Placebo in Paediatric Clinical Trials: Systematic Literature Review and Framework‐Based Synthesis

INTRODUCTION: Placebo-controlled trials can provide strong evidence on safety and efficacy, but their ethical acceptability in paediatric research is contested because children have limited decisional capacity and placebo use may entail withholding effective therapy. OBJECTIVE: To identify the ethical and methodological conditions under which placebo controls are acceptable in paediatric clinical trials, using a systematic review of the literature and regulatory guidance. METHODS: We searched Medline, Scopus and Embase for sources addressing the ethics, acceptability or regulation of placebo use in paediatric trials. We extracted study characteristics and ethical arguments, mapped them to beneficence, non-maleficence, autonomy and justice, and then synthesised findings using Emanuel, Wendler and Grady's seven requirements for ethical clinical research. We also obtained expert guidance from UK, USA and European regulators. RESULTS: We included 51 sources spanning neonatal research, disease-specific paediatric contexts, parental perspectives and general ethics/regulatory discussions. Placebo was generally considered acceptable when methodologically necessary and scientifically sound, when no proven effective therapy was withheld (or any withholding carried minimal incremental risk), and when safeguards such as rescue therapy, early escape, and close monitoring were in place. Common emphases included limits on non-beneficial risk in children, assent and parental permission, and fair participant selection. CONCLUSION: Placebo use in paediatric trials is acceptable only under constrained conditions centred on scientific necessity, minimising harm from withholding therapy, robust safeguards and appropriate permission/assent processes. Further work should translate these conditions into disease-specific, operational guidance.