Background
In recent years, there has been a rapid increase in the use of blood-based circulating tumor DNA (ctDNA) sequencing tests for cancer, with the first commercially available test offered by Guardant Health in 2014. So-called liquid biopsy tests are used to select targeted therapy and monitor nonresponding or progressive tumors. Although most somatic (tumor) testing is performed on resected biopsy specimens, ctDNA tests can be used at the time of a cancer diagnosis to identify genomic alterations that may be effectively treated using targeted therapies. Furthermore, they are frequently used after a patient experiences disease progression on targeted therapy to determine the mechanism of therapeutic resistance, and after definitive therapy to detect recurrence.1–9 Blood-based assays are particularly valuable when testing needs to be performed rapidly and when tissue-based samples are unavailable.
The objective of this study was to review coverage policies for ctDNA-based testing panels in cancer to examine trends from 2015 to 2019, with 2015 being the first instance of an available payer coverage policy. Payer coverage for genomic medicine continues to be an important determinant of access to testing, including whether patients are tested and how they are tested. These types of coverage decisions are a key element in care, because testing and the subsequent use of targeted therapy ultimately influence patients’ clinical outcomes.10–13 This study is the first to analyze current coverage of private and Medicare policies for ctDNA-based panel tests and to provide historical analysis.
The growth and adoption of ctDNA-based testing for cancer is expected to increase, as is the number of genes included in the test (eg, the Guardant360 test, which included 54 genes in 2014, now includes 73 genes in 2020).14 In addition, similar liquid biopsy techniques are being applied beyond targeting cancer treatments to the early detection of cancer, which will further increase the scope of these tests as their use expands to healthy populations. In addition to providing tumor information, many of these assays may identify nontumor germline cell-free DNA (cfDNA) (eg, BRCA1/2 mutations), but reporting of such findings is inconsistent across laboratories.15 Thus, our study addresses broader important clinical and policy issues that are emerging. Our systematic assessment of coverage policies provides greater insight into the development of coverage policies and underscores how payers make coverage decisions over time.
Methods
We analyzed private commercially available payer coverage policies, Medicare (national coverage determinations [NCDs]), and Medicare Administrative Contractor (MAC) coverage policies (local coverage determinations [LCDs]) for ctDNA-based panel tests for cancer from January 1, 2015 through July 1, 2019. Definitions of terms are provided in supplemental eAppendix 1, available with this article at JNCCN.org.
Data Sources and Payer Cohorts
We used the Canary Insights Database (supplemental eAppendix 2) as the source of private policies and the Centers for Medicare & Medicaid Services (CMS) coverage database for Medicare NCDs and LCDs (https://www.cms.gov/medicare-coverage-database/search/advanced-search.aspx). The Canary Insights Database (http://canaryinsights.com/) is a medical policy library containing >40,000 medical policies from >200 commercial payers and links to public payer policies with >100,000 members.
The private payer cohort was determined by including all payers that had a positive or negative coverage policy for ctDNA in the Canary Insights Database. The Medicare payer cohort was determined by reviewing all local and national Medicare policies on the CMS website with a positive coverage policy for ctDNA.16 Medicare has not issued negative coverage policies for these types of tests.
Types of Coverage Policies
Private Payer
Private policies are coverage policies issued by private companies for commercially available plans. They do not cover Medicare Advantage or payers that do not make their policies publicly available (eg, Kaiser Permanente).
Medicare
Medicare policies are coverage policies issued directly from CMS in the form of NCDs and by MACs in the form of LCDs. Before they are finalized, NCDs and LCDs are first issued as drafts. Draft policies are available for a public comment period and revision before the issuance of a Final NCD or LCD. There are 7 MACs (in 12 jurisdictions) in the United States that issue relevant coverage policies.
Search Strategy and Policy Selection
Policy titles and text were individually screened to determine whether they met inclusion criteria. We included policies that specifically addressed ctDNA-based panels as a clinical diagnostic test and excluded policies that addressed single-gene ctDNA testing (eg, EGFR, ALK, BRAF) that did not include a provision for ctDNA-based panel testing (supplemental eAppendix 3).
Private Payers
We searched the Canary Insights Database with the terms “liquid biopsy” and “circulating tumor DNA.” We confirmed that these terms captured all relevant policies from January 1, 2015 through July 1, 2019 (supplemental eAppendix 3).
Medicare
We searched the CMS database for NCDs and LCDs with the terms “liquid biopsy” and “circulating tumor DNA” using the “all states” and “entire document” functions. We confirmed that these terms captured all relevant policies from January 1, 2018 (the date of the first positive policy) through July 1, 2019.
Variables and Data Abstraction Policies
We chose variables that described the structure of the policy (eg, how the policy was written, whether the policy was developed by a third party). For positive coverage policies, we chose variables that described how the coverage was worded, which cancers were included, if and how monitoring was included, and which specific ctDNA tests were covered. Specific variables that were coded for private and Medicare policies are listed in supplemental eTable 1.
We coded variables for private and Medicare policies for 2017 through 2019. We also coded whether a policy existed for 2015 to 2016 and if it provided coverage (as none provided coverage, no additional variables were coded). Data were independently coded by 2 individuals, and discrepancies were resolved by discussion. We described trends but did not statistically assess differences. Trends examined included the changes to policies (eg, noncoverage to coverage) and detailed coverage conditions (eg, test, genes, types of cancer).
Results
As of mid-2019, a total of 65 private payers and 4 MACs had published policies about ctDNA. We found a shift in private payers from no coverage in 2016 to 38% coverage in 2019 and a shift in Medicare policies from no LCDs for the use of ctDNA-based panel tests in cancer indications in 2017 to 8 final LCDs, 2 draft LCDs, and 2 future effective final LCD (February 3 and March 15, 2020) in 2019. From 2017 to 2019, policies increased in scope regarding the number of cancers included (from non–small cell lung cancer [NSCLC] to 12 solid/hematologic cancers) and from a single gene (EGFR) to 73 genes (eg, the Guardant360 test).
Specifically, we found that 38% (28/73) of private payer coverage policies provided coverage of ctDNA-based panel testing for some clinical indications as of July 1, 2019 (Table 1). Positive coverage policies were from 28 payers, of which 22 were Blue Cross Blue Shield Association (BCBSA) plans, and negative coverage policies were from 45 payers, of which 25 were BCBSA plans. Of the 200 payers in the Canary Insights Database, 33% of private payers had explicitly positive or negative coverage policies.
Coverage Policies for ctDNA
Of the positive policies, 87% (24/28) were for NSCLC only (Table 2) and nearly half (47%; 13/28) were written for testing EGFR gene analysis only (Table 3); 79% (22/28) named coverage only for specific tests (cobas EGFR Mutation Test v2, Guardant360, or OncoBEAM) (Tables 2 and 3). Furthermore, of all positive policies, 11% (3/28) specifically stated coverage for monitoring (eg, no prior testing and progression, or progression on tyrosine kinase inhibitors) (Table 2). Descriptions of all brand-named tests are provided in supplemental eAppendix 4.
Characteristics of 2019 Positive Coverage Policies by Payer
Coverage Clinical Scenarios by Private Payer and Medicare
We found wide variation in how payers structured their policies—that is, whether the policy focused on the technology generally or on a specific cancer or test (Table 4). Private payers used 9 different approaches; the most common structure was to organize their policy for liquid biopsy tests, including both ctDNA and circulating tumor cell tests (36%). Conversely, Medicare used 2 different approaches. The most common structure used by Medicare payers was to organize their policy based first on a specific named test (100%) (eg, Guardant360 or InVisionFirst) and then narrowly on ctDNA NSCLC tests (67%).
Policy Structure Types Issued by Private Payers and Medicare
There were no NCD policies explicitly providing coverage for ctDNA-based panel tests. Although the NCD on sequencing for advanced cancer1 included ctDNA-based panel test coverage if the test was FDA-approved, there are currently no FDA-approved ctDNA-based panel tests.
Although there is no national coverage policy, MACs can provide coverage for ctDNA-based tests with the issuance of an LCD. We found 12 draft or final LCDs (67% final and 33% draft) covering ctDNA-based panel tests (Table 1) from 4 MACs (out of 7). Four MACs issued final LCD policies in 2018 for the Guardant360 ctDNA-based panel test for NSCLC. The same 4 MACs issued final LCD policies in 2019 for the InVisionFirst ctDNA-based panel test for NSCLC (Table 2). Between March and May 2019, the same 4 MACs issued draft LCD policies (Table 1) that will cover use of Guardant360 in ctDNA-based panel testing in 12 solid tumors, in addition to the already approved coverage policy for NSCLC (Table 2), when finalized. On December 19, 2019, a final LCD was issued by Palmetto GBA that finalized the LCD effective February 3, 2020, with a key addition that “other liquid biopsies will be covered for the same indications if they display similar performance in their intended used applications to Guardant360.”17
The first instance of a positive coverage policy was by Blue Cross Blue Shield Massachusetts in September 2017 for the Guardant360 ctDNA-based panel test for NSCLC, including the use of monitoring (data not shown). In 2018, there was a sharp increase in coverage for both private payers and Medicare, especially after the NCD on sequencing for advanced cancer1 was issued in March 2018.
Discussion
The overall trends in both private payer and Medicare coverage for ctDNA-based panel testing have been an increasing number of coverage policies, an increasing number of positive policies, and an increasing scope of coverage. We found that most positive coverage policies were very specifically written with defined clinical scenarios, although we also found that Medicare coverage policies were evolving to pan-cancer uses, signifying a significant shift in coverage frameworks.
As might have been expected given that the only FDA-approved ctDNA test is a single-gene test for NSCLC, we found that most (87%) policies were for NSCLC and that nearly half (47%) were for EGFR gene analysis. Furthermore, of those policies for NSCLC, most (79%) only covered specifically named tests. One of the most interesting findings was in the case of EGFR gene analysis, in which 43% (12/28) payers stated that multigene panel tests (Guardant360 and OncoBEAM) would be a covered benefit for EGFR gene analysis only. Given that tests such as these are panel tests that evaluate multiple genes, the “limited” coverage decision may actually result in testing that is far more comprehensive than intended.
We found that BCBSA plans were heavily represented in our sample, but that such plans varied in their coverage policies. More than half (64%) of the private payer policies were BCBSA plans, comprising 56% of the covered lives for all policies included. Of these, 22 policies provided coverage, representing 76% of all positive covered lives, and 25 policies did not provide coverage. Although the national BCBSA issued a technology assessment for “Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management,”18 BCBSA plans operate independently and each plan determines its own policies.10,19
One complexity of private payer coverage is that payers structure their policies in many ways, ranging from policies focusing on very specific clinical conditions, genes, and brand-named tests to broad policies that cover many conditions and generic tests. This wide variation reflects the fact that private payers vary greatly in how they develop and structure their coverage policies.20,21 Such variation increases the challenges in assessing and tracking coverage policies and may make it difficult for patients and providers to understand relevant policies.
An important finding was that Medicare coverage policies are evolving rapidly. Although there is no NCD policy explicitly providing coverage for ctDNA-based panel tests (other than for FDA-approved tests), coverage is provided through LCDs. The policy framework for Medicare LCDs is evolving from coverage of specific cancers to policies providing coverage of pan-cancer scenarios, which marks a significant change from earlier LCDs. Early LCDs were written in a very specific manner in which each one addressed a specific brand-named test in a particular cancer. For example, 4 MACs issued final LCD policies in 2018 for the Guardant360 ctDNA-based panel test for NSCLC, and the same 4 MACs issued final LCD policies in 2019 for the InvisionFirst ctDNA-based panel test for NSCLC. However, in early 2019, the same 4 MACs issued draft LCD policies that would provide pan-cancer coverage in 12 solid tumors. Two MACs have since issued a final LCD (effective February 3 and March 15, 2020). This coverage is still brand-name–specific given that it covers Guardant360, but the move toward pan-cancer coverage is significant, and the policy includes a provision that “other liquid biopsies will be covered for the same indications.”17 We found in earlier studies that coverage of pan-cancer tests conflicts with many of the concepts of payer coverage frameworks, including that sequencing tests are considered a “bundle” of individual gene tests, which is counter to the one-marker-one-drug evaluation of medical necessity.21,22
We did not find any previous studies of payer coverage policies for ctDNA, but our results were consistent with other studies showing that coverage for sequencing tests is increasing in some clinical scenarios but that many tests are not covered. Our study evaluating payer coverage policies for exome sequencing in pediatric patients with neurodevelopmental disorders found that 50% of private payers changed from no coverage to positive coverage between 2015 and 2017,10 and our recent study of payer decision-making found that private payers were increasingly willing to cover such tests.13 However, our recent study of next-generation tumor sequencing coverage policies found that half of private payers were not providing coverage for such tests as of mid-2019.19
Implications and Future Research
Our results suggest that there is a conundrum between what the test actually evaluates, what the payer is willing to cover, and the information that the clinician receives and can use to guide clinical decisions. As noted earlier, several payers provide coverage for multigene tests but only allow the analysis of a single gene from those tests. For example, a clinician can order a particular test that interrogates 73 genes (eg, the Guardant360 test), but the payer will cover that test only for analysis of the single EGFR gene (43% of payers provide coverage in this manner), which leads to a report that may have results that are not covered by the payer but may still be used to inform the clinician’s ability to properly manage the patient’s cancer (reports are identical independent of payer coverage policy). In addition, limited policies, or having no policy, may burden clinicians with prior authorization requirements and appeals and thus delay or prevent access to testing. These issues will require further study. Another conundrum is that payer policies may not reflect what is found in reviews and guidelines. For example, ASCO and the College of American Pathologists published a review in 2018 that found no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection.7 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC indicate that ctDNA testing can be considered when a patient is medically unfit for invasive tissue sampling or if, after pathologic confirmation of an NSCLC diagnosis, there is insufficient material for molecular analysis.23 In addition, studies that support clinical utility will likely result in greater consistency among coverage policies.
Another conundrum is that the technology used by some laboratories to detect ctDNA interrogates all cfDNA. The cfDNA contains germline DNA, which can provide insight into both related and nonrelated cancer susceptibility (eg, BRCA1/2 mutations in breast cancer vs BRCA1/2 mutations in colon cancer). In addition to the ctDNA analysis, some laboratories provide the clinician with the results of cfDNA germline analysis for select genes. This fact presents a challenge given that these results may be unexpected and can confront both providers and patients with ethical and clinical dilemmas.
Although there has been a plethora of coverage for the use of ctDNA testing in NSCLC from both private payers and Medicare, the coverage has been primarily for treatment selection, with only 11% of payers with positive coverage including any monitoring indications. We expect that coverage may eventually be added for additional clinical indications, such as monitoring of minimal residual disease after definitive therapy or for detecting recurrence, although payers may be reluctant to adopt these indications because this would expand use to more extensive serial testing over time and thus may greatly increase costs.
Limitations
This study had several limitations. First, we did not include Medicaid policies, and the Canary Insights Database does not include all policies from all private payers in the United States, because it excludes self-insured and small payers. However, the Canary Insights Database includes >200 payers, and our analysis reflected coverage policies for 75% of the US population, including the 172 million individuals covered by private payers and the 75 million Medicare enrollees in 2019. Second, we were limited by the amount of information provided in the coverage policies by each payer, which were highly variable in their detail and clarity. We could not examine the actual decision-making process undertaken by individual payers. Third, published payer coverage policies do not necessarily reflect actual coverage or reimbursement for all “covered” tests, because plan purchasers can elect to exclude coverage for certain tests when purchasing plans for their employees. This is particularly true for self-insured groups, in which the insurer acts as a third-party administrator. Last, Medicare only issues positive coverage policies, which limited the comparison in both policy content and timing, given that the first Medicare policy was issued in 2018, whereas we included private payer policies from 2015 to 2019.
Conclusions
We found that coverage of ctDNA panel testing for cancer indications increased from 2015 to 2019. Two Medicare policies that have been finalized and additional policies that may be finalized in 2020 would provide a significant expansion of coverage to pan-cancer tests. Future research should continue to track coverage over time and evaluate the impact of coverage changes on test utilization. Given that genomic medicine is rapidly changing, payers and policymakers will need to continue to evolve policies to keep pace with emerging science and standards in clinical care.
Acknowledgments
We thank Bruce Quinn, MD, PhD (Bruce Quinn Associates LLC), for his insights, and Oliver Febbo, student intern (Urban School), for his assistance in data abstraction. Dr. Quinn and Mr. Febbo were not paid for their contributions.
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