A multiple ascending dose (MAD) study is an early-phase clinical trial for an investigational new drug. These studies represent one of the first times a new drug is administered to humans over a period of time. The core concept involves giving participants repeated doses of the drug, which distinguishes it from studies where only a single dose is given.
Purpose of Multiple Ascending Dose Studies
The primary purpose of a MAD study is to evaluate the safety and tolerability of a new drug when administered multiple times. Researchers closely monitor participants to identify any side effects that may only become apparent after the body has been exposed to the drug for an extended period. This helps determine the maximum tolerated dose (MTD), which is the highest dose that can be given without causing unacceptable side effects.
Another objective is to study the drug’s pharmacokinetics (PK), which is the study of how the drug is absorbed, distributed, metabolized, and excreted by the body. Repeated dosing allows researchers to see if the drug accumulates in the body or if it is cleared efficiently. This is particularly important for understanding whether the drug reaches a “steady state,” a point where the rate of the drug entering the body is equal to the rate of its elimination. Achieving a predictable steady state is often a desired outcome for drugs that will be taken regularly.
The Study Process
Participants, who are often healthy volunteers, are organized into small groups known as cohorts. The first cohort receives a low dose of the investigational drug for a specified duration. This initial dose is based on data from previous preclinical animal trials and single-dose studies in humans. After the first cohort completes its dosing period, there is a pause for observation and data review.
If the drug is determined to be safe at that level, the next cohort is enrolled and receives a higher dose. This dose-escalation process continues through subsequent cohorts until the planned maximum dose is reached or until side effects limit further increases. Within each cohort, some participants typically receive a placebo, an inactive substance, which allows researchers to differentiate the drug’s actual effects from psychological or other unrelated factors. Strict safety rules, known as stopping rules, are in place to pause or terminate the trial if significant safety concerns arise at any dose level.
Key Data Collected
To understand the drug’s pharmacokinetic profile, frequent blood and sometimes urine samples are taken from participants. These samples are analyzed to measure the concentration of the drug over time. This helps determine key parameters like Cmax (the maximum concentration the drug reaches in the blood) and AUC (the Area Under the Curve, which represents total drug exposure over time).
Investigators also gather pharmacodynamic (PD) data, which describes what the drug does to the body. This can involve measuring changes in biological indicators, known as biomarkers, that suggest the drug is having its intended effect. For example, if the drug is designed to lower blood pressure, researchers would monitor blood pressure closely.
Safety and tolerability data are collected through continuous monitoring, including regular physical exams, vital sign checks, and electrocardiograms (ECGs) to monitor heart activity. Participants are also asked to report any adverse events they experience.
Role in Drug Development
Multiple ascending dose studies are a component of Phase 1 clinical trials, which is the first stage of human testing. They typically follow single ascending dose (SAD) studies, where participants are given only one dose of the drug. While SAD studies provide an initial look at safety and pharmacokinetics, MAD studies offer a more complete picture of how the body responds to the drug over time, which is more representative of how most medicines are actually used.
The information gathered from a MAD study is used for planning later-stage trials. The established safety profile, tolerability limits, and pharmacokinetic data help researchers select an appropriate and safe dose for Phase 2 trials. In Phase 2, the drug is administered to a larger group of patients who have the specific disease the drug is intended to treat.