Reflections from the 2021 OARSI clinical trial symposium: Considerations for understanding biomarker assessments in osteoarthritis drug development - Should future studies focus on disease activity, rather than status?

Abstract

Objective: Osteoarthritis (OA) is heterogeneous disease, for which drug development has proven to be challenging, both facilitated and hampered by changing guidelines. This is evident by the current lack of approved treatments, which improve joint function and delay joint failure. There is a need to bring together key stakeholders to discuss, align and enhance the processes for OA drug development to benefit patients.

Design: To facilitate drug development, the Osteoarthritis Research Society International (OARSI) initiated a series of annual clinical trials symposia (CTS). The aim of these symposia was to bring together academics, translational and clinical scientists, regulators, drug developers, and patient advocacy groups to share, refine and enhance the drug development process for the benefit of patients.

Results: OARSI is now considered the leading organization to facilitate open dialogue between all these stakeholders, in the intersection of understanding of the pathologies and drug development. Clearly, such a pivotal task needs an annual forum to allow stakeholders to share and discuss information, as possible solutions are joint efforts rather than a single stakeholder contribution.

Conclusions: The main topic of the 2021 CTS was how to improve clinical studies to help patients through overcoming barriers to development of new disease modifying treatments for OA. One key aspect was the focus on definitions of disease activity, status and the definitions of "illness vs disease". There is a clear medical need to couple a given disease activity with the optimal intervention for the right patient.

Keywords: Clinical trial; Drug development; Osteoarthritis.

Fig. 1

Schematic illustration of disease activity versus disease status. A: Total disease activity may be independent of disease status. OA in particular has been demonstrated to have a dis-concordance between disease activity and status with long periods of inertia followed by fast progression [9]. We begin to appreciate that OA has multiple drivers of disease, most likely at different stages of disease [10,11], as illustrated in Fig. 1. The actual total disease activity may be divided into different types of disease activity at different stages of the disease trajectory. The total disease activity drives the pathology past the illness threshold, resulting in considerable pain and loss of function leading the individual to see a doctor, and likely yielding the diagnosis of a symptomatic OA patient. However, if we target a treatment to the disease activity driver A with a potential treatment that may work against disease driver B, there may be no benefit to the patient. This, treating the symptoms, i.e. the illness (pain), may not correct the underlying diseases. This may in part explain some of the discordance between structure and symptoms in OA.