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Being Precise About Precision Medicine: What Should Value Frameworks Incorporate to Address Precision Medicine? A Report of the Personalized Precision Medicine Special Interest Group

Open ArchivePublished:April 01, 2020DOI:https://doi.org/10.1016/j.jval.2019.11.010

      Highlights

      • Various stakeholder groups (eg, developers, regulators, payers, providers, patients) view the value attributes associated with precision medicine in different ways, not all of which are reflected in value assessment models.
      • Value assessment of precision medicine is inconsistent and, in some cases, unclear across different geographies and health technology assessment, bodies, irrespective of some groups articulating approaches. Currently, there is not uniform standard, which has potential to result in variable patient access to precision medicine.
      • Rapid expansion of diagnostic testing, including evolution of next-generation testing, whole genome and exome testing and integration of evidence with machine learning are also key areas that health technology assessment, processes will need to adapt around.

      Abstract

      Precision medicine is a dynamic area embracing a diverse and increasing type of approaches that allow the targeting of new medicines, screening programs or preventive healthcare strategies, which include the use of biologic markers or complex tests driven by algorithms also potentially taking account of patient preferences. The International Society for Pharmacoeconomics and Outcome Research expanded its current work around precision medicine to (1) describe the evolving paradigm of precision medicine with examples of current and evolving applications, (2) describe key stakeholders perspectives on the value of precision medicine in their respective domains, and (3) define the core factors that should be considered in a value assessment framework for precision medicine. With the ultimate goal of improving health of well-defined patient groups, precision medicine will affect all stakeholders in the healthcare system at multiple levels spanning the individual perspective to the societal perspective. For an efficient, timely and practical precision medicine value assessment framework, it will be important to address these multiple perspectives through building consensus among the stakeholders for robust procedures and measures of value aspects, including performance of precision mechanism; aligned reimbursement processes of precision mechanism and subsequent treatment; transparent expectations for evidence requirements and study designs adequately matched to the intended use of the precision mechanism and to the smaller target patient populations; recognizing the potential range of value-generation such as ruling-in and ruling-out decisions.

      Keywords

      Introduction

      Precision medicine means many things to many people. The concept and terminology “personalized medicine” has existed since 1995, but recently precision medicine has become a ubiquitous term.
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      Personalized medicine.
      ,
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      Personalized medicine in diabetes: the role of 'omics' and biomarkers.
      Tailoring the practice of medicine better to use known heterogeneity among individuals has been facilitated by advances such as gene sequencing, computational approaches for large datasets, and linkage of genomic data with longitudinal data.
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      Disease risk factors identified through shared genetic architecture and electronic medical records.
      Public funding streams, such as those supporting large scale research programs in Canada
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      as well as private funding streams, such as IBM Watson
      IBM
      IBM Watson for Genomics.
      and Human Longevity,
      Human Longevity.
      are working toward broadening the role of precision medicine in clinical practice. Precision medicine is a dynamic and changing area that has transformational systems potential and is increasingly influencing patient care.
      The premise of this article is that a robust evidence base is necessary to inform reimbursement and appropriate use of precision medicine in clinical practice. This article builds on initial work of the Precision Medicine Special Interest Group to define core issues in value demonstration.
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      In response to the growing complexity in precision medicine, the International Society for Pharmacoeconomics and Outcome Research expanded its work on this topic to cover the following three objectives:
      • Describe the evolving paradigm of precision medicine with examples of current and evolving applications;
      • Describe key stakeholders and their associated perspectives, who have an interest in understanding the potentially unique value of precision medicine in their domains;
      • Suggest indicative core factors that should be considered in a value framework that includes assessment of precision medicine.

      Precision Medicine: Evolving Definitions, Understanding, and Applications

      The terms precision, personalized, stratified, and individualized medicine are related terms, with evolving use across multiple disciplinary domains,
      • Pearson E.R.
      Personalized medicine in diabetes: the role of 'omics' and biomarkers.
      yet no interdisciplinary consensus has been reached on formal definitions. The lack of specificity around the meaning of these terms has resulted in different stakeholders loosely using whichever term that is “fashionable” or familiar. While there have been many suggestions
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      for how to define terms in this space, there is no consensus at a clinical practice or policy level.
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      “Personalized medicine”: what’s in a name?.
      Overall, use of terminology in this area is highly variable, with some stakeholders using terms interchangeably and others feeling strongly about specific meanings, but few terms have stuck more than personalized medicine or precision medicine. It is beyond the scope of this article to formulate specific definitions that would be agreed upon by all stakeholders, but helpful to describe specific uses for these different terms for broader discussion.
      A fundamental dimension of precision or personalized medicine is identification of subtypes of diseases, most often viewed as driven by knowledge of molecular biomarkers that influence disease presentation,
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      although some may include patient preferences in definitions.
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      ,
      Genetics Home Reference
      What is the difference between precision medicine and personalized medicine? What about pharmacogenomics?.
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      Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers.
      Precision medicine, can involve the use of genomics, biomarkers, or algorithms for different purposes: disease or therapy risk assessment, screening, prognosis, diagnosis, treatment selection, and surveillance or monitoring. Precision medicine has also been used to describe strategies, such as pharmacogenomics, that help better target patient care using known individual characteristics.
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      A less frequently used term is stratified medicine, where success has been found in tailoring treatment to a specific patient subgroup with common molecular characteristics.
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      Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers.
      However, truly individualized medicine is only feasible in limited situations (eg, gene and cell therapies).
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      • Hall A.
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      • Burton H.
      “Personalized medicine”: what’s in a name?.
      ,
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      In the absence of a clear definition, we use the umbrella term precision medicine in this article to mean the use of molecular or other biomarkers (or related algorithms) that characterize differential disease risk, severity or ability to apply targeted treatment approaches to a defined subpopulation of patients.

      Expanding Patient Data and Knowledge of Biomarkers Leads to Greater Decision Complexity

      The underlying premise supporting precision medicine is the ability to leverage known heterogeneity in a population of patients to improve patient management and outcomes. A defined strategy, or mechanism, is therefore required to realize the application in practice. Such strategies could be a single diagnostic test, for example use of polymerase chain reaction to test for a specific mutation in a tumor (eg, epidermal growth factor receptor tyrosine kinase mutation), prioritizing the use of specific treatments (eg, gefitinib). More recently, however, our knowledge of biomarkers is driving us toward broader tests that include dozens or hundreds of genetic variants, often requiring sophisticated algorithms for interpretation and use.
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      Evaluation of a stratified national breast screening program in the United Kingdom: an early model-based cost-effectiveness analysis.
      With significant developments in new “liquid” detection technologies (that use blood samples rather than tissue), such variants can be identified quickly and with increasing affordability, allowing precise treatment monitoring.
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      As our knowledge continues to grow and become interconnected, precision medicine will further change how we manage patient decisions. Table 1 illustrates some example strategies used in precision medicine, showing increasing levels of complexity.
      Table 1Examples of strategies used to deliver precision medicine in practice.
      StrategyExampleUnderlying PremiseFocus of Strategy
      Single genetic testDetection of TMPT genetic mutationGenetic variations in drug metabolizing enzyme affect risk of adverse effectsTo identify individuals at risk of profound neutropenia from azathioprine
      Single genetic testDetection of EGFR-TK genetic mutationGenetic variations in solid tumor affect response to treatmentsTo identify individuals with lung cancer who will respond to gefitinib
      Next generation sequencingFoundationOne CDx to detect genetic mutation in one of 324 genes

      Multi-marker tests with ability to estimate tumor mutational burden (TMB) or microsatellite instabiliity
      Genetic variations in solid tumors affect response to treatments.To select relevant targeted therapies for the treatment of a range of cancers
      Gene panel testDiagnostic test for hereditary diseases such as cancer, many rare diseases, and retinal dystrophiesGenetic variation in specific germlineTo diagnose the genetic cause of inherited retinal dystrophies. Currently no treatments are available but gene therapies are in development for specific genetic mutations
      Gene expression profiling testOncotype DX including approximately 30 genesGenetic variations in solid tumors affect the risk of tumor recurrence.To identify the risk of tumor recurrence in early stage breast cancer patients who are hormone receptor positive and their need for systemic anticancer chemotherapy, based on the risk of recurrence
      Risk-prediction algorithmTyrer-Cuzick algorithmGenetic mutations affect the risk of developing diseases such as cancer.BRCA-gene mutation or single nucleotide variant information are incorporated into traditional risk-prediction algorithms based on age, age at menarche, height, weight, parity, menopausal status, use of HRT and family history information to inform the relevant screening interval as part of a risk-based national breast screening program.
      Prescribing algorithm‘Biologic calculator’Genetic variation in addition to factors including: activity of immune system, intake of alcohol and smoking, family history, sex and age affect response to a biologicTo inform the selection and dose of the appropriate biologic for individuals with an auto-immune condition. Currently research context only.
      EGFR_TK indicates epidermal growth factor receptor tyrosine kinase.
      Our expanding knowledge of biomarkers and the interconnections among them is enabling development of more complex tests sometimes embedded into algorithms. Specific diseases, such as non-small cell lung cancer now have multiple tests available, including epidermal growth factor receptor tyrosine kinase, BRAF, anaplastic lymphoma kinase (ALK), and programmed death-ligand 1, which can support selection of specific medicines. Where applicable, single biomarker tests are being replaced by multi-marker genomic tests. For example, one of the tests that has helped usher in a wave of broader molecular tests, Oncotype DX, uses gene expression profiling of 21 markers to assess early stage breast cancer patients for risk of recurrence, informing use of adjuvant chemotherapy.
      • Carlson J.J.
      • Roth J.A.
      The impact of the Oncotype Dx breast cancer assay in clinical practice: a systematic review and meta-analysis.
      ,
      • Sparano J.A.
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      • et al.
      Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer.
      More recently, a 324 gene panel test using next-generation sequencing (NGS), FoundationOne, detects a range of variants to inform a number of care decisions. We are also beginning to consider the implications of different testing platforms, scenarios where nonconcordance of results may occur, and risks of testing that may influence care management.
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      The case for more active policy attention to health promotion.
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      • et al.
      Identification of factors that may influence the selection of first-line biological therapy for people with psoriasis: a prospective, multicentre cohort study.
      Advances in NGS are opening the door to interrogation of the entire human genome and exome. Although the cost of sequencing continues to drop, the cost and complexity of implementation in primary care settings are not well described and not yet routinely used in clinical practice, but a focus of intensive ressearch.
      • Christensen K.D.
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      • Siebert U.
      • Green R.C.
      Assessing the costs and cost-effectiveness of genomic sequencing.
      Clinical practice is beginning to see integration of complex biomarker platforms with population-based data and “smart” decision analytic platforms. Some applications combining testing using NGS with artificial intelligence and machine learning may ultimately have the potential to help chart entire clinical pathways. Vanguard efforts such as IBM’s Watson, Human Longevity’s Health Nucleus, and Cyft Analytics represent different approaches attempting to incorporate our expanding biomarker data into decision platforms.

      Faulkner E, Poulios N, Husereau D, Zah V. Valuing precision: how will next generation diagnostics change the landscape for HEOR and patient management? Paper presented at: International Society for Pharmacoeconomics and Outcomes Research 21st Annual International Congress; May, 2017; Boston, MA.

      ,

      Shah F, Payne K, Faulkner E, Siebert U, Shandu G, Barr C. Generating evidence of the added value of precision medicine. ISPOR Forum. Paper presented at: International Society for Pharmacoeconomics and Outcomes Research, 19th Annual European Congress; October, 2016; Vienna, Austria.

      This evolving complexity in the delivery of precision medicine must be considered in value assessment. The more we progress toward integrating precision mechanisms into the standard clinical processes, the greater the requirement will be for equitable patient access and approaches that measure and value all components of precision medicine.

      Linking Stakeholder Perspective to Value Assessment for Precision Medicine

      The adoption of precision medicine will affect all stakeholders and touch many health systems levels. This will include individual-level perspectives through societal perspectives (Table 2). Stakeholders will have their own definition of value and requirements for acceptance and uptake. All stakeholders desire technologies to be backed by evidence but there are likely to be variable views on what constitutes “sufficient” or “high quality” evidence, and these elements should be considered in the context of value assessment.
      Table 2Value drivers, gaps and challenges, and opportunities for stakeholders in precision medicine.
      Stakeholder TypeValue Drivers for Precision MedicineGaps and ChallengesOpportunities for HEOR and Access Solutions
      Patient-Level Perspective
      The patient perspective is simultaneously simple and complex. The patient perspective can be considered at the individual level or at the level of a collective view from patient groups. Patients make decisions about their own care and seek clear diagnosis and selection of the most appropriate and effective treatment that improve the chances for favorable outcomes. Challenges remain in describing the broader value of precision medicine to the patient at the collective level and shared decision-making at the individual level that incorporates patient individual preferences and personal tradeoffs in value and benefit/risk.
      Patient
      • Accurate, timely diagnosis
      • More certain and more favorable treatment outcomes “Will I get better?” and “Can I be my best?”
      • Greater confidence in health decisions
      • Inclusion of personal preferences and tradeoffs
      • Value of knowing (eg, rare disease)
      • Improvement of quality of life
      • Improved decisions that lead to improved outcomes (eg, survival, toxicities)
      • Access to clinical trials
      • Timely access, affordability, uncertainty of reimbursement across provider or insurers
      • Potential harm resulting from data sharing or lapses in data security
      • Impact of personal genetic information on family members and relatives
      • Incomplete or lack of knowledge of implications of biomarkers
      • Incomplete or lack of understanding of risk prediction and interpretation
      • Incomplete or lack of understanding of differences among treatment options
      • Preparedness for prognostic features and future insurance coverage (ability to provide truly informed consent)
      • Patient preferences not systematically taken into account
      • Value assessment that takes patient perspectives (both qualitative and quantitative preferences) into account in certain scenarios (eg, knowledge of long-term risk for degenerative or fatal conditions)
      • New approaches to consent and data sharing
      System-Level Perspective
      The healthcare system comprises five key stakeholders: Life Sciences Industry Developers, Providers (including Hospital or Health Systems), Regulators, Agencies Conducting the Value Assessment, and Payers. Although all these stakeholders are notionally working to a common purpose, the provision of healthcare to defined patient populations, there still exist differences in the individual objectives of each of these stakeholders.
      Providers (eg, prescribing clinicians)Best evidence-based practice:
      • Accurate diagnosis along with other decision inputs
      • More certain, less risky, and improved treatment outcomes
      • Greater confidence in health decisions
      • Consistent evidence of tests value
      • Interpretation of some tests
      • Increasing number and complexity of available tests
      • Knowledge of tradeoffs associated with different available tests
      • Timely access to tests
      • Uncertainty on reimbursement for diagnostic tests owing to payer reimbursement hurdles
      • Provider-level value communications on available tests
      • Comparative evidence of available tests
      • Evidence-based decision support on test use and interpretation
      Hospital or Health System
      • Quality patient care and facility/system reputation
      • Effective treatment outcomes
      • Financial efficiency
      • Avoidance of malpractice suits
      • Lack of certainty of test reimbursement
      • Limited information on clinical pathway and financial impacts of available tests
      • To define an internal (hospital based) and external (ie, regional/national) organizational model
      • To define criteria and services to guarantee and monitor the follow-up of patients
      • Accessibility of samples/data across in/out-services
      • Studies of provider-level impacts of testing on patient management and operational efficiencies
      • Real-world evidence (RWE) of the value of clinical pathways
      Life Science Industry
      • Ability to identify certain patients as candidates for/better responders to certain therapeutic applications based on genetic or other biomarker status
      • Ability to enable stronger outcomes in patient subsets based on patient genetics or other biomarker status
      • Improved potential ability to gain acceptance versus broader population strategies with more dilute outcomes
      • Unclear reward mechanism for diagnostic component of precision medicines
      • Insufficient transparency for clinical and economic requirements for precision medicine, particularly more complex scenarios
      • Insufficient agreement on Dx study design under different test application scenarios
      • Variable integration of test evidence in assessment of the precision mechanism
      • Uncertainty of reimbursement for diagnostic test component of precision medicine
      • Funding for diagnostic tests
      • Enhanced understanding and acceptance of those attributes of precision medicine that may not be appropriately considered in value assessment, access, and uptake decisions
      • Increased homogeneity of evidence and access requirements, and greater transparency and insight into decision context
      • Clarity of acceptable approaches that begin to involve complex multi-marker tests
      • Clearer alignment between health technology assessment process and reimbursement channels
      Regulator
      • Improving safety and efficacy of health technologies
      • Identify sub-groups of patients (responders, non-responders, safety risk, etc.)
      • Differentiation of companion diagnostic and stand-alone precision scenarios and therapeutic decision in terms of evidence requirements
      • Lack of clear and aligned regulatory processes for the constituent components of precision medicine
      • Increasing use of diagnostics to enable basket studies that “shotgun” across multiple disease areas
      • Rapid entry of tests with various numbers of biomarkers
      • Limited experience with emerging scenarios combining test data with AI, machine learning, and decision algorithms
      • Clear framework for when co-diagnostic scenarios are or are not appropriate
      • An integrated framework for companion diagnostics and treatment strategies including aligned incentives for both manufacturers of diagnostics and therapies
      • Understand new test safety and effectiveness compared with other available tests or test/treat scenarios in real life application
      • Identify opportunities for test/treatment improvements after-market authorization through real world evidence
      Agency Conducting Value Assessment
      • Improving clinical effectiveness of health technologies
      • Confirming cost-effectiveness of health technologies
      • Lack of understanding of evidence issues unique to diagnostics
      • Inconsistency of evidence frameworks for diagnostics
      • Lack of specificity of evidence expectations for different test applications
      • Inconsistent standards for demonstrating clinical utility
      • Some markets have channels that evaluate tests separately from treatments in precision medicine scenarios
      • Limits on appropriately integrating diagnostic information in precision medicine assessment in some markets
      • Lack of clarity or consistency of evidence expectations for emerging complex next-generation tests
      • Uncertainty around emerging precision medicine-driven basket studies that “shotgun” across multiple disease areas
      • Rapid entry of tests with various numbers of biomarkers and substantial variability in supporting evidence
      • Lack of clarity on value demonstration requirements for complex tests that involve hundreds of biomarkers
      • Concerns about patient treatment implications, risks, and ethical consideration for tests that expand to hundreds of biomarkers or more (including whole genome sequencing)
      • Concerns about diagnostics driving unnecessary spending (for workup or treatment)
      • Limited experience with emerging scenarios combining test data with AI, machine learning, and decision algorithms
      • Need for value frameworks or adaptations to existing processes that properly address precision medicine
      • Need for value frameworks or adaptations to existing processes that appropriately consider various test applications
      • Clarification of value expectations for scenarios of use of single-marker precision tests versus broader panel tests for precision medicine decisions
      • Clarification of expectations and development of adapted HEOR approaches for emerging scenarios (eg, basket trials, broadening test panels, integration of Dx with AI and decision support)
      Payer
      • Improving clinical effectiveness of health technologies
      • Achieving cost-effectiveness of health technologies
      • Managing efficient patient access across beneficiary population
      • Fiscal certainty in health spending – predict budget impact
      • Ability to cleanly tie access and reimbursement to biomarkers
      • Funding for diagnostics tests
      • In general, similar to the agency delivering the value assessment framework gaps and challenges noted above
      • Concerns about safety, financial and ethical implications of approving insufficiently validated and complex diagnostics
      • Broad heterogeneity of evidence supporting diagnostics
      • Overuse or underuse of testing
      • Uncertainty of test actionability (eg, some risk assessment or prognostic test panels not directly connected to action steps)
      • Concerns about growing financial implications of testing
      • Broad coding for diagnostics makes it difficult to track and evaluate use of individual tests
      • Lack of value-based payment models for diagnostics or the test-component of precision medicines
      • Need for value frameworks or adaptations to existing processes that properly address precision medicine
      • Need for value frameworks or adaptations to existing processes that appropriately consider various test applications
      • Clarification of value expectations for scenarios of use of single marker precision tests versus broader panel tests for precision medicine decisions
      • Clarification of expectations and development of adapted HEOR approaches for emerging scenarios (eg, basket trials, broadening next generation test panels, integration of Dx with AI and decision support)
      • New HEOR approaches that consider clinical pathway implications and outcomes of test use
      • Tools to tie pricing/reimbursement to (bio)markers
      Societal Perspective
      The societal perspective can be constrained to a national point of view, or extended to consider the global impact of precision medicine, but for purposes of this paper represents a policy perspective. This policy perspective may be influenced by perspectives and objectives of the system-level stakeholders. At the global level, rapidly expanding research in precision medicine may increase the gap between developed and emerging health systems.
      • Estape E.S.
      • Mays M.H.
      • Sternke E.A.
      Translation in data mining to advance personalized medicine for health equity.
      ,
      • Joly Y.
      • Saulnier K.M.
      • Osien G.
      • Knoppers B.M.
      The ethical framing of personalized medicine.
      Policy Makers
      • Safe, effective, and clear health policies
      • Fiscal responsibility in health spending
      • Protection of patient rights
      • Limited understanding of patient perspectives on use of tests
      • Limited knowledge of the impact of testing on health efficiencies and outcomes
      • Competing pressures for health policy issues that may not prioritize impact of testing
      • Development of an evidence-based multicriteria decision-making framework that encompasses the range of diagnostic applications and variability of test entries to inform policy decisions
      • Landscape implications of new testing to inform precision of patient management & clinical pathways/resource use
      • Evidence of the value of convergence of diagnostics with AI/machine learning and implications for policymaking at the system- and societal-level
      Note. By test applications, we refer to the different uses of tests including prediction, screening, diagnosis, treatment selection, and monitoring. Constituents of precision medicine include the diagnostics, the therapeutic choices, the prescribing algorithm, and possible clinical pathways.
      AI indicates artificial intelligence; HEOR, health economics and outcomes research.
      Although there are many commonalities among stakeholder goals (eg, safer, more effective, and affordable care), there are also significant differences both across and within stakeholder groups. The following section provides a brief overview of key stakeholder perspectives. It is based on an overview of ongoing debate in the scientific literature and via professional societies in the decade until 2019.
      The patient-level can be considered at the level of an individual patient or patient group. This level is likely to reflect preferences of the specific example of precision or the harms and benefits (disutilities or utilities) related to outcomes.
      • Rogowski W.
      • Payne K.
      • Schnell-Inderst P.
      • et al.
      Concepts of ‘personalization' in personalized medicine: implications for economic evaluation.
      However, test results can pose a dilemma at the individual level where a specific patient does not want to understand genetic status (eg, risks for Alzheimer or Huntington disease)
      Genetic Alliance UK
      Taking the patient and family perspective to the centre of genomic sequencing policy-making.
      ,
      • Mendes A.
      • Metcalfe A.
      • Paneque M.
      • Sousa L.
      • Clarke A.J.
      • Sequeiros J.
      Communication of information about genetic risks: putting families at the center.
      particularly in absence of effective treatment. This can be compounded by factors like poor awareness, communication, or health literacy.
      • Budin-Ljosne I.
      • Harris J.R.
      Patient and interest organizations' views on personalized medicine: a qualitative study.
      Patient groups have requested that adoption of precision medicine is accompanied by equitable access policies.
      • Schleidgen S.
      • Klingler C.
      • Bertram T.
      • Rogowski W.H.
      • Marckmann G.
      What is personalized medicine: sharpening a vague term based on a systematic literature review.
      ,
      • Budin-Ljosne I.
      • Harris J.R.
      Patient and interest organizations' views on personalized medicine: a qualitative study.
      • Estape E.S.
      • Mays M.H.
      • Sternke E.A.
      Translation in data mining to advance personalized medicine for health equity.
      • Joly Y.
      • Saulnier K.M.
      • Osien G.
      • Knoppers B.M.
      The ethical framing of personalized medicine.
      • Salari P.
      • Larijani B.
      Ethical issues surrounding personalized medicine: a literature review.
      Some policy protections have already emerged, such as the Genetic Information Non-discrimination Act in the United States.

      110th Congress. Genetic Nondiscrimination Act of 2008, Pub. L. 110-223, 122 Stat. 881. 2008.

      Truly patient-centered policies would link therapies to personal treatment goals and enable input of patient groups.
      • Daack-Hirsch S.
      • Campbell C.A.
      The role of patient engagement in personalized healthcare.
      There is also a move toward active patient input at all stages of the precision medicine life cycle.
      • Cook N.S.
      • Cave J.
      • Holtorf A.P.
      Patient preference studies during early drug development: aligning stakeholders to ensure development plans meet patient needs.
      • Facey K.M.
      • Bedlington N.
      • Berglas S.
      • Bertelsen N.
      • Single A.N.V.
      • Thomas V.
      Putting patients at the centre of healthcare: progress and challenges for health technology assessments.

      Holtorf A-P CN. The Role of Patients in Market Access. In: Koçkaya G, Wertheimer AI, editors. Pharmaceutical Market Access in Developed Markets. http://books.seedmedicalpublishers.com/index.php/seed/catalog/view/Pharmaceutical_MA_developed/PDF/747.ch18.

      US Food Drug Administration (FDA)
      Patient-focused drug development: collecting comprehensive and representative input. Guidance for industry. Food and Drug Administration staff, and other stakeholders draft guidance.
      At the system-level multiple stakeholder types have a role in of precision medicine adoption, including manufacturers, providers, regulators, health technology assessment (HTA), agencies, and payers. Most system-level stakeholders view higher certainty of linking the right patient to the right treatment at the right time as the key benefit of precision medicine. However, system players place differential emphasis on certain value attributes of precision medicine (Table 2). For example, payers and policy makers would more heavily integrate value for money as a key benefit of precision medicine.
      Precision medicine involves the participation of established industries who already work within the healthcare market, such as pharmaceutical or diagnostic industries, but also new players, such as information technology industries, working to deliver decision support or news to patients. For these industries, precision medicine may offer opportunities, such as focused value propositions, efficient clinical trials, reduced development risk, new treatment targets, or high-margin markets. However, each of these opportunities requires evidence that suggested benefits are realized in practice.
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      • et al.
      Translational research: precision medicine, personalized medicine, targeted therapies: marketing or science?.
      For regulatory approval there is a lack of aligned processes for the constituent components of precision medicine, which causes substantial uncertainty in the potential for return on investment.
      • Fugel H.J.
      • Nuijten M.
      • Postma M.
      Stratified medicine and reimbursement issues.
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      • Ruzicic A.
      Personalized medicine at crossroads.
      • Luo D.
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      • Meadows N.A.
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      A quantitative assessment of factors affecting the technological development and adoption of companion diagnostics.
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      • Leonard D.
      Codevelopment of genome-based therapeutics and companion diagnostics: insights from an Institute of Medicine roundtable.
      • Ou S.H.
      • Soo R.A.
      • Kubo A.
      • Kawaguchi T.
      • Ahn M.J.
      Will the requirement by the US FDA to simultaneously co-develop companion diagnostics (CDx) delay the approval of receptor tyrosine kinase inhibitors for RTK-rearranged (ROS1-, RET-, AXL-, PDGFR-alpha-, NTRK1-) non-small cell lung cancer globally?.
      • Payne K.
      Fish and chips all round? Regulation of DNA-based genetic diagnostics.
      • Shabaruddin F.H.
      • Fleeman N.D.
      • Payne K.
      Economic evaluations of personalized medicine: existing challenges and current developments.
      The advent of tests using NGS is likely to compound regulatory approval of precision medicines. Such issues suggest need for modernized approval mechanisms to guide the required evidence base and address evolving development scenarios.
      • Bertier G.
      • Carrot-Zhang J.
      • Ragoussis V.
      • Joly Y.
      Integrating precision cancer medicine into healthcare-policy, practice, and research challenges.
      • Braff J.P.
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      • et al.
      Patient-tailored medicine, part two: personalized medicine and the legal landscape.
      • Craig P.
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      • Macintyre S.
      • Michie S.
      • Nazareth I.
      • Petticrew M.
      Developing and evaluating complex interventions: new guidance.
      HTA and payer evaluations are even more complex and variable, because there are many more groups involved. Lack of homogenous expectations, resulting from varying national priorities and cultural differences, has resulted in different HTA recommendations on the same intervention. One example is inclusion of epidermal growth factor receptor testing before gefitinib treatment. The manufacturer submitted cost-effectiveness estimates of £23 615 per quality-adjusted life-year (QALY) and the National Institute for Health and Care Excellence in England estimated cost per additional QALY at £35 700 while the Scottish Medicines consortium estimated £154 022 per additional QALY resulting in an acceptance and rejection from the same data.
      NICE
      Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer.
      ,
      Scottish Medicines Consortium
      ADVICE following a resubmission for gefitinib (Iressa).
      Such discrepancies are not unique to precision medicine, but reflect challenges to moving innovations to market. As NGS expands, the challenges associated with producing robust evidence of costs and consequences are manifold and are likely to require specific considerations.
      • Faulkner E.
      • Annemans L.
      • Garrison L.
      • et al.
      Challenges in the development and reimbursement of personalized medicine-payer and manufacturer perspectives and implications for health economics and outcomes research: a report of the ISPOR personalized medicine special interest group.
      ,
      • Payne K.
      • Eden M.
      • Davison N.
      • Bakker E.
      Toward health technology assessment of whole-genome sequencing diagnostic tests: challenges and solutions.
      At the societal-level, some aspects of precision medicine such as ethical and legal implications of patient biomarker information and the push-pull incentives of ensuring population-level equity and access to care are more pronounced in precision medicine versus other technology applications. There are already substantial discrepancies in access to and quality of healthcare around the globe and some concern that introduction of precision may further widen disparities in availability and access.
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      Patient and interest organizations' views on personalized medicine: a qualitative study.
      ,
      • McClellan K.A.
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      Personalized medicine and access to health care: potential for inequitable access?.
      Although it likely infeasible to address the nuances of each stakeholder perspective, commonalities and exceptions should be carefully considered in evolving a value assessment framework that incorporates issues specific to precision medicine. The following highlights key scenarios that may apply to addressing precision medicine in value frameworks.

      Toward Integrating Precision Medicine into Existing Value Assessment Frameworks

      Value assessment frameworks have now become embedded in different countries and jurisdictions, such as the United States (eg, Institute for Clinical and Economic Review), the United Kingdom.
      ISPOR
      ISPOR announces new initiative on value assessment frameworks.
      Professional societies such as the European Society for Medical Oncology, the American Society of Clinical Oncology, and International Society for Pharmacoeconomics and Outcomes Research, Inc (ISPOR) have developed their own specific value-frameworks.
      • Cherny N.I.
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      • et al.
      A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).
      • Garrison Jr., L.P.
      • Pauly M.V.
      • Willke R.J.
      • Neumann P.J.
      An overview of value, perspective, and decision context-a health economics approach: An ISPOR special task force report [2].
      • Lakdawalla D.N.
      • Doshi J.A.
      • Garrison Jr., L.P.
      • Phelps C.E.
      • Basu A.
      • Danzon P.M.
      Defining elements of value in health care-a health economics approach: an ISPOR special task force report [3].
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      • et al.
      American Society of Clinical Oncology statement: a conceptual framework to assess the value of cancer treatment options.
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      Review of recent US value frameworks-a health economics approach: an ISPOR special task force report [6].
      The basic premise of a value assessment framework is to provide a set of methods, underpinned by HTA, and processes to evaluate the benefits and risks, and in some instances costs and added value of healthcare interventions.
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      There is variability among published value assessment frameworks and processes to deliver them, owing to factors, such as perceptions, decision context, validity and reliability, and transparency. Sources and implications of variability are amplified when considering complex interventions (eg, precision medicines) involving variable understanding and agreement on technology language, value drivers and assessment needs.
      To design value-frameworks for each new type of technology is not practical for agencies who must assess the flood of technologies flowing through evaluation processes and be cognizant of opportunity cost of healthcare service provision. A nontechnology specific approach may however limit acceptance and uptake of innovator technologies that have potential to unlock system efficiencies. Although a generic value assessment framework is likely to be preferred, ideally it should take into account unique value attributes of technology types such as precision medicine.
      Most evaluation processes for precision medicines remain rudimentary for addressing evolving complexity in this space, and there is a literature illustrating challenges.
      • Annemans L.
      • Redekop K.
      • Payne K.
      Current methodological issues in the economic assessment of personalized medicine.
      ,
      • Degeling K.
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      A systematic review and checklist presenting the main challenges for health economic modeling in personalized medicine: towards implementing patient-level models.
      It has frequently been argued that value assessment frameworks have not optimally incorporated the impact of diagnostics.

      Faulkner E, Poulios N, Husereau D, Zah V. Valuing precision: how will next generation diagnostics change the landscape for HEOR and patient management? Paper presented at: International Society for Pharmacoeconomics and Outcomes Research 21st Annual International Congress; May, 2017; Boston, MA.

      ,
      • Garfield S.
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      • D SS
      • et al.
      Health technology assessment for molecular diagnostics: practices, challenges, and recommendations from the medical devices and diagnostics special interest group.
      ,
      • Pitini E.
      • De Vito C.
      • Marzuillo C.
      • et al.
      How is genetic testing evaluated? A systematic review of the literature.
      Value frameworks have been developed for evaluating genetic testing in the United States (eg, the Analytic validity, Clinical validity, Clinical utility and Ethical, legal and social implications framework)
      and United Kingdom (eg, the Gene Dossier); however, they either do not cover broad evidence-related issues of precision medicine highlighted herein or have faced inconsistent uptake.
      • Cohen J.T.
      • Anderson J.E.
      • Neumann P.J.
      Three sets of case studies suggest logic and consistency challenges with value frameworks.
      ,
      • Mandelblatt J.S.
      • Ramsey S.D.
      • Lieu T.A.
      • Phelps C.E.
      Evaluating frameworks that provide value measures for health care interventions.
      Variability across markets and systems also creates uncertainty on the appropriate evidence package required and increases heterogeneity in patient access.
      • Philipson T.J.
      • Sun E.
      Blue pill or red pill: the limits of comparative effectiveness research.
      Importantly, existing value assessment frameworks for genetic tests are not consistent with methods used for other healthcare technologies, such as pharmaceuticals that take account of opportunity cost.
      • Faulkner E.
      • Spinner D.
      • Ransom J.
      Developing appropriate evidence for demonstrating the value of diagnostics: where are we now and what is appropriate for the future state?.

      Garfield S, Faulkner E, Potsulka A, Berndt K. Navigating a changing landscape: the next generation of diagnostic reimbursement and healthcare management models. Paper presented at: International Society for Pharmacoeconomics and Outcomes Research, 17th Annual European Congress; November 2014; Amsterdam, Netherlands.

      The purpose of this article is to highlight key areas that a value assessment framework involving precision medicine should acknowledge. It is beyond the scope of this document to propose a specific framework for precision medicine, but to encourage integration of core components that should be considered in precision medicine value assessment or are currently missing from existing frameworks.

      Proposed Core Components of a Value Assessment Framework Relevant to Precision Medicine

      The issues below reflect a broader view of the current and future evidence needs and gaps associated with precision medicine that appropriate value assessment processes would consider. Other considerations such as the value of knowing, value of hope, real option value, and other factors have been discussed elsewhere in a similar context.
      • Towse A.
      • Garrison L.
      Value assessment in precision cancer medicine.
      If the value assessment framework extends beyond the typical use by HTA agencies, additional consideration may include items, such as fit with existing reimbursement mechanisms and use in clinical practice. These are important considerations in a comprehensive value assessment framework for precision medicine and will be worthy of exploration beyond this article.

      Incorporating the Performance of the “Precision” Mechanism

      The performance (sensitivity, specificity, positive, and negative predictive value) of the precision mechanism, such as a diagnostic test or algorithm, establishes analytic and clinical validity with significant implications for the clinical utility of precision medicine. Potential for false positive or false negative results can provoke inaccurate care decisions leading to unnecessary testing, suboptimal treatment, avoidable side effects, disease progression or even mortality, and avoidable costs. Although being one of the most fundamental value drivers for precision medicine, uncertainty around test performance is often not considered by agencies administering value assessment frameworks.
      • Faulkner E.
      • Ransom J.
      • Briggs G.
      • Hanna J.U.S.
      managed care perspectives on assessment and uptake of molecular diagnostics: state of the union and areas for additional improvement.
      This is particularly important, as the number needed to test can influence the therapy decision and cost-effectiveness. Other factors such as penetrance, pathogenicity, linkage to patient management and outcomes.
      • Faulkner E.
      • Spinner D.
      • Ransom J.
      Developing appropriate evidence for demonstrating the value of diagnostics: where are we now and what is appropriate for the future state?.
      ,
      • Faulkner E.
      • Ransom J.
      • Briggs G.
      • Hanna J.U.S.
      managed care perspectives on assessment and uptake of molecular diagnostics: state of the union and areas for additional improvement.
      Beyond performance, consensus on what evidence base is sufficient to characterize clinical utility of diagnostics, remains a key challenge.

      Tighter Alignment of Evidence and Reimbursement of the Precision Mechanism and Subsequent Treatment/Management

      Due to historically different decision pathways, agencies may review the “diagnostic” and the “therapeutic” element of a precision medicine separately and different methods or processes for HTA or funding pools for each element are applied. Without integration of evaluation and reimbursement models, there are risks for variable and disconnected assessment of the evidence supporting different elements and if either the medicine or diagnostic is rejected, inadvertent patient access limitations. A more integrated evaluation process should consider implications of using a precision medicine across the care pathway.
      The disconnect between study designs and reimbursement in the precision medicine arena has been broadly by the ISPOR Precision Medicine Special Interest Group and ISPOR Medical Devices and Diagnostics Special Interest Group over the past several years.
      • Faulkner E.
      • Annemans L.
      • Garrison L.
      • et al.
      Challenges in the development and reimbursement of personalized medicine-payer and manufacturer perspectives and implications for health economics and outcomes research: a report of the ISPOR personalized medicine special interest group.
      Some groups such as European Network for Health Technology Assessment have also looked at study designs for precision medicines.
      European Network for Health Technology Assessment (EUnetHTA)
      Personalised medicine and co-dependent technologies, with a special focus on issues of study design.
      However, in the light of continuing innovation in this area, challenges associated with precision medicine value assessment have not yet been addressed satisfyingly.
      • Faulkner E.
      • Annemans L.
      • Garrison L.
      • et al.
      Challenges in the development and reimbursement of personalized medicine-payer and manufacturer perspectives and implications for health economics and outcomes research: a report of the ISPOR personalized medicine special interest group.
      ,,

      Faulkner E, Poulios N, Husereau D, Zah V. Valuing precision: how will next generation diagnostics change the landscape for HEOR and patient management? Paper presented at: International Society for Pharmacoeconomics and Outcomes Research 21st Annual International Congress; May, 2017; Boston, MA.

      ,

      Shah F, Payne K, Faulkner E, Siebert U, Shandu G, Barr C. Generating evidence of the added value of precision medicine. ISPOR Forum. Paper presented at: International Society for Pharmacoeconomics and Outcomes Research, 19th Annual European Congress; October, 2016; Vienna, Austria.

      ,
      • Garfield S.
      • Polisena J.
      • D SS
      • et al.
      Health technology assessment for molecular diagnostics: practices, challenges, and recommendations from the medical devices and diagnostics special interest group.
      ,

      Garfield S, Faulkner E, Potsulka A, Berndt K. Navigating a changing landscape: the next generation of diagnostic reimbursement and healthcare management models. Paper presented at: International Society for Pharmacoeconomics and Outcomes Research, 17th Annual European Congress; November 2014; Amsterdam, Netherlands.

      ,

      Zah VRK, Berndt K, Faulkner E. Diagnostics evidentiary dinosaur evolution: conventional health economics and market access approaches vs. advanced analytics as the new norm? International Society for Pharmacoeconomics and Outcomes Research ISPOR Europe 2018; November 2018; Barcelona, Spain.

      Clarification of Acceptable Study Designs and Expectations Toward Evidence Supporting the Precision Mechanism

      There is no general agreement about what a sufficient evidence base looks like for precision mechanism, be it a diagnostic test or a risk-based algorithm.

      Garfield S, Faulkner E, Potsulka A, Berndt K. Navigating a changing landscape: the next generation of diagnostic reimbursement and healthcare management models. Paper presented at: International Society for Pharmacoeconomics and Outcomes Research, 17th Annual European Congress; November 2014; Amsterdam, Netherlands.

      ,

      Faulkner E. How are critical success factors for precision medicine acceptance and uptake changing as we move into the next generation of personalized patient care? BioTech Pharma Summit 2017; October 2016; Porto, Portugal.

      Simply applying a process similar to drugs, would ignore the practical and business realities of evidence development in the diagnostic sector (eg, weak intellectual property, lack of value-based payment, commoditization of test payment).

      Garfield S, Faulkner E, Poisena J, Longacre M. How variation in HTA processes and requirements for molecular diagnostics creates challenges for manufacturer, payer and clinical stakeholders. Paper presented at: International Society for Pharmacoeconomics and Outcomes Research, 18th Annual International Congress; June 2014; Montreal, Canada.

      A range of nonrandomized approaches for addressing evidence demands for diagnostics have been discussed.
      • Faulkner E.
      • Spinner D.
      • Ransom J.
      Developing appropriate evidence for demonstrating the value of diagnostics: where are we now and what is appropriate for the future state?.
      Because value-based reimbursement models for diagnostics do not yet exist on a global basis, expectations for study designs must balance the need to demonstrate safety and effectiveness of tests with the reality of the diagnostics business model. Some agencies with high evidence requirements, such as National Institute for Health and Care Excellence and the BlueCross BlueShield Technology Center (named Evidence Street) have over the years softened their stance on diagnostic assessment as they have gained deeper experience in the nuances this technology type.

      Shah F, Payne K, Faulkner E, Siebert U, Shandu G, Barr C. Generating evidence of the added value of precision medicine. ISPOR Forum. Paper presented at: International Society for Pharmacoeconomics and Outcomes Research, 19th Annual European Congress; October, 2016; Vienna, Austria.

      Some agencies have also indicated that they do not have the experience or time to develop diagnostic evidence requirements given competing healthcare priorities, but they would prefer to react to an industry-proposed framework.

      Faulkner E, Garfield S, Jensen T, Polios N. How novel diagnostics are changing the healthcare value proposition? Paper presented at: Advanced Medical Technology Industry Association. AdvaMed 2015 Annual Meeting; October 2015; San Diego, CA.

      ,

      Faulkner E, Tunis S, Branham C, Towse A. Cutting the fog: have we reached clarity on diagnostics and personalized medicine evidence expectations? Paper presented at: International Society for Pharmacoeconomics and Outcomes Research, 16th Annual International Meeting; June 2012; Washington, DC.

      Establishing clear and consistent evidentiary “rules of the road” for diagnostics evidence expectations is important to all stakeholders.
      • Faulkner E.
      • Annemans L.
      • Garrison L.
      • et al.
      Challenges in the development and reimbursement of personalized medicine-payer and manufacturer perspectives and implications for health economics and outcomes research: a report of the ISPOR personalized medicine special interest group.

      Clarification of Expectations Supporting Different Applications of the Precision Mechanism

      Different test applications (ie, risk assessment, screening, diagnosis, treatment selection, monitoring) will have different underlying evidence questions and drivers of value.
      • Quinn B.
      Utility and adoption of clinical genomics: foundations of assessments.
      For example, a screening test may have broad use and expose patients to helpful and harmful downstream interventions, whereas a drug monitoring test may simply indicate whether a particular treatment is working. Minimally invasive liquid biopsies used to analyze circulating tumor DNA and circulating tumor cells is a specific example of a precision medicine mechanism that is being studied to identify tumor evolution and better guide treatment noninvasively.
      • Mattox A.K.
      • Bettegowda C.
      • Zhou S.
      • Papadopoulos N.
      • Kinzler K.W.
      • Vogelstein B.
      Applications of liquid biopsies for cancer.
      ,
      • Rossi G.
      • Ignatiadis M.
      Promises and pitfalls of using liquid biopsy for precision medicine.
      Some efforts have been made to formulate core questions for each test application type, but significant work remains to align these questions to a fully structured set of expectations per test application.
      • Faulkner E.
      • Ransom J.
      • Briggs G.
      • Hanna J.U.S.
      managed care perspectives on assessment and uptake of molecular diagnostics: state of the union and areas for additional improvement.
      A value assessment framework for precision medicine should provide for appropriate contextual consideration of how the precision mechanism is applied and overall value.

      Value of Precision Mechanism Should Include Their Ability to “Rule Out” Treatment and Management Approaches

      Ruling out disease risks or need for certain downstream tests or treatments can be one of the most valuable implications of precision mechanisms. However, this value aspect is often missed by HTA. In general, despite diagnostics representing only about 5% of healthcare costs, they inform over 70% of healthcare actions, the value of “ruling out” often remains overlooked.
      As we expand toward broader testing approaches (eg, whole genome sequencing), such information will further broaden the options for ruling out conditions or therapies and should be accounted for in value assessment.

      Providing for Future Diagnostic or Predictive Technologies

      Use of NGS as a companion test to a novel ovarian cancer drug approved in late 2016, illustrates how as technology complexity increases, HTA complexity also increases.
      CNBC
      Clovis oncology spikes; receives early FDA approval for advanced cancer drug.
      A recent Market Watch study predicted that the NGS market will rapidly grow to more than $12 billion by 2022, resulting in a flood of complex diagnostics into the global marketplace.
      Market Watch
      Next generation sequencing NGS market is projected to reach US$ 12445 million By 2022.
      Along with increasing complexity, such tests raise novel evidentiary value assessment considerations, including the following highlighted in Table 3.

      Faulkner E, Poulios N, Husereau D, Zah V. Valuing precision: how will next generation diagnostics change the landscape for HEOR and patient management? Paper presented at: International Society for Pharmacoeconomics and Outcomes Research 21st Annual International Congress; May, 2017; Boston, MA.

      ,
      Institute of Medicine. National Academy of Sciences
      Roundtable on genomics and precision health - resources on implementation, public health, and disparities.
      At present, none of the implications of broad diagnostic tests have been incorporated into global assessment frameworks, but they have profound implications for patient care.
      Table 3Novel Considerations of Evidence and Value Associated with Precision Medicine.
      • Uncertainties around standards and expectations for validation of individual biomarkers in a test or of the algorithm driving test interpretation
      • Uncertainties around number needed to test to support good value for money, particularly as we move towards multi-marker testing
      • Uncertainties around insufficiently validated biomarkers
      • Implications of identifying patient risk factors or diseases not anticipated by the broader test
      • Potential for overuse, harms, or ethical considerations after use of a precision mechanism
      • Potential for a test to indicate the use of more than one targeted therapy
      • Potential to identify treatments that have not been proven in specific indication
      • Payment requirements as numbers of biomarker tests expand
      • Value of the precision mechanism in establishing or increasing efficiency of clinical pathways
      • Health system effects of precision medicine beyond obvious standard clinical or economic metrics

      Innovative Study Design in Precision Medicine

      Our ability to broadly leverage biomarkers has enabled novel trial designs that cut across disease areas or enable unique enrichment scenarios. Adaptive and so-called “umbrella,” “basket,” or “bucket” trials create the potential to determine treatment effectiveness in multiple diseases simultaneously.
      • Ijzerman M.J.
      • Berghuis A.M.S.
      • de Bono J.S.
      • Terstappen L.
      Health economic impact of liquid biopsies in cancer management.
      ,
      • Stallard J.
      Clinical trial shows promise of “basket studies” for cancer drugs. Memorial Sloan Kettering Cancer Center.
      This ability is driven both by approvals of next-generation tests (eg, FoundationOne) as well as applications such as the NTRK fusion “driver” mutation treatment studies that span diseases.
      • Nanda N.
      • Fennell T.
      • et al.
      Identification of tropomyosin kinase receptor (TRK) point mutations in cancer. American Society of Clinical Oncology.
      ,
      National Cancer Institute
      Genomic profiling tests cleared by FDA can help guide cancer treatment, clinical trial enrollment.
      Such studies may involve different patient numbers and approaches not typically involved in historic study designs. Future value assessment frameworks should consider new trial approaches as they will apply to an increasing number of development scenarios.
      Similarly, successful precision medicines have opened the door for an increasing number of therapies going to market with single arm phase II data based on promising outcomes. In these scenarios, observational data collected in clinical practice (called real-world evidence [RWE]) supports a full value package. ISPOR has for some time supported task force activities in indirect treatment comparisons/network meta-analyses regarding approaches to support robust comparisons across different treatments, including single-arm trials. This opens the way for the Precision Medicine Special Interest Group and groups engaged in RWE to collaborate on best practices. This, coupled with the recent ability to leverage the use of RWE in regulatory submissions is altering our expectations for iterative evidence.
      • Faulkner E.
      • Spinner D.
      • Ransom J.
      Developing appropriate evidence for demonstrating the value of diagnostics: where are we now and what is appropriate for the future state?.
      ,
      • Mihos M.
      • Spinner D.
      • Rino M.
      • Faulkner E.
      Leveraging real-world evidence for regenerative medicine and advanced therapy success beyond the regulator. The Evidence Forum.
      As such launches expand, HTA processes will become increasingly iterative across the product life cycle, and value frameworks must shift accordingly.

      Faulkner E, Garfield S, Jensen T, Polios N. How novel diagnostics are changing the healthcare value proposition? Paper presented at: Advanced Medical Technology Industry Association. AdvaMed 2015 Annual Meeting; October 2015; San Diego, CA.

      ,
      • Agarwala V.
      • Khozin S.
      • Singal G.
      • et al.
      Real-world evidence in support of precision medicine: clinico-genomic cancer data as a case study.

      Evolving Value Assessment to Accommodate Precision Targeting of Multiple Biomarkers/Pathways

      Precision medicines targeting multiple markers in a single treatment are also beginning to evolve. These therapies may be based on DNA, RNA, synthetic peptides, and have the potential to replace existing therapies or combinations. As disease progresses, the process behind these treatments may ultimately enable iterative development of a truly individualized therapy customized to disease progression, creating a novel HTA scenario.
      • Cornelis J.M.
      • van Hall T.
      • Arens R.
      • et al.
      Therapeutic cancer vaccines.
      Emerging therapies leveraging a “multi-target” approach may improve effectiveness, potentially yielding transformative disease knockdown or cure effect.,
      • Faulkner E.
      • Spinner D.S.
      • Ringo M.
      • Carroll M
      Are global health systems ready for transformative therapies?.
      Ability to address multiple targets raises a number of issues for precision medicine value assessment, including factors highlighted in Table 4. Although such therapies are still early, anticipating their unique assessment considerations requires further work.
      Table 4New Evidentiary Considerations for Multi-target Precision Medicines.
      • What is the right comparator for a precision medicine that hits multiple targets?
      • What if the new treatment has the potential to replace existing combination therapies or cost significantly less than existing combination therapies? Do different willingness to pay thresholds apply?
      • What if the new treatment targets marker combinations are not fully covered by existing agents?
      • Are there different safety considerations associated with multi-target therapies?
      • Are patients less likely to become refractory versus alternatives?
      • Will such therapies offer prolonged duration of therapeutic effect?
      • Do such therapies have transformative or curative potential? If so, does this change value assessment processes and how?

      Integration of the Precision Information with Artificial Intelligence and Machine Learning and Decision Support Systems

      A future manifestation of precision medicine can include integration of diagnostic and treatment information with emerging artificial intelligence or machine learning platforms.
      • Love-Koh J.
      • Peel A.
      • Rejon-Parrilla J.C.
      • et al.
      The future of precision medicine: potential impacts for health technology assessment.
      A range of such integrated applications are currently in development.

      Faulkner E, Poulios N, Husereau D, Zah V. Valuing precision: how will next generation diagnostics change the landscape for HEOR and patient management? Paper presented at: International Society for Pharmacoeconomics and Outcomes Research 21st Annual International Congress; May, 2017; Boston, MA.

      Other factors such as rapid genome sequencing (eg, the UK 100 000 genome project) may ultimately feed into this trend as information linkages occur. Emerging decision support products may have differing abilities to inform decisions and differing levels of uncertainty. Some may seek direct reimbursement from payers, while others may emerge as subscription platform services.

      Ringo M, Pereira L, Faulkner E. Machine learning integration with molecular diagnostics: progress and potential pitfalls. Paper presented at: International Society for Pharmacoeconomics and Outcomes Research 21th Annual International Congress; May 2017; Boston, MA.

      For those that emerge as reimbursable products, they will enter value assessment processes that global systems are ill prepared to address.
      • Mesko B.
      The role of artificial intelligence in precision medicine.
      Table 5 below highlights key considerations for these emerging applications.
      Table 5Considerations for precision data management and decision tools that leverage biomarker data.
      • Should AI/machine-learning applications driven or strongly influenced/by biomarker data be considered precision medicine?
      • How should these evidence applications be regulated and assessed? Where does the similarity between a product or tool used to actively inform patient interventions begin and end (eg, spanning the spectrum of biomarker-based diagnostic algorithms to population-level AI an advanced decision analytics that incorporate biomarker data)?
      • Should evaluation only be limited to commercial products? Should it extend to subscription platforms?
      • What appropriate study types and evidence base are relevant here? What does “good” look like?
      • How and to what extent should such applications be integrated into or subject to a value assessment framework if use of such tools has profound impact on patient care decisions, outcomes, and resource use?
      • While AI/machine learning may help identify trends by mining genomic and biomarker data, how will our use of this information include patient preferences?
      • How should we address scenarios where the outputs of AI/machine learning in precision medicine may change over time or differ among platforms that may be developed?
      AI indicates artificial intelligence.

      Conclusions

      A strong evidence base for precision medicine is clearly important for expanded clinical use. There is a need for concerted effort in defining and applying a relevant and consistent value assessment approach to precision medicine. Next-generation sequencing and evolving decision tools are also pushing the bounds of evidentiary complexity and decision making far beyond early scenarios.

      Faulkner E, Poulios N, Husereau D, Zah V. Valuing precision: how will next generation diagnostics change the landscape for HEOR and patient management? Paper presented at: International Society for Pharmacoeconomics and Outcomes Research 21st Annual International Congress; May, 2017; Boston, MA.

      ,
      • Toll D.B.
      • Janssen K.J.
      • Vergouwe Y.
      • Moons K.G.
      Validation, updating and impact of clinical prediction rules: a review.
      To develop a value assessment framework and decision-making tools relevant for precision medicine requires assimilation of relevant components from existing generic frameworks and specific frameworks applicable to the precision components (eg, diagnostic tests). Such a value assessment framework needs to be cognizant of the implications of using different technologies to address the “precision” component of precision medicine and also of opportunity cost. Any value assessment framework must consider key stakeholders’ perspectives and “end-to-end” component elements of precision medicine. This is where the collective efforts of a society such as ISPOR can help to develop approaches relevant for precision medicine (that may be overlaid on existing processes). This may also require input from relevant disciplines, including biomedical research, statistics, economics, and ethics, input from key health stakeholders, and careful consideration of the value attributes specific to this transformational and evolving field, which are not consistently integrated into today’s value assessment processes.

      Acknowledgements

      We extend special thanks to Theresa Tesoro and Clarissa Cooblall at ISPOR, the professional society for health economics and outcomes research. We especially thank the individuals who submitted written comments on drafts of our manuscript; Gouri Shankar Bhattacharyya, Cornelis Boersma, Benjamin Craig, Godofreda Dalmacion, Beth Devine, Tatiana Dilla, Clare Foy, Lou Garrison, M. Ragan Hart, John Hornberger, Reuben Howden, J Ross Maclean, Ethna McFerran, Kathryn Phillips, Molly Purser, Brock Schroeder, Scott Spencer, Vincenzo Straccia, Renske ten Ham, Kevin Wilson, and Lin Zhang. All authors volunteered their time for discussion, research, and writing of this report. This research was supported in part by ISPOR, which contributed two staff liaisons for this project.

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