Incidence of mental health conditions by seizure control among adults with epilepsy in the United States.

BACKGROUND: Mental health conditions (MHCs) are frequent comorbidities among people with epilepsy; however, the influence of seizure control on the incidence of MHCs is not well reported. This retrospective observational cohort study based on claims data evaluated the effects of indicators of poor seizure control on the incidence of MHCs among MHC-naïve people with epilepsy. We hypothesized that poor seizure control is associated with new-onset MHC diagnoses and/or new prescription drugs for MHCs. METHODS: This study utilized a sample of patients from HealthVerity Marketplace, which includes more than 150 US commercial, Medicare, and Medicaid payers, to identify a cohort of adults (age ≥18 years) with prevalent epilepsy. Follow-up started on day 1 (January 1) after a 1-year eligibility assessment period occurring in calendar year 2017 or 2018. Patients were followed up until the occurrence of an incident MHC event (primary outcome), defined as a mental health diagnosis or psychotropic drug prescription. Time from follow-up to incident MHC diagnosis or to a drug prescription specific to depression or anxiety disorder was analyzed as a secondary outcome. Multivariate Cox proportional hazards regressions were estimated with time-varying covariates, measured in 6-month intervals during follow-up. Time-varying covariates were based on the occurrence of 4 variables used as indicators of poor seizure control in the prior period: epilepsy-related emergent care admissions, epilepsy-related inpatient admissions, epilepsy electroencephalography referrals, and exposure to one or more new antiseizure medications (ASMs). RESULTS: From a random sample of 40,000 people with epilepsy, 2563 (mean age 46.1 years; 50.6% male) were included in the analysis. Incident MHC events were observed in 27.7% (incidence rate 24.4 events per 100 person-years over 2,915.7 total person-years of follow-up). Mean (standard deviation [SD]) time to event was 232.7 (186.3) days. Among the 4 variables, epilepsy-related emergent care admissions were associated with an increased risk of incident MHC events in the following 6-month period (hazard ratio [HR] = 1.676, 95% confidence interval [CI]: 1.386, 2.026, p < 0.001) as were prescriptions for new ASMs in the previous period (HR = 1.702, 95% CI: 1.359, 2.132, p < 0.001). Previous epilepsy-related emergent care admissions (HR = 1.650, 95% CI: 1.347, 2.021, p < 0.001) and new ASMs (HR = 1.632, 95% CI: 1.280, 2.081, p < 0.001) also predicted an increased risk of incident depression or anxiety in the following 6-month period. CONCLUSIONS: Previous indicators of poor seizure control, including epilepsy-related emergent care admissions and new ASMs, predicted increased risk of new MHC events, including depression and anxiety, during the following 6-month interval in MHC-naïve patients with prevalent epilepsy. These data suggest that poor seizure control can increase the subsequent risk of new mental health diagnoses and treatment among people with epilepsy.

The History and Future of the "ISPOR Value Flower": Addressing Limitations of Conventional Cost-Effectiveness Analysis.

OBJECTIVES: Since its publication as part of the 2018 ISPOR Special Task Force (STF) on US Value Assessments, the "ISPOR value flower," with its petals highlighting elements that may be overlooked or underappreciated in conventional drug value assessments, has been discussed and debated. We review the history of the value flower, describe recent developments, and consider implications for future value assessments. METHODS: We discuss various antecedents to the value flower, as well as conceptual and empirical articles published in the past 4 years. RESULTS: Since the publication of the ISPOR STF report, researchers have provided more rigorous theoretical and mathematical foundations for certain novel value elements (eg, severity of illness, value of insurance, value of hope) through "generalized risk-adjusted cost-effectiveness analysis," which incorporates risk aversion in people's preferences and uncertainty in treatment outcomes. Empirical estimates are also emerging to support key elements, such as insurance value, real option value, value of hope, and value of knowing. Although health technology assessment bodies have applied or are considering certain elements (eg, severity modifiers to cost-effectiveness thresholds), other elements have yet to gain traction. CONCLUSIONS: Five years after the STF began its work, the development of novel value measures continues to evolve. Although it is encouraging to see supporting empirical studies emerging, more are needed. Additional efforts are also needed to illustrate how the estimates can be used in the deliberative processes that are integral to health technology assessments.

Comparative effectiveness and safety of pharmaceuticals assessed in observational studies compared with randomized controlled trials.

BACKGROUND: There have been ongoing efforts to understand when and how data from observational studies can be applied to clinical and regulatory decision making. The objective of this review was to assess the comparability of relative treatment effects of pharmaceuticals from observational studies and randomized controlled trials (RCTs). METHODS: We searched PubMed and Embase for systematic literature reviews published between January 1, 1990, and January 31, 2020, that reported relative treatment effects of pharmaceuticals from both observational studies and RCTs. We extracted pooled relative effect estimates from observational studies and RCTs for each outcome, intervention-comparator, or indication assessed in the reviews. We calculated the ratio of the relative effect estimate from observational studies over that from RCTs, along with the corresponding 95% confidence interval (CI) for each pair of pooled RCT and observational study estimates, and we evaluated the consistency in relative treatment effects. RESULTS: Thirty systematic reviews across 7 therapeutic areas were identified from the literature. We analyzed 74 pairs of pooled relative effect estimates from RCTs and observational studies from 29 reviews. There was no statistically significant difference (based on the 95% CI) in relative effect estimates between RCTs and observational studies in 79.7% of pairs. There was an extreme difference (ratio < 0.7 or > 1.43) in 43.2% of pairs, and, in 17.6% of pairs, there was a significant difference and the estimates pointed in opposite directions. CONCLUSIONS: Overall, our review shows that while there is no significant difference in the relative risk ratios between the majority of RCTs and observational studies compared, there is significant variation in about 20% of comparisons. The source of this variation should be the subject of further inquiry to elucidate how much of the variation is due to differences in patient populations versus biased estimates arising from issues with study design or analytical/statistical methods.

Linked Pharmacometric-Pharmacoeconomic Modeling and Simulation in Clinical Drug Development.

Market access and pricing of pharmaceuticals are increasingly contingent on the ability to demonstrate comparative effectiveness and cost-effectiveness. As such, it is widely recognized that predictions of the economic potential of drug candidates in development could inform decisions across the product life cycle. This may be challenging when safety and efficacy profiles in terms of the relevant clinical outcomes are unknown or highly uncertain early in product development. Linking pharmacometrics and pharmacoeconomics, such that outputs from pharmacometric models serve as inputs to pharmacoeconomic models, may provide a framework for extrapolating from early-phase studies to predict economic outcomes and characterize decision uncertainty. This article reviews the published studies that have implemented this methodology and used simulation to inform drug development decisions and/or to optimize the use of drug treatments. Some of the key practical issues involved in linking pharmacometrics and pharmacoeconomics, including the choice of final outcome measures, methods of incorporating evidence on comparator treatments, approaches to handling multiple intermediate end points, approaches to quantifying uncertainty, and issues of model validation are also discussed. Finally, we have considered the potential barriers that may have limited the adoption of this methodology and suggest that closer alignment between the disciplines of clinical pharmacology, pharmacometrics, and pharmacoeconomics, may help to realize the potential benefits associated with linked pharmacometric-pharmacoeconomic modeling and simulation.

Improving Transparency to Build Trust in Real-World Secondary Data Studies for Hypothesis Testing-Why, What, and How: Recommendations and a Road Map from the Real-World Evidence Transparency Initiative.

Real-world data (RWD) and the derivations of these data into real-world evidence (RWE) are rapidly expanding from informing healthcare decisions at the patient and health system level to influencing major health policy decisions, including regulatory approvals and coverage. Recent examples include the approval of palbociclib in combination with endocrine therapy for male breast cancer and the inclusion of RWE in the label of paliperidone palmitate for schizophrenia. This interest has created an urgency to develop processes that promote trust in the evidence-generation process. Key stakeholders and decision-makers include patients and their healthcare providers; learning health systems; health technology assessment bodies and payers; pharmacoepidemiologists and other clinical reseachers, and policy makers interested in bioethical and regulatory issues. A key to optimal uptake of RWE is transparency of the research process to enable decision-makers to evaluate the quality of the methods used and the applicability of the evidence that results from the RWE studies. Registration of RWE studies-particularly for hypothesis evaluating treatment effectiveness (HETE) studies-has been proposed to improve transparency, trust, and research replicability. Although registration would not guarantee better RWE studies would be conducted, it would encourage the prospective disclosure of study plans, timing, and rationale for modifications. A joint task force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) recommended that investigators preregister their RWE studies and post their study protocols in a publicly available forum before starting studies to reduce publication bias and improve the transparency of research methods. Recognizing that published recommendations alone are insufficient, especially without accessible registration options and with no incentives, a group of experts gathered on February 25 and 26, 2019, in National Harbor, Maryland, to explore the structural and practical challenges to the successful implementation of the recommendations of the ISPOR/ISPE task force for preregistration. This positioning article describes a plan for making registration of HETE RWE studies routine. The plan includes specifying the rationale for registering HETE RWE studies, the studies that should be registered, where and when these studies should be registered, how and when analytic deviations from protocols should be reported, how and when to publish results, and incentives to encourage registration. Table 1 summarizes the rationale, goals, and potential solutions that increase transparency, in addition to unique concerns about secondary data studies. Definitions of terms used throughout this report are provided in Table 2.

Improving transparency to build trust in real-world secondary data studies for hypothesis testing-Why, what, and how: recommendations and a road map from the real-world evidence transparency initiative.

Real-world data (RWD) and the derivations of these data into real-world evidence (RWE) are rapidly expanding from informing healthcare decisions at the patient and health system level to influencing major health policy decisions, including regulatory approvals and coverage. Recent examples include the approval of palbociclib in combination with endocrine therapy for male breast cancer and the inclusion of RWE in the label of paliperidone palmitate for schizophrenia. This interest has created an urgency to develop processes that promote trust in the evidence-generation process. Key stakeholders and decision-makers include patients and their healthcare providers; learning health systems; health technology assessment bodies and payers; pharmacoepidemiologists and other clinical reseachers, and policy makers interested in bioethical and regulatory issues. A key to optimal uptake of RWE is transparency of the research process to enable decision-makers to evaluate the quality of the methods used and the applicability of the evidence that results from the RWE studies. Registration of RWE studies-particularly for hypothesis evaluating treatment effectiveness (HETE) studies-has been proposed to improve transparency, trust, and research replicability. Although registration would not guarantee better RWE studies would be conducted, it would encourage the prospective disclosure of study plans, timing, and rationale for modifications. A joint task force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) recommended that investigators preregister their RWE studies and post their study protocols in a publicly available forum before starting studies to reduce publication bias and improve the transparency of research methods. Recognizing that published recommendations alone are insufficient, especially without accessible registration options and with no incentives, a group of experts gathered on February 25 and 26, 2019, in National Harbor, Maryland, to explore the structural and practical challenges to the successful implementation of the recommendations of the ISPOR/ISPE task force for preregistration. This positioning article describes a plan for making registration of HETE RWE studies routine. The plan includes specifying the rationale for registering HETE RWE studies, the studies that should be registered, where and when these studies should be registered, how and when analytic deviations from protocols should be reported, how and when to publish results, and incentives to encourage registration. Table 1 summarizes the rationale, goals, and potential solutions that increase transparency, in addition to unique concerns about secondary data studies. Definitions of terms used throughout this report are provided in Table 2.

Criteria and Process for Initiating and Developing an ISPOR Good Practices Task Force Report.

The International Society for Pharmacoeconomics and Outcomes Research (ISPOR)'s "Good Practices Task Force" reports are highly cited, multistakeholder perspective expert guidance reports that reflect international standards for health economics and outcomes research (HEOR) and their use in healthcare decision making. In this report, we discuss the criteria, development, and evaluation/consensus review and approval process for initiating a task force. The rationale for a task force must include a justification, including why this good practice guidance is important and its potential impact on the scientific community. The criteria include: (1) necessity (why is this task force required?); (2) a methodology-oriented focus (focus on research methods, approaches, analysis, interpretation, and dissemination); (3) relevance (to ISPOR's mission and its members); (4) durability over time; (5) broad applicability; and 6) an evidence-based approach. In addition, the proposal must be a priority specifically for ISPOR. These reports are valuable to researchers, academics, students, health technology assessors, medical technology developers and service providers, those working in other commercial entities, regulators, and payers. These stakeholder perspectives are represented in task force membership to ensure the report's overall usefulness and relevance to the global ISPOR membership. We hope that this discussion will bring transparency to the process of initiating, approving, and producing these task force reports and encourage participation from a diverse range of experts within and outside ISPOR.

Reflections on the ISPOR Special Task Force on U.S. Value Frameworks: Implications of a Health Economics Approach for Managed Care Pharmacy.

In 2016, The Professional Society for Health Economics and Outcomes Research (ISPOR) formed a special task force (STF) to review approaches and methods to support the definition and use of high-quality U.S. value frameworks. As the leadership group of that initiative, we present our perspective, focusing on implications for the managed care pharmacy community. Our reflections are organized by 9 key observations and conclude with a summary recommendation. We begin by emphasizing the importance of distinguishing among "perspectives" and "decision contexts." Possible perspectives include patient, payer, provider, health care sector, and societal. Decision contexts range from formulary inclusion to guideline development to clinical shared decision making, and multiple perspectives can be taken on each of these decisions. The STF focused on value in the context of including a new medicine in a formulary and, thus, health plan, using a health economics approach that compares marginal benefit (gross value) and marginal (opportunity) cost, yielding the net value. Health care is unique compared with other markets. While economists often use market purchases as indicators of value, they also recognize that this does not work well in health care, since most patent-protected drugs are covered by insurance. To assess the likely health and economic impact, health economists often employ cost-effectiveness analysis, using the quality-adjusted life-year (QALY), a metric that combines mortality and morbidity into a single preference-based index. We strongly endorse the STF's recommendation that payers should use the cost-per-QALY metric as a starting point. However, like the STF, and many of those stakeholders who provided input, we recognize that this metric has some limitations in theory and in practice. Nonetheless, the cost-per-QALY metric is a pragmatic tool that can be augmented to address some of its limitations by integrating other elements of value, particularly those related to uncertainty, such as financial risk protection, health risk protection, the value of hope, real option value, and the value of knowing. The resulting adjusted ratio can be compared with a willingness-to-pay threshold or combined in a measure of net monetary benefit. Alternatively, the array of elements can be valued using multi-criteria decision analysis. We end with the key recommendation that further development and testing of these promising approaches is needed to improve the deliberative process of health technology assessment. DISCLOSURES: No outside funding supported the writing of this article. The authors are leaders of the ISPOR Special Task Force on U.S. Value Frameworks. Willke is employed by ISPOR. Garrison and Neumann have nothing to disclose. The opinions expressed in this article should be considered as belonging only to the authors.

A Health Economics Approach to US Value Assessment Frameworks-Introduction: An ISPOR Special Task Force Report [1].

Concerns about rising spending on prescription drugs and other areas of health care have led to multiple initiatives in the United States designed to measure and communicate the value of pharmaceuticals and other technologies for decision making. In this section we introduce the work of the International Society for Pharmacoeconomics and Outcomes Research Special Task Force on US Value Assessment Frameworks formed to review relevant perspectives and appropriate approaches and methods to support the definition and use of high-quality value frameworks. The Special Task Force was part of the International Society for Pharmacoeconomics and Outcomes Research Initiative on US Value Assessment Frameworks, which enlisted the expertise of leading health economists, concentrating on what the field of health economics can provide to help inform the development and use of value assessment frameworks. We focus on five value framework initiatives: the American College of Cardiology/American Heart Association, the American Society of Clinical Oncology, the Institute for Clinical and Economic Review, the Memorial Sloan Kettering Cancer Center, and the National Comprehensive Cancer Network. These entities differ in their missions, scope of activities, and methodological approaches. Because they are gaining visibility and some traction in the United States, it is essential to scrutinize whether the frameworks use approaches that are transparent as well as conceptually and methodologically sound. Our objectives were to describe the conceptual bases for value and its use in decision making, critically examine existing value frameworks, discuss the importance of sound conceptual underpinning, identify key elements of value relevant to specific decision contexts, and recommend good practice in value definition and implementation as well as areas for further research.

An Overview of Value, Perspective, and Decision Context-A Health Economics Approach: An ISPOR Special Task Force Report [2].

The second section of our Special Task Force builds on the discussion of value and perspective in the previous article of the report by 1) defining a health economics approach to the concept of value in health care systems; 2) discussing the relationship of value to perspective and decision context, that is, how recently proposed value frameworks vary by the types of decisions being made and by the stakeholders involved; 3) describing the patient perspective on value because the patient is a key stakeholder, but one also wearing the hat of a health insurance purchaser; and 4) discussing how value is relevant in the market-based US system of mixed private and public insurance, and differs from its use in single-payer systems. The five recent value frameworks that motivated this report vary in the types of decisions they intend to inform, ranging from coverage, access, and pricing decisions to those defining appropriate clinical pathways and to supporting provider-clinician shared decision making. Each of these value frameworks must be evaluated in its own decision context for its own objectives. Existing guidelines for cost-effectiveness analysis emphasize the importance of clearly specifying the perspective from which the analysis is undertaken. Relevant perspectives may include, among others, 1) the health plan enrollee, 2) the patient, 3) the health plan manager, 4) the provider, 5) the technology manufacturer, 6) the specialty society, 7) government regulators, or 8) society as a whole. A valid and informative cost-effectiveness analysis could be conducted from the perspective of any of these stakeholders, depending on the decision context.

Review of Recent US Value Frameworks-A Health Economics Approach: An ISPOR Special Task Force Report [6].

The sixth section of our Special Task Force (STF) report reviews and comments on recent US-oriented value assessment frameworks, specifically those published by the American College of Cardiology/American Heart Association, the Institute for Clinical and Economic Research, the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the Memorial Sloan Kettering Cancer Center. We review published commentaries that address the validity, reliability, and conceptual underpinnings of these frameworks. We find common themes of critique regarding the strengths and limitations across frameworks. Particular shortcomings of some frameworks pose greater threats to their face validity and utility compared with others. The most significant limitations include lack of clear perspective (e.g., patient vs. health plan) and poor transparency in accounting for costs and benefits. We then review how each framework adheres to core STF recommendations, with particular emphasis on whether the framework can be used to support coverage decisions by health insurers, and whether it adheres to core principles of cost-effectiveness analysis. The Institute for Clinical and Economic Research framework most closely adheres to core STF recommendations. Others have significant limitations that vary widely from framework to framework. We also review how the frameworks follow STF recommendations for addressing potentially relevant issues beyond cost-effectiveness analysis - for example, equity in resource allocation and patient heterogeneity. Finally, we review whether and how each framework uses value thresholds and addresses affordability concerns. We conclude with suggestions for further research, particularly in the areas of testing the measurement and use of novel elements of value and deliberative processes.

A Health Economics Approach to US Value Assessment Frameworks-Summary and Recommendations of the ISPOR Special Task Force Report [7].

This summary section first lists key points from each of the six sections of the report, followed by six key recommendations. The Special Task Force chose to take a health economics approach to the question of whether a health plan should cover and reimburse a specific technology, beginning with the view that the conventional cost-per-quality-adjusted life-year metric has both strengths as a starting point and recognized limitations. This report calls for the development of a more comprehensive economic evaluation that could include novel elements of value (e.g., insurance value and equity) as part of either an "augmented" cost-effectiveness analysis or a multicriteria decision analysis. Given an aggregation of elements to a measure of value, consistent use of a cost-effectiveness threshold can help ensure the maximization of health gain and well-being for a given budget. These decisions can benefit from the use of deliberative processes. The six recommendations are to: 1) be explicit about decision context and perspective in value assessment frameworks; 2) base health plan coverage and reimbursement decisions on an evaluation of the incremental costs and benefits of health care technologies as is provided by cost-effectiveness analysis; 3) develop value thresholds to serve as one important input to help guide coverage and reimbursement decisions; 4) manage budget constraints and affordability on the basis of cost-effectiveness principles; 5) test and consider using structured deliberative processes for health plan coverage and reimbursement decisions; and 6) explore and test novel elements of benefit to improve value measures that reflect the perspectives of both plan members and patients.

ISPOR Code of Ethics 2017 (4th Edition).

As the leading health economics and outcomes research (HEOR) professional society, ISPOR has a responsibility to establish a uniform, harmonized international code for ethical conduct. ISPOR has updated its 2008 Code of Ethics to reflect the current research environment. This code addresses what is acceptable and unacceptable in research, from inception to the dissemination of its results. There are nine chapters: 1 - Introduction; 2 - Ethical Principles respect, beneficence and justice with reference to a non-exhaustive compilation of international, regional, and country-specific guidelines and standards; 3 - Scope HEOR definitions and how HEOR and the Code relate to other research fields; 4 - Research Design Considerations primary and secondary data related issues, e.g., participant recruitment, population and research setting, sample size/site selection, incentive/honorarium, administration databases, registration of retrospective observational studies and modeling studies; 5 - Data Considerations privacy and data protection, combining, verification and transparency of research data, scientific misconduct, etc.; 6 - Sponsorship and Relationships with Others (roles of researchers, sponsors, key opinion leaders and advisory board members, research participants and institutional review boards (IRBs) / independent ethics committees (IECs) approval and responsibilities); 7 - Patient Centricity and Patient Engagement new addition, with explanation and guidance; 8 - Publication and Dissemination; and 9 - Conclusion and Limitations.

Good Practices for Real-World Data Studies of Treatment and/or Comparative Effectiveness: Recommendations from the Joint ISPOR-ISPE Special Task Force on Real-World Evidence in Health Care Decision Making.

PURPOSE: Real-world evidence (RWE) includes data from retrospective or prospective observational studies and observational registries and provides insights beyond those addressed by randomized controlled trials. RWE studies aim to improve health care decision making. METHODS: The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) created a task force to make recommendations regarding good procedural practices that would enhance decision makers' confidence in evidence derived from RWD studies. Peer review by ISPOR/ISPE members and task force participants provided a consensus-building iterative process for the topics and framing of recommendations. RESULTS: The ISPOR/ISPE Task Force recommendations cover seven topics such as study registration, replicability, and stakeholder involvement in RWE studies. These recommendations, in concert with earlier recommendations about study methodology, provide a trustworthy foundation for the expanded use of RWE in health care decision making. CONCLUSION: The focus of these recommendations is good procedural practices for studies that test a specific hypothesis in a specific population. We recognize that some of the recommendations in this report may not be widely adopted without appropriate incentives from decision makers, journal editors, and other key stakeholders.

Good practices for real-world data studies of treatment and/or comparative effectiveness: Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in health care decision making.

PURPOSE: Real-world evidence (RWE) includes data from retrospective or prospective observational studies and observational registries and provides insights beyond those addressed by randomized controlled trials. RWE studies aim to improve health care decision making. METHODS: The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) created a task force to make recommendations regarding good procedural practices that would enhance decision makers' confidence in evidence derived from RWD studies. Peer review by ISPOR/ISPE members and task force participants provided a consensus-building iterative process for the topics and framing of recommendations. RESULTS: The ISPOR/ISPE Task Force recommendations cover seven topics such as study registration, replicability, and stakeholder involvement in RWE studies. These recommendations, in concert with earlier recommendations about study methodology, provide a trustworthy foundation for the expanded use of RWE in health care decision making. CONCLUSION: The focus of these recommendations is good procedural practices for studies that test a specific hypothesis in a specific population. We recognize that some of the recommendations in this report may not be widely adopted without appropriate incentives from decision makers, journal editors, and other key stakeholders.