Bayesian Methods for Quality Tolerance Limit (QTL) Monitoring.

In alignment with the ICH guideline for Good Clinical Practice [ICH E6(R2)], quality tolerance limit (QTL) monitoring has become a standard component of risk-based monitoring of clinical trials by sponsor companies. Parameters that are candidates for QTL monitoring are critical to participant safety and quality of trial results. Breaching the QTL of a given parameter could indicate systematic issues with the trial that could impact participant safety or compromise the reliability of trial results. Methods for QTL monitoring should detect potential QTL breaches as early as possible while limiting the rate of false alarms. Early detection allows for the implementation of remedial actions that can prevent a QTL breach at the end of the trial. We demonstrate that statistically based methods that account for the expected value and variability of the data generating process outperform simple methods based on fixed thresholds with respect to important operating characteristics. We also propose a Bayesian method for QTL monitoring and an extension that allows for the incorporation of partial information, demonstrating its potential to outperform frequentist methods originating from the statistical process control literature.