Quantifying Potential Bias Introduced by Imbalanced Disease Assessment Schedule in PFS Analysis

Music City Center 

It is well known that imbalanced disease assessment schedule (DAS) between arms could introduce bias in Progression-free survival (PFS) analysis. Understanding the magnitude of such potential bias on key study parameters would be greatly helpful to trial design and analysis, although have not been well-studied.

In this paper, we simulate comprehensive settings that are commonly seen in oncology clinical trials. We consider the scenarios with median PFS (mPFS) on the control arm ranging from 1.5 months to 24 months, and treatment cycles occurring every 3 weeks, 4 weeks or 6 weeks, and evaluate the impact of various disease assessment schedules on the following parameters: mPFS estimate, hazard ratio (HR) estimate, type 1 error and power. We use a real study to further illustrate how the factors including patients' deviations from the scheduled visits can impact the estimates.

In general, type 1 error is inflated and hazard ratio (treatment / control) is under-estimated when subjects in treatment arm are assessed less frequently, compared to control arm. The magnitude of the impact depends on the true median PFS, the frequency of the assessments, and how far apart the assessm

Progression-free Survival,

Disease Assessment Schedule

Clinical Trial Design 

Biopharmaceutical Section