Background: There exists no prior systematic review of human challenge trials (HCTs) that focuses on participant safety. Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective. Methods: A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 10/7/2021. Results: Of 2,838 articles screened, 276 were reviewed in full. 15,046 challenged participants were described in 308 studies that met inclusion criteria. 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies which reported on SAEs, 0.2% of participants experienced at least one challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded "severe" were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. 80% of studies published after 2010 were registered in a trials database. Conclusions: HCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. From the available data, most HCTs do not lead to a high number of severe symptoms or SAEs. This study was preregistered on PROSPERO as CRD42021247218.
A Systematic Review of Human Challenge Trials, Designs, and Safety