FIH dose selection beyond MABEL: Optimizing phase 1 clinical trial starting dose whilst protecting patient safety

The HESI Global Immuno-Safety Technical Committee (ITC) is pleased to share their latest publication: “FIH dose selection beyond MABEL: Optimizing phase 1 clinical trial starting dose whilst protecting patient safety” published in Regulatory Toxicology and Pharmacology.

Selecting first-in-human (FIH) doses for immunomodulators remains one of the most technically challenging aspects of translational drug development. While the MABEL paradigm strengthened patient safety following TGN1412, experience has shown that highly conservative starting doses can lead to prolonged dose escalation and sub-therapeutic exposure in early-phase trials.

In this commentary, the ITC's First in Human Dose working group presents a refined, integrative framework for FIH dose selection that:

• Expands traditional MABEL-based decision making through a structured, risk-informed decision tree
• Clarifies distinctions between MABEL, PAD, and NOAEL-based approaches
• Incorporates forward and reverse translational PK/PD modeling
• Highlights the evolving role of Model-Informed Drug Development (MIDD) and QSP
• Demonstrates practical application through cross-company case studies

This work reflects collaboration across regulatory, industry, and academic scientists with a shared objective: maintaining patient safety while improving scientific precision in early clinical dose selection.

Read the full paper here: Matsumoto et al., 2026. FIH dose selection beyond MABEL: Optimizing phase 1 clinical trial starting dose whilst protecting patient safety. Regulatory Toxicology and Pharmacology. https://doi.org/10.1016/j.yrtph.2026.106038