Division of Neonatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Center for Pediatric Clinical Effectiveness, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Clin Trials. 2020 Oct;17(5):552-559. doi: 10.1177/1740774520941428. Epub 2020 Jul 15.
BACKGROUND/AIMS: Noninferiority clinical trials are susceptible to false confirmation of noninferiority when the intention-to-treat principle is applied in the setting of incomplete trial protocol adherence. The risk increases as protocol adherence rates decrease. The objective of this study was to compare protocol adherence and hypothesis confirmation between superiority and noninferiority randomized clinical trials published in three high impact medical journals. We hypothesized that noninferiority trials have lower protocol adherence and greater hypothesis confirmation.
We conducted an observational study using published clinical trial data. We searched PubMed for active control, two-arm parallel group randomized clinical trials published in JAMA: The Journal of the American Medical Association, The New England Journal of Medicine, and The Lancet between 2007 and 2017. The primary exposure was trial type, superiority versus noninferiority, as determined by the hypothesis testing framework of the primary trial outcome. The primary outcome was trial protocol adherence rate, defined as the number of randomized subjects receiving the allocated intervention as described by the trial protocol and followed to primary outcome ascertainment (numerator), over the total number of subjects randomized (denominator). Hypothesis confirmation was defined as affirmation of noninferiority or the alternative hypothesis for noninferiority and superiority trials, respectively.
Among 120 superiority and 120 noninferiority trials, median and interquartile protocol adherence rates were 91.5 [81.4-96.7] and 89.8 [83.6-95.2], respectively; = 0.47. Hypothesis confirmation was observed in 107/120 (89.2%) of noninferiority and 64/120 (53.3%) of superiority trials, risk difference (95% confidence interval): 35.8 (25.3-46.3), < 0.001.
Protocol adherence rates are similar between superiority and noninferiority trials published in three high impact medical journals. Despite this, we observed greater hypothesis confirmation among noninferiority trials. We speculate that publication bias, lenient noninferiority margins and other sources of bias may contribute to this finding. Further study is needed to identify the reasons for this observed difference.
背景/目的：当意向治疗原则应用于不完全遵守试验方案的情况下，非劣效性临床试验容易错误地确认非劣效性。随着方案依从率的降低，风险会增加。本研究的目的是比较在三个高影响力医学期刊上发表的优效性和非劣效性随机临床试验的方案依从性和假设确认。我们假设非劣效性试验的方案依从性较低，假设确认率较高。
我们使用已发表的临床试验数据进行了一项观察性研究。我们在 PubMed 上搜索了 2007 年至 2017 年期间在《美国医学会杂志》（JAMA：美国医学会杂志）、《新英格兰医学杂志》（New England Journal of Medicine）和《柳叶刀》（The Lancet）上发表的主动对照、双臂平行组随机临床试验。主要暴露因素是试验类型，优效性与非劣效性，由主要试验结果的假设检验框架确定。主要结局是试验方案依从率，定义为按照试验方案描述接受分配干预并随访至主要结局评估的随机受试者数量（分子）与随机受试者总数（分母）之比。假设确认定义为非劣效性或非劣效性和优效性试验的替代假设的确认。
在 120 项优效性和 120 项非劣效性试验中，中位数和四分位距方案依从率分别为 91.5 [81.4-96.7]和 89.8 [83.6-95.2]； = 0.47。在 120 项非劣效性和 120 项优效性试验中，分别有 107/120（89.2%）和 64/120（53.3%）的试验观察到假设确认，差异风险（95%置信区间）：35.8（25.3-46.3），<0.001。
在三个高影响力医学期刊上发表的优效性和非劣效性试验的方案依从率相似。尽管如此，我们观察到非劣效性试验的假设确认率更高。我们推测，发表偏倚、宽松的非劣效性边界和其他来源的偏倚可能是造成这种结果的原因。需要进一步研究以确定这种观察到的差异的原因。
