R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 15.

In this latest update we discuss real-world evidence (RWE) guidance from the leading oncology professional societies, the American Society of Clinical Oncology and the European Society for Medical Oncology, and the PRINCIPLED practical guide on the design and analysis of causal RWE studies.

The Optimal Sample Size for Usability Testing, From the Manufacturer's Perspective: A Value-of-Information Approach.

OBJECTIVES: For medical devices, a usability assessment is mandatory for market access; the objective is to detect potentially harmful use errors that stem from the device's design. The manufacturer assesses the final version of the device and determines the risk-benefit ratio for remaining errors. Nevertheless, the decision rule currently used to determine the sample size for this testing has statistical limitations and the lack of a clear decision-making perspective. METHODS: As an alternative, we developed a value-of-information analysis from the medical device manufacturer's perspective. The consequences of use errors not detected during usability testing and the errors' probability of occurrence were embedded in a loss function. The value of further testing was assessed as a reduction in the expected loss for the manufacturer. The optimal sample size was determined using the expected net benefit of sampling (ENBS) (the difference between the value provided by new participants and the cost of their inclusion). RESULTS: The value-of-information approach was applied to a real usability test of a needle-free adrenaline autoinjector. The initial estimate (performed on the first n = 20 participants) gave an optimal sample size of 100 participants and an ENBS of €255 453. This estimation was updated iteratively as new participants were included. After the inclusion of 90 participants, the ENBS was null for any sample size; hence, the cost of adding more participants outweighed the expected value of information, and therefore, the study could be stopped. CONCLUSIONS: On the basis of these results, our method seems to be highly suitable for sample size estimation in the usability testing of medical devices before market access.

A Systematic Review of Health Technology Assessments of Chimeric Antigen Receptor T-Cell Therapies in Young Compared With Older Patients.

OBJECTIVES: The objective of this review was to identify sources of variability in cost-effectiveness analyses of chimeric antigen receptor T-cell (CAR-T) therapies, tisagenlecleucel and axicabtagene ciloleucel, evaluated by health technology assessment (HTA) agencies, focusing on young compared with older patients. METHODS: HTA evaluations in pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma (DLBCL) were included from Australia, Canada, England, Norway, and the United States. Key clinical evidence, economic approach, and outcomes (costs, quality-adjusted life-years [QALYs] and incremental cost-effectiveness ratios) were summarized. RESULTS: Fourteen HTA evaluations were identified (5 ALL, 9 DLBCL [4 tisagenlecleucel, 5 axicabtagene]). Analyses were naive comparisons of prospective single-arm studies for the CAR-Ts with retrospective cohort studies for the comparators. Key clinical evidence and economic model approaches were generally consistent by CAR-T and indication, although outcomes varied. Notably, incremental QALYs varied substantially in ALL (3.67-10.6 QALYs gained), whereas variation in DLBCL was less (1.21-1.97 [tisagenlecleucel], 1.97-3.40 [axicabtagene]). Discounting of costs and outcomes varied, with the highest QALYs generated for tisagenlecleucel in ALL (10.95) associated with the lowest discount rate (1.5%) and vice versa (4.97 QALYs; 5% discount rate). The approach to extrapolation of overall survival data varied, even where the same empirical data were used. CONCLUSION: Modeled, long-term treatment benefit in young patients may be associated with greater uncertainty compared with adults because of potential life-long benefits with cell and gene therapies. This reflects the methodological challenges identified by HTA agencies associated with single-arm, short-term studies.

A Review of Current Approaches to Defining and Valuing Innovation in Health Technology Assessment.

OBJECTIVES: The growing focus on the value of new drugs for patients and society has led to a more differentiated notion of innovation in the context of pharmaceutical products. The goal of this article is to provide an overview of the current debate about the definition and assessment of innovation and how innovation is considered in reimbursement and pricing decisions. METHODS: To compile the relevant literature, we followed a 2-step approach. First, we searched for peer-reviewed literature that deals with the definition of pharmaceutical innovation. Second, we reviewed health technology assessment (HTA) guidelines of 11 selected countries (Australia, Belgium, Canada, England, France, Germany, Italy, Japan, Norway, Sweden, and The Netherlands) regarding aspects of innovation that are currently considered as relevant by the respective HTA bodies. RESULTS: All countries in our sample use 1 of 2 types of reward mechanism for novel drugs that they consider provide some sort of benefit. Generally, the focus is on the therapeutic benefit of a drug, whereas, depending on the exact arrangement, other aspects can also be taken into account. A reduction in side effects and aspects of treatment convenience can be invoked in some of the countries. Mostly, however, they are not considered unless they are already captured in the clinical outcomes used to measure the therapeutic benefit. CONCLUSION: Our review shows that although the health economic literature discusses a range of aspects on how innovation may generate value even without providing an immediate added therapeutic benefit (or on top of it), these are only selectively considered in the reviewed HTA guidelines. For most part, only the added therapeutic value is crucial when it comes to pricing and reimbursement decisions.

Implementation Barriers to Value of Information Analysis in Health Technology Decision Making: Results From a Process Evaluation.

OBJECTIVES: Value of information (VOI) analysis can support health technology assessment decision making, but it is a long way from being standard use. The objective of this study was to understand barriers to the implementation of VOI analysis and propose actions to overcome these. METHODS: We performed a process evaluation of VOI analysis use within decision making on tomosynthesis versus digital mammography for use in the Dutch breast cancer population screening. Based on steering committee meeting attendance and regular meetings with analysts, we developed a list of barriers to VOI use, which were analyzed using an established diffusion model. We proposed actions to address these barriers. Barriers and actions were discussed and validated in a workshop with stakeholders representing patients, clinicians, regulators, policy advisors, researchers, and the industry. RESULTS: Consensus was reached on groups of barriers, which included characteristics of VOI analysis itself, stakeholder's attitudes, analysts' and policy makers' skills and knowledge, system readiness, and implementation in the organization. Observed barriers did not only pertain to VOI analysis itself but also to formulating the objective of the assessment, economic modeling, and broader aspects of uncertainty assessment. Actions to overcome these barriers related to organizational changes, knowledge transfer, cultural change, and tools. CONCLUSIONS: This in-depth analysis of barriers to implementation of VOI analysis and resulting actions and tools may be useful to health technology assessment organizations that wish to implement VOI analysis in technology assessment and research prioritization. Further research should focus on application and evaluation of the proposed actions in real-world assessment processes.

Accounting for Heterogeneity in Resource Allocation Decisions: Methods and Practice in UK Cancer Technology Appraisals.

OBJECTIVES: The availability of novel, more efficacious and expensive cancer therapies is increasing, resulting in significant treatment effect heterogeneity and complicated treatment and disease pathways. The aim of this study is to review the extent to which UK cancer technology appraisals (TAs) consider the impact of patient and treatment effect heterogeneity. METHODS: A systematic search of National Institute for Health and Care Excellence TAs of colorectal, lung and ovarian cancer was undertaken for the period up to April 2020. For each TA, the pivotal clinical studies and economic evaluations were reviewed for considerations of patient and treatment effect heterogeneity. The study critically reviews the use of subgroup analysis and real-world translation in economic evaluations, alongside specific attributes of the economic modeling framework. RESULTS: The search identified 49 TAs including 49 economic models. In total, 804 subgroup analyses were reported across 69 clinical studies. The most common stratification factors were age, gender, and Eastern Cooperative Oncology Group performance score, with 15% (119 of 804) of analyses demonstrating significantly different clinical outcomes to the main population; economic subgroup analyses were undertaken in only 17 TAs. All economic models were cohort-level with the majority described as partitioned survival models (39) or Markov/semi-Markov models. The impact of real-world heterogeneity on disease progression estimates was only explored in 2 models. CONCLUSION: The ability of current modeling approaches to capture patient and treatment effect heterogeneity is constrained by their limited flexibility and simplistic nature. This study highlights a need for the use of more sophisticated modeling methods that enable greater consideration of real-world heterogeneity.

Are Drugs Priced in Accordance With Value? A Comparison of Value-Based and Net Prices Using Institute for Clinical and Economic Review Reports.

OBJECTIVES: The Institute for Clinical and Economic Review (ICER) is an independent organization that reviews drugs and devices with a focus on emerging agents. As part of their evaluation, ICER estimates value-based prices (VBP) at $50 000 to $150 000 per quality-adjusted life-year (QALY) gained thresholds. We compared actual estimated net prices to ICER-estimated VBPs. METHODS: We reviewed ICER final evidence reports from November 2007 to October 2020. List prices were combined with average discounts obtained from SSR Health to estimate net prices. If a drug had been evaluated more than once for the same indication, only the more recent VBP was included. RESULTS: A total of 34 ICER reports provided unique VBPs for 102 drugs. The net price of 81% of drugs exceeded the $100 000 per QALY VBP and 71% exceeded the $150 000 per QALY VBP. The median change in net price needed to reach the $150 000 per QALY VBP was a 36% reduction. The median decrease in net price needed was highest for drugs targeting rare inherited disorders (n = 15; 62%) and lowest for cardiometabolic disorders (n = 6; 162% price increase). The reduction in net prices needed to reach ICER-estimated VBPs was higher for drugs evaluated for the first approved indication, rare diseases, less competitive markets, and if the drug approval occurred before the ICER report became available. CONCLUSION: Net prices are often above VBPs estimated by ICER. Although gaining awareness among decision makers, the long-term impact of ICER evaluations on pricing and access to new drugs continues to evolve.

Vignette-Based Utilities: Usefulness, Limitations, and Methodological Recommendations.

Health technology assessment agencies often prefer that utilities used to calculate quality-adjusted life years in cost-utility analyses (CUAs) are derived using standardized methods, such as generic preference-based measures completed by patients in clinical trials. However, there are situations when no standardized approach is feasible or appropriate for a specific medical condition or treatment that must be represented in a CUA. When this occurs, vignette-based methods are often used to estimate utilities. A vignette (sometimes called a "scenario," "health state description," "health state vignette," or "health state") is a description of a health state that is valued in a preference elicitation task to obtain a utility estimate. This method is sometimes the only feasible way to estimate utilities representing a concept that is important for a CUA. Consequently, vignette-based studies continue to be conducted and published, with the resulting utilities used in economic models to inform decision making about healthcare resource allocation. Despite the potential impact of vignette-based utilities on medical decision making, there is no published guidance or review of this methodology. This article provides recommendations for researchers, health technology assessment reviewers, and policymakers who may be deciding whether to use vignette-based methods, designing a vignette study, using vignette-based utilities in a CUA, or evaluating a CUA that includes vignette-based utilities. Recommendations are provided on: (A) when to use vignette-based utilities, (B) methods for developing vignettes, (C) valuing vignettes, (D) use of vignette-based utilities in models, and (E) limitations of vignette methods.

Does Cost-Effectiveness Analysis Overvalue Potential Cures? Exploring Alternative Methods for Applying a "Shared Savings" Approach to Cost Offsets.

OBJECTIVES: To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies. METHODS: We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation: (1) capping annual costs in the comparator arm at $150 000 per year; (2) "sharing" the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALY gains over the lifetime horizon. The impact of each alternative method was evaluated by applying it in an economic model of 3 hypothetical condition-treatment scenarios meant to reflect a diversity of chronicity and background healthcare costs. RESULTS: The alternative with greatest impact on threshold price for the fatal pediatric condition spinal muscular atrophy type 1 was the 12-year cutoff scenario. For a hypothetical one-time treatment for hemophilia A, capping cost offsets at $150 000 per year had the greatest impact. For chimeric antigen receptor T-cell treatment of non-Hodgkin's lymphoma, capping cost offsets or using 12-year threshold had little impact, whereas 50% sharing of surplus including QALY gains and cost offsets greatly reduced threshold pricing. CONCLUSIONS: Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.

The Use of Decision Analytic Modeling in the Evaluation of Surgical Innovations: A Scoping Review.

OBJECTIVES: The main objective of this review was to map how decision analytic models are used in surgical innovation (in which research phase, with what aim) and to understand how challenges related to the assessment of surgical interventions are incorporated. METHODS: We systematically searched PubMed, Embase, and the Cochrane Library for studies published in 2018. We included original articles using a decision analytic model to compare surgical strategies. We included modeling studies of surgical innovations. General, innovation, and modeling characteristics were extracted, as were outcomes, recommendations, and handling of challenges related to the assessment of surgical interventions (learning curve, incremental innovation, dynamic pricing, quality variation, organizational impact). RESULTS: We included 46 studies. The number of studies increased with each research phase, from 4% (n = 2) in the preclinical phase to 40% (n = 20) in phase 3 studies. Eighty-one studies were excluded because they investigated established surgical procedures, indicating that modeling is predominantly applied after the innovation process. Regardless of the research stage, the aim to determine cost-effectiveness was most frequently identified (n = 40, 87%), whereas exploratory aims (eg, exploring when a strategy becomes cost-effective) were less common (n = 9, 20%). Most challenges related to the assessment of surgical interventions were rarely incorporated in models (eg, learning curve [n = 1, 2%], organizational impact [n = 2, 4%], and incremental innovation [n = 1, 2%]), except for dynamic pricing (n = 10, 22%) and quality variation (n = 6, 13%). CONCLUSIONS: In surgical innovation, modeling is predominantly used in later research stages to assess cost-effectiveness. The exploratory use of modeling seems still largely overlooked in surgery; therefore, the opportunity to inform research and development may not be optimally used.

Inaugural Pharmacogenomics Access and Reimbursement Symposium.

The Pharmacogenomics Access & Reimbursement Symposium, a landmark event presented by the Golden Helix Foundation and the Pharmacogenomics Access & Reimbursement Coalition, was a 1-day interactive meeting comprised of plenary keynotes from thought leaders across healthcare that focused on value-based strategies to improve patient access to personalized medicine. Stakeholders including patients, healthcare providers, industry, government agencies, payer organizations, health systems and health policy organizations convened to define opportunities to improve patient access to personalized medicine through best practices, successful reimbursement models, high quality economic evaluations and strategic alignment. Session topics included health technology assessment, health economics, health policy and value-based payment models and innovation.

Early technology assessment of using whole genome sequencing in personalized oncology.

Introduction: Personalized medicine-based treatments in advanced cancer hold the promise to offer substantial health benefits to genetic subgroups, but require efficient biomarker-based patient stratification to match the right treatment and may be expensive. Standard molecular diagnostics are currently very heterogeneous, and tests are often performed sequentially. The alternative to whole genome sequencing (WGS) i.e. simultaneously testing for all relevant DNA-based biomarkers thereby allowing immediate selection of the most optimal therapy, is more costly than current techniques. In the current implementation stage, it is important to explore the added value and cost-effectiveness of using WGS on a patient level and to assess optimal introduction of WGS on the level of the healthcare system.Areas covered: First, an overview of current worldwide initiatives concerning the use of WGS in clinical practice for cancer diagnostics is given. Second, a comprehensive, early health technology assessment (HTA) approach of evaluating WGS in the Netherlands is described, relating to the following aspects: diagnostic value, WGS-based treatment decisions, assessment of long-term health benefits and harms, early cost-effectiveness modeling, nation-wide organization, and Ethical, Legal and Societal Implications.Expert opinion: This study provides evidence to guide further development and implementation of WGS in clinical practice and the healthcare system.

The representation of public values in health technology assessment to inform funding decisions: the case of Australia's national funding bodies.

Over the past few years, there has been an increasing recognition of the value of public involvement in health technology assessment (HTA) to ensure the legitimacy and fairness of public funding decisions [Street J, Stafinski T, Lopes E, Menon D. Defining the role of the public in Health Technology Assessment (HTA) and HTA-informed decision-making processes. Int J Technol Assess Health Care. 2020;36:87-95]. However, important challenges remain, in particular, how to reorient HTA to reflect public priorities. In a recent international survey of thirty HTA agencies conducted by the International Network of Agencies for HTA (INAHTA), public engagement in HTA was listed as one of the "Top 10" challenges for HTA agencies [O'Rourke B, Werko SS, Merlin T, Huang LY, Schuller T. The "Top 10" challenges for health technology assessment: INAHTA viewpoint. Int J Technol Assess. 2020;36:1-4].Historically, Australia has been at the forefront of the application of HTA for assessing the effectiveness and cost-effectiveness of new health technologies to inform public funding decisions. However, current HTA processes in Australia lack meaningful public inputs. Using Australia as an example, we describe this important limitation and discuss the potential impact of this gap on the health system and future directions.

Health Technology Assessment and Health Care Reimbursement in the European Union: Permissive Dissensus and the Limits of Harmonization through the Backdoor.

Member states have consistently limited the European Union's competences in the area of health care reimbursement. Despite these efforts, there has been a slow but steady tendency toward harmonization of a key tool in reimbursement decision-making: health technology assessment (HTA), a multidisciplinary evaluation of "value for money" of medicines, devices, diagnostics, and interventions, which provides expert advice for reimbursement decisions. This article examines the origins of this paradoxical appetite for harmonization as well as of the dissensus that has, at the moment, somewhat stalled further integration in HTA. It finds that the prointegration neofunctionalist "permissive dissensus" is still present in decision making on HTA but potentially offset by dissensus or outright opposition from key actors, including member states and the medical device industry. These actors are able to decipher the potential consequences of highly technical issues, such as HTA, for national systems of social protection. Despite that, they have little interest in politicizing the issue, potentially opening the door to integrative policy solutions in the future.

Exploring the status and views of managed entry agreements in Saudi Arabia: mixed-methods approach.

BACKGROUND: Healthcare payers are increasingly adopting managed entry agreements (MEAs) between themselves and manufacturers, to overcome the challenge of sustaining access in an era of innovative and high-cost medicines. This study aims to investigate current MEA activity in Saudi Arabia and explore the challenges encountered when implementing such agreements. METHODS: An explanatory sequential mixed-methods approach was used. Quantitative data on MEAs were collected, followed by qualitative semi-structured interviews with different stakeholders. RESULTS: Our questionnaire garnered responses from 18 pharmaceutical companies from 3 different continents and identified 25 agreements in Saudi Arabia since 2010. Financial-based agreements were more prevalent than outcomes-based agreements at 44% versus 32%, respectively. Stakeholders showed positive attitudes toward MEAs, valuing their benefits in facilitating market access for both costly and innovative medicines. The main challenges included data availability, administrative and financial burden, lack of expertise, confidentiality, and lack of clear regulations. CONCLUSIONS: Despite clear implementation challenges, a growing tendency toward MEAs exists in Saudi Arabia because of the potential benefits they bring to patients, healthcare providers, payers, and manufacturers. It is believed that the newly established health technology assessment center in Saudi Arabia will bring more clarity and shape the concept of MEAs in the country.

Assessing the capacity of Ghana to introduce health technology assessment: a systematic review of economic evaluations conducted in Ghana.

OBJECTIVES: Ghana is in the process of formally introducing health technology assessment (HTA) for health decision making. Similar to other low- and middle-income countries, evidence suggests that the lack of data and human capacity is a major barrier to the conduct and use of HTA. This study assessed the current human and data capacity available in Ghana to undertake HTA. METHODS: As economic evaluation (EE) forms an integral part of HTA, a systematic review of EE studies undertaken in Ghana was conducted to identify the quality and number of studies available, methods and source of data used, and local persons involved. The literature search was undertaken in EMBASE (including MEDLINE), PUBMED, and Google Scholar. The quality of studies was evaluated using the Consolidated Health Economics Evaluation Reporting Standards. The number of local Ghanaians who contributed to authorship were used as a proxy for assessing human capacity for HTA. RESULTS: Thirty-one studies were included in the final review. Overall, studies were of good quality. Studies derived their effectiveness, resource utilization and cost data mainly from Ghana. The most common source of cost data was from the National Health Insurance Scheme pricing list for medicines and tariffs. Effectiveness data were mostly derived from either single study or intervention programs. Sixty out of 199 authors were Ghanaians (30 percent); these authors were mostly involved in data collection and study conceptualization. CONCLUSIONS: Human capacity for HTA in Ghana is limited. To introduce HTA successfully in Ghana, policy makers would need to develop more local capacity to undertake Ghanaian-specific HTA.

The transferability of health technology assessment: the European perspective with focus on central and Eastern European countries.

INTRODUCTION: Lower-income European countries have a worse health status and less funds for health care compared to Western Europe. Despite their limited human and financial capacities for conducting Health Technology Assessment (HTA), the need for evidence-based decision-making is growing. Two main approaches emerged as potential solutions: joint clinical assessments on the European level, and simplified procedures relying on the judgments of well-established HTA agencies of Western countries. AREAS COVERED: Based on considerations of transferability, the European Network for Health Technology Assessment (EUnetHTA) was built up to harmonize HTA methodologies across the European Union, and to develop an HTA Core Model by focusing on joint production of relative effectiveness assessment, which can be used as a basis for national value assessments. The second approach has been suggested in various forms without considering transferability issues. EXPERT OPINION: Joint clinical assessments reduce duplication of efforts based on appropriate scientific rationale. On the other hand, recent examples show that relying on judgments of HTA agencies from wealthier countries with potentially different health-care priorities can lead to suboptimal allocation decisions. In the short term, some stakeholders may benefit from ignoring transferability, but it will ultimately lead to limited access in other disease areas.

Shedding Light on Reimbursement Policies of Companion Diagnostics in European Countries.

OBJECTIVES: Ensuring access to precision medicine has been an issue because in some European countries, desynchronized reimbursement decision-making occurs between the medicine and the companion diagnostic (CDx). This has resulted in cases in which precision medicine is reimbursed but not the CDx. In overcoming this issue, an alignment of the decision-making process for reimbursement between the 2 entities should be considered. As pharmaceutical reimbursement procedures are meticulously covered in the literature, we set out to systematically map in vitro diagnostic (IVD) reimbursement procedures and identify policies for aligning these procedures with the pharmaceutical reimbursement procedures. METHODS: We selected 8 European countries for this analysis. For each country, we characterized the national benefit basket entailing the IVD medical acts in outpatient care, evaluated the procedure for inclusion, and identified alternative reimbursement practices for CDx. Targeted searches, using publicly accessible sources, were conducted to identify relevant reimbursement policies and laws. RESULTS: We systematically describe the reimbursement process in 8 European countries. Alternative procedures for CDx reimbursement were identified in Belgium and Germany. Alternative policies attributed to the practice of precision medicine were identified in England and Italy. In France, some CDx are included in the "coverage with evidence" development program. Specifically, the health technology assessment agencies of France and England commented on the assessment of companion diagnostics and their clinical utility. CONCLUSION: CDx reimbursement procedures have recently been implemented in some countries. This was seemingly done primarily to ensure access to the precision medicine and only secondary to the value they would provide.

Include Payers in Your Product Development and Clinical Use Processes.

Wound/ulcer management scientists, researchers, manufacturers, professionals, and providers cannot assume that clearance or approval by the Food and Drug Administration (FDA) will guarantee reimbursement for medical devices they develop or wish to use in their practices. Even if a relative code and a published payment rate for the code exist, if the payers do not provide coverage for the technology, the devices may not be able to be sold and used in all settings throughout the continuum of care. Unfortunately, reimbursement (particularly coverage) is often an after-thought once FDA clearance or approval is achieved. This article describes two new Medicare coverage processes that should encourage all stakeholders to educate payers early and often why important medical devices should be covered for their patients with wounds/ulcers.