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ObjectiveThere are few guidelines for clinical trials of interventions for prevention of post-traumatic osteoarthritis (PTOA), reflecting challenges in this area. An international multi-disciplinary expert group including patients was convened to generate points to consider for the design and conduct of interventional studies following acute knee injury.DesignAn evidence review on acute knee injury interventional studies to prevent PTOA was presented to the group, alongside overviews of challenges in this area, including potential targets, biomarkers and imaging. Working groups considered pre-identified key areas: eligibility criteria and outcomes, biomarkers, injury definition and intervention timing including multi-modality interventions. Consensus agreement within the group on points to consider was generated and is reported here after iterative review by all contributors.ResultsThe evidence review identified 37 studies. Study duration and outcomes varied widely and 70% examined surgical interventions. Considerations were grouped into three areas: justification of inclusion criteria including the classification of injury and participant age (as people over 35 may have pre-existing OA); careful consideration in the selection and timing of outcomes or biomarkers; definition of the intervention(s)/comparator(s) and the appropriate time-window for intervention (considerations may be particular to intervention type). Areas for further research included demonstrating the utility of patient-reported outcomes, biomarkers and imaging outcomes from ancillary/cohort studies in this area, and development of surrogate clinical trial endpoints that shorten the duration of clinical trials and are acceptable to regulatory agencies.ConclusionsThese considerations represent the first international consensus on the conduct of interventional studies following acute knee joint trauma.

In the EU, conditional marketing authorization is a pragmatic tool for early approval of a medicine that fulfills an unmet medical need. In the pharmaceutical legislation, an unmet medical need means that a condition lacks a satisfactory method for diagnosis, prevention, or treatment. If such satisfactory methods exist, the new medicinal product must hold a major therapeutic advantage for those affected, meaning that it must demonstrate an improvement in efficacy or safety over existing methods or, in exceptional cases, a major improvement in patient care. This review evaluates the approaches taken to justify a major therapeutic advantage in oncology and hematology products recommended for approval between 2006 and 2023. The review confirmed an increase in the number of conditional marketing authorizations over time. Out of a total of 65 CMAs, a satisfactory treatment method was available for 40 cases (61.5%), thereby requiring a demonstration of major therapeutic advantage to fulfill the unmet medical need requirement. Satisfactory treatments existed more often for the more recently approved medicinal products. Qualitative arguments and quantitative comparisons were common to demonstrate meaningful improvement in efficacy or safety. In the absence of head-to-head trials, indirect comparisons were often used. Most quantitative comparisons used naïve side-by-side comparisons, lacking adjustments for trial differences or quantification of uncertainty. Regulatory guidance on indirect comparisons and data requirements may be helpful to support applicants and assessors in making available promising medicines early that fulfill an unmet medical need and continue to meet rigorous efficacy and safety standards pending availability of comprehensive data post-approval., (© 2025 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: The aim of this study was to build a predictive model of operative difficulty in open liver resections (LRs)., Summary Background Data: Recent attempts at classifying open-LR have been focused on postoperative outcomes and were based on predefined anatomical schemes without taking into account other anatomical/technical factors., Methods: Four intraoperative variables were perceived by the authors as to reflect operative difficulty: operation and transection times, blood loss, and number of Pringle maneuvers. A hierarchical ascendant classification (HAC) was used to identify homogeneous groups of operative difficulty, based on these variables. Predefined technical/anatomical factors were then selected to build a multivariable logistic regression model (DIFF-scOR), to predict the probability of pertaining to the highest difficulty group. Its discrimination/calibration was assessed. Missing data were handled using multiple imputation., Results: HAC identified 2 clusters of operative difficulty. In the "Difficult LR" group (20.8% of the procedures), operation time (401 min vs 243 min), transection time (150 vs.63 minute), blood loss (900 vs 400 mL), and number of Pringle maneuvers (3 vs 1) were higher than in the "Standard LR" group. Determinants of operative difficulty were body weight, number and size of nodules, biliary drainage, anatomical or combined LR, transection planes between segments 2 and 4, 4, and 8 or 7 and 8, nonanatomical resections in segments 2, 7, or 8, caval resection, bilioentric anastomosis and number of specimens. The c-statistic of the DIFF-scOR was 0.822. By contrast, the discrimination of the DIFF-scOR to predict 90-day mortality and severe morbidity was poor (c-statistic: 0.616 and 0.634, respectively)., Conclusion: The DIFF-scOR accurately predicts open-LR difficulty and may be used for various purposes in clinical practice and research., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)