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.