<p>Developing countries bear 93% of the global disease burden yet host less than 5% of clinical trials, limiting treatment generalizability and access. A 2018 systematic review catalogued key barriers to conducting clinical trials in developing countries, but their persistence and the evolution of solutions have since not being assessed. This review determines whether barriers identified by Alemayehu et al. (2018) persist in recent literature and synthesizes emerging facilitators and solutions. We systematically searched four databases for studies published after 2015 reporting barriers or facilitators to clinical trials in developing countries. A hybrid thematic analysis mapped data onto the prior framework while allowing new themes to emerge. Barriers were categorized by trial phase (pre-, during, post-trial). Of 942 records screened, 18 studies were included. Quantitative mapping revealed varied persistence: lack of infrastructure and skilled personnel showed moderate persistence (5/18 studies), while most 2018 sub-themes (e.g., regulatory delays) showed low persistence (3/18 studies). The literature’s focus may have shifted, with sociocultural beliefs and mistrust emerging as a dominant, highly persistent sub-theme (9/18 studies). Correspondingly, reported solutions are increasingly community-engaged and adaptive, including Rapid Ethical Assessment (REA) to improve consent, partnerships with traditional healers, mobile clinics, and regulatory harmonization models. While foundational systemic barriers endure, contemporary discourse emphasizes overcoming sociocultural mistrust through community partnership. Advancing equity requires dual investment in research infrastructure (e.g., digital infrastructure, efficient ethics review) and a fundamental shift from conducting trials in to with communities, centering local voices as partners in global health research.</p>