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Multiple Ascending Dose Studies

Overview

A Multiple Ascending Dose study is one of the earliest studies performed in the clinical development of a drug, preceded only by an initial Single Ascending Dose study. “Multiple” indicates that each subject receives multiple doses of the study drug. “Ascending” indicates that the amount of drug increases for each new cohort of subjects (i.e., the dose level ascends as the study goes on). Multiple Ascending Dose studies are intended to fully characterize the pharmacokinetics of a drug and its metabolites at steady state, investigate a drug’s accumulation potential, explore its dose proportionality, and determine the Maximum Tolerated Dose (MTD).

Nuventra can show you how to make the most out of your Multiple Ascending Dose study. Our consultants will work with you to optimize your study design and data analysis to maximize the return on your investment and provide you with the information you need to make a go/no-go decision about your drug.

Single Ascending Dose vs Multiple Ascending Dose

The main difference between a Multiple Ascending Dose (MAD) study and a Single Ascending Dose (SAD) study is the number of doses given to individual study subjects. Subjects in a MAD study receive multiple doses of the study drug, whereas subjects in a SAD study receive only one dose of the study drug. SAD and MAD studies are both performed early in clinical development. SAD studies are almost always performed first in order to obtain a rough understanding of a drug’s single dose pharmacokinetics. The repetitive dosing in a MAD study allows steady state to be reached, which is when the rate of drug absorption is equal to the rate of drug elimination. When this occurs, the concentration of drug in the body is in equilibrium. Although steady state concentrations can be predicted from a single-dose study, a multiple-dose study provides empirical confirmation.

FDA Guidance

Many new drugs are designed to be repeatedly administered, and thus a Multiple-Dose Study is necessary to understand how to use the drug in a clinical setting. However, the FDA also recommends that a Multiple-Dose Study be performed in the following circumstances:

  • When there is a difference in the rate of absorption but not in the extent of absorption
  • When there is excessive variability in bioavailability from subject to subject
  • If the concentration of the drug or its metabolite(s) in the blood resulting from a single dose is too low for accurate determination by the analytical method
  • If the drug product is an extended release dosage form

The federal regulations in 21 CFR 320.27 list other requirements related to study design, achievement of steady-state conditions, collection of samples, steady-state parameters, and measurement of pharmacological effect. The Regulatory Affairs experts at Nuventra are well-versed in all of the guidance documents related to multiple-dose studies and can help you meet all Health Authority requirements.

Study Design

The appropriate Multiple Ascending Dose study design will depend upon the needs and resources of each development program. In some instances, Multiple Ascending Dose study designs can be integrated with others study designs (e.g., Thorough QT study or a Food Effect study) to provide needed information without having to run separate studies. The number of doses used in Multiple Ascending Dose studies varies, but is typically between three and six, with an enrollment of approximately 40 subjects. Healthy subjects are usually recruited for Multiple Ascending Dose studies, although a Phase 1 dose escalation study design can also include patients under certain circumstances (e.g., oncology therapies).

Scientific & PK Considerations

Multiple Ascending Dose studies require careful planning of the dosing regimen in order to attain steady state levels of the study drug. Dosing interval estimates rely heavily on 1) an accurate pharmacokinetic analysis of single-dose studies and 2) appropriate scaling of preclinical toxicology studies. Small mistakes and unjustifiable assumptions become compounded in multiple-dose studies, and the associated costs can be difficult to overcome. An adequate pharmacokinetic sampling schedule is another crucial design element for multiple-dose studies. Sampling too infrequently or during the wrong time window can render an expensive multiple dose study useless. Similarly, oversampling can be costly and increase the burden on study subjects without adding significant data to the study. Optimization of the sampling schedule requires knowledge and experience. Nuventra recommends the evaluation of interim pharmacokinetic data between cohorts in a multiple dose escalation study. This allows for adjustment of the pharmacokinetic sampling schedule to ensure the most efficient use of resources possible.

Nuventra’s scientists are experts in helping our clients get the most out of their data through efficient study design, data analysis, and interpretation. Nuventra’s deep knowledge of drug development and experience with both traditional and non-traditional study designs across a wide range of therapeutics and dosage forms can increase the efficiency and utility of your trials and set your program on a path for success.

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