A well-designed clinical trial is essential for the collection of reliable, robust and meaningful data to ensure the protection of participants rights and safety and also minimise economic losses and timelines associated with the execution of a clinical trial. These factors all contribute to supporting the timely access to safe and effective therapeutic interventions. Selecting an optimal clinical trial design is a critical step and should precede the writing of the clinical trial protocol. While the gold standard traditional randomised controlled clinical trial is still the most common approach, trial design has evolved to accommodate the progress of the interventions under investigation and to accelerate drug development. The innovation around clinical trial design and its added complexity has led regulatory agencies to support sponsors and other stakeholders by providing feedback via scientific advice and protocol assistance procedures or through the issuance of guidelines. The feedback is designed to address the challenges posed by nonstandard clinical trial designs. However, it has been shown to be insufficient in mitigating the perceived regulatory risks associated with these designs, particularly for pivotal clinical trials. As a result, clinical trial designs are not being developed to their full potential. In this article, we provide an overview of the most relevant innovative clinical trial designs and the regulatory challenges associated with them.