Abstract

Objectives

Rare diseases pose methodological challenges in determining meaningful change thresholds for clinical outcome assessments (COAs) because of small sample sizes and disease heterogeneity. This article presents qualitative approaches for establishing patient-informed meaningful change thresholds on global impression anchor measures for rare diseases.

Methods

Two Food and Drug Administration-funded studies used novel cognitive debriefing methods to determine within-patient meaningful change on custom-developed anchors. Northwestern University Clinical Outcome Assessment Team debriefed Patient Global Impression of Severity and Change anchors referencing 5 physical function performance outcomes with 34 adults with idiopathic pulmonary fibrosis, systemic sclerosis, or myositis. Prepare-NS developed swelling-related patient-reported outcome and observer-reported outcome measures for nephrotic syndrome using Patient Global Impression of Severity/Global Impression of Severity and Change and Observer Global Impression of Severity/Change anchors with 12 patients and 8 caregivers.

Results

Qualitative anchor debriefing proved feasible across rare disease populations and COA types. Though many participants identified smaller (eg, 1-category) changes as meaningful, there was strong variation by anchor type and disease group. Anchors focusing on severity (vs impact) tended to require larger changes to be meaningful. In Prepare-NS, most patient-reported outcome participants and all caregivers viewed “No change” after 3 months of hypothetical treatment negatively. In Northwestern University Clinical Outcome Assessment Team, some participants experienced cognitive difficulties with PerfO anchors, struggling to translate objective metrics into meaningful impact.

Conclusions

Qualitative methods can provide patient-informed meaningful change thresholds on global impression anchors, although patients may struggle to identify meaningful change for performance anchors. Nonetheless, qualitative patient-informed thresholds can inform quantitative COA interpretation and strengthen endpoint development and regulatory dialog in rare disease clinical trials.