Using External Control Arm Studies in HTA Submissions: An Alternative, When RCTs are not Feasible

Matthias Hunger, Céline Taveau, and Ankit Pahwa present the challenges and opportunities when using external control arm studies in submissions to HTA agencies.

Randomized controlled trials (RCTs) are considered the gold standard to determine the efficacy of a new therapy or to evaluate its comparative effectiveness against standard of care. However, regulators acknowledge situations when a RCT may not be operationally or ethically feasible, such as in rare disease patient populations. In those cases, data from single arm trials complemented by external control arms are becoming more commonly accepted as evidence by both regulatory and Health Technology Assessment (HTA) bodies.

Due to the lack of randomization, submissions based on external control arm studies should apply rigorous analytical methods to adjust for potential confounding caused by imbalances between treatment groups. While regulatory bodies have published guidance on the use of non-randomized evidence, recommendations from HTA agencies have long been limited.