Objectives: The sample sizes of phase I trials are typically small; some designs may lead to inaccurate estimation of the maximum tolerated dose (MTD). The objective of this study was to propose a metric assessing whether the MTD decision is sensitive to enrolling a few additional subjects in a phase I dose-finding trial. Methods: Numerous model-based and model-assisted designs have been proposed to improve the efficiency and accuracy of finding the MTD. The Fragility Index (FI) is a widely used metric quantifying the statistical robustness of randomized controlled trials by estimating the number of events needed to change a statistically significant result to non-significant (or vice versa). We propose a modified Fragility Index (mFI), defined as the minimum number of additional participants required to potentially change the estimated MTD, to supplement existing designs identifying fragile phase I trial results. Findings: Three oncology trials were used to illustrate how to evaluate the fragility of phase I trials using mFI. The results showed that two of the trials were not sensitive to additional subjects’ participation while the third trial was quite fragile to one or two additional subjects. Conclusions: The mFI can be a useful metric assessing the fragility of phase I trials and facilitating robust identification of MTD.
目的：I期临床试验的样本量通常较小；某些设计可能导致对最大耐受剂量（MTD）的估计不准确。本研究旨在提出一种评估指标，用于衡量在I期剂量探索试验中，MTD的决策是否对纳入少量额外受试者敏感。方法：为提高寻找MTD的效率和准确性，已有多种基于模型和模型辅助的设计被提出。脆弱性指数（FI）是一种广泛使用的指标，通过估计改变统计显著性结果所需的事件数量（或反之）来量化随机对照试验的统计稳健性。我们提出了一种改进的脆弱性指数（mFI），定义为可能改变估计MTD所需的最小额外参与者数量，以补充现有设计，识别I期试验结果的脆弱性。结果：通过三个肿瘤学试验展示了如何使用mFI评估I期试验的脆弱性。结果显示，其中两个试验对额外受试者的参与不敏感，而第三个试验对一至两名额外受试者相当脆弱。结论：mFI可作为评估I期试验脆弱性的有用指标，有助于稳健地识别MTD。
Robustness Assessment of Oncology Dose-Finding Trials Using the Modified Fragility Index
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