Demographic Representation in Clinical Trials for Transthyretin-Associated Cardiac Amyloidosis: A Systematic Review.

Background: Underrepresentation of minority groups in clinical trials exacerbates health disparities and limits the generalizability of findings. Transthyretin amyloid cardiomyopathy (ATTR-CM) is a condition that disproportionately affects certain racial and ethnic groups, yet the extent to which trial enrollment reflects disease burden remains unclear. Misalignment between disease prevalence and trial representation may delay treatment development and increase the economic burden associated with late diagnosis and suboptimal management. To evaluate racial and ethnic representation in completed U.S.-based ATTR-CM clinical trials by comparing observed participant enrollment with expected enrollment based on disease prevalence, and to assess whether demographic reporting and representation improved following the 2017 Food and Drug Administration (FDA) Final Rule. Methods: This systematic review assessed US-based ATTR clinical trials registered on ClinicalTrials.gov through 2025 (search date: February 12, 2025). Only completed trials with publicly available results were included. Demographic data were extracted at the trial level. For each group, an enrollment fraction (EF) was calculated as observed enrollment ÷ expected enrollment, based on the Cardiac Amyloidosis Registry Study (CARS) prevalence; adequacy was defined as EF ≥0.75. Results: Of the 264 clinical trials on ATTR identified, 16 met the inclusion criteria. African American individuals/individuals of African descent had EFs below the adequacy threshold of 0.75 across all reviewed trial phases compared with their Asian or White counterparts. Following implementation of the FDA Final Rule in 2017, reporting of demographic data increased in the overall study population (from 60% to 83.3%). Although the racial distribution remained significantly different from the expected population distribution in both periods, the enrollment fraction for Black participants declined from 0.291 before 2017 to 0.125 after 2017, with similar decreases observed among other minority groups. Conclusions: Black individuals remain substantially underrepresented in US-based ATTR-CM clinical trials despite improved demographic reporting after the 2017 FDA Final Rule. Actionable strategies, including community engagement, diversification of trial sites, enrollment targets, and sponsor accountability, are urgently needed to improve representativeness and expand access.