We propose to develop and validate publicly available clinical outcome assessments (COAs) of physical function (PF) as they relate to a range of chronic conditions, fit for regulatory purpose. These COAs will assess PF as a patient-reported outcome (PRO) and a performance outcome (PerfO). The PRO and PerfO will be derived, and expanded as necessary, from publicly-available HealthMeasures (www.healthmeasures.net) assessments, including the Patient Reported Outcomes Measurement Information System (PROMIS), the NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox), and the Short Physical Performance Battery (SPPB), co-validated with accelerometer monitoring of physical activity. To validate COAs for use across the spectrum of physical function impairment, we propose 6 common conditions associated with sarcopenia and 5 rare disorders for consideration during the UG3 phase. In both cases (sarcopenia and rare disorders), we aim to sample the full range of PF impairment from mild to severe, and to sample different aspects of PF impairment as they affect different diagnostic groups. Our goal is to produce core PF outcome sets that can be applied broadly across the PF severity continuum for regulatory use in sarcopenia and rare disorders. In the UG3 planning phase, we will work with a broad range of stakeholders, experts, and the FDA, to identify target disease areas that are chronic, symptomatic, and have an impact on PF.
The specific aims i n this phase include (1) convening stakeholders, including patients, care partners, clinicians, measurement experts, payers, regulators, and pharmaceutical industry representatives, around the topic of PF related to approval of new drugs; (2) proposing model conditions in which to test measures of PF (e.g., rare diseases, sarcopenia), and identify potential gaps in our proposed PF measures; and (3) proposing plans for refining and testing. In the UH3 implementation phase, we will identify existing, revised, and newly developed assessment tools to be evaluated as COAs. Substantial COA core building blocks can be drawn from PROMIS and NIH Toolbox. These PF measures are appropriate for children and adults with a variety of chronic conditions and thus are ideal for deriving the cross-cutting COA core sets that the agency seeks to develop. We will then conduct the research required for validation, in accordance with FDA recommendations.
The specific aims i n this phase include (1) Produce a PF PRO, derived from mixed-methods research and the PROMIS PF bank v2.0, including short forms for mildly-, moderately-, and severely-impaired PF, and full-range PF; (2) Produce a PF Performance Outcome (PerfO), derived from the NIH Toolbox and the SPPB, optimized for responsiveness to conditions that affect PF; and (3) Validate the PF PRO and PerfO in three longitudinal studies: one addressing mild / moderate PF impairment, one addressing moderate / severe PF impairment, and one addressing a full range of PF impairment. This will produce publicly-available and accessible core clinical outcome sets for measuring physical function in pharmaceutical clinical trials, with the potential for widespread generalizability across conditions.
The overall objective is to solicit extensive stakeholder input on our existing patient-reported and performance measures of physical function, then adapt and validate them to be fit for regulatory use across a range of chronic diseases and disorders. The impact of this work will be the advancing of FDA core outcome sets for physical function that can be used in future clinical trials to better understand the impact of new treatments on people's lives. The long-term contribution of this research is the potential to reduce or remove the adverse impact of chronic disease and aging on physical function.
