A novel patient-Centered approach to clinical trial readiness in rare diseases: Application in Aicardi-Gouti`eres Syndrome (AGS

Introduction: Aicardi-Goutières Syndrome (AGS) is a genetic type 1 interferonopathy that causes white matter abnormalities and intracranial calcifications, resulting in varying degrees of neurologic impairment and systemic manifestations. Novel disease-modifying therapies for AGS are forthcoming. The 2022 Food and Drug Administration guidance, "Patient-Focused Drug Development" (PFDD), emphasizes the importance of including patients' voices early in the design of clinical trials. This represents an urgent unmet need in rare disease research. In this study, we propose and pilot a new methodology to identify patient-centered Concepts of Interest (COIs) and suitable Clinical Outcome Assessments (COAs) for clinical trials. Methods: The study was performed under the Myelin Disease Biorepository Project within the Global Leukodystrophy Initiative Clinical Trial Network. A sequential multicomponent approach, piloted in AGS, was designed to (i) identify COIs, (ii) select COAs capable of measuring the COIs through expert consensus, and (iii) assess the feasibility of COA application. Experts were identified based on relevant scientific publications and expertise in AGS (disease experts for COI) and/or their application of relevant COAs (outcome experts for COA). Expert consensus was achieved using the modified eDelphi approach for COIs, expertise-specific multi-panel focus group discussions, and pre-and post-surveys for COA selection. Consensus was defined as ≥70% agreement among the experts. This was followed by a virtual stakeholder discussion with patients and/or patient representatives to assess the feasibility of the COA application in the context of a clinical trial. Results: Based on the health priorities identified by patient caregivers, the proposed approach revealed a set of fit-for-purpose COIs across the motor, adaptive behavior, and neurologic functional domains. All experts acknowledged the significance of each caregiver-identified priority but expressed differing opinions on the likelihood of observing changes in the functional domain within a 6- to 12-month timeframe. Following this, a consensus-building approach for COA selection for each identified COI resulted in a paired COI-COA panel applicable to future AGS clinical trials. Finally, the discussion on the feasibility of application of the selected COAs with the patients and/or patient representatives elicited critical information to design a patient-centered prospective COA protocol, applicable to clinical trials and natural history studies. Discussion: The proposed approach marks the first step toward a patient-centered clinical trial design for rare diseases. It establishes a paired COI-COA panel, as well as informs the design of a patient-centered prospective COA protocol for upcoming AGS clinical trials and natural history studies. Additionally, the identified COA panel facilitates the creation of a multicomponent endpoint for clinical trials, which is especially crucial in phenotypically diverse disorders like AGS. This approach is widely applicable across leukodystrophies and rare diseases.