Search Results (302)

The Joint Clinical Assessment (JCA) evaluates the relative effectiveness (RE) of interventions over comparators. While randomised control trials (RCTs) are considered the gold standard, single-arm trials (SATs) require an external control for accurate RE estimation. This study reviewed Health Technology Assessment (HTA) outcomes for medicinal products supported by SATs in France, Germany, Poland, and Spain, and simulated the JCA for these products based on evidence submitted in France. Among HTA evaluations published in France in 2019–2024, 16% were SAT-driven, and 5.6% of them included external controls. SAT-supported drugs had a high reimbursement approval rate (74%) and showed better HTA outcomes when controls were used. In Germany, 64% of SAT-based HTA outcomes indicated no added benefit and 30% a non-quantifiable benefit. In Poland and Spain, 63% and 72% HTA evaluations recommend reimbursement, respectively. Despite wide acceptance by Member States, experts determined that 94% of SAT-supported products would not qualify for JCA review due to insufficient evidence. Only 6% would qualify for JCA for a likely limited number of PICOs (Population–Intervention–Comparator–Outcome), but the certainty rating would be low. These findings suggest that SATs, as primary evidence, may not be suitable for JCA, potentially undermining HTA in EU Member States. Full article

Background/Objectives: Recurrent acute otitis media (AOM) in children is known to cause cumulative cochlear and vestibular injury. Whether a single fulminant episode severe enough to require surgical intervention produces an analogous long-term audiovestibular signature, and whether infection severity contributes to outcome independently of cumulative episode count, is unclear. The present study addressed this gap. Methods: In this single-centre retrospective cohort study, 65 paediatric patients who had undergone surgical treatment for acute mastoiditis—the fulminant form of AOM—between July 2001 and March 2021 were assessed a median of 11.5 years after surgery. Of these, 35 had undergone mastoidectomy with tympanostomy and 30 had undergone tympanostomy alone because their episode had not been severe enough to require mastoidectomy. Thirty-two age-matched healthy volunteers (one ear each) formed the control group, yielding 97 ears in three groups (Group TM, 35 ears; Group T, 30 ears; Group C, 32 ears). Extended high-frequency pure-tone audiometry (125–20 kHz), distortion-product otoacoustic emissions (DPOAEs), single-frequency and wideband tympanometry, ipsilateral acoustic reflex thresholds, and lateral-canal vestibulo-ocular reflex gain were measured. Results: Both operated groups showed significantly elevated audiometric thresholds in the high- and extended high-frequency ranges compared with controls (HTA: χ² = 24.25, p < 0.001), with corresponding reductions in DPOAE amplitudes (HTA: χ² = 25.04, p < 0.001). Group TM did not differ significantly from Group T at any frequency band, indicating a negligible additional contribution of mastoidectomy itself. Acoustic reflex thresholds were elevated in Group TM. Vestibulo-ocular reflex gain was within reference ranges in all groups. Conclusions: A single fulminant episode of acute middle-ear infection in childhood—whether severe enough to require mastoidectomy or treated by tympanostomy alone—was associated, more than a decade later, with significantly elevated audiometric thresholds closely resembling those reported after multiple recurrent infections, supporting an effect of infection severity independent of cumulative episode count. Long-term audiological follow-up with extended high-frequency audiometry and otoacoustic emission testing is warranted, irrespective of whether mastoidectomy was required. Full article

Four years after the European Regulation on Health Technology Assessment (EU HTAR) came into force and a little over a year after the implementation phase of the Regulation started, with the publication of the first Joint Clinical Assessment (JCA) report imminent, it is good timing to take a step back and revisit what has been achieved and look at what the main challenges on the way forward are [...] Full article

Background/Objectives: Precision medicine has moved into routine practice, but its evaluation through Health Technology Assessment (HTA) remains ethically underdeveloped. Existing instruments do not address the distinctive ethical demands of genomic profiling, AI-based clinical decision-support, and the equitable distribution of benefits from high-cost targeted therapies. Methods: A modified two-round Delphi study was conducted with a multidisciplinary panel of 18 Greek experts in bioethics, HTA, genomic medicine, nursing, and health policy. In Round 1, 32 candidate ethical statements across seven thematic domains were rated on a three-point scale; retention required a Content Validity Ratio (CVR) ≥ 0.42 and ≥80% agreement. Retained statements were re-evaluated in Round 2 with consensus defined as median ≥ 2.0 and ≥80% agreement. Reporting follows ACCORD guidelines. Results: Fifteen of 32 statements satisfied retention criteria. In Round 2, all 15 achieved consensus with a median of 3.0 and agreement of 94.4–100% (interquartile range, IQR = 0.00). Five domains constituted the final framework: fundamental ethical principles; transparency, stakeholder participation, and institutional accountability; equity and access; digital health and artificial intelligence (AI); and pandemic preparedness and system resilience. Domains addressing environmental sustainability and social acceptability did not meet the threshold. Conclusions: This study presents, to our knowledge, one of the first empirically grounded ethical frameworks for precision medicine HTA developed within an EU Member State through a formal Delphi process. The framework is operationalised through a ready-to-use ethics checklist designed for direct integration into national HTA submission and appraisal processes. Conducted in Greece—a late-aligning EU Member State—the study provides a transferable methodological template for comparable health systems across Europe. Full article

Background: Real-world evidence (RWE) can complement clinical trials to inform health technology assessments (HTAs). This study examined the extent to which RWE is considered in HTAs of non-oncology orphan medicinal products across six agencies globally. Methods: Published European Medicines Agency decisions were reviewed to identify approved non-oncology orphan medicinal products (2018–2023) that included RWE within their submission package, which was anticipated to align with the inclusion of RWE in HTA submissions. Data were extracted from the corresponding HTA reports published by six national agencies (Australia, Canada, France, Germany, Sweden, and the UK). Results: RWE was included in 105 regulatory submissions and 52.6% of the corresponding HTA reports (range: 29.9% [Germany] to 78.8% [Canada]), nearly 90% of which received a positive decision (range: 44.4% [Australia] to 100.0% [Germany]). RWE was derived from a variety of study designs and commonly supported clinical efficacy across many therapeutic areas. Conclusions: RWE commonly supports HTAs of recently approved non-oncology orphan medicinal products, strengthening the evidence base and contributing to demonstration of product value. Full article

This study investigates the impact of user workflows and iterative decision-making on task efficiency in 3D Gaussian splatting (3DGS)-based 3D reconstruction. In current 3DGS workflows, the absence of clearly defined stages and structured processes leads users to repeatedly interpret intermediate results and revisit earlier phases, thereby increasing cognitive load and reducing efficiency. To address this issue, data were collected from ten expert users experienced in 3DGS-based workflows through semi-structured interviews and shadowing observations. To systematically decompose complex and iterative user workflows, hierarchical task analysis (HTA) was employed. The results show that the workflow can be organized into six stages: (1) Data Acquisition, (2) Project Setup, (3) 3DGS Training, (4) Result Inspection, (5) Quality Refinement, and (6) Output Utilization. User workload was primarily concentrated in the Result Inspection and Quality Refinement stages, characterized by repeated retraining and decision-making processes. Based on this analysis, four issues were identified: ambiguity in early-stage configuration, limited visibility of progress status, difficulty in identifying the causes of failure, and inefficiencies in editing operations. To address these issues, an interface design consisting of four functional areas is proposed: (1) Mode & Capture Setup, (2) Progress Management, (3) Error Review, and (4) Editing Efficiency. Evaluation by expert users indicates that the proposed interface was rated significantly higher than the existing 3DGS interface across all functional areas (p < 0.01). Higher scores were observed in Error Review (M = 4.05 vs. 1.53) and Editing Efficiency (M = 4.55 vs. 1.88) compared to the existing interface. These findings suggest that interface support for error review and editing tasks plays an important role in improving workflow usability. This study structures 3DGS workflows from a user-centered perspective and identifies the key stages where iterative decision-making is most concentrated. Based on these findings, it proposes directions for 3DGS interface design and empirically demonstrates the effectiveness of the proposed design. Full article

Clay minerals in coal play a key role in controlling mineralogical composition, geochemical signatures, and the industrial behavior of coal and its combustion residues. This study investigates the occurrence, provenance, and potential applications of clay minerals in Carboniferous ash-rich coals from the Bogatyr, Lenin, and Saradyr coal mines in northeastern Kazakhstan. A total of 60 coal samples were analyzed using XRD, SEM–EDS/BSE, XRF, and ICP-OES following acid leaching. Based on ash yield, 52 samples were classified as coal (<50% ash), while 8 samples were classified as carbonaceous shale or mudstone (>50% ash). Mineralogical assemblages show clear variability among the studied mines. Saradyr samples are strongly quartz-dominated with lower clay proportions, Bogatyr samples exhibit highly heterogeneous quartz–clay–mica assemblages, whereas Lenin samples are relatively more clay-rich and dominated by kaolinite and illite-group minerals. Across all samples, kaolinite is the dominant clay mineral (16.6–46 wt.%), occurring mainly as authigenic pore- and cell-filling aggregates. Minor phases include illite–muscovite (7.1–29.9 wt.%), illite–smectite (up to 7.6 wt.% in Bogatyr), and smectite–montmorillonite (0.4–0.7 wt.%). Clay minerals occur as discrete particles, coatings, and pore fillings, contributing to ash formation; however, their correlation with ash yield is weak (R = 0.03–0.05), reflecting heterogeneous mineral inputs and diagenetic overprinting. All geochemical data are reported on a high-temperature coal ash (HTA) basis (815 °C). Geochemical indices (CIA, CIW, CIX) and Al₂O₃/TiO₂ ratios (1.8–17.4) indicate variable provenance and moderate to high weathering intensity, reflecting mixed mafic to intermediate source rocks. A total of 23 trace elements were identified. Au occurs at trace levels (up to 0.02 ppm), while selected rare earth elements (REE: Ce, Dy, Eu, La, Nd, Sm, Y, Yb) average 0.2–0.3 ppm, indicating negligible economic recovery potential. REEs show a strong positive correlation with clay minerals (r = 0.93), indicating adsorption and minor structural incorporation. In contrast, Au correlates with As, V, Zn, Cu, Ni, and Nb, suggesting sulfide association. HTA is enriched in SiO₂–Al₂O₃ phases dominated by kaolinite and quartz, indicating strong potential for cement, geopolymer, ceramic, and zeolite applications. Full article

Indirect treatment comparisons (ITCs) are essential in the context of joint clinical assessments (JCAs) under Regulation (European Union [EU]) 2021/2282, bridging evidence gaps where head-to-head data are lacking and enabling assessment across diverse national patient, intervention, comparator, and outcome (PICO) requirements. This paper critically reviews the EU Health Technology Assessment Coordination Group’s (HTACG) guidelines on direct and indirect comparisons, with particular focus on ITCs. While the guidelines promote transparency and rigorous evaluation of assumptions, they adopt a restrictive stance on assumption violations, the use of unanchored comparisons, and population-adjusted methods such as matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STC). The guidance shows limited support for Bayesian methods and undervalues meta-regression in favor of subgroup analyses. Operational implications for health technology developers (HTDs) are substantial, including new requirements for dual systematic reviews, multiple network structures, and shifted null hypothesis testing. Moreover, the guidelines effectively dissuade the use of non-randomized comparisons in rare or rapidly evolving indications and may inadvertently hinder access to effective treatments. Emerging practices such as external control arms (ECA) or target trial emulation are underdeveloped. Notably, there is no indication that the guidelines are grounded in systematic methodological validation studies. As JCAs evolve, greater methodological flexibility, empirical grounding, and clear operational guidance will be essential. Refining the guidelines along these principles would enhance their practical utility, mitigate intrinsic assessment variability, support consistent assessments across Member States (MS), and ultimately improve patient access to innovative therapies. Full article

Background: The benefit of pharmaceutical innovation manifests when patients access treatment. Following regulatory approval in Europe and Canada, reimbursement decisions depend on health technology assessments (HTAs), which can be prolonged. To quantify the impact of delays on patients, we evaluated market access timelines for olaparib, osimertinib, durvalumab, acalabrutinib, and trastuzumab deruxtecan across six high-income countries with established HTA systems (Canada, England, France, Germany, Italy, Spain). Methods: Time to access was from regulatory approval to reimbursement. Survival benefit was median overall survival (OS) and progression-free survival (PFS) assessed versus the comparator at approval and the latest data cut-off. The number of eligible patients per year multiplied by the years to patient access and survival benefit reflects the lost survival benefit. Results: Efficacy benefits observed at approval continued to the latest data cut-offs. The mean time to patient access was 18 months. Although this varied by country and treatment, with England and Germany typically being the fastest and France and Spain the slowest, timelines often exceeded the 180-day EU target despite identical evidence used in HTA submissions. This resulted in an estimated mean of 2836 patients being unable to access treatment and 3391 OS-derived and 2739 PFS-derived life-years lost. Conclusions: Access processes must evolve to ensure the timely realization of new medicines’ benefits. Full article

Health Technology Assessment (HTA) frameworks increasingly recognize the broader value elements of vaccines; however, their adoption remains inconsistent across jurisdictions and often incomplete in practice. Many HTA processes continue to prioritize narrow clinical outcomes and direct costs, leading to the underrepresentation of the full preventive and long-term benefits of vaccination. Building on the ISPOR “Elements of Value” framework and recent evidence, this study adapts and expands existing models specifically for vaccines to enhance HTA applicability in both high-income and resource-limited settings. We introduce an updated vaccine value framework comprising 21 distinct value elements. Notably, the original model was expanded by introducing four entirely new value drivers: (1) real-world evidence; (2) control of antimicrobial resistance; (3) health system strengthening; and (4) environmental impact. Additionally, existing elements were refined, such as broadening “fear of contagion” to “peace of mind” and expanding “productivity” to capture education and leisure gains. We map these elements to potential data sources and methodological tools to facilitate their inclusion in HTA. This study offers an operational, holistic, and context-sensitive framework that reflects current advancements in assessment. By capturing the full spectrum of vaccine value, this framework aims to support more comprehensive, transparent, and equitable HTA decision-making for global immunization programs, while considering conceptual overlap between value elements to reduce the risk of double counting. Full article

Background/objectives: Gram-negative bacterial infections are associated with significant morbidity and mortality. This targeted literature review (TLR) aimed to descriptively synthesise safety outcomes reported for polymyxins, aminoglycosides, and imipenem/cilastatin/relebactum (IMI/REL) in adult patients with Gram-negative infections. Methods: A TLR was conducted to identify published literature from 2015 to 2025. A database search was conducted on 14 February 2025, using the OVID^® platform and grey literature search reviewed publications from the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) and Infectious Disease (ID) Week. Safety outcomes included nephrotoxicity, other toxicities (e.g., haematological, hepatological), renal impairment, treatment-related (i.e., explicitly related to the antimicrobial treatment or its complications) discontinuation, and treatment-related mortality. Results: Sixty-eight publications were included. Definitions of nephrotoxicity varied between publications; RIFLE and KDIGO classifications were typically used. Definitions of renal impairment included renal risk/injury/failure and acute kidney injury (AKI). Colistin (n = 63) showed nephrotoxicity rates of 30.8–56.4%; renal impairment of 15.0–53.8%; treatment-related discontinuation of 12.5–23.0%; and treatment-related mortality from 20.0 to 39.1%. Polymyxin B showed nephrotoxicity rates of 14.6–54.9%; renal impairment rates ranging from 5.3 to 58.1%; and treatment-related mortality of 7.0% (n = 1). Aminoglycoside data were limited (n = 2) but showed nephrotoxicity rates of 77.8% and renal impairment of 18.8%. IMI/REL (n = 6) demonstrated nephrotoxicity of 10.3–17.2%; renal impairment of 0.0–20.7%; treatment-related discontinuation of 0.0–2.3%; and treatment-related mortality of 0.0–0.7%. Conclusions: Polymyxins/aminoglycosides had more frequently reported safety events. Fewer safety events were reported for IMI/REL across studies. These findings support the clinical use of IMI/REL and may inform Health Technology Assessment (HTA) decisions. Full article

Methodological guidelines for real-world evidence (RWE) in European Union (EU) joint clinical assessments (JCA) are lacking. This manuscript explores RWE potential in EU health technology assessment (HTA) and offers recommendations for generating high-quality RWE. An environmental scan of peer-reviewed and gray literature was conducted to review RWE frameworks and documents in EU regulatory and HTA decision-making. Extraction elements were standardized across key RWE themes: data quality, methodological rigor, stakeholder engagement, and applications. In JCA, RWE has multiple uses, including informing PICO simulation exercises, understanding disease landscape, identifying prognostic factors and effect modifiers, and directly or indirectly informing comparative clinical assessments. Methodological guidance from the HTA Coordination Group is limited to cases in which evidence from non-randomized studies is used as direct inputs in comparative assessments. Individual HTA bodies provide more detailed guidance, missing an opportunity to leverage RWE within JCAs that can offer insight for local Member State submissions. Generating high-quality RWE that is credible, actionable, and acceptable for JCA submissions and local HTA bodies requires careful attention to methodological considerations and early planning. Broader RWE integration that reflects patient journeys is needed. Expanding the HTA Coordination Group guidance can unlock RWE’s full potential in supporting EU JCA submissions. Full article

Objective: This exploratory study presents an international, multi-stakeholder snapshot of perceptions regarding real-world data and real-world evidence in health technology assessment. The aim is to identify perceived opportunities, barriers, and enabling conditions rather than to generate generalizable conclusions. Methods: A 21-item, expert-validated questionnaire was distributed via LimeSurvey to diverse health technology assessment stakeholders, including academia, industry, health technology assessment agencies, healthcare providers, policymakers, patients, and payers. The survey explored perceptions of value, methodological and regulatory challenges, and future outlooks for RWD/RWE use in HTA. Ethical approval was obtained by the University of West Attica Ethics Committee, and pilot testing was conducted prior to dissemination. Data were analyzed using descriptive statistics, consistent with the study’s exploratory intent and acknowledging that results are preliminary and not statistically generalizable. Results: Thirty-two completed responses demonstrated preliminary stakeholder support for integrating real-world data and real-world evidence into health technology assessment. Respondents represented academia, industry, HTA agencies, healthcare providers, policymakers, and patient/advocacy groups; however, no payer responses were obtained. Respondents emphasized the value of real-world data in complementing clinical trials by capturing real-world effectiveness, patient diversity, and long-term outcomes, especially in rare diseases and cancer. Key challenges included poor data quality, confounding biases, and regulatory barriers. Stakeholders highlighted the importance of standardization, transparency, and international collaboration. Opportunities included better decision-making, personalized healthcare, and improved post-market monitoring, with strong calls for robust infrastructure, clear methodologies, patient involvement, and supportive health policy frameworks. Conclusions: Real-world data and evidence enhance health technology assessment by supporting better decisions and personalized care. However, issues like data quality, methods, and trust must be addressed through standardization, strong infrastructure, and collaboration to ensure effective and impactful implementation in healthcare, while acknowledging these insights are based on a small exploratory sample. Full article

Background and Objectives: Rapid diagnosis is fundamental to acute ischemic stroke management; however, access to neuroradiological expertise remains limited. This scoping review maps the diagnostic accuracy, workflow impact, and cost-effectiveness of leading AI platforms (Brainomix, Aidoc, RapidAI, and Viz.ai), characterizing industry and peer-reviewed metrics. Materials and Methods: Following PRISMA-ScR guidelines, we searched PubMed, Cochrane Library, and HTA repositories for studies (2019–2025). Using a PICO-based framework, 29 studies were included for thematic mapping of the technological landscape. Results: Twenty-nine studies were included. Platforms show high proximal LVO sensitivity (78–97%), while performance for distal/MVO and posterior circulation occlusions was more variable. RapidAI is frequently mapped using historical perfusion trial parameters; however, volumetric discrepancies with platforms like Viz.ai indicate outputs are not interchangeable. Brainomix shows extensive validation for automated NCCT ASPECTS in triage. Aidoc demonstrates operational advantages via worklist prioritization, while. Viz.ai is associated with door-to-puncture time reductions (11–25 min). Economically, cost-effectiveness is driven by improved functional outcomes and expanded access to thrombectomy, rather than labor substitution. Conclusions: AI platforms function as diagnostic safety nets and workflow optimizers. Reported roles, such as perfusion-centric analysis (RapidAI) or workflow coordination (Viz.ai), reflect current research trends rather than definitive technological superiority. Institutional selection should consider these evidence clusters alongside local validation and specific clinical priorities. Full article