Early-Stage Clinical Trials with Patient Choice

Clemson University, Clemson SC

Investigators

Abstract

This project investigates mathematical approaches for designing efficient mechanisms for early-stage clinical trials. Early-stage clinical trials aim to establish safe and therapeutic doses of an investigational drug for subsequent clinical trial phases. Because little is known in advance about the toxicity profile of investigational drugs, current approaches to early-stage trials employ dose-escalation methods, in which consecutive groups of patients receive increasing doses until dose-limiting toxicities are observed. This practice often results in significant challenges in recruiting and retaining patients, as many patients perceive the benefits of participation to be low. For example, terminally ill patients who have exhausted all other options often volunteer for early trials, in which the doses prescribed are low and nontherapeutic, whereas relatively healthy patients may postpone their involvement to wait for more information on dosing safety and efficacy. Overly conservative dose-escalation methods often result in substantial trial delays and expense, with little gain in patient safety. This project studies the effect on trial safety and efficacy of allowing limited patient input based on individual patient risk preferences to guide dosage decisions. The PIs aim to involve both undergraduate students (through Clemson's Creative Inquiry learning program) and graduate students in the research, through both coursework and research support. The project introduces a new class of dynamic dose-selection games with learning that integrate evolving patient preferences and beliefs about dose efficiency and dose toxicity with optimal stopping rules to determine when evidence converges on acceptable dosage to move to later trials. The research plan employs a pseudo-market mechanism that addresses a novel exploration-and-efficiency tradeoff created by delegating the centralized dose allocation decision to self-interested agents (patients and their physicians), while the central authority evaluates the results of study data. Methods are investigated to resolve potential conflicts between allocation efficiency (maximizing current participants’ utility) and exploration (maximizing the general population utility) so as to maximize learning, explore the dose-range uniformly, and avoid concentration within a small dosage range. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.