A Systematic Review of Human Challenge Trials, Designs, and Safety

Author:

Adams-Phipps Jupiter1,Toomey Danny12,Więcek Witold1,Schmit Virginia1,Wilkinson James1,Scholl Keller3,Jamrozik Euzebiusz456,Osowicki Joshua78,Roestenberg Meta910,Manheim David11112ORCID

Affiliation:

1. 1Day Sooner Research Team , Lewes, Delaware , USA

2. Warren Alpert Medical School of Brown University , Providence, Rhode Island , USA

3. RAND Corporation, Pardee RAND Graduate School , Santa Monica, California , USA

4. The Ethox Centre & Wellcome Centre for Ethics and the Humanities, Nuffield Department of Population Health, University of Oxford , Oxford , United Kingdom

5. Monash Bioethics Centre, Monash University , Clayton, VIC , Australia

6. Royal Melbourne Hospital Department of Medicine, University of Melbourne , Parkville, VIC , Australia

7. Murdoch Children's Research Institute , Parkville, VIC , Australia

8. Infectious Diseases Unit, Department of General Medicine, Royal Children's Hospital Melbourne , Parkville, VIC , Australia

9. Department of Parasitology, Leiden University Medical Centre , Leiden , The Netherlands

10. Department of Infectious Diseases, Leiden University Medical Center , Leiden, ZA The Netherlands

11. Technion, Israel Institute of Technology , Haifa , Israel

12. ALTER, Association for Long Term Existence and Resilience , Rehovot , Israel

Abstract

AbstractBackgroundFew studies have assessed participant safety in human challenge trials (HCTs). 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.MethodsA systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021.ResultsOf 2838 articles screened, 276 were reviewed in full. A total of 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 that reported on SAEs, 0.2% of participants experienced at least 1 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. Eighty percent of studies published after 2010 were registered in a trials database.ConclusionsHCTs 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. We found very few severe symptoms or SAEs in studies that reported them, but many HCTs did not report relevant safety data. This study was preregistered on PROSPERO as CRD42021247218.

Funder

1Day Sooner

Center for Effective Altruism’s Long Term Future Fund

Wellcome Trust

National Health and Medical Research Council

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Microbiology (medical)

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