Ethical Requirements for Human Challenge Studies: A Systematic Review of Reasons

Abstract

Human challenge studies (HCS) are controlled clinical trials in which participants are deliberately infected with a pathogen. Such trials are being developed for an increasing number of diseases. Partly as a result of the coronavirus disease 2019 (COVID-19) pandemic, there has been a recent ethical debate about the reasons for and against HCS in general, or rather, about the requirements that individual HCS must fulfill to be ethically acceptable. A systematic review was conducted to categorize and summarize such requirements and the reasons given for them. Ethics literature was searched in PubMed, Google Scholar, BELIT, and PhilPapers; eligibility criteria were articles published in a scientific/scholarly journal (original research, reviews, editorials, opinion pieces, and conference/meeting reports). Of 1,322 records identified, 161 publications were included, with 183 requirements (with associated reasons) in 10 thematic categories extracted via qualitative content analysis. In synthesizing and interpreting the requirements and their reasons, three issues emerge as particularly sensitive in the case of HCS: the meaning of the right to withdraw from research procedures, communication of researchers with the public and various stakeholders, and the conditions of informed consent. However, four other issues, not specific to HCS, stand out as the most controversial: the acceptable level of risk to participants, payment of participants, protection of vulnerable groups, and standards for international collaborations. Controversies in these areas indicate that further debate is warranted, possibly leading to more specific instructions in ethics guidance documents.