{"title":"Optimization the design of fixed and group sequential three-arm non-inferiority trials with dichotomous endpoints of risk difference and odds ratio","authors":"","doi":"10.1016/j.conctc.2024.101383","DOIUrl":null,"url":null,"abstract":"<div><div>Although the risk difference (RD) is the most common and well explored functional form for testing efficacy with dichotomous endpoint, odds ratio (OR) is also suggested and well applied measure for non-inferiority (NI) trials. Since the construction and interpretation of these function forms are quite different, this study aims to provide detailed discussions and comprehensive comparisons on the design and testing approach for RD and OR scales for the fixed and group sequential three-arm NI trials under various of situations. The sample size determinations and testing approaches for assessing NI of a new treatment in three-arm clinical trials for RD and OR scales were reviewed comprehensively. Simulation studies are conducted for hundreds of scenarios with parameter configurations of the response rates, randomized allocations, NI margins and interim analysis. The operating characteristic (OC) of RD and OR scales based on the MLE and RMLE methods were thoroughly investigated. A trial example was designed and analyzed to demonstrate the methodologies. It is found that sample size determination on OR scale gives smaller sample size and robust procedure compared to RD scale in the majority of situations. When evaluating the behaviors of the attained power, the RMLE methods based on OR scale outperforms the MLE method and tend to have more power to reject the null hypothesis especially under the small sample size situations. Compared to the fixed design, the group sequential design has better OC, which provides a comparable power while needing smaller total average sample sizes for all cases. In addition, we suggest a lower significance level with a higher power for the sample size determination in the superiority test stage in the group sequential design, which can significantly reduce the total sample sizes while the number of subjects in the placebo group does not increase much. It can offer some recommendations for the investigators to choose the optimal endpoints and parameter configurations to design a three-arm NI trial under certain situations.</div></div>","PeriodicalId":37937,"journal":{"name":"Contemporary Clinical Trials Communications","volume":null,"pages":null},"PeriodicalIF":1.4000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Contemporary Clinical Trials Communications","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2451865424001303","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Although the risk difference (RD) is the most common and well explored functional form for testing efficacy with dichotomous endpoint, odds ratio (OR) is also suggested and well applied measure for non-inferiority (NI) trials. Since the construction and interpretation of these function forms are quite different, this study aims to provide detailed discussions and comprehensive comparisons on the design and testing approach for RD and OR scales for the fixed and group sequential three-arm NI trials under various of situations. The sample size determinations and testing approaches for assessing NI of a new treatment in three-arm clinical trials for RD and OR scales were reviewed comprehensively. Simulation studies are conducted for hundreds of scenarios with parameter configurations of the response rates, randomized allocations, NI margins and interim analysis. The operating characteristic (OC) of RD and OR scales based on the MLE and RMLE methods were thoroughly investigated. A trial example was designed and analyzed to demonstrate the methodologies. It is found that sample size determination on OR scale gives smaller sample size and robust procedure compared to RD scale in the majority of situations. When evaluating the behaviors of the attained power, the RMLE methods based on OR scale outperforms the MLE method and tend to have more power to reject the null hypothesis especially under the small sample size situations. Compared to the fixed design, the group sequential design has better OC, which provides a comparable power while needing smaller total average sample sizes for all cases. In addition, we suggest a lower significance level with a higher power for the sample size determination in the superiority test stage in the group sequential design, which can significantly reduce the total sample sizes while the number of subjects in the placebo group does not increase much. It can offer some recommendations for the investigators to choose the optimal endpoints and parameter configurations to design a three-arm NI trial under certain situations.
虽然风险差异(RD)是二分终点疗效测试中最常见、最受关注的函数形式,但在非劣效性(NI)试验中,几率比(OR)也是被建议和广泛应用的测量方法。由于这些函数形式的构建和解释有很大不同,本研究旨在详细讨论和全面比较在各种情况下固定和分组顺序三臂非劣效性试验中,RD 和 OR 的设计和测试方法。全面回顾了三臂临床试验中RD量表和OR量表评估新疗法NI的样本量确定和测试方法。通过对反应率、随机分配、净住院率和中期分析的参数配置,对数百种情况进行了模拟研究。深入研究了基于 MLE 和 RMLE 方法的 RD 和 OR 量表的运行特征(OC)。设计并分析了一个试验示例来演示这些方法。结果发现,在大多数情况下,与 RD 量表相比,用 OR 量表确定样本量的样本量更小,程序更稳健。在评估获得功率的行为时,基于 OR 标度的 RMLE 方法优于 MLE 方法,尤其是在样本量较小的情况下,往往具有更强的拒绝零假设的能力。与固定设计相比,分组序列设计具有更好的 OC,在所有情况下都需要较小的总平均样本量,但却能提供相当的功率。此外,我们还建议在分组序列设计中,在优效性检验阶段用较低的显著性水平和较高的功率来确定样本量,这样可以显著减少总样本量,而安慰剂组的受试者人数不会增加太多。这为研究者在特定情况下选择最佳终点和参数配置设计三臂 NI 试验提供了一些建议。
期刊介绍:
Contemporary Clinical Trials Communications is an international peer reviewed open access journal that publishes articles pertaining to all aspects of clinical trials, including, but not limited to, design, conduct, analysis, regulation and ethics. Manuscripts submitted should appeal to a readership drawn from a wide range of disciplines including medicine, life science, pharmaceutical science, biostatistics, epidemiology, computer science, management science, behavioral science, and bioethics. Contemporary Clinical Trials Communications is unique in that it is outside the confines of disease specifications, and it strives to increase the transparency of medical research and reduce publication bias by publishing scientifically valid original research findings irrespective of their perceived importance, significance or impact. Both randomized and non-randomized trials are within the scope of the Journal. Some common topics include trial design rationale and methods, operational methodologies and challenges, and positive and negative trial results. In addition to original research, the Journal also welcomes other types of communications including, but are not limited to, methodology reviews, perspectives and discussions. Through timely dissemination of advances in clinical trials, the goal of Contemporary Clinical Trials Communications is to serve as a platform to enhance the communication and collaboration within the global clinical trials community that ultimately advances this field of research for the benefit of patients.