Patient Retreat in Dose Escalation for Phase I Clinical Trials With Rare Diseases

Phase I clinical trials aim to identify the maximum tolerated dose (MTD), a task that becomes challenging in rare disease due to limited patient recruitment. Traditional dose-finding designs, which assign one dose per patient, require a sufficient sample size that may be infeasible for rare disease trials. To address these limitations, we propose the patient retreat in dose escalation (PRIDE) scheme, which integrates intra-patient dose escalation and considers intra-patient correlations by incorporating random effects into a Bayesian hierarchical framework. We further introduce PRIDE-FA (flexible allocation), an extension of PRIDE with a flexible allocation strategy. By allowing retreated patients to be assigned to any dose level based on trial needs, PRIDE-FA improves resource efficiency, leading to greater reductions in required sample size and trial duration. This paper incorporates random effects into established dose-finding designs, including the calibration-free odds (CFO) design, the Bayesian optimal interval (BOIN) design, and the continual reassessment method (CRM) to account for intra-patient correlations when each patient may receive multiple doses. Simulation studies demonstrate that PRIDE and PRIDE-FA significantly improve the accuracy of MTD selection, reduce required sample size, and shorten trial duration compared to existing dose-finding methods. Together, PRIDE and PRIDE-FA provide a robust and efficient framework for phase I clinical trials with rare diseases.