Study DesignGlossary Term
ICH M3(R2)
The highest dose of an investigational product that can be administered without causing unacceptable toxicity, typically determined through dose escalation studies.
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.
Traditional definition
"The Phase I trial established the MTD at 200 mg daily after two of six participants at the 250 mg dose level experienced dose-limiting toxicities of grade 3 fatigue and grade 3 nausea."
Oncology dose selection
"Although the MTD was determined to be 400 mg, the sponsor selected 300 mg as the recommended Phase II dose based on pharmacokinetic data showing complete target saturation at the lower dose with an improved tolerability profile."
The fraction of an administered dose of a drug that reaches the systemic circulation unchanged, and the rate at which this occurs.
A group of participants in a clinical trial who receive a comparator treatment, placebo, or no treatment to serve as a baseline for evaluating the effects of the investigational intervention.
A clinical trial design in which participants receive multiple treatments in sequence, with each participant serving as their own control by receiving all study treatments during different periods.
A systematic approach to increasing the dose of an investigational product during a clinical trial, typically employed in early-phase studies to identify safe and potentially effective dose levels.
A clinical trial in which both the participants and the investigators are unaware of the treatment assignments, providing maximal protection against bias in the conduct and assessment of the study.
ICH M3(R2)
The highest dose of an investigational product that can be administered without causing unacceptable toxicity, typically determined through dose escalation studies.
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.
Traditional definition
"The Phase I trial established the MTD at 200 mg daily after two of six participants at the 250 mg dose level experienced dose-limiting toxicities of grade 3 fatigue and grade 3 nausea."
Oncology dose selection
"Although the MTD was determined to be 400 mg, the sponsor selected 300 mg as the recommended Phase II dose based on pharmacokinetic data showing complete target saturation at the lower dose with an improved tolerability profile."
The fraction of an administered dose of a drug that reaches the systemic circulation unchanged, and the rate at which this occurs.
A group of participants in a clinical trial who receive a comparator treatment, placebo, or no treatment to serve as a baseline for evaluating the effects of the investigational intervention.
A clinical trial design in which participants receive multiple treatments in sequence, with each participant serving as their own control by receiving all study treatments during different periods.
A systematic approach to increasing the dose of an investigational product during a clinical trial, typically employed in early-phase studies to identify safe and potentially effective dose levels.
A clinical trial in which both the participants and the investigators are unaware of the treatment assignments, providing maximal protection against bias in the conduct and assessment of the study.