Christine B. Weldon

Barriers to the Use of Personalized Medicine in Breast Cancer

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.

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

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

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

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.

Payer coverage policies for multigene tests

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

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

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 (

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

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

Cancer care is highly complex and suffers from fragmentation and lack of coordination across provider specialties and clinical domains. As a result, patients often find that they must coordinate care on their own. Coordinated delivery teams may address these challenges and improve quality of cancer care. Task interdependence is a core principle of rigorous teamwork and is essential to addressing the complexity of cancer care, which is highly interdependent across specialties and modalities. We examined challenges faced by a patient with early-stage breast cancer that resulted from difficulties in understanding and managing task interdependence across clinical domains involved in this patients care. We used team science supported by the project management discipline to discuss how various task interdependence aspects can be recognized, deliberately designed, and systematically managed to prevent care breakdowns. This case highlights how effective task interdependence management facilitated by project management methods could markedly improve the course of a patients care. This work informs efforts of cancer centers and practices to redesign cancer care delivery through innovative, practical, and patient-centered approaches to management of task interdependence in cancer care. Future patient-reported outcomes research will help to determine optimal ways to engage patients, including those who are medically underserved, in managing task interdependence in their own care.

What do providers, payers and patients need from comparative effectiveness research on diagnostics? the case of HER2/Neu testing in breast cancer

Radiologists aspire to improve patient experience and engagement, as part of the Triple Aim of health reform. Patient engagement requires active partnerships among health providers and patients, and rigorous teamwork provides a mechanism for this. Patient and care team engagement are crucial at the time of cancer diagnosis and care initiation but are complicated by the necessity to orchestrate many interdependent consultations and care events in a short time. Radiology often serves as the patient entry point into the cancer care system, especially for breast cancer. It is uniquely positioned to play the value-adding role of facilitating patient and team engagement during cancer care initiation. The 4R approach (Right Information and Right Care to the Right Patient at the Right Time), previously proposed for optimizing teamwork and care delivery during cancer treatment, could be applied at the time of diagnosis. The 4R approach considers care for every patient with cancer as a project, using project management to plan and manage care interdependencies, assign clear responsibilities, and designate a quarterback function. The authors propose that radiology assume the quarterback function during breast cancer care initiation, developing the care initiation sequence, as a project care plan for newly diagnosed patients, and engaging patients and their care teams in timely, coordinated activities. After initial consultations and treatment plan development, the quarterback function is transitioned to surgery or medical oncology. This model provides radiologists with opportunities to offer value-added services and solidifies radiologys relevance in the evolving health care environment. To implement 4R at cancer care initiation, it will be necessary to change the radiology practice model to incorporate patient interaction and teamwork, develop 4R content and local adaption approaches, and enrich radiology training with relevant clinical knowledge, patient interaction competence, and teamwork skill set.

Company Profile: Center for Business Models in Healthcare

AIMS Comparing effectiveness of diagnostic tests is one of the highest priorities for comparative effectiveness research (CER) set by the Institute of Medicine. Our study aims to identify what information providers, payers and patients need from CER on diagnostics, and what challenges they encounter implementing comparative information on diagnostic alternatives in practice and policy. MATERIALS & METHODS Using qualitative research methods and the example of two alternative protocols for HER2 testing in breast cancer, we conducted interviews with 45 stakeholders: providers (n = 25) from four academic and eight nonacademic institutions, executives (n = 13) from five major US private payers and representatives (n = 7) from two breast cancer patient advocacies. RESULTS The need for additional scientific evidence to determine the preferred HER2 protocol was more common for advocates than payers (100 vs 54%; p = 0.0515) and significantly more common for advocates than providers (100 vs 40%; p = 0.0077). The availability of information allowing assessment of the implementation impact from alternative diagnostic protocols on provider institutions may mitigate the need for additional scientific evidence for some providers and payers (24 and 46%, respectively). The cost-effectiveness of alternative protocols from the societal perspective is important to payers and advocates (69 and 71%, respectively) but not to providers (0%; p = 0.0001 and p = 0.0001). The lack of reporting laboratory practices is a more common implementation challenge for payers and advocates (77 and 86%, respectively) than for providers (32%). The absence of any mechanism for patient involvement was recognized as a challenge by payers and advocates (69 and 100%, respectively) but not by providers (0%; p = 0.0001 and p = 0.0001). CONCLUSION Comparative implementation research is needed to inform the stakeholders considering diagnostic alternatives. Transparency of laboratory practices is an important factor in enabling implementation of CER on diagnostics in practice and policy. The incongruent views of providers versus patient advocates and payers on involving patients in diagnostic decisions is a concerning challenge to utilizing the results of CER.

Do hospitals in a large metropolitan area utilize published breast cancer care practices and guidelines

The Center for Business Models in Healthcare (CBM-HC; IL, USA) is an independent investigator firm conducting health services research and facilitating collaborative interventions focused on personalized medicine and personalized healthcare. CBM-HCs objective is to encourage the adoption of personalized medicine in care delivery and reimbursement. CBM-HCs work focuses primarily on oncology, but also includes autoimmune, cardiovascular and other diseases. CBM-HC conducts studies of barriers to adoption of personalized medicine in care delivery and reimbursement, and facilitates development and implementation of solutions to these barriers in the form of care delivery interventions, and new models of coverage and reimbursement. This work is conducted using the 4R Framework© developed by CBM-HC - Right Information and Right Care to the Right Patient at the Right Time. The framework allows the examination and addressing of complex interdependent barriers to personalized medicine arising from care delivery and reimbursement. CBM-HC conducts its work in collaboration with several noted academic centers and via its network of other stakeholders, including health systems, patient advocates, payers and product developers.