Key Differences Between Phase 0 and Phase 1 Clinical Trials
Introduction
Both Phase 0 and Phase 1 trials are part of early-phase clinical research, but they serve distinct purposes in drug development. Understanding their differences is critical for planning development strategies, regulatory submissions, and timelines. This article compares the two phases side-by-side to clarify how they fit into the larger clinical trial landscape.
What Is a Phase 0 Trial?
Also known as microdosing studies, Phase 0 trials are exploratory clinical studies that occur before traditional Phase 1 trials. They use sub-therapeutic doses to gather pharmacokinetic (PK), pharmacodynamic (PD), or imaging data without evaluating safety or efficacy. These studies help determine whether a drug behaves in humans as predicted from preclinical data.
What Is a Phase 1 Trial?
Phase 1 trials are the first-in-human (FIH) studies conducted with therapeutic or near-therapeutic doses. They focus on evaluating safety, tolerability, PK, and sometimes PD of a new drug. Phase 1 is a regulatory milestone that determines whether a drug can move to larger, efficacy-driven trials.
Comparison Table: Phase 0 vs. Phase 1
| Aspect | Phase 0 Trial | Phase 1 Trial |
|---|---|---|
| Objective | Explore PK/PD and target engagement using microdoses | Evaluate safety, tolerability, and full-dose PK |
| Dose Range | Sub-therapeutic (≤1/100th of therapeutic dose or ≤100 μg) | Therapeutic or near-therapeutic dose; dose escalation used |
| Duration | Typically 1–7 days | Usually 2–6 weeks per cohort |
| Number of Participants | 6–15 volunteers | 20–100 volunteers/patients |
| Type of Subjects | Usually healthy volunteers or select patients (oncology) | Healthy volunteers or patients depending on drug type |
| Toxicology Requirements | Single-dose tox in one species | GLP tox in two species (rodent + non-rodent) |
| Regulatory Filing | Exploratory IND (FDA) / CTA (EMA/CDSCO) | Full IND or CTA with detailed preclinical data |
| Endpoints | PK parameters, receptor occupancy, biodistribution | Adverse events, dose-limiting toxicities, MTD, PK/PD |
| Ethical Consideration | No therapeutic intent | Therapeutic intent begins, especially in oncology |
| Trial Cost | Lower (~$0.5–1 million) | Higher (~$2–5 million) |
When to Use a Phase 0 Trial
- You need to de-risk clinical development before committing large investments
- You have multiple candidates and want to prioritize based on human PK
- Your molecule has novel delivery or uncertain absorption characteristics
When to Go Directly to Phase 1
- You have a strong preclinical safety package and well-predicted PK
- The molecule has clear therapeutic intent (e.g., oncology agents)
- You need to rapidly begin clinical development under regulatory pressure
How Phase 0 Supports Phase 1
Phase 0 results can:
- Inform starting dose and dose escalation schemes for Phase 1
- Support go/no-go decisions based on human PK and target engagement
- Validate or challenge preclinical ADME predictions
Some sponsors also combine both phases into a seamless exploratory-to-FIH strategy to save time and resources.
Conclusion
While both Phase 0 and Phase 1 trials take place early in clinical development, their goals, designs, and regulatory demands are fundamentally different. Used strategically, Phase 0 trials can enhance the precision and success rate of Phase 1 trials. Understanding these distinctions allows clinical teams to choose the right approach for each molecule and maximize the efficiency of development pipelines.