Clinical trials determine if a new drug or medical treatment is safe and effective for human use. These investigations are traditionally structured into sequential phases—Phase I, Phase II, and Phase III—each designed to answer specific questions. Phase 0 is a unique, optional stage taken before the standard Phase I trial to gather initial, time-saving data about a drug’s behavior in the human body. This early step helps scientists decide which drug candidates are worth the significant investment required for full-scale clinical development.
Defining the Phase 0 Concept
Phase 0 studies are formally known as Exploratory Investigational New Drug (IND) studies in the United States, a designation established by the Food and Drug Administration (FDA) in 2006. The primary purpose is to accelerate the lengthy drug development process by quickly identifying compounds unlikely to succeed. These studies involve a small number of participants, typically 10 to 15 individuals, for a short duration, often about a week. The goal is not to test the drug’s effectiveness or safety at therapeutic levels, but to gain an initial understanding of its basic properties in humans. This limited exposure allows the amount of required preclinical testing to be significantly reduced compared to a traditional IND application.
The Role of Microdosing
The defining characteristic of a Phase 0 trial is the use of a microdose, which is a subtherapeutic amount of the investigational drug. A microdose is defined as less than one-hundredth of the dose calculated to produce a pharmacological effect. For small molecule drugs, the dose is always limited to a maximum of 100 micrograms. Administering this minute quantity minimizes the risk to participants because it is too low to cause noticeable therapeutic effects or adverse toxic side effects. This non-pharmacologically active dose allows scientists to track the drug’s initial movement in the human body while maintaining a high safety profile.
Data Gathered and Primary Goals
The main objective of a Phase 0 study is to gather Pharmacokinetic (PK) data, which describes how the body handles the drug. This involves analyzing the four steps of Absorption, Distribution, Metabolism, and Excretion (ADME). Scientists utilize highly sensitive analytical techniques, such as Accelerator Mass Spectrometry, to measure the microdose and its breakdown products in blood and tissue samples. The results reveal whether the drug is absorbed into the bloodstream, distributed to its intended target tissue, metabolized, and cleared from the body as predicted by animal studies. The data collected is not intended to measure Pharmacodynamics (PD)—the drug’s effect on the body—or to assess efficacy. Instead, it ensures the compound behaves correctly before larger, more expensive trials begin.
Key Differences from Phase 1 Trials
Phase 0 trials function as a screening tool, which contrasts sharply with the objectives of a traditional Phase I study. Phase 0 uses a single, non-pharmacologically active microdose. In contrast, Phase I trials involve giving escalating, therapeutic doses to volunteers to determine the Maximum Tolerated Dose (MTD). The primary goal of Phase 0 is to gather early PK data to make a go/no-go decision about the compound’s viability in humans. The main goal of Phase I is to establish the drug’s short-term safety profile and identify common side effects at therapeutically relevant levels. Furthermore, the duration of a Phase 0 trial is extremely short, often involving a single administration, whereas Phase I trials typically involve weeks or months of observation.