EMA has opened a public consultation on a Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation that discusses key concepts for single-arm clinical trials that are submitted as pivotal evidence in support of marketing authorisation applications for medicines in the European Union (EU). This is the first guidance document by an international medicine regulator articulating the considerations and challenges associated with this type of clinical trials. Stakeholders are invited to send their comments via an online form by midnight (CET) on 30 September 2023.

Randomised clinical trials (RCTs) in which a new treatment is compared against a placebo or an existing standard of care are widely considered as the gold standard for generating evidence needed by regulatory authorities to assess the efficacy and safety of a new medicine. In RCTs, patients are randomly assigned to either the active treatment or the control arm. Usually, large numbers of patients are included for these trials to generate robust data on the efficacy of a treatment.

In certain areas such as rare diseases, including rare cancers, where target populations of new medicines are often very small, a proportion of marketing authorisation applications are submitted to EMA with clinical data from single-arm trials as pivotal evidence. Because there is no randomised comparator in a single-arm trial, all patients in the trial receive the experimental treatment and only the outcomes under the experimental treatment can be observed.

The reflection paper outlines considerations on single-arm trials that are submitted as pivotal evidence to demonstrate efficacy in a marketing authorisation application. It aims to stimulate the scientific discussion around key concepts and challenges associated with single-arm trials and to improve their design and conduct.

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).

Following the public consultation, comments from stakeholders will be analysed and considered in the final document that is planned to be published in 2024.

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