背景:现场监测是临床试验质量控制的重要组成部分。然而,由于各种问题,许多人对其成本效益表示怀疑,例如缺乏监测重点,这可能有助于在现场访问期间优先考虑有限的资源。因此,越来越多的试验申办方正实施将现场监测与集中监测相结合的混合监测策略.集中监控的主要目标之一,如临床试验指南所述,是指导和调整现场监测的程度和频率。ICHE6(R2)中引入的质量容差限值(QTL)和TransCelerateBiopharma提出的阈值是在试验和现场水平上实现这一目标的两种现有方法。分别。漏斗图,作为另一种基于阈值的站点级别方法,通过根据站点大小灵活调整阈值,克服了TransCelerate方法的局限性。尽管如此,两种方法都不能透明地解释选择他们使用的阈值的原因,或者他们的选择在任何某种意义上都是最优的。此外,相关的贝叶斯监测方法也很缺乏。
方法:我们提出了一个简单的,透明,和用户友好的基于贝叶斯的风险边界,用于确定试验和现场级别的现场监测的范围和频率。我们开发了一个四步方法,包括:1)建立关键风险指标(KRI)的风险水平及其相应的监测措施和估计;2)计算最佳风险边界;3)将KRI的结果与最佳风险边界进行比较;4)根据比较结果提供建议。我们的方法可用于确定既定风险水平范围内的最优风险边界,适用于连续、离散,和时间到事件的端点。
结果:我们通过模拟各种现实的临床试验方案来评估所提出的风险边界的性能。使用真实的临床试验数据将建议的风险边界的性能与漏斗图进行比较。结果证明了所提出的临床试验监测方法的适用性和灵活性。此外,我们确定了影响拟议风险边界最优性和性能的关键因素,分别。
结论:鉴于上述建议的风险边界的优点,我们希望它们将使整个临床试验界受益,特别是在基于风险的监控领域。
BACKGROUND: On-site monitoring is a crucial component of quality control in clinical trials. However, many cast doubt on its cost-effectiveness due to various issues, such as a lack of monitoring focus that could assist in prioritizing limited resources during a site visit. Consequently, an increasing number of trial sponsors are implementing a hybrid monitoring strategy that combines on-site monitoring with centralised monitoring. One of the primary objectives of centralised monitoring, as stated in the clinical trial guidelines, is to guide and adjust the extent and frequency of on-site monitoring. Quality tolerance limits (QTLs) introduced in ICH E6(R2) and thresholds proposed by TransCelerate Biopharma are two existing approaches for achieving this objective at the trial- and site-levels, respectively. The funnel plot, as another threshold-based site-level method, overcomes the limitation of TransCelerate\'s method by adjusting thresholds flexibly based on site sizes. Nonetheless, both methods do not transparently explain the reason for choosing the thresholds that they used or whether their choices are optimal in any certain sense. Additionally, related Bayesian monitoring methods are also lacking.
METHODS: We propose a simple, transparent, and user-friendly Bayesian-based risk boundary for determining the extent and frequency of on-site monitoring both at the trial- and site-levels. We developed a four-step approach, including: 1) establishing risk levels for key risk indicators (KRIs) along with their corresponding monitoring actions and estimates; 2) calculating the optimal risk boundaries; 3) comparing the outcomes of KRIs against the optimal risk boundaries; and 4) providing recommendations based on the comparison results. Our method can be used to identify the optimal risk boundaries within an established risk level range and is applicable to continuous, discrete, and time-to-event endpoints.
RESULTS: We evaluate the performance of the proposed risk boundaries via simulations that mimic various realistic clinical trial scenarios. The performance of the proposed risk boundaries is compared against the funnel plot using real clinical trial data. The results demonstrate the applicability and flexibility of the proposed method for clinical trial monitoring. Moreover, we identify key factors that affect the optimality and performance of the proposed risk boundaries, respectively.
CONCLUSIONS: Given the aforementioned advantages of the proposed risk boundaries, we expect that they will benefit the clinical trial community at large, in particular in the realm of risk-based monitoring.