for using non-invasive tests to screen for CRC. As a suitable screening test likely to lead to improvements in health outcomes, the evidence is sufficient to conclude that CRC screening in Medicare beneficiaries using the mt-sDNA test, the mt-sRNA test, and the BBB test are suitable for prevention or early detection of CRC.

We will apply the same approach to determine which CRC screening tests are appropriate to include in the Medicare program as used with previous non-invasive CRC screening tests. Previous NCAs discussed appropriate test performance criteria such as point sensitivity and specificity compared to colonoscopy. We note that the determination of appropriateness is similar to the consideration of what is appropriate for a device to be “at least as beneficial as an existing and available medically appropriate alternative.”

Sensitivity and specificity measure the accuracy of the test to assess clinical validity of the test. These outcomes assess the ability of the test to accurately identify CRC in patients screened for cancer. Sensitivity and specificity do not provide direct evidence on net health outcomes. Mortality is direct evidence of the net health outcome of the CRC screening test. Mortality, or survival, measures the impact of the screening test on health outcomes to assess clinical utility of the test and is dependent on the detection of large adenomas and early-stage cancer where treatments have been shown to be more effective. Mortality is a health outcome relevant to Medicare beneficiaries being screened for CRC. 

Through the evaluation of evidence from published studies, the clinical data for the test must reach the threshold for being appropriate. The direct evidence by Shaukat, et al. (2013) and Levin et al. (2018) suggests that there is clinical utility in using FOBT and FIT for early detection of CRC because these tests reduce mortality of the disease. In the USPSTF systematic review of observational studies, receipt of screening colonoscopy or FIT was associated with lower risk of CRC mortality, in addition to similar results for randomized clinical trials of flexible sigmoidoscopy and gFOBT (USPSTF, 2021). Conversely, there is no direct evidence on outcomes such as mortality for newer stool-based or BBB tests used in screening for CRC. USPSTF notes that “newer screening tests with similar sensitivity may result in CRC mortality reductions similar to reductions shown in existing trials. If sensitivity is better, without a trade-off in specificity (e.g., various FITs), mortality reductions could be greater” (USPSTF, 2021). Therefore, we assessed whether there was supporting indirect evidence from studies that used FOBT or FIT as comparators to establish a link to the screening test under consideration. By comparing the test performance characteristics, defined as sensitivity and specificity, of new screening tests to FOBT or FIT, we can assess whether other, newer stool-based and blood-based tests might translate into similar reductions in disease mortality for Medicare beneficiaries. Thus, if the sensitivity and specificity of the new screening tests are as good as or better than the sensitivity and specificity of FOBT or FIT, then we have indirect evidence suggesting that the new stool-based or BBB tests may reduce CRC mortality.

As suggested by Cochrane and Holland (1971), test performance characteristics are defined as sensitivity and specificity. However, the validation of a screening test does not include an assessment of adherence or compliance with CRC screening guidelines (Cochrane & Holland, 1971). Level 2 diagnostic accuracy efficacy, or test performance characteristics, is defined as sensitivity and specificity in a defined clinical problem setting, not compliance with screening guidelines (Fryback & Thornbury, 1991).

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

Yes - The published evidence demonstrates that the available mt-sDNA test, mt-sRNA test, and the BBB screening test will identify CRC biomarkers sufficiently early to perform interventions to prevent progression of AAs to cancer or to improve health outcomes for patients found to have CRC during screening. To provide clarity to innovators and to reduce burden of a reconsideration of this NCD, we provide a direct pathway for coverage of appropriate mt-sDNA, mt-sRNA, and BBB CRC screening tests when the criteria are met.

Among the cited key pivotal studies, individuals at least 65 years of age were included in the study populations.  Both men and women were adequately represented in the evidence base, especially among the key pivotal studies. 

Medicare is a defined benefit program.  For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act. Congress has specifically authorized coverage of certain screening tests under Part B of the Medicare program. CRC screening tests have a benefit category under §1832, §1861(s)(2)(R) and §1861(pp) of the Act. Specifically, we are using the NCD under section 1861(pp)(1)(D) (and implementing regulations at 42 CFR 410.37(a)(1)(v)) to determine the details of the changes to NCD (210.3) Colorectal Cancer Screening Tests.

For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in §1812 (Scope of Part A); §1832 (Scope of Part B); or §1861(s) (Definition of Medical and Other Health Services) of the Act.

CRC screening tests qualify as:

• Colorectal Cancer Screening Tests

Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

V.            History of Medicare Coverage

This is a reconsideration of NCD (210.3) Colorectal Cancer Screening Tests. This reconsideration was externally initiated. CMS received a complete, formal request to open a reconsideration of the topic from Geneoscopy, Inc. The request letter is available at https://www.cms.gov/files/document/id319.pdf.

VI.         Appendices

Appendix A: Medicare National Coverage Determinations Manual Language

210.3 – Colorectal Cancer Screening Tests

A. General

Sections 1861(s)(2)(R) and 1861(pp) of the Social Security Act (the Act) and regulations at 42 CFR 410.37 authorize Medicare coverage for screening colorectal cancer tests under Medicare Part B. The statute and regulations authorize the Secretary to add other tests and procedures (and modifications to tests and procedures for colorectal cancer screening) as the Secretary finds appropriate based on consultation with appropriate organizations.

B. Nationally Covered Indications

1. Fecal Occult Blood Tests (FOBT)

Fecal occult blood tests (FOBTs) are generally divided into two types: immunoassay and guaiac types. Immunoassay (or immunochemical) fecal occult blood tests (iFOBT) use “antibodies directed against human globin epitopes. While most iFOBTs use spatulas to collect stool samples, some use a brush to collect toilet water surrounding the stool. Most iFOBTs require laboratory processing.

Guaiac fecal occult blood tests (gFOBT) use a peroxidase reaction to indicate presence of the heme portion of hemoglobin. Guaiac turns blue after oxidation by oxidants or peroxidases in the presence of an oxygen donor such as hydrogen peroxide. Most FOBTs use sticks to collect stool samples and may be developed in a physician’s office or a laboratory. In 1998, Medicare began reimbursement for gFOBTs, but not immunoassay type tests for colorectal cancer screening. Since the fundamental process is similar for other iFOBTs, the Centers for Medicare & Medicaid Services evaluated colorectal cancer screening using immunoassay FOBTs in general.

Medicare covers one screening FOBT per annum for the early detection of colorectal cancer. This means that Medicare will cover one gFOBT or one iFOBT at a frequency of every 12 months; i.e., at least 11 months have passed following the month in which the last covered screening FOBT was performed, for beneficiaries aged 45 years and older. The beneficiary completes the existing gFOBT by taking samples from two different sites of three consecutive stools; the beneficiary completes the iFOBT by taking the appropriate number of stool samples according to the specific manufacturer’s instructions. This screening requires a written order from the beneficiary’s attending physician (“Attending physician” means a doctor of medicine or osteopathy (as defined in §1861(r)(1) of the Act), physician assistant, nurse practitioner, or clinical nurse specialist who is fully knowledgeable about the beneficiary’s medical condition, and who would be responsible for using the results of any examination performed in the overall management of the beneficiary’s specific medical problem.)

The minimum age for FOBT is reduced to 45 years and older. 

D. Other

N/A

(This NCD was last reviewed June 2026 and includes policy updates finalized in the Calendar Year 2025 Physician Fee Schedule final rule 89 FR 97710)

Appendix B: Referenced Materials

Table 2. Study outline for non-invasive CRC screening multi-targeted & other stool- & blood-based tests

Note: NR: Not reported; CRC: Colorectal Cancer; AA: Advanced Adenomas; non-AA or NAA or NA: Nonadvanced adenomas; APL: Advanced precancerous lesions; MRA: Medium-risk adenomas; LRA: Low-risk adenomas; PPV: Positive predictive value; NPV: Negative predictive value

Table 3. Specificity & sensitivity for non-invasive CRC screening multi-targeted stool-& blood-based tests

Note: NR: Not reported; CRC: Colorectal Cancer; AA: Advanced Adenomas; non-AA or NAA or NA: Nonadvanced adenomas; APL: Advanced precancerous lesions; MRA: Medium-risk adenomas; LRA: Low-risk adenomas

Table 4. Professional guidelines for CRC screening in asymptomatic average-risk adults

Note: ACS guidelines: strong recommendation conveys the consensus that the benefits of adherence to that intervention outweigh the undesirable effects that may result from screening. Qualified recommendations indicate there is clear evidence of benefit (or harm) of screening, but less certainty about the balance of benefits and harms or about patients’ values and preferences, which could lead to different decisions about screening. USPSTF guidelines: Evidence Grade A: The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service. Evidence Grade B: USPSTF recommends the service. There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. Offer or provide this service. Evidence Grade C: The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small. Offer or provide this service for selected patients depending on individual circumstances.

Table 5. Sensitivities and Specificities of Stool-based CRC Screening Tests from Screening for Colorectal Cancer - Blood-Based Biomarker Tests (CAG-00454N; CMS, 2021)

Table 6.  FDA, Summary of Safety and Effectiveness Data (SSED) for Stool RNA-Based Colorectal Cancer Screening Test ColoSense® -(Table 11) Test Result Classification System by Histopathological Categories from Summary of Safety and Effectiveness Data (SSED) for Stool RNA-Based Colorectal Cancer Screening Test

Table 7. Summary of Safety and Effectiveness Data (SSED) for Stool RNA-Based Colorectal Cancer Screening Test-(Table 7) Secondary performance characteristics by colonoscopy categories-specificity

Table 8. Barnell (2023) publication on CRC-PREVENT which examined the multitarget stool RNA (mt-sRNA) test (Table 2) Sensitivity and Specificity of mt-SRNA and FIT

Table 9. Imperiale (2024) study on the next-generation multitarget stool DNA test (Table 1) Sensitivity and Specificity of mt-SDNA and FIT

Table 10.  2025 NCCN Guidelines

Table 11.  Shaukat (2025) study on Circulating Tumor DNA-Based Blood-Based (ct-DNA) Test (Table 2) Sensitivity and Specificity

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