SINGLE ASCENDING DOSE studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. Typically, a small number of participants, usually three, are entered sequentially at a particular dose. If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose (MTD)). MULTIPLE ASCENDING DOSEstudies are conducted to better understand the pharmacokinetics and pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
FIRST-IN-HUMAN SINGLE ASCENDING DOSE ESCALATION DESIGNS
In contrast to traditional dose escalation designs, where for example, cohorts of subjects are allocated to ascending doses (and placebo) until a maximum tolerated dose (MTD) is empirically determined, the continual reassessment method (CRM) models the dose- and/or exposure-toxicity relationship to focus on the identification of the dose-range of interest near the MTD and for this to be explored further. These adaptive dose escalation designs can be expanded to also efficiently establish proof-of-mechanism or proof-of-target modulation, if validated biomarker endpoints are available. The traditional First in Human study objectives of safety and tolerability can be extended to include an assessment of proof-of-mechanism in the very first study conducted with the investigational compound. The ability to assess proof-of-mechanism in this early developmental setting provides an opportunity to greatly enhance the clinical development strategy for the compound. The adaptation is intended to quickly hone in on the predicted dose-range of interest. is avoids the risks associated with exposing patients in an in effective low dose range, whilst minimizing exposure to high doses with an unacceptable tolerability and safety profile.
SEAMLESS MULTIPLE ASCENDING DOSE AND PROOF-OF-CONCEPT STUDY DESIGNS
The objective of seamless multiple ascending dose and proof-of-concept studies is to combine a multiple ascending dose (MAD) study in patients with the proof-of-concept of the investigational compound.