EMA finalizes their perspective of the use of single-arm trials for regulatory decision-making

The EMA has finalized their reflection paper on using single-arm trials submitted as key evidence in regulatory applications, while emphasizing that randomized controlled trials (RCTs) remain the ‘expected standard’ for establishing efficacy.

After releasing a draft reflection paper last year for public consultation, the European Medicines Agency (EMA) has now revised and finalized its position on the use of pivotal evidence generated by single-arm trials (SATs) for regulatory decision-making. Following the period of public feedback, the “Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorization application,” has been endorsed by the EMA’s Methodology Working Party and formally adopted by the Committee for Medicinal Products for Human Use (CHMP) in September 2024.

The paper provides detailed guidance on when and how SATs can be used to support regulatory decisions in situations where RCTs may not be feasible. The EMA places the onus on manufacturers to justify the use of SATs instead of ‘gold standard’ RCTs, requiring them to demonstrate why a SAT is appropriate to provide robust evidence in the given clinical context.

“If the pivotal clinical data in a marketing authorization application dossier are intended to stem from SATs, it is the responsibility of the applicant to justify to regulators the reasons for deviating from the expected standard and the appropriateness of the SATs as alternative. As part of such justification, it must be substantiated that the SATs provide adequate pivotal evidence of efficacy.”

In a changing regulatory landscape, SATs are increasingly being used in decision-making to provide substantial evidence of effectiveness and safety, often in clinical situations where accelerated drug approvals are required or the sample size for a RCT is unfeasible; for example, a recent study found that of the 563 new oncology drug indications approved by the FDA between 2002 and 2021, 31% were based on SATs.

The EMA’s reflection paper outlines when SATs would be considered acceptable to provide pivotal evidence for regulatory decision-making, stressing that this decision “strongly depends on the full clinical context and attributes of the investigational treatment.” As such, the EMA underscores the importance of obtaining scientific advice early in the process to ensure compliance with regulatory standards. The paper emphasizes that SATs must be meticulously planned, with predefined efficacy endpoints and robust trial designs, ensuring that the absence of a control group does not compromise the validity of the results. Detailed guidance is provided on mitigating bias throughout the trial design, conduct, and analysis phases to ensure reliable and valid results.

While SATs provide a viable alternative in specific cases where RCTs are unfeasible, the EMA maintains that RCTs remain the gold standard for establishing efficacy. As Patrice Verpillat, Head of Real World Evidence at the EMA noted in his recent interview with The Evidence Base:

“From a regulatory perspective, RCTs are and will continue to be the gold standard. However, in some specific situations, which must be discussed with the regulatory agency and payers, SATs may be acceptable. SATs themselves should bring the evidence needed to determine efficacy and be interpretable on its own.” Patrice Verpillat. Head of Real World Evidence, EMA