Dose Selection Strategies for First-in-Human Trials: From NOAEL to MABEL
Determining an appropriate starting dose for first-in-human (FIH) clinical trials is one of the most critical decisions in early-phase drug development. Regulatory guidance from the FDA and EMA encourages the use of scientifically grounded dose selection strategies that incorporate both preclinical toxicity findings and mechanistic pharmacology data. Traditionally, the No Observed Adverse Effect Level (NOAEL) derived from animal studies serves as the basis for calculating the Human Equivalent Dose (HED), adjusted by safety factors to establish a conservative starting dose.
More recently, the Minimum Anticipated Biological Effect Level (MABEL) approach has gained favor for biologics, immunomodulatory compounds, and first-in-class agents. MABEL considers pharmacodynamic data, target engagement, receptor occupancy, and in vitro potency in addition to toxicology endpoints. When integrated with toxicokinetic (TK) and pharmacokinetic (PK) modeling, MABEL allows developers to identify a starting dose that minimizes risk while preserving early pharmacological relevance. In practice, both NOAEL- and MABEL-based approaches are often evaluated in parallel, with justification provided in the clinical trial application (CTA) or IND.
An optimal FIH starting dose balances ethical exposure limits, scientific rationale, and safety margins, requiring a collaborative effort between toxicologists, pharmacologists, and clinical scientists.