Evaluating Safety Rules in Ongoing Dose-Escalation Trials Using BOIN: A Comparative Analysis of Criteria and Their Impact on Dose-Level Safety Assessments.

Abstract

Ongoing dose-escalation trials present unique challenges in assessing safety, all with the goal to establish the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D). Due to the extended duration of trials, it is common to declare doses as safe even if the entire adaptive and iterative dose escalation process has not been completed. This practice is often applied to aid trial management decisions, such as starting region-specific dose-escalation studies, initiating combination therapies, or allowing intra-patient dose escalation in previous cohorts, to enhance efficiency and accelerate the pace of drug development. Whereas regulatory agencies often require a safety margin for the starting dose for regional or combination dose-escalation studies, there exists a misperception within the research community that once an escalation assessment team has cleared a cohort for escalation, the associated dose level is inherently safe. Given that dose escalation algorithms permit repeated de-escalations, previously cleared doses may not be truly safe, necessitating a quantification of this risk and identifying an adequate safety margin. Through rigorous simulation studies, we identified criteria that must be met to confidently declare dose levels as safe within the Bayesian optimal interval (BOIN) design. Our comparative analysis of safety criteria shows that evaluating a minimum of three subjects at the dose level above the one to be declared safe is essential for accurate safety assessments and protecting patients. More aggressive dose-escalation paradigms would risk exposing patients to doses that are not ultimately declared safe.