Following the release of a reflection paper, the European Medicines Agency (EMA) has invited a discussion around single-arm clinical trials as pivotal evidence for marketing authorisation applications. The public consultation began on April 21 and will end on 30 September 2023.

The paper, adopted by the Committee for Medicinal Products for Human Use (CHMP), explores concepts that can stimulate scientific discussion around the importance of the trials and how they can be improved.

Although randomised clinical trials (RCTs) are the gold standard, they cannot be used for all diseases. Rare disease trials often have small target populations, and a sample size is not large enough for a treatment and placebo group. Single-arm trials, where all subjects receive an experimental treatment and are then followed for a specific time period, are used in these cases and provide pivotal evidence for marketing authorisation applications for new medicines.

The guidance document touches on the choice of endpoints, targets, and trial population, using general knowledge about the disease and external clinical data, statistical rigour, and sources of bias.

“If results derived from [single-arm trials] are to be used as pivotal evidence for approval, it is essential that their adequacy is systematically addressed in terms of their characteristics, limitations and remaining uncertainties,” the document states.

This is the first guidance document by a medicine regulator that focuses on key concepts of single-arm trials. According to the EMA, its aim is to “stimulate the scientific discussion around key concepts and challenges associated with single-arm trials and to improve their design and conduct.”