Sponsors should consider the following regarding structural endpoints for developing medical products for the treatment of OA:
- FDA recognizes that OA can be a serious disease with an unmet medical need for therapies that modify the underlying pathophysiology of the disease and potentially change its natural course to prevent long-term disability. However, there are several ongoing issues with developing such products, including the multifactorial and complex etiopathogenesis of the disease, the well-recognized discordance between structural changes and signs/symptoms/function, the lack of standard definitions of disease progression, and, correspondingly, the absence of endpoints to reliably assess the ability of a product to alter OA disease progression.
- Because of the complex and variable pathologic changes through which OA impairs function and leads to long-term disability and/or joint replacement, at this time it is unclear what magnitude of change in structural endpoints would translate to a clinically meaningful benefit to patients (i.e., reliably predict both reduced pain and increased function or prolonged time to end-stage disease). Thus, no structural endpoints have been used for traditional or accelerated approval in OA to date.
- To accept structural endpoints as valid outcome measures for accelerated approval, there should be substantial confidence, either based on empirical evidence from randomized, controlled comparisons from clinical trials and/or based on a comprehensive understanding of the disease process and product mechanism of action, that an effect on the candidate structural endpoint will reliably predict an effect on the clinical outcomes of interest.5 70 The ultimate goal of treatments related to inhibition of structural damage or targeting the underlying pathophysiology associated with OA is to avoid or significantly delay the complications of joint failure and the need for joint replacement, and also to reduce the deterioration of function and worsening of pain.
