In contrast to randomised controlled trials (RCTs), single-arm clinical trials (SATs) are relatively simple by design: a sample of individuals receive an experimental treatment for a targeted condition, and are followed over a period of time to observe and evaluate their response to the treatment. RCTs are the gold standard when it comes to evaluating the efficacy of a new treatment, and are vital for marketing authorisation (MA) applications. However, in a distinct subset of MA applications, efficacy data derives from SATs. This is important because for some diseases (rare genetic disorders or cancers, for example), the target population is very small and it may be very difficult (if not impossible) to recruit a sufficient sample population for RCTs.

On 21 April 2023, a draft reflection paper was published by the European Medicines Agency (EMA). The aim of the paper is to consider how SATs are used in MA applications, especially where the SAT provides the pivotal evidence for that application. Although the reflection paper is focused primarily on establishing efficacy, it reaffirms the importance of safety in light of the “substantial shortcomings” of SATs.

The paper helpfully sets out what the EMA considers to be important with respect to design, conduct, interpretation, and assessment of SATs used for MA applications:

• Choosing an endpoint – these are outcomes that highlight the efficacy of a treatment, such as survival or relief of symptoms.
• Target and trial population – how to recruit an adequate trial population, especially where the potential impact of unknown diagnostic or predictive variables can not be controlled.
• Role of external information – how can “extra-study” information be used to interpret the results of the SAT.
• Statistical principles – how to interpret results accurately and efficiently using statistical best-practice (for example interpreting results, dealing with missing data and sample size considerations ).
• Source of bias and potential mitigation – how to measure and deal with potential bias in a SAT.

Parties are invited to submit any comments before 30 September 2023. The EMA is expected to reveal the results of the consultation in 2024.