12: An Adaptive Two-Stage Design: Integrating Single-Arm Trials with Hybrid RCTs and External Controls

Music City Center 

Randomized control trials (RCTs) are considered as gold standard, encounter challenges due to insufficient sample size. Single-arm trials provide an approach in such circumstance, but its outcomes might be biased. The increasing application of RWD has drawn attention to the study of hybrid RCT, which features a control arm that integrates concurrent control and external control. Our article introduces an adaptive two-stage design, consisting of a single-arm trial stage and a hybrid RCT stage. Researchers allow to assess treatment efficacy and futility or decide continuation to hybrid RCT at interim analysis. Prior to conducting hybrid RCT, two steps are needed: 1) Sample size re-estimation adjust the number of subjects in treatment arm; 2) Propensity score matching are applied to identify well-matched subjects between external control and treatment arm. Concurrent control subjects are incorporated to supplement control arm when external control does not match requirement. Our approach offers a promising alternative to RCTs and single-arm trials by adjusting design after interim analysis, which enhances the efficiency and flexibility, especially rare diseases and pediatric trials.

RWD/RWE

External control

Single arm trial

Sample Size Re-estimation

Hybrid RCT

Propensity score 

International Chinese Statistical Association