Introduction: For more than two decades several initiatives have emerged to increase recruitment of paediatric patients in drug trials. While trials of newly approved drugs have successfully included paediatric patients in their drug development plan, the collection of safety and efficacy data in paediatric patients treated with off-patent drugs poses a major challenge. Aim: This paper aims to draw attention to problems and solutions across countries in investigator-initiated trials with off-patent drugs and recommendations for improvement. Discussion: Off-patent drugs represent a particular challenge when they are included in a paediatric trial; these trials are frequently investigator-initiated and have limited resources, off-patent drugs are used in clinical settings and the trial protocol must accommodate e.g. flexible dosing and specimen sampling schedules, off-patent drugs typically exist in few formulations and concentrations which necessitates special or imported formulations. Paediatric trials are in some countries confined by e.g. consent from both parents, regardless of whether the Investigational Medicinal Product (IMP) is a well-known drug or a new experimental drug. Conclusion: Facilitation of research in off-patent drugs can improve evidence-based and safe treatment for the paediatric population. The following supportive initiatives are recommended: Harmonised regulatory change that improves the consent process in low risk trials to prevent inadequate recruitment. Pharmaceutical expertise should be prioritized to secure the best choice of IMP and supply. Constant focus on flexibility in design to accommodate a multifaceted paediatric population and ensure that trial protocols fit in well with routine clinical care and family life.