Response to Comments: MolDX: Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies (DL38176)

Comment from College of American Pathologists
On behalf of the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP), we thank you for the opportunity to review and comment on Palmetto GBA’s proposed coverage policy for MOLDX: Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies (DL38047).

AMP is an international medical and professional association representing approximately 2,500 physicians, doctoral scientists, and medical 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.

As the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the CAP serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide.
We are submitting joint comments because at this time both of our organizations share the same perspective regarding this draft LCD. We appreciate the effort that has gone into the development of this proposed LCD, and we offer the following recommendations for Palmetto’s consideration.
Proposed Coverage Policy

AMP and CAP applaud Palmetto’s efforts to clarify coverage for next-generation sequencing (NGS) lab-developed tests (LDTs) for myeloid malignancies and suspected myeloid malignancies. We hope this policy will ensure patients with cytopenias and cytoses, as well as diagnosed myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia (AML) will have access to medically necessary testing.

The proposed LCD references more than 70 genes that have been identified as having clinical utility in acute and chronic myeloid disorders. AMP and CAP believe that there are at least 65 genes that, when mutated, are clinically informative for therapeutic decision making, e.g. diagnosis, risk stratification for hematopoietic stem cell transplant, and/or targeted therapy) – as listed in the attached table 1. Based on this detailed list of clinically relevant gene mutations for myeloid malignancies, we recommend that Palmetto expand coverage for NGS-based testing to include panels with 51 or more genes, consistent with CPT code 81455. (Mukherjee et al., 2017). This specific CPT code change is included later in this letter.

Recommendations Regarding Criteria for Coverage

1. The policy provides the following coverage criteria:
   
   The assay performed includes at least the minimum genes and positions indicated for its intended use, as described in an associated coverage Article and found in the technical assessment (TA) forms.
   
   AMP and CAP applaud the transparency associated with connecting DL38047 to a specific list of biomarkers, described in Form #M00154. This content is of enormous importance to MolDx, to those who design and validate such tests, and to the beneficiaries impacted by their results. We suggest the following to ensure this list achieves its goals:
   1. Please clarify the scientific evidence for the selected “required variant coverage” biomarkers (variants in 26 genes) listed in Form #M00154.
      1. Some of the specific loci listed are of unclear clinical significance to AMP and CAP experts and should not be required for panels to be reimbursed.
      2. For those genes with documented myeloid cell pathogenicity due to loss of protein function (i.e., tumor suppressor genes such as ASXL1, RUNX1, and TET2), it has been shown that any loss of function mutation, and not just mutations at “hotspots”, can contribute to disease pathogenicity (Sperling et al., 2017).
   2. AMP and CAP suggest the creation of a workgroup of experts whose sole objective would be to finalize a gene/variant list that satisfies the MolDx “at least” criteria.
      1. 2-3 meetings would suffice to compile this gene/variant, and a July 2019 completion date would be feasible
      2. A sample gene list is attached to this letter (Table 1 – FINAL)
2. The policy provides the following coverage criteria:
   
   Testing is performed on bone marrow biopsies or peripheral blood samples.
   
   AMP and CAP are supportive of Palmetto’s proposal to cover testing performed on bone marrow biopsies or peripheral blood samples. However, we recommend that these criteria be revised to also allow for biopsies of hematopoietic tissues located outside of bone marrow and peripheral blood. Bone marrow aspirate or bone marrow clot is a more common sample type than bone marrow biopsies that can be utilized for next generation sequencing analysis. We also recommend that specimen type be expanded to include extramedullary tissue biopsies, since myeloid malignancies (i.e., myeloid sarcoma) not uncommonly present at extramedullary sites. The ICD-10 code for myeloid sarcoma is an accepted diagnosis code, so it is important that testing can be performed for these patients on involved tissue. Although uncommon, acute myeloid leukemia can present in the skin (as cutaneous myeloid sarcoma, or leukemia cutis) or other solid organs prior to peripheral blood or bone marrow involvement (Moyer et al., 2018).
   
   Therefore, we recommend revising the proposed coverage statement to read:
   
   Testing is performed on an appropriate biopsy specimen such as extramedullary tissue biopsies, bone marrow biopsies, bone marrow aspirate or clot, or peripheral blood samples.
   
   Testing is performed on an appropriate biopsy specimen such as extramedullary tissue biopsies, bone marrow biopsies, bone marrow aspirate or clot, or peripheral blood samples.
   
   
3. The policy includes the following regarding repeat testing:
   
   For patients that do not have a diagnosis of a myeloid malignancy, where one is suspected, the patient must have an undefined cytopenia for greater than 6 months, other possible causes have been reasonably excluded.
   
   The proposed policy states that NGS detection of clonal hematopoiesis with mutation detection in patients with an unexplained cytopenia of greater than 4 months is a strong predictor of who has or will have a myeloid disorder. AMP and CAP are concerned that the coverage criteria specifies that initial testing is only covered after more than 6 months for an undefined cytopenia, and we recommend that Palmetto revise this criterion to allow more frequent testing for the evaluation of clinically-relevant clonal evolution. Results of residual disease testing are also used to make adjustments to the level of immunosuppressive agents after transplant, or to alter levels of post-transplant targeted therapy to maximize response while minimizing adverse side effects.
   
   In addition, the National Comprehensive Cancer Network (NCCN) guidelines and key new literature state that, for AML and MDS, repeat testing is appropriate after one month (and before stem cell transplantation) for prognostically-relevant minimal residual disease (MRD) detection. We recommend that the coverage policy should reflect these repeat testing guidelines (Acute myeloid leukemia NCCN Guidelines, 2019; Jongen-Lavrencic et al., 2018). Furthermore, allogenic hematopoietic stem-cell transplantation is the only curative treatment for patients with myelodysplastic syndrome (MDS). However, disease progression after transplantation remains a problem in patients with MDS. NGS to monitor the detection of tumor cells and MRD at pre-relapse time points, such as 30 days after transplantation, has the potential to improve outcomes for patients with myeloid malignancies (Duncavage et al., 2018). Therefore, repeat testing for the evaluation of MRD in both AML and MDS is clinically relevant.
   
   Recommendations Regarding Situations in which a Test Should Not Be Used or Coverage is Denied
   
   
4. The policy provides for non-coverage in cases where no TA has been completed:
   
   A Technical Assessment has not been satisfactorily completed by MOLDX. For tests that are currently covered but a TA submission has not been made, providers must submit complete TA materials by October 1st, 2019 or coverage will be denied.
   
   We understand that a test must successfully undergo a TA by MolDx in order to be eligible for coverage. However, we believe that there is a need for increased transparency regarding how responses in the TA document may impact coverage determinations. For example, the TA for myeloid panels, Form #M00154, is onerous and difficult to understand.
   
   Many of the indicated variant positions listed on this form are not frequently mutated in myeloid malignancies, and others are not the correct amino acid at the indicated position using preferred reference sequences. As mentioned previously in this letter, clarification is necessary regarding whether the listed genes represent a “minimum required list.” We note that some key genes in myeloid neoplasia are not included, and one listed gene, STAT3, is primarily implicated in lymphoid rather than myeloid malignancies and would not be included in many hot spot myeloid panels, despite its utility in the work-up of non-myeloid causes of neutropenia.
   
   In addition, a “minimum required list” is likely to be a moving target since new FDA-approvals for therapies targeting mutations in myeloid malignancies (e.g., gene fusion) are likely to be forthcoming. Given the complexity of an NGS validation study, laboratories and manufacturers will need a reasonable time period to develop and validate expanded panels before MolDx changes coverage eligibility. It is also possible that a laboratory may need to supplement an NGS assay with a single gene assay (e.g., gene fusion). When and if this occurs, we encourage MolDx to work with providers to ensure that an update to the required list does not result in non-coverage and reduced patient access to these procedures.
   
   
5. Above, we documented the clinical and scientific rationale for our recommendation to allow repeat NGS-based testing. We also want to express our concerns about the following language included in the non-coverage section:
   
   Another NGS test was performed for the same indication within the past 6 months.
   
   There is convincing evidence in the literature that 6 months is too long of a time interval to have to wait for a repeat NGS-based test. In AML patients, the detection of post-treatment MRD has thus been shown to be an excellent prognosticator of future relapse at various post-treatment time points including after induction chemotherapy, (day 30) (Jongen 2018; Rothenberg 2018; NCCN guidelines) before stem cell transplantation (Press 2019; Thol 2018; NCCN guidelines), and after stem cell transplantation (Kim 2018).
   
   Given that these well-documented clinically-relevant MRD assessment time points typically all occur within a few months of the initial AML diagnosis, we urge Palmetto to not automatically reject repeat NGS-based testing within 6 months of the prior NGS test, but instead consider covering repeat MRD testing more frequently than every 6 months in the appropriate clinical context.
   
   CPT Coding
   We recommend the inclusion of additional CPT codes for targeted genomic sequencing. The additional codes include, but may not be limited to, those listed below:
   
   81455 Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA analysis, and RNA analysis when performed, 51 or greater genes (eg, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation
   for sequence variants and copy number variants or rearrangements, if performed
   ICD-10 Coding
   We request that additional ICD-10 codes be added to the local coverage article A54795 including, but not be limited to the following list:
   C88.8      Other malignant immunoproliferative diseases
   C92         Myeloid leukemia
   C92.0      Acute myeloblastic leukemia
   C92.01    Acute myeloblastic leukemia, in remission
   C92.1      Chronic myeloid leukemia, BCR/ABL-positive
   C92.2      Atypical chronic myeloid leukemia, BCR/ABL-negative
   C92.3      Myeloid sarcoma
   C92.31    Myeloid sarcoma, in remission
   C92.4      Acute promyelocytic leukemia
   C92.41    Acute promyelocytic leukemia, in remission
   C92.5      Acute myelomonocytic leukemia
   C92.51    Acute myelomonocytic leukemia, in remission
   C92.6      Acute myeloid leukemia with 11q23-abnormality
   C92.61    Acute myeloid leukemia with 11q23-abnormality, in remission
   C92.90    Myeloid leukemia, unspecified, not having achieved remission
   C92.92    Myeloid leukemia, unspecified in relapse
   C92.A      Acute myeloid leukemia with multilineage dysplasia
   C92.A1    Acute myeloid leukemia with multilineage dysplasia, in remission
   C92.Z      Other myeloid leukemia
   C92.Z1    Other myeloid leukemia, in remission
   C92.9      Myeloid leukemia, unspecified
   C92.90    Myeloid leukemia, unspecified, not having achieved remission
   C92.91    Myeloid leukemia, unspecified in remission
   C92.92    Myeloid leukemia, unspecified in relapse
   C93.00    Acute monoblastic/monocytic leukemia, not having achieved remission
   C93.01    Acute monoblastic/monocytic leukemia, in remission
   C93.02    Acute monoblastic/monocytic leukemia, in relapse
   C93.12    Chronic myelomonocytic leukemia, in relapse
   C93.Z0    Other monocytic leukemia, not having achieved remission
   C93.Z2    Other monocytic leukemia, in relapse
   C93.90    Monocytic leukemia, unspecified, not having achieved remission
   C93.92    Monocytic leukemia, unspecified in relapse
   C94.01    Acute erythroid leukemia, in remission
   C94.21    Acute megakaryoblastic leukemia, in remission
   C94.8      Other specified leukemias
   C94.80    Other specified leukemias not having achieved remission
   C94.81    Other specified leukemias, in remission
   C94.82    Other specified leukemias, in relapse
   C95.00    Acute leukemia of unspecified cell type not having achieved remission
   C95.02    Acute leukemia of unspecified cell type, in relapse
   C95.10    Chronic leukemia of unspecified cell type not having achieved remission
   C95.12    Chronic leukemia of unspecified cell type, in relapse
   C95.90    Leukemia, unspecified not having achieved remission
   C95.92    Leukemia, unspecified, in relapse
   C96.2      Malignant mast cell tumor
   C96.9      Malignant neoplasm of lymphoid, hematopoietic and related tissue, unspecified
   C96.Z      Other specified malignant neoplasms of lymphoid, hematopoietic and related tissue
   D47         Other neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue
   D47.2      Monoclonal gammopathy
   D47.Z      Other specified neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue
   D47.Z1    Post-transplant lymphoproliferative disorder (PTLD)
   D59.1      Other autoimmune hemolytic anemias
   D59.4      Other nonautoimmune hemolytic anemias
   D59.8      Other acquired hemolytic anemias
   D59.9      Acquired hemolytic anemia, unspecified
   D61.09    Other constitutional aplastic anemia
   D61.3      Idiopathic aplastic anemia
   D61.818  Other pancytopenia
   D61.9      Aplastic anemia, unspecified
   D61.818  Other pancytopenia
   D61.8/D61.89  Other specified aplastic anemias and other bone marrow failure syndromes
   D61.9      Aplastic anemia, unspecified
   D64.9      Anemia, unspecified
   D69.49    Other primary thrombocytopenia
   D69.6      Thrombocytopenia, unspecified
   D69.8      Other specified hemorrhagic conditions
   D69.9      Hemorrhagic condition, unspecified
   D69.3      Immune thrombocytopenic purpura
   D69.49    Other primary thrombocytopenia
   D69.59    Other secondary thrombocytopenia
   D69.6      Thrombocytopenia, unspecified
   D70.4      Cyclic neutropenia
   D70.8      Other neutropenia
   D70.9      Neutropenia, unspecified
   D72         Other disorders of white blood cells
   D72.0      Genetic anomalies of leukocytes
   D72.1      Eosinophilia
   D72.8      Other specified disorders of white blood cells
   D72.81    Decreased white blood cell count
   D72.810  Lymphocytopenia
   D72.818  Other decreased white blood cell count
   D72.819  Decreased white blood cell count, unspecified
   D72.82    Elevated white blood cell count
   D72.818  Other decreased white blood cell count
   D72.819  Decreased white blood cell count, unspecified
   D72.820  Lymphocytosis (symptomatic)
   D72.828  Other elevated white blood cell count
   D72.829  Elevated white blood cell count, unspecified
   D72.89    Other specified disorders of white blood cells
   D72.9      Disorder of white blood cells, unspecified
   D75         Other and unspecified diseases of blood and blood-forming organs
   D75.8      Other specified diseases of blood and blood-forming organs
   D77        Other disorders of blood and blood-forming organs in diseases classified elsewhere
   J82         Pulmonary eosinophilia, not elsewhere classified
   Q82.2     Mastocytosis
   R16.1     Splenomegaly, not elsewhere classified
   R16.2     Hepatomegaly with splenomegaly, not elsewhere classified
   
   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. Please direct your correspondence to Tara Burke, AMP Senior Director of Public Policy, at tburke@amp.org or Nonda Wilson, CAP’s Manager, Economic and Regulatory Affairs, at nwilson@cap.org.

We would like to thank both AMP and CAP for their helpful feedback and suggestions regarding this policy. We will address each question or comment to our best ability below.

1. Criteria for coverage:
   1. Biomarkers required for coverage. This policy sets forth a requirement that both targeted panels and CGP tests meet a minimum criteria of clinically-relevant biomarkers for coverage. These are not included in the policy but are part of the technical assessment review required in the policy for coverage. As such, they can be modified as necessary as the science and standards of practice change. We seek to work with both provider subject matter experts and leading societies such as AMP and CAP to create and modify the biomarkers that fulfill this requirement. The current list is an amalgamation of criteria set forth by subject matter experts and established leading laboratories. We welcome a critical evaluation of the list created and any input your organizations wish to provide on this matter. The current list includes single nucleotide positions with information relating to alternate transcripts which has demonstrated to be confusing to several providers. This will be clarified in upcoming modifications to these documents, which is a separate process from finalizing this policy.
   2. Specimen type. Thank you for this feedback. Bone marrow aspirates and clots have been added as acceptable specimen types, in addition to extramedullary sites suspected of harboring a myeloid malignancy. Specific ICD-10 codes are no longer included as part of the policy but will be addressed in the associated Billing and Coding Article.
   3. Testing for a suspected myeloid malignancy. Based on the recommendations provided here and through other communications, time requirement for testing with an unexplained cytopenia has been reduced to 4 months.
   4. Repeat testing for Minimal Residual Disease. Per NCD 90.2, an NGS test for a patient with cancer cannot be repeated for the same primary tumor. Please see Article A57503 for a clarification of when a recurrent or metastatic cancer can be considered a primary tumor. Other restrictions are hereby removed.

Comment from American Society of Hematology
The American Society of Hematology (ASH) is pleased to offer comments on the proposed local coverage determination (LCD), Next-Generation Sequencing (NGS) Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies.

ASH represents over 17,000 clinicians and scientists worldwide, who are committed to the study and treatment of blood and blood-related diseases. These disorders encompass malignant hematologic disorders such as leukemia, lymphoma, and multiple myeloma, as well as non-malignant conditions such as sickle cell anemia, thalassemia, bone marrow failure, venous thromboembolism, and hemophilia. In addition, hematologists are pioneers in demonstrating the potential of treating various hematologic diseases and continue to be innovators in the field of stem cell biology, regenerative medicine, transfusion medicine, and gene therapy. The ASH membership is comprised of basic, translational, and clinical scientists, as well as physicians providing care to patients in diverse settings including teaching and community hospitals, as well as private practice.

ASH was impressed with the comprehensiveness of the proposed LCD but has concerns related to the limitations on repeat testing under the section, Situations in which Test should not be used or coverage is denied. The proposed LCD states that the test in question will be non-covered if “another NGS test was performed for the same indication within the past 6 months.” ASH urges reconsideration of this 6-month limitation to allow for more flexibility. Unfortunately, many hematologic malignancies progress very quickly and NGS tests may be needed more frequently than every 6 months for the same indication.
Thank you for the opportunity to provide comments on the proposed LCD, Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Meyloid Malignancies. We welcome the opportunity to discuss these comments with you and your team. If you have any questions or require further clarification, please contact leslie Brady, Policy and Practice Manager, at lbrady@hematology.org or 202-2929-0264.

Thank you very much for your response and suggestions. As stated above, provided that the testing is performed on the same primary tumor, NGS testing is not allowed by the NCD 90.2. The term “Primary Tumor”, as related to progressive disease, is clarified in Article A57503. Further limitations have been removed from the policy.

Comment from Foundation Medicine
On behalf of Foundation Medicine, Inc., the developer of the FDA-approved broad companion diagnostic assay, FoundationOne®CDx (“F1CDx”), I am pleased to submit comments regarding the above-captioned proposed local coverage determinations (the “Draft LCDs”).

F1CDx is a next generation sequencing (NGS) based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations and copy number alterations in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability and tumor mutational burden using DNA isolated from formalin-fixed paraffin embedded tumor tissue specimens. The test is intended as a companion diagnostic to identify patients who may benefit from treatment with the targeted therapies listed in the product’s labeling in accordance with the approved therapeutic product labeling. Additionally, F1CDx is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for cancer patients with solid malignant neoplasms. The F1CDx test is a single-site assay performed at Foundation Medicine, Inc. Medicare covers F1CDx for beneficiaries nationwide, including patients in Jurisdictions J and M.1
We recognize that the National Coverage Determination for Next Generation Sequencing in Advanced Cancer (CAG-00450N) permits local coverage through an LCD approach and that the MolDX program, through these Draft LCDs, is proposing to operationalize coverage in a way that will be more efficient for both providers and the Medicare program.

We would like to stress that biomarkers are validated and useful in patient management only if the performance characteristics of the particular test have been well established as reasonable and necessary by each laboratory seeking coverage. Such performance cannot be assumed or inferred from CLIA-certification and state licensure—especially across the broad range of diseases potentially included under the Draft LCDs. Therefore, we strongly support the requirement for rigorous analytical validation and submission of an evidence dossier showing such validation in order for individual tests to be eligible for coverage under the LCD.

Under the Draft LCD, a clinical laboratory seeking coverage for an NGS-based cancer test that is not nationally covered would be required to submit documentation allowing MolDX to complete a technical assessment (TA). The TA would be based on information provided by the test’s developer on certain forms available on the MolDX website (e.g., M00119 “Analytical Validity – Performance Specifications for Comprehensive Genomic Profiling Checklist: Somatic and Germline”, M00153 “Analytical Validity, Clinical Validation Summary Worksheet, NGS Solid Tumors, and M00154 “Analytical Validation and Clinical Validation Summary Worksheet, Myeloid Malignancies”). On these forms, MolDX requests analytical validation data, including information establishing the sensitivity, specificity, positive percent agreement, negative percent agreement, variant-level reproducibility, and reported limit of detection.

However, the TA is not transparent about how the information provided on these forms will be evaluated to determine coverage of each NGS-based comprehensive genomic profile test or if there are minimum requirements that must be met. Additionally, we cannot underscore how important it is to understand and evaluate the bioinformatics processes the laboratory is using to interpret the sequencing data and generate the reports.

We appreciate the recognition by the MolDX program that not all NGS-based assays are equal. To that end, we request that the coverage framework set forth in the Draft LCDs and associated forms, ensure that a test will be covered only to the extent that its developer individually establishes that test’s analytical validity for the range of cancer types for which coverage is sought. Additionally, we request that the coverage framework evaluation criteria be made transparent in the TA documents. The ability of any individual assay to accurately and reliably identify patients with such variants is, by definition, specific to the assay being performed. For example, our analytic validation of F1CDx for use in patients with solid malignant neoplasms was based, at least in part, on a retrospective analysis of 80,715 specimens from 43 unique tissue types.2 It would only be appropriate to grant a new NGS-based assay comparable coverage if the new test’s developer is similarly able to establish that specific assay’s analytic performance across multiple tissue types. At the very least, and if not already the case, the TA threshold should be set at a level consistent with New York State Department of Health review standards as outlined by the U.S. Food and Drug Administration.

Thank you for the helpful suggestions. We agree that tests must demonstrate Analytical Validity for coverage for the indicated uses of the test. Criteria are established by a review of the published literature, standards set by regulatory agencies, as well as subject matter experts and advocating medical associations. We seek to continue a dialogue with experts as the criteria for a properly validated test evolve and are refined. We also seek to be as transparent as possible about this process.

Comment from XXXXXXXX, Regence
Coding:

• CPT codes listed in the draft are currently limited to 81450 and 81479.
• While it is understood the LCD does not address solid tumors, the definition of CPT 81455 includes solid organ or hematolymphoid neoplasms (see below).
• Therefore, should 81455 also be included in the LCD for any NGS solid organ panel test that has 51 or more genes? Even if these panels are generally considered to be “not medically necessary,” a statement to that affect added to the LCD would be very helpful.
  Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA analysis and RNA analysis when performed, 51 or greater genes (eg, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed

Approved Tests:

• This Draft states a test must “satisfactorily complete a TA by MolDX.”
• As a Medicare Advantage plan, we are required to implement and provide coverage consistent with the local contractors LCDs and LCAs, yet we don’t have access to the Change Healthcare database to know if a given test has completed the TA process.
• Thus, it is unknown how we would know if a test has been approved by MolDX or not.
• Will this be provided in some format, or will it be added to the LCD over time?
• Strict time frames to complete prior authorization requests make submitting a request to MolDX to determine if a test has been approved or not unrealistic, and not ideal.
• It would be useful to know what tests have completed this process, and either been determined eligible for coverage, or non-covered.

Thank you for your comments. We will address your comments below.

Coding: This policy is for coverage of lab-developed tests or FDA-cleared tests defined in article A54795 as either Targeted Panels or CGPs. Although not part of the policy itself, the billing and coding Article identifies the appropriate CPT code for Targeted Panels as 81445 or the NOC code 81479 for CGP tests as we do not believe these to be sufficiently described by an existing CPT code. CGP tests may have more than 51 genes as a component of the test. MolDX-associated MACs have the capability to adjudicate claims based on a Z-identifier code, which allows us to know what test is being performed and utilize the NOC code with specificity.

Approved tests: Anyone can create a public account on the DEX Diagnostic Exchange website and look up tests or companies that perform tests. Included in the public information is payor coverage information. Additionally, we will be creating an article to accompany this policy that will refer to all the tests that successfully complete the TA.

Comment from ThermoFisher
On behalf of Thermo Fisher Scientific’s Clinical Next-Generation Sequencing Division, we thank you for the opportunity to provide comments on the proposed MolDX Local Coverage Determination (DL38047: Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies).

Thermo Fisher Scientific Inc. is the world leader in serving science, with revenues of more than $24 billion and approximately 70,000 employees globally. Our mission is to enable our customers to make the world healthier, cleaner and safer. We help our customers accelerate life sciences research, solve complex analytical challenges, improve patient diagnostics, deliver medicines to market and increase laboratory productivity. Through our premier brands – Thermo Scientific, Applied Biosystems, Invitrogen, Fisher Scientific and Unity Lab Services – we offer an unmatched combination of innovative technologies, purchasing convenience and comprehensive services. For more information, please visit www.thermofisher.com.

Our Clinical Next-Generation Sequencing Division supports molecular diagnostics by creating and manufacturing a portfolio of assays that enhance performance in applications which range from translational research to therapy selection in patient care of Medicare beneficiaries. Tests include molecular profiling of solid and myeloid tumor indications, liquid biopsy, and immuno-oncology. We manufacture multi-biomarker targeted assays designed for cancer research, enabling next- generation sequencing analysis of multiple biomarker types: fusions, insertion/deletions (indels), single nucleotide variants, and copy number variations. Of note is Oncomine Myeloid Research Assay: a comprehensive, targeted NGS assay designed to assist in the understanding of myeloid cancer. Specifically, it interrogates relevant DNA mutations and fusion transcripts associated with myeloid disorders in a quick and easy NGS run.

We applaud the MolDX program’s proposal to update how NGS testing is covered, coded, and reimbursed today. We wish to submit the following comments:
Panel Design Requirements
Our first concern is this language “assay performed includes at least the minimum genes and genomic positions required for the identification of all FDA-approved therapies with a companion diagnostic biomarker for its intended use that can be reasonably detected by the test.” We believe the “all” criteria should be removed.
The companion diagnostic space is rapidly evolving, and DL#38047 asks CLIA labs to either update their assay frequently (revalidate) or adopt a broad “future-proof” assay.
Clinical laboratories often wish to take a modular approach to assay adoption. Having multiple assays that address companion diagnostic biomarkers allow labs to “pick-and-choose” based on indication and/or serialize testing based on prevalence, with the goal to maximize tissue availability and reduce testing cost per patient.
While there are merits for using a broad NGS assay, laboratories that decide to use a different approach should not be penalized for maintaining their existing assay, providing it continues to report (all FDA-approved therapies) and demonstrate clinical utility by detecting other established companion diagnostic biomarkers.

We suggest the following alternatives:

1. Allow “all” content to be satisfied by multiple tests; this would be confirmed/updated through specific Z-code reporting, limiting administrative complexities of coverage, coding, and pricing
2. At minimum, add language to final LCD that affords time for CLIA labs and approved assays to expand tested/reported biomarkers – allowing for proper reaction to future test content expansions

Second, we urge MolDX to publish a revised clinical validation worksheet (M00154), specifically Section 6: Variant Coverage. This content is critical to the LCD’s success, and its gene list seems inconsistent with guidelines. We expect others will comment on specific biomarkers and pathways to a variant list which gains consensus approval of key opinion leaders in Jurisdiction M.
Thank you again for the opportunity to comment, and please let us know if we may support your efforts in any aspect of policy development around DL38047.

Thank you for your feedback. Regarding the specific suggestions:

1. This policy does not prohibit multiple components with differing methodologies to be described as one test. The Z-identifier must describe one test for adjudication.
2. We will work with providers and associations to create timelines that will minimize burden to providers for rolling out changes to the minimum requirements for coverage. These time frames are not explicitly listed in the policy and we do not believe that to be necessary.
3. As stated above, we will work with providers and relevant associations to revise the TA forms as appropriate.