First-in-Human (FIH), or First-in-Man (FIM), studies are conducted based on the nonclinical data package submitted to regulatory authorities. Nonclinical toxicology, pharmacology, pharmacokinetics, in vitro assays, etc. conducted with the investigational compound are used to establish a safe starting dose among other parameters. FIH studies are typically conducted in healthy volunteers utilizing a single dose, dose escalation study design (single ascending dose or SAD study) to identify the maximum tolerated dose and/or dose limiting toxicity.
Typically, regulatory agencies are requiring pre-defined clinical stopping criteria incorporated into clinical protocols based on empirical safety data collected during the conduct of the FIH study. As such, sponsors will commonly include interim analysis of safety data prior to dose escalation. Also, Nuventra recommends the evaluation of interim pharmacokinetic data between cohorts in a dose escalation study. This will allow an opportunity to confirm or adjust the pharmacokinetic sampling schedule that was originally based on nonclinical data from IND-enabling studies.
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.
Scientific & PK Considerations
A common question from clients is should they include a placebo group or placebo dose in FIH, single ascending dose studies? More often than not the answer is “yes.” In fact, in one instance, the inclusion of a placebo group in a first-in-human study likely saved an entire drug development program or at least helped avoid the need for additional work in later stage development for the compound. In this example, two subjects appeared to have drug-related cardiac issues during the conduct of a double-blind, placebo-controlled FIH study. However, when the treatment assignments were unblinded it was determined that both subjects had received a placebo dose.
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.
Nuventra’s scientists are experts in helping our clients get the most out of their data through efficient study design, data analysis, and interpretation. Contact us for help with your first time in human and single ascending dose study.