The Reality of Randomized Controlled Trials forAssessing the Benefit of Proton Therapy: Critically Examining the Intent-to-Treat Principle in the Presence of Insurance Denial

ABSTRACT Purpose This study hypothesized that insurance denial would lead to bias and loss of statistical power when evaluating the results from an intent-to-treat (ITT), per-protocol, and as-treated analysis using a simulated randomized clinical trial comparing proton therapy to intensity-modulated x-ray therapy (IMRT) where patients incurred increasing rates of insurance denial. Methods and Materials Simulations utilized a binary endpoint to assess differences between treatment arms after applying ITT, per-protocol, and as-treated analyses. Two scenarios were developed: one with clinical success independent of age and another assuming dependence on age. Insurance denial was assumed possible for patients Results Increasing rates of insurance denial demonstrated inherent weaknesses among all three analytic approaches. With clinical success independent of age, a per-protocol analysis demonstrated the least bias and loss of power. When clinical success was dependent on age, the per-protocol and ITT analyses resulted in a similar trend with respect to bias and loss of power, with both outperforming the as-treated analysis. Conclusions Insurance denial leads to misclassification bias in the ITT analysis, a missing data problem in the per-protocol analysis, and covariate imbalance between treatment arms in the as-treated analysis. Moreover, insurance denial forces the critical appraisal of patient features (e.g., age) affected by the denial and potentially influencing clinical success. In the presence of insurance denial, our study suggests cautious reporting of ITT and as-treated analyses, and placing primary emphasis on the results of the per-protocol analysis.