Implementing an EU pull incentive for antimicrobial innovation and access: blueprint for action.

In June, 2023, the Council of the EU published a recommendation that the European Commission should contribute to the design and governance of an EU cross-country pull incentive to stimulate antimicrobial innovation and access. In this Personal View, we discuss six key considerations to support the implementation of the new pull incentive-ie, the size of the potential pull incentive and possible contributions of the member states, design of the incentive model, interplay of the new pull incentive with the proposed revisions of the EU pharmaceutical legislation, roles and responsibilities of both the EU and member states, balance between pull and push incentives, and global cooperation and responsibility. As the involvement of the member states with the EU pull incentive will be voluntary, member states should have confidence that the processes used to identify eligible antimicrobials, negotiate terms and conditions, and oversee access agreements are transparent, inclusive, and methodologically robust.

It Takes 2 to Tango. Setting Out the Conditions in Which Performance-Based Risk-Sharing Arrangements Work for Both Parties.

OBJECTIVES: Faster regulatory approval processes often fail to achieve faster patient access. We seek an approach, using performance-based risk-sharing arrangements, to address uncertainty for payers regarding the relative effectiveness and value for money of products launched through accelerated approval schemes. One important reason for risk sharing is to resolve differences of opinion between innovators and payers about a technology's underlying value. To date, there has been no formal attempt to set out the circumstances in which risk sharing can address these differences. METHODS: We use a value of information framework to understand what a performance-based risk-sharing arrangements can, in principle, add to a reimbursement scheme, separating payer perspectives on cost-effectiveness and the value of research from those of the innovator. We find 16 scenarios, developing 5 rules to analyze these 16 scenarios, identifying cases in which risk sharing adds value for both parties. RESULTS: We find that risk sharing provides an improved solution in 9 out of 16 combinations of payer and innovator expectations about treatment outcome and the value of further research. Among our assumptions, who pays for research and scheme administration costs are key. CONCLUSIONS: Steps should be undertaken to make risk sharing more practical, ensuring that payers consider it an option. This requires additional costs to the health system falling on the innovator in an efficient way that aligns incentives for product development for global markets. Health systems benefits are earlier patient access to cost-effective treatments and payers with higher confidence of not wasting money. Innovators get greater returns while conducting research.

A theory on ICER pricing and optimal levels of cost-effectiveness thresholds: a bargaining approach.

In many health systems around the world, decisions about the reimbursement of-and patient access to-new medicines are based on health technology assessments (HTA) which, in some countries, include the calculation of an incremental cost-effectiveness ratio (ICER). Decision-makers compare the ICER against a pre-specified value for money criterion, known as the cost-effectiveness threshold (CET), to decide in favour of or against reimbursement. We developed a general model of pharmaceutical markets to analyse the relationship between the CET value and the distribution of the health and economic value of new medicines between consumers (payers) and producers (life science industry developers). We added to the existing literature in three ways: including research and development (R&D) cost for developers as a sunk cost; incorporating bargaining using the Nash bargaining solution to model payer bargaining power from regulation and use of competition; and analysing the impact of a non-uniform distribution of developers R&D costs on the supply of innovation. In some circumstances of bargaining power distribution and R&D cost, we found that using a CET value in HTA decision-making higher than the supply-side CET is socially efficient. Decision-makers should consider adjustable levels of the CET or interpretation of ICERs higher than the CET according to the bargaining power effect. The findings of this research pointed to the need for more research on the impact of bargaining power, how R&D investment responds to rewards, i.e. the elasticity of innovation, and pre- and post-patent expiry modelling.

The Societal Value of Vaccines: Expert-Based Conceptual Framework and Methods Using COVID-19 Vaccines as a Case Study.

Health technology assessments (HTAs) of vaccines typically focus on the direct health benefits to individuals and healthcare systems. COVID-19 highlighted the widespread societal impact of infectious diseases and the value of vaccines in averting adverse clinical consequences and in maintaining or resuming social and economic activities. Using COVID-19 as a case study, this research work aimed to set forth a conceptual framework capturing the broader value elements of vaccines and to identify appropriate methods to quantify value elements not routinely considered in HTAs. A two-step approach was adopted, combining a targeted literature review and three rounds of expert elicitation based on a modified Delphi method, leading to a conceptual framework of 30 value elements related to broader health effects, societal and economic impact, public finances, and uncertainty value. When applying the framework to COVID-19 vaccines in post-pandemic settings, 13 value elements were consensually rated highly important by the experts for consideration in HTAs. The experts reviewed over 10 methods that could be leveraged to quantify broader value elements and provided technical forward-looking recommendations. Limitations of the framework and the identified methods were discussed. This study supplements ongoing efforts aimed towards a broader recognition of the full societal value of vaccines.

The Allocation of the Economic Value of Second-Generation Antipsychotics Over the Product Life Cycle: The Case of Risperidone in Sweden and the United Kingdom.

OBJECTIVE: This article estimates the life-cycle value of risperidone as representative of second-generation antipsychotics (SGA) relative to haloperidol (first-generation antipsychotics). METHODS: We estimated the number of patients treated with risperidone in Sweden and the United Kingdom, from 1994 to 2017, using data of usage and volume sales. We collected data from the literature on the effectiveness (quality-adjusted life-years per patient per year), direct costs (health services), and indirect costs (productivity) of risperidone and haloperidol. We proxied the incremental value added by the new class (SGA) using a comparator from the inferior class. Next, we modeled the life-cycle uptake of risperidone to estimate the life-cycle incremental cost (ie, direct, indirect, and medicine costs), incremental quality-adjusted life-years, and net monetary benefit of risperidone. We also assessed the life-cycle distribution of the social surplus between the payer (consumer surplus) and the innovator (producer surplus). RESULTS: For the United Kingdom, consumer surplus represents around 72% of the total surplus before patent expiration and around 95% after patent expiration. For Sweden, the consumer surplus represents around 94% of the total surplus before patent expiration and around 99% after generic competition. CONCLUSION: These results suggest that the value added by SGAs to the system is higher than the expected value estimated using cost-effectiveness analysis at launch. Pricing and reimbursement decisions could recognize the full life cycle of value of innovative medicines. This not only presents a challenge of estimation but also of assessing the appropriate division of shares of social value.

Estimating health system opportunity costs: the role of non-linearities and inefficiency.

BACKGROUND: Empirical estimates of health system opportunity costs have been suggested as a basis for the cost-effectiveness threshold to use in Health Technology Assessment. Econometric methods have been used to estimate these in several countries based on data on spending and mortality. This study examines empirical evidence on four issues: non-linearity of the relationship between spending and mortality; the inclusion of outcomes other than mortality; variation in the efficiency with which expenditures generate health outcomes; and the relationship among efficiency, mortality rates and outcome elasticities. METHODS: Quantile Regression is used to examine non-linearities in the relationship between mortality and health expenditures along the mortality distribution. Data Envelopment Analysis extends the approach, using multiple measures of health outcomes to measure efficiency. These are applied to health expenditure data from 151 geographical units (Primary Care Trusts) of the National Health Service in England, across eight different clinical areas (Programme Budget Categories), for 3 fiscal years from 2010/11 to 2012/13. RESULTS: The results suggest differences in efficiency levels across geographical units and clinical areas as to how health resources generate outcomes, which indicates the capacity to adjust to a decrease in health expenditure without affecting health outcomes. Moreover, efficient units have lower absolute levels of mortality elasticity to health expenditure than inefficient ones. CONCLUSIONS: The policy of adopting thresholds based on estimates of a single system-wide cost-effectiveness threshold assumes a relationship between expenditure and health outcomes that generates an opportunity cost estimate which applies to the whole system. Our evidence of variations in that relationship and therefore in opportunity costs suggests that adopting a single threshold may exacerbate the efficiency and equity concerns that such thresholds are designed to counter. In most health care systems, many decisions about provision are not made centrally. Our analytical approach to understanding variability in opportunity cost can help policy makers target efficiency improvements and set realistic targets for local and clinical area health improvements from increased expenditure.

Why We Need a New Outcomes-Based Value Attribution Framework for Combination Regimens in Oncology.

BACKGROUND: Novel oncology treatment strategies increasingly use medicines with distinct but complementary mechanisms of action in combination or in close sequence. Payers, when confronted with higher total cost of providing combination regimens involving multiple therapies and usually longer treatment durations, are reluctant to reimburse them, particularly when they perceive the expected incremental benefits from adding a new medicine (the add-on) to a currently reimbursed medicine (the backbone) not to represent value for money to the health system. Nevertheless, depending on how value is attributed to the add-on versus the backbone, a clinically effective medicine used as part of a regimen that increases treatment duration might be found "not cost-effective at zero price." This phenomenon, signaling a policy problem not a pricing issue, first needs to be better understood before a generalizable and transparent solution can be presented. OBJECTIVE: This article sets out when this policy challenge arises and describes general principles that any proposed solution to the value attribution problem must satisfy. METHODS: We develop a simplified conceptual framework and use this to address 2 topics. The first is to understand the origin of problems posed by the current approach for attributing value in incremental cost-effectiveness analyses of combination regimens. The second is to discuss 2 new approaches in the literature designed to address the challenge. FINDINGS: We find that neither meets our criteria, meaning that further work is needed to resolve the issue. Finally, we briefly discuss the implications of relaxing the simplifying assumptions in our conceptual framework.

Supply-Side Cost-Effectiveness Thresholds: Questions for Evidence-Based Policy.

There is growing interest in cost-effectiveness thresholds as a tool to inform resource allocation decisions in health care. Studies from several countries have sought to estimate health system opportunity costs, which supply-side cost-effectiveness thresholds are intended to represent. In this paper, we consider the role of empirical estimates of supply-side thresholds in policy-making. Recent studies estimate the cost per unit of health based on average displacement or outcome elasticity. We distinguish the types of point estimates reported in empirical work, including marginal productivity, average displacement, and outcome elasticity. Using this classification, we summarise the limitations of current approaches to threshold estimation in terms of theory, methods, and data. We highlight the questions that arise from alternative interpretations of thresholds and provide recommendations to policymakers seeking to use a supply-side threshold where the evidence base is emerging or incomplete. We recommend that: (1) policymakers must clearly define the scope of the application of a threshold, and the theoretical basis for empirical estimates should be consistent with that scope; (2) a process for the assessment of new evidence and for determining changes in the threshold to be applied in policy-making should be created; (3) decision-making processes should retain flexibility in the application of a threshold; and (4) policymakers should provide support for decision-makers relating to the use of thresholds and the implementation of decisions stemming from their application.

Considering Severity in Health Technology Assessment: Can We Do Better?

There is strong evidence that individuals and the public assign relatively greater value to health gains from relatively more severe health states. This preference is increasingly reflected in health technology assessment, with some consideration of severity incorporated by health technology assessment bodies in, among others, The Netherlands, England and Wales, Norway, Sweden, and the United States. If a societal "severity premium" is to be considered fairly and consistently, we argue that a more explicit and quantitative approach is needed. We highlight drawbacks of categorical approaches, especially discontinuities between severity categories that arguably violate concepts of vertical equity, and argue that a more continuous approach to understanding severity is needed. We also note challenges to more explicit approaches, including implications of a lower threshold for less severe conditions and the relative complexity of calculating a continuous severity adjustment.

Should We Pay for Scientific Knowledge Spillovers? The Underappreciated Value of "Failed" R&D Efforts.

Recent experience with COVID-19 has reminded us of the importance of scientific progress in enabling pharmaceutical innovation. Developing novel therapies is a highly risky but rewarding process: it not only produces innovative drugs, but also valuable scientific knowledge that benefits the community of innovators. This paper examines whether the existing reward system for pharmaceutical research and development (R&D) leads to socially optimal levels of scientific knowledge generation and sharing, with a particular focus on the value of failures in the pharmaceutical R&D efforts. We first outline a conceptual approach based on the idea that pharmaceutical R&D efforts produce both medicines and scientific knowledge, and illustrate this with some examples of how failures may generate information beneficial to concurrent and subsequent R&D efforts. We then summarize the relatively small literature on failures in pharmaceutical R&D and their impact on R&D decision making. Lastly, we discuss several market-based and nonmarket-based policy approaches that can address potential shortcomings in the current reward system which may lead to suboptimal R&D and knowledge sharing.

The cost-per-QALY threshold in England: Identifying structural uncertainty in the estimates.

Introduction: There are increasing numbers of estimates of opportunity cost to inform the setting of thresholds as ceiling cost-per-quality-adjusted life year (QALY) ratios. To understand their ability to inform policy making, we need to understand the degree of uncertainty surrounding these estimates. In particular, do estimates provide sufficient certainty that the current policy "rules" or "benchmarks" need revision? Does the degree of uncertainty around those estimates mean that further evidence generation is required? Methods: We analyse uncertainty and methods from three papers that focus on the use of data from the NHS in England to estimate opportunity cost. All estimate the impact of expenditure on mortality in cross-sectional regression analyses and then translate the mortality elasticities into cost-per-QALY thresholds using the same assumptions. All three discuss structural uncertainty around the regression analysis, and report parameter uncertainty derived from their estimated standard errors. However, only the initial, seminal, paper explores the structural uncertainty involved in moving from the regression analysis to a threshold. We discuss the elements of structural uncertainty arising from the assumptions that underpin the translation of elasticities to thresholds and seek to quantify the importance of some of the effects. Results: We find several sets of plausible structural assumptions that would place the threshold estimates from these studies within the current National Institute for Health and Care Excellence (NICE) range of £20,000 to £30,000 per QALY. Heterogeneity, an additional source of uncertainty from variability, is also discussed and reported. Discussion: Lastly, we discuss how decision uncertainty around the threshold could be reduced, setting out what sort of additional research is required, notably in improving estimates of disease burden and of the impact of health expenditure on quality of life. Given the likely value to policy makers of this research it should be a priority for health system research funding.

Hemophilia Gene Therapy Value Assessment: Methodological Challenges and Recommendations.

Gene therapy for hemophilia is designed to produce health gains for patients over many years. Rewarding that value creation on the basis of a one-time treatment implies a large upfront cost. This cost can only be justified by long-term health benefits and being cost-effective compared with conventional treatments. Yet, uncertainties about the long-term benefits make it challenging to assess clinical and economic value of gene therapies at launch. We identify and discuss key methodological challenges in assessing the value of gene therapy for hemophilia, including the immaturity of evidence on the durability of benefits, lack of definition and valuation of cure for chronic diseases, absence of randomized controlled trials, limitations of traditional quality of life measures in hemophilia, approach for qualifying cost-savings compared with current treatments, and choice of perspective. The Institute for Clinical and Economic Review has developed a framework for assessing single or short-term therapies (ICER-SST) and has applied it in hemophilia. After reviewing this framework and its application, we recommend the following when assessing the value of hemophilia gene therapies: (1) leveraging expert clinical opinion to justify assumptions on the durability of benefits; (2) using external synthetic controls and lead-in, self-controlled trials to assess comparative effectiveness; (3) addressing limitations of traditional quality of life measures through the use of modified utility collection approaches; (4) adjusting cost offsets from gene therapies with caution; (5) considering outcome-based contracting to address uncertainties about prices and long-term outcomes; and (6) presenting societal and healthcare system perspectives in parallel.

Challenges in valuing and paying for combination regimens in oncology: reporting the perspectives of a multi-stakeholder, international workshop.

BACKGROUND: It is increasingly common for two or more treatments for cancer to be combined as a single regimen. Determining value and appropriate payment for such regimens can be challenging. This study discusses these challenges, and possible solutions. METHODS: Stakeholders from around the world attended a 2-day workshop, supported by a background paper. This study captures key outcomes from the discussion, but is not a consensus statement. RESULTS: Workshop attendees agreed that combining on-patent treatments can result in affordability and value for money challenges that delay or deny patient access to clinically effective treatments in many health systems. Options for addressing these challenges include: (i) Increasing the value of combination therapies through improved clinical development; (ii) Willingness to pay more for combinations than for single drugs offering similar benefit, or; (iii) Aligning the cost of constituent therapies with their value within a regimen. Workshop attendees felt that (i) and (iii) merited further discussion, whereas (ii) was unlikely to be justifiable. Views differed on the feasibility of (i). Key to (iii) would be systems allowing different prices to apply to different uses of a drug. CONCLUSIONS: Common ground was identified on immediate actions to improve access to combination regimens. These include an exploration of the legal challenges associated with price negotiations, and ensuring that pricing systems can support implementation of negotiated prices for specific uses. Improvements to clinical development and trial design should be pursued in the medium and longer term.

How Should the World Pay for a Coronavirus Disease (COVID-19) Vaccine?

The potential health and economic value of a vaccine for coronavirus disease (COVID-19) is self-evident given nearly 2 million deaths, "collateral" loss of life as other conditions go untreated, and massive economic damage. Results from the first licensed products are very encouraging; however, there are important reasons why we will likely need second and third generation vaccines. Dedicated incentives and funding focused explicitly on nurturing and advancing competing second and third generation vaccines are essential. This article proposes a collaborative, market-based financing mechanism for the world to incentivize and pay for the development of, and provide equitable access to, second and third generation COVID-19 vaccines. Specifically, we propose consideration of a Benefit-Based Advance Market Commitment (BBAMC). The BBAMC uses health technology assessment to determine value-based prices to guarantee overall market revenues, not revenue for any specific product or company. The poorest countries would not pay a value-based price but a discounted "tail-price." Innovators must agree to supply them at this tail price or to facilitate technology transfer to local licensees at low or zero cost to enable them to supply at this price. We expect these purchases to be paid for in full or large part by global donors. The BBAMC therefore sets prices in relation to value, protects intellectual property rights, encourages competition, and ensures all populations get access to vaccines, subject to agreed priority allocation rules.

Cornerstones of 'fair' drug coverage: appropriate cost sharing and utilization management policies for pharmaceuticals.

At the heart of all health insurance programs lies ethical tension between maximizing the freedom of patients and clinicians to tailor care for the individual and the need to make healthcare affordable. Nowhere is this tension more fiercely debated than in benefit design and coverage policy for pharmaceuticals. This paper focuses on three areas over which there is the most controversy about how to judge whether drug coverage is appropriate: cost-sharing provisions, clinical eligibility criteria, and economic-step therapy and required switching. In each of these domains we present 'ethical goals for access' followed by a series of 'fair design criteria' that can be used by stakeholders to drive more transparent and accountable drug coverage.

Reconciling ACEA and MCDA: is there a way forward for measuring cost-effectiveness in the U.S. healthcare setting?

BACKGROUND: The ISPOR Special Task Force (STF) on US Value Assessment Frameworks was agnostic about exactly how to implement the quality-adjusted life year (QALY) as a key element in an overall cost-effectiveness evaluation. But the STF recommended using the cost-per-QALY gained as a starting point in deliberations about including a new technology in a health plan benefit. The STF offered two major alternative approaches-augmented cost-effectiveness analysis (ACEA) and multi-criteria decision analysis (MCDA)-while emphasizing the need to apply either a willingness-to-pay (WTP) or opportunity cost threshold rule to operationalize the inclusion decision. METHODS: The MCDA model uses the multi-attribute utility function. The ACEA model is based on the expected utility theory. In both ACEA and MCDA models, value trade-offs are derived in a hierarchical model with two high-level objectives which measure overall health gain separately from financial attributes affecting consumption. RESULTS: Even though value trade-offs can be elicited or revealed without considering budget constraints, we demonstrate that they can be used similarly to WTP-based cost-effectiveness thresholds for resource allocation decisions. The consideration of how costs of medical technology, income, and severity of disease affect value trade-offs demonstrates, however, that reconciling decisions in ACEA and MCDA requires that health and consumption are either complements or independent attributes. CONCLUSIONS: We conclude that value trade-offs derived either from ACEA or MCDA move similarly with changes in main factors considered by enrollees and decision makers-costs of the medical technology, income, and severity of disease. Consequently, this complementarity between health and consumption is a necessary condition for reconciling ACEA and MCDA. Moreover, their similarity would be further enhanced if the QALY is used as the key attribute or anchor in the MCDA value function: the choice between the two is a pragmatic question that is still open.