Some essential considerations in the design and conduct of non-inferiority trials.
Some essential considerations in the design and conduct of non-inferiority trials.
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DOI：
10.1177/1740774511410994
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Li Shen Y
中科院分区：
文献类型：
--
作者：
Fleming TR;Odem-Davis K;Rothmann MD;Li Shen Y
假设已经建立了一种标准治疗（标准），以提供临床上重要的不可逆发病率或死亡率风险降低。在这种情况下，实验性干预措施的安全性和有效性可能会在临床试验中进行评估，提供与标准组而不是安慰剂组的比较。这种试验通常旨在评估实验性干预措施的有效性是否比标准组差得不可接受，称为非劣效性试验。形式上，非劣效性试验通常旨在排除非劣效性界值，定义为构成不可接受的疗效损失的最低阈值。尽管文献中有许多重要的文章确定了非劣效性试验设计和实施的各种方法，但仍然存在混淆，特别是关于选择非劣效性界值的关键考虑因素。本文的目的是进一步澄清这些考虑。我们提出了在设计和实施非劣效性试验时应解决的许多因素的科学见解，以提高其完整性和可靠性，并为指导非劣效性边界选择的关键考虑因素提供动力。我们还从最近的经验中提供了例证和见解。在制定非劣效性界值时，有两个考虑因素是必不可少的，应在单独的步骤中加以说明。首先，应使用调整来制定界值，以解释非劣效性试验中标准品效应估计的偏倚或缺乏可靠性。其次，应制定非劣效性界值，以达到保留标准效果的适当百分比。考虑因素，特别是关于保持效果的重要性，可能不适用于在试验中纳入标准和安慰剂组以与实验干预组进行直接比较的伦理和临床相关的设置。非劣效性试验（边界不严格）允许接受不充分有效的实验方案的重大风险，导致医疗质量下降的风险。非劣效性试验的设计和实施，包括非劣效性界值的选择，应考虑许多可能导致非劣效性试验中标准品估计效应偏倚的因素，从而导致实验治疗估计效应偏倚，以确保实验治疗保留标准品效应的临床可接受分数，以及非劣效性试验的完整性特别容易受到试验实施中的违规行为的影响。由于非劣效性试验固有的不确定性，应尽可能采用替代设计。
Suppose a standard therapy (Standard) has been established to provide a clinically important reduction in risk of irreversible morbidity or mortality. In that setting, the safety and efficacy of an experimental intervention likely would be assessed in a clinical trial providing a comparison with Standard rather than a placebo arm. Such a trial often is designed to assess whether the efficacy of the experimental intervention is not unacceptably worse than that of Standard, and is called a non-inferiority trial. Formally, the non-inferiority trial usually is designed to rule out a non-inferiority margin, defined as the minimum threshold for what would constitute an unacceptable loss of efficacy. Even though the literature has many important articles identifying various approaches to the design and conduct of non-inferiority trials, confusion remains especially regarding key considerations for selecting the non-inferiority margin. The purpose of this article is to provide improved clarity regarding these considerations. We present scientific insights into many factors that should be addressed in the design and conduct of non-inferiority trials to enhance their integrity and reliability, and provide motivation for key considerations that guide the selection of non-inferiority margins. We also provide illustrations and insights from recent experiences. Two considerations are essential, and should be addressed in separate steps, in the formulation of the non-inferiority margin. First, the margin should be formulated using adjustments to account for bias or lack of reliability in the estimate of the effect of Standard in the non-inferiority trial setting. Second, the non-inferiority margin should be formulated to achieve preservation of an appropriate percentage of the effect of Standard. The considerations, in particular regarding the importance of preservation of effect, might not apply to settings where it would be ethical as well as clinically relevant to include both Standard and placebo arms in the trial for direct comparisons with the experimental intervention arm. Non-inferiority trials with non-rigorous margins allow substantial risk for accepting inadequately effective experimental regimens, leading to the risk of erosion in quality of health care. The design and conduct of non-inferiority trials, including selection of non-inferiority margins, should account for many factors that can induce bias in the estimated effect of Standard in the non-inferiority trial and thus lead to bias in the estimated effect of the experimental treatment, for the need to ensure the experimental treatment preserves a clinically acceptable fraction of Standard's effect, and for the particular vulnerability of the integrity of a non-inferiority trial to the irregularities in trial conduct. Due to the inherent uncertainties in non-inferiority trials, alternative designs should be pursued whenever possible.
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影响因子：
24
作者：
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