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

TL;DR

This paper introduces PRIDE and PRIDE-FA, new methods for dose escalation in phase I clinical trials for rare diseases, which improve efficiency and accuracy.

Contribution

PRIDE and PRIDE-FA are novel dose-finding designs that incorporate intra-patient correlations and flexible allocation to improve trial efficiency in rare diseases.

Findings

PRIDE and PRIDE-FA improve the accuracy of maximum tolerated dose selection in rare disease trials.

The proposed methods reduce required sample size and trial duration compared to existing designs.

Incorporating random effects enhances performance in dose-finding for multi-dose patient scenarios.

Abstract

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.

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