Clinical Trials最新文献

{"title":"Commentary on Adaptive versus fixed designs in confirmatory clinical trials: centering the choice on ethics, by Bass et al.","authors":"Janet Wittes","doi":"10.1177/17407745261468003","DOIUrl":"10.1177/17407745261468003","url":null,"abstract":"","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"484-485"},"PeriodicalIF":2.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trial informed consent forms, the Declaration of Helsinki and the SPIRIT 2025 statement.","authors":"Rafael Dal-Ré, Arthur L Caplan","doi":"10.1177/17407745261449402","DOIUrl":"10.1177/17407745261449402","url":null,"abstract":"","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"538-539"},"PeriodicalIF":2.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surrogate markers used as efficacy endpoints in NIH-sponsored clinical trials.","authors":"Ayman Mohammad, Samuel Yoon, Joshua D Wallach, Reshma Ramachandran, Joseph S Ross","doi":"10.1177/17407745261437294","DOIUrl":"10.1177/17407745261437294","url":null,"abstract":"","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"535-537"},"PeriodicalIF":2.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase I design for partially ordered groups with late-onset toxicity.","authors":"Rami Hawila, Susan Halabi, Ruitao Lin, Nolan A Wages","doi":"10.1177/17407745261448830","DOIUrl":"10.1177/17407745261448830","url":null,"abstract":"<p><strong>Background: </strong>In this article, we introduce a Phase I clinical trial design that utilizes late-onset toxicity outcomes to determine group-specific doses when groups are partially ordered before the trial. By \"partially ordered groups,\" we mean that the frailty order is known between some, but not all, groups. Previous research has addressed dose finding for partially ordered groups and for late-onset toxicity separately, but no solution has been proposed for dose finding that incorporates both aspects simultaneously.</p><p><strong>Methods: </strong>Motivated by a Phase Ib study involving heterogeneous groups with metastatic castration-resistant prostate cancer, we extend the continual reassessment method shift model framework to tackle the problem of dose finding in partially ordered groups with late-onset toxicity. Our simulations compare the proposed method with an approach that incorporates group information without considering late-onset toxicity. An alternative strategy could involve conducting independent parallel trials for each group; however, this approach risks dose reversals, where a more sensitive group is assigned a higher dose than a less sensitive group.</p><p><strong>Results: </strong>In comparison with a similar dose-finding method that does not incorporate late-onset toxicity, our proposed method shows similar performance in selecting the correct dose. Through an extensive simulation study, the generated results demonstrate good operating characteristics for the proposed method in terms of the proportion of correct dose selection within groups, while accounting for late-onset toxicities.</p><p><strong>Conclusion: </strong>Our proposed method avoids dose reversals and demonstrates favorable operating characteristics in recommending appropriate doses for each group.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"509-516"},"PeriodicalIF":2.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13225609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148101299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adaptive versus fixed designs in confirmatory clinical trials: centering the choice on ethics.","authors":"Stef Baas, Lukas Pin, David S Robertson, Frank Bretz, Hearn Jay Cho, Laura Flight, Rieke van der Graaf, Mackenzie Graham, Peter Jacko, Thomas Jaki, Jonathan Kimmelman, Andrea Manfrin, Richard Milne, Pavel Mozgunov, Philip Pallmann, Tom Parke, Mahesh K B Parmar, Vinciane Pirard, Kate Sahan, Jerome Amir Singh, Brian D M Tom, John C Whittaker, Katie Wozniak, David Wright, Haiyan Zheng, Alex John London, Mark Sheehan, Sofía S Villar","doi":"10.1177/17407745261468001","DOIUrl":"10.1177/17407745261468001","url":null,"abstract":"<p><strong>Background: </strong>Because confirmatory clinical trials are costly, large-scale endeavors, the choice of their design carries significant weight. While the current methodological landscape offers tools to address residual pre-trial uncertainty through prespecified adaptations to design elements, design choices remain frequently constrained by prevailing orthodoxies.</p><p><strong>Methods: </strong>We examine how unacknowledged design uncertainties (e.g., sample size calculations based on incorrect effect size or variance estimates) impact the statistical, ethical, and resource-stewardship goals of confirmatory trials. We contrast how fixed and adaptive design strategies handle these uncertainties, detailing the operational safeguards, firewalls, and trade-offs (e.g., complexity, operational bias) required to preserve trial integrity.</p><p><strong>Results: </strong>Strict adherence to default templates prevents stakeholders from matching the design strategy to the specific complexities of the research question. We observe that the gold standard status of fixed designs often obscures their limitations in handling design uncertainties. A rigid adherence to these conventions can ethically hinder a trial's ability to deliver conclusive results. Conversely, while adaptive designs can offer tools to efficiently reduce uncertainty, we acknowledge that adaptive elements are not without cost; their implementation requires rigorous safeguards to manage specific risks to trial integrity and potential operational biases.</p><p><strong>Conclusion: </strong>To better align clinical research with its ethical and scientific mandates, we issue two calls to action. First, trial designers, including statisticians, must clearly articulate how target and design uncertainties impact ethical obligations, promoting an open-minded evaluation of both fixed and adaptive methods. Second, stakeholders must foreground ethical considerations during design selection, requiring explicit justification for the use-or non-use-of adaptive elements. The ethical path forward is not to default to the old or blindly adopt the new, but to explicitly justify the chosen design based on its responsiveness to the specific uncertainties of the trial. We posit that trial design must transition from a habit-based process to one where pre-trial uncertainties are openly discussed and addressed.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"472-481"},"PeriodicalIF":2.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on \"Adaptive versus fixed designs in confirmatory clinical trials: Centering the choice on ethics\".","authors":"Stephen Senn","doi":"10.1177/17407745261468002","DOIUrl":"10.1177/17407745261468002","url":null,"abstract":"","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"482-483"},"PeriodicalIF":2.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rejoinder: \"Adaptive versus fixed designs in confirmatory clinical trials: Centering the choice on ethics\".","authors":"Stef Baas, Lukas Pin, David S Robertson, Alex John London, Mark Sheehan, Sofía S Villar","doi":"10.1177/17407745261469874","DOIUrl":"10.1177/17407745261469874","url":null,"abstract":"","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"486-489"},"PeriodicalIF":2.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A statistical evaluation of decision-making methods and the efficiency of Bayesian multi-arm multi-stage trials.","authors":"Abigail McGrory, Haolun Shi, Anna Heath","doi":"10.1177/17407745261453566","DOIUrl":"10.1177/17407745261453566","url":null,"abstract":"<p><p><b>Background/Aims</b>: Multi-arm multi-stage trials benefit patients by providing a flexible and versatile clinical trial design compared with standard randomized controlled trials. Multi-arm multi-stage trials can evaluate multiple interventions for a single disease, which avoids the need to run multiple trials. Multi-arm multi-stage trials incorporate decision-making at interim analysis, which enables the trial to stop early for futility or efficacy of a treatment. As a result, multi-arm multi-stage trials reach conclusions faster, requiring less time and resources. Despite their growing popularity, limited research has been done to examine how decision-making methods used in Bayesian multi-arm multi-stage trials impact the efficiency of the trial.<b>Methods</b>: This study examines how decision-making strategies influence the efficiency of Bayesian multi-arm multi-stage trials, including approaches for setting thresholds to declare superiority or futility and evaluating multiple treatments simultaneously. We apply the Nelder-Mead optimization algorithm to determine the decision thresholds that maximize statistical power while maintaining family-wise type I error rate below 5%. We conduct a simulation study to compare the conventional method to evaluate multiple treatments in a Bayesian multi-arm multi-stage trial to three alternatives. At each interim analysis, posterior probabilities are derived from a Normal-Gamma conjugate model, and trial decisions are made by comparing decision criteria derived from the posterior probabilities to the optimized decision thresholds. Simulation scenarios vary by treatment effect size and number of treatment arms to assess the robustness of each decision-making strategy.<b>Results</b>: All treatment comparison methods achieve similar power across simulation scenarios. However, the optimal decision thresholds vary substantially among methods. These thresholds are also lower than those currently used in Bayesian multi-arm multi-stage trials, which are often conservative and lead to reduced power. Thus, adjusting decision thresholds to the optimized values can improve trial efficiency.<b>Conclusion</b>: This study provides an exploration of alternative decision-making methods in Bayesian multi-arm multi-stage trials. Initial findings show that optimizing decision-making thresholds can improve the power of the trial without inflating the family-wise type I error rate, thus improving the efficiency of the trial. Further research should include the implementation of complex trial designs and non-normal outcomes to confirm that the results apply to adaptive platform trials.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"526-534"},"PeriodicalIF":2.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148327205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are safety lead-in phase II clinical trials really safe?","authors":"Emily N Potts, Marie Ferron, Lucie Biard, Shing M Lee","doi":"10.1177/17407745261474080","DOIUrl":"https://doi.org/10.1177/17407745261474080","url":null,"abstract":"<p><p>Background/AimsPhase II trials with a safety lead-in (SLI), allowing one or two dose de-escalations based on toxicities from the first several patients at a dose, are increasingly common in oncology. Despite increased demand, formal evaluation of SLI designs remains limited to dose selection without evaluating the performance of the phase II efficacy recommendation. This study proposes a novel framework to evaluate phase II SLI trials with one to three dose levels and examines their operating characteristics compared to more rigorous dose-finding and monitoring alternatives.MethodsInformed by a review of registered and published phase II SLI trials, we simulated trials comparing the commonly used Simon two-stage design with an SLI of six-patient cohorts to an extension adding toxicity monitoring at the end of each stage. For two and three dose levels, we further compared against phase I dose-finding using the Continual Reassessment Method (CRM), Bayesian Optimal Interval (BOIN), or 3 + 3, followed by Simon with toxicity monitoring, where patients treated at the selected dose in phase I are rolled over to phase II efficacy evaluation. Methods were evaluated by simulation on overall performance (based on joint correctness of dose selection and phase II recommendation) and average sample size. Sensitivity analyses assessed alternative specifications, including phase II design parameters, omission of rollover, and toxicity-monitoring frequency.ResultsFor one dose level, adding toxicity monitoring to Simon with SLI decreased recommendations of toxic but efficacious doses from 24% to 7%, with little difference for safe doses. For two or three dose levels with at least one acceptable dose, SLI approaches had decreased overall success compared to using CRM or BOIN first for dose selection (up to 19% and 23% lower, respectively). Algorithm-based approaches (SLI and 3 + 3) more often terminated trials incorrectly for toxicity, even with acceptable doses, but had up to 36% higher success when all doses exceeded the toxicity threshold. Without phase II toxicity monitoring, unsafe recommendations exceeded 30% for SLI Simon, decreasing to 6% when toxicity monitoring was incorporated. Rollover modestly reduced sample size without substantial loss of overall success.ConclusionsThe Simon with SLI often results in unsafe or inefficient trial recommendations. Incorporating toxicity monitoring throughout phase II is necessary to reduce such recommendations, while using CRM or BOIN for initial dose selection can improve overall success when candidate doses are expected to be well-tolerated. Given that trials differ in prior dose-toxicity information, candidate dose levels, and design priorities, we provide a framework to conduct study-specific evaluations and quantify the trade-offs of using SLI compared to more formal dose selection and toxicity-monitoring alternatives.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"17407745261474080"},"PeriodicalIF":2.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A classification of incomplete stepped wedge cluster randomised trial designs.","authors":"Ehsan Rezaei-Darzi, Andrew B Forbes, Kelsey L Grantham, Jessica Kasza","doi":"10.1177/17407745261474443","DOIUrl":"https://doi.org/10.1177/17407745261474443","url":null,"abstract":"<p><strong>Background/aims: </strong>Stepped wedge designs are cluster randomised trial designs for testing new interventions through a phased rollout of the intervention across clusters. In many trial settings, a complete stepped wedge design can place a substantial burden on clusters by requiring data collection over the entire trial duration. Incomplete stepped wedge designs, for example, \"staircase designs,\" where clusters collect data for a limited duration of time, are frequently used to overcome this issue. However, the term \"incomplete stepped wedge design\" is also used when transition or implementation periods are incorporated in an otherwise complete stepped wedge design. Thus, \"incomplete\" is an imprecise term that does not convey any specific design characteristics.</p><p><strong>Methods: </strong>We introduce terminology to enable a classification of incomplete stepped wedge designs, with a particular focus on different variants of staircase designs.</p><p><strong>Results: </strong>We provide definitions of variants of staircase designs with their sub-variants. We also describe two types of mid-sequence breaks in data collection: inter-treatment breaks occurring between control and intervention durations of data collection (i.e. implementation or transition periods), and intra-treatment breaks occurring between durations of data collection under the same treatment condition. These breaks introduce different forms of incompleteness into designs.</p><p><strong>Conclusion: </strong>Through the use of this terminology and associated classifications, trialists can more clearly communicate the way in which their \"incomplete stepped wedge design\" is incomplete, and health researchers can classify trials in systematic reviews involving complete stepped wedge designs and any incomplete variants.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"17407745261474443"},"PeriodicalIF":2.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}