A Review of Human Phase 0 (Microdosing) Clinical Trials Following the US Food and Drug Administration Exploratory Investigational New Drug Studies Guidance

Microdosing, or human phase 0 clinical trials, is a technique whereby subpharmacological doses of prospective drug candidates are administered to human volunteers. A microdose study provides early pharmacokinetic data in humans and only requires minimal preclinical toxicology safety testing. A microdose is defined as 100th of the pharmacological dose (or predicted pharmacological dose) or a maximum of 100µg. Microdosing is a relatively recent innovation and there remains a degree of uncertainty as to whether such a small dose will adequately predict the pharmacokinetics of the therapeutically active dose. Notwithstanding this, in situations when traditional methods such as in vitro and laboratory animal models prove to be unreliable, microdosing can offer the supporting and alternative data on which to select suitable drug candidates for development, prior to commencing expensive full phase I clinical trials. The current published data on microdosing is somewhat sparse, although there have been a few papers in recent times. This paper is the first compressive review of the microdosing concept since the publication of the US Food and Drug Administration exploratory IND study guidance in January 2006, which covers the preclinical requirements to enable a microdose study in humans to take place.