Establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation

Following a public consultation, the Methodology Working Party (MWP) has finalised the Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation.

The reflection paper discusses key issues and requirements for single-arm clinical trials that are submitted as pivotal evidence in support of marketing authorisation applications for medicines in the European Union (EU).

During the public consultation phase comments from 45 stakeholders were received. The comments were taken into careful consideration and have resulted in the following major changes compared to the draft version:

• The reflection paper includes a clearer statement that as a regulatory standard, randomised controlled evidence is expected and that deviation from this standard by proposing a SAT needs justification.
• The scope of the reflection paper has been clarified to exclude guidance on the use of external controls. This led to a rephrased wording in the introductory section and the removal of the section on the role of external information and external-control focused biases from table 1.

The final version adapts a more targeted implementation of ICH E9(R1) with respective changes implemented in section 3. It expresses more clearly that regulatory assessment of efficacy of an investigational treatment conceptually requires comparative information and that single-arm trials only allow to observe outcomes under the investigational treatment. A previously drafted subsection on “internal validity” was removed and a new section on the “target of estimation” was introduced which outlines estimand attributes such as treatment condition, intercurrent events and population summary measures. 

In addition, it is emphasized that the results from clinical trials usually are intended to address several objectives, and a single-arm-trial intended to address a primary question to elucidate a treatment effect, may still not be capable to serve other objectives or decisions.

The reflection paper has been adopted by EMA’s human medicines committee (CHMP) with contributions from the Committee for Advanced Therapies (CAT), the Methodology Working Party (MWP) and the Oncology Working Party (ONCWP).

Keywords: Single-arm trials, non-randomised trials, regulatory decision making

Current version

Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation application

Adopted Reference Number: EMA/CHMP/430688/2024

Draft reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation

Draft: consultation closed Consultation dates: 21/04/2023 to 30/09/2023 Reference Number: EMA/CHMP/564424/2021