Study DesignGlossary Term
ICH M3(R2)
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.
Dose escalation represents a fundamental methodology in early clinical development, providing a structured approach to exploring the safety and tolerability of increasing doses of an investigational product in humans. Beginning with doses predicted to be safe based on preclinical studies, investigators carefully advance to higher doses only after demonstrating adequate safety at each level. This methodical progression allows identification of the maximum tolerated dose while minimizing participant exposure to potentially harmful dose levels.
The starting dose for human studies is typically derived from preclinical toxicology studies, often calculated as a fraction of the dose causing serious toxicity in the most sensitive animal species, adjusted for body surface area. From this starting point, doses are escalated according to a predetermined scheme, with common approaches including the traditional 3+3 design, modified Fibonacci sequences, and more sophisticated model-based methods such as the continual reassessment method. Each approach balances the competing goals of minimizing participant exposure to subtherapeutic or toxic doses while efficiently identifying the optimal dose range.
Safety monitoring during dose escalation requires particular vigilance. Dose-limiting toxicities are predefined adverse events of specified severity that trigger protocol-defined responses, which may include cohort expansion to gather additional safety data, dose reduction, or cessation of further escalation. Safety review committees evaluate accumulating data before each dose increase, typically requiring resolution of any acute toxicities in the current cohort before advancing. This careful, stepwise approach allows early identification of safety signals while establishing the foundation for dose selection in subsequent development.
First-in-human study
"The Phase I dose escalation study enrolled cohorts of three participants at each dose level, advancing to the next dose only after a safety review committee confirmed no dose-limiting toxicities in the current cohort."
Oncology development
"The accelerated titration design allowed single-participant cohorts at low doses where toxicity was unlikely, transitioning to standard 3+3 cohorts once the first grade 2 or higher toxicity was observed."
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 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.
The time required for the concentration or amount of a drug in the body to decrease by one-half, reflecting the combined effects of elimination processes.
ICH M3(R2)
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.
Dose escalation represents a fundamental methodology in early clinical development, providing a structured approach to exploring the safety and tolerability of increasing doses of an investigational product in humans. Beginning with doses predicted to be safe based on preclinical studies, investigators carefully advance to higher doses only after demonstrating adequate safety at each level. This methodical progression allows identification of the maximum tolerated dose while minimizing participant exposure to potentially harmful dose levels.
The starting dose for human studies is typically derived from preclinical toxicology studies, often calculated as a fraction of the dose causing serious toxicity in the most sensitive animal species, adjusted for body surface area. From this starting point, doses are escalated according to a predetermined scheme, with common approaches including the traditional 3+3 design, modified Fibonacci sequences, and more sophisticated model-based methods such as the continual reassessment method. Each approach balances the competing goals of minimizing participant exposure to subtherapeutic or toxic doses while efficiently identifying the optimal dose range.
Safety monitoring during dose escalation requires particular vigilance. Dose-limiting toxicities are predefined adverse events of specified severity that trigger protocol-defined responses, which may include cohort expansion to gather additional safety data, dose reduction, or cessation of further escalation. Safety review committees evaluate accumulating data before each dose increase, typically requiring resolution of any acute toxicities in the current cohort before advancing. This careful, stepwise approach allows early identification of safety signals while establishing the foundation for dose selection in subsequent development.
First-in-human study
"The Phase I dose escalation study enrolled cohorts of three participants at each dose level, advancing to the next dose only after a safety review committee confirmed no dose-limiting toxicities in the current cohort."
Oncology development
"The accelerated titration design allowed single-participant cohorts at low doses where toxicity was unlikely, transitioning to standard 3+3 cohorts once the first grade 2 or higher toxicity was observed."
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 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.
The time required for the concentration or amount of a drug in the body to decrease by one-half, reflecting the combined effects of elimination processes.