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

项目总结：FDA认为骨关节炎是一种严重的疾病，因为它是导致骨关节炎的主要原因

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.