Shi Amy X, Zhou Heng, Nie Lei, Lin Lifeng, Li Hongjian, Chu Haitao
Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Durham, NC 27703, USA.
Biostatistics and Research Decision Sciences, Merck & Co. Inc., Rahway, NJ 07065, USA.
Cancers (Basel). 2024 Oct 17;16(20):3504. doi: 10.3390/cancers16203504.
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.
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.
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.
The mFI can be a useful metric assessing the fragility of phase I trials and facilitating robust identification of MTD.
I期试验的样本量通常较小；某些设计可能会导致对最大耐受剂量（MTD）的估计不准确。本研究的目的是提出一种指标，用于评估在I期剂量探索试验中纳入少数额外受试者时，MTD决策是否敏感。
已经提出了许多基于模型和模型辅助的设计，以提高寻找MTD的效率和准确性。脆弱性指数（FI）是一种广泛使用的指标，通过估计将具有统计学意义的结果变为无统计学意义（或反之亦然）所需的事件数量，来量化随机对照试验的统计稳健性。我们提出了一种修正的脆弱性指数（mFI），定义为潜在改变估计的MTD所需的最少额外参与者数量，以补充现有的用于识别脆弱的I期试验结果的设计。
三项肿瘤学试验被用于说明如何使用mFI评估I期试验的脆弱性。结果表明，其中两项试验对额外受试者的参与不敏感，而第三项试验对一两名额外受试者相当脆弱。
mFI可以作为一种有用的指标，用于评估I期试验的脆弱性，并有助于稳健地识别MTD。
