Recent years have seen the development of clinical study protocols that introduce more complex design features into the usual gold-standard randomised controlled trials (RCTs). Complex protocols are potentially useful for drug evaluation in the setting of rare disease indications, to optimise the efficiency of investigational drug development. They often involve a development of a master protocol alongside disease-specific sub- protocols. This article describes an approach used to develop a complex protocol for a Phase 3 trial involving an investigational treatment being studied for use in two distinct rare diseases. In a somewhat unusual approach, detailed subprotocols were developed that contained all information required by the investigator, while the master protocol highlighted differences between the subprotocols and provided rationale justifying use of a complex study design. Use of complex study designs aims to promote efficiency in the clinical investigation process but also needs to offer optimal clarity to both study investigators and regulatory reviewers.

Medical Writing. 2025;34(1):32–35. https://doi.org/10.56012/lmmt8627