Keywords: Real World Evidence, Intra-patient comparison, Virtual matched control analysis, Tipping point analysis, Consistenciy criterion, Randomization ratio
We consider a clinical development program consisting of a prospective observation real-world evidence (RWE) study of patients receiving a standard of care (SOC), and a phase 3 randomized enrichment study where qualified patients from the observational study are randomized to receive a new treatment or continue with the SOC. We propose that the primary analysis be based on an intra-patient analysis for patients randomized to receive the new treatment by which intra-patient treatment effect is defined as the difference between the observed treatment outcome and the predicted outcome had the patient continued with the SOC. We develop a virtual matched control inter-group analysis as a supportive analysis of intra-patient analysis. We choose a randomization ratio to ensure consistency of inter-group and intra-patient comparisons. We also develop a tipping point analysis to address potential volitional effects for settings where the primary endpoint may be affected by patients’ effort. The required sample size for the proposed design is 50% to 65% more efficient than the parallel group design with the traditional primary inter-group comparison; and thus, making an adequate and well-controlled phase 3 trial for rare disease drug development feasible.