Making Go/No-Go Decisions Using Phase 0 Trial Data

Why Early Decision-Making Is Critical

Drug development is time-consuming and resource-intensive. Making informed go/no-go decisions as early as possible can prevent costly failures later. Phase 0 trials, through microdosing and focused pharmacokinetic/pharmacodynamic (PK/PD) evaluations, provide real-world human data to evaluate whether a drug candidate is worth advancing to Phase 1 and beyond.

What Data Can Phase 0 Trials Generate?

Despite using microdoses, Phase 0 studies yield high-impact data points that include:

• Pharmacokinetics – absorption, bioavailability, half-life, clearance
• Tissue distribution – especially in oncology or CNS indications using PET
• Target engagement – biomarker changes, receptor occupancy
• Comparative data – when evaluating multiple candidates

These data, though non-therapeutic in isolation, can de-risk or redirect an entire development program.

Criteria for Go/No-Go Decisions Based on Phase 0 Data

1. Systemic Exposure

If the compound fails to reach detectable levels in plasma despite microdosing, it may indicate poor absorption or rapid metabolism—justifying a no-go.

2. Oral Bioavailability

Drugs with <10% oral bioavailability at microdose levels may require formulation changes or alternate routes. If no path forward exists, this may be a no-go trigger.

3. PK Linearity

Linear pharmacokinetics between microdose and projected therapeutic dose support predictive modeling. If saturation or nonlinear effects are observed early, development strategies may need adjustment.

4. Target Engagement or Imaging Outcomes

For biologics or oncology compounds, lack of measurable receptor occupancy or tumor uptake (e.g., via PET imaging) often signals a no-go decision—despite good preclinical results.

5. Safety Red Flags

Even though doses are subtherapeutic, unexpected adverse events or immunogenicity may prompt reassessment before entering Phase 1.

Case-Based Examples of Phase 0 Impact

Case 1: Oncology Compound with Dual Candidates

Two kinase inhibitors were tested in a head-to-head Phase 0 study. Compound A demonstrated better tumor targeting via PET and favorable PK, while Compound B showed poor uptake. The company advanced Compound A and terminated B, reducing development costs by 40%.

Case 2: CNS Drug with Poor Human Absorption

Despite good preclinical results, a CNS-targeted microdose trial revealed that the drug had poor BBB penetration and rapid clearance in humans. The candidate was deprioritized in favor of a backup molecule with a stronger profile.

Strategic Uses of Phase 0 Data

• Optimize formulation or delivery before full Phase 1
• Support funding decisions and investor confidence
• Prioritize pipeline molecules with real human data
• Accelerate decisions in high-risk indications like oncology

How to Structure a Decision Framework

Develop a predefined matrix or checklist that includes:

• Thresholds for PK parameters (e.g., AUC, t½)
• Imaging uptake targets or biomarker thresholds
• Formulation stability and detection sensitivity
• Regulatory path viability and projected development cost

These tools remove ambiguity and allow cross-functional teams to make data-driven decisions post-study.

Role of Cross-Functional Review

After data is analyzed, hold an internal review involving:

• Clinical pharmacologists
• Nonclinical safety experts
• Regulatory strategists
• Portfolio and commercial leads

The decision should balance scientific data, future development costs, unmet medical need, and return on investment.

Documentation for Audits and Submissions

• Retain raw data, validated PK reports, and decision meeting minutes
• Summarize Phase 0 results in the Investigator’s Brochure for Phase 1
• Use the data in regulatory interactions and grant applications