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Background: Chronic leg ulcers present a global challenge in healthcare, necessitating precise wound measurement for effective treatment evaluation. This study is the first to validate the \"split-wound design\" approach for wound studies using objective measures. We further improved this relatively new approach and combined it with a semi-automated wound measurement algorithm. Method: The algorithm is capable of plotting an objective halving line that is calculated by splitting the bounding box of the wound surface along the longest side. To evaluate this algorithm, we compared the accuracy of the subjective wound halving of manual operators of different backgrounds with the algorithm-generated halving line and the ground truth, in two separate rounds. Results: The median absolute deviation (MAD) from the ground truth of the manual wound halving was 2% and 3% in the first and second round, respectively. On the other hand, the algorithm-generated halving line showed a significantly lower deviation from the ground truth (MAD = 0.3%, p < 0.001). Conclusions: The data suggest that this wound-halving algorithm is suitable and reliable for conducting wound studies. This innovative combination of a semi-automated algorithm paired with a unique study design offers several advantages, including reduced patient recruitment needs, accelerated study planning, and cost savings, thereby expediting evidence generation in the field of wound care. Our findings highlight a promising path forward for improving wound research and clinical practice.

Evidence of clinical impact is critical to unlock the potential of digital health solutions (DHSs), yet many solutions are failing to deliver positive clinical results. We argue in this viewpoint that this failure is linked to current approaches to DHS evaluation design, which neglect numerous key characteristics (KCs) requiring specific scientific and design considerations. We first delineate the KCs of DHSs: (1) they are implemented at health care system and patient levels; (2) they are \"complex\" interventions; (3) they can drive multiple clinical outcomes indirectly through a multitude of smaller clinical benefits; (4) their mechanism of action can vary between individuals and change over time based on patient needs; and (5) they develop through short, iterative cycles-optimally within a real-world use context. Following our objective to drive better alignment between clinical evaluation design and the unique traits of DHSs, we then provide methodological suggestions that better address these KCs, including tips on mechanism-of-action mapping, alternative randomization methods, control-arm adaptations, and novel end-point selection, as well as innovative methods utilizing real-world data and platform research.

BACKGROUND: Although stakeholder involvement in policymaking is attracting attention in the fields of medicine and healthcare, a practical methodology has not yet been established. Rare-disease policy, specifically research priority setting for the allocation of limited research resources, is an area where evidence generation through stakeholder involvement is expected to be effective. We generated evidence for rare-disease policymaking through stakeholder involvement and explored effective collaboration among stakeholders.
METHODS: We constructed a space called \'Evidence-generating Commons\', where patients, family members, researchers, and former policymakers can share their knowledge and experiences and engage in continual deliberations on evidence generation. Ten rare diseases were consequently represented. In the \'Commons\', 25 consecutive workshops were held predominantly online, from 2019 to 2021. These workshops focused on (1) clarification of difficulties faced by rare-disease patients, (2) development and selection of criteria for priority setting, and (3) priority setting through the application of the criteria. For the first step, an on-site workshop using sticky notes was held. The data were analysed based on KJ method. For the second and third steps, workshops on specific themes were held to build consensus. The workshop agendas and methods were modified based on participants\' feedback.
RESULTS: The \'Commons\' was established with 43 participants, resulting in positive effects such as capacity building, opportunities for interactions, mutual understanding, and empathy among the participants. The difficulties faced by patients with rare diseases were classified into 10 categories. Seven research topics were identified as priority issues to be addressed including \'impediments to daily life\', \'financial burden\', \'anxiety\', and \'burden of hospital visits\'. This was performed by synthesising the results of the application of the two criteria that were particularly important to strengthen future research on rare diseases. We also clarified high-priority research topics by using criteria valued more by patients and family members than by researchers and former policymakers, and criteria with specific perspectives.
CONCLUSIONS: We generated evidence for policymaking in the field of rare diseases. This study\'s insights into stakeholder involvement can enhance evidence-informed policymaking. We engaged in comprehensive discussions with policymakers regarding policy implementation and planned analysis of the participants\' experiences in this project.
Stakeholder involvement is significant for effective policymaking in the field of rare diseases. However, practical methods for this involvement have not yet been established. Therefore, we developed the ‘Commons project’ to generate valuable policymaking information and explore effective ways for stakeholders’ collaboration. This article explains the process and results of 25 continuous workshops, held from 2019 to 2021 with 43 participants, including patients, family members, researchers, and former policymakers. The main achievements of the discussion that took place in the ‘Commons’ included a presentation of the overview of the difficulties faced by patients with rare diseases and formulation of high priority research topics.First, the difficulties faced by patients with rare diseases were grouped into 10 categories. Second, seven research topics were identified as priority issues including ‘impediments to daily life’, ‘financial burden’, ‘anxiety’, and ‘burden of hospital visits’. During the project process, positive effects such as capacity building, opportunities for interactions, mutual understanding, and empathy among the participants, were identified. Beyond the context of the field of rare diseases and science of policy, these findings are useful for the future of society, including co-creation among stakeholders and patient and public involvement. Based on this study’s results, we have initiated communications with policy stakeholders in the field of rare diseases, with the aim of policy implementation.

UNASSIGNED: Evidence generation for the health technology assessment (HTA) of a new technology is a long and expensive process with no guarantees that the health technology will be adopted and implemented into a health-care system. This would suggest that there is a greater risk of failure for a company developing a high-cost technology and therefore incentives (such as increasing the funding available for research or additional market exclusivity) may be needed to encourage development of such technologies as has been seen with many high-cost orphan drugs.
UNASSIGNED: This paper discusses some of the key issues relating to the evaluation of high-cost technologies through the use of existing HTA processes and what the challenges will be going forward.
UNASSIGNED: We propose that while the current HTA process is robust, its evolution into accommodating the incorporation of real-world data and evidence alongside a life-cycle HTA approach should better enable developers to produce the evidence required on effectiveness and cost-effectiveness. This should lead to reduced decision uncertainty for HTA agencies to make adoption decisions in a more timely and efficient manner. Furthermore, budget impact analysis remains important in understanding the actual financial impact on health-care systems and budgets outside of the cost-effectiveness framework used to aid decision-making.

UNASSIGNED: Evidentiary requirements for relative effectiveness assessment vary among European health technology assessment (HTA) bodies, affecting the time to HTA decision-making and potentially delaying time to patient access. Improved alignment may reduce this time; therefore, we aim to analyze the differences in evidentiary requirements for oncology drug assessments among European HTA bodies and provide recommendations toward an increased alignment.
UNASSIGNED: Interviews were conducted with stakeholders in drug assessments of Italy, the Netherlands, Poland, Portugal, England and Wales, and Sweden about evidentiary requirements for several subdomains to identify differences and obtain recommendations for addressing differences. The interview results were analyzed on degrees of evidence acceptability per HTA body and alignment on evidentiary requirements among HTA bodies.
UNASSIGNED: Subdomains demonstrating noteworthy differences concerned the acceptability of extrapolation to other populations, class effects, progression-free survival and (other) surrogate endpoints as outcomes, the absence of quality-of-life data, single-arm trials, cross-over trial designs, short trial duration, and the clinical relevance of effect size.
UNASSIGNED: Alignment can be enhanced to reduce time to decision-making and to improve equity in patient access. Proposed recommendations to achieve this included joint early dialogues, intensified collaboration and exchange between countries, joint relative effectiveness assessments, and the use of access agreements.

Artificial intelligence (AI) has attracted much attention because of its enormous potential in healthcare, but uptake has been slow. There are substantial barriers that challenge health technology assessment (HTA) professionals to use AI-generated evidence for decision-making from large real-world databases (e.g., based on claims data). As part of the European Commission-funded HTx H2020 (Next Generation Health Technology Assessment) project, we aimed to put forward recommendations to support healthcare decision-makers in integrating AI into the HTA processes. The barriers, addressed by the paper, are particularly focusing on Central and Eastern European (CEE) countries, where the implementation of HTA and access to health databases lag behind Western European countries.
We constructed a survey to rank the barriers to using AI for HTA purposes, completed by respondents from CEE jurisdictions with expertise in HTA. Using the results, two members of the HTx consortium from CEE developed recommendations on the most critical barriers. Then these recommendations were discussed in a workshop by a wider group of experts, including HTA and reimbursement decision-makers from both CEE countries and Western European countries, and summarized in a consensus report.
Recommendations have been developed to address the top 15 barriers in areas of (1) human factor-related barriers, focusing on educating HTA doers and users, establishing collaborations and best practice sharing; (2) regulatory and policy-related barriers, proposing increasing awareness and political commitment and improving the management of sensitive information for AI use; (3) data-related barriers, suggesting enhancing standardization and collaboration with data networks, managing missing and unstructured data, using analytical and statistical approaches to address bias, using quality assessment tools and quality standards, improving reporting, and developing better conditions for the use of data; and (4) technological barriers, suggesting sustainable development of AI infrastructure.
In the field of HTA, the great potential of AI to support evidence generation and evaluation has not yet been sufficiently explored and realized. Raising awareness of the intended and unintended consequences of AI-based methods and encouraging political commitment from policymakers is necessary to upgrade the regulatory and infrastructural environment and knowledge base required to integrate AI into HTA-based decision-making processes better.

Scientific advancements, new US FDA approval pathways and limited competition have contributed to rapid growth in the number of approved rare disease treatments in recent years. While the rising numbers of orphan drug approvals are a sign of success, the rapid growth in approved rare disease treatments has created concerns about the pricing of orphan drugs and their cumulative affordability to the health system. To support efforts to build a policy and practice infrastructure that drives innovation within a platform that is affordable to patients and the health system, this paper provides an analysis of potential risks as well as advantages of reform options related to drug development, pricing and coverage.

Background: The target product profile (TPP) outlines the desired profile of a target product aimed at a particular disease and is used by companies to plan clinical development. Considering the increasing importance of health technology assessment (HTA) in informing reimbursement decisions, a robust TPP needs to be built to address HTA needs, to guide an integrated evidence generation plan that will support HTA submissions. This study assessed current practices and experiences of companies in building HTA considerations into TPP development. Methods: An opinion survey was designed and conducted in 2019, as a cross-sectional questionnaire consisting of multiple-choice questions. The questionnaire provided a qualitative assessment of companies\' strategies and experiences in building HTA considerations into the TPP. Eligible survey participants were the senior management of Global HTA/Market Access Departments at 18 top international pharmaceutical companies. Results: 11 companies responded to the survey. All companies included HTA requirements in TPP development, but the timing and process varied. The key focus of HTA input related to health problems and treatment pathways, clinical efficacy/effectiveness, and safety. Variance of HTA methods and different value frameworks were identified as a challenge for development plans. Stakeholder engagement, such as HTA scientific advice, was used to pressure test the TPP. Conclusion: This research provides insight into current practice and potential opportunities for value-based drug development. It demonstrates the evolution of the TPP to encompass HTA requirements and suggests that the TPP could have a role as an iterative communication tool for use with HTA agencies to enhance an integrated evidence generation plan.

National health technology assessments (HTAs) across Europe show differences in evidentiary requirements from assessments by the European Medicines Agency (EMA), affecting time to patient access for drugs after marketing authorization. This article analyzes the differences between EMA and HTA bodies\' evidentiary requirements for oncology drugs and provides recommendations on potential further alignment to minimize and optimally manage the remaining differences.
Interviews were performed with representatives and drug assessment experts from EMA and HTA bodies to identify evidentiary requirements for several subdomains and collect recommendations for potentially more efficiently addressing differences. A comparative analysis of acceptability of the evidence by EMA and the HTA bodies and for potential further alignment between both authorities was conducted.
Acceptability of available evidence was higher for EMA than HTA bodies. HTA bodies and EMA were aligned on evidentiary requirements in most cases. The subdomains showing notable differences concerned the acceptance of limitation of the target population and extrapolation of target populations, progression-free survival and (other) surrogate endpoints as outcomes, cross-over designs, short trial duration, and clinical relevance of the effect size. Recommendations for reducing or optimally managing differences included joint early dialogues, joint relative effectiveness assessments, and the use of managed entry agreements.
Differences between assessments of EMA and HTA bodies were identified in important areas of evidentiary requirements. Increased alignment between EMA and HTA bodies is suggested and recommendations for realization are discussed.