P06 An Objective Review of 3+3, i3+3, and BOIN Designs for Phase I Dose-Finding Trials

Phase I dose-finding trials are essential for determining the safety and maximum tolerated dose (MTD) of new drugs. Statistical designs for phase I trials can be broadly categorized as algorithm-based (e.g., 3+3 and i3+3), model-based (e.g., CRM), and model-assisted designs (e.g., mTPI, mTPI-2/Keyboard, BOIN), each rooted in distinct theoretical frameworks and implementation strategies. The i3+3 design and model-assisted designs all use the "up-and-down" decision rules denoted as E (escalate to the next higher dose), S (stay at the current dose), and D (de-escalate to the next lower dose) for dose finding. Some recent reviews in the literature aim to compare various designs, mostly based on comparing operating characteristics (OCs) from simulated clinical trials, which can be influenced by the specific assumptions and settings used in the simulations.

We suggest comparing simple designs like 3+3 and other model-assisted designs directly via decision tables in addition to the OCs. We show the pros and cons of three popular and simple designs: 3+3, BOIN, and i3+3. We aim to impartially evaluate the three designs using a fair comparison process in which choices of simulation parameters are determined by a third party. We developed an open-source R package, "FIND," accompanied by demonstration examples to facilitate the comparison. This review seeks to offer readers comprehensive and unbiased insights into current mainstream dose-finding designs, along with practical tools for implementation, thereby contributing to the advancement of clinical trial methodology in drug development.

Clinical Trial Design (e.g., Innovative/Complex Design, Estimands, Master Protocol)

ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop 2024