Phase 1 Trial

A Phase 1 trial is the first deliberate exposure of humans to a compound under an investigational new drug application. Its objectives are tolerability, the dose-exposure relationship and the pharmacokinetic profile, not efficacy. The usual architecture is single ascending dose followed by multiple ascending dose, in small cohorts of twenty to a hundred subjects, healthy volunteers for most indications and patients where the drug is inherently toxic. The starting dose is derived downward from animal toxicology with a safety factor applied.

Two failures shaped current practice. In 2006 the CD28 superagonist antibody TGN1412 caused catastrophic cytokine release in six healthy volunteers in London at a dose far below the animal no-observed-adverse-effect level, which is why starting doses for immune-active biologics are now set from the minimal anticipated biological effect level and why staggered sentinel dosing became standard. In 2016 a Phase 1 study of the FAAH inhibitor BIA 10-2474 in Rennes caused one death and lasting neurological injury.

What a completed Phase 1 delivers is exposure data, a half-life, a tolerated dose range and any dose-limiting toxicity, which set up the Phase 2 dose choice. What it cannot deliver is evidence of benefit, because it is neither powered nor designed for an efficacy endpoint. Attrition after this point remains severe; only a small minority of compounds entering human study reach approval.

The commonest abuse is a research compound advertised as having human safety data on the strength of one Phase 1 cohort. Thirty healthy young men dosed for two weeks surface common acute reactions and nothing else: no rare event, no interaction with the drugs a real patient takes, nothing about chronic exposure. Completion of Phase 1 is a permission to keep studying, not a safety clearance.