Combining Phase 0 and Adaptive Phase 1 Trials: A Seamless Early Development Strategy

Introduction

Phase 0 trials provide early human pharmacokinetic and target engagement data. Phase 1 trials explore safety and dose tolerance. Combining these phases into a seamless development strategy using adaptive trial designs offers speed, efficiency, and data continuity. This approach is especially valuable for high-risk, high-reward programs such as oncology, CNS, or rare disease pipelines.

What is an Adaptive Phase 1 Trial?

An adaptive Phase 1 trial allows for modifications to key parameters—like dose level, cohort size, or schedule—based on interim data. Unlike fixed designs, adaptive trials respond dynamically to what’s being learned in real time.

By integrating Phase 0 data into an adaptive Phase 1 framework, developers can:

• Shorten timelines between studies
• Use human PK data to guide dose escalation
• Reduce exposure to subtherapeutic or unsafe doses

How the Integration Works

1. Conduct Phase 0 as a Lead-In

• Run a microdose study with ≤100 µg of drug
• Collect human PK and target binding data
• Model dose-exposure curves using PBPK simulation

2. Transition Directly into Adaptive Phase 1

• Design Phase 1 to adapt based on Phase 0 results
• Modify dose escalation scheme or starting dose if needed
• Optionally embed a ‘sentinel’ dosing strategy for safety

3. Use Combined Data for Dose Selection

• Define Minimum Anticipated Biological Effect Level (MABEL)
• Integrate biomarker response or imaging data
• Confirm target engagement before dose escalation

Design Options

Design A: Seamless Protocol

Single protocol includes a microdose cohort followed by adaptive dose escalation. Requires pre-approval of both stages by ethics and regulators.

Design B: Bridged Design

Separate protocols but use common investigator sites and teams. Phase 0 data is used to refine the Phase 1 protocol and submitted as an amendment.

Regulatory Considerations

• FDA: Allows exploratory INDs to transition into traditional INDs via amendments
• EMA: Supports integrated protocols under Clinical Trials Regulation with risk mitigation
• CDSCO: Requires protocol separation but permits transition with approval

Early engagement through pre-IND or Scientific Advice meetings is essential.

Benefits of Seamless Transition

• Accelerated time to first therapeutic dose
• Early human data reduces uncertainty in dose escalation
• Integrated safety monitoring from microdose through therapeutic range
• Cost-efficiency through shared infrastructure and CRO partners

Operational Tips for Execution

• Ensure assay sensitivity can cover both microdose and therapeutic levels
• Use cross-trained site staff to manage both study parts smoothly
• Keep SOPs aligned and approved for both stages from the outset
• Document data integration plan in clinical development plan (CDP)

Example: Seamless Oncology Early Development

A biotech company conducting a microdose PET imaging study transitioned immediately into an adaptive Phase 1 using the same site and investigators. Human PK and tumor uptake data informed the initial dose and escalation speed. The approach saved 4 months and significantly improved sponsor-investigator collaboration and decision-making.

Challenges and How to Manage Them

• Protocol complexity: Use modular designs and clear progression criteria
• Ethical committee approvals: Justify low risk in Phase 0 and transitional design
• Operational readiness: Coordinate CROs and clinical sites for immediate transition

Conclusion

Combining Phase 0 and adaptive Phase 1 trials is a forward-thinking strategy for data-driven, time-efficient drug development. With the right planning, modeling support, and regulatory engagement, it transforms the development timeline without compromising safety or data quality—turning exploratory trials into a springboard for success.