European Medicines Agency Starts Public Consultation Regarding Single-Arm Trials
On 21 April 2023, the European Medicines Agency (EMA) launched a public consultation regarding single-arm trials (SATs) whose results are intended to be submitted as pivotal evidence in support of applications for medicine marketing authorisations in the EU. Stakeholders are requested to submit comments on EMA’s reflection paper by 30 September 2023 (see, attachment).
In SATs, all subjects are planned to receive the same experimental treatment and be followed for a period of time. SATs are markedly different from randomised controlled double-blind trials (RCTs), the sector’s “gold standard” for gauging the efficacy and safety of a treatment. RCTs involve the comparison of a new treatment with a placebo or an existing standard of care. Central features of RCTs include (i) randomisation in that all entered persons have a similar illness, were randomly selected and are equally likely to receive the treatment subject to testing or the control (placebo or standard of care); (2) a pre-established measure of treatment success (e.g., an outcome such as pain relief); and (iii) a state of unawareness (“being blinded”) on the part of all engaged parties (physicians and tested individuals) as to whether an individual subject is receiving the test treatment or the control.
Despite the scientific superiority of RCTs over SATs and the inherent risk for bias and increased uncertainty in SATs, EMA is increasingly compelled to accept SATs as the origin for pivotal clinical data across a range of therapeutic areas, and not just for rare disease treatments. EMAs reflection paper acknowledges this reality and seeks to maximise the quality of SATs by discussing the key trial features that will generate pivotal evidence for marketing authorisation, including the trial’s design, conduct, interpretation and assessment. In the light of the specific challenges posed by SATs in terms of lack of control, reduced randomisation, increased uncertainty and bias, the reflection paper thus reviews the choice of endpoints, the target and trial population, the role of external information, statistical principles and sources of potential biases and ways to mitigate such biases.