Phase 0 Trial

A Phase 0 trial — also called an exploratory IND study — is a very small, short-duration human study run before traditional Phase 1 dose-escalation testing, using pharmacologically sub-active microdoses to gather early pharmacokinetic, receptor-binding, or imaging data on a candidate compound. 21 CFR 312.21 defines exactly three phases — Phase 1, Phase 2, and Phase 3 — and has no subsection for “Phase 0.” The label comes entirely from FDA’s 2006 Exploratory IND Studies guidance, which states that any study meeting exploratory-IND criteria legally qualifies as a Phase 1 trial under 312.21(a) and is filed under the same IND. See CASRAI’s Clinical Trial Phases guide for where this informal category sits alongside the phases FDA actually defines in regulation.

What makes a dose a “microdose”

FDA’s guidance sets a specific numeric threshold for microdosing, the most common exploratory-IND design: a microdose is less than 1/100th of the dose calculated (from animal pharmacology/toxicology data) to produce a pharmacologic effect, capped at no more than 100 micrograms total — or, for protein products, no more than 30 nanomoles. At that exposure level, the dose is expected to be pharmacologically inactive; the study measures how the compound is absorbed, distributed, metabolized, and eliminated (or, in imaging applications, where a radiolabeled microdose localizes), not whether it produces a therapeutic effect.

Study size, duration, and a reduced nonclinical package

Exploratory IND studies enroll very few participants — typically under 15, sometimes stated as a ceiling of 30 — and limit dosing to a short window, commonly cited as seven days or less of exposure. Because the exposure is so limited and, for true microdose studies, comparable to routine environmental or diagnostic exposures, FDA’s guidance allows a reduced nonclinical toxicology package relative to a traditional Phase 1 IND: sponsors can often forgo the full battery of repeat-dose toxicology and routine genetic toxicology testing that a standard first-in-human dose-escalation study would require, since a single microgram-level exposure carries negligible genotoxic risk. This is the practical reason companies use Phase 0: it lets them test human PK or target engagement for a candidate — or choose among several related candidates — before committing to the full IND-enabling toxicology program a conventional Phase 1 would need.

What Phase 0 doesn’t establish

A Phase 0 study has no therapeutic or diagnostic intent and does not attempt to establish safety at a therapeutic dose, tolerability, or a maximum tolerated dose — the questions a genuine Phase 1 trial answers through dose-escalation. It also can’t substitute for Phase 1: a compound that looks favorable in an exploratory IND microdose study still has to go through full dose-escalation, safety, and tolerability testing before moving toward Phase 2 efficacy testing. Because of this narrow scope, Phase 0 is used selectively — most commonly in oncology drug and imaging-agent development, where it helps sponsors screen or prioritize candidates and confirm mechanism-relevant human PK early, rather than as a routine first step for every investigational drug.

Administrative and regulatory context

Because an exploratory IND study is legally a Phase 1 trial, it’s submitted and reviewed under the same IND mechanism described in Investigational New Drug (IND), with the same 30-day FDA review clock before dosing can begin. What changes is the content of the submission — a smaller nonclinical package tailored to the microdose exposure — not the regulatory pathway itself. See CASRAI’s Clinical Trial Phases guide for how Phase 0 fits alongside Phase 1, Phase 2, Phase 3, and Phase 4.