DDT-BMQ-00086 End-Stage Knee Osteoarthritis as a Prognostic Biomarker for Knee Osteoarthritis Trials

FDA认为骨关节炎是一种严重的疾病，因为它是导致关节炎的主要原因。 疼痛、残疾和关节成形术，几乎没有有效的治疗方法，也没有人接受减少其整体 进展开发有效疗法的障碍包括未能丰富研究样本， 进展和缺乏结构性终点，“可靠地预测疼痛减轻，功能增加，或 终末期疾病的时间延长”。具体来说，我们缺乏一个严重的结构性终点或代理指标， 膝关节骨性关节炎。接受膝关节置换术通常被用作膝关节置换术的以患者为中心的终点。 骨关节炎，但这与膝关节骨关节炎严重程度的生物学指标之间存在高度可变的关系 以及对外来影响的强烈依赖（例如，期望，心理和身体准备， 外科手术）。这些方面使得膝关节置换术作为一致的疾病严重度终点不可靠。还有， 膝关节置换的低频率作为结果需要的样本量对于大多数临床试验来说是不可行的。 为了克服这些障碍，我们引入了一个反映“终末期膝关节骨关节炎”的复合定义 （esKOA），将患者报告的结局与结构严重程度指标相结合，以消除 在指定这种疾病状态的外来因素的影响。我们的专家共识小组改编了这个 膝关节置换术适当性算法的定义，该算法进一步开发和确认， 流行病学研究。简而言之，esKOA存在于1）严重放射学骨关节炎（Kellgren- Lawrence [KL]等级= 4/4）中度-剧烈疼痛或2）KL等级< 4伴有剧烈或重度疼痛 以及有限的移动性或不稳定性。FDA药物评估和研究中心接受了我们的申请 将esKOA纳入其生物标志物资格认证计划，并建议将其用作“预后 用于诊断为膝骨关节炎的受试者的临床试验中以识别患者的生物标志物组 可能经历长期疾病进展.需要膝关节置换手术”。解决 接下来的关键步骤，我们将使用基于膝关节的数据分析，这些数据来自骨关节炎倡议（8，888个膝关节 来自4，479人），这是一项纵向多中心观察性队列研究，明确设计用于膝关节 骨关节炎生物标志物。具体来说，我们将致力于确定esKOA的每个组成部分及其 提出的阈值“与疾病向esKOA的进展有关[目标1]，以及它们[和esKOA]如何 有助于识别进展或不会进展至膝关节置换术的患者[目标2]"。 此外，我们将评估是否“生物标志物和临床结果评估的复合物”， 组件可能不必要地复杂”，并且可以简化。这一建议将进一步推动 开发esKOA作为未来膝关节置换术的预后生物标志物。这种预后生物标志物将 公开提供，以丰富临床试验或早期试验的研究样本，以证明 干预的治疗潜力。

PROJECT SUMMARY The FDA recognizes osteoarthritis as a serious disease since it is a leading cause of pain, disability, and arthroplasty with few effective treatments and none accepted to reduce its overall progression. Barriers to developing effective therapies include failure to enrich study samples with people likely to progress and an absence of structural endpoints that “reliably predict reduced pain, increased function, or prolonged time to end-stage disease”. Specifically, we lack a structural endpoint or proxy indicator of severe knee osteoarthritis. Receipt of a knee replacement is often used as a patient-centered endpoint for knee osteoarthritis, but this has a highly variable relationship with biological measures of knee osteoarthritis severity and a strong dependence on extraneous influences (e.g., expectations, mental and physical readiness for surgery). These aspects render knee replacements unreliable as a consistent disease severity endpoint. Also, the low frequency of knee replacement as an outcome requires sample sizes infeasible for most clinical trials. To overcome these barriers, we introduced a composite definition reflecting “end-stage knee osteoarthritis” (esKOA), which combines patient-reported outcomes with structural severity measures to eliminate the influence of extraneous factors in designating this disease status. Our consensus panel of experts adapted this definition from an appropriateness algorithm for knee arthroplasty that was further developed and validated for epidemiologic studies. In brief, esKOA is present in a knee with 1) severe radiographic osteoarthritis (Kellgren- Lawrence [KL] grade = 4 out of 4) with moderate-intense pain or 2) KL grade < 4 with intense or severe pain and limited mobility or instability. The FDA Center for Drug Evaluation and Research accepted our application to enroll esKOA into their Biomarker Qualification Program with a proposed context of use as a “prognostic biomarker panel for use in clinical trials with subjects with a diagnosis of knee osteoarthritis to identify patients who are likely to experience long-term disease progression…requiring knee replacement surgery”. To address the critical next steps, we will use knee-based analyses of data from the Osteoarthritis Initiative (8,888 knees from 4,479 people), which is a longitudinal multicenter observational cohort explicitly designed to develop knee osteoarthritis biomarkers. Specifically, we will aim to determine how each component of esKOA and their proposed thresholds “relate to disease progression towards esKOA [Aim 1] and how they [and esKOA] may contribute to identification of patients who progress or will not progress to knee replacement [Aim 2]”. Furthermore, we will assess whether a “composite made of both biomarker and clinical outcome assessment components may be unnecessarily complicated” and could be simplified. This proposal will further the development of esKOA as a prognostic biomarker for future knee replacement. This prognostic biomarker will be made publicly available to enrich a study sample for clinical trials or in early-phase trials to demonstrate an intervention’s therapeutic potential.