SLCO1B1 functional variants and statin-induced myopathy in people with recent genealogical ancestors from Africa: a population-based real-world study.

Background: Clinical pharmacogenetic implementation guidelines for statin therapy are derived from evidence of primarily Eurocentric study populations. Functional SLCO1B1 variants that are rare in these study populations have not been investigated as a determinant of statin myotoxicity and are thus missing from guideline inclusion. Objective: Determine the relationship between candidate functional SLCO1B1 variants and statin-induced myopathy in people with recent genealogical ancestors from Africa. Design: Population-based pharmacogenetic study using real-world evidence from electronic health record-linked biobanks. Setting: Various health care settings. Participants: Self-identified white and Black statin users with genome-wide genotyping data available. Measurements: Primarily, the odds of statin-induced myopathy + rhabdomyolysis. Secondarily, total bilirubin levels. Thirdly, cell-based functional assay results. Results: Meta-analyses results demonstrated an increased risk of statin-induced myopathy + rhabdomyolysis with c.481+1G>T (odds ratio [OR] = 3.27, 95% confidence interval [CI] 1.43-7.46, P =.005) and c.1463G>C (OR = 2.45, 95% CI 1.04-5.78, P =.04) for Black participants. For White participants, c.521T>C was also significantly associated with increased risk of statin-induced myopathy + rhabdomyolysis (OR = 1.41, 95% CI 1.20-1.67, P =5.4x10 -5 ). This effect size for c.521T>C was similar in the Black participants, but did not meet the level of statistical significance (OR = 1.47, 95% CI 0.58-3.73, P =0.41). Supporting evidence using total bilirubin as an endogenous biomarker of SLCO1B1 function as well as from cell-based functional studies corroborated these findings. Limitations: Data limited to severe statin myotoxicity events. Conclusion: Our findings implicate Afrocentric SLCO1B1 variants on preemptive pharmacogenetic testing panels, which could have an instant impact on reducing the risk of statin-associated myotoxicity in historically excluded groups. Primary Funding Source: National Institutes of Health, Office of the Director - All of Us (OD-AoURP).

Clinical validity and utility of circulating tumor DNA (ctDNA) testing in advanced non-small cell lung cancer (aNSCLC): a systematic literature review and meta-analysis.

Purpose: Circulating tumor DNA (ctDNA) testing has become a promising tool to guide first-line (1L) targeted treatment for advanced non-small cell lung cancer (aNSCLC). This study aims to estimate the clinical validity (CV) and clinical utility (CU) of ctDNA-based next-generation sequencing (NGS) for oncogenic driver mutations to inform 1L treatment decisions in aNSCLC through a systematic literature review and meta-analysis. Methods: A systematic literature search was conducted in PubMed/MEDLINE and Embase to identify randomized control trials or observational studies reporting CV/CU on ctDNA testing in patients with aNSCLC. Meta-analyses were performed using bivariate random-effects models to estimate pooled sensitivity and specificity. Progression-free/overall survival (PFS/OS) was summarized for CU studies. Results: Eighteen studies were identified: 17 CV only, 2 CU only, and 1 both. Thirteen studies were included for the meta-analysis on multi-gene detection. The overall sensitivity and specificity for ctDNA detection of any mutation were 0.69 (95% CI, 0.63-0.74) and 0.99 (95% CI, 0.97-1.00) respectively. However, sensitivity varied greatly by driver gene, ranging from 0.29 (95% CI, 0.13-0.53) for ROS 1 to 0.77 (95% CI, 0.63-0.86) for KRAS . Two studies compared PFS with ctDNA versus tissue-based testing followed by 1L targeted therapy found no significant differences. One study reported OS curves on ctDNA-matched and tissue-matched therapies but no hazard ratios were provided. Conclusion: ctDNA testing demonstrated an overall acceptable diagnostic accuracy in aNSCLC patients, however, sensitivity varied greatly by driver mutation. Further research is needed, especially for uncommon driver mutations, to better understand the CU of ctDNA testing in guiding targeted treatments for aNSCLC.

The Health Inequality Impact of Liquid Biopsy to Inform First-Line Treatment of Advanced Non-Small Cell Lung Cancer: A Distributional Cost-Effectiveness Analysis.

OBJECTIVES: To perform a distributional cost-effectiveness analysis of liquid biopsy (LB) followed by, if needed, tissue biopsy (TB) (LB-first strategy) relative to a TB-only strategy to inform first-line treatment of advanced non-small cell lung cancer (aNSCLC) from a US payer perspective by which we quantify the impact of LB-first on population health inequality according to race and ethnicity. METHODS: With a health economic model, quality-adjusted life-years (QALYs) and costs per patient were estimated for each subgroup. Given the lifetime risk of aNSCLC, and assuming equally distributed opportunity costs, the incremental net health benefits of LB-first were calculated, which were used to estimate general population quality-adjusted life expectancy at birth (QALE) by race and ethnicity with and without LB-first. The degree of QALYs and QALE differences with the strategies was expressed with inequality indices. Their differences were defined as the inequality impact of LB-first. RESULTS: LB-first resulted in an additional 0.21 (95% uncertainty interval: 0.07-0.39) QALYs among treated patients, with the greatest gain observed among Asian patients (0.31 QALYs [0.09-0.61]). LB-first resulted in an increase in relative inequality in QALYs among patients, but a minor decrease in relative inequality in QALE. CONCLUSIONS: LB-first to inform first-line aNSCLC therapy can improve health outcomes. With current diagnostic performance, the benefit is the greatest among Asian patients, thereby potentially widening racial and ethnic differences in survival among patients with aNSCLC. Assuming equally distributed opportunity costs and access, LB-first does not worsen and, in fact, may reduce inequality in general population health according to race and ethnicity.

Private Payer and Medicare Coverage Policies for Use of Circulating Tumor DNA Tests in Cancer Diagnostics and Treatment.

BACKGROUND: Circulating tumor DNA (ctDNA) is used to select initial targeted therapy, identify mechanisms of therapeutic resistance, and measure minimal residual disease (MRD) after treatment. Our objective was to review private and Medicare coverage policies for ctDNA testing. METHODS: Policy Reporter was used to identify coverage policies (as of February 2022) from private payers and Medicare Local Coverage Determinations (LCDs) for ctDNA tests. We abstracted data regarding policy existence, ctDNA test coverage, cancer types covered, and clinical indications. Descriptive analyses were performed by payer, clinical indication, and cancer type. RESULTS: A total of 71 of 1,066 total policies met study inclusion criteria, of which 57 were private policies and 14 were Medicare LCDs; 70% of private policies and 100% of Medicare LCDs covered at least one indication. Among 57 private policies, 89% specified a policy for at least 1 clinical indication, with coverage for ctDNA for initial treatment selection most common (69%). Of 40 policies addressing progression, coverage was provided 28% of the time, and of 20 policies addressing MRD, coverage was provided 65% of the time. Non-small cell lung cancer (NSCLC) was the cancer type most frequently covered for initial treatment (47%) and progression (60%). Among policies with ctDNA coverage, coverage was restricted to patients without available tissue or in whom biopsy was contraindicated in 91% of policies. MRD was commonly covered for hematologic malignancies (30%) and NSCLC (25%). Of the 14 Medicare LCD policies, 64% provided coverage for initial treatment selection and progression, and 36% for MRD. CONCLUSIONS: Some private payers and Medicare LCDs provide coverage for ctDNA testing. Private payers frequently cover testing for initial treatment, especially for NSCLC, when tissue is insufficient or biopsy is contraindicated. Coverage remains variable across payers, clinical indications, and cancer types despite inclusion in clinical guidelines, which could impact delivery of effective cancer care.

Perspectives of private payers on multicancer early-detection tests: informing research, implementation, and policy.

Emerging blood-based multicancer early-detection (MCED) tests may redefine cancer screening, reduce mortality, and address health disparities if their benefit is demonstrated. U.S. payers' coverage policies will impact MCED test adoption and access; thus, their perspectives must be understood. We examined views, coverage barriers, and evidentiary needs for MCED from 19 private payers collectively covering 150 000 000 enrollees. Most saw an MCED test's potential merit for cancers without current screening (84%), but fewer saw its merit for cancers with existing screening (37%). The largest coverage barriers were inclusion of cancers without demonstrated benefits of early diagnosis (73%), a high false-negative rate (53%), and lack of care protocols for MCED-detected but unconfirmed cancers (53%). The majority (58%) would not require mortality evidence and would accept surrogate endpoints. Most payers (64%) would accept rigorous real-world evidence in the absence of a large randomized controlled trial. The majority (74%) did not expect MCED to reduce disparities due to potential harm from overtreatment resulting from an MCED and barriers to downstream care. Payers' perspectives and evidentiary needs may inform MCED test developers, researchers producing evidence, and health systems framing MCED screening programs. Private payers should be stakeholders of a national MCED policy and equity agenda.

Transmission of SARS-CoV-2 Delta variant from an infected aircrew member on a short-haul domestic flight, Australia 2021.

In June 2021, when COVID-19 incidence in Australia was low, a COVID-19 (Delta variant) cluster occurred on an 81-minute domestic flight, with an aircrew member as the likely source. Outbreak investigation demonstrated that SARS-CoV-2 may be transmitted during short-haul flights and that mask use protected against infection.

Geriatricians' Perspectives on the Multiple Dimensions of Utility of Genetic Testing for Alzheimer's Disease: A Qualitative Study.

BACKGROUND: Research advancements in Alzheimer's disease (AD) raise opportunities for genetic testing to improve diagnostic and risk assessment. Despite emerging developments, it is unclear how geriatricians perceive the potential clinical and personal utility of genetic testing for their patients. Geriatricians' perspectives are essential to understanding potential ethical, policy, and clinical challenges. OBJECTIVE: In this paper, we report on geriatricians' perspectives on the utility of genetic testing for AD. METHODS: Semi-structured interviews with California geriatricians within different practices settings to collect and characterize their perspectives on genetic testing for AD. We used an adapted grounded theory approach to analyze recorded and transcribed interviews. RESULTS: We identified geriatricians' (n = 10) perspectives on the clinical and personal utility of testing, alongside their views on clinical care approaches for older adults. Geriatricians perceived minimal clinical utility of genetic testing for AD, though that may change with the availability of disease-modifying therapies. Yet, they recognized the potential personal utility of testing (e.g., assisting with future financial planning). Finally, geriatricians expressed concerns regarding patients' anxiety from learning about genetic status, particularly through direct-to-consumer (DTC) testing. CONCLUSION: Our data highlight that the decision to order genetic testing requires clinical and ethical considerations, including balancing limited clinical utility with the potential personal utility. Although DTC testing is available, geriatricians perceive that they have an important role in managing the decision to test and interpreting the results. Further research is needed to inform policy and ethical guidelines to support geriatricians' critical role to counsel patients considering clinical and DTC genetic testing.

Genetic counselors' experience with reimbursement and patient out-of-pocket cost for multi-cancer gene panel testing for hereditary cancer syndromes.

Multi-cancer gene panels for hereditary cancer syndromes (hereditary cancer panels, HCPs) are widely available, and some laboratories have programs that limit patients' out-of-pocket (OOP) cost share. However, little is known about practices by cancer genetic counselors for discussing and ordering an HCP and how insurance reimbursement and patient out-of-pocket share impact these practices. We conducted a survey of cancer genetic counselors based in the United States through the National Society of Genetic Counselors to assess the impact of reimbursement and patient OOP share on ordering of an HCP and hereditary cancer genetic counseling. Data analyses were conducted using chi-square and t tests. We received 135 responses (16% response rate). We found that the vast majority of respondents (94%, 127/135) ordered an HCP for patients rather than single-gene tests to assess hereditary cancer predisposition. Two-thirds of respondents reported that their institution had no protocol related to discussing HCPs with patients. Most respondents (84%, 114/135) indicated clinical indications and patients' requests as important in selecting and ordering HCPs, while 42%, 57/135, considered reimbursement and patient OOP share factors important. We found statistically significant differences in reporting of insurance as a frequently used payment method for HCPs and in-person genetic counseling (84% versus 59%, respectively, p < 0.0001). Perceived patient willingness to pay more than $100 was significantly higher for HCPs than for genetic counseling(41% versus 22%, respectively, p < 0.01). In sum, genetic counselors' widespread selection and ordering of HCPs is driven more by clinical indications and patient preferences than payment considerations. Respondents perceived that testing is more often reimbursed by insurance than genetic counseling, and patients are more willing to pay for an HCP than for genetic counseling. Policy efforts should address this incongruence in reimbursement and patient OOP share. Patient-centered communication should educate patients on the benefit of genetic counseling.

Analyzing Precision Medicine Utilization with Real-World Data: A Scoping Review.

Precision medicine (PM), specifically genetic-based testing, is currently used in over 140,000 individual tests to inform the clinical management of disease. Though several databases (e.g., the NIH Genetic Testing Registry) demonstrate the availability of these sequencing-based tests, we do not currently understand the extent to which these tests are used. There exists a need to synthesize the body of real-world data (RWD) describing the use of sequencing-based tests to inform their appropriate use. To accomplish this, we performed a scoping review to examine what RWD sources have been used in studies of PM utilization between January 2015 and August 2021 to characterize the use of genome sequencing (GS), exome sequencing (ES), tumor sequencing (TS), next-generation sequencing-based panels (NGS), gene expression profiling (GEP), and pharmacogenomics (PGx) panels. We abstracted variables describing the use of these types of tests and performed a descriptive statistical analysis. We identified 440 articles in our search and included 72 articles in our study. Publications based on registry databases were the most common, followed by studies based on private insurer administrative claims. Slightly more than one-third (38%) used integrated datasets. Two thirds (67%) of the studies focused on the use of tests for oncological clinical applications. We summarize the RWD sources used in peer-reviewed literature on the use of PM. Our findings will help improve future study design by encouraging the use of centralized databases and registries to track the implementation and use of PM.

Multicancer Screening Tests: Anticipating And Addressing Considerations For Payer Coverage And Patient Access.

There is a tremendous public health need to identify potentially lethal cancers at earlier stages, when there is a greater chance for improved survival. Although in the US there are currently screening recommendations for only five cancers (breast, colorectal, cervical, lung, and prostate), new tests can screen for up to fifty cancers simultaneously based on a simple blood draw. However, these multicancer screening tests (also called "liquid biopsy" tests) will also present challenges to payers because of intrinsic features of the tests and the complexity of payer coverage assessments for screening tests. We describe these considerations while also offering potential solutions that can inform payers' decision making if these tests prove to be beneficial.

Hereditary cancer panel testing challenges and solutions for the latinx community: costs, access, and variants.

Hereditary breast and ovarian cancers (HBOCs) are common among the Latinx population, and risk testing is recommended using multi-gene hereditary cancer panels (HCPs). However, little is known about how payer reimbursement and out-of-pocket expenses impact provider ordering of HCP in the Latinx population. Our objective is to describe key challenges and possible solutions for HCP testing in the Latinx population. As part of a larger study, we conducted semi-structured interviews with key provider informants (genetic counselors, oncologist, nurse practitioner) from safety-net institutions in the San Francisco Bay Area. We used a deductive thematic analysis approach to summarize themes around challenges and possible solutions to facilitating HCP testing in Latinx patients. We found few financial barriers for HCP testing for the Latinx population due to laboratory patient assistance programs that cover testing at low or no cost to patients. However, we found potential challenges related to the sustainability of low-cost testing and out-of-pocket expenses for patients, access to cascade testing for family members, and pathogenic variants specific to Latinx. Providers questioned whether current laboratory payment programs that decrease barriers to testing are sustainable and suggested solutions for accessing cascade testing and ensuring variants specific to the Latinx population were included in testing. The use of laboratories with payment assistance programs reduces barriers to HCP testing among the US population; however, other barriers are present that may impact testing use in the Latinx population and must be addressed to ensure equitable access to HCP testing for this population.

Influence of payer coverage and out-of-pocket costs on ordering of NGS panel tests for hereditary cancer in diverse settings.

The landscape of payment for genetic testing has been changing, with an increase in the number of laboratories offering testing, larger panel offerings, and lower prices. To determine the influence of payer coverage and out-of-pocket costs on the ordering of NGS panel tests for hereditary cancer in diverse settings, we conducted semi-structured interviews with providers who conduct genetic counseling and order next-generation sequencing (NGS) panels purposefully recruited from 11 safety-net clinics and academic medical centers (AMCs) in California and North Carolina, states with diverse populations and divergent Medicaid expansion policies. Thematic analysis was done to identify themes related to the impact of reimbursement and out-of-pocket expenses on test ordering. Specific focus was put on differences between settings. Respondents from both safety-net clinics and AMCs reported that they are increasingly ordering panels instead of single-gene tests, and tests were ordered primarily from a few commercial laboratories. Surprisingly, safety-net clinics reported few barriers to testing related to cost, largely due to laboratory assistance with prior authorization requests and patient payment assistance programs that result in little to no patient out-of-pocket expenses. AMCs reported greater challenges navigating insurance issues, particularly prior authorization. Both groups cited non-coverage of genetic counseling as a major barrier to testing. Difficulty of access to cascade testing, particularly for family members that do not live in the United States, was also of concern. Long-term sustainability of laboratory payment assistance programs was a major concern; safety-net clinics were particularly concerned about access to testing without such programs. There were few differences between states. In conclusion, the use of laboratories with payment assistance programs reduces barriers to NGS panel testing among diverse populations. Such programs represent a major change to the financing and affordability of genetic testing. However, access to genetic counseling is a barrier and must be addressed to ensure equity in testing.

US private payers' perspectives on insurance coverage for genome sequencing versus exome sequencing: A study by the Clinical Sequencing Evidence-Generating Research Consortium (CSER).

PURPOSE: There is limited payer coverage for genome sequencing (GS) relative to exome sequencing (ES) in the U.S. Our objective was to assess payers' considerations for coverage of GS versus coverage of ES and requirements payers have for coverage of GS. The study was conducted by the NIH-funded Clinical Sequencing Evidence-Generating Research Consortium (CSER). METHODS: We conducted semi-structured interviews with representatives of private payer organizations (payers, N = 12) on considerations and evidentiary and other needs for coverage of GS and ES. Data were analyzed using thematic analysis. RESULTS: We described four categories of findings and solutions: demonstrated merits of GS versus ES, enhanced methods for evidence generation, consistent laboratory processes/sequencing methods, and enhanced implementation/care delivery. Payers see advantages to GS vs. ES and are open to broader GS coverage but need more proof of these advantages to consider them in coverage decision-making. Next steps include establishing evidence of benefits in specific clinical scenarios, developing quality standards, ensuring transparency of laboratory methods, developing clinical centers of excellence, and incorporating the role of genetic professionals. CONCLUSION: By comparing coverage considerations for GS and ES, we identified a path forward for coverage of GS. Future research should explicitly address payers' conditions for coverage.

Laboratory business models and practices: implications for availability and access to germline genetic testing.

PURPOSE: Germline testing laboratories have evolved over several decades. We describe laboratory business models and practices and explore their implications on germline testing availability and access. METHODS: We conducted semistructured interviews with key informants using purposive sampling. We interviewed 13 key informants representing 14 laboratories. We used triangulation and iterative data analysis to identify topics concerning laboratory business models and practices. RESULTS: We characterized laboratories as full-service (FSL), for-profit germline (PGL), and not-for-profit germline (NGL). Relying on existing payer contracts is a key characteristic of the FSL business models. FSLs focus on high-volume germline tests with evidence of clinical utility that have reimbursable codes. In comparison, a key business model characteristic of PGLs is direct patient billing facilitated by commodity-based pricing made possible by investors and industry partnerships. Client billing is a key business model characteristic of NGLs. Because many NGLs exist within academic settings, they are challenged by their inability to optimize laboratory processes and billing practices. CONCLUSION: Continued availability of, and access to germline testing will depend on the financial success of laboratories; organizational characteristics of laboratories and payers; cultural factors, particularly consumer interest and trust; and societal factors, such as regulation and laws surrounding pricing and reimbursement.

Availability and funding of clinical genomic sequencing globally.

The emergence of next-generation genomic sequencing (NGS) tests for use in clinical care has generated widespread interest around the globe, but little is known about the availability and funding of these tests worldwide. We examined NGS availability across world regions and countries, with a particular focus on availability of three key NGS tests-Whole-Exome Sequencing or Whole-Genome Sequencing for diagnosis of suspected genetic diseases such as intellectual disability disorders or rare diseases, non-invasive prenatal testing for common genetic abnormalities in fetuses and tumor sequencing for therapy selection and monitoring of cancer treatment. We found that these NGS tests are available or becoming available in every major region of the world. This includes both high-income countries with robust genomic programmes such as the USA and the UK, and growing availability in countries with upper-middle-income economies. We used exploratory case studies across three diverse health care systems (publicly funded/national (UK), publicly funded/provincial (Canada) and mixed private/public system (USA)) to illustrate the funding challenges and approaches used to address those challenges that might be adopted by other countries. We conclude by assessing what type of data and initiatives will be needed to better track and understand the use of NGS around the world as such testing continues to expand.

Private payer coverage policies for ApoE-e4 genetic testing.

PURPOSE: ApoE-e4 has a well-established connection to late-onset Alzheimer disease (AD) and is available clinically. Yet, there have been no analyses of payer coverage policies for ApoE. Our objective was to analyze private payer coverage policies for ApoE genetic testing, examine the rationales, and describe supporting evidence referenced by policies. METHODS: We searched for policies from the eight largest private payers (by member numbers) covering ApoE testing for late-onset AD. We implemented content analysis methods to evaluate policies for coverage decisions and rationales. RESULTS: Seven payers had policies with positions on ApoE testing. Five explicitly state they do not cover ApoE and two apply generic preauthorization criteria. Rationales supporting coverage decisions include: reference to guidelines or national standards, inadequate data supporting testing, characterizing testing as investigational, or that testing would not alter patients' clinical management. CONCLUSION: Seven of the eight largest private payers' coverage policies reflect standards that discourage ApoE testing due to a lack of clinical utility. As the field advances, ApoE testing may have an important clinical role, particularly considering that disease-modifying therapies are under evaluation by the US Food and Drug Administration. These types of field advancements may not be consistent with private payers' policies and may cause payers to reevaluate existing coverage policies.

Private Payer and Medicare Coverage for Circulating Tumor DNA Testing: A Historical Analysis of Coverage Policies From 2015 to 2019.

BACKGROUND: Clinical adoption of the sequencing of circulating tumor DNA (ctDNA) for cancer has rapidly increased in recent years. This sequencing is used to select targeted therapy and monitor nonresponding or progressive tumors to identify mechanisms of therapeutic resistance. Our study objective was to review available coverage policies for cancer ctDNA-based testing panels to examine trends from 2015 to 2019. METHODS: We analyzed publicly available private payer policies and Medicare national coverage determinations and local coverage determinations (LCDs) for ctDNA-based panel tests for cancer. We coded variables for each year representing policy existence, covered clinical scenario, and specific ctDNA test covered. Descriptive analyses were performed. RESULTS: We found that 38% of private payer coverage policies provided coverage of ctDNA-based panel testing as of July 2019. Most private payer policy coverage was highly specific: 87% for non-small cell lung cancer, 47% for EGFR gene testing, and 79% for specific brand-name tests. There were 8 final, 2 draft, and 2 future effective final LCDs (February 3 and March 15, 2020) that covered non-FDA-approved ctDNA-based tests. The draft and future effective LCDs were the first policies to cover pan-cancer use. CONCLUSIONS: Coverage of ctDNA-based panel testing for cancer indications increased from 2015 to 2019. The trend in private payer and Medicare coverage is an increasing number of coverage policies, number of positive policies, and scope of coverage. We found that Medicare coverage policies are evolving to pan-cancer uses, signifying a significant shift in coverage frameworks. Given that genomic medicine is rapidly changing, payers and policymakers (eg, guideline developers) will need to continue to evolve policies to keep pace with emerging science and standards in clinical care.

Insights From a Temporal Assessment of Increases in US Private Payer Coverage of Tumor Sequencing From 2015 to 2019.

OBJECTIVES: To examine the temporal trajectory of insurance coverage for next-generation tumor sequencing (sequencing) by private US payers, describe the characteristics of coverage adopters and nonadopters, and explore adoption trends relative to the Centers for Medicare and Medicaid Services' National Coverage Determination (CMS NCD) for sequencing. METHODS: We identified payers with positive coverage (adopters) or negative coverage (nonadopters) of sequencing on or before April 1, 2019, and abstracted their characteristics including size, membership in the BlueCross BlueShield Association, and whether they used a third-party policy. Using descriptive statistics, payer characteristics were compared between adopters and nonadopters and between pre-NCD and post-NCD adopters. An adoption timeline was constructed. RESULTS: Sixty-nine payers had a sequencing policy. Positive coverage started November 30, 2015, with 1 payer and increased to 33 (48%) as of April 1, 2019. Adopters were less likely to be BlueCross BlueShield members (P < .05) and more likely to use a third-party policy (P < .001). Fifty-eight percent of adopters were small payers. Among adopters, 52% initiated coverage pre-NCD over a 25-month period and 48% post-NCD over 17 months. CONCLUSIONS: We found an increase, but continued variability, in coverage over 3.5 years. Temporal analyses revealed important trends: the possible contribution of the CMS NCD to a faster pace of coverage adoption, the interdependence in coverage timing among BlueCross BlueShield members, the impact of using a third-party policy on coverage timing, and the importance of small payers in early adoption. Our study is a step toward systematic temporal research of coverage for precision medicine, which will inform policy and affordability assessments.

Use of Real-World Evidence in US Payer Coverage Decision-Making for Next-Generation Sequencing-Based Tests: Challenges, Opportunities, and Potential Solutions.

OBJECTIVES: Given the potential of real-world evidence (RWE) to inform understanding of the risk-benefit profile of next-generation sequencing (NGS)-based testing, we undertook a study to describe the current landscape of whether and how payers use RWE as part of their coverage decision making and potential solutions for overcoming barriers. METHODS: We performed a scoping literature review of existing RWE evidentiary frameworks for evaluating new technologies and identified barriers to clinical integration and evidence gaps for NGS. We synthesized findings as potential solutions for improving the relevance and utility of RWE for payer decision-making. RESULTS: Payers require evidence of clinical utility to inform coverage decisions, yet we found a relatively small number of published RWE studies, and these are predominately focused on oncology, pharmacogenomics, and perinatal/pediatric testing. We identified 3 categories of innovation that may help address the current undersupply of RWE studies for NGS: (1) increasing use of RWE to inform outcomes-based contracting for new technologies, (2) precision medicine initiatives that integrate clinical and genomic data and enable data sharing, and (3) Food and Drug Administration reforms to encourage the use of RWE. Potential solutions include development of data and evidence review standards, payer engagement in RWE study design, use of incentives and partnerships to lower the barriers to RWE generation, education of payers and providers concerning the use of RWE and NGS, and frameworks for conducting outcomes-based contracting for NGS. CONCLUSIONS: We provide numerous suggestions to overcome the data, methodologic, infrastructure, and policy challenges constraining greater integration of RWE in assessments of NGS.