Julia Rachel Trosman

The economic value of personalized medicine tests: what we know and what we need to know

Purpose:There is uncertainty about when personalized medicine tests provide economic value. We assessed evidence on the economic value of personalized medicine tests and gaps in the evidence base.Methods:We created a unique evidence base by linking data on published cost–utility analyses from the Tufts Cost-Effectiveness Analysis Registry with data measuring test characteristics and reflecting where value analyses may be most needed: (i) tests currently available or in advanced development, (ii) tests for drugs with Food and Drug Administration labels with genetic information, (iii) tests with demonstrated or likely clinical utility, (iv) tests for conditions with high mortality, and (v) tests for conditions with high expenditures.Results:We identified 59 cost–utility analyses studies that examined personalized medicine tests (1998–2011). A majority (72%) of the cost/quality-adjusted life year ratios indicate that testing provides better health although at higher cost, with almost half of the ratios falling below

Barriers to the Use of Personalized Medicine in Breast Cancer

50,000 per quality-adjusted life year gained. One-fifth of the results indicate that tests may save money.Conclusion:Many personalized medicine tests have been found to be relatively cost-effective, although fewer have been found to be cost saving, and many available or emerging medicine tests have not been evaluated. More evidence on value will be needed to inform decision making and assessment of genomic priorities.Genet Med 2014:16(3):251–257

Health Technology Assessment and Private Payers' Coverage of Personalized Medicine

PURPOSE Personalized medicine--the use of genomics and molecular diagnostics to direct care decisions--may improve outcomes by more accurately individualizing treatment to patients. Using qualitative research, we explored care delivery barriers to the use of personalized medicine for patients with breast cancer using examples of BRCA and gene expression profile testing. METHODS We conducted 51 interviews with multidisciplinary stakeholders in breast cancer care: clinicians (n = 25) from three academic and nine nonacademic organizations, executives (n = 20) from four major private insurers, and patient advocates (n = 6). RESULTS Barriers were common to the BRCA and gene expression profile tests and were classified under two categories: poor coordination of tests relative to treatment decisions and reimbursement-related disincentives. Perception of specific barriers varied across groups. Difficulty coordinating diagnostics relative to decisions was the most frequent concern by clinicians (60%), but only 35% of payers and 17% of advocates noted this barrier. For 60% of payers, drug- and procedure-based reimbursement was a significant barrier, but only 40% of clinicians and none of the advocates expressed the same concern. The opinion that patient out-of-pocket expenses are a barrier varied significantly between advocates and clinicians (83% v 20%, P < .007), and advocates and payers (83% v 15%, P < .004). Barriers were reported to result in postponement or avoidance of tests, delayed treatment decisions, and proceeding with decisions before test results. CONCLUSION Poorly coordinated diagnostic testing and the current oncology reimbursement model are barriers to the use of genomic and molecular diagnostic tests in cancer care.

Coverage Policy Development for Personalized Medicine: Private Payer Perspectives on Developing Policy for the 21-Gene Assay

PURPOSE Health technology assessment (HTA) plays an increasing role in translating emerging technologies into clinical practice and policy. Private payers are important users of HTA whose decisions impact adoption and use of new technologies. We examine the current use of HTA by private payers in coverage decisions for personalized medicine, a field that is increasingly impacting oncology practice. STUDY DESIGN Literature review and semistructured interviews. METHODS We reviewed seven HTA organizations used by private payers in decision making and explored how HTA is used by major US private payers (n = 11) for coverage of personalized medicine. RESULTS All payers used HTA in coverage decisions, but the number of HTA organizations used by an individual payer ranged from one (n = 1) to all seven (n = 1), with the majority of payers (n = 8) using three or more. Payers relied more extensively on HTAs for reviews of personalized medicine (64%) than for other technologies. Most payers (82%) equally valued expertise of reviewers and rigor of evaluation as HTA strengths, whereas genomic-specific methodology was less important. Key reported shortcomings were limited availability of reviews (73%) and limited inclusion of nonclinical factors (91%), such as cost-effectiveness or adoption of technology in clinical practice. CONCLUSION Payers use a range of HTAs in their coverage decisions related to personalized medicine, but the current state of HTA to comprehensively guide those decisions is limited. HTA organizations should address current gaps to improve their relevance to payers and clinicians. Current HTA shortcomings may also inform the national HTA agenda.

Payer decision making for next-generation sequencing-based genetic tests: insights from cell-free DNA prenatal screening

PURPOSE Personalized medicine is changing oncology practice and challenging decision making. A key challenge is the limited clinical evidence for many personalized medicine technologies. We describe the strategies private payers employed to develop coverage policy for personalized medicine using the example of the 21-gene assay in breast cancer. METHODS We examined the coverage policies of six private payers for the 21-gene assay. We then interviewed senior executives (n = 7) from these payers to elucidate factors informing coverage decisions. We additionally focused on the timing of payer decisions compared with the timing of evidence development, measured by publication of primary studies and relevant clinical guidelines. RESULTS The 21-gene assay became commercially available in 2004. The interviewed payers granted coverage between 2005 and 2008. Their policies varied in structure (eg, whether prior authorization was required). All payers reported clinical evidence as the most important factor in decision making, but all used some health care system factors (eg, physician adoption or medical society endorsement) to inform decision making as well. Payers had different perceptions about the strength of clinical evidence at the time of the coverage decision. CONCLUSION Coverage of the 21-gene assay is currently widespread, but policies differ in timing and structure. A key approach private payers use to develop coverage policies for novel technologies is considering both clinical evidence and health care system factors. Policy variation may emerge from the range of factors used and perception of the evidence. Future research should examine the role of health care system factors in policy development and related policy variations.

Biomarker Testing for Breast, Lung, and Gastroesophageal Cancers at NCI Designated Cancer Centers

Purpose:Cell-free DNA (cfDNA) prenatal screening tests have been rapidly adopted into clinical practice, due in part to positive insurance coverage. We evaluated the framework payers used in making coverage decisions to describe a process that should be informative for other sequencing tests.Methods:We analyzed coverage policies from the 19 largest US private payers with publicly available policies through February 2016, building from the University of California San Francisco TRANSPERS Payer Coverage Policy Registry.Results:All payers studied cover cfDNA screening for detection of trisomies 21, 18, and 13 in high-risk, singleton pregnancies, based on robust clinical validity (CV) studies and modeled evidence of clinical utility (CU). Payers typically evaluated the evidence for each chromosomal abnormality separately, although results are offered as part of a panel. Starting in August 2015, 8 of the 19 payers also began covering cfDNA screening in average-risk pregnancies, citing recent CV studies and updated professional guidelines. Most payers attempted, but were unable, to independently assess analytic validity (AV).Conclusion:Payers utilized the standard evidentiary framework (AV/CV/CU) when evaluating cfDNA screening but varied in their interpretation of the sufficiency of the evidence. Professional guidelines, large CV studies, and decision analytic models regarding health outcomes appeared highly influential in coverage decisions.Genet Med advance online publication 22 September 2016

Payer coverage policies for multigene tests

BACKGROUND Molecular biomarkers, a cornerstone of precision oncology, are critical in breast, gastroesophageal, and non-small cell lung cancer management (BC, GEC, NSCLC). Testing practices are intensely debated, impacting diagnostic quality and affecting pathologists, oncologists and patients. However, little is known about testing approaches used in practice. Our study described biomarker practices in BC, GEC, and NSCLC at the leading US cancer centers. METHODS We conducted a survey of the National Cancer Institute (NCI) designated centers on BC, GEC, and NSCLC biomarker testing. We used simple frequencies to describe practices, two-sided Fishers exact test and two-sided McNemars test for cross-cancer comparison. All statistical tests were two-sided. RESULTS For BC human epidermal growth factor receptor 2 (HER2), 39% of centers combine guidelines by using in situ hybridization (ISH) and immunohistochemistry (IHC) concurrently, and 21% reflex-test beyond guideline-recommended IHC2+. For GEC HER2, 44% use ISH and IHC concurrently, and 28% reflex-test beyond IHC2+. In NSCLC, the use of IHC is limited to 4% for epidermal growth factor receptor (EGFR) and 7% for anaplastic lymphoma kinase (ALK). 43.5% test NSCLC biomarkers on oncologist order; 34.5% run all biomarkers upfront, and 22% use a sequential protocol. NSCLC external testing is statistically significantly higher than BC (P < .0001) and GEC (P < .0001). NSCLC internally developed tests are statistically significantly more common than BC (P < .0001) and GEC (P < .0001). CONCLUSIONS At the NCI cancer centers, biomarker testing practices vary, but exceeding guidelines is a common practice for established biomarkers and emerging practice for newer biomarkers. Use of internally developed tests declines as biomarkers mature. Implementation of multibiomarker protocols is lagging. Our study represents a step toward developing a biomarker testing practice landscape.

Availability and payer coverage of BRCA1/2 tests and gene panels

VOLUME 35 NUMBER 7 JULY 2017 NATURE BIOTECHNOLOGY conditions; other analyses have examined coverage for panels including BRCA1/2 (ref. 5), coverage of non-invasive prenatal screening tests6, and the evidence cited in coverage decisions7. Our initial version (Version 1.0) of the registry includes publicly available national policies from the five largest US private (commercial) payers, representing 112 million enrollees8, though these policies do not necessarily reflect regional polices pertaining to particular benefit designs of states, unions, or individual private companies. (To our knowledge, it would be unlikely that such policies would single out multigene tests for separate coverage.) Policies current as of June 2015 were systematically coded by two authors (M.P.D. and P.A.D., with review by a third author K.A.P.) (Supplementary Methods). As noted previously9, policies are contextspecific and thus we classified tests into the following categories: tumor profiling; inherited disease testing for neurologic, cancer, cardiovascular, or biochemical disorders; drug metabolism testing; whole exome or whole genome sequencing; and prenatal testing or carrier testing (Table 2). Policies discuss multigene tests using either a general description for the type of panel (e.g., “cancer susceptibility testing”) or a specific brand name (e.g., “BreastNext”). Tests may be included (‘mentioned’) or not included in a policy. When included, tests can be determined to be covered or not covered. Thus, some tests may have unknown coverage because they are not included or mentioned in a policy. Tests were placed into one of three mutually exclusive categories. 1. Covered when mentioned. Test is covered for at least one indication in that policy and not specifically excluded in any other policy. Multigene tests within the same policy that were covered for some clinical indications but not others were coded as “covered.” 2. Not covered when mentioned. Not covered in any policies that specifically mention the test. Payer coverage policies for multigene tests

Care for a Patient With Cancer As a Project: Management of Complex Task Interdependence in Cancer Care Delivery

CORRESPONDENCE are essential. Increased funding will help but will not be enough. COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. Mark Kessel Mark Kessel is at FIND, Geneva, Switzerland. e-mail: mark.kessel@shearman.com 1. Hwang, T.J., Powers, J.H., Carpenter, D. & Kesselheim, A.S. Nat. Biotechnol. 33, 589–590 (2015). 2. WHO. Global action plan on antimicrobial resistance. (WHO, May 2015). http://www.who.int/drugresistance/ global_action_plan/en/ International Federation of Pharmaceutical Manufacturers & Associations. Rethinking The Way We Fight Bacteria. (IFPMS, April 2015). http://www. ifpma.org/fileadmin/content/Publication/2015/IFPMA_ Rethinking_the_way_we_fight_bacteria_April2015_ FINAL.pdf 4. Davies, S. WISH 2015 policy briefing. Developing an action plan to tackle antimicrobial resistance (AMR): where to start? (World Innovation Summit for Health, 2015). http://dpnfts5nbrdps.cloudfront.net/app/ media/1696 Availability and payer coverage of BRCA1/2 tests and gene panels To the Editor: In recent years, genetic testing for heritable cancer syndromes has been shifting from single-gene analysis to multigene panels, typically using next-generation sequencing (NGS) technologies. As a correspondence in your October issue 1 described, despite the increasing use of NGS in clinical practice, regulatory standards remain vague and payers have not adopted clear coding and reimbursement guidelines 1 . To help clarify the impact of these issues on the availability of testing, we review pricing and payer coverage of BRCA1/2 tests (providing determination of the entire nucleotide sequence for the BRCA1 and BRCA2 genes) and panels containing BRCA1/2 (‘panels’). We find that the number of BRCA1/2-only tests and panels has increased since June 2013, and average price has decreased. Even so, many payers consider panels investigational or experimental, although they have positive coverage policies for BRCA1/2 testing. Although 76% of payers have coverage policies about panels, none of these policies provides positive coverage. Of payers with policies on panels, most (77%) consider panels investigational or experimental, and the remainder limits coverage to those panels on which all the genes are considered medically necessary. The experience with BRCA1/2 may be instructive in understanding the evolution of testing and payer coverage toward multigene panels in other indications as well, particularly those with a substantial patient population eligible for testing. For BRCA1/2 testing, the shift toward gene panels has primarily occurred because the US Supreme Court ruled in June 2013 that companies may not patent isolated genes, thus invalidating five patents held by Myriad Genetics (Salt Lake City, UT, USA) and clearing the way for other laboratories to offer tests with the BRCA1/2 genes 2 . Before June 2013, Myriad was the sole provider of BRCA1/2-only tests for clinical use, other than tests limited to single-site analysis, and there were no commercially available BRCA1/2 panels. The analysis of the BRCA1/2 testing landscape presented here is the first since the historic 2013 Supreme Court decision that allowed the entry of new testing providers. We identified commercially available and soon-to-be-available BRCA1/2- only tests and panels and collected data about the price and scope of testing for each. Because access to genetic tests is considerably influenced by insurance coverage 3,4 , we also reviewed publicly available coverage policies from private payers. Although past studies have demonstrated that most payers cover BRCA1/2 testing in indicated populations in accordance with National Comprehensive Cancer Network guidelines 5–7 , coverage policies have not been examined since the launch of new BRCA1/2-only tests and panels to assess whether and how policies have changed. We identified laboratories offering BRCA1/2 tests and panels through test registries and gray literature (the US National Institutes of Health Genetic Testing Registry, http://www.ncbi.nlm.nih.gov/gtr/; Genetests. org, http://genetests.org; the Association for Molecular Pathology Test Directory, http://www.amptestdirectory.org/index.cfm; Myriad’s integrated BRACAnalysis Price (

Radiology as the Point of Cancer Patient and Care Team Engagement: Applying the 4R Model at a Patient’s Breast Cancer Care Initiation

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