The maximum tolerated dose represents a critical milestone in drug development, defining the upper boundary of the tolerable dose range for an investigational product. Identified through systematic dose escalation studies, the MTD serves as a key reference point for selecting doses in subsequent efficacy trials. For oncology drugs and other treatments where efficacy may correlate with dose, the MTD often becomes the recommended Phase II dose, though modern development increasingly emphasizes optimal biological dosing over maximum tolerated dosing.

Determination of the MTD involves careful observation of dose-limiting toxicities across escalating dose cohorts. When a specified proportion of participants at a given dose level experiences dose-limiting toxicities, that dose is typically declared to exceed the MTD. The MTD is then defined as the highest dose at which the rate of dose-limiting toxicities remains below the protocol-specified threshold, often set at one-third of participants. Statistical models can refine MTD estimates by incorporating the full dose-toxicity relationship rather than relying solely on the observed rates at individual dose levels.

The concept of MTD has evolved as understanding of dose-response relationships has matured. Traditional oncology development assumed that efficacy increased with dose up to the MTD, leading to selection of the highest tolerable dose for efficacy studies. Contemporary approaches recognize that optimal dosing may lie below the MTD, particularly for targeted therapies and immunotherapies where biological activity may plateau at doses below maximum tolerability. Regulatory guidance now emphasizes identification of the optimal biological dose through integration of pharmacokinetic, pharmacodynamic, and clinical data rather than automatic selection of the MTD.