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Evaluating the use of text-message reminders and personalised text-message reminders on the return of participant questionnaires in trials, a systematic review and meta-analysis.
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-12 DOI: 10.1177/17407745251320888
Laura Doherty, Catherine Arundel, Elizabeth Coleman, Ailish Byrne, Katherine Jones
<p><strong>Background: </strong>Randomised controlled trials are widely accepted as the gold standard research methodology for the evaluation of interventions. However, they often display poor participant retention. To prevent this, various participant interventions have been identified and evaluated through the use of studies within a trial. Two such interventions are participant short message service reminders (also known as text-messages) and personalised participant short message service reminders, designed to encourage a participant to return a study questionnaire. While previous studies within a trial have evaluated the effectiveness of these two retention strategies, trialists continue to spend both time and money on these strategies while the evidence remains inconclusive.</p><p><strong>Methods: </strong>This systematic review and meta-analysis compared the use of short message service reminders with no short message service reminder and personalised short message service reminders with non-personalised short message service reminders, on participant retention. Eligible studies were identified through advanced searches of electronic databases (MEDLINE, EMBASE and Cochrane Library) and hand-searching of alternative information sources. The review primary outcome was the proportion of study questionnaires returned for the individual study within a trial primary analysis time points.</p><p><strong>Results: </strong>Nine eligible studies within a trial were identified, of which four compared short message service versus no short message service and five compared personalised short message service versus non-personalised short message service. For those that compared personalised short message service versus non-personalised short message service, only three were deemed appropriate for meta-analysis. The primary outcome results for short message service versus no short message service concluded that short message service led to a statistically non-significant increase in the odds of study questionnaire return by 9% (odds ratio = 1.09, 95% confidence interval = 0.92 to 1.30). Similarly, comparison of personalised short message service versus non-personalised short message service concluded that personalised short message service caused a statistically non-significant increase in odds by 22% (odds ratio = 1.22, 95% confidence interval = 0.95 to 1.59).</p><p><strong>Conclusion: </strong>The effectiveness of both short message service and personalised short message service as retention tools remains inconclusive and further study within a trial evaluations are required. However, as short message services are low in cost, easy to use and generally well accepted by participants, it is suggested that trialists adopt a pragmatic approach and utilise these reminders until further research is conducted. Given both the minimal addition in cost for studies already utilising short message service reminders and some evidence of effect, personalisation shoul
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引用次数: 0
Impact of differences between interim and post-interim analysis populations on outcomes of a group sequential trial: Example of the MOVe-OUT study.
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-02 DOI: 10.1177/17407745251313925
Yoseph Caraco, Matthew G Johnson, Joseph A Chiarappa, Brian M Maas, Julie A Stone, Matthew L Rizk, Mary Vesnesky, Julie M Strizki, Angela Williams-Diaz, Michelle L Brown, Patricia Carmelitano, Hong Wan, Alison Pedley, Akshita Chawla, Dominik J Wolf, Jay A Grobler, Amanda Paschke, Carisa De Anda
<p><strong>Background: </strong>Pre-specified interim analyses allow for more timely evaluation of efficacy or futility, potentially accelerating decision-making on an investigational intervention. In such an analysis, the randomized, double-blind MOVe-OUT trial demonstrated superiority of molnupiravir over placebo for outpatient treatment of COVID-19 in high-risk patients. In the full analysis population, the point estimate of the treatment difference in the primary endpoint was notably lower than at the interim analysis. We conducted a comprehensive assessment to investigate this unexpected difference in treatment effect size, with the goal of informing future clinical research evaluating treatments for rapidly evolving infectious diseases.</p><p><strong>Methods: </strong>The modified intention-to-treat population of the MOVe-OUT trial was divided into an interim analysis cohort (i.e. all participants included in the interim analysis; prospectively defined) and a post-interim analysis cohort (i.e. all remaining participants; retrospectively defined). Baseline characteristics (including many well-established prognostic factors for disease progression), clinical outcomes, and virologic outcomes were retrospectively evaluated. The impact of changes in baseline characteristics over time was explored using logistic regression modeling and simulations.</p><p><strong>Results: </strong>Baseline characteristics were well-balanced between arms overall. However, between- and within-arm differences in known prognostic baseline factors (e.g. comorbidities, SARS-CoV-2 viral load, and anti-SARS-CoV-2 antibody status) were observed for the interim and post-interim analysis cohorts. For the individual factors, these differences were generally minor and otherwise not notable; as the trial progressed, however, these shifts in combination increasingly favored the placebo arm across most of the evaluated factors in the post-interim cohort. Model-based simulations confirmed that the reduction in effect size could be accounted for by these longitudinal trends toward a lower-risk study population among placebo participants. Infectivity and viral load data confirmed that molnupiravir's antiviral activity was consistent across both cohorts, which were heavily dominated by different viral clades (reflecting the rapid SARS-CoV-2 evolution).</p><p><strong>Discussion: </strong>The cumulative effect of randomly occurring minor differences in prognostic baseline characteristics within and between arms over time, rather than virologic factors such as reduced activity of molnupiravir against evolving variants, likely impacted the observed outcomes. Our results have broader implications for group sequential trials seeking to evaluate treatments for rapidly emerging pathogens. During dynamic epidemic or pandemic conditions, adaptive trials should be designed and interpreted especially carefully, considering that they will likely rapidly enroll a large post-interim overrun populat
背景:预先指定的中期分析可以更及时地评估疗效或无效性,从而加快对研究干预措施的决策。在这种分析中,随机双盲 MOVe-OUT 试验证明,在门诊治疗 COVID-19 的高危患者中,莫仑吡韦的疗效优于安慰剂。在全面分析人群中,主要终点的治疗差异点估计值明显低于中期分析。我们进行了一次全面评估,以调查治疗效果大小的这一意外差异,目的是为未来评估快速发展的传染病治疗方法的临床研究提供信息:MOVe-OUT试验的修改后意向治疗人群被分为中期分析队列(即所有纳入中期分析的参与者;前瞻性定义)和中期分析后队列(即所有剩余参与者;回顾性定义)。对基线特征(包括许多公认的疾病进展预后因素)、临床结果和病毒学结果进行了回顾性评估。采用逻辑回归模型和模拟方法探讨了基线特征随时间变化的影响:结果:总体而言,各组间的基线特征非常均衡。然而,在中期和中期后分析组别中,观察到已知预后基线因素(如合并症、SARS-CoV-2 病毒载量和抗 SARS-CoV-2 抗体状态)在组别间和组别内存在差异。就单个因素而言,这些差异通常较小,并不显著;但随着试验的进展,在大多数评估因素上,这些综合因素的变化越来越有利于安慰剂治疗组。基于模型的模拟证实,安慰剂参与者中风险较低的研究人群的这些纵向趋势可以解释效应大小的减少。感染率和病毒载量数据证实,molnupiravir的抗病毒活性在两个队列中都是一致的,而这两个队列中主要是不同的病毒支系(反映了SARS-CoV-2的快速演变):讨论:随着时间的推移,随机出现的各组内和各组间预后基线特征的微小差异所产生的累积效应,而不是病毒学因素(如molnupiravir对不断演变的变异株的活性降低),可能会影响观察到的结果。我们的研究结果对寻求评估快速出现的病原体治疗方法的分组序贯试验具有更广泛的意义。在流行病或大流行的动态条件下,适应性试验的设计和解释应特别谨慎,因为这些试验很可能会迅速纳入大量中期后超支人群,而且即使多个基线变量发生微小的纵向变化,也会对不同时间点的预设疗效结果产生不成比例的影响。预后因素的变化可能会带来额外的变异性,而这种变异性很难与流行病学(如致病病原体的进化变化)或疾病管理的时间趋势区分开来(ClinicalTrials.gov: NCT04575597.)。
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引用次数: 0
From RAGs to riches: Utilizing large language models to write documents for clinical trials.
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-27 DOI: 10.1177/17407745251320806
Nigel Markey, Ilyass El-Mansouri, Gaetan Rensonnet, Casper van Langen, Christoph Meier

Background/aims: Clinical trials require numerous documents to be written: Protocols, consent forms, clinical study reports, and many others. Large language models offer the potential to rapidly generate first-draft versions of these documents; however, there are concerns about the quality of their output. Here, we report an evaluation of how good large language models are at generating sections of one such document, clinical trial protocols.

Methods: Using an off-the-shelf large language model, we generated protocol sections for a broad range of diseases and clinical trial phases. Each of these document sections we assessed across four dimensions: Clinical thinking and logic; Transparency and references; Medical and clinical terminology; and Content relevance and suitability. To improve performance, we used the retrieval-augmented generation method to enhance the large language model with accurate up-to-date information, including regulatory guidance documents and data from ClinicalTrials.gov. Using this retrieval-augmented generation large language model, we regenerated the same protocol sections and assessed them across the same four dimensions.

Results: We find that the off-the-shelf large language model delivers reasonable results, especially when assessing content relevance and the correct use of medical and clinical terminology, with scores of over 80%. However, the off-the-shelf large language model shows limited performance in clinical thinking and logic and transparency and references, with assessment scores of ≈40% or less. The use of retrieval-augmented generation substantially improves the writing quality of the large language model, with clinical thinking and logic and transparency and references scores increasing to ≈80%. The retrieval-augmented generation method thus greatly improves the practical usability of large language models for clinical trial-related writing.

Discussion: Our results suggest that hybrid large language model architectures, such as the retrieval-augmented generation method we utilized, offer strong potential for clinical trial-related writing, including a wide variety of documents. This is potentially transformative, since it addresses several major bottlenecks of drug development.

{"title":"From RAGs to riches: Utilizing large language models to write documents for clinical trials.","authors":"Nigel Markey, Ilyass El-Mansouri, Gaetan Rensonnet, Casper van Langen, Christoph Meier","doi":"10.1177/17407745251320806","DOIUrl":"https://doi.org/10.1177/17407745251320806","url":null,"abstract":"<p><strong>Background/aims: </strong>Clinical trials require numerous documents to be written: Protocols, consent forms, clinical study reports, and many others. Large language models offer the potential to rapidly generate first-draft versions of these documents; however, there are concerns about the quality of their output. Here, we report an evaluation of how good large language models are at generating sections of one such document, clinical trial protocols.</p><p><strong>Methods: </strong>Using an off-the-shelf large language model, we generated protocol sections for a broad range of diseases and clinical trial phases. Each of these document sections we assessed across four dimensions: <i>Clinical thinking and logic; Transparency and references; Medical and clinical terminology</i>; and <i>Content relevance and suitability</i>. To improve performance, we used the retrieval-augmented generation method to enhance the large language model with accurate up-to-date information, including regulatory guidance documents and data from ClinicalTrials.gov. Using this retrieval-augmented generation large language model, we regenerated the same protocol sections and assessed them across the same four dimensions.</p><p><strong>Results: </strong>We find that the off-the-shelf large language model delivers reasonable results, especially when assessing <i>content relevance</i> and the <i>correct use of medical and clinical terminology</i>, with scores of over 80%. However, the off-the-shelf large language model shows limited performance in <i>clinical thinking and logic</i> and <i>transparency and references</i>, with assessment scores of ≈40% or less. The use of retrieval-augmented generation substantially improves the writing quality of the large language model, with <i>clinical thinking and logic</i> and <i>transparency and references</i> scores increasing to ≈80%. The retrieval-augmented generation method thus greatly improves the practical usability of large language models for clinical trial-related writing.</p><p><strong>Discussion: </strong>Our results suggest that hybrid large language model architectures, such as the retrieval-augmented generation method we utilized, offer strong potential for clinical trial-related writing, including a wide variety of documents. This is potentially transformative, since it addresses several major bottlenecks of drug development.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"17407745251320806"},"PeriodicalIF":2.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514403","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}
引用次数: 0
Hybrid sample size calculations for cluster randomised trials using assurance.
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-11 DOI: 10.1177/17407745241312635
S Faye Williamson, Svetlana V Tishkovskaya, Kevin J Wilson

Background/aims: Sample size determination for cluster randomised trials is challenging because it requires robust estimation of the intra-cluster correlation coefficient. Typically, the sample size is chosen to provide a certain level of power to reject the null hypothesis in a two-sample hypothesis test. This relies on the minimal clinically important difference and estimates for the overall standard deviation, the intra-cluster correlation coefficient and, if cluster sizes are assumed to be unequal, the coefficient of variation of the cluster size. Varying any of these parameters can have a strong effect on the required sample size. In particular, it is very sensitive to small differences in the intra-cluster correlation coefficient. A relevant intra-cluster correlation coefficient estimate is often not available, or the available estimate is imprecise due to being based on studies with low numbers of clusters. If the intra-cluster correlation coefficient value used in the power calculation is far from the unknown true value, this could lead to trials which are substantially over- or under-powered.

Methods: In this article, we propose a hybrid approach using Bayesian assurance to determine the sample size for a cluster randomised trial in combination with a frequentist analysis. Assurance is an alternative to traditional power, which incorporates the uncertainty on key parameters through a prior distribution. We suggest specifying prior distributions for the overall standard deviation, intra-cluster correlation coefficient and coefficient of variation of the cluster size, while still utilising the minimal clinically important difference. We illustrate the approach through the design of a cluster randomised trial in post-stroke incontinence and compare the results to those obtained from a standard power calculation.

Results: We show that assurance can be used to calculate a sample size based on an elicited prior distribution for the intra-cluster correlation coefficient, whereas a power calculation discards all of the information in the prior except for a single point estimate. Results show that this approach can avoid misspecifying sample sizes when the prior medians for the intra-cluster correlation coefficient are very similar, but the underlying prior distributions exhibit quite different behaviour. Incorporating uncertainty on all three of the nuisance parameters, rather than only on the intra-cluster correlation coefficient, does not notably increase the required sample size.

Conclusion: Assurance provides a better understanding of the probability of success of a trial given a particular minimal clinically important difference and can be used instead of power to produce sample sizes that are more robust to parameter uncertainty. This is especially useful when there is difficulty obtaining reliable parameter estimates.

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引用次数: 0
Characterization of studies considered and required under Medicare's coverage with evidence development program.
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-08 DOI: 10.1177/17407745251313979
Maryam Mooghali, Osman Moneer, Guneet Janda, Joseph S Ross, Sanket S Dhruva, Reshma Ramachandran
<p><strong>Introduction: </strong>In 2005, the Centers for Medicare and Medicaid Services introduced the Coverage with Evidence Development program for items and services with limited evidence of benefit and harm for Medicare beneficiaries, aiming to generate evidence to determine whether they meet the statutory "reasonable and necessary" criteria for coverage. Coverage with Evidence Development requires participation in clinical studies approved by the Centers for Medicare and Medicaid Services (i.e. Coverage with Evidence Development-approved studies) as a condition of coverage. We examined the quality of evidence generated by Coverage with Evidence Development-approved studies compared with those that informed Centers for Medicare and Medicaid Services' initial Coverage with Evidence Development decisions (i.e. National Coverage Determination studies).</p><p><strong>Methods: </strong>Using Centers for Medicare and Medicaid Services' webpage, we identified all items and services covered under Coverage with Evidence Development and their Coverage with Evidence Development-approved studies. Through searching PubMed and Google Scholar, we identified original research articles that reported results for primary endpoints of Coverage with Evidence Development-approved studies. We then reviewed the initial Coverage with Evidence Development decision memos and identified National Coverage Determination studies that were original research.We characterized and compared Coverage with Evidence Development-approved studies and National Coverage Determination studies.</p><p><strong>Results: </strong>From 2005 to 2023, 26 items and services were covered under the Coverage with Evidence Development program, associated with 196 National Coverage Determination studies (170 (86.7%) clinical trials and 26 (13.3%) registries) and 116 unique Coverage with Evidence Development-approved studies (86 (74.1%) clinical trials, 23 (19.8%) registries, 4 (3.4%) claims-based studies, and 3 (2.6%) expanded access studies). Among clinical trial studies, National Coverage Determination studies and Coverage with Evidence Development-approved studies did not differ with respect to multi-arm design (59.4% vs 68.6%; <i>p</i> = 0.15). However, among multi-arm clinical trial studies, National Coverage Determination studies were less likely than Coverage with Evidence Development-approved studies to be randomized (52.5% vs 93.2%; <i>p</i> < 0.001). Overall, National Coverage Determination studies less frequently had ≥ 1 primary endpoint focused on a clinical outcome measure (65.8% vs 87.9%; <i>p</i> = 0.006) and less frequently exclusively enrolled Medicare beneficiaries (3.1% vs 25.9%; <i>p</i> < 0.001). In addition, National Coverage Determination studies had smaller population sizes than Coverage with Evidence Development-approved studies (median 100 (interquartile range, 45-414) vs 302 (interquartile range, 93-1000) patients; <i>p</i> = 0.002). Among Coverage with Evidence Developm
{"title":"Characterization of studies considered and required under Medicare's coverage with evidence development program.","authors":"Maryam Mooghali, Osman Moneer, Guneet Janda, Joseph S Ross, Sanket S Dhruva, Reshma Ramachandran","doi":"10.1177/17407745251313979","DOIUrl":"https://doi.org/10.1177/17407745251313979","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;In 2005, the Centers for Medicare and Medicaid Services introduced the Coverage with Evidence Development program for items and services with limited evidence of benefit and harm for Medicare beneficiaries, aiming to generate evidence to determine whether they meet the statutory \"reasonable and necessary\" criteria for coverage. Coverage with Evidence Development requires participation in clinical studies approved by the Centers for Medicare and Medicaid Services (i.e. Coverage with Evidence Development-approved studies) as a condition of coverage. We examined the quality of evidence generated by Coverage with Evidence Development-approved studies compared with those that informed Centers for Medicare and Medicaid Services' initial Coverage with Evidence Development decisions (i.e. National Coverage Determination studies).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Using Centers for Medicare and Medicaid Services' webpage, we identified all items and services covered under Coverage with Evidence Development and their Coverage with Evidence Development-approved studies. Through searching PubMed and Google Scholar, we identified original research articles that reported results for primary endpoints of Coverage with Evidence Development-approved studies. We then reviewed the initial Coverage with Evidence Development decision memos and identified National Coverage Determination studies that were original research.We characterized and compared Coverage with Evidence Development-approved studies and National Coverage Determination studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;From 2005 to 2023, 26 items and services were covered under the Coverage with Evidence Development program, associated with 196 National Coverage Determination studies (170 (86.7%) clinical trials and 26 (13.3%) registries) and 116 unique Coverage with Evidence Development-approved studies (86 (74.1%) clinical trials, 23 (19.8%) registries, 4 (3.4%) claims-based studies, and 3 (2.6%) expanded access studies). Among clinical trial studies, National Coverage Determination studies and Coverage with Evidence Development-approved studies did not differ with respect to multi-arm design (59.4% vs 68.6%; &lt;i&gt;p&lt;/i&gt; = 0.15). However, among multi-arm clinical trial studies, National Coverage Determination studies were less likely than Coverage with Evidence Development-approved studies to be randomized (52.5% vs 93.2%; &lt;i&gt;p&lt;/i&gt; &lt; 0.001). Overall, National Coverage Determination studies less frequently had ≥ 1 primary endpoint focused on a clinical outcome measure (65.8% vs 87.9%; &lt;i&gt;p&lt;/i&gt; = 0.006) and less frequently exclusively enrolled Medicare beneficiaries (3.1% vs 25.9%; &lt;i&gt;p&lt;/i&gt; &lt; 0.001). In addition, National Coverage Determination studies had smaller population sizes than Coverage with Evidence Development-approved studies (median 100 (interquartile range, 45-414) vs 302 (interquartile range, 93-1000) patients; &lt;i&gt;p&lt;/i&gt; = 0.002). Among Coverage with Evidence Developm","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"17407745251313979"},"PeriodicalIF":2.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374119","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}
引用次数: 0
Examining the bias-efficiency tradeoff from incorporation of nonconcurrent controls in platform trials: A simulation study example from the adaptive COVID-19 treatment trial.
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-08 DOI: 10.1177/17407745251313928
Tyler Bonnett, Gail E Potter, Lori E Dodd

Background: Platform trials typically feature a shared control arm and multiple experimental treatment arms. Staggered entry and exit of arms splits the control group into two cohorts: those randomized during the same period in which the experimental arm was open (concurrent controls) and those randomized outside that period (nonconcurrent controls). Combining these control groups may offer increased statistical power but can lead to bias if analyses do not account for time trends in the response variable. Proposed methods of adjustment for time may increase type I error rates when time trends impact arms unequally or when large, sudden changes to the response rate occur. However, there has been limited exploration of the degree of type I error inflation one can plausibly expect in real-world scenarios.

Methods: We use data from the Adaptive COVID-19 Treatment Trial (ACTT) to mimic a realistic platform trial with a remdesivir control arm. We compare four strategies for estimating the effect of interferon beta-1a (the ACTT-3 experimental arm) relative to remdesivir (data from ACTT-1, ACTT-2, and ACTT-3) on recovery and death by day 29: utilizing concurrent controls only (the prespecified analysis), pooling all remdesivir arm data without adjustment (the "unadjusted-pooled" analysis), adjusting for time as a categorical variable, and a Bayesian hierarchical model implementation which adjusts for time trends using smoothing techniques (the "Bayesian time machine"). We compare type I error rates and relative efficiency of each method in simulation settings based on observed ACTT remdesivir arm data.

Results: The unadjusted-pooled approach provided substantially different estimates of the effect of interferon beta-1a relative to remdesivir compared with the concurrent-only and model-based approaches, indicating that changes in recovery and death rates over time were not ignorable across different stages of ACTT. The model-based approaches rely on an assumption of constant treatment effects for each arm in the platform relative to control; error rates more than doubled in settings where this was not satisfied. Relative efficiency of the model-based approaches compared with the concurrent-only analysis was moderate.

Conclusions: In simulation settings where key model assumptions were not met, potential efficiency gains from incorporation of nonconcurrent controls were outweighed by the risk of substantial type I error rate inflation. This leads us to advise against these strategies for primary analyses in confirmatory clinical trials, aligning with current FDA guidance advising against comparisons to nonconcurrent controls in COVID-19 settings. The model-based adjustment methods may be useful in other settings, but we recommend performing the concurrent-only analysis as a reference for assessing the degree to which nonconcurrent controls drive results.

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引用次数: 0
The ethical value of consulting community members in non-emergency trials conducted with waivers of informed consent for research. 在放弃知情同意研究的非紧急试验中咨询社区成员的伦理价值。
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-06-25 DOI: 10.1177/17407745241259360
Emily A Largent, Steven Joffe, Neal W Dickert, Stephanie R Morain

There is growing interest in using embedded research methods, particularly pragmatic clinical trials, to address well-known evidentiary shortcomings afflicting the health care system. Reviews of pragmatic clinical trials published between 2014 and 2019 found that 8.8% were conducted with waivers of informed consent; furthermore, the number of trials where consent is not obtained is increasing with time. From a regulatory perspective, waivers of informed consent are permissible when certain conditions are met, including that the study involves no more than minimal risk, that it could not practicably be carried out without a waiver, and that waiving consent does not violate participants' rights and welfare. Nevertheless, when research is conducted with a waiver of consent, several ethical challenges arise. We must consider how to: address empirical evidence showing that patients and members of the public generally prefer prospective consent, demonstrate respect for persons using tools other than consent, promote public trust and investigator integrity, and ensure an adequate level of participant protections. In this article, we use examples drawn from real pragmatic clinical trials to argue that prospective consultation with representatives of the target study population can address, or at least mitigate, many of the ethical challenges posed by waivers of informed consent. We also consider what consultation might involve to illustrate its feasibility and address potential objections.

越来越多的人开始关注使用嵌入式研究方法,尤其是实用临床试验,来解决困扰医疗保健系统的众所周知的证据缺陷。对2014年至2019年期间发表的务实临床试验的审查发现,8.8%的试验是在放弃知情同意的情况下进行的;此外,未获得同意的试验数量也在与日俱增。从监管的角度来看,在满足一定条件的情况下,放弃知情同意是允许的,这些条件包括研究涉及的风险不超过最低限度、不放弃同意就无法切实开展研究、放弃同意不会侵犯参与者的权利和福利。然而,在放弃同意权的情况下开展研究时,会出现一些伦理挑战。我们必须考虑如何处理以下问题:根据经验证据,病人和公众一般更倾向于预期同意;使用同意书以外的工具来体现对个人的尊重;促进公众信任和研究者的诚信;以及确保对参与者的充分保护。在本文中,我们用实际临床试验中的例子来论证,与目标研究人群的代表进行前瞻性磋商可以解决或至少减轻放弃知情同意所带来的许多伦理挑战。我们还考虑了磋商可能涉及的内容,以说明其可行性并解决潜在的反对意见。
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引用次数: 0
Strategies to promote contraception use by female volunteers in Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia trial. 促进阿尔茨海默氏症预防倡议常染色体显性阿尔茨海默氏症(API ADAD)哥伦比亚试验中的女性志愿者使用避孕药具的策略。
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-08-14 DOI: 10.1177/17407745241264217
Christian Bustamante, Juan F Martinez, Alexander Navarro, Margarita Lopera, Gustavo Villegas, Sindy Duque, Natalia Acosta-Baena, Silvia Ríos-Romenets, Francisco Lopera

Background/aims: Including women of childbearing age in a clinical trial makes it necessary to consider two factors from a bioethical perspective: first, the lack of knowledge about the potential teratogenic effects of an investigational product, and also, the principle of justice not to exclude any population from the benefits of research. The most common way to address this issue is by requiring volunteers to use contraceptives before, during, and a few weeks after the clinical trial. This work presents all the strategies used to promote contraception use and prevent pregnancy during the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia clinical trial. Two characteristics of this trial make it of special interest for closely monitoring contraception use. One is that the trial lasted more than 7 years, and the other is that participants could be carriers of the E280A PSEN1 mutation, leading to a mild cognitive impairment as early as their late 30s.

Methods: An individual medical evaluation to select the contraception method that best fits the volunteer was carried out during the screening visit, remitting to the gynecologist when necessary. All non-surgical contraception methods were supplied by the sponsor. Staff were trained on contraception counseling, correctly dispensing contraceptive drugs to volunteers, and identifying, reporting, and following up on pregnancies. Two comprehensive educational campaigns on contraception use were performed, and the intervention included all volunteers. In addition, volunteers were asked on an annual survey to evaluate the dispensing procedure. Finally, the effectiveness of these strategies was retrospectively evaluated, comparing by extrapolation the number of pregnancies presented throughout the trial with the General Fertility Rate in Colombia.

Results: A total of 159 female volunteers were recruited. All strategies were implemented as planned, even during the COVID-19 contingency. Ten pregnancies occurred during the evaluation period (2015-2021). Two were planned; the rest were associated with a potential therapeutic failure or incorrect use of contraceptive methods for a contraceptive failure of 0.49% per year. Sixty percent of pregnancies led to an abortion, either miscarriage or therapeutic abortion. However, there was not enough data to associate the pregnancy outcome with the administration of the investigational product. Finally, we observed a lower fertility rate in women participating in the trial compared to the Colombian population.

Conclusion: The lower rates of contraceptive failure and the decrease in the incidence of pregnancies in women participating in the trial compared to the Colombian population across the 7 years of evaluation suggest that the strategies used in API ADAD Colombia were adequate and effective in addressing contraception use.

背景/目的:将育龄妇女纳入临床试验需要从生物伦理的角度考虑两个因素:一是对研究产品的潜在致畸作用缺乏了解,二是不能将任何人群排除在研究利益之外的公正原则。解决这一问题的最常见方法是要求志愿者在临床试验前、试验期间和试验后几周内使用避孕药具。本研究介绍了在阿尔茨海默氏症预防倡议常染色体显性阿尔茨海默氏症(API ADAD)哥伦比亚临床试验期间为促进避孕和防止怀孕而采取的所有策略。该试验的两个特点使其在密切监测避孕药具使用情况方面具有特殊意义。其一是该试验持续了 7 年多,其二是参与者可能是 E280A PSEN1 基因突变的携带者,导致他们早在 30 多岁时就出现轻度认知障碍:方法:在筛查访问期间进行个人医学评估,以选择最适合志愿者的避孕方法,必要时可向妇科医生咨询。所有非手术避孕方法均由赞助方提供。工作人员接受了有关避孕咨询、为志愿者正确发放避孕药物以及识别、报告和跟踪妊娠等方面的培训。开展了两次全面的避孕教育活动,并对所有志愿者进行了干预。此外,还在年度调查中要求志愿者对发放程序进行评估。最后,对这些策略的效果进行了回顾性评估,并将整个试验期间的怀孕人数与哥伦比亚的总体生育率进行了比较:结果:共招募了 159 名女性志愿者。所有策略均按计划实施,甚至在 COVID-19 突发事件期间也是如此。在评估期间(2015-2021 年),共有 10 例怀孕。其中 2 例是计划内怀孕,其余都与潜在的治疗失败或不正确使用避孕方法有关,每年的避孕失败率为 0.49%。60%的妊娠导致流产,要么是流产,要么是治疗性流产。但是,没有足够的数据将妊娠结果与服用研究产品联系起来。最后,我们观察到,与哥伦比亚人口相比,参与试验的妇女生育率较低:在 7 年的评估过程中,与哥伦比亚人口相比,参与试验的妇女避孕失败率较低,怀孕率也有所下降,这表明哥伦比亚 API ADAD 在解决避孕问题方面所采用的策略是适当而有效的。
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引用次数: 0
Successful completion of large, low-cost randomized cancer trials at an academic cancer center. 在学术癌症中心成功完成大型、低成本的随机癌症试验。
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-10-15 DOI: 10.1177/17407745241284044
Andrew J Vickers, Behfar Ehdaie, Hanae K Tokita, Jonas Nelson, Evan Matros, Andrea L Pusic, Michael D'Angelica

Background: Concerns about low accrual have long been a standard part of the discourse on cancer clinical trials, reaching even as far as the news media. Indeed, so many trials are closed before completing accrual that a cottage industry has recently developed creating statistical models to predict trial failure. We previously proposed four methodologic fixes for the current crisis in clinical trials: (1) dramatically reducing the number of eligibility criteria, (2) using data routinely collected in clinical practice for trial endpoints; then lowering barriers to accrual by (3) cluster randomization or (4) staged consent.

Methods: We report our practical experience of applying these fixes to randomized trials at Memorial Sloan Kettering Cancer Center.

Results: We have completed seven single-center randomized trials, with several more underway and accruing rapidly, with a total accrual approaching 10,000. Many of the trials have compared surgical interventions, an area where trials have traditionally been hard to complete. Only one of these trials was externally funded. While low costs were possible due to the existing research infrastructure at our institution, such infrastructure is common at major cancer centers.

Conclusions: Further research on innovative clinical trial designs is warranted, particularly in higher-stakes settings, and in trials of medical and radiotherapy interventions.

背景:长期以来,对低应计率的担忧一直是癌症临床试验讨论的标准内容,甚至影响到了新闻媒体。事实上,有很多试验在完成应计制之前就已经结束,以至于最近出现了一种建立统计模型来预测试验失败的山寨产业。我们曾针对当前的临床试验危机提出了四种方法论解决方案:(1)大幅减少资格标准的数量;(2)使用临床实践中常规收集的数据作为试验终点;然后通过(3)分组随机化或(4)分阶段同意来降低应征门槛:我们报告了纪念斯隆-凯特琳癌症中心将这些固定方法应用于随机试验的实际经验:结果:我们已经完成了七项单中心随机试验,还有几项正在进行中,且进展迅速,试验总人数已接近 10,000 人。其中许多试验对外科干预措施进行了比较,而这一领域的试验历来难以完成。这些试验中只有一项是由外部资助的。我们机构现有的研究基础设施使低成本成为可能,但这种基础设施在大型癌症中心很常见:结论:有必要进一步研究创新性临床试验设计,尤其是在风险较高的环境中,以及在医疗和放疗干预试验中。
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引用次数: 0
Comparison of outcomes of the 50-year follow-up of a randomized trial assessed by study questionnaire and by data linkage: The CONCUR study. 通过研究问卷和数据链接评估随机试验 50 年随访结果的比较:CONCUR 研究。
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-06-22 DOI: 10.1177/17407745241259088
Mohammad Shahbaz, Jane E Harding, Barry Milne, Anthony Walters, Lisa Underwood, Martin von Randow, Lois Xu, Greg D Gamble

Background/aims: Self-reported questionnaires on health status after randomized trials can be time-consuming, costly, and potentially unreliable. Administrative data sets may provide cost-effective, less biased information, but it is uncertain how administrative and self-reported data compare to identify chronic conditions in a New Zealand cohort. This study aimed to determine whether record linkage could replace self-reported questionnaires to identify chronic conditions that were the outcomes of interest for trial follow-up.

Methods: Participants in 50-year follow-up of a randomized trial were asked to complete a questionnaire and to consent to accessing administrative data. The proportion of participants with diabetes, pre-diabetes, hyperlipidaemia, hypertension, mental health disorders, and asthma was calculated using each data source and agreement between data sources assessed.

Results: Participants were aged 49 years (SD = 1, n = 424, 50% male). Agreement between questionnaire and administrative data was slight for pre-diabetes (kappa = 0.10), fair for hyperlipidaemia (kappa = 0.27), substantial for diabetes (kappa = 0.65), and moderate for other conditions (all kappa >0.42). Administrative data alone identified two to three times more cases than the questionnaire for all outcomes except hypertension and mental health disorders, where the questionnaire alone identified one to two times more cases than administrative data. Combining all sources increased case detection for all outcomes.

Conclusions: A combination of questionnaire, pharmaceutical, and laboratory data with expert panel review were required to identify participants with chronic conditions of interest in this follow-up of a clinical trial.

背景/目的:随机试验后对健康状况的自我报告问卷调查耗时长、成本高,而且可能不可靠。行政数据集可以提供成本效益高、偏差较小的信息,但目前还不确定行政数据和自我报告数据在新西兰队列中识别慢性病方面的比较情况。本研究旨在确定记录链接是否能取代自我报告问卷,以确定试验随访结果所关注的慢性疾病:方法:一项随机试验的 50 年随访参与者被要求填写一份调查问卷,并同意访问管理数据。利用每个数据源计算了患有糖尿病、糖尿病前期、高脂血症、高血压、精神疾病和哮喘的参与者比例,并评估了数据源之间的一致性:参与者年龄为 49 岁(SD = 1,n = 424,50% 为男性)。对于糖尿病前期,调查问卷与行政数据的吻合度较低(kappa = 0.10);对于高脂血症,吻合度一般(kappa = 0.27);对于糖尿病,吻合度较高(kappa = 0.65);对于其他疾病,吻合度中等(所有吻合度均大于 0.42)。在所有结果中,行政数据单独发现的病例数是问卷调查的 2 到 3 倍,但高血压和精神疾病除外,在这两种疾病中,问卷调查单独发现的病例数是行政数据的 1 到 2 倍。在所有结果中,综合所有来源的数据可提高病例发现率:结论:在一项临床试验的后续研究中,需要将问卷、药物和实验室数据与专家小组审查相结合,才能识别出患有慢性疾病的参与者。
{"title":"Comparison of outcomes of the 50-year follow-up of a randomized trial assessed by study questionnaire and by data linkage: The CONCUR study.","authors":"Mohammad Shahbaz, Jane E Harding, Barry Milne, Anthony Walters, Lisa Underwood, Martin von Randow, Lois Xu, Greg D Gamble","doi":"10.1177/17407745241259088","DOIUrl":"10.1177/17407745241259088","url":null,"abstract":"<p><strong>Background/aims: </strong>Self-reported questionnaires on health status after randomized trials can be time-consuming, costly, and potentially unreliable. Administrative data sets may provide cost-effective, less biased information, but it is uncertain how administrative and self-reported data compare to identify chronic conditions in a New Zealand cohort. This study aimed to determine whether record linkage could replace self-reported questionnaires to identify chronic conditions that were the outcomes of interest for trial follow-up.</p><p><strong>Methods: </strong>Participants in 50-year follow-up of a randomized trial were asked to complete a questionnaire and to consent to accessing administrative data. The proportion of participants with diabetes, pre-diabetes, hyperlipidaemia, hypertension, mental health disorders, and asthma was calculated using each data source and agreement between data sources assessed.</p><p><strong>Results: </strong>Participants were aged 49 years (SD = 1, <i>n</i> = 424, 50% male). Agreement between questionnaire and administrative data was slight for pre-diabetes (kappa = 0.10), fair for hyperlipidaemia (kappa = 0.27), substantial for diabetes (kappa = 0.65), and moderate for other conditions (all kappa >0.42). Administrative data alone identified two to three times more cases than the questionnaire for all outcomes except hypertension and mental health disorders, where the questionnaire alone identified one to two times more cases than administrative data. Combining all sources increased case detection for all outcomes.</p><p><strong>Conclusions: </strong>A combination of questionnaire, pharmaceutical, and laboratory data with expert panel review were required to identify participants with chronic conditions of interest in this follow-up of a clinical trial.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"24-35"},"PeriodicalIF":2.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440284","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}
引用次数: 0
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Clinical Trials
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