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 Roadmap for Improving Medicare's Application of Coverage With Evidence Development.

The Centers for Medicare and Medicaid Services' coverage with evidence development (CED) policy allows the agency to provide coverage for an item or service through a National Coverage Determination (NCD), conditional upon an agreement to collect evidence designed to address specific questions or uncertainties. The goals of this policy are to expedite beneficiary access to new items and services and to generate additional evidence on the impact of these items or services for Medicare beneficiaries. However, these goals have not been fully realized because of several issues with the way the policy has been implemented, including (1) a lack of clear criteria for when CED will be applied, (2) examples of CED data collection activities placing unnecessary burdens on clinicians and the potential for undue inducement on beneficiaries, and (3) a lack of clarity around the process and timeline for reconsidering and ending CED requirements. Additionally, there are cases in which the application of CED has failed to improve access to services for certain Medicare beneficiaries because no data collection activity was implemented in response to the CED requirement or because the NCD only allows the technology to be provided and studied in certain centers of excellence. We describe a roadmap for addressing these issues, which includes, for example, developing a framework to guide the application of coverage constraints in NCDs with CED requirements. Once these issues are addressed, the Centers for Medicare and Medicaid Services could consider expanding the use of CED to technologies that are not subject to NCDs.

How donanemab data address the coverage with evidence development questions.

The Centers for Medicare & Medicaid Services (CMS) established a class-based National Coverage Determination (NCD) for monoclonal antibodies directed against amyloid for Alzheimer's disease (AD) with patient access through Coverage with Evidence Development (CED) based on three questions. This review, focused on donanemab, answers each of these CED questions with quality evidence. TRAILBLAZER-ALZ registration trials are presented with supporting literature and real-world data to answer CED questions for donanemab. TRAILBLAZER-ALZ registration trials demonstrated that donanemab significantly slowed cognitive and functional decline in amyloid-positive early symptomatic AD participants, and lowered their risk of disease progression while key safety risks occurred primarily within the first 6 months and then declined. Donanemab meaningfully improved health outcomes with a manageable safety profile in an early symptomatic AD population, representative of Medicare populations across diverse practice settings. The donanemab data provide the necessary level of evidence for CMS to open a reconsideration of their NCD. HIGHLIGHTS: Donanemab meaningfully improved outcomes in trial participants with early symptomatic Alzheimer's disease. Comorbidities in trial participants were consistent with the Medicare population. Co-medications in trial participants were consistent with the Medicare population. Risks associated with treatment tended to occur in the first 6 months. Risks of amyloid-related imaging abnormalities were managed with careful observation and magnetic resonance imaging monitoring.

Improving Food and Drug Administration-Centers for Medicare and Medicaid Services Coordination for Drugs Granted Accelerated Approval.

Policy Points The increasing number of drugs granted accelerated approval by the Food and Drug Administration (FDA) has challenged the Medicare program, which often pays for expensive therapies despite substantial uncertainty about benefits and risks to Medicare beneficiaries. We recommend several administrative and legislative approaches for improving FDA-Centers for Medicare and Medicaid Services (CMS) coordination around accelerated-approval drugs, including promoting earlier discussions among the FDA, the CMS, and drug companies; strengthening Medicare's coverage with evidence development program; linking Medicare payment to evidence generation milestones; and ensuring that the CMS has adequate staffing and resources to evaluate new therapies. These activities can help improve the integrity; transparency; and efficiency of approval, coverage, and payment processes for drugs granted accelerated approval. CONTEXT: The Food and Drug Administration (FDA)'s accelerated-approval pathway expedites patient access to promising treatments. However, increasing use of this pathway has challenged the Medicare program, which often pays for expensive therapies despite substantial uncertainty about benefits and risks to Medicare beneficiaries. We examined approaches to improve coordination between the FDA and Centers for Medicare and Medicaid Services (CMS) for drugs granted accelerated approval. METHODS: We argue that policymakers have focused on expedited pathways at the FDA without sufficient attention to complementary policies at the CMS. Although differences between the FDA and CMS decisions are to be expected given the agencies' different missions and statutory obligations, procedural improvements can ensure that Medicare beneficiaries have timely access to novel therapies that are likely to improve health outcomes. To inform policy options and recommendations, we conducted semistructured interviews with stakeholders to capture diverse perspectives on the topic. FINDINGS: We recommend ten areas for consideration: clarifying the FDA's evidentiary standards; strengthening FDA authorities; promoting earlier discussions among the FDA, the CMS, and drug companies; improving Medicare's coverage with evidence development program; tying Medicare payment for accelerated-approval drugs to evidence generation milestones; issuing CMS guidance on real-world evidence; clarifying Medicare's "reasonable and necessary" criteria; adopting lessons from international regulatory-reimbursement harmonization efforts; ensuring that the CMS has adequate staffing and expertise; and emphasizing equity. CONCLUSIONS: Better coordination between the FDA and CMS could improve the transparency and predictability of drug approval and coverage around accelerated-approval drugs, with important implications for patient outcomes, health spending, and evidence generation processes. Improved coordination will require reforms at both the FDA and CMS, with special attention to honoring the agencies' distinct authorities. It will require administrative and legislative actions, new resources, and strong leadership at both agencies.

Pushing the boundaries of evaluation, diffusion, and use of medical devices in Europe: Insights from the COMED project.

The field of medical devices has attracted considerable interest from scholarly research in health economics in recent years. Medical devices are indispensable tools for quality health care delivery, but their assessment and appropriate use pose significant challenges to healthcare systems. More research is needed to overcome existing gaps associated with evaluation of digital technologies, address challenges in the use of real-world data in generating evidence for decision-making and to uncover drivers of variation in access to medical devices across countries. Furthermore, the translation of the results and recommendations stemming from research projects into health technology assessment practices needs to be strengthened. The European Union (EU) project COMED aimed to address these gaps by improving existing research and developing new research streams on the methods for evaluation and diffusion of medical devices. The project also intended to provide directly applicable policy advice and tools to inform decision-making, with the aim of impacting public health in the EU. This Health Economics Supplement, together with references of other published outputs of the project, is intended to be the main source for researchers and policy makers seeking information on the COMED project.

Implementation of coverage with evidence development schemes for medical devices: A decision tool for late technology adopter countries.

Experiences with coverage with evidence development (CED) schemes are fairly limited in Central and Eastern European (CEE) countries, which are usually late adopters of new health technologies. Our aim was to put forward recommendations on how CEE health technology assessment bodies and payer organizations can apply CED to reduce decision uncertainty on reimbursement of medical devices, with a particular focus on transferring the structure and data from CED schemes in early technology adopter countries in Western Europe. Structured interviews on the practices and feasibility of transferring CED schemes were conducted and subsequently, a draft tool for the systematic classification of decision alternatives and recommendations was developed. The decision tool was reviewed in a focus group discussion and validated within a wider group of CEE experts in a virtual workshop. Transferability assessment is needed in case of (1) joint implementation of a CED scheme; (2) transferring the structure of an existing CED scheme to a CEE country; (3) reimbursement decisions that are linked to outcomes of an ongoing CED scheme in another country and (4) real-world evidence transferred from completed CED schemes. Efficient use of available resources may be improved by adequately transferring evidence and policy tools from early technology adopter countries.

An Ethical Analysis of Coverage With Evidence Development.

Sometimes a government or other payer is called on to fund a new health technology even when the evidence leaves a lot of uncertainty. One option is for the payer to provisionally fund the technology and reduce uncertainty by developing evidence. This is called coverage with evidence development (CED). Only-in-research CED, when the payer funds the technology only for patients who participate in the evidence development, raises the sharpest ethical questions. Is the patient coerced or induced into participating? If so, under what circumstances, if any, is this ethically justified? Building on work by Miller and Pearson, we argue that patients have a right to funding for a technology only when the payer can be confident that the technology provides reasonable value for money. Technologies are candidates for CED precisely because serious questions remain about value for money, and therefore patients have no right to technologies under a CED arrangement. This is why CED induces rather than coerces. The separate question of whether the inducement is ethically justified remains. We argue that CED does pose risks to patients, and the worse these risks are, the harder it is to justify the inducement. Finally, we propose conditions under which the inducement could be ethically justified and means of avoiding inducement altogether. We draw on the Australian context, and so our conclusions apply most directly to comparable contexts, where the payer is a government that provides universal coverage with a regard for cost-effectiveness that is prominent and fairly clearly defined.

Conditional Financing of Drugs in the Netherlands: Past, Present, and Future-Results From Stakeholder Interviews.

BACKGROUND: Conditional financing (CF) of hospital drugs was implemented in the Netherlands as a form of managed entry agreements between 2006 and 2012. CF was a 4-year process comprising 3 stages: initial health technology assessment of the drug (T = 0), conduct of outcomes research studies, and reassessment of the drug (T = 4). OBJECTIVES: To analyze stakeholder experiences in implementing CF in practice. METHODS: Public and private stakeholders were approached for participation in stakeholder interviews through standardized email invitations. An interview guide was developed to guide discussions that covered the following topics: perceived aims of CF, functioning of CF, impact of CF, and conclusions and future perspectives. Extensive summaries were generated for each interview and subsequently used for directed content analysis. RESULTS: Thirty stakeholders were interviewed. Differences emerged among the stakeholders on the perceived aims of CF. Conversely, there was some agreement among stakeholders on the shortcomings in the functioning of CF, the positive impact of CF on the Dutch healthcare setting, and improvement points for CF. CONCLUSIONS: Despite stakeholders' belief that CF either did not meet its aims or only partially did so, there was agreement on the need for new policy to address the same aims of CF in the future. Nevertheless, stakeholders diverged on whether CF should be improved on the basis of learnings identified and reintroduced into practice or replaced with new policy schemes.

Improving Access to High-Cost Technologies in the Asia Region.

OBJECTIVES: Discussions at the Health Technology Assessment International (HTAi) Asia Policy Forum (HAPF) aimed to understand the meaning of "high-cost technologies," and to explore mechanisms to increase access to these technologies in publicly funded health systems in the Asia region. METHODS: Discussions and presentations at the 2018 HAPF, informed by a literature review and a premeeting survey of HTA agencies and industry, form the basis of this paper. RESULTS: Challenges payers in the public health system face when investing in high-cost technologies include a lack of data, especially real-world data, affordability, and the budgetary impact of high-cost technologies. Managed entry schemes (MES) are one means to enable earlier access to high-cost technologies, or at reduced cost to the system. Most countries surveyed had used an MES to introduce a new health technology and most industry representatives had experience with financial-based MES, such as discounts or rebates, with most put in place to increase access to pharmaceuticals. Little experience of outcome-based or evidence-generation MES was reported. CONCLUSIONS: Although it is early days in the implementation of MES in Asia, they have the potential to play an important role enabling access to new, mainly pharmaceutical, health technologies. The development of a "road map" of MES in the region should outline the intent and need for a MES, articulating the "rules of engagement" for all stakeholders-patients, providers, payers, and industry-which will assist countries to clearly identify the problem trying to be solved, and how an MES can be part of the solution.

Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation.

BACKGROUND: An emerging immunotherapy is infusion of tumor infiltrating Lymphocytes (TIL), with objective response rates of around 50% versus 19% for ipilimumab. As an Advanced Therapeutic Medicinal Products (ATMP), TIL is highly personalized and complex therapy. It requests substantial upfront investments from the hospital in: expensive lab-equipment, staff expertise and training, as well as extremely tight hospital logistics. Therefore, an early health economic modelling study, as part of a Coverage with Evidence Development (CED) program, was performed. METHODS: We used a Markov decision model to estimate the expected costs and outcomes (quality-adjusted life years; QALYs) for TIL versus ipilimumab for second line treatment in metastatic melanoma patients from a Dutch health care perspective over a life long time horizon. Three mutually exclusive health states (stable disease (responders)), progressive disease and death) were modelled. To inform further research prioritization, Value of Information (VOI) analysis was performed. RESULTS: TIL is expected to generate more QALYs compared to ipilimumab (0.45 versus 0.38 respectively) at lower incremental cost (presently €81,140 versus €94,705 respectively) resulting in a dominant ICER (less costly and more effective). Based on current information TIL is dominating ipilimumab and has a probability of 86% for being cost effective at a cost/QALY threshold of €80,000. The Expected Value of Perfect Information (EVPI) amounted to €3 M. CONCLUSIONS: TIL is expected to have the highest probability of being cost-effective in second line treatment for advanced melanoma compared to ipilimumab. To reduce decision uncertainty, a clinical trial investigating e.g. costs and survival seems most valuable. This is currently being undertaken as part of a CED program in the Netherlands Cancer Institute, Amsterdam, the Netherlands, in collaboration with Denmark.

Physicians' Decision Making on Adoption of New Technologies and Role of Coverage with Evidence Development: A Qualitative Study.

OBJECTIVES: To foster value-based pricing and coverage with evidence development in Germany, certain new diagnostic and treatment methods have been subject to a benefit assessment since 2016 to determine their reimbursement. Although this is a paradigm shift, the German approach is limited to some few specific technologies for which reimbursement is requested. As physicians encounter this regulatory instrument, the aim of the study was to understand physicians' decision making regarding the adoption of new medical technologies and to identify their perspectives on the evidence base and financing with additional reimbursement systems. METHODS: From April to August 2017, semistructured interviews with chief and senior physicians of vascular surgery and cardiology in inpatient care in Germany were conducted (N = 23). The interviews were carried out by one researcher in one-to-one appointments or via telephone. Data were analyzed inductively to identify factors and generate thematic categories using qualitative content analysis. RESULTS: We identified 52 factors in eight categories influencing physicians' adoption of new technologies. The evidence base for new technologies was criticized (e.g., lack of available studies). Physicians' knowledge of the regulation of market approval and innovation payments varied. They recommended the utilization of new technologies in certain specialist centers and the facilitation of observational studies. CONCLUSIONS: Physicians saw the need for the new approach and supported its aim. However, its design and implementation appeared to be questionable from their medical perspective. The provision of summarized information on the benefit of technologies might be a possibility to assist physicians' decision making.

Decision uncertainty and value of further research: a case-study in fenestrated endovascular aneurysm repair for complex abdominal aortic aneurysms.

BACKGROUND: Fenestrated endovascular aneurysm repair (fEVAR) is a new approach for complex abdominal aortic aneurysms, limited to a few specialist centers, with limited evidence base. We developed a cost-effectiveness decision model of fEVAR compared to open surgical repair (OSR) to investigate the likely direction of costs and benefits and inform further research projects on this technology. METHODS: A systematic review with meta-analysis and a four-state Markov model were used to estimate the cost-effectiveness of fEVAR versus OSR. We used a recent coverage with evidence development framework to characterize the main sources of uncertainty and inform decisions about the type of further research that would be most worthwhile and feasible. RESULTS: Seven observational comparative studies were identified, of which four presented odds ratios adjusted for confounders. The odds ratios for operative mortality varied widely between studies. Assuming a central estimate of the odds ratio of 0.54 (95% CI 0.05-6.24), the decision model estimated that the incremental cost per quality adjusted life year (QALY) was £74,580/QALY with a probability of 9 and 16% of being cost-effective at standard cost-effectiveness thresholds of £20,000/QALY and £30,000/QALY, respectively. The Expected Value of Perfect Information over 10 years at a threshold of £20,000/QALY was £11.2 million. Operative mortality contributed to most of the uncertainty in the decision model. CONCLUSIONS: In the case of "maturing technologies", decision modelling indicates the likely direction of costs and benefits and guides the development of further research projects. In our analysis of fEVAR versus OSR, decision uncertainty, particularly around operative mortality, might be effectively resolved by a short-term RCT, or possibly a well-conducted comparative observational study. Decision makers may consider that a conditional coverage decision is warranted with assessments required to make this type of recommendation depending on local priorities and circumstances.

The Challenge of Conditional Reimbursement: Stopping Reimbursement Can Be More Difficult Than Not Starting in the First Place!

BACKGROUND: Conditional reimbursement of new health technologies is increasingly considered as a useful policy instrument. It allows gathering more robust evidence regarding effectiveness and cost-effectiveness of new technologies without delaying market access. Nevertheless, the literature suggests that ending reimbursement and provision of a technology when it proves not to be effective or cost-effective in practice may be difficult. OBJECTIVES: To investigate how policymakers and the general public in the Netherlands value removing a previously reimbursed treatment from the basic benefits package relative to not including a new treatment. METHODS: To investigate this issue, we used discrete-choice experiments. Mixed multinomial logit models were used to analyze the data. Compensating variation values and changes in probability of acceptance were calculated for withdrawal of reimbursement. RESULTS: The results show that, ceteris paribus, both the general public (n = 1169) and policymakers (n = 90) prefer a treatment that is presently reimbursed over one that is presently not yet reimbursed. CONCLUSIONS: Apparently, ending reimbursement is more difficult than not starting reimbursement in the first place, both for policymakers and for the public. Loss aversion is one of the possible explanations for this result. Policymakers in health care need to be aware of this effect before engaging in conditional reimbursement schemes.

New French Coverage with Evidence Development for Innovative Medical Devices: Improvements and Unresolved Issues.

We describe here recent modifications to the French Coverage with Evidence Development (CED) scheme for innovative medical devices. CED can be defined as temporary coverage for a novel health product during collection of the additional evidence required to determine whether definitive coverage is possible. The principle refinements to the scheme include a more precise definition of what may be considered an innovative product, the possibility for device manufacturers to request CED either independently or in partnership with hospitals, and the establishment of processing deadlines for health authorities. In the long term, these modifications may increase the number of applications to the CED scheme, which could lead to unsustainable funding for future projects. It will also be necessary to ensure that the study conditions required by national health authorities are suitable for medical devices and that processing deadlines are met for the scheme to be fully operational. Overall, the modifications recently applied to the French CED scheme for innovative medical devices should increase the transparency of the process, and therefore be more appealing to medical device manufacturers.

A Comprehensive Algorithm for Approval of Health Technologies With, Without, or Only in Research: The Key Principles for Informing Coverage Decisions.

BACKGROUND: The value of evidence about the performance of a technology and the value of access to a technology are central to policy decisions regarding coverage with, without, or only in research and managed entry (or risk-sharing) agreements. OBJECTIVES: We aim to outline the key principles of what assessments are needed to inform "only in research" (OIR) or "approval with research" (AWR) recommendations, in addition to approval or rejection. METHODS: We developed a comprehensive algorithm to inform the sequence of assessments and judgments that lead to different types of guidance: OIR, AWR, Approve, or Reject. This algorithm identifies the order in which assessments might be made, how similar guidance might be arrived at through different combinations of considerations, and when guidance might change. RESULTS: The key principles are whether the technology is expected to be cost-effective; whether the technology has significant irrecoverable costs; whether additional research is needed; whether research is possible with approval and whether there are opportunity costs that once committed by approval cannot be recovered; and whether there are effective price reductions. Determining expected cost-effectiveness is only a first step. In addition to AWR for technologies expected to be cost-effective and OIR for those not expected to be cost-effective, there are other important circumstances when OIR should be considered. CONCLUSIONS: These principles demonstrate that cost-effectiveness is a necessary but not sufficient condition for approval. Even when research is possible with approval, OIR may be appropriate when a technology is expected to be cost-effective due to significant irrecoverable costs.

Unifying Research and Reimbursement Decisions: Case Studies Demonstrating the Sequence of Assessment and Judgments Required.

BACKGROUND: The key principles regarding what assessments lead to different types of guidance about the use of health technologies (Only in Research, Approval with Research, Approve, or Reject) provide an explicit and transparent framework for technology appraisal. OBJECTIVE: We aim to demonstrate how these principles and assessments can be applied in practice through the use of a seven-point checklist of assessment. METHODS: The value of access to a technology and the value of additional evidence are explored through the application of the checklist to the case studies of enhanced external counterpulsation for chronic stable angina and clopidogrel for the management of patients with non-ST-segment elevation acute coronary syndromes. RESULTS: The case studies demonstrate the importance of considering 1) the expected cost-effectiveness and population net health effects; 2) the need for evidence and whether the type of research required can be conducted once a technology is approved for widespread use; 3) whether there are sources of uncertainty that cannot be resolved by research but only over time; and 4) whether there are significant (opportunity) costs that once committed by approval cannot be recovered. CONCLUSIONS: The checklist demonstrates that cost-effectiveness is a necessary but not sufficient condition for approval. Only in Research may be appropriate when a technology is expected to be cost-effective due to significant irrecoverable costs. It is only approval that can be ruled out if a technology is not expected to be cost-effective. Lack of cost-effectiveness is not a necessary or sufficient condition for rejection.

Coverage with evidence development program on stereotactic body radiotherapy in Belgium (2013-2019): a nationwide registry-based prospective study.

Background: Although stereotactic body radiotherapy (SBRT) was progressively adopted in clinical practice in Belgium, a reimbursement request in 2011 was not granted because of remaining clinical and economic uncertainty. A coverage with evidence development (CED) program on SBRT started in 2013, with the aim to assess clinical and technical patterns-of-care in Belgium and monitor survival per indication, in view of supporting inclusion in the reimbursement system. Methods: The Belgian National Institute for Health and Disability Insurance (NIHDI) initiated this prospective observational registry. Participating departments, using SBRT in clinical practice, signed the 'NIHDI convention'. Eligible patients had a primary tumour (PT) or oligometastatic disease (OMD). Patient, tumour, and treatment characteristics were collected through an online module of the Belgian Cancer Registry, prerequisite for financing. Five-year overall survival (5YOS) and 30- and 90-days mortality were primary outcomes, derived from vital status information. Findings: Between 10/2013 and 12/2019, 20 of the 24 accredited radiotherapy departments participated, 6 were academic. Registered cases per department ranged from 21 to 867. Of 5675 registrations analysed, the majority had good performance status and limited number of lesions. Enrolment of PTs remained stable over time, OMDs almost doubled. Peripheral lung lesions dominated in PTs as in OMDs. Other metastases were (para)spinal, 'non-standard' and hepatic. Thirty- and 90-days mortalities remained below 0.5% [95% CI 0.3%-0.8%] respectively 2.1% [95% CI 1.6%-2.7%]. 5YOS varied by indication, primary prostate patients performing best (85%, 95% CI [76%, 96%]), those with liver metastases worst (19%, 95% CI [15%, 24%]). Better OS was observed in academic departments, department size did not significantly impact survival. OMD survival was better in 2018-19. Interpretation: CED can be used to define patterns-of-care and real-life outcome of innovative radiotherapy. As the observed survival for different indications was in line with outcome in emerging literature, SBRT was included in the Belgian reimbursement system as of January 2020. Funding: NIHDI financed participating departments per registered case.

Real-world evidence for coverage determination of treatments for rare diseases.

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making.

Performance-based risk-sharing arrangements-good practices for design, implementation, and evaluation: report of the ISPOR good practices for performance-based risk-sharing arrangements task force.

There is a significant and growing interest among both payers and producers of medical products for agreements that involve a "pay-for-performance" or "risk-sharing" element. These payment schemes-called "performance-based risk-sharing arrangements" (PBRSAs)-involve a plan by which the performance of the product is tracked in a defined patient population over a specified period of time and the amount or level of reimbursement is based on the health and cost outcomes achieved. There has always been considerable uncertainty at product launch about the ultimate real-world clinical and economic performance of new products, but this appears to have increased in recent years. PBRSAs represent one mechanism for reducing this uncertainty through greater investment in evidence collection while a technology is used within a health care system. The objective of this Task Force report was to set out the standards that should be applied to "good practices"-both research and operational-in the use of a PBRSA, encompassing questions around the desirability, design, implementation, and evaluation of such an arrangement. This report provides practical recommendations for the development and application of state-of-the-art methods to be used when considering, using, or reviewing PBRSAs. Key findings and recommendations include the following. Additional evidence collection is costly, and there are numerous barriers to establishing viable and cost-effective PBRSAs: negotiation, monitoring, and evaluation costs can be substantial. For good research practice in PBRSAs, it is critical to match the appropriate study and research design to the uncertainties being addressed. Good governance processes are also essential. The information generated as part of PBRSAs has public good aspects, bringing ethical and professional obligations, which need to be considered from a policy perspective. The societal desirability of a particular PBRSA is fundamentally an issue as to whether the cost of additional data collection is justified by the benefits of improved resource allocation decisions afforded by the additional evidence generated and the accompanying reduction in uncertainty. The ex post evaluation of a PBRSA should, however, be a multidimensional exercise that assesses many aspects, including not only the impact on long-term cost-effectiveness and whether appropriate evidence was generated but also process indicators, such as whether and how the evidence was used in coverage or reimbursement decisions, whether budget and time were appropriate, and whether the governance arrangements worked well. There is an important gap in the literature of structured ex post evaluation of PBRSAs. As an innovation in and of themselves, PBRSAs should also be evaluated from a long-run societal perspective in terms of their impact on dynamic efficiency (eliciting the optimal amount of innovation).

Clinical and Scientific Challenges to Effectiveness Studies Under Coverage with Evidence Development in Alzheimer's Disease.

The Centers for Medicare and Medicaid Services (CMS) has recently issued a national coverage determination for US Food and Drug Administration (FDA)-approved anti-amyloid monoclonal antibodies (mAbs) for the treatment of Alzheimer's disease (AD) under coverage with evidence development (CED). CED schemes are complex, costly, and challenging, and often fail to achieve intended objectives because of administrative and implementation issues. AD is a heterogeneous, progressive neurodegenerative disorder with complex care pathway that additionally presents scientific challenges related to the choice of study design and methods used in evaluating CED schemes. These challenges are herein discussed. Clinical findings from the US Veterans Affairs healthcare system help inform our discussion of specific challenges to CED-required effectiveness studies in AD.