A single dose is usually tested first, followed by multiple ascending dose studies; however, the study design is influenced by the type of compound. Study designs may be open-label, baseline-controlled or may use randomization and blinding. The most common study design used for these early studies is the parallel group, placebo-controlled, randomized, double-blind ascending dose study (Figure 3.2). Each group is typically made up of three to six subjects who receive single or multiple doses of the compound and one to two subjects who receive placebo. Safety and tolerability at the very least (in some cases PK and PD endpoints also) are evaluated before the next ascending dose group receives treatment.
Tolerability is an aspect of safety. It is a term used to indicate how well a patient is able to endure treatment such that AEs do not result in the discontinuation of treatment. A comparator drug, a marketed drug in the same class, can be included in the FIH study to evaluate the differences in tolerability between the two compounds if the comparator drug has a significant frequency of well-characterized AEs. The new chemical entity may possess a better tolerability profile than the comparator drug leading to a greater proportion of treated patients that successfully receive the full course of treatment.
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