Response to Comments: MolDX: Prognostic and Predictive Molecular Classifiers for Bladder Cancer

The following comment was submitted to Palmetto GBA, CGS, WPS, and Noridian:

On behalf of the Association for Molecular Pathology (AMP), we thank you for the opportunity to review and comment on the proposed policy for MolDX: Prognostic and Predictive Molecular Classifiers for Bladder Cancer.

AMP is an international medical and professional association representing approximately 2,600 physicians, doctoral scientists, and medical laboratory scientists (technologists) who perform or are involved with laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Membership includes professionals from academic medicine, hospital-based and private clinical laboratories, the government, and the in-vitro diagnostics industry.

AMP commented on the previous version of this proposed policy in June 2020, and we plan to share similar comments in this letter. We appreciate your approach to proposing coverage for tests that demonstrate valuable information when used to make significant clinical decisions for cancer patients, rather than providing recommendations regarding the use of a specific drug or treatment. The policy parameters support coverage for the care needed to help manage bladder cancer patients and this approach to coverage will facilitate the development of better tests for bladder cancer and other tumors by accelerating their market introduction and reducing clinical uncertainty.

After reviewing the proposed policy’s coverage criteria, we ask that you consider the following recommendations.

Coverage Indications, Limitations, and/or Medical Necessity

1. Coverage criteria #2 states the following:

The beneficiary is within the population and has the indication for which the test was developed and is covered. The lab providing the test is responsible for clearly indicating to treating clinicians the population and indication for test use.

AMP is concerned about the requirement for laboratories to verify that a patient meets a policy’s coverage criteria. Laboratories do not keep patient medical records, nor do they always have access to them. The treating physician, and not the laboratory, must take responsibility for the medical necessity of a test because only the treating physician, not the laboratory, will have the necessary information to make that determination. For this reason, it would not be reasonable to hold the laboratory responsible for substantiating the medical necessity of a test. This is especially pertinent as there are many tests for which there is no FDA-approved alternative, and under Clinical Laboratory Improvement Amendments (CLIA), it is the laboratory’s responsibility to only document the validity of the test for the analyte it purports to assay.

For these reasons, we recommend you remove the last sentence in coverage criteria #2 which makes laboratories responsible for the appropriate beneficiary population and indications for test usage by treating clinicians.

Alternatively, if you do not wish to strike the last sentence, as indicated above, we recommend the proposed language be revised as follows: “The laboratory will make available the appropriate indications of the test to the ordering physician.”

2. Coverage criteria #6 states the following:

The test successfully completes a Molecular Diagnostic Services Program (MolDX^®) technical assessment that ensures the test is reasonable and necessary as described in 4. and 5. above.

The Molecular Diagnostic Services Program (MolDX^®) Technical Assessment (TA) has been a well- established requirement of the MolDX^® program since 2011. Since that time, laboratory developed tests or tests with undefined or unproven clinical utility have had to undergo a TA to ensure coverage. The TA process is detailed on your website and is a coverage requirement that applies to all molecular diagnostic tests covered under MolDX^® and, therefore, does not need to be reiterated in individual LCDs. Accordingly, AMP recommends removing the requirement that a test must successfully complete a TA, as it is redundant and unnecessary.

Thank you again for the opportunity to review and comment on this proposed policy. We are happy to be of assistance in providing additional clinical or other information to assist you with this draft LCD.

Thank you for your comments.

We have used your suggestion and will edit the last sentence under the coverage criteria #2 to refine the coverage as follows: “The laboratory will make available the appropriate indications of the test to the treating/ordering physician”.

While we agree the coverage criteria #6 appears redundant it has been placed for emphasis of the TA process which AMP is well aware of but may not be always evident to new laboratories. The criteria will remain as stated.

The following comment was submitted to Palmetto GBA:

We again thank MolDX for creating an LCD for Medicare beneficiaries with Bladder cancers. We are in full support of the policy, as written, and respectfully request some modifications to the draft LCD as follows:

Add the following references, which provide additional published evidence in support of the LCD as written:

• To this sentence, “Luminal tumors (non-infiltrated) demonstrated acomparatively good prognosis that appeared minimally affected by differences between patients who did and did not receive neoadjuvant therapy,” please add the following reference:

Lotan, Y. et al. Patients with Muscle-Invasive Bladder Cancer with Non-luminal Subtype Derive Greatest Benefit from Platinum Based Neoadjuvant Chemotherapy. J Urol 207, 541-550, doi:10.1097/JU.0000000000002261 (2022). <https://www.ncbi.nlm.nih.gov/pubmed/34643090>.

• To this sentence, “Gene-expression data has also been found to identify NElike bladder cancers that histologically appear like urothelial carcinomas,” please add the following reference:

Grivas, P. et al. Validation of a neuroendocrine-like classifier confirms poor outcomes in patients with bladder cancer treated with cisplatin based

neoadjuvant chemotherapy. Urol Oncol 38, 262-268, doi:10.1016/j.urolonc.2019.11.004 (2020). <https://www.ncbi.nlm.nih.gov/pubmed/31812633>.

Thanking you in advance for your consideration.

Thank you for your support of the policy. We will add the references cited as suggested.

The following comment was submitted to Palmetto GBA:

We would like to make two requests regarding the Draft Billing and Coding: MolDX: Prognostic and Predictive Molecular Classifiers for Bladder Cancer:

1) Group 1 codes: We request ICD-10 code C67.9 Malignant neoplasm of bladder, unspecified be added to the ICD-10-CM Codes that Support Medical Necessity.

1. Providers sometimes use this code to describe Medicare beneficiaries that are covered under the LCD

2) Please change “209” to “219” in the following CPT code description for 0016M: ONCOLOGY (BLADDER), MRNA, MICROARRAY GENE EXPRESSION PROFILING OF 209 219 GENES, UTILIZING FORMALINFIXED PARAFFIN-EMBEDDED TISSUE, ALGORITHM REPORTED AS MOLECULAR SUBTYPE (LUMINAL, LUMINAL INFILTRATED, BASAL, BASAL CLAUDIN-LOW, NEUROENDOCRINE-LIKE)

1. This typographical correction was approved by the American Medical Associated CPT Editorial Panel in February 2022 and became effective July 1, 2022.

Thanking you in advance for your consideration.

Thank you for your comment. The typographical error will be corrected in the final policy.

The following comment was submitted to WPS:

The National Comprehensive Cancer Network^®(NCCN^®) appreciates the opportunity to comment on the Proposed Local Coverage Determination (LCD) Prognostic and Predictive Molecular Classifiers for Bladder Cancer as it relates to NCCN's mission of improving and facilitating, quality, effective, equitable, and accessible cancer care. NCCN will focus our comments on areas of alignment between NCCN Guidelines^® and the proposed LCD and ways NCCN content can be used as a resource to inform coverage determinations to keep LCDs evergreen as the science evolves.

NCCN Background

As an alliance of 32 leading academic cancer centers in the United States that treat hundreds of thousands of patients with cancer annually, NCCN^® is a developer of authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Clinical Practice Guidelines in Oncology^® (NCCN Guidelines^®) are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97 percent of cancers affecting patients in the United States.

NCCN Guidelines^® and Library of Compendia products help ensure access to appropriate care, clinical decision-making, and assessment of quality improvement initiatives. The NCCN Drugs & Biologics Compendium (NCCN Compendium^®) has been recognized by CMS and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications. NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified Provider Led Entity (PLE) for the Medicare Appropriate Use Criteria (AUC) Program for the development of AUC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer.

NCCN Guidelines

NCCN develops authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Guidelines are a comprehensive set of 84 guidelines detailing the sequential management decisions and interventions across 218 algorithms that currently apply to 97 percent of cancers affecting patients in the United States. More than 1700 panel members participate in Guideline development. In 2021, there were 13 million downloads of the Guidelines across web-based and mobile applications. NCCN Guidelines are developed by multidisciplinary expert panels from NCCN Member Institutions in an evidence-based process integrated with expert consensus. The NCCN Guidelines are updated at least annually, but quite often are updated more frequently, with 215 total version updates across all guidelines in 2021.

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

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

Guideline Adherence as a Tool to Improve Outcomes, Reduce Costs, and Keep Coverage Evergreen

Numerous independent studies have found adherence to NCCN Guidelines improves care delivery and outcomes for patients with cancer. Improved health outcomes proven through concordance with NCCN Guidelines include: improved rates of survival for colon cancer, ovarian cancer, gastric cancer, nasopharyngeal cancer, and pancreatic cancer; decreased locoregional recurrence of melanoma; and improved pain control.^1,2,3,4,5,6

Guideline adherent care has also been shown to decrease costs to both the payer and the patient. A peer-reviewed, published study by United, eviCore, and NCCN entitled "Transforming Prior Authorization to Decision Support" demonstrated mandatory adherence to NCCN Guidelines and NCCN Compendium^® using a real-time Clinical Decision Support Mechanism by United Healthcare significantly reduced total and episodic costs of care by 20% compared to trend while also reducing denials and increasing access to guideline-concordant care.⁷ A 2019 study "Guideline Discordance and Patient Cost Responsibility in Medicare Beneficiaries With Metastatic Breast Cancer" by Williams, et.al found median cost for metastatic breast cancer patients receiving guideline-discordant treatment was $7,421 versus $5,171 for those receiving guideline-concordant care.⁸ This study found an additional $1,841 in out-of-pocket cost savings for patients receiving guideline concordant care versus patients who received care that did not adhere to guidelines. These cost savings have also been found in studies evaluating the Medicare population. At this year's ASCO annual conference, CVS Health presented two abstracts looking at total costs of care beginning with the first treatment and for the subsequent 180 days for breast and colon cancer patients in relation to adherence to NCCN Guidelines.⁹,¹⁰ In both studies, there was a significant reduction in total cost of care with concordance with NCCN Guidelines. In the colon cancer study, this was most prominent and significant in the Medicare population. In the breast cancer study, significant reductions were observed across both commercially insured and Medicare patients, with the greatest reductions again seen in the Medicare population.

NCCN Biomarkers Compendium^®

The NCCN Biomarkers Compendium^® is intended to be a resource for payers, providers, and health care entities navigating the rapidly changing evidence-base for medically necessary biomarker testing in oncology. The NCCN Biomarkers Compendium^® contains information derived directly from the NCCN Guidelines to support decision-making around the use of biomarker testing in patients with cancer. The NCCN Biomarkers Compendium is updated continuously in conjunction with the NCCN guidelines to stay evergreen. The goal of the NCCN Biomarkers Compendium is to provide essential details for testing methodologies which have been approved by NCCN Guideline Panels and are recommended within the NCCN Guidelines. Included in the Biomarkers Compendium are testing methodologies that measure changes in genes or gene products and used for the purposes of diagnosis, screening, monitoring, surveillance, prediction, and prognostication.

Launched in 2012 and updated in 2021 to have shared data fields with other Compendia in the Library, the information within the Biomarkers Compendium is extracted directly from Guideline algorithms, principles pages, and footnotes, and all entries are reviewed and approved by the Guideline Panel pathologist or other panel member with expertise in the area. Information within the Biomarkers Compendium focuses on the biology or abnormality being measured rather than on commercially available tests or test kits, with methodologic information provided only if included in the parent Clinical Practice Guideline.

The Biomarkers Compendium is intended to be user friendly in an easy to navigate format for payers and providers alike. The displayed fields can be customized to the user, and include links to the Guideline Page on which the biomarker is addressed. Compendium entries can be printed, providing the summary of the recommendations with details regarding each field within the Compendium, in a format that is concise and easy to read. With this resource, the NCCN Biomarkers Compendium aims to ensure that patients have coverage and access to appropriate biomarker testing based on the evaluations and recommendations of NCCN Panel Members.

Nationally Recognized Guidelines as an Evergreening Mechanism for Coverage Determination

Public and commercial payers employ NCCN Guidelines within their coverage mechanisms to ensure evergreening of coverage while also reducing administrative burden. As noted above, adherence to NCCN Guidelines has been proven to improve quality across a variety of outcome measures, reduce costs to the payer and health care system, and reduce costs to the patient. The NCCN Compendium^® has been recognized by CMS and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications. NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified Provider Led Entity for the Medicare Appropriate Use Criteria (ADC) Program for the development of ADC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer.

Recognizing the value of continuously updated evidence-based guidelines, numerous Medicare Administrative Contractors have cited NCCN Guidelines within their coverage policies as a mechanism to evergreen coverage. NCCN recommends to consider the incorporation of nationally recognized guidelines, and specifically, the NCCN Biomarkers Compendium into the proposed LCD coverage indications to establish clinical utility. This would ensure the LCD stays evergreen while also significantly reducing administrative burden.

NCCN Guideline Recommendations of Relevance to the Proposed LCD

Within the proposed LCD, it proposes to cover will cover molecular diagnostic tests for use in a beneficiary with bladder cancer when all of the following conditions are met:

1. The beneficiary is being actively managed for bladder cancer.
2. The beneficiary is within the population and has the indication for which the test was developed and is covered. The lab providing the test is responsible for clearly indicating to treating clinicians the population and indication for test use.
3. At least 1 of the 2 criteria are met:
   1. The patient is a candidate for multiple potential treatments, which could be considered to have varied or increasing levels of intensity based on a consensus guideline, and the physician and patient must decide among these treatments. OR
   2. The patient is a candidate for multiple therapies, and the test has shown that it predicts response to a specific therapy among accepted therapy options based on nationally recognized society consensus guidelines (i.e., National Comprehensive Cancer Network [NCCN}, American Society of Clinical Oncology [ASCOJ, Society of Urologic Oncology [SUOJ, or American Urological Association [AUAJ).
4. The test demonstrates analytical validity including both analytical and clinical validations. If the test relies on an algorithm (which may range in complexity from a threshold determination of a single numeric value to a complex mathematical or computational function), the algorithm must be validated in a cohort that is not a development cohort for the algorithm.
5. The test has demonstrated clinical validity and utility, establishing a clear and significant biological/molecular basis for stratifying patients and subsequently selecting (either positively or negatively) a clinical management decision in 4. And above) in a clearly defined population.
6. The test successfully completes a Molecular Diagnostic Services Program (MolDX^®) technical assessment that ensures the test is reasonable and necessary as described in 4. and 5. above.

NCCN thanks you for citing NCCN Guidelines as a mechanism to determine if the test predicts response to an appropriate guideline recommended therapy within this coverage LCD. NCCN would like to note that the NCCN Biomarkers Compendium is also a useful tool to establish clinical utility of tests that is continuously updated.

NCCN respectfully offers recommended clarifications to the proposed LCD. The NCCN Guidelines recommend molecular/genomic testing for all patients with stage IVA or stage IVB bladder cancer and consideration of testing for patients with stage IIIB bladder cancer. Specifically, the NCCN Bladder Cancer Panel recommends that molecular/genomic testing be conducted early, ideally at diagnosis of advanced bladder cancer, to facilitate treatment decision-making and to prevent delays in administering later lines of therapy.¹¹ In addition to determining eligibility for FDA­ approved therapies, molecular/genomic testing may be used to screen for clinical trial eligibility.¹¹

NCCN is concerned that the current proposed coverage indication may not permit molecular/genomic testing early enough in treatment planning. The NCCN Guidelines panel considers it important that patients with advanced bladder cancer be offered molecular testing at diagnosis, generally before targeted therapies would be indicated. As such, NCCN encourages WPS to specify that for patients with advanced Bladder Cancer (stages IVA, IVB, and IIIB), these tests are covered beginning at diagnosis.

NCCN would like to respectfully note that the Proposed LCD cites an outdated version of the guidelines which are frequently updated. The current NCCN Guidelines for Bladder Cancer are currently on Version 2 of 2022. A notable difference between the current version and version cited within the LCD is that NCCN Guidelines now recommend treatment based on AUA risk stratification for Non-Muscle Invasive Bladder Cancer (NMIBC), and these recommendations have been revised accordingly. The most up to date version of our guidelines can always be found on our website at NCCN.org. Additionally, citing to the NCCN Biomarkers Compendium for Clinical Utility will ensure that the coverage mechanism stay evergreen with the latest recommendations and would reduce administrative burden.

In sum, NCCN respectfully requests to consider:

• Clarifying that for patients with advanced (Stage IIIB, IVA, or IVB) bladder cancer testing is covered beginning at diagnosis
• Citing to the NCCN Biomarker Compendium as a source of evidence to establish clinical utility
• Citing the most recently updated version of the NCCN Guidelines for Bladder Cancer (currently Version 2.2022)

NCCN appreciates the opportunity to comment on the Proposed Local Coverage Determination Prognostic and Predictive Molecular Classifiers for Bladder Cancer. NCCN is happy to serve as a resource and looks forward to working together to ensure Medicare beneficiary access to high-quality cancer care.

References were provided for review.

Thank you for your comments.

We will update the policy to reflect the latest NCCN publication as suggested. This will address your concern in advanced bladder cancer indications.

While we acknowledge the NCCN Biomarker Compendium and find it a great resource the MolDx program performs an independent technical assessment to determine Analytical validity, Clinical validity and Clinical utility. We use the published literature and review it to determine the above criteria and do not rely exclusively on one source.