Approaches to the Assessment of Clinical Benefit of Treatments for Conditions That Have Heterogeneous Symptoms and Impacts: Potential Applications in Rare Disease.

Evaluating the clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present differently across and within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) US Food and Drug Administration (FDA)–approved labeling claims that used these approaches. A targeted literature review was conducted examining peer-reviewed publications and FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating clinical outcome assessments. Approaches were then assessed for their potential application in rare diseases. A total of 6 assessment approaches were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling claims associated with these approaches were identified: composite or other multicomponent endpoints (n = 49), MBS (n = 9), and adequate relief (n = 1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints, were identified for rare diseases. Multicomponent, MBS, and adequate relief have been included in FDA-approved labeling claims. Multicomponent endpoints, including composite endpoints, were the most frequent way to address heterogeneous manifestations of both common and rare diseases. MBS may be acceptable to regulators, whereas multidomain responder index is unlikely to be. The goal attainment scaling and adequate relief approaches may have potential utility in rare disease trials, assuming the theoretical and statistical challenges inherent in each approach are managed. • Evaluating the clinical benefit of interventions aimed at treating conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present quite differently across individuals and change within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) Food and Drug Administration-approved labeling claims that used these approaches. • A total of 6 approaches to assessing clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom, goal attainment scaling, sliding dichotomy, and adequate relief. Based on Food and Drug Administration-approved labeling claims, multicomponent endpoints have been the most successful approach in common and rare diseases. The most bothersome symptom, goal attainment scaling, multidomain responder index, and adequate relief approaches may also have potential applications in rare disease trials. [ABSTRACT FROM AUTHOR]