OBJECTIVE: Estimates of minimally important differences (MID) can assist interpretation of data collected using patient-reported outcomes (PRO), but variability exists in the emphasis placed on MIDs in health technology assessment (HTA) guidelines. This study aimed to identify to what extent information on the MID of a commonly used PRO, the EQ-5D, is required and utilised by selected HTA agencies.
METHODS: Technology appraisal (TA) documents from HTA agencies in England, France, Germany, and the US between 2019 and 2021 were reviewed to identify documents which discussed MID of EQ-5D data as a clinical outcome assessment (COA) endpoint.
RESULTS: Of 151 TAs utilising EQ-5D as a COA endpoint, 58 (38%) discussed MID of EQ-5D data. Discussion of MID was most frequent in Germany, in 75% (n = 12/16) of Gemeinsamer Bundesausschuss (G-BA) and 44% (n = 34/78) of Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, (IQWiG) TAs. MID was predominantly applied to the EQ-VAS (n = 50), most frequently using a threshold of > 7 or > 10 points (n = 13). G-BA and IQWiG frequently criticised MID analyses, particularly the sources of MID thresholds for the EQ-VAS, as they were perceived as being unsuitable for assessing the validity of MID.
CONCLUSIONS: MID of the EQ-5D was not frequently discussed outside of Germany, and this did not appear to negatively impact decision-making of these HTA agencies. While MID thresholds were often applied to EQ-VAS data in German TAs, analyses were frequently rejected in benefit assessments due to concerns with their validity. Companies should pre-specify analyses of continuous data in statistical analysis plans to be considered for treatment benefit assessment in Germany.

Aim: Regulatory and health technology assessment (HTA) agencies have increasingly published frameworks, guidelines, and recommendations for the use of real-world evidence (RWE) in healthcare decision-making. Variations in the scope and content of these documents, with updates running in parallel, may create challenges for their implementation especially during the market authorization and reimbursement phases of a medicine\'s life cycle. This environmental scan aimed to comprehensively identify and summarize the guidance documents for RWE developed by most well-established regulatory and reimbursement agencies, as well as other organizations focused on healthcare decision-making, and present their similarities and differences. Methods: RWE guidance documents, including white papers from regulatory and HTA agencies, were reviewed in March 2024. Data on scope and recommendations from each body were extracted by two reviewers and similarities and differences were summarized across four topics: study planning, choosing fit-for-purpose data, study conduct, and reporting. Post-authorization or non-pharmacological guidance was excluded. Results: Forty-six documents were identified across multiple agencies; US FDA produced the most RWE-related guidance. All agencies addressed specific and often similar methodological issues related to study design, data fitness-for-purpose, reliability, and reproducibility, although inconsistency in terminologies on these topics was noted. Two HTA bodies (National Institute for Health and Care Excellence [NICE] and Canada\'s Drug Agency) each centralized all related RWE guidance under a unified framework. RWE quality tools and checklists were not consistently named and some differences in preferences were noted. European Medicines Agency, NICE, Haute Autorité de Santé, and the Institute for Quality and Efficiency in Health Care included specific recommendations on the use of analytical approaches to address RWE complexities and increase trust in its findings. Conclusion: Similarities in agencies\' expectations on RWE studies design, quality elements, and reporting will facilitate evidence generation strategy and activities for manufacturers facing multiple, including global, regulatory and reimbursement submissions and re-submissions. A strong preference by decision-making bodies for local real-world data generation may hinder opportunities for data sharing and outputs from international federated data networks. Closer collaboration between decision-making agencies towards a harmonized RWE roadmap, which can be centrally preserved in a living mode, will provide manufacturers and researchers clarity on minimum acceptance requirements and expectations, especially as novel methodologies for RWE generation are rapidly emerging.

OBJECTIVE: To assess the potential number of EU PICOs based on EUnetHTA 21 guidance and to explore further evidence-based opportunities to produce more predictable and workable EU PICOs.
METHODS: The consolidated EU PICOs of two future hypothetical medicines in first line non small cell lung cancer (1L NSCLC) and third line multiple myeloma (3L MM) were derived using published HTA reports of two recent medicines in similar indications based on EUnetHTA 21 proposed guidance. Sensitivity analysis assessed the impact of additional PICO requests. The number of analyses requested was estimated.
RESULTS: In 1L NSCLC and 3L MM, six and nine EU Member States (MS), respectively, had published HTA reports. PICO consolidation resulted in 10 PICOs for 1L NSCLC and 16 PICOs for 3L MM, increasing to 14 and 18 PICOs respectively when England\'s NICE scope was included to proxy remaining MS. A minimum of 280 and 720 analyses would be requested, exponentially increasing as additional outcome measures and subgroups are requested.
CONCLUSIONS: The PICO approach outlined by EUnetHTA 21 results in a significant number of analysis requests and substantial resources. Use of complementary analyses alongside evidence-based methods to derive PICOs and engaging with the health technology developer throughout the process, would create a workable EU PICO that is predictable and most impactful for the EU, resulting in a timely and high-quality assessment report that is more usable at a MS level.

OBJECTIVE: Valuing and pricing the components of combination therapies can be difficult due to competition law issues, difficulty implementing different prices for the same product in alternative uses, and attributing value to each component of the combination. We propose a value attribution solution that allows all combination components to be priced according to their relative value in the combination.
METHODS: We developed a value attribution solution that is universal, symmetrical, and neutral to each combination constituent, regardless of whether it is the backbone or the add-on; and complete, meaning it will always attribute the full value of the combination between the component parts. Moreover, it can be applied to any number of components in the combination (e.g. triplets or quadruplets). We compared this solution to two other existing approaches.
RESULTS: The results of the proposed value attribution solution sit between those of the two other value attribution approaches as it combines elements of each. As the degree of additivity moves further away from one in either direction, then our general approach ratios also move, reflecting the impact of the incremental value.
CONCLUSIONS: The proposed value attribution solution for combination therapies differs from two existing approaches by being universally applicable and allowing for symmetry when neutral to the constituent components of the combination. To optimally contribute to policy debate and practice, various requirements for its implementation need to be well understood including how to overcome (1) partial information, (2) whether its assumptions can be relaxed, and (3) implementation issues.

There has been a transition from broad to more specific research questions in the practice of network meta-analysis (NMA). Such convergence is also taking place in the context of individual registrational trials, following the recent introduction of the estimand framework, which is impacting the design, data collection strategy, analysis and interpretation of clinical trials. The language of estimands has much to offer to NMA, particularly given the \"narrow\" perspective of treatments and target populations taken in health technology assessment.

UNASSIGNED: Identify, through a systematic review, the main domains and methods to support health technology assessment of Medical Devices (MD) from the perspective of technological incorporation into healthcare systems.
UNASSIGNED: Performed structured searches in MEDLINE, Embase, BVS, Cochrane Library, and Web of Science for full studies published between 2017 and May 2023. Selection, extraction, and quality assessment were performed by two blinded reviewers, and discrepancies were resolved by a third reviewer.
UNASSIGNED: A total of 5,790 studies were retrieved, of which 41 were included. We grouped the identified criteria into eight domains for the evaluations.
UNASSIGNED: Overall, studies discuss the need to establish specific methods for conducting HTA in MD. Due to the wide diversity of MD types, a single methodological guideline may not encompass all the specificities and intrinsic characteristics of the plurality of MD. Studies suggest using clustering criteria through technological characterization as a strategy to make the process as standardized as possible.

In the pursuit of universal health coverage, countries are invariably confronted with questions about which services to pay with public funds, to whom, and at what cost. Such priority-setting processes have major ramifications for the costs and benefits of care delivered. These processes are not just technical, but also highly political and organizational in nature and expressions of social values. This special issue focuses on building institutions for priority setting in health. These institutions serve a public purpose and are primarily concerned with conducting or using health technology assessment (HTA) to inform resource allocation decisions. We first define the concept of institutions for priority setting in health and the methodological considerations of assessing and evaluating these institutions. Next, we present key common themes and summarize key messages across the articles, including lessons learned and future challenges in building these institutions.

BACKGROUND: Countries designing a health benefit package (HBP) to support progress towards universal health coverage (UHC) require robust cost-effectiveness evidence. This paper reports on Pakistan\'s approach to assessing the applicability of global cost-effectiveness evidence to country context as part of a HBP design process.
METHODS: A seven-step process was developed and implemented with Disease Control Priority 3 (DCP3) project partners to assess the applicability of global incremental cost-effectiveness ratios (ICERs) to Pakistan. First, the scope of the interventions to be assessed was defined and an independent, interdisciplinary team was formed. Second, the team familiarized itself with intervention descriptions. Third, the team identified studies from the Tufts Medical School Global Health Cost-Effectiveness Analysis (GH-CEA) registry. Fourth, the team applied specific knock-out criteria to match identified studies to local intervention descriptions. Matches were then cross-checked across reviewers and further selection was made where there were multiple ICER matches. Sixth, a quality scoring system was applied to ICER values. Finally, a database was created containing all the ICER results with a justification for each decision, which was made available to decision-makers during HBP deliberation.
RESULTS: We found that less than 50% of the interventions in DCP3 could be supported with evidence of cost-effectiveness applicable to the country context. Out of 78 ICERs identified as applicable to Pakistan from the Tufts GH-CEA registry, only 20 ICERs were exact matches of the DCP3 Pakistan intervention descriptions and 58 were partial matches.
CONCLUSIONS: This paper presents the first attempt globally to use the main public GH-CEA database to estimate cost-effectiveness in the context of HBPs at a country level. This approach is a useful learning for all countries trying to develop essential packages informed by the global database on ICERs, and it will support the design of future evidence and further development of methods.

UNASSIGNED: Next-generation sequencing (NGS) identifies genetic variants to inform personalized treatment plans. Insufficient evidence of cost-effectiveness impedes the integration of NGS into routine cancer care. The complexity of personalized treatment challenges conventional economic evaluation. Clearly delineating challenges informs future cost-effectiveness analyses to better value and contextualize health, preference-, and equity-based outcomes.
UNASSIGNED: We conducted a scoping review to characterize the applied methods and outcomes of economic evaluations of NGS in oncology and identify existing challenges. We included 27 articles published since 2016 from a search of PubMed, Embase, and Web of Science. Identified challenges included defining the evaluative scope, managing evidentiary limitations including lack of causal evidence, incorporating preference-based utility, and assessing distributional and equity-based impacts. These challenges reflect the difficulty of generating high-quality clinical effectiveness and real-world evidence (RWE) for NGS-guided interventions.
UNASSIGNED: Adapting methodological approaches and developing life-cycle health technology assessment (HTA) guidance using RWE is crucial for implementing NGS in oncology. Healthcare systems, decision-makers, and HTA organizations are facing a pivotal opportunity to adapt to an evolving clinical paradigm and create innovative regulatory and reimbursement processes that will enable more sustainable, equitable, and patient-oriented healthcare.

OBJECTIVE: Health technology assessment (HTA) of advanced therapy medicinal products (ATMPs), such as high-cost, one-time cell and gene therapies, is particularly challenging. Outcomes-based agreements (OBAs) are a potential solution to mitigate the risks while providing access to patients but are not widely used across Europe. This study aimed to develop policy recommendations to support the acceptability and implementation of OBAs in Europe.
METHODS: A policy sandbox approach was used to engage with stakeholders and explore how HTA organisations can support reimbursement decisions regarding OBAs for ATMPs. A panel of 38 experts from across the European region was convened in two workshops, representing payers, HTA organisations, patients, registries, and an industry trade body.
RESULTS: Policy recommendations were developed to support the appropriate consideration of OBAs for reimbursing highly uncertain technologies, such as ATMPs. If a positive HTA recommendation cannot be made at the proposed price, then a simple price discount reflecting the uncertainty is preferred over complex solutions like OBAs. If an OBA is pursued, it should be designed collaboratively with all stakeholders to understand data collection feasibility and minimise burden to patients and providers. Payers are encouraged to approach OBAs as a tool for informed decision-making, including a readiness to make negative reimbursement decisions based on unfavourable evidence.
CONCLUSIONS: The study presents a policy framework for using OBAs in reimbursement decisions. OBAs must be carefully designed, focusing on appropriateness and the burden of implementation. The relevant authorities should be committed to making decisions in light of the resulting evidence.