The use of complex clinical trials: a regulatory review

BACKGROUND: Complex clinical trials offer flexibility in evaluating multiple treatments or diseases simultaneously. These trials often feature adaptive designs, common controls, and the potential to add new arms. However, the increased complexity raises methodological challenges particularly regarding multiple testing or the adequate choice of control groups. Despite guidance from regulatory bodies like the European Medicines Agency and the U.S. Food and Drug Administration, uncertainties remain about the regulatory acceptance of these trials. METHODS: This systematic review examines scientific advice procedures of products in the remit of the Paul-Ehrlich-Institut for complex clinical trials to highlight key concerns and regulatory feedback. We identified 30 scientific advice procedures corresponding to 29 different complex clinical trials. RESULTS: Our findings reveal an increasing number of complex trial designs proposed by applicants. A lack of multiplicity control due to multiple arms was generally considered acceptable by regulators in exploratory trials and if cohorts can be considered independent. Additionally, the use of common control groups is frequently proposed by applicants. The review underscores the importance of pre-planning for new treatment arms, appropriate multiplicity control, and the definition of control groups in trial designs. CONCLUSION: Overall, our findings suggest that regulatory concerns regarding complex trials largely align with those in traditional trial designs, though their complexity requires careful, case-by-case consideration. Early engagement with regulatory agencies can be crucial to ensure the successful design and implementation of these trials.