Optimizing the Population Representativeness of Older Adults in Alzheimer's Disease and Related Dementia Clinical Trials

摘要 临床试验通常在理想化和严格控制的条件下进行，以确保内部 有效性，但矛盾的是，这样的条件考验外部有效性(即对目标的概括性 人口)。低试验可推广性长期以来一直是一个令人担忧的问题，并在不同的临床中得到了广泛的记录 区域。例如，阿尔茨海默病和相关痴呆症(ADRD)临床试验的参与者是 在一般人群中，系统性地比ADRD患者年轻。过于严格的资格标准是 可以说，最大的但可修改的障碍导致通用性较低。FDA已经推出了许多 倡议，主要是通过扩大资格标准，以促进登记做法，以便试验 参与者可以更好地反映如果获得批准，最有可能使用该治疗的人群。 尽管如此，试验赞助商和调查人员不愿扩大资格标准，因为 严重不良事件(SAE)风险的潜在增加及其对调查的负面影响 药物的安全性和有效性概况。因此，许多老年患者也被排除在ADRD试验之外 明确地通过年龄限制或通过排除更普遍的临床特征来暗示 老年人。扩大试验标准的需要与满足#年需要的现有方法之间存在差距。 练习一下。以前的研究，包括我们的研究，已经验证并使用了研究特征的概括性指数 (GIST)，最佳可用的量化的、资格驱动的、先验的概化衡量标准，在许多方面 疾病领域。GIST分数可以潜在地用于指导对标准的调整，以实现更好的 人口代表性。然而，在实践中采用它存在着关键障碍，特别是在反兴奋剂机构 试验：(1)缺乏将标准转化为数据的标准化、可计算的资格标准(CEC)框架 查询-定义总体以进行概化评估的必要步骤，(2)缺乏验证 在ADRD试验中评估GIST的可靠性和有效性的研究，以及(3)需要绘制数学地图 资格标准与GIST以及患者预后(即SAE)之间的关系，这回答了 关键问题是扩大标准将如何同时影响试验的普适性和患者结果。 为了消除这些障碍，我们建议系统分析临床试验中现有的ADRD试验。 为ADRD试验创建本体驱动的标准化CEC库，在ADRD试验中验证GIST，以及 建立统计模型，说明资格标准的调整，特别是年龄的调整将如何影响(1)试验 由GIST衡量的概括性，以及(2)目标人群的结果(即，SAE)，使用 真实世界的电子健康记录(EHR)数据。我们将回答一个关键的研究问题：什么和如何 超过明确年龄标准的排除标准限制了老年人参与ADRD试验。

ABSTRACT Clinical trials are often conducted under idealized and rigorously controlled conditions to ensure internal validity, but such conditions, paradoxically, compromise trials external validity (i.e., generalizability to the target population). Low trial generalizability has long been a concern and widely documented across different clinical areas. For instance, participants of Alzheimer's disease and related dementias (ADRD) clinical trials are systematically younger than ADRD patients in the general population. Overly restrictive eligibility criteria are arguably the biggest yet modifiable barriers causing low generalizability. The FDA has launched numerous initiatives, primarily through broadening eligibility criteria, to promote enrollment practices so that trial participants can better reflect the population who would most likely use the treatment if approved. Nevertheless, trial sponsors and investigators are reluctant to broaden eligibility criteria due to concerns over potential increases in risk of serious adverse events (SAEs) and its negative impact on the investigational drug’s safety and effectiveness profile. As a result, many elderly patients are excluded from ADRD trials either explicitly through an age restriction or implicitly through excluding clinical characteristics more prevalent in the elderly. There is a gap between the need to broaden trial criteria and ways available to fulfill the need in practice. Previous studies, including ours, have validated and used the Generalizability Index of Study Traits (GIST), the best available quantitative, eligibility-driven, a priori generalizability measure, in a number of disease domains. GIST scores can potentially be used to guide adjustments to criteria towards better population representativeness. However, there are key barriers for its adoption in practice, especially in ADRD trials: (1) the lack of a standardized, computable eligibility criteria (CEC) framework to translate criteria to data queries – a necessary step to define the populations for generalizability assessment, (2) the lack of a validation study that assesses GIST’s reliability and validity in ADRD trials, and (3) the need to map the mathematical relationships between eligibility criteria and GIST as well as patient outcomes (i.e. SAE), which answers the critical question how broadened criteria will affect trial’s generalizability and patient outcomes simultaneously. To remove these barriers, we propose to systematically analyze existing ADRD trials in clinicaltrails.gov to create an ontology-driven, standardized library of CEC for ADRD trials, validate GIST among ADRD trials, and develop statistical models on how adjustments to eligibility criteria, especially age, would affect (1) trial generalizability measured by GIST, and (2) outcomes (i.e., SAEs) of the target population, approximated using real-world electronic health record (EHR) data. We will answer a key research question: what and how exclusion criteria beyond the explicit age criterion limit older adults’ participation in ADRD trials.