Microdosing and Phase-0 Studies

Microdosing and Phase-0 Studies

1. 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 (KDT 8e Ch.5, p.90).
• KDT explicitly names it: "the microdosing human study undertaken before phase-1 trial, and is also called phase '0' study" — a new strategy to reduce the cost and time of the drug development process (KDT 8e Ch.5, p.90).
• The defining dose limit: a very low dose, generally about 1/100th of the estimated human (pharmacological) dose, OR a maximum of 100 µg total dose of candidate drug, whichever is lower (KDT 8e Ch.5, p.90).
• For protein/biologic candidates the regulatory microdose ceiling is set differently — ≤ 30 nanomoles total — because 100 µg of a large protein is a very different molar exposure than 100 µg of a small molecule [FDA].
• These sub-pharmacological doses are not expected to produce any therapeutic or toxic effect; the only readout sought is human PK / biodistribution, not efficacy and not safety/tolerability (KDT 8e Ch.5, p.90).
• Phase 0 sits "below" Phase I in the development ladder — it is pre-first-dose-escalation. Browner's staging table lists the conventional ladder as Preclinical → Phase I (unblinded, uncontrolled, few volunteers, safety) → Phase II → Phase III → Phase IV; Phase 0 is an optional exploratory wedge inserted before Phase I (Browner Ch.11, Table 11.2, p.~22; KDT 8e Ch.5, pp.89–90).
• Phase 0 is NOT a standard Phase I–IV trial. It does not test a clinical end point, has no dose-escalation, no therapeutic intent, and is conducted under a streamlined regulatory pathway (the exploratory IND, US) rather than a traditional IND (KDT 8e Ch.5, p.90) [FDA].
• The strategic driver (KDT): the rate of rejection (attrition) of candidate drugs at various stages of clinical development has progressively increased, discouraging companies from venturing into the risky business of new-drug invention — alarming the FDA (USA) and the European Medicines Agency (EMA) into encouraging novel cost-cutting approaches in drug development, of which microdosing is one (KDT 8e Ch.5, p.90).
• Core rationale: "Many candidate drugs fail during clinical trials due to sub-optimal human pharmacokinetics" — microdosing lets a sponsor obtain genuine human PK on several candidates cheaply and early, and kill the PK-doomed molecules before the expensive full animal-toxicology package and Phase I (KDT 8e Ch.5, p.90).
• Conceptually, microdosing/Phase-0 belongs to the "recent advances" in drug development within experimental and clinical pharmacology (KDT 8e Ch.5, drug-development section).

1.1 Terminology map (one concept, several regulator-specific names)

• Microdosing study — the bioanalytical/PK technique-centred name (KDT 8e Ch.5, p.90).
• Phase 0 study / Phase '0' trial — the developmental-position name (it precedes Phase I) (KDT 8e Ch.5, p.90).
• Exploratory IND (eIND) study — the US regulatory name; the FDA 2006 guidance is the founding document. An eIND study is one conducted early in Phase 1, involves very limited human exposure, and has no therapeutic or diagnostic intent (e.g. screening studies, microdose studies) [FDA].
• Exploratory clinical trial — ICH M3(R2) umbrella term for the same family of limited-exposure pre-Phase-I studies; ICH M3(R2) Section/Table on "Exploratory Clinical Studies" defines five approaches with their respective nonclinical-support requirements [ICH].
• ⚠ The four names are near-synonyms but not identical in scope: "microdosing" denotes only the ≤100 µg / ≤1/100th-dose subtype, whereas "exploratory IND" and "exploratory clinical trial" also cover pharmacologically-active single sub-therapeutic doses (mechanism/target-occupancy studies) that exceed the microdose ceiling (KDT silent on these wider approaches; FDA/ICH define them) [FDA][ICH].