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Who should be included in first-in-human trials? A systematic review of reasons
Lieke van Kempen1, Martine C de Vries2, Eelco J P de Koning3,4
1Department of Medical Ethics and Health Law, Leiden University Medical Center, Leiden, The Netherlands. l.van_kempen@lumc.nl.
Background:
First-in-human trials mark a significant turning point in translational research, with novel therapies being tested in humans for the first time. Who should be included in FIH trials is a topic of ongoing debate amongst researchers, clinicians, ethicists, and sponsors. Yet, no comprehensive overview of the literature on this topic has been constructed before.
Methods:
A systematic review of reasons was conducted, following the methodology outlined by Stretch and Sofaer for conducting systematic reviews of argument-based literature. Six online databases were consulted across various disciplines, including medicine (PubMed and Embase), philosophy (The Philosopher's Index and PhilPapers), and multidisciplinary studies (Web of Science and Academic Search Premier). Additionally, relevant books and book chapters were identified through the library of Leiden University. After data extraction and analysis, 80 publications were included.
Results:
181 reasons were identified amongst six potential participant categories: healthy volunteers, patients (general), patients with less advanced-stage diseases, patients with more advanced-stage diseases, vulnerable populations, and diverse participant groups. These reasons relate to six themes: non-maleficence, beneficence, scientific value, efficiency, respect for persons, and justice. This review highlights multiple challenges in the existing literature, including ambiguous or poorly defined reasons and unspecified use of moral theory, framework, or method, the use of beneficence as an important theme for including participants in FIH trials, and the complexity of identifying and defining vulnerable populations.
Conclusions:
This review provides the first comprehensive overview of the reasons for and against including potential participant groups in FIH trials. The results highlight considerations that are relevant to reflect upon when determining and justifying participant selection for FIH trials. Additionally, this review offers guidance for further normative inquiry.
