First-in-human dose: current status review for better future perspectives.

Area of Science:

• Drug Development
• Clinical Pharmacology
• Toxicology

Background:

• Early phase clinical trials are foundational for pharmaceutical development.
• Decisions on initial dosing and escalation strategies are paramount.
• Past trial failures highlight the need for robust FIH dose calculation methods.

Purpose of the Study:

• To evaluate the advantages and disadvantages of different first-in-human (FIH) dose calculation methods.
• To inform decisive actions during dose escalation for determining the maximum tolerated dose (MTD).

Main Methods:

• Review of early phase clinical trial methodologies for FIH dose and dose escalation.
• Analysis of trial registration trends from clinical trial registries.
• Discussion of methods in the context of current regulatory guidelines.

Main Results:

• Common FIH dose calculation principles include no observed adverse effect level (NOAEL), minimum anticipated biological effect level (MABEL), and pharmacokinetic/pharmacodynamic (PK/PD) approaches.
• Historical failures like TGN 1412 and BIA10-2474 underscore the risks in early phase trials.
• Healthy volunteers often participate in Phase 1 studies, emphasizing the need for safety.

Conclusions:

• FIH dose determination is a crucial step requiring integration of preclinical data.
• A conservative approach is essential for volunteer safety in early phase trials.
• Robust methodology in early phase trials underpins successful later-stage development.