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A survey on UK researchers' views regarding their experiences with the de-identification, anonymisation, release methods and re-identification risk estimation for clinical trial datasets.
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-06-19 DOI: 10.1177/17407745241259086
Aryelly Rodriguez, Steff C Lewis, Sandra Eldridge, Tracy Jackson, Christopher J Weir

Background: There are increasing pressures for anonymised datasets from clinical trials to be shared across the scientific community. However, there is no standardised set of recommendations on how to anonymise and prepare clinical trial datasets for sharing, while an ever-increasing number of anonymised datasets are becoming available for secondary research. Our aim was to explore the current views and experiences of researchers in the United Kingdom about de-identification, anonymisation, release methods and re-identification risk estimation for clinical trial datasets.

Methods: We used an online exploratory cross-sectional descriptive survey that consisted of both open-ended and closed questions.

Results: We had 38 responses to invitation from June 2022 to October 2022. However, 35 participants (92%) used internal documentation and published guidance to de-identify/anonymise clinical trial datasets. De-identification, followed by anonymisation and then fulfilling data holders' requirements before access was granted (controlled access), was the most common process for releasing the datasets as reported by 18 (47%) participants. However, 11 participants (29%) had previous knowledge of re-identification risk estimation, but they did not use any of the methodologies. Experiences in the process of de-identifying/anonymising the datasets and maintaining such datasets were mostly negative, and the main reported issues were lack of resources, guidance, and training.

Conclusion: The majority of responders reported using documented processes for de-identification and anonymisation. However, our survey results clearly indicate that there are still gaps in the areas of guidance, resources and training to fulfil sharing requests of de-identified/anonymised datasets, and that re-identification risk estimation is an underdeveloped area.

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引用次数: 0
Are pragmatism and ethical protections in clinical trials a zero-sum game? 临床试验中的实用主义和伦理保护是零和游戏吗?
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-10-15 DOI: 10.1177/17407745241284798
Hayden P Nix, Charles Weijer, Monica Taljaard

Background: Randomized controlled trials with pragmatic intent aim to generate evidence that directly informs clinical decisions. Some have argued that the ethical protection of informed consent can be in tension with the goals of pragmatism. But the impact of other ethical protections on trial pragmatism has yet to be explored.

Purpose: In this article, we analyze the relationship between additional ethical protections for vulnerable participants and the degree of pragmatism within the PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) domains of trial design.

Methods: We analyze three example trials with pragmatic intent that include vulnerable participants.

Conclusion: The relationship between ethical protections and trial pragmatism is complex. In some cases, additional ethical protections for vulnerable participants can promote the pragmatism of some of the PRECIS-2 domains of trial design. When designing trials with pragmatic intent, researchers ought to look for opportunities wherein ethical protections enhance the degree of pragmatism.

背景:以实用主义为目的的随机对照试验旨在产生直接为临床决策提供依据的证据。有些人认为,知情同意的伦理保护可能会与实用主义的目标产生矛盾。目的:在本文中,我们分析了对弱势参与者的额外伦理保护与试验设计的实用主义解释连续性指标摘要-2(PRECIS-2)领域中的实用主义程度之间的关系:我们分析了三项包含易受伤害参与者的实用主义试验:结论:伦理保护与试验实用主义之间的关系非常复杂。结论:伦理保护与试验实用性之间的关系很复杂。在某些情况下,为易受伤害的参与者提供额外的伦理保护可以促进 PRECIS-2 中某些试验设计领域的实用性。在设计具有实用性意图的试验时,研究人员应该寻找机会,让伦理保护提高实用性的程度。
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引用次数: 0
2024 Peer Reviewers.
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 DOI: 10.1177/17407745251314089
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引用次数: 0
Scaling and interpreting treatment effects in clinical trials using restricted mean survival time. 使用受限平均生存时间对临床试验中的治疗效果进行缩放和解释。
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-06-13 DOI: 10.1177/17407745241254995
Theodore Karrison, Chen Hu, James Dignam

Background: Restricted mean survival time is the expected duration of survival up to a chosen time of restriction τ. For comparison studies, the difference in restricted mean survival times between two groups provides a summary measure of the treatment effect that is free of assumptions regarding the relative shape of the two survival curves, such as proportional hazards. However, it can be difficult to judge the magnitude of the effect from a comparison of restricted means due to the truncation of observation at time τ.

Methods: In this article, we describe additional ways of expressing the treatment effect based on restricted means that can be helpful in this regard. These include the ratio of restricted means, the ratio of life-years (or time) lost, and the average integrated difference between the survival curves, equal to the difference in restricted means divided by τ. These alternative metrics are straightforward to calculate and provide a means for scaling the effect size as an aid to interpretation. Examples from two randomized, multicenter clinical trials in prostate cancer, NRG/RTOG 0521 and NRG/RTOG 0534, with primary endpoints of overall survival and biochemical/radiological progression-free survival, respectively, are presented to illustrate the ideas.

Results: The four effect measures (restricted mean survival time difference, restricted mean survival time ratio, time lost ratio, and average survival rate difference) were 0.45 years, 1.05, 0.81, and 0.038 for RTOG 0521 and 1.36 years, 1.17, 0.56, and 0.12 for RTOG 0534 with τ = 12 and 11 years, respectively. Thus, for example, the 0.45-year difference in the first trial translates into a 19% reduction in time lost and a 3.8% average absolute difference between the survival curves over the 12-year horizon, a modest effect size, whereas the 1.36-year difference in the second trial corresponds to a 44% reduction in time lost and a 12% absolute survival difference, a rather large effect.

Conclusions: In addition to the difference in restricted mean survival times, these alternative measures can be helpful in determining whether the magnitude of the treatment effect is clinically meaningful.

背景:对于比较研究而言,两组间受限平均生存时间的差异提供了一个治疗效果的概括衡量指标,它不需要对两组生存曲线的相对形状(如比例危险)进行假设。然而,由于在时间τ处的观察被截断,因此很难从受限平均值的比较中判断效果的大小:在本文中,我们介绍了基于受限均值来表示治疗效果的其他方法,这些方法在这方面可能会有所帮助。这些方法包括受限均值之比、损失的生命年(或时间)之比以及生存曲线之间的平均综合差异(等于受限均值之差除以τ)。本文以两项前列腺癌多中心随机临床试验(NRG/RTOG 0521 和 NRG/RTOG 0534)为例,分别以总生存期和无生化/放射进展生存期为主要终点,来说明上述观点:RTOG 0521 的四个效应指标(受限平均生存时间差、受限平均生存时间比、时间损失比和平均生存率差)分别为 0.45 年、1.05 年、0.81 年和 0.038 年,RTOG 0534 的四个效应指标(τ = 12 年和 11 年)分别为 1.36 年、1.17 年、0.56 年和 0.12 年。因此,举例来说,第一项试验中0.45年的差异相当于减少了19%的时间损失,12年生存曲线之间的平均绝对差异为3.8%,效应大小适中;而第二项试验中1.36年的差异相当于减少了44%的时间损失,12%的绝对生存差异,效应相当大:除了限制性平均生存时间的差异外,这些替代指标还有助于确定治疗效果的大小是否具有临床意义。
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引用次数: 0
Optimizing accrual to a large-scale, clinically integrated randomized trial in anesthesiology: A 2-year analysis of recruitment. 优化麻醉学大规模临床综合随机试验的招募:为期两年的招募分析。
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-06-19 DOI: 10.1177/17407745241255087
Hanae K Tokita, Melissa Assel, Joanna Serafin, Emily Lin, Leslie Sarraf, Geema Masson, Tracy-Ann Moo, Jonas A Nelson, Brett A Simon, Andrew J Vickers
<p><strong>Background: </strong>Performing large randomized trials in anesthesiology is often challenging and costly. The clinically integrated randomized trial is characterized by simplified logistics embedded into routine clinical practice, enabling ease and efficiency of recruitment, offering an opportunity for clinicians to conduct large, high-quality randomized trials under low cost. Our aims were to (1) demonstrate the feasibility of the clinically integrated trial design in a high-volume anesthesiology practice and (2) assess whether trial quality improvement interventions led to more balanced accrual among study arms and improved trial compliance over time.</p><p><strong>Methods: </strong>This is an interim analysis of recruitment to a cluster-randomized trial investigating three nerve block approaches for mastectomy with immediate implant-based reconstruction: paravertebral block (arm 1), paravertebral plus interpectoral plane blocks (arm 2), and serratus anterior plane plus interpectoral plane blocks (arm 3). We monitored accrual and consent rates, clinician compliance with the randomized treatment, and availability of outcome data. Assessment after the initial year of implementation showed a slight imbalance in study arms suggesting areas for improvement in trial compliance. Specific improvement interventions included increasing the frequency of communication with the consenting staff and providing direct feedback to clinician investigators about their individual recruitment patterns. We assessed overall accrual rates and tested for differences in accrual, consent, and compliance rates pre- and post-improvement interventions.</p><p><strong>Results: </strong>Overall recruitment was extremely high, accruing close to 90% of the eligible population. In the pre-intervention period, there was evidence of bias in the proportion of patients being accrued and receiving the monthly block, with higher rates in arm 3 (90%) compared to arms 1 (81%) and 2 (79%, p = 0.021). In contrast, in the post-intervention period, there was no statistically significant difference between groups (p = 0.8). Eligible for randomization rate increased from 89% in the pre-intervention period to 95% in the post-intervention period (difference 5.7%; 95% confidence interval = 2.2%-9.4%, p = 0.002). Consent rate increased from 95% to 98% (difference of 3.7%; 95% confidence interval = 1.1%-6.3%; p = 0.004). Compliance with the randomized nerve block approach was maintained at close to 100% and availability of primary outcome data was 100%.</p><p><strong>Conclusion: </strong>The clinically integrated randomized trial design enables rapid trial accrual with a high participant compliance rate in a high-volume anesthesiology practice. Continuous monitoring of accrual, consent, and compliance rates is necessary to maintain and improve trial conduct and reduce potential biases. This trial methodology serves as a template for the implementation of other large, low-cost randomized
背景:在麻醉学领域开展大型随机试验通常具有挑战性且成本高昂。临床综合随机试验的特点是将简化的后勤工作嵌入到常规临床实践中,使招募工作变得简单高效,为临床医生以低成本开展大型、高质量的随机试验提供了机会。我们的目的是:(1) 证明临床综合试验设计在大容量麻醉科实践中的可行性;(2) 评估试验质量改进干预措施是否能使各研究臂之间的应征人数更加均衡,并随着时间的推移改善试验的依从性:这是一项集群随机试验的中期招募分析,该试验研究了乳房切除术与即时植入物重建的三种神经阻滞方法:椎旁阻滞(第 1 组)、椎旁加胸骨间平面阻滞(第 2 组)和锯肌前平面加胸骨间平面阻滞(第 3 组)。我们对应征率和同意率、临床医生对随机治疗的依从性以及结果数据的可用性进行了监测。实施最初一年后的评估显示,研究臂略有失衡,这表明试验依从性有待改善。具体的改进措施包括增加与同意人员沟通的频率,并向临床研究人员提供有关其个人招募模式的直接反馈。我们对总体招募率进行了评估,并检测了改进干预前后招募率、同意率和依从率的差异:结果:总体招募率非常高,接近 90% 的合格人群都参与了招募。在干预前,有证据表明患者的入组比例和每月接受治疗的比例存在偏差,与第一组(81%)和第二组(79%,P = 0.021)相比,第三组的比例更高(90%)。相比之下,在干预后阶段,组间差异无统计学意义(p = 0.8)。符合随机化条件的比例从干预前的 89% 提高到干预后的 95%(差异为 5.7%;95% 置信区间 = 2.2%-9.4%,p = 0.002)。同意率从 95% 提高到 98%(差异为 3.7%;95% 置信区间 = 1.1%-6.3%;P = 0.004)。随机神经阻滞方法的依从性保持在接近 100%,主要结果数据的可用性达到 100%:结论:临床综合随机试验设计能在麻醉科高工作量的实践中实现试验的快速累积和较高的参与者依从率。有必要对试验的参与率、同意率和符合率进行持续监控,以保持和改善试验的进行并减少潜在的偏差。该试验方法可作为麻醉科实施其他大型、低成本随机试验的模板。
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引用次数: 0
Composite endpoints in COVID-19 randomized controlled trials: a systematic review. COVID-19 随机对照试验中的复合终点:系统综述。
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-10-10 DOI: 10.1177/17407745241276130
Pedro Nascimento Martins, Mateus Henrique Toledo Lourenço, Gabriel Paz Souza Mota, Alexandre Biasi Cavalcanti, Ana Carolina Peçanha Antonio, Fredi Alexander Diaz-Quijano

Background/aims: This study aimed to determine the prevalence of ordinal, binary, and numerical composite endpoints among coronavirus disease 2019 trials and the potential bias attributable to their use.

Methods: We systematically reviewed the Cochrane COVID-19 Study Register to assess the prevalence, characteristics, and bias associated with using composite endpoints in coronavirus disease 2019 randomized clinical trials. We compared the effect measure (relative risk) of composite outcomes and that of its most critical component (i.e. death) by estimating the Bias Attributable to Composite Outcomes index [ln(relative risk for the composite outcome)/ln(relative risk for death)].

Results: Composite endpoints accounted for 152 out of 417 primary endpoints in coronavirus disease 2019 randomized trials, being more frequent among studies published in high-impact journals. Ordinal endpoints were the most common (54% of all composites), followed by binary or time-to-event (34%), numerical (11%), and hierarchical (1%). Composites predominated among trials enrolling patients with severe disease when compared to trials with a mild or moderate case mix (odds ratio = 1.72). Adaptations of the seven-point World Health Organization scale occurred in 40% of the ordinal primary endpoints, which frequently underwent dichotomization for the statistical analyses. Mortality accounted for a median of 24% (interquartile range: 6%-48%) of all events when included in the composite. The median point estimate of the Bias Attributable to Composite Outcomes index was 0.3 (interquartile range: -0.1 to 0.7), being significantly lower than 1 in 5 of 24 comparisons.

Discussion: Composite endpoints were used in a significant proportion of coronavirus disease 2019 trials, especially those involving severely ill patients. This is likely due to the higher anticipated rates of competing events, such as death, in such studies. Ordinal composites were common but often not fully appreciated, reducing the potential gains in information and statistical efficiency. For studies with binary composites, death was the most frequent component, and, unexpectedly, composite outcome estimates were often closer to the null when compared to those for mortality death. Numerical composites were less common, and only two trials used hierarchical endpoints. These newer approaches may offer advantages over traditional binary and ordinal composites; however, their potential benefits warrant further scrutiny.

Conclusion: Composite endpoints accounted for more than a third of coronavirus disease 2019 trials' primary endpoints; their use was more common among studies that included patients with severe disease and their point effect estimates tended to underestimate those for mortality.

背景/目的:本研究旨在确定冠状病毒病2019年试验中序数、二值和数值复合终点的流行程度,以及使用这些终点可能导致的偏倚:我们系统回顾了Cochrane COVID-19研究登记册,以评估冠状病毒病2019年随机临床试验中使用复合终点的流行率、特征和相关偏倚。我们通过估算综合结果的偏倚指数[ln(综合结果的相对风险)/ln(死亡的相对风险)],比较了综合结果的效应度量(相对风险)及其最关键部分(即死亡)的效应度量:在冠状病毒疾病2019年随机试验的417个主要终点中,复合终点占152个,在高影响力期刊上发表的研究中复合终点更为常见。顺序终点最常见(占所有复合终点的54%),其次是二元终点或时间到事件终点(34%)、数字终点(11%)和层次终点(1%)。与轻度或中度病例组合的试验相比,在招募重症患者的试验中,复合终点最常见(几率比=1.72)。40%的序数主要终点采用了世界卫生组织的七分量表,在进行统计分析时经常对其进行二分法处理。死亡率在所有事件中的中位数为 24%(四分位间范围:6%-48%)。综合结果偏倚指数的中位点估计值为0.3(四分位间范围:-0.1至0.7),在24项比较中的5项明显低于1:讨论:冠状病毒疾病2019年试验中有很大一部分使用了复合终点,尤其是那些涉及重症患者的试验。这可能是由于此类研究中死亡等竞争事件的预期发生率较高。二元组合很常见,但往往未得到充分重视,从而降低了潜在的信息增益和统计效率。在采用二元复合方法的研究中,死亡是最常见的组成部分,出乎意料的是,与死亡率死亡相比,复合结果估计值往往更接近于空。数字复合结果不太常见,只有两项试验使用了分层终点。与传统的二元复合终点和序数复合终点相比,这些新方法可能更有优势;但是,它们的潜在优势还需要进一步研究:综合终点占2019年冠状病毒疾病试验主要终点的三分之一以上;在纳入重症患者的研究中,综合终点的使用更为普遍,其点效应估计值往往低估了死亡率估计值。
{"title":"Composite endpoints in COVID-19 randomized controlled trials: a systematic review.","authors":"Pedro Nascimento Martins, Mateus Henrique Toledo Lourenço, Gabriel Paz Souza Mota, Alexandre Biasi Cavalcanti, Ana Carolina Peçanha Antonio, Fredi Alexander Diaz-Quijano","doi":"10.1177/17407745241276130","DOIUrl":"10.1177/17407745241276130","url":null,"abstract":"<p><strong>Background/aims: </strong>This study aimed to determine the prevalence of ordinal, binary, and numerical composite endpoints among coronavirus disease 2019 trials and the potential bias attributable to their use.</p><p><strong>Methods: </strong>We systematically reviewed the Cochrane COVID-19 Study Register to assess the prevalence, characteristics, and bias associated with using composite endpoints in coronavirus disease 2019 randomized clinical trials. We compared the effect measure (relative risk) of composite outcomes and that of its most critical component (i.e. death) by estimating the Bias Attributable to Composite Outcomes index [ln(relative risk for the composite outcome)/ln(relative risk for death)].</p><p><strong>Results: </strong>Composite endpoints accounted for 152 out of 417 primary endpoints in coronavirus disease 2019 randomized trials, being more frequent among studies published in high-impact journals. Ordinal endpoints were the most common (54% of all composites), followed by binary or time-to-event (34%), numerical (11%), and hierarchical (1%). Composites predominated among trials enrolling patients with severe disease when compared to trials with a mild or moderate case mix (odds ratio = 1.72). Adaptations of the seven-point World Health Organization scale occurred in 40% of the ordinal primary endpoints, which frequently underwent dichotomization for the statistical analyses. Mortality accounted for a median of 24% (interquartile range: 6%-48%) of all events when included in the composite. The median point estimate of the Bias Attributable to Composite Outcomes index was 0.3 (interquartile range: -0.1 to 0.7), being significantly lower than 1 in 5 of 24 comparisons.</p><p><strong>Discussion: </strong>Composite endpoints were used in a significant proportion of coronavirus disease 2019 trials, especially those involving severely ill patients. This is likely due to the higher anticipated rates of competing events, such as death, in such studies. Ordinal composites were common but often not fully appreciated, reducing the potential gains in information and statistical efficiency. For studies with binary composites, death was the most frequent component, and, unexpectedly, composite outcome estimates were often closer to the null when compared to those for mortality death. Numerical composites were less common, and only two trials used hierarchical endpoints. These newer approaches may offer advantages over traditional binary and ordinal composites; however, their potential benefits warrant further scrutiny.</p><p><strong>Conclusion: </strong>Composite endpoints accounted for more than a third of coronavirus disease 2019 trials' primary endpoints; their use was more common among studies that included patients with severe disease and their point effect estimates tended to underestimate those for mortality.</p>","PeriodicalId":10685,"journal":{"name":"Clinical Trials","volume":" ","pages":"77-87"},"PeriodicalIF":2.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399650","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
Modeling impact of inflation reduction act price negotiations on new drug pipeline considering differential contributions of large and small biopharmaceutical companies. 考虑到大型和小型生物制药公司的不同贡献,建立降低通货膨胀率的价格谈判对新药研发管线的影响模型。
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-07-24 DOI: 10.1177/17407745241259112
Gregory Vaughan, Roger Du, Fred D Ledley
<p><strong>Background/aims: </strong>Provisions of the Inflation Reduction Act mandating drug price negotiation by the Centers for Medicare & Medicaid Services have been criticized as a threat to pharmaceutical innovation. This study models potential impacts of the Inflation Reduction Act on drug approvals based on the differential contributions of large pharmaceutical companies and smaller biotechnology firms to clinical trials and the availability of capital.</p><p><strong>Methods: </strong>This study examined research and development expense, revenue, and new investment (sale of common and preferred stock) by public biopharmaceutical companies and sponsorship of phased clinical trials in ClinicalTrials.gov. Financial data were incorporated in a model that estimates the number of drugs in each phase and approvals from reported phase-specific costs and transition rates, proportional sponsorship of trials by companies of different size, projected reductions in research and development spending based on company size, and three scenarios by which large companies may allocate reductions in research and development spending among clinical phases: (1) research and development proportionally reduced across phases; (2) research and development disproportionally reduced in phases 2-3; and (3) research and development disproportionately reduced in phases 1-2.</p><p><strong>Results: </strong>Financial data were examined for 1378 public biopharmaceutical companies (2000-2018). Research and development expense was associated with revenue for 79 large companies with market capitalization ≥$7 billion with a 10% reduction in revenue reducing research and development expense by 8.4%. For 1299 smaller companies with market capitalization <$7 billion, research and development was associated with new investment, but not revenue. Smaller companies sponsored 55.2% of phase 1, 55.6% of phase 2, and 49.8% of phase 3 trials in ClinicalTrials.gov 2013-2018. In a model of clinical development that apportions clinical trials between large and smaller companies and determines the number of trials based on research and development resources, 400 drugs entering development produced 47.3 approvals (11.83% rate). A 10% reduction in revenue, reflecting the upper boundary of observed changes 2000-2018, with (1) proportional reduction across phases 1-3 produced 45.1 approvals (4.61% reduction); (2) disproportional reduction of phases 2-3 produced 42.8 approvals (9.55% reduction); and (3) disproportional reduction of phases 1-2 produced 46.9 approvals (0.95% reduction).</p><p><strong>Conclusion: </strong>This work suggests that the drug price negotiation provisions of the Inflation Reduction Act could have little or no impact on the number of drug approvals. While large pharmaceutical companies may reduce research and development spending, continued research and development by smaller companies and strategic allocation of research and development resources by large companies may mi
背景/目的:通货膨胀削减法》中规定由医疗保险与医疗补助服务中心进行药品价格谈判,这一条款被批评为对医药创新的威胁。本研究根据大型制药公司和小型生物技术公司对临床试验的不同贡献以及资金供应情况,模拟了《通胀削减法》对药品审批的潜在影响:本研究考察了上市生物制药公司的研发费用、收入和新投资(普通股和优先股的出售),以及对 ClinicalTrials.gov 中分阶段临床试验的赞助情况。财务数据被纳入一个模型中,该模型根据报告的特定阶段成本和过渡率、不同规模公司的试验赞助比例、基于公司规模的研发支出预计减少量以及大公司可能在临床阶段之间分配研发支出减少量的三种情况来估算每个阶段的药物数量和批准量:(1)各阶段的研发支出按比例减少;(2)2-3 阶段的研发支出按比例减少;(3)1-2 阶段的研发支出按比例减少:研究了 1378 家上市生物制药公司(2000-2018 年)的财务数据。79家市值≥70亿美元的大型公司的研发费用与收入相关,收入减少10%,研发费用减少8.4%。对于 1299 家市值较小的公司,结论是:研发费用与收入相关:这项研究表明,《通货膨胀削减法》中的药品价格谈判条款对药品批准数量的影响很小,甚至没有影响。虽然大型制药公司可能会减少研发支出,但小型公司的持续研发以及大型公司对研发资源的战略性分配可能会减轻《通胀抑制法案》的负面影响。
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引用次数: 0
A review of current practice in the design and analysis of extremely small stepped-wedge cluster randomized trials. 对当前设计和分析极小型阶梯楔形分组随机试验实践的回顾。
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-10-08 DOI: 10.1177/17407745241276137
Guangyu Tong, Pascale Nevins, Mary Ryan, Kendra Davis-Plourde, Yongdong Ouyang, Jules Antoine Pereira Macedo, Can Meng, Xueqi Wang, Agnès Caille, Fan Li, Monica Taljaard
<p><strong>Background/aims: </strong>Stepped-wedge cluster randomized trials tend to require fewer clusters than standard parallel-arm designs due to the switches between control and intervention conditions, but there are no recommendations for the minimum number of clusters. Trials randomizing an extremely small number of clusters are not uncommon, but the justification for small numbers of clusters is often unclear and appropriate analysis is often lacking. In addition, stepped-wedge cluster randomized trials are methodologically more complex due to their longitudinal correlation structure, and ignoring the distinct within- and between-period intracluster correlations can underestimate the sample size in small stepped-wedge cluster randomized trials. We conducted a review of published small stepped-wedge cluster randomized trials to understand how and why they are used, and to characterize approaches used in their design and analysis.</p><p><strong>Methods: </strong>Electronic searches were used to identify primary reports of full-scale stepped-wedge cluster randomized trials published during the period 2016-2022; the subset that randomized two to six clusters was identified. Two reviewers independently extracted information from each report and any available protocol. Disagreements were resolved through discussion.</p><p><strong>Results: </strong>We identified 61 stepped-wedge cluster randomized trials that randomized two to six clusters: median sample size (Q1-Q3) 1426 (420-7553) participants. Twelve (19.7%) gave some indication that the evaluation was considered a "preliminary" evaluation and 16 (26.2%) recognized the small number of clusters as a limitation. Sixteen (26.2%) provided an explanation for the limited number of clusters: the need to minimize contamination (e.g. by merging adjacent units), limited availability of clusters, and logistical considerations were common explanations. Majority (51, 83.6%) presented sample size or power calculations, but only one assumed distinct within- and between-period intracluster correlations. Few (10, 16.4%) utilized restricted randomization methods; more than half (34, 55.7%) identified baseline imbalances. The most common statistical method for analysis was the generalized linear mixed model (44, 72.1%). Only four trials (6.6%) reported statistical analyses considering small numbers of clusters: one used generalized estimating equations with small-sample correction, two used generalized linear mixed model with small-sample correction, and one used Bayesian analysis. Another eight (13.1%) used fixed-effects regression, the performance of which requires further evaluation under stepped-wedge cluster randomized trials with small numbers of clusters. None used permutation tests or cluster-period level analysis.</p><p><strong>Conclusion: </strong>Methods appropriate for the design and analysis of small stepped-wedge cluster randomized trials have not been widely adopted in practice. Greater awareness
背景/目的:由于对照和干预条件之间的切换,阶梯楔形分组随机试验所需的分组数往往少于标准的平行臂设计,但目前还没有关于最少分组数的建议。随机分组数量极少的试验并不少见,但分组数量少的理由往往不明确,也往往缺乏适当的分析。此外,阶梯楔形聚类随机试验因其纵向相关结构而在方法学上更为复杂,如果忽略了不同时期内和不同时期间的聚类内相关性,就会低估小型阶梯楔形聚类随机试验的样本量。我们对已发表的小阶梯楔形群组随机试验进行了综述,以了解这些试验的使用方式和原因,以及设计和分析方法的特点:通过电子检索,确定了2016年至2022年期间发表的全面阶梯式楔形分组随机试验的主要报告;确定了对2至6个分组进行随机试验的子集。两名审稿人从每份报告和任何可用的方案中独立提取信息。分歧通过讨论解决:我们确定了61项阶梯式楔形分组随机试验,这些试验随机了2至6个分组:样本量中位数(Q1-Q3)为1426(420-7553)名参与者。有 12 项(19.7%)试验表明该评价是一项 "初步 "评价,有 16 项(26.2%)试验认为分组数量少是一项限制因素。有 16 人(26.2%)对群组数量有限做出了解释:需要尽量减少污染(如通过合并相邻的 单位)、群组数量有限以及后勤方面的考虑是常见的解释。大多数研究(51 项,83.6%)提供了样本量或功率计算结果,但只有一项研究假设了不同时期内和不同时期间的群内相关性。少数研究(10 项,16.4%)采用了限制性随机方法;超过半数研究(34 项,55.7%)确定了基线不平衡。最常见的统计分析方法是广义线性混合模型(44 项,72.1%)。只有四项试验(6.6%)报告了考虑到少量分组的统计分析:一项试验使用了带小样本校正的广义估计方程,两项试验使用了带小样本校正的广义线性混合模型,一项试验使用了贝叶斯分析法。另有 8 项研究(13.1%)使用了固定效应回归法,其性能需要在具有少量聚类的阶梯楔形聚类随机试验中进一步评估。没有一项研究使用了置换检验或群组-时期水平分析:结论:适合设计和分析小型阶梯式分组随机试验的方法在实践中尚未得到广泛采用。需要进一步认识到,使用标准样本量计算方法可能会虚假地提供较低的所需分组数。广义估计方程或带小样本校正的广义线性混合模型、贝叶斯方法和置换检验等方法可能更适合分析小阶梯楔形分组随机试验。今后还需要开展研究,为具有少量分组的阶梯式楔形分组随机试验确立最佳实践。
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引用次数: 0
Challenges in designing a randomized, double-blind noninferiority trial for treatment of acne: The SD-ACNE trial. 设计治疗痤疮的随机双盲非劣效性试验所面临的挑战:SD-ACNE 试验。
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-02-01 Epub Date: 2024-07-27 DOI: 10.1177/17407745241265094
John S Barbieri, Susan Ellenberg, Elizabeth Grice, Ann Tierney, Suzette Baez VanderBeek, Maryte Papadopoulos, Jennifer Mason, Anabel Mason, James Dattilo, David J Margolis

Background/aims: Excessive use of antibiotics has led to development of antibiotic resistance and other antibiotic-associated complications. Dermatologists prescribe more antibiotics per clinician than any other major specialty, with much of this use for acne. Alternative acne treatments are available but are used much less often than antibiotics, at least partially because dermatologists feel that they are less effective. Spironolactone, a hormonal therapy with antiandrogen effects that can address the hormonal pathogenesis of acne, may represent a therapeutic alternative to oral antibiotics for women with acne. However, the comparative effects of spironolactone and oral antibiotics in the treatment of acne have not been definitively studied. The Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation (SD-ACNE) trial aims to answer whether spironolactone, in addition to standard topical therapy, is noninferior to doxycycline (an oral antibiotic) for women with acne. Several interesting challenges arose in the development of this study, including determining acceptability of the comparative regimens to participating dermatologists, identifying data to support a noninferiority margin, and establishing a process for unblinding participants after they completed the study while maintaining the blind for study investigators.

Methods: We present the scientific and clinical rationale for the decisions made in the design of the trial, including input from key stakeholders through a Delphi consensus process.

Results: The Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial (NCT04582383) is being conducted at a range of community and academic sites in the United States. To maximize external validity and inform clinical practice, the study is designed with broad eligibility criteria and no prohibition of use of topical medications. Participants in the trial will be randomized to receive either spironolactone 100 mg/day or doxycycline hyclate 100 mg/day for 16 weeks. The primary outcome is the absolute decrease in inflammatory lesion count, and we have established a noninferiority margin of four inflammatory lesions. Secondary outcomes include the percentage of participants achieving Investigator Global Assessment success, change in quality of life, and microbiome changes and diversity.

Conclusions: The Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial will have substantial implications for the treatment of acne and antibiotic stewardship. In addition, this study will provide important information on the effect of these systemic agents on the development of changes to the microbiome and antibiotic resistance in a healthy population of patients.

背景/目的:抗生素的过度使用导致了抗生素耐药性的产生以及其他与抗生素相关的并发症。皮肤科医生给每位临床医生开出的抗生素处方比其他任何主要专科都多,其中大部分用于治疗痤疮。虽然有其他治疗痤疮的方法,但使用的频率远远低于抗生素,至少部分原因是皮肤科医生认为这些方法效果较差。螺内酯是一种具有抗雄激素作用的荷尔蒙疗法,可以解决痤疮的荷尔蒙致病机理,对于患有痤疮的女性来说,它可能是口服抗生素的一种治疗替代品。然而,关于螺内酯和口服抗生素在治疗痤疮方面的效果比较,尚未进行明确的研究。螺内酯与强力霉素治疗痤疮:疗效比较、非劣效性评估(SD-ACNE)试验旨在回答,对于患有痤疮的女性患者来说,除了标准的局部治疗外,螺内酯是否不劣于强力霉素(一种口服抗生素)。在这项研究的发展过程中出现了一些有趣的挑战,包括确定参与研究的皮肤科医生对比较方案的可接受性,确定支持非劣效边际的数据,以及建立一个程序,在参与者完成研究后解除对他们的盲法,同时保持对研究调查人员的盲法:我们介绍了试验设计决策的科学和临床依据,包括主要利益相关者通过德尔菲共识程序提出的意见:螺内酯与强力霉素治疗痤疮:比较效果、非劣效性评价试验(NCT04582383)正在美国一系列社区和学术机构进行。为了最大限度地提高外部有效性并为临床实践提供信息,该研究设计了广泛的资格标准,并且不禁止使用外用药物。试验参与者将随机接受螺内酯 100 毫克/天或强力霉素 100 毫克/天,为期 16 周。主要结果是炎症病灶数量的绝对减少,我们已经确定了4个炎症病灶的非劣效值。次要结果包括获得研究者全球评估成功的参与者百分比、生活质量变化以及微生物组变化和多样性:螺内酯与强力霉素治疗痤疮:非劣效性比较评价试验将对痤疮治疗和抗生素管理产生重大影响。此外,这项研究还将提供重要信息,说明这些系统性药物对健康患者体内微生物组的变化和抗生素耐药性的影响。
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引用次数: 0
NHS-Galleri trial: Enriched enrolment approaches and sociodemographic characteristics of enrolled participants.
IF 2.2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-01-25 DOI: 10.1177/17407745241302477
Charles Swanton, Velicia Bachtiar, Chris Mathews, Adam R Brentnall, Ian Lowenhoff, Jo Waller, Martine Bomb, Sean McPhail, Heather Pinches, Rebecca Smittenaar, Sara Hiom, Richard D Neal, Peter Sasieni

Background/aims: Certain sociodemographic groups are routinely underrepresented in clinical trials, limiting generalisability. Here, we describe the extent to which enriched enrolment approaches yielded a diverse trial population enriched for older age in a randomised controlled trial of a blood-based multi-cancer early detection test (NCT05611632).

Methods: Participants aged 50-77 years were recruited from eight Cancer Alliance regions in England. Most were identified and invited from centralised health service lists; a dynamic invitation algorithm was used to target those in older and more deprived groups. Others were invited by their general practice surgery (GP-based Participant Identification Centres in selected regions); towards the end of recruitment, specifically Asian and Black individuals were invited via this route, as part of a concerted effort to encourage enrolment among these individuals. Some participants self-referred, often following engagement activities involving community organisations. Enrolment took place in 11 mobile clinics at 151 locations that were generally more socioeconomically deprived and ethnically diverse than the England average. We reduced logistical barriers to trial participation by offering language interpretation and translation and disabled access measures. After enrolment, we examined (1) sociodemographic distribution of participants versus England and Cancer Alliance populations, and (2) number needed to invite (NNI; the number of invitations sent to enrol one participant) by age, sex, index of multiple deprivation (IMD) and ethnicity, and GP surgery-level bowel screening participation.

Results: Approximately 1.5 million individuals were invited and 142,924 enrolled (98% via centralised health service lists/invitation algorithm) in 10.5 months. The enrolled population was older and more deprived than the England population aged 50-77 years (73.3% vs 56.8% aged 60-77 years; 42.3% vs 35.3% in IMD groups 1-2). Ethnic diversity was lower in the trial than the England population (1.4% vs 2.8% Black; 3.3% vs 5.3% Asian). NNI was highest in Black (32.8), Asian (28.2) and most-deprived (21.5) groups, and lowest in mixed ethnicity (8.1) and least-deprived (4.6) groups.

Conclusions: Enrolment approaches used in the NHS-Galleri trial enabled recruitment of an older, socioeconomically diverse participant population relatively rapidly. Compared with the England and Cancer Alliance populations, the enrolled population was enriched for those in older age and more deprived groups. Better ethnicity data availability in central health service records could enable better invitation targeting to further enhance ethnically diverse recruitment. Future research should evaluate approaches used to facilitate recruitment from underrepresented groups in clinical trials.

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引用次数: 0
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