Phase 0 vs. First-in-Human Trials: Transitioning Safely from Microdosing to Therapeutic Dosing
Introduction
Phase 0 trials offer early insight into drug behavior in humans using sub-therapeutic microdoses. First-in-Human (FIH) trials, on the other hand, initiate therapeutic dosing to assess safety and tolerability. Bridging the gap between these two stages requires careful planning, regulatory awareness, and a clear understanding of pharmacology. This article explores the key distinctions and offers guidance on how to transition safely and effectively.
Key Differences Between Phase 0 and FIH Trials
| Feature | Phase 0 Trial | First-in-Human (FIH) Trial |
|---|---|---|
| Purpose | Exploratory PK/PD, target engagement | Evaluate safety, tolerability, PK, and initial dose response |
| Dose | Sub-therapeutic (≤100 µg or 1/100th of therapeutic) | Starting at therapeutic or biologically active levels |
| Toxicology Requirement | Single-dose tox in one species | Full preclinical safety package required (GLP tox) |
| Participants | Healthy volunteers or select patients | Healthy volunteers (non-cytotoxic) or patients (e.g., oncology) |
| Risk | Minimal; no therapeutic intent | Moderate; possible pharmacologic or adverse responses |
Why Transition from Phase 0 to FIH?
Phase 0 generates human PK/PD, receptor binding, or tissue distribution data that helps:
- Validate preclinical models
- Support FIH dose selection using observed data
- De-risk FIH trial design with better predictions of exposure
Step-by-Step Guide to a Safe Transition
1. Analyze and Integrate Phase 0 Data
- Determine observed AUC, Cmax, t½ from microdose PK
- Evaluate tissue targeting using PET imaging, if applicable
- Validate linearity between microdose and predicted full dose via PBPK modeling
2. Define the Minimum Effective Dose (MABEL)
Use in vitro and in vivo pharmacology data, combined with human PK predictions, to establish a starting dose that is safe but biologically informative.
- Include receptor occupancy, EC50/IC50 data, and human volume of distribution
- Consult ICH S6(R1) and ICH M3(R2) for guidance
3. Scale from Microdose to Therapeutic Dose
Ensure the compound demonstrates linear pharmacokinetics. Use allometric scaling and PBPK models to project safe dose levels.
- If Cmax from microdose is 50 pg/mL and therapeutic target is 5 ng/mL, scale accordingly with a built-in safety margin
4. Update Regulatory Submissions
- Submit a protocol amendment or a new IND/CTA
- Include updated Investigator’s Brochure with Phase 0 results
- Provide revised clinical development plan and justification for FIH design
5. Implement Safety Measures in FIH Trial
- Use sentinel dosing for the first cohort
- Implement dose escalation rules (e.g., 3+3 or model-based)
- Monitor adverse events, vitals, ECG, labs post-dose
Common Challenges in the Transition
Misinterpretation of Microdose Data
Microdose PK may not always predict full-dose PK due to saturation or non-linear metabolism.
Formulation Differences
Microdose formulations often differ from clinical dosage forms. Ensure formulation equivalence during transition.
Regulatory Inconsistencies
If countries require separate applications, coordination is needed to ensure smooth approval between exploratory and full trials.
Case Example: Seamless Oncology Development
A novel kinase inhibitor underwent a Phase 0 PET study to assess tumor uptake. Data showed high tumor accumulation but rapid systemic clearance. Based on this, the starting dose for the FIH trial was adjusted downward to reduce systemic AEs. The adaptive design allowed dose escalation based on early PK/tumor response correlation, leading to a more efficient Phase 1 program.
Best Practices for Effective Transition
- Plan the transition from the outset—build it into the clinical development roadmap
- Use consistent teams, sites, and vendors between phases for smoother handover
- Ensure robust data integration (bioanalysis, PK, modeling, safety)
- Hold internal go/no-go meetings with cross-functional input before advancing
Conclusion
Phase 0 and First-in-Human trials are complementary tools in modern clinical research. With careful planning, model-informed dose selection, and proactive regulatory engagement, you can leverage the strengths of both to minimize risk and accelerate early development. Transitioning from microdose to therapeutic dose isn’t just about increasing quantity—it’s about preserving quality and safety every step of the way.