Transformative approaches for effective clinical trials to reduce the disease burden of osteoarthritis

• Customize clinical trials design and outcomes to the OA disease states and subtypes targeted by the therapeutic mechanism. • Determine primary clinical trial outcomes based on the OA disease state and the therapeutic target. • Recognize that pain and symptoms may be absent, minimal, or inconsistent, particularly in earlier disease states, and therefore should not be the primary outcome measure where symptoms are not the mechanistic target. • Employ structural criteria measuring bone and soft tissue (cartilage, meniscus, synovium) changes for initial stratification of OA disease state as a framework within which mechanistic subtypes can be identified, tracked, and targeted for intervention. • Prioritize research on improving understanding of pre-OA to OA subtypes, endotypes, and OA pathogenic pathways. Osteoarthritis (OA) is a leading cause of disability and morbidity that has eluded development of effective disease modifying drugs and therapies. While established OA in the form of symptomatic radiographic disease is a recognizable final common pathway, OA development encompasses a broad spectrum of pathological changes, susceptibilities, and etiological pathways that cannot be considered a single disease process. Beginning with preclinical disease where radiographs are normal, the concept of pre-osteoarthritis (pre-OA) offers a systems-based approach to OA prevention by targeting reduction of OA risk prior to the onset of definable OA. Early OA ensues when cellular, molecular, and joint tissue changes begin to overlap that of OA, a process that can begin before the onset of definitive symptoms or radiographic changes. A myriad of pathways and crossroads of pre-OA and early OA eventually leads to poorly irreversible symptomatic radiographic OA. With increasing recognition of pre-OA and early OA markers, pathways and subtypes, opportunities arise to address these new therapeutic targets. The current status of clinical trials in OA was identified as a critical barrier to progress by the 2022 National Institute of Arthritis, Musculoskeletal, and Skin Diseases (NIAMS) Roundtable on “Cartilage Preservation and Restoration in Knee Osteoarthritis: Challenges, Gaps, and Opportunities”. This manuscript summarizes the recommendations of the work group established from the Roundtable to address this issue. The work group recommends that clinical trial design and endpoints evolve to effectively evaluate new treatment approaches suitable for pre-osteoarthritis and early OA by different criteria than what has been set for symptomatic radiographic OA. While symptomatic improvement is the primary goal for palliation of irreversible established OA, important goals for treating earlier disease states include disease modification and prevention, with the potential to alter the natural history of progressive OA. Because symptoms may not correlate with structural changes in pre-OA and early OA, the primary outcomes in these trials need to match the intended mechanistic target and the therapeutic goal for the disease state being treated. The purpose of this manuscript is to transform the approach to clinical trials in OA by establishing a new benchmark of identifying critical outcomes that are appropriate for the joint disease states and subtypes of the target patient population, and the therapeutic or mechanistic target of the intervention being tested. By shifting the approach from using standardized outcomes based on established OA towards customizing clinical trials according to these principles, new precision medicine strategies to address the full spectrum of disease from pre-OA to OA can be more readily advanced into clinical practice.