Selecting a starting dose for a first-in-human (FIH) trial requires balancing two priorities: protecting participants from unnecessary risk and selecting a dose that can provide useful information about a drug’s biological activity.
In June 2026, the US Food and Drug Administration (FDA) issued draft guidance on using quantitative systems pharmacology (QSP) to determine the minimum anticipated biological effect level (MABEL) for certain drugs entering Phase I trials.
The guidance is part of Operation TrialBlazer, an FDA and US Department of Health and Human Services initiative focused on modernizing clinical development while maintaining standards for safety and effectiveness. It also reflects the FDA’s broader interest in model-informed drug development and reducing reliance on animal toxicology when other approaches can provide relevant information.
A Different Approach to First-in-Human Dose Selection
FIH starting doses have historically been informed by animal toxicology studies followed by conversion to a human-equivalent dose. These approaches remain appropriate for many drugs but can have limitations when mechanisms do not translate well between animals and humans.
Some drugs act on targets that are absent or expressed differently in laboratory animals. Others can produce steep pharmacodynamic responses, such as cytokine release or T-cell activation. In these situations, animal findings may not adequately predict human response.
MABEL takes a different approach by estimating a dose expected to produce a minimal biological effect in humans. The calculation can incorporate pharmacologic activity, receptor binding, pharmacokinetic (PK) data and other relevant evidence.
How QSP Adds to the Picture
QSP uses mathematical models to represent the interactions among a drug, its target and the biological system. For MABEL dose selection, models can integrate data from human-cell assays, animal PK and pharmacodynamic (PD) studies, ex vivo experiments, studies conducted using computer models and simulations (e.g., in silico studies) and related compounds to predict human responses at different doses.
QSP does not simply replace animal data. When animal findings are included, the FDA recommends accounting for differences such as receptor density, physiological parameters and pharmacodynamic responses rather than relying on straightforward dose scaling.
Sponsors can also simulate responses around a proposed starting dose to understand the expected dose-response relationship and identify where additional caution may be needed.
Connecting Modeling With Trial Design
The potential value of QSP extends beyond selecting the first dose. The FDA recommends using emerging human data to test and refine model predictions as an FIH trial progresses.
Protocols should include plans to collect early PK and pharmacodynamic biomarker data and compare those findings with predicted responses. That information can help sponsors refine the model and inform subsequent dose-escalation decisions.
The guidance also addresses the risks of starting too low. For patients with life-threatening diseases, prolonged escalation through subtherapeutic doses can expose participants to treatment with little prospect of benefit. In some circumstances, the FDA indicates that a minimal active dose above the absolute MABEL may be justified, with QSP helping support that determination.
This highlights the balance at the center of FIH dose selection: protecting participants from excessive exposure while avoiding unnecessarily prolonged exposure to doses unlikely to provide therapeutic benefit.
What the Guidance Means for Drug Sponsors
Sponsors considering QSP-based MABEL dose selection will need to show how their model supports a specific clinical and regulatory decision. The FDA recommends defining the model’s intended use, assessing its risk and documenting its assumptions, parameters, validation and uncertainty.
Early regulatory interaction can also be valuable. Sponsors can seek FDA feedback through pre-IND meetings or Model-Informed Drug Development Paired Meetings. Caution remains essential when different methods produce conflicting estimates. For novel targets without clinical precedent, the FDA recommends selecting the more conservative starting dose when QSP and traditional approaches disagree.
The draft guidance reflects a broader shift toward integrating quantitative methods earlier in drug development. Under Operation TrialBlazer, the FDA is exploring ways to modernize clinical research, including greater use of computational tools for dose selection.
QSP cannot eliminate the uncertainty inherent in FIH studies. It can provide a framework for integrating available evidence, testing predictions against emerging human data and refining dosing decisions as a trial progresses. For sponsors, that creates a closer connection between translational modeling and clinical trial design while keeping participant safety at the center of early development.
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