EMA Proposes New Considerations for Single-Arm Trials

The reflection paper, which is the first guidance document by an international medicine regulator of its kind, offers suggestions on how to best reduce bias in SATs to support new marketing authorization applications.

Because there are no comparator drugs in these trials, the EMA wants to address sources of bias “throughout the design, conduct, analysis and reporting of results derived from a SAT.”

The objective of the paper is to “stimulate the scientific discussion around key concepts and challenges associated with single-arm trials and to improve their design and conduct,” the agency said in a statement.

The EMA maintains that randomized clinical trials where new treatments are compared against placebos are “the gold standard for generating evidence needed by regulatory authorities.” However, in certain therapeutic areas where target populations are small, such as rare diseases and cancers, a proportion of marketing authorization applications are submitted to the EMA using data from single-arm trials as pivotal evidence.

Avoiding Bias

The paper highlights that SATs lack the key features needed to avoid bias, which include a control arm, randomized allocation to treatment, the blinding of investigators and participants, and the enrollment of patients without knowledge of their subsequent assignment.

The paper states, “unbiased estimates are difficult to obtain from SATs. Consequently, multiple potential sources of bias need to be addressed throughout the design, conduct, analysis and reporting of results derived from a SAT.” The lack of a control arm also means that “use of external information in the analysis or interpretation of a SAT is a crucial design element and should be pre-specified in the study protocol.”

Public Consultation through September

A public consultation on the paper is open until September 30 and comes just a month after the US Food and Drug Administration (FDA) issued draft guidance aimed at improving oncology clinical trials. In the guidance, the FDA highlighted the advantage of randomized clinical trials over SATs, but outlines suggestions on how the two trial types could work together.

The EMA’s reflection paper has been adopted by the regulatory body’s human medicines committee, with contributions from the Committee for Advanced Therapies, the Methodology Working Party and the Oncology Working Party. Following the public consultation, comments from stakeholders will be considered in the final document set to be published in 2024.

If you would like to comment on the EMA’s reflection paper, please email RP-SATs@ema.europa.eu