Lu Rong
The Quantitative Sciences Unit, Division of Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California.
medRxiv. 2024 Mar 12:2024.03.06.24303862. doi: 10.1101/2024.03.06.24303862.
On December 10, 2021, the FDA published a Determination Letter, along with a Statistical Review and Evaluation Report, and concluded that under the non-informative prior, the local Bayesian optimal interval design (BOIN) design, in its revised form, can be designated fit-for-purpose for identifying the maximum tolerated dose (MTD) of a new drug, assuming that dose-toxicity relationship is monotonically increasing. Although setting the BOIN design parameter = 1.4 * is recommended in almost all BOIN methodology articles and is the default value in the R package , it's unclear if the choice of should only depend on the target DLT rate and whether certain range of p.tox could produce the same BOIN boundary table.
In this simulation study, following parameters were varied one at a time, using R package , to explore each parameter's effect on the equivalence intervals of and : 1) target DLT rate, 2) , 3) , 4) , and 5) . And a simple 3+3 design was used as an example to explore equivalent sets of BOIN design parameters that can generate the same boundary table.
When the early stopping parameter is relatively small or the value is not optimized via simulation, it might be better to use p.tox < 1.4 * , or try out different cohort sizes, or increase , whichever is both feasible and provides better operating characteristics. This is because if the cohortsize was not optimized via simulation, even when = 12 and > 3, the BOIN escalation/de-escalation rules generated using p.tox = 1.4 * could be exactly the same as those calculated using p.tox > 3 * , which might not be acceptable for some pediatric trials targeting 10% DLT rate.The traditional 3+3 design stops the dose finding process when 3 patients have been treated at the current dose level, 0 DLT has been observed, and the next higher dose has already been eliminated. If additional 3 patients were required to be treated at the current dose in the situation described above, the decision rules of this commonly used 3+3 design could be generated using BOIN design with target DLT rates ranging from 18% to 29%, ranging from 8% to 26%, and different values ranging from 39% to 99%. To generate this commonly used 3+3 design table, BOIN parameters also need to satisfy a set of conditions.
2021年12月10日，美国食品药品监督管理局（FDA）发布了一份判定函以及一份统计审查与评估报告，得出结论：在非信息先验条件下，假设剂量 - 毒性关系单调递增，经修订的局部贝叶斯最优区间设计（BOIN）可指定用于确定新药的最大耐受剂量（MTD）。尽管几乎所有BOIN方法学文章都推荐将BOIN设计参数 设置为1.4 * ，并且这是R包中的默认值，但尚不清楚 的选择是否仅应取决于目标剂量限制毒性（DLT）率，以及特定范围的p.tox是否会产生相同的BOIN边界表。
在本模拟研究中，使用R包一次改变一个以下参数，以探索每个参数对 和 的等效区间的影响：1）目标DLT率，2） ，3） ，4） ，以及5） 。并以简单的3 + 3设计为例，探索可生成相同边界表的等效BOIN设计参数集。
当初始停药参数 相对较小时，或者 值未通过模拟进行优化时，可能最好使用p.tox < 1.4 * ，或者尝试不同的队列大小，或者增加 ，只要可行且能提供更好的操作特性即可。这是因为如果队列大小未通过模拟进行优化，即使 = 12且 > 3，使用p.tox = 1.4 * 生成的BOIN递增/递减规则可能与使用p.tox > 3 * 计算的规则完全相同，这对于一些以10% DLT率为目标的儿科试验可能是不可接受的。传统的3 + 3设计在当前剂量水平治疗了3名患者、未观察到0例DLT且已排除下一个更高剂量时停止剂量探索过程。如果在上述情况下需要在当前剂量下额外治疗3名患者，则可以使用目标DLT率从18%到29%、 从8%到26%以及不同的 值从39%到99%的BOIN设计生成这种常用3 + 3设计的决策规则。要生成此常用的3 + 3设计表，BOIN参数还需要满足一组条件。
