Microdosing and Phase-0 Studies

Definition & overview

• Microdosing study — administration of a sub-pharmacological (sub-therapeutic) dose of a candidate drug to humans before a conventional Phase I trial, purely to obtain early human pharmacokinetic (PK) and biodistribution data; it is the operational core of what regulators call a Phase '0' or exploratory-IND (eIND) study — a strategy to cut the cost and time of drug development.
• Defining dose ceiling — a very low dose — generally about 1/100th of the estimated pharmacological dose, OR a maximum of 100 µg total, whichever is lower (KDT teaching definition). For a protein / biologic candidate the ceiling is set on a molar basis as ≤ 30 nanomoles total. [FDA]
• No effect expected — the sub-pharmacological dose is not expected to produce any therapeutic or toxic effect; the only readout sought is human PK / biodistribution — not efficacy and not safety / tolerability.
• Not a standard Phase I–IV trial — Phase 0 sits below Phase I in the ladder — it is pre-first-dose-escalation, tests no clinical endpoint, has no dose-escalation and no therapeutic intent, and runs under a streamlined exploratory IND pathway rather than a traditional IND.
• Terminology map — microdosing = the bioanalysis/PK-technique name; Phase 0 = the developmental-position name; exploratory IND (eIND) = the US regulatory name; exploratory clinical trial = the ICH M3(R2) umbrella term. "Microdosing" denotes only the ≤100 µg / ≤1/100th subtype; "eIND" / "exploratory clinical trial" also cover pharmacologically-active single sub-therapeutic (mechanism / target-occupancy) doses.