Understanding Phase 0 Trials: Purpose, Design, and Why They Matter

What are Phase 0 Clinical Trials?

Phase 0 trials, also known as microdosing studies, are the earliest phase of human clinical research. Introduced as part of an exploratory IND (Investigational New Drug) framework by the U.S. FDA, Phase 0 studies are designed to collect preliminary pharmacokinetic (PK) and pharmacodynamic (PD) data in humans using very low doses of investigational drugs.

Unlike traditional Phase 1–3 trials, Phase 0 trials do not aim to assess safety or efficacy. Instead, they serve as a critical go/no-go checkpoint that helps developers make faster and better-informed decisions.

Why Do Phase 0 Trials Exist?

Drug development is costly and time-consuming. Many candidates fail during Phase 1 or 2, resulting in major financial loss. Phase 0 trials provide a low-risk way to:

• Screen multiple drug candidates quickly
• Understand human pharmacokinetics before full-scale trials
• Reduce overall R&D costs by filtering out poor candidates early
• Test target engagement or mechanism of action using biomarkers

In essence, Phase 0 studies enhance efficiency in drug development pipelines, especially for oncology, CNS, and biologic therapies.

Primary Objectives of Phase 0 Trials

Phase 0 studies are designed to address specific scientific questions, such as:

• Does the drug reach the intended tissue or site of action?
• Is the drug absorbed and metabolized as expected in humans?
• Can target engagement be confirmed at a microdose level?
• Should further development be pursued or abandoned?

These insights are critical for early decision-making and derisking the drug development process.

What is a Microdose?

A microdose is defined by regulatory agencies as:

• 1/100th of the pharmacologically active dose, or
• Not more than 100 micrograms for small molecules

At such low levels, the drug is not expected to produce a therapeutic or toxic effect, making it safer for administration to healthy volunteers or select patient populations.

Design and Structure of Phase 0 Trials

1. Sample Size

Phase 0 trials typically include 6–15 subjects. The small sample size is adequate for early PK/PD measurements and feasibility testing.

2. Duration

These studies are short, often lasting just 1–7 days, depending on the drug’s half-life and endpoint collection timelines.

3. Study Population

• Healthy volunteers are usually enrolled
• Cancer patients may be enrolled in oncology-targeted Phase 0 studies

4. Dosing and Route of Administration

The drug is administered via the intended clinical route—oral, IV, inhalation, etc.—but at microdose levels. Serial sampling is conducted to capture plasma, urine, or tissue levels.

5. Endpoint Measurements

• Pharmacokinetics (Cmax, AUC, half-life)
• Pharmacodynamics (biomarker changes)
• Tissue penetration or receptor binding (e.g., using PET imaging)

Regulatory Framework: Phase 0 and the FDA

The U.S. FDA first formalized Phase 0 trials under its Exploratory IND guidance (2006). This allowed sponsors to begin human trials with:

• Reduced animal toxicology requirements
• Limited preclinical data (e.g., single-dose tox in one species)
• Shorter timelines and lower costs

Other regulatory bodies like EMA, CDSCO, and PMDA have also acknowledged microdosing studies under their respective risk-based frameworks.

Advantages of Conducting a Phase 0 Study

• Speeds up development by providing early human data
• Allows comparison of multiple drug candidates
• Supports rational decision-making with limited investment
• Reduces failure rates in later clinical phases

Limitations and Considerations

Despite the advantages, Phase 0 studies have limitations:

• Microdose PK may not extrapolate to therapeutic doses
• No safety or efficacy evaluation is performed
• Not all drugs are suitable for microdosing (e.g., nonlinear kinetics)

Therefore, careful candidate selection and predictive modeling (e.g., PBPK) are essential.

Real-World Example

An oncology company evaluated two small-molecule inhibitors using Phase 0 design. Volunteers received microdoses of both drugs, and plasma PK and PET imaging were used to assess tumor uptake. One drug showed high tissue penetration; the other did not. Based on Phase 0 data, the company progressed only the promising candidate to Phase 1, saving millions in development costs.

Summary for Clinical Research Students

Phase 0 trials represent a paradigm shift in drug development—small, focused, data-driven studies that provide early human insight. As a student or aspiring clinical researcher, understanding the objectives and structure of Phase 0 trials prepares you to contribute meaningfully to early-phase program design and regulatory strategy.

They are not replacements for Phase 1 studies but rather an exploratory tool to streamline discovery and development while minimizing risk and cost.