Screening for Colorectal Cancer - Stool DNA Testing

I manage Cable Car Capital LLC, an investment adviser based in San Francisco. In full disclosure, Cable Car currently holds a short position on behalf of clients in Exact Sciences, the sponsor of Cologuard. In the process of researching Exact Sciences, I have carefully reviewed the available scientific literature on colon cancer diagnostics and spoken with several members of the medical community. My financial interest to the contrary notwithstanding, I support the proposed CMS coverage of Cologuard. However, I believe the NCD should be modified to lengthen the screening interval and cover only the USPSTF-recommended ages of 50 to 75. For reasons discussed below, three years is too often, and screening of patients over age 75 should not be covered.

The high rate of non-compliance with recommended colon cancer screening is a serious problem, which unfortunately leads to many avoidable deaths. Due to its relatively slow progression, colon cancer is generally one of the most readily treated cancers if detected early. I am in support of any efforts to develop new screening modalities, and I believe that CMS should provide coverage for any diagnostic tool that has demonstrated efficacy at encouraging subsequent intervention. Given the wide availability of screening alternatives and the unchallenged superiority of colonoscopy to any stool-based or blood-based approach, the primary social benefit of new tests, such as Cologuard, lies in referring otherwise recalcitrant patients to colonoscopy, where they may receive additional intervention such as polypectomy if required.

Cologuard's low specificity of 89.8% (83.8% in the Medicare population according to the company data provided in the proposed NCD Memo) has been cited by some critics as reason to consider not covering the test. However, I believe this is actually a strong argument in favor of coverage, albeit with appropriate reconsideration of the proper screening interval. It should also factor in the separate reimbursement decision. The data suggest that Cologuard will generate a significant number of false positives, which will be referred to colonoscopy at additional cost. Assuming a 6% rate of CRC incidence and a 10.2-16.2% false positive rate, Cologuard could reasonably be expected to refer as many as 22% of its screened patients for colonoscopy. With a three-year screening interval, the majority of patients undergoing Cologuard screening would be referred to the colonoscopy they should have had within a 10-year window anyway. I believe a longer interval would be more appropriate given this dynamic.

Although such patients ideally would have completed colonoscopies anyway, it is probable that some of them would have gone unscreened. The benefit to society from even a small increase in screening far outweighs the pecuniary interests of any investor positions with respect to any individual diagnostic company.

As regards patients over the age of 75, however, it is surprising given the USPSTF citations in the NCD memo that CMS proposes to cover Cologuard for patients who are older than the recommended screening age range. Screening older patients is likely to result in medically unnecessary colonoscopies and unnecessary end-of-life expenses. I defer to the USPSTF as cited in the proposed memo:

Zauber (2008, http://www.ncbi.nlm.nih.gov/pubmed/18838717) found in a study for the USPSTF that using 75 as the stopping age for non-invasive screening had a minimal cost in life-years gained, while significantly reducing unnecessary colonoscopies. Physicians maintain risk-based discretion with respect to colonoscopies, so there is no need to cover routine screening beyond age 75. For example, CMS already provides coverage for colonoscopies every two years regardless of age for higher-risk patients. Cologuard would not be a suitable replacement for this patient pool.

While I support coverage, I urge CMS to carefully consider the appropriate age range and interval in light of overall costs to the healthcare system.

Respectfully submitted.

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Note: My comments, questions and suggestions are informed by my 35 years of experience studying medical decision making and the clinical, comparative and cost-effectiveness of diagnostic tests and my experience as a member/former member of the US Preventive Services Task Force, CMS MEDCAC, Blue Cross and Blue Shield Associations Medical Advisory Panel, various NIH Consensus Development Committees and Clinical Guideline Committees and Centers for Disease Control and World Health Organization laboratory test evaluation advisory committees, and founding Director of the American College of Physicians Clinical Efficacy Assessment Program.

Recommendation:
The Cologuard™ test is very promising and has the potential to improve and increase screening for colorectal cancer in the U.S. However, until the information required to answer questions below is provided and made publicly available, CMS coverage of the test is premature.

The original and pivotal clinical study funded by Exact Sciences and published in the New England Journal of Medicine (Imperiale TF, Ransohoff DF, Itzkowitz SH, et al, Multitarget Stool DNA Testing for Colorectal-Cancer Screening. N Engl J Med. Published online March 19, 2014 at NEJM.org) concluded that “In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancer than did FIT but had more false positive results.”

The information provided by this study, the accompanying appendices and the public information provided to the FDA and CMS is not sufficient for physicians or patients to make informed decisions about Cologuard’s diagnostic performance (i.e., sensitivity and specificity), comparative benefits and harms vs. the FIT studied (let alone other FIT tests) and thus whether or when to use the Cologuard™ test, FIT or colonoscopy for colorectal cancer screening.

Diagnostic Performance Questions
1. More complete information on test results is required before any informed assessment can be made of Cologuard™performance and its comparative effectiveness vs. FIT and colonoscopy.
In the pivotal NEJM study, 689 subjects (6% of eligible subjects) had multi-target DNA test results excluded (474 due to leakage in shipping or delayed receipt of specimen; 213 due to insufficient DNA; 2 due to missing samples). For FIT, results from 34 subjects (0.3%) were excluded because of insufficient hemoglobin samples.
While the analysis was performed per protocol, it is incomplete. It is inherently biased to exclude non-diagnostic studies from the analysis, especially when the number of exclusions differed so dramatically across the tests being compared. (Assessment of the direction and the impact of any bias cannot be determined until the data are analyzed.)

To appropriately interpret the results so that physicians and patients are able to understand Cologurad’s performance in clinical practice and the incremental benefits, harms and tradeoffs among Cologuard™, FIT and colonoscopy (which should be the primary focus for CMS), one needs to know the results of the FIT and colonoscopy in the 689 subjects in which Cologuard™ was unable to be performed and of the Cologuard™ and colonoscopy in the excluded FIT samples.

Thus, the full data table of Cologuard™, FIT and colonoscopy test results by subjects (including those for excluded subjects) needs to be made available for independent analysis before any definitive determination can be made (i.e., FIT and colonoscopy results for subjects whose DNA tests were excluded/not performed and multitarget DNA test and colonoscopy results and final categorization for the subjects whose FIT results were excluded).

Without the data on these results, it is not possible to determine the extent and impact of any bias on test performance. It is expected that the FIT will have detected additional colorectal cancers and advanced adenomas that were excluded from the analysis because the Cologuard™ test was unable to be performed (which should be considered ‘missed’ by the Cologuard™). Thus, it is possible that the performance of the two tests in practice may be closer to one another than reported.

2. Quantitative assay results for Cologuard™ and the studied FIT: Since both the FIT and DNA tests are quantitative tests that are analyzed on a continuous scale, a table is needed for independent analysis that provides the actual quantitative results for each test for both CRC and advanced neoplasms. This is required to assess comparative test performance using both Receiver Operating Curve and likelihood ratio analyses (with confidence intervals) across a range of test values. Such analyses are essential for comparing all diagnostic tests. For Cologuard™™ and FIT, such analyses are required to determine how much (if any) of the reported differences between Cologuard™ and the studied FIT are a result of differences in diagnostic performance as opposed to selection of different criteria for setting each test’s (somewhat subjective) cutoff point. This is particularly important (indeed essential) when, as is the case with Cologuard™ and the studied FIT, one test exhibits higher sensitivity but lower specificity than the comparator test.

(Note: The Cologuard™ may be considered to be a combination of a FIT and multi–target DNA test. As such, the criteria for interpretation of the test combination can be modified so as to increase either sensitivity or specificity – but not both sensitivity and specificity simultaneously – of the test combination compared to either test alone. This underscores the importance of the questions above.)

Quality control questions:
1. The DNA tests were performed at one of three laboratories. Results should be provided to determine whether there were any meaningful performance differences among the three labs. This should include any cross-comparison of data or sample exchange routinely performed in a study of this nature to ensure consistency across the labs.

2. The lab that performed the FIT should be identified (as were the three labs that performed the Cologuard™ tests). It also should be determined whether the lab that analyzed the FIT is accredited by CAP or adhered to other quality control standards (e.g., ISO15189). If so, the results of any external validations of the lab’s performance of FIT in which the lab participated should be provided.

The information in #1 and #2 above is required to assess the validity of the FIT assay performance.

(In addition, the technical descriptions of Cologuard™ and FIT tests as perfomed in the pivotal studies are somewhat limited and may not be adequate to assess validity of the results. Thus, independent laboratory pathologists expert in the conduct of these and similar immunochemical and DNA tests who ‘do not have a dog in this fight’ (or, failing that, expert laboratory pathologists with conflicting beliefs and potential biases about the two tests) should be consulted RE: methodological and quality control.)

Other questions and potential concerns:

Clinical validity of the comparison of Cologuard™ and FIT
1. The studies presented to support approval and use of the Cologuard™ assay assessed its performance compared to a FIT

Different FIT assays have their own performance characteristics, different antibodies to different globin epitopes, different assay cutoffs points, and different collection techniques (e.g., # of samples obtained; sampling techniques; preservation buffers). This issue should be examined with gastroenterologists and clinical laboratory pathologists with expertise in and experience with the various FITs marketed in the U.S.

2. The FIT is designed to be used every 1-2 years. With repetitive use it may (or may not – from the data presented we do not have enough information to know) achieve the same sensitivity of the Cologuard™ with the same or better specificity. Thus, biannual FIT may or may not exhibit equivalent or superior diagnostic performance as the Cologuard™ when ‘used as directed’. This should be the standard and primary criterion considered by CMS, as it is the most clinically relevant endpoint. This becomes even more relevant considering the substantial cost difference between the tests which are advocated to be performed in tens of millions of Medicare beneficiaries every 2-3 years.

(While it may be beyond the authority of CMS to consider cost and cost-effectiveness in its coverage decisions, this information is essential to patients and physicians. Thus, at a minimum, the information required to allow patients, providers, payers and managed care groups to assess cost–effectiveness should be available.)

3. In the absence of longitudinal data, there does not appear to be sufficient evidence to support proposed coverage of Cologuard™ testing every three years. Cologuard™ testing frequency should be determined after examining the results of the the ongoing study being conducted by Exact Sciences. (Note: If Medicare has not yet done so, it should review the protocol of the ongoing study and communicate any data needs to the study sponsors and investigators.)

4. There is inadequate information to support Cologuard™ testing routinely in Medicare beneficiaries until age 85. In the pivotal study by Imperiale et al., Colorguard™ specificity was meaningful lower in those =75 years of age. Given this and the smaller subset of subjects within this category (and thus wider confidence intervals surrounding estimates of test performance characteristics in this population), further evidence is required before extending screening with Cologuard™ to this age group.

Summary/Conclusion
The Cologuard™ multitarget DNA stool CRC screening test is very promising and has the potential to improve and increase the number of Medicare beneficiaries undergoing CRC screening. However, the information (publicly) available to date are not sufficient to support the proposed CMS coverage decision. Independent analysis of this additional data (much of which should be available from Exact Sciences and Imperiale et al.) are required before such a coverage decision is warranted.

Thank you for the opportunity to submit and for your consideration of these thoughts, concerns, suggestions and recommendations.

Please contact me if you any questions, desire or require any additional information, want to discuss anything or there if is anyway I might be of possible assistance to you and your colleagues.

Sincerely,

J. Sanford Schwartz, MD
Leon Hess Professor of Medicine and Health Management & Economics
Perelman School of Medicine and Wharton School of Business
University of Pennsulvania

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September 10, 2014

Marilyn Tavenner
Administrator
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, MD 21244-1850

Re: Proposed Decision Memo for Screening for Colorectal Cancer – Stool DNA Testing (CAG-00440N)

Dear Ms. Tavenner,

The College of American Pathologists (CAP) appreciates the opportunity to submit comments to the Centers for Medicare and Medicaid Services (CMS) in response to its Proposed Decision Memo for Screening for Colorectal Cancer-Stool DNA Testing (CAG-00440N).

The CAP is a national medical specialty society representing more than 17,000 physicians who practice anatomic and/or clinical pathology. College members practice their specialty in clinical laboratories, academic medical centers, research laboratories, community hospitals and federal and state health facilities.

Encouraged by the recent clinical trial data, the CAP supports national coverage for triennial screening with Cologuard stool DNA test as an adjunctive colon cancer screening tool. Important sessile serrated adenomas, or flat premalignant lesions, can go undetected in both conventional and computed tomographic colonography (CTC), thus there is a need for alternative surveillance methods for polyps that are hard to detect. Cologuard detected an impressive 92 percent of colorectal cancers and 42 percent of advanced adenomas in the study population, while the fecal immunochemical test (FIT) detected 74 percent of cancers and 24 percent of advanced adenomas.

The FIT test performed better at correctly identifying those who were negative for colorectal cancer or advanced adenomas, providing accurate negative test screening results for 95 percent of the study population, compared to Cologuard's 87 percent. However, used as an adjunct to a colonoscopy or sigmoidoscopy, Cologuard will likely expand screening effectiveness and help curb colorectal cancer rates.

According to the CDC, while the percentage of adults screened for colorectal cancer increased 13 percent from 2002 to 2010, one in three adults between the ages of 50 and 75 are not up-to-date with colorectal cancer screening. As a result, CRC has become the second-leading cause of cancer death in the United States. Screening is crucial because when found early, CRC is one of the most preventable and treatable forms of cancer.

The clinical data show that Cologuard represents the highest sensitivity of any noninvasive test to date. Based on performance, it is feasible that triennial screening with Cologuard between colonoscopies can increase screening compliance and reduce the number of colon cancers. It is our opinion that this screening tool be approved for reimbursement.

Thank you for the opportunity to submit these comments. If you have any questions please contact Jennifer Madsen, Sr. Director for Economic and Regulatory Affairs, at 202-354-7100.

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September 9, 2014

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244

RE: Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD) Proposed Decision Memo for Screening for Colorectral™ Cancer – Stool DNA Testing (CAG-00440N)

Dear Ms. Jensen:

Thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services (CMS) Proposed Decision Memo Screening for Colorectral Cancer – Stool DNA Testing (CAG-00440N). America’s Health Insurance Plans (AHIP) is the national association for the health insurance industry. Our members provide coverage to more than 200 million Americans, offering a broad range of health insurance products in the commercial market and demonstrating a strong commitment to participation in public programs.

General Comments
AHIP and its member health plans believe that a strong evidence base developed through rigorous research on the safety, effectiveness, and value of new technologies, biologics, and pharmacological products, is critical to ensuring that patients receive the most effective and appropriate treatments. According to the Proposed Decision Memo dated August 11, 2014, CMS is proposing to cover colorectal cancer screening once every three years using a multi-target stool DNA (sDNA) test for asymptomatic average risk beneficiaries aged 50 to 85 years. The focus of the CMS review is on the commercially available Cologuard™.

The CMS issued its proposed decision memo on the same day that the Food and Drug Administration (FDA) approved Cologuard™. Our plans have expressed concern that CMS is moving too quickly with its review process without sufficient time for a thorough review of the evidence. This concern about the proposed NCD comes largely from the lack of data to support the efficacy of the Cologuard™ test, especially as compared to currently approved screening tests. The evidence to support this test appears to be very small, and largely based on comparative diagnostic performance rather than based on any health outcomes. In other instances where a new product lacked the evidence to support a determination, the USPSTF found the evidence, “insufficient to assess the benefits and harms of computed tomographic colonography and fecal DNA testing as screening modalities for colorectal cancer.”¹

Most health plan medical advisory panels have not had an opportunity to meet to review evidence on this new test. Typically health plans look to the input from sources such as the USPSTF, MEDCAC and published studies in the peer review literature to help inform their decision to update their policies. To date, Cologuard™ has not been reviewed by the United States Preventive Services Task Force. Likewise, the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) has not convened to review the recommendation. Each of these entities should have sufficient opportunity to weigh the benefits, risks, and unknown factors related to this new colorectal cancer screening option before recommending for or against a national coverage determination.

Support for Evidence-Based Screening
Our members support evidence-based screening. Health plans have supported the USPSTF recommended colorectal cancer screening tests²:

1. fecal occult blood testing (FOBT) (recommended annually);
2. sigmoidoscopy (every five (5) years, with FOBT every three (3) years); and
3. colonoscopy (every ten (10) years).

Health plans are just beginning to carefully review the available medical literature to establish the benefits and the possible harms of Cologuard™ for colorectal cancer screening, and to compare it to currently recommended screening protocols. While it is reasonable to consider stool DNA testing as a screening option for colorectal cancer, it is important to evaluate the way this test would compliment or become integrated with the standard three tests. For instance, there is no evidence presented to indicate that a negative stool DNA screening should obviate the need for a regular colonoscopy every ten years. No evidence has been suggested on how the Cologuard™ screening should be incorporated into a set of recommendable strategies for colorectal cancer screening. Therefore, to accept this recommendation without more evidence and without considering how it should be used in relation to other available tests would not be prudent at this time.

Our member plans believe that further review and consideration by the USPSTF should take place before Cologuard™ is listed as a covered Medicare preventive service.

In conclusion, our member health plans do not support the proposed decision of CMS coverage of colorectal cancer screening using Cologuard™ at this time. Thank you for the opportunity to comment on this important issue.

Sincerely,

Carmella Bocchino
Executive Vice President

1 The USPSTF noted in its October 2008, recommendation on colorectal screening that its evaluation did not include newer screening tests, such as computed tomographic colography or the DNA stool test. http://www.uspreventiveservicestaskforce.org/uspstf08/colocancer/coloartzaub.htm
2 U.S. Preventive Services Task Force. Screening for Colorectal Cancer: Clinical Summary of U.S. Preventive Services Task Force Recommendation. AHRQ Publication No. 08-05124-EF-4, October 2008. http://www.uspreventiveservicestaskforce.org/uspstf08/colocancer/colosum.htm

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RE: Proposed Decision Memorandum for Screening for Colorectal Cancer Using Cologuard – A Multitarget Stool DNA Test

The American College of Gastroenterology (ACG) appreciates the opportunity to offer comments in support of the Centers for Medicare and Medicaid Services’ (CMS) proposal to include Cologuard as a covered benefit in Medicare Part B. The ACG agrees with CMS that while diagnostic/therapeutic colonoscopy is a required and necessary step to complete the continuum of colorectal cancer screening, adding the Cologuard test to current list of screening benefits will improve screening utilization rates and health outcomes through early detection of precancerous adenomas and colorectal cancer at early stages.

The ACG is a physician organization representing gastroenterologists and other gastrointestinal specialists. Founded in 1932, our organization currently includes over 13,000 physicians among its membership of health care providers of gastroenterology specialty care. We focus on the issues confronting the gastrointestinal specialist in treatment of patients. The primary activities of ACG have been, and continue to be, promoting evidence-based medicine and optimizing quality of patient care.

ACG applauds CMS for expanding coverage to colorectal cancer screening tests to Medicare beneficiaries and supports the Cologuard test. ACG also appreciates the Agency for recognizing in this proposed coverage determination that a follow-up colonoscopy is essential to reduce the incidence of and mortality from colorectal cancer. This is one reason why the College continues to urge CMS to consider the necessary follow-up colonoscopy, as well as the therapeutic effect of screening colonoscopy, to be considered part of a “screening” for Medicare coverage purposes and Medicare beneficiaries’ preventive services cost-sharing implications. Cologuard should not be viewed as replacement for complete optical colonoscopy for either the asymptomatic and high-risk populations. As explained further below, there are differences between colorectal cancer prevention tests and colorectal cancer detection tests.

The ACG also agrees with CMS that in light of this proposal, Medicare beneficiaries should continue using recommended colorectal cancer screening as appropriate. The ACG requests that CMS stipulate in the final coverage determination that Medicare will still cover a screening colonoscopy and/or other recommended tests even within 3 years of the Medicare beneficiary undergoing screening via the Cologuard test.

DISCUSSION

Colorectal Cancer Prevention Tests vs. Colorectal Cancer Detection Tests

The ACG agrees with other organizations and interested stakeholders in dividing the various screening modalities into “colorectal cancer prevention” versus “colorectal cancer detection.” In 2008, the ACG was an integral part of the U.S. Multi Society Task Force (MSTF) on Colorectal Cancer Screening¹, together with the American Cancer Society and the American College of Radiology, which concluded that colorectal cancer prevention is the preferred strategy and primary goal over colorectal cancer detection². These tests include tests that are designed to detect both early cancer and adenomatous polyps.

The ACG’s own guideline on colorectal cancer screening also divide tests into cancer prevention versus detection tests, in recommending the preferred cancer prevention test (colonoscopy every 10 years) and a preferred cancer detection test (annual fecal immunochemical test (FIT)) to detect occult bleeding³.

The ACG recommends complete, optical colonoscopy as the preferred method used to screen asymptomatic patients for colon cancer as the procedure examines the entire colon and allows for simultaneous therapeutic intervention.

These guidelines were published in 2009. The Cologuard test was not available at that time. ACG is currently reviewing the medical literature to assess whether an update to these guidelines is necessary and appropriate

.

The most recent version of the American College of Gastroenterology Guidelines for Colorectal Cancer Screening states:

Preferred Cancer Screening Modalities
	Cancer prevention tests should be offered first. The preferred prevention test is colonoscopy every 10 years, beginning at age 50. Screening should begin at age 45 years in African Americans
	Cancer detection test. This test should be offered to patients who decline colonoscopy or another cancer prevention test. The preferred cancer detection test is annual FIT for blood

Am J Gastroenterology. 2009 Jun;104(6):1613

Complete Optical Colonoscopy

There is a clear consensus that colorectal cancer prevention is the primary goal⁴. Unlike other cancer screenings where early detection is the goal, screening with optical colonoscopy has the unique ability to prevent colorectal cancer by examining the entire colon and removing precancerous polyps during the same encounter. That is why the College believes that complete optical colonoscopy is the preferred standard in colorectal cancer prevention. Findings published in The New England Journal of Medicine (NEJM) in March 2012 highlight the ability to reduce colorectal cancer deaths through polyp detection and removal. This NEJM study reports a 53 percent reduction in colorectal cancer deaths following removal of adenomatous polyps during colonoscopy⁵. This underscores ACG’s position that colonoscopy remains the preferred colorectal cancer prevention strategy over all currently available options.⁶

FIT and Cologuard

ACG guidelines conclude that the preferred cancer detection test is annual FIT or high sensitivity fecal occult blood tests (FOBT). CMS recognizes that this recommendation was made without evaluating the Cologuard test. However, the guidelines demonstrate that there is a place for the more accurate non invasive tests including Cologuard to increase colorectal cancer screening utilization rates.

While the College has endorsed FIT as the preferred cancer detection test, we must note that the evidence for the interval testing was low. As another fecal-based test, Cologuard incorporates a FIT test but cannot be classified under an existing category of colorectal cancer screening tests. The degree to which Cologuard improves detection of cancer and adenomatous polyps beyond the traditional FIT test will be important as the College undertakes its medical literature review and makes a determination regarding any necessary changes to its current guideline recommendations. This underscores the need for CMS to provide screening colonoscopy (and the cost-sharing benefits associated with recommended colorectal cancer screenings) an option for beneficiaries even within this 3 year interval of undergoing screening using the Cologuard test.

Rationale for a “preferred” strategy

The ACG recommends that clinicians have access to a “preferred” strategy for making colorectal cancer (CRC) screening recommendations, as an alternative to the “menu of options” approach by the performance characteristics and effectiveness of each test. Consistent with the various organizations’ conclusion that colorectal cancer prevention is the goal, ACG recommends colonoscopy every 10 years based on the evidence of colonoscopy effectiveness, cost-effectiveness, and acceptance by patients. The ACG also recommended FIT as the preferred colorectal cancer detection test based on the medical evidence available at the time our guideline was produced.

A “preferred” strategy simplifies and clarifies discussions with patients and could also increase the likelihood that screening is offered to patients. One randomized trial showed that patients were more likely to undergo screening with the “preferred” strategy approach compared with the “menu of options.”⁷ Another study found no improvement in screening rates when multiple options were presented.⁸ Maintaining simplicity in guidelines may have value, in that patients may forgo the necessary follow-up diagnostic colonoscopy subsequent to a positive finding of another colorectal cancer prevention or detection test. However, the MSTF notes that patients may benefit from a set of options based on the needs of those individual patients, in consultation with their physician, and the technology available.⁹

The ACG also acknowledges that listing complete optical colonoscopy as a “preferred” CRC prevention strategy places greater emphasis on effectiveness than on risk or the ability to increase screening utilization rates. Preferred screening modalities are not infallible and each have their limitations in access to care and increasing colorectal cancer screening utilizations rates: While optical colonoscopy is the “gold standard” in colorectal cancer screening, any discussion regarding a “gold standard” in colorectal cancer screening must not be misinterpreted as a “silver bullet” in preventing and eradicating colorectal cancer. The best test is the test that gets done. That said, the expert review of the medical literature supports ACG’s determination that there are preferred screening modalities when dividing colorectal cancer prevention versus colorectal cancer detection tests. What’s more, the MSTF concluded that complete optical colonoscopy is required to confirm positive findings in all other colorectal cancer prevention and detection tests, both non-invasive and invasive tests (even flexible sigmoidoscopy).¹⁰

ACG Recommendations: Age to begin screening

The ACG continues to recommend that screening begin at age 50 years in average-risk persons (i.e., those without a family history of colorectal neoplasia). ACG also recommends that screening begin at age 45 years in African Americans.¹¹

The mean age of CRC development in African Americans is younger than that of other ethnicities. There is also evidence for a more proximal colonic distribution of cancers and adenomas in African Americans. African Americans are less likely to have undergone diagnostic testing and screening for colorectal cancer.¹²

The “average risk” population is large and complex with regard to risk. Certain other subgroups of the average-risk population might warrant initiation of screening at an earlier or later age, depending on their risk. For example, the age-adjusted risk of incident cancers and prevalent adenomas is greater in men than in women. Pending further study and evaluation of this issue, the ACG recommends that screening begin at age 50 years for both the genders but at age 45 years for African-American men and women.

CONCLUSION

The falling rates of colorectal cancer is a public health success story in the United States. No other country can claim that both incidence and death rates from colorectal cancer are on the decline. CMS should be commended for its role in this success story as recent data show that screening rates are among the highest in the Medicare-aged population. Yet, more needs to be done. ACG has joined the Centers for Disease Control (CDC), the U.S. Department of Health and Human Services Office of the Assistant Secretary for Health, the American Cancer Society, and other stakeholder groups to work toward the goal of screening 80% of eligible individuals by 2018. It is important that we work together to mitigate preventable colorectal cancer incidence rates and deaths. Please contact Brad Conway, Vice President of Public Policy, Coverage & Reimbursement at 301.263.9000 or bconway@gi.org to discuss further.

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“U.S. Multi-Society Task Force on Colorectal Cancer”: the American College of Gastroenterology, the American Gastroenterological Associations, and the American Society for Gastrointestinal Endoscopy
Levin B, Lieberman D, McFarland B, et al. Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin, May 2008; 58: 130 – 160.
Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, et al. American College of Gastroenterology guidelines for colorectal cancer screening 2009. Am J Gastroenterol. 2009. 104: 739–750.
A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Page 133.
Zauber AG, Winawer SJ, O'Brien MJ, Lansdorp-Vogelaar I, van Ballegooijen M, Hankey BF, Shi W, Bond JH, Schapiro M, Panish JF, Stewart ET, Waye JD. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med. 2012 Feb 23;366(8):687-96)
American College of Gastroenterology guidelines for colorectal cancer screening 2009. Page 739
Inadomi J, Kuhn L, Vijan S et al. Adherence to competing colorectal cancer screening strategies. Am J Gastroenterol 2005;100:S387–8
Griffith JM, Lewis CL Brenner AR et al. The effect of offering different numbers of colorectal cancer screening test options in a decision aid: a pilot randomized trial. BMC Med Inform Decis Mak 2008;8:4; Available at http://www.biomedcentral.com/1472-6947/8/4
A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Page 132.
A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Page 144.
American College of Gastroenterology guidelines for colorectal cancer screening 2009. Page 741.
Agrawal S , Bhupinderjit A , B hutani MS et al. Colorectal cancer in African Americans . Am J Gastroenterol 2005 ; 100 : 515 – 23.

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Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd
Baltimore MD 21244

RE: Proposed Medicare Coverage Decision Memorandum for Screening for Colorectal Cancer – Stool DNA Testing (CAG-00440N)

Dear Ms. Syrek Jensen:

The Advanced Medical Technology Association (AdvaMed) and AdvaMedDx are pleased to offer the following comments on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Coverage Decision Memorandum for Screening for Colorectal Cancer – Stool DNA Testing. We support the proposed coverage determination, as well as the joint efforts of the Food and Drug Administration (FDA) and CMS to reduce the time between FDA approval and Medicare coverage through the parallel review pilot program.

AdvaMed member companies produce the medical devices, diagnostic products, and health information systems that are transforming health care through earlier disease detection, less invasive procedures, and more effective treatments. AdvaMedDx functions as an association within AdvaMed, and its member companies produce advanced in vitro diagnostic tests that facilitate evidence-based medicine, improve quality of patient care, enable early detection of disease and often reduce overall health care costs.

Proposed Coverage Determination

AdvaMed supports the proposal to cover the Cologuard test once every three years as a screening tool for asymptomatic, average risk beneficiaries meeting specific criteria. This non-invasive stool DNA test will provide beneficiaries with another option in the fight against colorectal cancer, one of the most common and yet most treatable cancers.

Parallel Review

AdvaMed has long supported the use of sound evidence to inform medical practice. We have been supportive of the voluntary Parallel Review pilot program, and we agreed with the program’s objective to provide timely access to innovative medical technologies to patients and improve the quality of the overall health system.

We applaud CMS for moving quickly to propose national coverage of the Cologuard test upon the announcement of the test’s FDA approval in the United States, as requested by the applicant.

AdvaMed supports a process that can close the gap between FDA approval and CMS coverage, particularly in cases where a more efficient process supports an important public health need, such as colorectal cancer.

We are hopeful that lessons learned from the parallel review pilot can be applied to other new and innovative devices and technologies. We look forward to working with our member companies and with CMS toward the continued success of the program.

Thank you for the opportunity to provide these comments. Please feel free to contact me or Chandra Branham, JD, Vice President, Payment & Health Care Delivery Policy, at cbranham@advamed.org if you have any questions concerning these comments.

Sincerely,

Donald May
Executive Vice President
Payment & Health Care Delivery Policy
AdvaMed

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The American Cancer Society Cancer Action Network (ACS CAN) appreciates the opportunity to provide comments on the Centers for Medicare and Medicaid Services’ (CMS’) proposed decision memo on screening for colorectal cancer – stool DNA testing. We are writing to support CMS’ proposed decision memo that will provide Medicare beneficiaries with another important colorectal cancer screening option.

ACS CAN, the nonprofit, nonpartisan advocacy affiliate of the American Cancer Society (ACS), supports evidence-based policy and legislative solutions designed to eliminate cancer as a major health problem. As the nation’s leading advocate for public policies that are helping to defeat cancer, ACS CAN ensures that cancer patients, survivors, and their families have a voice in public policy matters at all levels of government.

Colorectal cancer is the third most common cancer and cause of death from cancer in both men and women. In 2014, an estimated 137,000 people will be diagnosed with colorectal cancer and over 50,000 will die from the disease. In the Medicare population, colorectal cancer is the second leading cause of cancer related deaths. Colorectal cancer accounted for nearly 11 percent of Medicare fee-for-service cancer payments in 2011.

Colorectal cancer is one of the most preventable forms of cancer, and thousands of deaths could be avoided with routine colorectal cancer screening. Due to the importance of this public health issue, over 100 health-related organizations have committed to increase the nation’s colorectal cancer screening rate to 80 percent by the year 2018. To achieve this goal, we must remove the obstacles that prevent Americans from getting tested.

Currently, only 64 percent of people age 65 or older report having received a colorectal cancer screening consistent with current guidelines. Colorectal cancer screening compliance is one of the biggest challenges in preventing and treating colorectal cancer. While increased patient education and awareness about the importance of screening is needed, patients report a fear of the invasive tests as one barrier to obtaining a colorectal cancer screening test. Therefore, patient-friendly, non-invasive options with high detection rates for colorectal cancer and higher risk pre-cancers are needed in order to increase the use of screenings.

We ask that CMS waive the cost sharing for this test to reduce barriers to utilization. Research shows that cost sharing creates financial barriers that discourage the use of recommended preventive services. Furthermore, a positive stool DNA test should be followed by a screening colonoscopy to determine diagnosis. Since the follow-up colonoscopy is an essential part of the screening continuum, we ask that you waive the co-insurance and the deductible for the follow-up screening colonoscopy.

As noted in the proposed decision memorandum, the ACS current guidelines for colorectal cancer screening recommend an earlier version of a stool-DNA test, which is no longer commercially available. ACS currently is in the process of updating and revising its colorectal cancer screening guidelines and expects the process to be completed in the next 12 months. We will share with CMS our revised guidelines once the process has been concluded, but recognize that CMS’ coverage determination process may be concluded by then. Finally, ACS CAN would like to commend CMS and the Food and Drug Administration (FDA) for undertaking the parallel review process for FDA approval and Medicare coverage. We believe this concurrent review process has the potential to improve patient access to new and innovative medical devices.

Conclusion

On behalf of the American Cancer Society Cancer Action Network we thank you for the opportunity to comment on the proposed decision memorandum for screening for colorectal cancer – stool DNA testing. If you have any questions, please feel free to contact me or have your staff contact Anna Schwamlein Howard, Policy Principal, Access and Quality of Care at Anna.Howard@cancer.org or 202-585-3261.

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September 9, 2014

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, Maryland 21244

RE: Proposed Decision Memorandum for Screening for Colorectal Cancer Using Cologuard™ – A Multitarget Stool DNA Test

Dear Ms. Jensen,

The American Gastroenterological Association (AGA) is the trusted voice of the GI community. Founded in 1897, the AGA has grown to include 17,000 members from around the globe who are involved in all aspects of the science practice and advancement of gastroenterology. The AGA appreciates the opportunity to provide comment on the Centers for Medicare and Medicaid Services (CMS) proposed national coverage determination (NCD) on Cologuard™.

On August 11, 2014, as part of a pilot FDA-CMS program, CMS issued a proposed national coverage determination (NCD) stating that there is sufficient evidence to cover Cologuard™ – a multitarget stool DNA test – as a colorectal cancer screening (CRC) test for asymptomatic average risk beneficiaries aged 50 – 85. We applaud HHS, the FDA and CMS for the parallel review pilot program for concurrent review of medical devices for FDA approval and Medicare coverage to increase patient access to innovative devices that improve clinical outcomes.

CMS proposes to cover the Cologuard™ test once every three years for beneficiaries who meet all of the following criteria:

• Age 50 to 85 years
• Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test or fecal immunochemical test), and
• At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s disease and ulcerative colitis; no family history of colorectal cancers or an adenomatous polyp, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

The CDC estimates that 90 percent of all colon cancers occur after the age of 50. The United States Preventive Services Task Force recommends screening for those at average risk beginning at age 50 by several current modalities. Currently there are four tests available for colon cancer Page 1 of 3 screening approved by CMS (colonoscopy, barium enema, flexible sigmoidoscopy, and fecal occult blood test). Colonoscopy is the only test that allows physicians to examine the entire colon and find and remove precancerous polyps (growths) during the same procedure and is the exam that follows positive results from all other screening tests. We strongly support the recently stated goal of having 80% of eligible American citizens undergo colorectal cancer screening by 2018. As a result of this commitment, we would support any screening test that would offer additional choices for effective screening as long as there is firm scientific support for its efficacy. This position is stated in our current guideline (Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps¹). The AGA notes that use of Cologuard for colorectal cancer screening is based in part on a randomized controlled trial with almost 10,000 participants, published in the New England Journal of Medicine².

We would offer the following additional input.

Age Range
The proposed age range for coverage of Cologuard™ is for beneficiaries age 50 to 85 years. Other modalities (i.e., fecal occult blood testing, sigmoidoscopy, and colonoscopy) do not cover beneficiaries older than 75. As noted in the proposed NCD, the U.S. Preventive Services Task Force does not recommend routine screening in individuals aged 76-84 and recommends against screening in individuals aged 85 and older³. There does not appear to be compelling evidence to treat Cologuard differently from all other modalities.

Frequency of screening
The proposed NCD correctly points out that determining the interval of application from cross-sectional studies is not really possible. Therefore, how the test will function programmatically (i.e., with repeated application over time) is not known. Fecal immunochemical test (FIT) and guaiac-fecal occult blood test (gFOBT) have randomized controlled trials and other longitudinal studies to support the recommended annual testing (in the US, biennial in some other countries) and we look forward to the establishment of further evidence, which could include modeling methodology, to aid in determining the appropriate interval for Cologuard™.

Use of CologuardTM After a Negative Colonoscopy
The AGA has been actively involved in the Choosing Wisely® campaign and supports the analysis done for that program indicating that if a patient has a high quality screening colonoscopy and no abnormalities are found, the patient does not need to have any colorectal cancer screening tests for the next decade⁴. Published studies indicate the risk of cancer is low for 10 years after a high-quality colonoscopy fails to detect neoplasia at baseline.

FIT test as part of Cologuard™
The multitarget stool DNA test contains a fecal immunochemical test created by the company. The threshold/algorithm used by the company in their FIT determination is proprietary, so it is impossible to know which FIT is being used and whether it influences the sensitivity and specificity of Cologuard™. However, the testing and validation of the modeling underpinning the current version of the test has been well documented⁵. The FIT component of the test supports the usefulness and importance of occult blood as a biomarker for colorectal cancer screening.

Previously, the Cancer Intervention and Surveillance Modeling Network (CISNET) has conducted comparative approaches of colorectal cancer simulation models to help inform decision makers regarding fecal immunochemical, CT colonography, and the first version of the stool DNA test for CRC screening in the Medicare population. It is our understanding that CISNET is in the process of developing a simulation model for Cologuard that takes into account the changes in preventive services and risk sharing for Medicare beneficiaries as a result of the Affordable Care Act. We look forward to this analysis and trust that it will be incorporated into future re-evaluation of CologuardTM.

We thank CMS for the opportunity to offer comments on the proposed NCD for Cologuard™ and appreciate all efforts to reduce the incidence and death rate from colorectal cancer including enhancing opportunities and choices for effective screening. Please contact Leslie Narramore via email at Lnarramore@gastro.org or telephone at 410-349-7455 if you have any questions.

Sincerely,

John I. Allen, MD, MBA, AGAF
President, AGA Institute

1 Levin, Bernard et al. Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline From the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology, 2008; 134, 5: 1570 - 1595
2 Imperiale, Ransohoff et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014 Apr 3;370(14):1287-97. doi: 10.1056/NEJMoa1311194. Epub 2014 Mar 19. PubMed PMID: 24645800.
3 Ann Intern Med. 2008;149:627-637
4 Choosing Wisely (2012, April 5). Five Things Physicians and Patients Should Question. Retrieved August 26, 2014 from http://www.choosingwisely.org/wp-content/uploads/2013/01/5things_12_factsheet_AGA.pdf
5 Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology. 2012 Feb;142(2):248-56

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September 9, 2014

Joseph Chin, MD, MS
Lead Medical Officer

Jamie Hermansen, MPP
Lead Health Policy Analyst

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

BY ELECTRONIC DELIVERY

RE: Proposed Decision Memo for Screening for Colorectal Cancer Stool DNA Testing (CAG-00440N)

Dear Dr. Chin and Ms. Hermansen:

On behalf of the Association of Community Cancer Centers (ACCC), we appreciate this opportunity to comment on the proposed decision memorandum for Cologuard™ —a multitarget stool DNA test—as a colorectal cancer screening test for asymptomatic average risk Medicare beneficiaries aged 50 to 85 years (CAG-00440N).¹

ACCC represents more than 20,000 cancer care professionals from approximately 1,100 hospitals and more than 1,000 private practices nationwide. These include Cancer Program Members, Individual Members, and members from 32 state oncology societies. It is estimated that 60 percent of cancer patients nationwide are treated by a member of ACCC. Similar to the Centers for Medicare & Medicaid Services (CMS), ACCC is committed to improving health outcomes for Medicare beneficiaries. Colorectal cancer screening tests are a critical tool for the primary prevention, early detection, and early treatment of colorectal cancer that literally can make the difference between life and death.

Accordingly, ACCC supports CMS’s proposal to cover the Cologuard™ colorectal cancer screening test once every three years for Medicare beneficiaries ages 50 to 85 years who are asymptomatic and at average risk of developing colorectal cancer. ACCC also commends CMS for opening a national coverage determination for Cologuard on the same day that the Food & Drug Administration’s (FDA) Center for Devices and Radiological Health approved the test. Cologuard represents the first time that the two agencies have undertaken parallel review of a new product pursuant to the voluntary pilot program established in 2011 to facilitate the development of innovative products and to increase the efficiency of the review processes for both CMS and FDA.

ACCC has long been committed to ensuring that patients have access to innovative cancer detection technologies. In keeping with that commitment, we have urged CMS to streamline the review processes for Medicare coverage, coding, and reimbursement of new technologies, and have expressed concerns that the CMS-FDA parallel review process be implemented in a manner that expedites, rather than delays, access to those technologies. The Cologuard screening test serves as only one example of the many life-saving technological advances that are on the horizon, and we believe that it is more important than ever that the latest cancer detection tools reach providers and patients as quickly as possible. We agree that there is sufficient evidence to support the coverage of Cologuard for detecting colorectal cancer and advanced adenomas, and we appreciate CMS’s clear recognition that there is a clinical benefit to Medicare beneficiaries and their providers having a range of available screening tests for colorectal cancer that are performed at different time intervals. We hope that CMS and FDA will continue to work together to use the parallel review process to reduce the time between FDA’s approval of qualifying medical technologies and Medicare coverage of these innovations.

We look forward to continuing to work with CMS to ensure that Medicare beneficiaries have timely access to potentially life-saving cancer detection tools. If you have any questions about our comments or if ACCC can be of further assistance, please contact Matthew Farber, Director, Provider Economics and Public Policy, at (301) 984-9496, ext. 221.

Sincerely,

/s/
Becky L. DeKay
President
Association of Community Cancer Centers

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1 Proposed Decision Memo for Screening for Colorectal Cancer Stool DNA Testing (CAG- 00440N) (Aug. 11, 2014), http://www.cms.gov/medicare-coverage-database/details/nca-proposeddecision-memo.aspx?NCAId=277 (last visited Sept. 8, 2014).

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[PHI Redacted]

I am well aware that roughly 50,000 Americans die each year from colon cancer, and I think that that speaks to the fact that our current screening methodologies just aren't getting the job done. Although my family has no previous history of colon cancer, [PHI Redacted] underwent a colonoscopy 6 years ago at age 42 and his procedure was not without complications. And even though I am aware of several friends of mine that have had family members diagnosed with colon cancer, I have not been keen on undergoing such an invasive screening procedure as colonoscopy; a procedure that is not without risk.

In any event, I am very excited about a new non-invasive test such as Cologuard coming onto the market and offering me (and others) another option to become compliant with CRC screening. I applaud the FDA and CMS for working together and offering people such as myself a high-performance non-invasive alternative to the legacy screening method FIT/FOBT; which as we all know does nothing but detect blood in one's stool.

Hopefully, a non-invasive screening option such as Cologuard will get more people like myself screened(who have been "sitting on the fence") as well as aid GI physicians who perform colonoscopy to take their time with the scope and do a thorough screening should a patient initially test positive after using Cologuard.

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September 8, 2014

VIA electronic submission to Medicare Coverage Database

Marilyn Tavenner
Administrator
Centers for Medicare and Medicaid Service
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, MD 21244-1850

Re: Proposed Decision Memo for Screening for Colorectal Cancer – Stool DNA Testing (CAG-00440N)

Dear Ms. Tavenner:

We appreciate CMS’s issuance of the Proposed Decision Memo for Screening for Colorectal Cancer – Stool DNA Test (CAG-00440N) in response to our formal request for reconsideration of the National Coverage Determination for Colorectal Cancer Screening Tests (210.3). We also appreciate the opportunity to submit comments in response to the Proposed Decision Memorandum.

We are in support of the Proposed Decision Memorandum and encourage CMS to finalize its decision. The strength of the evidence, in terms of number and quality of studies, supports coverage of Cologuard™ as a colorectal cancer screening test for asymptomatic average risk beneficiaries aged 50 to 85 years. Furthermore, the coverage criteria proposed by CMS are appropriate and are consistent with the evidence. The Proposed Decision Memorandum demonstrates the successful start of the parallel review process, which supports innovation while assuring public health and reasonable coverage goals are met. We believe CMS’s proposed coverage decision will result in a benefit to patients and the Medicare program in terms of expanded options for colorectal cancer (CRC) screening, hopefully leading to greater screening, reduction in cancers and ultimately reductions in cancer deaths.

1. Evidence Supporting Coverage Determinations

CMS conducted a thorough literature search and review in the Technical Assessment for the Proposed Decision Memorandum, and we agree that the evidence supports the proposed coverage determination. As CMS states in the decision memo, there is sufficient evidence to determine that the Cologuard™ test is a suitable colorectal cancer screening test for prevention or early detection in Medicare beneficiaries, and that there is sufficient evidence to determine that colorectal cancer screening using the Cologuard™ is appropriate for Medicare beneficiaries.

The Imperiale (2014) study provides strong evidence for Cologuard™ as a screening test for CRC, by demonstrating that the Cologuard™ test had a significantly higher sensitivity for colorectal cancer and advanced precancerous lesions compared to FIT. We support CMS’s conclusion that colorectal cancer screening using the Cologuard™ test is appropriate for Medicare beneficiaries, based on the patient population included in the Imperiale study, which included an over-sampling of individuals aged 65 years and older.

A full listing of studies with evidence supporting coverage of Cologuard™ is listed in Appendix A.

As noted in the Proposed Decision Memorandum, to add to the evidence base supporting the use of Cologuard™, Exact Sciences is conducting a post-approval study. The post approval study is a prospective, longitudinal, multi-center study of 1,830 men and women between the ages of 50 and 84 to collect longitudinal data on subjects prescribed Cologuard™ over the course of 3 years. In the study, subjects will be required to complete the Cologuard™ test at baseline (T0) and at year 3 (T3) and the study will determine the positive predictive value (PPV) at T3 (PPV3) and 1 minus the negative predictive value (NPV) at T3 (NPV3). This post-approval study is reasonable and should provide additional data to inform CMS policymaking in the future.

2. Appropriateness of Coverage Criteria

CMS proposes to cover the Cologuard™ test once every three years for beneficiaries who meet all of the following criteria:

• Age 50 to 85 years,
• Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test or fecal immunochemical test), and
• At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or an adenomatous polyp, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

We support these coverage criteria, and feel that the criteria are consistent with the clinical evidence. Furthermore, the criteria are consistent with the indications for use for Cologuard™.

We recognize the need to incorporate established evidence on CRC screening and models to design a coverage policy with an appropriate interval. The approach that CMS has taken in drafting the benefit incorporates the effectiveness modeling data that supports a 3-year interval as reasonable and reflective of the high point sensitivity of the Cologuard test for curable stage cancer and high grade dysplasia.

3. Success of Parallel Review Process

The CMS Proposed Decision Memorandum, issued in conjunction with the FDA approval of Cologuard™, demonstrates the successful start of the parallel review process that supports innovation while assuring public health and reasonable coverage goals are met. The intent of the program is to reduce the interval between FDA marketing approval and Medicare coverage, in order to facilitate the development of innovative products and shorten the time it takes to bring important products to Medicare beneficiaries. The Cologuard™ approval by FDA and the anticipated Medicare coverage within a short timeframe fulfills the intent of the program by ensuring quicker access to safe and effective and reasonable and necessary products for Medicare beneficiaries. The proposed coverage determination will yield a benefit to Medicare beneficiaries and to the Medicare program in terms of expanded options for CRC screening hopefully leading to greater screening, reduction in cancers and ultimately reductions in cancer deaths.

In summary, we support the Proposed Decision Memorandum and encourage CMS to finalize the policy. We appreciate the opportunity to submit comments in response to the Proposed Decision Memorandum, and please do not hesitate to reach out with additional questions. Please reach out to Paul Radensky, MD JD, at pradensky@mwe.com or 202-756-8794.

Sincerely,

Barry M. Berger, M.D. FCAP
Chief Medical Officer
Exact Sciences Corporation

cc: Maneesh Arora

Appendix A: List of Reference Materials

1. Ahlquist DA, Zou H, Domanico M, Mahoney DW, Yab TC, Taylor WR, Butz ML, Thibodeau SN, Rabeneck L, Paszat LF, Kinzler KW, Vogelstein B, Bjerregaard NC, Laurberg S, Sørensen HT, Berger BM, Lidgard GP. Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology. 2012 Feb;142(2):248-56; quiz e25-6. Epub 2011 Nov 4.
2. Ahlquist DA, Taylor WR, Mahoney DW, Zou H, Domanico M, Thibodeau SN, Boardman LA, Berger BM, Lidgard GP. The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia. Clin Gastroenterol Hepatol. 2012 Mar;10(3):272-7.e1.Epub 2011 Oct 20.
3. Ahlquist DA, Sargent DJ, Loprinzi CL, Levin TR, Rex DK, Ahnen DJ, Knigge K, Lance MP, Burgart LJ, Hamilton SR, Allison JE, Lawson MJ, Devens ME, Harrington JJ, Hillman SL. Stool DNA and occult blood testing for screen detection of colorectal neoplasia. Ann Intern Med. 2008 Oct 7; 149(7):441-50, W81.
4. Diehl F, Schmidt K, Durkee KH, Moore KJ, Goodman SN, Shuber AP, Kinzler KW, Vogelstein B. Analysis of mutations in DNA isolated from plasma and stool for colorectal cancer patients. Gastroenterology. 2008 Aug;135(2):489-98. Epub 2008 May 15.
5. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-97.
6. Lee JK, L.E. Accuracy of fecal immunochemical tests for colorectal cancer: systematic review and meta-analysis. Ann Intern Med. 2014;160(3):171-81.
7. Lidgard GP, Domanico MJ, Bruinsma JJ et al. Clinical performance of an automated stool DNA assay for detection of colorectal neoplasia. Clin Gastroenterol Hepatol. 2013 Oct;11(10):1313-8. Epub 2013 April 29.
8. Melotte V, Lentjes MH, van den Bosch SM, Hellebrekers DM, de Hoon JP, Wouters KA, Daenen KL, Partouns-Hendriks IE, Stessels F, Louwagie J, Smits KM, Weijenberg MP, Sanduleanu S, Khalid-de Bakker CA, Oort FA, Meijer GA, Jonkers DM, Herman JG, de Bruïne AP, van Engeland M. N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst. 2009 Jul 1;101(13):916-27. Epub 2009 Jun 17.
9. Onouchi S, Matsushita H, Moriya Y, et al. New method for colorectal cancer diagnosis based on SSCP analysis of DNA from exfoliated colonocytes in naturally evacuated feces. Anticancer Res. 2008 Jan;28(1A):145-50.
10. Zou H, Allawi H, Cao X, et al. Quantification of methylated markers with a multiplex methylation-specific technology. Clin Chem. 2012;58(2):375-383

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September 8, 2014

Marilyn B. Tavenner, MHA, BSN, RN
Administrator
The Centers for Medicare and Medicaid Services
U.S. Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

Re: CAG-00440N; Proposed Decision Memorandum for Screening for Colorectal Cancer Using CologuardR – A Multitarget Stool DNA Test

Dear Administrator Tavenner:

The American Society for Gastrointestinal Endoscopy (ASGE) appreciates the opportunity to provide comment on CMS’ proposed decision memorandum to cover CologuardR for screening of colorectal cancer. ASGE is a 13,000-member, professional medical society whose mission is to advance patient care and digestive health by promoting excellence in gastrointestinal endoscopy.

The falling rate of colorectal cancer (CRC) in the United States is a public health success story. No other country can claim that both incidence and death rates from colorectal cancer are declining. This decline is due in part to the wide uptake of screening colonoscopy. The incidence of CRC declined 30% in the United States in the 10 years after reimbursement for screening colonoscopy was introduced. Colonoscopy is the only screening test that can find and remove precancerous polyps before they become cancerous.

CMS should be commended for its role in this success story as recent data show that CRC screening rates are among the highest in the Medicare-age population. While mortality rates for CRC have declined over the last decade, colorectal cancer still accounted for over 50,000 deaths in 2013. Half of these deaths could have been prevented through early detection and treatment.

According to a 2013 report from the Centers for Disease Control and Prevention about one in three adults (23 million) between the ages of 50 and 75 years old are not getting screened for colorectal cancer as recommended. ASGE is an active participant in a campaign to increase the nation’s colorectal cancer screening rate to 80 percent by the year 2018. Much still remains to be done.

The approval of Cologuard by the Food and Drug Administration (FDA) makes available to patients another screening option to assist in increasing the early detection of colorectal cancer screening. Cologuard is a significant achievement and provides an important gain in sensitivity for detecting cancer and large polyps. Compared to Fecal Immunochemical Test (FIT) alone, Cologuard is better at detecting cancer (93% vs. 70%) and large pre-cancerous polyps (42% vs. 30%). ASGE believes that it is appropriate for CMS to offer Cologuard as a screening option for Medicare beneficiaries and is hopeful that Cologuard will help to decrease screening avoidance and increase utilization rates.

CMS has proposed to cover the Cologuard test once every three years for beneficiaries who meet all of the following criteria:

• Age 50 to 85 years,
• Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test or fecal immunochemical test), and
• At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or an adenomatous polyp, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

Until the FDA provides its post study results, ASGE encourages CMS to monitor its coverage criteria for Cologuard and modify where appropriate. There are some areas in which ASGE believes further evaluation and clarification will be needed.

As more Medicare beneficiaries consider screening using this new option, ASGE urges CMS to better explain the Medicare preventative screening benefit, as the current policy can be confusing to patients. Additionally, as CMS educates patients about this new technological advancement in non-invasive CRC screening, it is important that patients understand the benefits and limitations of using Cologuard as a screening option. Patients need to be aware that all positive and false positive tests will need to be followed up by a colonoscopy. Under current Medicare policy, the colonoscopy will be considered a diagnostic examination then requiring the patient to pay a deductible and coinsurance. In instances where false positives occur, ASGE requests that CMS cover the colonoscopy procedure as a screening, eliminating the cost-sharing responsibility for the patient. Furthermore, ASGE requests CMS to clarify at what screening interval it will cover for a Medicare beneficiary that received a positive screening using Cologuard, but received a subsequent negative screening using colonoscopy.

It is equally important that patients are made aware that the frequency of screening for Cologuard has not been established and the three year confidence interval of Cologuard compared to an annual or biannual FIT screening is indeterminate. Until further research validates the interval of Cologuard, CMS should not deny coverage of colonoscopy within the three-year window for average risk Medicare beneficiaries who choose to have a Cologuard test that produces a negative result.

Lastly, due to the unit cost of the test compared to other screening tests, Medicare beneficiaries must be educated on the importance of adhering to the directions for submission of Cologuard to yield the highest quality results and avoid rejection of the stool sample provided.

It is critical that more individuals get screened for CRC at the recommended age, because colorectal cancer screening by any screening mechanism is a step closer to saving a life. For those patients that avoid screening, ASGE believes that it is important to provide patients with multiple screening options including colonoscopy, FIT and Cologuard. However, ASGE still strongly endorses the use of screening colonoscopy as the primary screening options for patients. Colonoscopy has been shown in multiple case-control and cohort studies to reduce the risk of colorectal cancer and death from colorectal cancer arising from both the right and left sides of the colon. No other screening test approaches the sensitivity of colonoscopy for detection of polyps. Colonoscopy remains the gold standard of colorectal cancer screening. The superiority of colonoscopy for detection will continue to be viewed as a major advantage of colorectal cancer screening by many physicians and patients.

ASGE appreciates the opportunity to provide comment on CMS’ proposed determination to cover Cologuard. Should you need additional information please contact Lakitia Mayo, Director of Health Policy and Quality at lmayo@asge.org or 630-570-5641.

Colleen M. Schmitt, MD, MHS, FASGE
President
American Society for Gastrointestinal Endoscopy

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As somebody who is approaching 50, I am very excited about this new colon cancer screening test.

Colonoscopy as a screening test for an average risk individual is just too invasive physically and psychologically. [PHI Redacted]

I am not sure I would ever consider FIT test either as the sensitivity is just too low and it does not really detect pre-cancerous polyps. As a result, I would learn about the cancer from FIT test when I most likely will have some symptoms anyway.

I would be one of the people who could likely end up with a colon cancer because of not doing any screening.

However, Cologuard is a test that has a great chance to catch pre-cancerous polyps and is almost perfect at catching cancers. If performed regularly, it will catch every colon cancer in a pre-cancerous state or in stage 1! All easily curable! That is fantastic!

I certainly hope that the CMS reimburses this stool DNA test at a commercially viable rate for Exact Sciences. This company appears very committed to eradication of this type of cancer!

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Thank you for your timely review and support for the Cologuard diagnostic kit from Exact Sciences. I am a retired medical equipment executive with degrees in mathematical modeling, business, chemical engineering and economics. Because of colon cancer in our family, my relatives and I have endured regular colonoscopies and inaccurate FIT/FOBT tests despite the fact that we all are symptom free. With a sensitivity of over 92%, we will now schedule Colguard screenings every two or three years instead of invasive, expensive, worrisome, inconvenient colonoscopies. The proposed cross walked fee of $502 is extremely reasonable for me. I cannot imagine anyone over forty years old not availing themselves of a Cologuard test every three years for only $133/year! I professionally believe that Cologuard will significantly reduce the annual deaths and healthcare costs of CRC. The sooner I can use Cologuard the better!

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August 22, 2014

Marilyn Tavenner, Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Room 445-G, Hubert H. Humphrey Building
200 Independence Avenue, S.W.
Washington, DC 20201

Re: Proposed Decision Memo for Screening for Colorectal Cancer-Stool DNA testing (CAG-00440N)

Dear Ms. Tavenner,

On behalf of the Society for Women’s Health Research (SWHR), I am writing to the Centers for Medicare & Medicaid Services (CMS) with respect to its Proposed Decision Memo for Screening for Colorectal Cancer-Stool DNA testing (CAG-00440N). SWHR strongly believes in the development of molecular diagnostic tools that enable patients, particularly women, to be able to make informed decisions about their health through noninvasive tests which have the potential to reduce deaths, such as those from colorectal cancer.

SWHR is a national non-profit advocacy organization based in Washington, DC, that is widely recognized as the thought leader in research on sex differences and is dedicated to improving women’s health through advocacy, education, and research. Due to SWHR’s efforts in Washington, women are now more routinely included in most major medical research studies, though there are gaps still to be address and, with the recent announcement by NIH, scientists will begin to routinely consider biological sex as a variable in preclinical as well as clinical research.

Over the last decade, tremendous advancements have been made in our knowledge of how diseases and illnesses impact women differently, disproportionately or exclusively from men. Through research and innovation, women now have far more health care information and options to discuss with their providers than ever before. A critical part of the treatment decision making process is being able to accurately diagnose a disease early; not only to stop the course of the disease but to tailor treatments to meet an individual patient’s needs. In recent years, scientists have developed innovative diagnostic tools and technologies that improve health care decisions and, in some cases, preserve the lives of patients. Having access to these new technologies is critical to advancing care for patients and their providers and towards achieving better quality outcomes.

In 2014, the American Cancer Society estimates that there will be 96,830 new cases of colon cancer and that even with the annual death rate from colon cancer dropping approximately 50,310 Americans will die from colon cancer. A large percentage of these cancers are diagnosed at stage 3 and 4 when it is difficult and expensive to treat. The survival rate of stage 4 patients is only around 11% at five years and the average annual cost can be as high as $200,000; costing our health care system $14 billion annual to treat colon cancer. We need to do better.

SWHR supports the American Cancer Society goal of achieving an 80% rate of screening for colon cancer by 2018. Currently, only about two thirds of the targeted population is being screened for colorectal cancer. Likely patients are unwilling to take the time and effort needed to be screened through a colonoscopy. New molecular tests are changing the health care landscape by being less invasive while retaining accuracy. For individuals not willing or able to be screened by colonoscopy, SWHR believes clinicians and patients should have access to this new noninvasive molecular diagnostic testing option that will aid in the goal of increasing the screening rates for colorectal cancer. We feel that combination of the best noninvasive test and a dedicated patient support program may contribute to increasing screening rates, thereby favorably impacting colorectal cancer associated morbidity and mortality. In the 1950s, cervical cancer was a major cause of death for American women. With the introduction of the Pap smear diagnostic test, the cases of cervical cancer were dramatically- reduced. SWHR believes the scientific evidence demonstrates that this new noninvasive molecular diagnostic test holds a similar promise for colon cancer.

Your decision to cover this newly FDA approved molecular diagnostic test once every three years for Medicare beneficiaries who are between ages 50 and 85, asymptomatic and at average risk of developing colorectal cancer will ensure that Medicare beneficiaries, particularly women, who have a history of breast, ovarian or uterine cancer, who are at a somewhat higher risk of developing colon cancer, will have access to this procedure. Colorectal cancer is a significant issue for woman, their families, friends, and all affected patients.

Research and innovation drives science forward enabling doctors to discover problems earlier and, thus, enabling them to tailor appropriate therapy for patients. SWHR is committed to encouraging these advancements and providing access to them by patients, particularly women. We strongly encourage CMS to finalize its Proposed Decision Memo for Screening for Colorectal Cancer-Stool DNA testing (CAG-00440N) based on the scientific evidence. Without these important diagnostic tools, patients and health care practitioners will not be able to make the informed decisions needed at the earliest point in the health care treatment process.

We hope CMS will take our comments into consideration when making its final determinations. If you have any questions with respect to our comments please contact Martha Nolan, Vice President Public Policy at SWHR at martha@swhr.org or 202-496-5007.

Thank you for the opportunity to comment.

Sincerely,
Phyllis Greenberger
President and CEO, SWHR

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Over the past 20 years we have learned that there are alternative pathways to development of CRC besides that of the conventional adenoma – carcinoma pathway. This alternative pathway has been termed the serrated neoplastic pathway and is associated with mutations in BRAF and microsatellite instabilities while conventional adenomas are not [1]. This pathway is thought to lead to about 20-30% of all CRCs [2]. A growing body of evidence suggests that these lesions may be strongly associated with CRCs. Large serrated polyps are strongly and independently associated with synchronous advanced colorectal neoplasia [3]. In a study of over 10,000 subjects in Japan the presence of a large serrated polyp was the largest risk factor associated with CRC (especially proximal CRC) and was an even larger risk than having multiple conventional adenomas [4]. Differentiation of sessile serrated adenomas (SSAs) is important as there is new evidence that many of what are termed hyperplastic polyps are actually sessile serrated adenomas [5]. These polyps are pale and flat and are often covered in mucous making them difficult to pick up in both conventional and CTC colonography [1]. It is quite likely that interval cancers, caught between colonoscopies, may arise from these lesions [6]. The most recent evidence indicates that these may represent almost 15% of all polyps seen at pathology and many polyps classified as hyperplastic polyps need to be reclassified as SSAs [5,7]. This fact points out the need for extra surveillance of these lesions since there are wildly variable rates of detection of these lesions seen in comparisons between endoscopists with some apparently missing them completely [8-10]. Likewise detection of these lesions can be challenging for traditional sigmoidoscopy, with a very recent study concluding that “The findings at flexible sigmoidoscopy that traditionally serve as indications for colonoscopy (conventional adenomas), are likely to be ineffective for detection of proximal advanced serrated lesions” [11]. Thus, it is clear that another screening tool may aid in the detection and surveillance of these lesions given how they now appear to be an important path generating a very large fraction of CRCs. The known association of these lesions with microsatellite instabilities, BRAF mutations and CpG islands [1] makes them prime candidates for detection using a DNA screening tool like Cologuard – something completely lacking with current screening technologies. This platform also provides a great hope that there will be greatly improved future versions of the test incorporating new markers as they develop.

We also know that sessile serrated adenomas manifest little changes to the vascular network and are much less likely to bleed than conventional adenomas [1,3]. This fact likely accounts for the failed sensitivity of FIT for detection of these lesions seen in the DEEP-C trial that showed the excellent sensitivity of Cologuard to SSAs. In that study FIT showed 5.1% sensitivity vs. 42.4% for Cologuard to SSAs [12]. It is hard to avoid the conclusion that FIT is next to worthless for detection of these very important lesions – no matter how good the programmatic compliance that may be attained. As well documented, Cologuard also outperformed FIT (in the same subjects) with respect to almost every other category including cancers, cancer overall, adenomas and adenomas overall [12]. I note that this is one of the largest studies (>10,000 subjects) performed directly comparing FIT to colonoscopy in the same subjects, and the results of this trial for FIT came out very similar to those reported in the largest trial of FIT ever performed of over 20,000 subjects in Japan [13]. Thus, it is hard to directly compare results from much smaller trials since much smaller trials are less reliable and, for instance, have yielded even better performance for stool-DNA tests as well as for FIT. Thus, this trial looks to be another standard-setting trial of FIT vs. colonoscopy. FIT is a rather static technology - it is hard to see dramatic improvement in detection of blood in stool. In contrast Cologuard is readily seen for what it is – an effective first generation tool that outperforms the current non-invasive standard – a platform that is readily extensible to other markers improvements and it is not hard to envision a future where stool-DNA performs at a level comparable to optical colonoscopy.

The one place where Cologuard failed when compared to FIT was in the specificity values. The low specificity of Cologurad, however comes with many caveats. First, there is a well known association between aging and gene methylation. When one looks at the specificity of Cologuard in the age group 50-64, with a negative result on colonoscopy, it reached 94%, or very similar to FIT. Further, in accord with current screening policy Further, according to current screening policy [14] Imperiale et al. stated that “However, two thirds of the false positive results were associated with nonadvanced polyps, which most clinicians would not consider false positive findings because surveillance colonoscopy may be recommended” [15]. Further, Cologuard was compared to the gold standard of colonscopy, however, as discussed above, Colonoscopy may also miss adenomas, polyps and cancers – i.e. most estimates of the sensitivity of colonoscopy are not at 100% but closer to 95%. In short, more work needs to be performed, and future studies will likely inform us as to the true specificity of Cologuard, however it is very likely that a positive Cologuard test will likely lead to more attention paid during the subsequent colonoscopy and may lead to an overall decrease in the false positive rate.

Another issue that is of extreme importance is that of cost. It is certainly likely, based upon performance, that triennial screening with Cologuard has the potential to greatly reduce the number of CRCs similar to what has occurred for cervical cancer with Pap smears. Since CMS spends about $14 billion per year on CRC related costs Cologuard, even with a generous reimbursement, has the potential to greatly reduce overall spending on CRC. The last detailed study of the cost efficiency by CMS was published in 2009 using performance parameters derived from much older, now discarded, versions of stool DNA testing [16]. That study showed that stool-DNA was dominated by other screening technologies at the assumed cost of $350 unless one could show dramatic increases (50%) in screening compliance with stool-DNA compared to other techniques. It is not improbable that screening compliance could be greatly increased since there is evidence that many clinicians don’t recommend fecal blood screening due to perceived lack of sensitivity. If primary care physicians believe that a new tool is relatively easy to use, and has good performance characteristics, it is not unlikely that they will recommend it. Cologuard, as designed by Exact Sciences, will take the compliance monitoring out of the hands of the physician (who has very little financial incentive in the compliance monitoring) and into the hands of the Exact Sciences. It remains to be seen of course, if this will occur. As thorough as the older cost-efficacy study performed for CMS was [16], it will likely need to be performed again not only to incorporate the new performance characteristics of Cologuard but also to incorporate the natural history of CRC with the new appreciation of the serrated neoplastic pathway. The original study that was performed only included the adenoma-carcinoma pathway. Given that we now know that FIT has almost no sensitivity to those lesions [12], and given the importance of that pathway in development of CRC [2], it is almost certain that the conclusions of the original study will change. I would strongly urge CMS NOT to perform another cost-benefit study without including the serrated neoplastic pathway in revised versions of the the models (Sim-CRC, MISCAN). Then one could easily perform simulations with different performance characteristics for SSAs.

A further issue is that the costs of DNA sequencing have dramatically dropped in the past decade. There is no reason to believe that such a trajectory will not also lower the costs of Cologuard in the near future. A commercially sustainable reimbursement for Cologuard now will enable future efficiencies of DNA detection to lower the costs of the test. Conversely, a commercially un-sustainable reimbursement will likely greatly dampen future research and development of similar tests.

Summary:

1. Cologuard represents a novel tool for screening colorectal cancer using a completely different mechanism (DNA testing) than currently used technologies.
2. There are important CRC pathways, the serrated neoplastic pathway, that have been recently appreciated and may be the source for up to 30% of all CRCs. FIT has almost NO sensitivity to the pre-cursor lesions of this pathway whilst Cologuard has good sensitivity (42%). Colonoscopy has variable sensitivity to lesions of this pathway. Therefore, this provides a strong rationale for the use and reimbursement of Cologuard.
3. Cologuard already greatly outperforms FIT in sensitivity to pre-cancers, those most important to catch and remove before the great personal and societal burden of CRC occurs. Further, the specificity of Cologuard is likely better than the first large study found and may be improved in the near term.
4. Cologuard has the potential, unlike FIT, to see dramatic increases in performance in coming years, by leveraging academic research in marker development as well as decreases in DNA detection costs. Commercially sustainable reimbursement for Cologuard will provide suitable incentive to develop both more efficacious, as well as cheaper tests.

Therefore, it is my informed opinion that this screening tool of the future be approved for a commericially sustainable reimbursement now.

[1]. Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 2010; 138:2088-2100.
[2]. Kalady MF. Sessile serrated polyps: an important route to colorectal cancer. J Natl Compr Canc Netw. 2013; 11:1585-1594.
[3]. Li D, Jin C, McCulloch, et al. Association of large serrated polyps with synchronous advanced colorectal neoplasia. Am J Gastroenterol 2009; 104:695–702.
[4]. Hiraoka S, Kato J, Fujiki S, Kaji E, Morikawa T, Murakami T, Nawa T, Kuriyama M, Uraoka T, Ohara N, Yamamoto K. The presence of large serrated polyps increases risk for colorectal cancer. Gastroenterology. 2010;139:1503-1510.
[5]. Tinmouth J, Henry P, Hsieh E, et al. Sessile Serrated Polyps at Screening Colonoscopy: Have They Been Under Diagnosed? Am J Gastroenterol. 2014; doi: 10.1038/ajg.2014.78. [Epub ahead of print]
[6]. Sawhney MS, Farrar WD, Gudiseva S, Nelson DB, Lederle FA, Rector TS, Bond JH. Microsatellite instability in interval colon cancers. Gastroenterology. 2006; 131:1700-1705.
[7]. Bettington M, Walker N, Rosty C, et al. Critical appraisal of the diagnosis of the sessile serrated adenoma. Am J Surg Pathol. 2014; 38(2):158-166.
[8]. Hetzel JT, Huang CS, Coukos JA, Omstead K, Cerda SR, Yang S, O'Brien MJ, Farraye FA. Variation in the detection of serrated polyps in an average risk colorectal cancer screening cohort. Am J Gastroenterol. 2010;105:2656-2664.
[9]. Kahi CJ, Hewett DG, Norton DL, Eckert GJ, Rex DK. Prevalence and variable detection of proximal colon serrated polyps during screening colonoscopy. Clin Gastroenterol Hepatol 2011; 9:42-46.
[10]. Sanaka MR, Gohel T, Podugu A, et al. Adenoma and sessile serrated polyp detection rates: variation by patient sex and colonic segment but not specialty of the endoscopist. Dis Colon Rectum. 2014; 57:1113-1119.
[11]. Kahi CJ, Vemulapalli KC, Snover DC, Abdel Jawad KH, Cummings OW, Rex DK. Findings in the Distal Colorectum are not associated with Proximal Advanced Serrated Lesions. Clin Gastroenterol Hepatol. 2014; pii: S1542-3565(14)01089-1. doi: 10.1016/j.cgh.2014.07.044. [Epub ahead of print].
[12]. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget Stool DNA Testing for Colorectal-Cancer Screening, New Eng. J Med 2014; 370:1287-1297.
[13]. Morikawa T1, Kato J, Yamaji Y, Wada R, Mitsushima T, Shiratori Y. A comparison of the immunochemical fecal occult blood test and total colonoscopy in the asymptomatic population. Gastroenterology. 2005; 129:422-428.
[14]. Lieberman DA, Rex DK, Winawer SJ, Giardiello FM, Johnson DA, Levin TR. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2012;143:844-57.
[15]. Imperiale TF, Ransohoff DF, Itzkowitz SH Authors Reply, New Engl J Med 2014; 371:184-188.
[16]. Lansdorp-Vogelaar I, Kuntz, KM, Knudsen, AB, Wilschut, JA, Zauber, AG, and van Ballegooijen M, Stool DNA Testing to Screen for Colorectal Cancer in the Medicare Population: A Cost-Effectiveness Analysis. Ann Intern Med. 2010; 153: 368–377.

Bruce G. Jenkins, PhD

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August 27, 2014

Tamara S. Syrek Jensen, J.D.
Acting Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, MD 21244

By Online Submission

Re: Proposed Decision Memo for Screening for Colorectal Cancer – Stool DNA Testing (CAG-00440N)

Dear Ms. Syrek Jensen:

The American College of Radiology (ACR), representing more than 35,000 diagnostic radiologists, radiation oncologists, nuclear medicine physicians and medical physicists, appreciates the opportunity to comment on the recent proposed approval of coverage of Cologuard stool DNA test by the Centers for Medicare and Medicaid Services (CMS). We believe that the stool DNA test provides another option in the armamentarium for colorectal cancer (CRC) screening. By encouraging unscreened individuals off the sidelines who may be reluctant to undergo optical colonoscopy, this decision will have a positive impact against this deadly cancer. At the same time, this precedent-setting approval should serve as the new evidence standard for Medicare coverage of colorectal cancer screening tests- including CT colonography (CTC). Initiating coverage of CTC would further improve adherence rates and help to reserve the most invasive and expensive procedure – optical colonoscopy – for those patients who are most likely to require therapy.

Although detection of cancer is obviously an important task, it should be noted that the greatest societal benefit from CRC screening is actually the prevention of cancer through detection of precursor advanced adenomas, as emphasized by the American Cancer Society screening guidelines.¹ Large (=10 mm) adenomas, which are at increased risk for developing into cancer, represent the target of highest yield in terms of both clinical efficacy and cost effectiveness. In a typical average-risk screening population, 1 in 20 individuals will harbor a large adenoma, whereas only 1 in 500 will have an invasive cancer.

While Cologuard may successfully detect up to 92% of CRC, the sensitivity for large advanced adenomas is only 42%, falling well short in this critical area of cancer prevention.² In comparison, CTC is 96% sensitive for cancer detection,³ but also has a sensitivity of 90% or greater for large adenomas,^4-6 providing for robust cancer prevention over at least a 5-year time horizon.⁷ In fact, CTC detection of advanced adenomas and cancer matches or exceeds that of the more invasive and expensive OC procedure in actual practice.⁸

Specificity and positive predictive value (PPV) data are often overlooked in favor of sensitivity when considering the performance of CRC screening tests, but these may have enormous implication in terms of cost-effectiveness, resource utilization, and patient anxiety. Assuming a typical cancer prevalence of 0.2%, the 87% specificity of Cologuard for cancer detection would translate into a PPV of less than 2%. In comparison, the PPV of CTC for large polyps is well over 90% and is even higher for cancer.^9-11 To put this into perspective, for a screening population of 10,000 adults, Cologuard would on average detect 18 cancers, miss 2 cancers, and generate about 1,300 false-positive results (i.e., no cancer). The ramifications of a false-positive “genetic” test (which will outnumber true-positive cancer detection over 70 to 1) are currently uncertain in terms of the need for additional testing with associated costs. Additionally, due to false positives and no knowledge about the location of a potential tumor, patients will still need a more specific test available to make the diagnosis. CTC should be one of those tools.

Although the Cologuard stool DNA test showed nearly twice the sensitivity of fecal immunochemical test (FIT) for advanced adenoma detection (42% vs 24%), the CTC sensitivity of 90% or greater is double that of Cologuard and nearly quadruple that of FIT. In addition, Cologuard showed a lower sensitivity for cancer detection in women (83%), as well as lower sensitivity for advanced adenoma detection in women (39% vs. 45%). There is no evidence that CTC has lower performance in women compared with men.

Beyond clinical performance, CTC is more cost-effective than stool DNA^{12, 13} and currently recommended to be performed at a 5 year interval compared with every 3 years for stool DNA. Unlike all other CRC screening tests, CTC also provides for extracolonic screening, particularly for abdominal aortic aneurysms (AAA), osteoporosis, and cancers outside the colon.^14-18 In terms of the low-dose radiation exposure associated with CTC, the health effects in adults are either too small to measure or are non-existent.¹⁹ The benefit to risk ratio comparing the potential lives saved using screening CTC to the potential deaths caused by fatal cancers induced due to the low radiation from the test demonstrated a large benefit to risk ratio in favor of screening CTC.²⁰

Of note, on September 9, 2013, the Office of the Commissioner of the U.S. Food and Drug Administration (FDA) convened a joint meeting of the Gastroenterology-Urology Devices Panel and the Radiological Devices Panel to discuss current evidence on the risks and benefits of computed tomography colonography (CTC) for the screening of asymptomatic patients for colorectal cancer (CRC).²¹ Members of the FDA panel unanimously agreed that, given the risks and benefits identified, CTC should be made available as an option for CRC screening of asymptomatic patients.

In summary, it is encouraging to see that CMS has begun to expand the available Medicare screening options by proposing to include the Cologuard stool DNA test for coverage, despite its current “I” rating from USPSTF. Given the superior performance profile of CTC over stool DNA, including the important benefit of cancer prevention, we anticipate that CMS will agree with the recent FDA conclusion and that it should soon cover CTC as a safe and effective minimally-invasive option as well to further benefit the Medicare population.

Sincerely,

Judy Yee, MD, FACR
Chair, ACR Colon Cancer Committee

References

1. Levin B, Lieberman DA, & McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 2008;58(3),130-60.
2. Imperiale, TF Ransohoff, DF, & Itzkowitz, SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 2014;370(14),1287-9.
3. Pickhardt, PF, Hassan, C. Halligan S, Marmo, R. Colorectal cancer: CT colonography and colonoscopy for detection - systematic review and meta-analysis. Radiology 2011; 259(2):393-405.
4. Graser, A, Steiber, P Nagel, D Schaefer, et al. (2009). Comparison of CT colonography, colonoscopy, sigmoidoscopy and faecal occult blood tests for the detection of advanced adenoma in an average risk population. Gut. 2009;58(2): 241-8.
5. Johnson CD, Chen MH, Toledano AY, et al. Accuracy of CT colonography for detection of large adenomas and cancers. N Engl J Med 2008; 359(12):1207-17.
6. Pickhardt PJ, Choi JR, Hwant I, et al. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med. 2004;349(23):2191-2200.
7. Kim DH, Pooler BD, Weiss JM, Pickhardt PJ. Five year colorectal cancer outcomes in a large negative CT colonography screening cohort. Eur Radiol. 2012; 22(7):1488-94.
8. Kim DH, Pickhardt PJ, Taylor AJ, et al. CT colonography versus colonoscopy for the detection of advanced neoplasia. N Engl J Med 2007;357(14):1403-12.
9. Iafrate F, Hassan C, Ciolina M, et al. High positive predictive value of CT colonography in a referral centre. Euro J Radiol. 2011; 80(3):E289-E92.
10. Pickhardt PJ, Wise SM, Kim DH. Positive predictive value for polyps detected at screening CT colonography. Eur Radiol. 2010;20:1651-6.
11. Zueco Zueco C, Sobrido Sampedro C, Corroto JD, Rodriguez Fernandez P, Fontanillo Fontanillo M. CT colonography without cathartic preparation: positive predictive value and patient experience in clinical practice. Eur Radiol. 2012; 22(6):1195-204.
12. Hassan C, Pickhardt PJ. Cost-Effectiveness of CT Colonography. Radiol Clin North Am 2013;51(1):89-97.
13. Skally M, Hanly P, Sharp L. Cost effectiveness of fecal DNA screening for colorectal cancer: a systematic review and quality appraisal of the literature. Appl Health Econ Health Policy 2013; 11(3):181-92
14. Pickhardt PJ, Lee LJ, del Rio AM, et al. Simultaneous Screening for Osteoporosis at CT Colonography: Bone Mineral Density Assessment Using MDCT Attenuation Techniques Compared With the DXA Reference Standard. J Bone Miner Res 2011;26(9):2194-203.
15. Veerappan GR, Ally MR, Choi JR, et al. Extracolonic findings on CT colonography increases yield of colorectal cancer screening. Am J Roentgenol. 2010;195:677-686.
16. Hassan C, Pickhardt P, Laghi A, et al. Computed tomographic colonography to screen for colorectal cancer, extracolonic cancer, and aortic aneurysm. Arch Intern Med 2008; 168(7):696-705.
17. Pickhardt PJ, Kim DH, Meiners RJ, et al. Colorectal and extracolonic cancers detected at screening CT colonography in 10,286 asymptomatic adults. Radiology 2010; 255(1):83-8.
18. Pickhardt PJ, Hassan C, Laghi A, Kim DH. CT Colonography to Screen for Colorectal Cancer and Aortic Aneurysm in the Medicare Population: Cost-Effectiveness Analysis. Am J Roentgenol. 2009;192:1332-40.
19. Radiation risk in perspective position: Position statement of the Health Physics Society. (2010, July). 1-3. Retrieved from http://hps.org/documents/risk_ps010-2.pdf.
20. Berrington de González A, Kim KP, Knudsen AB, et al. Radiation-related cancer risks from CT colonography screening: a risk-benefit analysis. Am J Roentgenol. 2011 Apr;196(4):816-23.
21. http://www.fda.gov/NewsEvents/MeetingsConferencesWorkshops/ucm366949.

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I am a Doctor of Pharmacy certified in Geriatric Pharmacology and I am delighted to offer a comment.

Cologuard will offer our ever growing population of those at risk for CRC a reasonable approach to reduction of the incidence of a very real and age related morbidity / mortality.

Cologuard will offer a huge health benefit to the ever growing older population. Empowering patients to actively participate in their own health is a winning approach to cost effective preventive health care. Currently available options do not offer the advantages of Cologuard. Patients can understand this test and are very likely to welcome a user-friendly tool.

Cologuard will offer an expected notable increase in CRC screening compliance by the at risk population, thus reducing the incidence of advanced CRC.

Cologuard is certainly a cost effective tool that will help avoid the enormous cost of treating advanced CRC. CMS will benefit greatly from the cost savings incurred.

It appears that PhRMA currently prices treatment options at whatever the market will bear. Often this is not workable for our senior population, nor is it a welcome expense for CMS, especially when new diagnostics are at hand. Early detection is cost effective.

All opinion just stated is just that, my opinion with no representation otherwise.
Thank you for the opportunity to speak.

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The Colon Cancer Alliance is the oldest and largest advocacy organization dedicated to the prevention of colorectal cancer and the empowerment of patients facing the challenge of this devastating disease. As a member of the National Colon Cancer Roundtable, we join with the Centers for Disease Control and Prevention and other members to achieve the goal of having 80% of at-risk adults screened for colorectal cancer by 2018.

It is a tragedy that this year almost 50,000 Americans will die from a disease that is largely preventable with timely screening. In the last decade there has been a 30% reduction in the incidence of colorectal cancer as a direct result of more adults being screened. It is a simple equation, the more at-risk adults who are screened, the more lives are saved. Screening also results in significant cost savings. The expense to treat colorectal cancer in the US is $14 billion; much of the cost due to the fact that it is diagnosed 60% of the time in late stages.

While we are pleased with the progress that has been made in increasing the screening rate, still one-third of at-risk adults have not been screened. While there are a host of barriers, one thing is clear: we will not achieve our goal of 80% by 2018 without new, less invasive screening methods. Certainly colonoscopy remains the ideal method in that polyps can be removed in the same procedure; however, many at-risk adults cannot and others simply will not get a colonoscopy. For our community it is a major communication challenge to convince the non-compliant to undergo this type of invasive medical procedure when they “feel perfectly fine.”

The Colon Cancer Alliance welcomed the FDA approval of Cologuard in that the DNA stool test showed superior detection of both cancer and advanced adenoma compared with stool tests currently available. We believe this is an important advance in that high sensitivity can be achieved through a non-invasive test and provides a screening option for those unable or unwilling to have a colonoscopy.

Since the FDA announcement there has been a great deal of excitement among our constituents regarding the DNA stool test and questions about where to get it and will it be covered. We hope that shortly we can respond that it is a benefit provided for Medicare patients and encourage CMS to complete its review as soon as possible with a favorable decision.

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I ask, that of the medical professionals recommending colonoscopy or FIT on cost alone, how is society to handle the exploding number of baby boomers?

1. There are not enough GI's to perform the greater than 100 million (and growing) population of those individuals age 50 years and older:

2. With regard to FIT, it has been mentioned that only one commercially available FIT was used during the 10,000 patient prospective double blinded study, and that there could be inconsistencies in different FIT's commercially available, to which I bring up the following points:

3. The Exact Sciences' Cologuard represents an opportunity for patients to get educated on the importance of screening for CRC. A non-invasive test, which has been proven to be more accurate than the competitive non-invasive screening test, represents an opportunity to convince patients of the importance of screening, and helps to move some people from an "average risk" population to the "high risk" population. At present capacity, we can handle the "high risk" population, with the concerns mentioned above.

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Recently the FDA approved the “Cologuard test” to screen for colorectal cancer (CRC), and the Centers for Medicare and Medicaid Services (CMS) announced proposed Medicare coverage of the test. The parallel review by the two agencies represented the first step in a pilot program to expedite approval and coverage of selected devices. CMS proposes to cover the Cologuard™ test for use once every three years for beneficiaries who meet all of the following criteria:

1. Age 50 to 85 years,
2. Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test or fecal immunochemical test)
3. At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or an adenomatous polyp, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

The study on which FDA approval was based was a good one and, Cologuard, in that study, was shown to have some performance characteristics (sensitivity for CRC and advanced adenoma) that are better than one fecal immunochemical test for hemoglobin (FIT), the OC FIT-CHEK Polymedco. This should qualify Cologuard as one of several choices of good screening tests for CRC, the others being optical colonoscopy, flexible sigmoidoscopy and the fecal immunochemical tests. My concerns about the FDA/CMS parallel review and decision are listed below:

1. It would be helpful to those of us who are active in the CRC screening world and, serve as consultants to the NCI, CDC, and AHRQ, were informed about what FDA’s and CMS’s rules of evidence are and how they were used to come to an every 3 year coverage decision for Cologuard. What evidence exists for the decision granting a 3 year interval between Cologuard tests? The manufacturer has committed to conducting a post approval study required by the FDA which will evaluate the validity of screening every three years and ensure that clinically important findings are not missed however; such a study will take years and, in the meantime, the test is being marketed with no warning from any agency about possible safety issues associated with an every 3 year test interval. (see http://www.latimes.com/business/la-fi-lazarus-20140822-column.html) An updated recommendation from the U.S. Preventive Services will not be available until next year and there is no guarantee as to what recommendation for Cologuard, if any, it will make.

In 2003, CMS issued a final Decision Memorandum indicating that effective with that date Medicare would cover a screening fecal immunoassay test (FIT) (See Pub. 100-03, Chapter 1, Section 210.3, screening immunoassay FOBT) on an annual basis as an alternative to the guaiac-based FOBT. The one year interval decision was made on the basis of what the interval had been for the guaiac FOBT despite the fact that the FIT sensitivity for CRC and advanced adenoma was significantly better than that of the standard guaiac FOBT. The rationale was that there was insufficient evidence that a longer interval was safe. This has yet to be changed even though much more clinical trial evidence has accumulated showing that annual FIT are not necessary. In most, if not all countries using a FIT based CRC screening program, the recommended interval is every 2 years. U.S. guidelines have not changed since 2008 and continue to recommend yearly FIT as per the CMS decision memorandum of 2003. There is only one study of Cologuard and the cohort screened and colonoscoped has yet to be followed for even 2 years.

2. What is covered by the price the manufacturer is asking to receive (somewhere between $300-600)? Who pays for the shipping the specimen? What is the actual cost to the lab to run the test? Does CMS have any regulations on how price is determined by the manufacturer? With FIT available at $23 maximum, is the small increased application sensitivity of Cologuard compared to OC Sensor (the FIT comparator) in the NEJM study worth it? A formal cost effective analysis should be done before recommending such reimbursement.

I understand that current government regulations prohibits cost as being a reason for denying coverage but, that shouldn’t prevent you from doing a cost effective analysis that every citizen and health plan could see and evaluate for themselves. This was done for the previous versions of the EXACT Sciences fecal DNA test and the analysis showed the test was not cost effective. (Lansdorp-Vogelaar I; Kuntz K,. Knudsen AB; Wilschut JA; Zauber AG; and van M Stool DNA Testing to Screen for Colorectal Cancer in the Medicare Population Ann Intern Med. 2010; 153:368-377.)

The conclusion of the authors was that stool DNA testing could be a cost-effective alternative for colorectal cancer screening if the cost of the test substantially decreased or if its availability would entice a large fraction of otherwise unscreened persons to receive screening. Perhaps Cologuard with its superior performance characteristics will be more likely to be cost effective but, factors such as lower specificity and poor patient performance of the test must be considered and factored into any analysis. Has the demonstrated decrease in specificity of Cologuard compared to the OC Sensor FIT been factored into the cost for a Cologuard screening program especially with our limited and expensive colonoscopic resources and the noted decrease specificity of Cologuard in older (Medicare) patients?

3. I could not determine if the FDA or CMS evidence search included extensive review of the literature on the fecal immunochemical test (FIT). In the Decision Memo it appears that the literature search was confined to literature on the stool DNA test. If the FIT literature was not reviewed, the Decision Memo conclusion that The Cologuard™ test is a technologically advanced, non-invasive CRC screening test with test performance that has been shown to be significantly better in detecting advanced adenomas and cancers than current fecal immunochemical tests (Imperiale, 2014) is questionable and likely incorrect.

FIT are not a class and, therefore; it must be understood that a comparative study such as the one in the NEJM could only show “superiority of Cologuard” over one FIT, the OC FIT-CHEK Polymedco with the cut off level for a positive test determined by the manufacturer. FIT are not all the same, even when the fecal hemoglobin concentration cut-offs are "adjusted" to give ostensibly the same results (in ug Hb/g feces). Moreover, sensitivity can be altered by adjustment of cut-off concentration - or by increasing the number of samples taken – maneuvers that are far less expensive than the molecular techniques. A recent review on FIT published in May is an excellent resource for decision makers who must know and understand the complexities of FIT. (Allison JE, Fraser CG, Halloran SP, Young GP. Population screening for colorectal cancer means getting FIT: the past, present, and future of colorectal cancer screening using the fecal immunochemical test for hemoglobin (FIT).Gut Liver. 2014 Mar; 8(2):117-30)

The Decision Memo suggests that CMS has adopted the idea promoted by Guidelines published in 2008 (Levin B, Lieberman DA, McFarland B, et al Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology 2008 May; 134(5):1570-95) and, not yet updated, that screening tests detecting the most polyps at a single application are the best. In the cited 2008 Guidelines this point was used to assert that only structural exams both decreased colorectal cancer mortality and incidence and that fecal tests only decreased CRC mortality, not incidence thus implying that fecal tests were poor at identifying advanced adenomas. Since 2008, this assertion has been dropped by the American Cancer Society, the American College of Physicians, the JAMA patient page on CRC screening tests and, even some endoscopy societies disavow it.

It is impressive that Cologuard has a better sensitivity than a FIT for those polyps most likely to become cancer (advanced adenomas) but, we don’t know yet if that increased sensitivity at one application done every 3 years is better than a FIT with a lower sensitivity for advanced adenomas done every year or every 2 years. The same is true for Cologuard’s increased sensitivity for colorectal cancer over the comparator FIT used in the EXACT NEJM Study. A recently published study demonstrated that repeated FIT screening (1/year for 3 years) detected all CRC’s and proved equivalent to colonoscopy in detecting advanced neoplasia in first-degree relatives of patients with CRC. (See: Quintero E, Carrillo M, Gimeno-García AZ, Hernández-Guerra M, Nicolás-Pérez D, Alonso-Abreu I, Díez-Fuentes ML, Abraira V, Equivalency of Fecal Immunochemical Tests and Colonoscopy in Familial Colorectal Cancer Screening, Gastroenterology (2014), doi: 10.1053/j.gastro.2014.08.004.)

The attached article on colonic polyps gives information on the real rather than the perceived threat of colonic adenomas (polyps). (See: Allison JE and Meijer GA Colonic Polyps: The Harm of Overdiagnosis Practical Gastroenterology November 2012 p. 25-38) It may help panel members better understand why Cologuard’s superior sensitivity for advanced adenomas over those of a FIT might not be as important as some make it seem if the FIT is used in a program of annual or biennial FIT screenings. Twenty five percent of the U.S. population has polyps by age 50 and, up to 50 percent of individuals will develop a colorectal adenoma (polyp) in their lifetime. Most Americans die with and not from their polyps.

Here are the facts about what many call “precancerous” polyps:

1. All colonic adenomas are potentially “precancerous” but, most (93 - 97%), even the “advanced” ones, do not directly lead to death from colon cancer. Since almost all adenomas are slow growing (years before they become fatal cancers), there are multiple opportunities in a program of repeated screens every year or every other year, to identify and remove them long before they become cancers.
2. Advanced neoplasia may be considered a convenient proxy for colorectal cancer but, its use as an outcome measure may be misleading in screening studies because the natural history of this lesion is unknown
3. The prevalence of high grade dysplasia in subjects found with small adenomas was only 1% in a large U.S. colonoscopy study
4. Longitudinal studies assessing follow-up of unresected small colorectal adenomas harboring high grade dysplasia is lacking. We have no idea how many will progress to fatal cancer or over what period of time
5. The term “advanced adenoma” is misleading because the natural history of this lesion is unknown
6. The definition of an advanced neoplasm as used in the gastroenterology literature is very different from that found in a standard pathology textbook. Most advanced neoplasms in the gastroenterology literature are polyps, not stage 4 cancers and, only a small percentage of them present a risk of progression from benign to malignant status. At present, our ability to identify those that will is limited and based on phenotype

4. What is the rationale for CMS to recommend utilization of the Cologuard test for Medicare beneficiaries up to age 85? The clinical study of Cologuard did include subjects up to age 84. In subgroup analysis, the specificity in the age groups 75 and older was considerably lower at 78%. This would lead to more false positives and more colonoscopies in the group of individuals who are most at risk of complications from colonoscopy (Warren JL et al. Adverse events after outpatient colonoscopy in the Medicare population. Ann Intern Med 2009; 150:849-57) and have the least data supporting ongoing screening. The USPSTF does not recommend routine screening in individuals aged 76-84 and recommends against screening in individuals aged 85 and older. Therefore, there appears to be a strong rationale not to use this particular test for patients 76-84 years old and the use of any screening test in this age group should be considered on a case by case basis.

5. Other important points to make include the following:

James E. Allison MD, FACP, AGAF
Clinical Professor of Medicine Emeritus UCSF
Division of Gastroenterology UCSF/SFGH
415-206-8709 (office) 415-641-0745 (Fax)
Emeritus Investigator Kaiser Division of Research
510-891-3250 (office) 510-891-3249 (Fax)
http://profiles.ucsf.edu/james.allison

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To whom it may concern:

In the context of the past few years, I am surprised by the CMS decision to reimburse stool DNA testing for colorectal cancer screening. CMS has noticeably raised the bar for supporting data for any new screening modality. However, there is a glaring omission in the potential risks and harms section of the CMS document. In the Imperiale trial, the false positive rate for this test was substantial.(1) As the authors themselves report in the paper, in a hypothetical expansion of trial results to a screening population, 76.4% of positive test results would be false positives. This statistic raises thorny issues that could have major downstream consequences. In the case of a false positive test which obviously leads to a negative colonoscopy, what happens next? With ‘cancerous DNA’ markers in stool, does the patient need upper endoscopy for possible esophageal or gastric cancer, capsule endoscopy for small bowel cancer, CT for pancreatic cancer?. . . The potential for work up of an incidental occult GI malignancy exists with this test that is not the case for other screening tests such as FIT, CT colonography, or colonoscopy. The extent of medical resources used, the number of subsequent complications, and the likely anxiety resulting to an otherwise ‘healthy’ person are all unknowns but possibly considerable.

Analogous to the case of incidental findings at CT colonography, data and outcomes are needed. CMS has taken the action in the past of requiring this information prior to reimbursement in order to balance the benefits and harms of a colorectal cancer screening test. In the case of CTC where we now have a decade of clinical experience and multiple large trials and series, this is largely known where the work up rate is less than 8% balanced against the beneficial discoveries of unsuspected abdominal aortic aneurysms (0.1%-0.8%) and extracolonic cancers (0.3%-0.8%).(2-8) Such information should be required for stool DNA testing prior to reimbursement. Albeit large numbers, there are only the results of this single trial. There is no longitudinal data regarding the impact of this false positive rate. If such a bar does not need to be met, it does represent an interesting departure from previous CMS decisions regarding other screening modalities such as CT colonography.

Regardless, I do believe that the decision for reimbursement is correct. However, I would say the same for CT colonography. Although not perfect, both tests are effective and will likely help in improving adherence to ultimately help decrease mortality from this preventable cancer.

Sincerely,

David H. Kim, MD FACR
Professor of Radiology
Vice Chair of Education
University of Wisconsin School of Medicine and Public Health

1. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget Stool DNA Testing for Colorectal-Cancer Screening. N Engl J Med 2014;370:1287-97.
2. Gluecker TM, Johnson CD, Wilson LA, et al. Extracolonic findings at CT colonography: Evaluation of prevalence and cost in a screening population. Gastroenterology 2003;124:911-6.
3. Yee J, Kumar NN, Godara S, et al. Extracolonic abnormalities discovered incidentally at CT colonography in a male population. Radiology 2005;236:519-26.
4. Pickhardt PJ, Hanson ME, Vanness DJ, et al. Unsuspected extracolonic findings at screening CT colonography: Clinical and economic impact. Radiology 2008;249:151-9.
5. Park SK, Il Park D, Lee SY, et al. Extracolonic findings of computed tomographic colonography in Koreans. World J Gastroenterol 2009;15:1487-92.
6. Veerappan GR, Ally MR, Choi JHR, Pak JS, Maydonovitch C, Wong RKH. Extracolonic Findings on CT Colonography Increases Yield of Colorectal Cancer Screening. Am J Roentgenol 2010;195:677-86.
7. Behrens C, Stevenson G, Eddy R, et al. The Benefits of Computed Tomographic Colonography in Reducing a Long Colonoscopy Waiting List. Can Assoc Radiol J 2010;61:33-40.
8. Atkin W, Dadswell E, Wooldrage K, et al. Computed tomographic colonography versus colonoscopy for investigation of patients with symptoms suggestive of colorectal cancer (SIGGAR): a multicentre randomised trial. Lancet 2013;381:1194-202.

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August 15, 2014

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Center for Medicare and Medicaid Services
7500 Security Blvd.
Baltimore, MD 21244

Re: Proposed Decision Memorandum for Screening for Colorectal Cancer Using Cologuard™—A Multitarget Stool DNA Test

Dear Ms. Syrek Jensen:

As the only national nonprofit organization in the United States dedicated solely to the prevention and early detection of cancer, the Prevent Cancer Foundation appreciates the opportunity to submit comments to the Centers for Medicare and Medicaid Services (CMS) on the national coverage determination for Cologuard™. This multitarget stool DNA (sDNA) test for colorectal cancer screening is an innovative, noninvasive product that is an important tool to detect this cancer. Having demonstrated the safety, effectiveness, and risk benefit profile, the U.S. Food and Drug Administration (FDA) approved Cologuard™ on August 11, 2014. As such, we strongly support coverage for Cologuard™ tests once every three years for Medicare beneficiaries who meet the CMS-outlined criteria.

Cologuard™ has demonstrated dramatic improvements in the detection of early-stage colorectal cancer and precancerous lesions with high-grade dysplasia. Compared to a commonly used, automated immunochemical test for fecal hemoglobin, Cologuard™ detected significantly more colorectal cancers overall.

Cologuard™ offers a non-invasive screening alternative for individuals who are unwilling or unable to be screened by colonoscopy. This is a particular challenge in areas of the country that are underserved and lack robust screening resources and coverage. Currently, one in three Americans between the ages of 50 and 75 (about 23 million people) is not getting any of the recommended tests. People of color, rural populations, men, those 50 to 64, and those with lower education and income are the least likely to get tested.

There are nearly 150,000 new cases of colorectal cancer each year in the United States at a cost of $14 billion. This disease is the second leading cause of cancer-related deaths in the nation, taking over 50,000 lives this year. However, screening asymptomatic people can greatly reduce these numbers, particularly in older Americans who are at higher risk for the disease.

Approximately 90 percent of people live five or more years when their colorectal cancer is found early. Medicare beneficiaries deserve access to this test. As evidenced by the Affordable Care Act and the U.S. Preventive Services Task Force (USPSTF), preventive services such as recommended cancer screenings must be affordable and accessible to all.

Again, we appreciate the opportunity to comment on this national coverage determination for Cologuard™. If we can provide further information, please feel free to contact me at Carolyn.Aldige@preventcancer.org or at 703.519.2114.

Sincerely,

Carolyn Aldigé
President and Founder

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August 14, 2014

SUBJECT: Proposed Decision Memorandum for Screening for Colorectal Cancer Using
Cologuard™ – A Multitarget Stool DNA Test (CAG-00440N)

Thank you for the opportunity to review the Centers for Medicare & Medicaid Services (CMS) proposal to cover Cologuard, a multitarget stool DNA test, as a colorectal cancer screening test for asymptomatic average risk beneficiaries aged 50 to 85 years. Colorectal cancer screening is an issue of great importance to women’s health. Each year, more than 24,000 women die from colorectal cancer, making it the third leading cause of cancer death in women, after lung cancer and breast cancer.¹ Despite consensus among health care organizations about the value of screening for colorectal cancer, a 2012 study reported that only approximately 65% of respondents (U.S. women aged 50–75 years) have been screened using colonoscopy or sigmoidoscopy in the past 10 years or fecal occult blood test within the past year.²

The College recognizes the benefits of colonoscopy as the preferred method of screening since it allows for a full examination of both the colon and rectum in one session, and also allows the clinician to perform a biopsy or polypectomy, if indicated. However, there are many acceptable methods of colorectal cancer screening, and overall, the best method is the one that the patient will complete. Data demonstrate that fear and embarrassment about the screening procedure are significant barriers to colorectal cancer screening.³ It is important for patients to have choices, and for clinicians to be able to counsel them on the benefits, limitations, and preparation for the different methods. Increased sensitivity by health care providers to patients' behaviors, feelings, cultural differences, and attitudes can result in increased patient and health care provider satisfaction and participation in screening for this serious disease.

The College is encouraged by recent data on the utility of multitarget stool DNA test.⁴ It will continue to monitor its effectiveness as a screening tool. Access to a variety of screening methods is an important step toward increasing screening rates, and the College supports the addition of the multitarget stool DNA test to the list of covered colorectal cancer screening tests.

Sincerely,
Gerald F. Joseph Jr, MD, FACOG
Vice President, Practice Activities

1 Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29.
2 Joseph DA, King JB, Miller JW, Richardson LC. Prevalence of colorectal cancer screening among adults Behavioral Risk Factor Surveillance System, United States, 2010. Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep 2012;61(suppl):51–6.
3 Ibid.
4 Imperiale TF, Ransohoff DF, Itzkowitz SH. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014 Jul 10;371(2):187-8

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Screening for Colorectal Cancer Stool DNA testing__(CAG 00440N)

ColoGuard is an advance in CRC detection, and CMS certainly was correct to approve it for reimbursement. However, as a follower and advocate of cost/benefit efforts for many years, I believe serious thought should be given to the level of reimbursement.

The incidence of CRC is about 0.06% in the US population with a 5% total lifetime risk mostly among those over 50. This means over a 35 year span of testing one can expect to identify only 5/100 tested with CRC. At $500/test done every 3 years with a 95% overall negative rate, it will cost $570,000 to screen those 95/100 without CRC, just to identify the 5 individuals who eventually develop CRC. That is true if it was 100% accurate and specific, which it is not. Thus each CRC incident carries a $114,000 dollar cost/non-detection. That is a pretty expensive way to detect CRC. It is far and away the most expensive way to do it.

Compare this with a colonoscopy, costing $1000/test and done once every 10 years at a total cost of detecting CRC of $285,000 to screen 95/100 individuals without CRC, or at a cost of $57,000/non-detection. Just to be comparable to colonoscopy costs, the ColoGuard test cost would have to decline to $250/test. Paying the equivalent of 2 times the current cost/each CRC detection is absurd. Since the ColoGuard test is not even equivalent to the accuracy of a colonoscopy it is silly to pay even $250/test for it.

Genomics is a rapidly advancing field in which costs are continually decreasing. I strongly support the use of genomics in diagnostics, but not its exploitative use in order to support massive profits at public expense. I am bothered by a company asking $502/test for a diagnostic like ColoGuard. The belief that "any improvement" in a diagnostic test justifies a premium price for it, is total nonsense. A new diagnostic should be a cost effective improvement over what already exists. That is not the case here. Moreover, the approach used by the company to arrive at their $502/test estimate is completely irrational. Bundling of tests should result in a lower overall cost. Here it simply leads to a summation of their separate costs.

I have a serious problem should CMS simply ignore the relevance of the test’s cost with respect to its benefit, and reimburse the test for whatever the company asks. Some sense of rationally needs to accompany pricing. Price for drugs and diagnostics should reflect the relative dollar benefits they provide society. In the absence of that rational aspect, companies seek reimbursement at whatever price they want, bundling whatever group of tests they wish, driven by their desired profit and not common sense. I certainly hope that will not happen here, encouraging more of the same type of foolish behavior in the future.

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