PMID- 36219704 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20230224 LR - 20240329 IS - 1537-6591 (Electronic) IS - 1058-4838 (Print) IS - 1058-4838 (Linking) VI - 76 IP - 4 DP - 2023 Feb 18 TI - A Systematic Review of Human Challenge Trials, Designs, and Safety. PG - 609-619 LID - 10.1093/cid/ciac820 [doi] AB - BACKGROUND: Few 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. 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 7 October 2021. RESULTS: Of 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. 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. 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. CI - (c) The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. FAU - Adams-Phipps, Jupiter AU - Adams-Phipps J AD - 1Day Sooner Research Team, Lewes, Delaware, USA. FAU - Toomey, Danny AU - Toomey D AD - 1Day Sooner Research Team, Lewes, Delaware, USA. AD - Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA. FAU - Wiecek, Witold AU - Wiecek W AD - 1Day Sooner Research Team, Lewes, Delaware, USA. FAU - Schmit, Virginia AU - Schmit V AD - 1Day Sooner Research Team, Lewes, Delaware, USA. FAU - Wilkinson, James AU - Wilkinson J AD - 1Day Sooner Research Team, Lewes, Delaware, USA. FAU - Scholl, Keller AU - Scholl K AD - RAND Corporation, Pardee RAND Graduate School, Santa Monica, California, USA. FAU - Jamrozik, Euzebiusz AU - Jamrozik E AD - The Ethox Centre & Wellcome Centre for Ethics and the Humanities, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. AD - Monash Bioethics Centre, Monash University, Clayton, VIC, Australia. AD - Royal Melbourne Hospital Department of Medicine, University of Melbourne, Parkville, VIC, Australia. FAU - Osowicki, Joshua AU - Osowicki J AD - Murdoch Children's Research Institute, Parkville, VIC, Australia. AD - Infectious Diseases Unit, Department of General Medicine, Royal Children's Hospital Melbourne, Parkville, VIC, Australia. FAU - Roestenberg, Meta AU - Roestenberg M AD - Department of Parasitology, Leiden University Medical Centre, Leiden, The Netherlands. AD - Department of Infectious Diseases, Leiden University Medical Center, Leiden, ZAThe Netherlands. FAU - Manheim, David AU - Manheim D AUID- ORCID: 0000-0001-8599-8380 AD - 1Day Sooner Research Team, Lewes, Delaware, USA. AD - Technion, Israel Institute of Technology, Haifa, Israel. AD - ALTER, Association for Long Term Existence and Resilience, Rehovot, Israel. LA - eng GR - WT_/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Infect Dis JT - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JID - 9203213 SB - IM PMC - PMC9938741 OTO - NOTNLM OT - adverse events OT - controlled human infection model OT - human challenge trial OT - risk mitigation OT - systematic review COIS- Potential conflicts of interest. 1DaySooner advocates for volunteers in HCTs and supports their broader usage. Several authors of the paper have volunteered for HCTs, though none have participated in a trial. Several authors of the paper were employed by 1DaySooner's research team for this work, which is intended to be independent of the advocacy group. For this reason, there was no review of the manuscript nor input about the results from the management nor from the advocacy team. D. M. has been paid externally for work with both the advocacy and research teams at 1DaySooner, as well as other related advocacy and policy research. W. W. provides scientific consulting for pharmaceutical companies and other organizations that conduct clinical trials, but not for HCTs. M. R. is a professor and the clinical head of the Controlled Human Infection Center at Leiden University, which conducts challenge trials. J. O. has worked on challenge trials and is working with an international collaborative group to drive development of a Group A Streptococcus pharyngitis Controlled Human Infection Model. E. J. has contributed to World Health Organization Ethics Guidance documents on Human Challenge Trials and has received funding from the Wellcome Trust, including current grants 221 719 and 216355, which supported work for this paper. D. T. reports grants or contracts from 1Day Sooner (paid to author), and HHV-6 Foundation (paid to author). D. M. reports grants or contracts from Future of Humanity Institute, Oxford (research contract), Council on Strategic Risks (research contract), Open Philanthropy (policy research), FIND, the global alliance for diagnostics (policy research), Guarding Against Pandemics (policy and political research); consulting fees from Ribbonfarm (corporate consulting) and Good judgment project (forecasting); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from CERI Fellowship (Biosecurity Reading Group), and SERI Mentorship (Mentorship Honorarium); support for attending meetings and/or travel from Guarding Against Pandemics (conference costs) and Global Priorities Institute (conference costs); D. M. is the founding director of Association for Long Term Existence and Resilience; and reports receipt of equipment, materials, drugs, medical writing, gifts, or other services from Center for Applied Rationality (LessWrong Good Heart Week, Prize for LessWrong 2020 Review) and Center for Effective Altruism (EA Forum Prize February 2021). M. R. reports grants or contracts from European Commission (participant in 3 grants), Merck (Malaria Challenge Trial), and Wellcome Trust (Schistosomiasis challenge trial); consulting fees from Wellcome Trust (expert advisor, payment to institution), and hVIVO, establishment of a guidance document (paid to institution); if she is an invited speaker, sometimes travel expenses get reimbursed; participation on a Data Safety Monitoring Board or Advisory Board as a member and chairwoman of several malaria vaccine trials and controlled human infection trials in the United States, Europe, Africa, and Asia and member of the Scientific advisory committee for EDCTP. M. R. is the chairman for Dutch Society for Parasitology (NVP) and the management board member for HICVAC. W. W. reports consulting fees from Certara UK Ltd (scientific consultant for Certara, which works with all major pharmaceutical companies; no involvement in human challenge trials). E. J. reports grants or contracts from Bill & Melinda Gates Foundation (institutional funding) and consulting fees from The Democracy Fund (report writing). K. S. reports grants or contracts from RAND Corporation (employment as an assistant policy analyst) and Pardee RAND Graduate School (Graduate School Scholarship covering tuition and a stipend); consulting fees from Guarding Against Pandemics (personal payments for research work analyzing Biomedical Adavanced Research and Development Authority with a political focus); and support for attending meetings and/or travel from Pardee Rand Graduate School (paid to author); stock or stock options from Wealthfront (invested in broad market index funds). All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. EDAT- 2022/10/12 06:00 MHDA- 2022/10/12 06:01 PMCR- 2022/10/11 CRDT- 2022/10/11 14:22 PHST- 2022/03/15 00:00 [received] PHST- 2022/10/12 06:00 [pubmed] PHST- 2022/10/12 06:01 [medline] PHST- 2022/10/11 14:22 [entrez] PHST- 2022/10/11 00:00 [pmc-release] AID - 6758436 [pii] AID - ciac820 [pii] AID - 10.1093/cid/ciac820 [doi] PST - ppublish SO - Clin Infect Dis. 2023 Feb 18;76(4):609-619. doi: 10.1093/cid/ciac820.