Clinical Trials最新文献

{"title":"Commentary on Astrachan et al. The transmutation of research risk in pragmatic clinical trials.","authors":"Jonathan Kimmelman","doi":"10.1177/17407745241266168","DOIUrl":"10.1177/17407745241266168","url":null,"abstract":"","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"666-668"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987543","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 comparison of computational algorithms for the Bayesian analysis of clinical trials.","authors":"Ziming Chen, Jeffrey S Berger, Lana A Castellucci, Michael Farkouh, Ewan C Goligher, Erinn M Hade, Beverley J Hunt, Lucy Z Kornblith, Patrick R Lawler, Eric S Leifer, Elizabeth Lorenzi, Matthew D Neal, Ryan Zarychanski, Anna Heath","doi":"10.1177/17407745241247334","DOIUrl":"10.1177/17407745241247334","url":null,"abstract":"<p><strong>Background: </strong>Clinical trials are increasingly using Bayesian methods for their design and analysis. Inference in Bayesian trials typically uses simulation-based approaches such as Markov Chain Monte Carlo methods. Markov Chain Monte Carlo has high computational cost and can be complex to implement. The Integrated Nested Laplace Approximations algorithm provides approximate Bayesian inference without the need for computationally complex simulations, making it more efficient than Markov Chain Monte Carlo. The practical properties of Integrated Nested Laplace Approximations compared to Markov Chain Monte Carlo have not been considered for clinical trials. Using data from a published clinical trial, we aim to investigate whether Integrated Nested Laplace Approximations is a feasible and accurate alternative to Markov Chain Monte Carlo and provide practical guidance for trialists interested in Bayesian trial design.</p><p><strong>Methods: </strong>Data from an international Bayesian multi-platform adaptive trial that compared therapeutic-dose anticoagulation with heparin to usual care in non-critically ill patients hospitalized for COVID-19 were used to fit Bayesian hierarchical generalized mixed models. Integrated Nested Laplace Approximations was compared to two Markov Chain Monte Carlo algorithms, implemented in the software JAGS and stan, using packages available in the statistical software R. Seven outcomes were analysed: organ-support free days (an ordinal outcome), five binary outcomes related to survival and length of hospital stay, and a time-to-event outcome. The posterior distributions for the treatment and sex effects and the variances for the hierarchical effects of age, site and time period were obtained. We summarized these posteriors by calculating the mean, standard deviations and the 95% equitailed credible intervals and presenting the results graphically. The computation time for each algorithm was recorded.</p><p><strong>Results: </strong>The average overlap of the 95% credible interval for the treatment and sex effects estimated using Integrated Nested Laplace Approximations was 96% and 97.6% compared with stan, respectively. The graphical posterior densities for these effects overlapped for all three algorithms. The posterior mean for the variance of the hierarchical effects of age, site and time estimated using Integrated Nested Laplace Approximations are within the 95% credible interval estimated using Markov Chain Monte Carlo but the average overlap of the credible interval is lower, 77%, 85.6% and 91.3%, respectively, for Integrated Nested Laplace Approximations compared to stan. Integrated Nested Laplace Approximations and stan were easily implemented in clear, well-established packages in R, while JAGS required the direct specification of the model. Integrated Nested Laplace Approximations was between 85 and 269 times faster than stan and 26 and 1852 times faster than JAGS.</p><p><strong>Conclusion: </str","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"689-700"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944214","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":"Individualized clinical decisions within standard-of-care pragmatic clinical trials: Implications for consent.","authors":"Isabel M Astrachan, James Flory, Scott Yh Kim","doi":"10.1177/17407745241266155","DOIUrl":"10.1177/17407745241266155","url":null,"abstract":"<p><p>Pragmatic clinical trials of standard-of-care interventions compare the relative merits of medical treatments already in use. Traditional research informed consent processes pose significant obstacles to these trials, raising the question of whether they may be conducted with alteration or waiver of informed consent. However, to even be eligible, such a trial in the United States must have no more than minimal research risk. We argue that standard-of-care pragmatic clinical trials can be designed to ensure that they are minimal research risk if the random assignment of an intervention in a pragmatic clinical trial can accommodate individualized, clinically motivated decision-making for each participant. Such a design will ensure that the patient-participants are not exposed to any risks beyond the clinical risks of the interventions, and thus, the trial will have minimal research risk. We explain the logic of this view by comparing three scenarios of standard-of-care pragmatic clinical trials: one with informed consent, one without informed consent, and one recently proposed design called Decision Architecture Randomization Trial. We then conclude by briefly showing that our proposal suggests a natural way to determine when to use an alteration versus a waiver of informed consent.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"659-665"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987544","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":"Challenges in conducting efficacy trials for new COVID-19 vaccines in developed countries.","authors":"Rafael Dal-Ré, Emmanuel Bottieau, Odile Launay, Frits R Rosendaal, Brigitte Schwarzer-Daum","doi":"10.1177/17407745241238925","DOIUrl":"10.1177/17407745241238925","url":null,"abstract":"<p><p>The protection from COVID-19 vaccination wanes a few months post-administration of the primary vaccination series or booster doses. New COVID-19 vaccine candidates aiming to help control COVID-19 should show long-term efficacy, allowing a possible annual administration. Until correlates of protection are strongly associated with long-term protection, it has been suggested that any new COVID-19 vaccine candidate must demonstrate at least 75% efficacy (although a 40%-60% efficacy would be sufficient) at 12 months in preventing illness in all age groups within a large randomized controlled efficacy trial. This article discusses four of the many scientific, ethical, and operational challenges that these trials will face in developed countries, focusing on a pivotal trial in adults. These challenges are (1) the comparator and trial population; (2) how to enroll sufficient numbers of adult participants of all age groups considering that countries will recommend COVID-19 booster doses to different populations; (3) whether having access to a comparator booster for the trial is actually feasible; and (4) the changing epidemiology of severe acute respiratory syndrome coronavirus 2 across countries involved in the trial. It is desirable that regulatory agencies publish guidance on the requirements that a trial like the one discussed should comply with to be acceptable from a regulatory standpoint. Ideally, this should happen even before there is a vaccine candidate that could fulfill the requirements mentioned above, as it would allow an open discussion among all stakeholders on its appropriateness and feasibility.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"754-758"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317946","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":"Taking clinical decisions seriously in standard-of-care pragmatic clinical trials.","authors":"Isabel M Astrachan, James Flory, Scott Yh Kim","doi":"10.1177/17407745241266152","DOIUrl":"10.1177/17407745241266152","url":null,"abstract":"","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"669-670"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987545","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":"15th Annual University of Pennsylvania conference on statistical issues in clinical trial/advances in time-to-event analyses in clinical trials (afternoon panel discussion).","authors":"Ionut Bebu, Rebecca A Betensky, Michael P Fay","doi":"10.1177/17407745241271939","DOIUrl":"10.1177/17407745241271939","url":null,"abstract":"","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"612-622"},"PeriodicalIF":2.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388715","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":"Analysis of composite time-to-event endpoints in cardiovascular outcome trials.","authors":"Rachel Marceau West, Gregory Golm, Devan V Mehrotra","doi":"10.1177/17407745241267999","DOIUrl":"10.1177/17407745241267999","url":null,"abstract":"<p><p>Composite time-to-event endpoints are commonly used in cardiovascular outcome trials. For example, the IMPROVE-IT trial comparing ezetimibe+simvastatin to placebo+simvastatin in 18,144 patients with acute coronary syndrome used a primary composite endpoint with five component outcomes: (1) cardiovascular death, (2) non-fatal stroke, (3) non-fatal myocardial infarction, (4) coronary revascularization ≥30 days after randomization, and (5) unstable angina requiring hospitalization. In such settings, the traditional analysis compares treatments using the observed time to the occurrence of the first (i.e. earliest) component outcome for each patient. This approach ignores information for subsequent outcome(s), possibly leading to reduced power to demonstrate the benefit of the test versus the control treatment. We use real data examples and simulations to contrast the traditional approach with several alternative approaches that use data for all the intra-patient component outcomes, not just the first.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"576-583"},"PeriodicalIF":2.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906134","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":"Estimands in clinical trials of complex disease processes.","authors":"Richard J Cook, Jerald F Lawless","doi":"10.1177/17407745241268054","DOIUrl":"10.1177/17407745241268054","url":null,"abstract":"<p><p>Clinical trials with random assignment of treatment provide evidence about causal effects of an experimental treatment compared to standard care. However, when disease processes involve multiple types of possibly semi-competing events, specification of target estimands and causal inferences can be challenging. Intercurrent events such as study withdrawal, the introduction of rescue medication, and death further complicate matters. There has been much discussion about these issues in recent years, but guidance remains ambiguous. Some recommended approaches are formulated in terms of hypothetical settings that have little bearing in the real world. We discuss issues in formulating estimands, beginning with intercurrent events in the context of a linear model and then move on to more complex disease history processes amenable to multistate modeling. We elucidate the meaning of estimands implicit in some recommended approaches for dealing with intercurrent events and highlight the disconnect between estimands formulated in terms of potential outcomes and the real world.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"604-611"},"PeriodicalIF":2.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046433","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":"Statistical approaches for component-wise censored composite endpoints.","authors":"Anne Eaton","doi":"10.1177/17407745241265628","DOIUrl":"10.1177/17407745241265628","url":null,"abstract":"<p><p>Composite endpoints defined as the time to the earliest of two or more events are often used as primary endpoints in clinical trials. Component-wise censoring arises when different components of the composite endpoint are censored differently. We focus on a composite of death and a non-fatal event where death time is right censored and the non-fatal event time is interval censored because the event can only be detected during study visits. Such data are most often analysed using methods for right censored data, treating the time the non-fatal event was first detected as the time it occurred. This can lead to bias, particularly when the time between assessments is long. We describe several approaches for estimating the event-free survival curve and the effect of treatment on event-free survival via the hazard ratio that are specifically designed to handle component-wise censoring. We apply the methods to a randomized study of breastfeeding versus formula feeding for infants of mothers infected with human immunodeficiency virus.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"595-603"},"PeriodicalIF":2.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901175","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":"Is inadequate risk stratification diluting hazard ratio estimates in randomized clinical trials?","authors":"Devan V Mehrotra, Rachel Marceau West","doi":"10.1177/17407745231222448","DOIUrl":"10.1177/17407745231222448","url":null,"abstract":"<p><p>In randomized clinical trials, analyses of time-to-event data without risk stratification, or with stratification based on pre-selected factors revealed at the end of the trial to be at most weakly associated with risk, are quite common. We caution that such analyses are likely delivering hazard ratio estimates that unwittingly dilute the evidence of benefit for the test relative to the control treatment. To make our case, first, we use a hypothetical scenario to contrast risk-unstratified and risk-stratified hazard ratios. Thereafter, we draw attention to the previously published 5-step stratified testing and amalgamation routine (5-STAR) approach in which a pre-specified treatment-blinded algorithm is applied to survival times from the trial to partition patients into well-separated risk strata using baseline covariates determined to be jointly strongly prognostic for event risk. After treatment unblinding, a treatment comparison is done within each risk stratum and stratum-level results are averaged for overall inference. For illustration, we use 5-STAR to reanalyze data for the primary and key secondary time-to-event endpoints from three published cardiovascular outcomes trials. The results show that the 5-STAR estimate is typically smaller (i.e. more in favor of the test treatment) than the originally reported (traditional) estimate. This is not surprising because 5-STAR mitigates the presumed dilution bias in the traditional hazard ratio estimate caused by no or inadequate risk stratification, as evidenced by two detailed examples. Pre-selection of stratification factors at the trial design stage to achieve adequate risk stratification for the analysis will often be challenging. In such settings, an objective risk stratification approach such as 5-STAR, which is partly aligned with guidance from the US Food and Drug Administration on covariate-adjustment in clinical trials, is worthy of consideration.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"571-575"},"PeriodicalIF":2.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139671450","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}