Phase Zero Studies in Radiopharmaceutical Development: An Early Pathway to Insight

Bracken

Why Phase 0 Studies Are Gaining Ground in Radiopharmaceutical Development

Phase 0 studies are appearing more frequently in radiopharmaceutical programs for a clear reason: they enable sponsors to answer critical questions early—before investing significant time, materials, and budget in Phase 1. These studies are not about testing safety or efficacy in the traditional sense. Instead, their strategic value lies in confirming whether a drug behaves in humans as expected, helping teams make sharper, faster development decisions.

This article outlines where Phase 0 adds meaningful value in radiopharma, common operational challenges, a key caveat around SUV-based PET readouts, and resources for teams looking to pressure-test their imaging strategy.

What Phase 0 Is (and Isn’t)

Phase 0—also called exploratory first-in-human—uses sub-therapeutic microdoses in a small cohort to collect decision-enabling data ahead of a traditional Phase 1 trial.[1]

Typical objectives include: - Biodistribution & target engagement: Does the agent reach the intended tissues? - Early PK/PD behavior: Does human data align with preclinical expectations? - Mechanism confirmation: Are we seeing signal in the right places to justify further investment?

Because exposures are low, toxicology requirements and overall study scope are reduced relative to Phase 1, though an appropriate regulatory submission and ethics review are still required.

Why Phase 0 Fits Radiopharmaceuticals

Radiopharmaceuticals paired with PET or SPECT imaging provide direct, time-resolved visualization of drug biodistribution and target localization. In practice, that can deliver:

Earlier go/no-go clarity: If imaging doesn’t show meaningful target engagement, teams can redirect before site activation and manufacturing scale-up.
Indication and cohort refinement: Imaging can prioritize tumor types or patient subgroups with consistent target expression.
Translational validation: Human data can confirm or challenge assumptions from animal and in vitro studies.
Efficient theranostic planning: For diagnostic/therapeutic isotope pairs, Phase 0 readouts can inform sequence and design of therapeutic studies.

Operational Realities Sponsors Often Underrate

Effective execution of Phase 0 in radiopharma depends on logistical and procedural precision. Commonly underestimated elements include:

Isotope and imaging logistics: Tight coordination of isotope production, QC/release, transport, patient preparation, and scanner scheduling within limited half-lives.
Site readiness: Pharmacy and radiation safety workflows must align with exploratory study needs.
Acquisition consistency: Standardization of prep, uptake times, acquisition parameters, and reconstruction methods is critical for meaningful comparison.
Reader approach and centralization: Pre-defined reading criteria and, when needed, centralized reads to reduce variability.
Regulatory and ethics framing: Clear communication that no direct clinical benefit is expected, supported by transparent consent language and oversight.

Teams that plan for these details early avoid costly rework and data ambiguity later.

Regulatory Considerations (At a Glance)

Pathway: Exploratory first-in-human studies typically proceed under an exploratory IND (or local equivalent). [1]
Scope: Reduced nonclinical requirements may be acceptable versus traditional Phase 1.
Oversight: Ethics/IRB review is required; materials must emphasize the non-therapeutic nature of participation.
Sites: Must be capable of radiotracer handling and advanced imaging per study requirements. [3]

Teams should align details with current agency guidance and specific program needs.

A Note of Caution: SUV Alone Can Mislead in Phase 0

PET standardized uptake values (SUVs) are convenient and widely recognized, but in exploratory, low-dose settings they can be highly variable. Influences include:

Patient prep and timing (uptake period, glucose status, motion)
Scanner/acquisition and reconstruction parameters
Partial-volume effects in small lesions
Non-target factors (perfusion, inflammation, background uptake)

Bottom line: Treat SUV as one input—not the decision. Whenever possible, pair SUV metrics with tumor-to-background ratios, lesion-level consistency checks, and kinetic or time-activity analyses aligned to tracer and mechanism.

Further reading: Limitations of SUV Quantitation in Phase 0 PET Trials (Bracken eBook). This guide covers common pitfalls, protocol optimization levers, and decision frameworks for exploratory imaging.

How Bracken Helps

Bracken partners with sponsors, CROs, and imaging sites to translate Phase 0 from an exploratory idea into decision-ready data.

Our support includes:

Translational read-through: Assess preclinical data for Phase 0 readiness and identify questions human microdosing can truly answer.
Protocol & imaging design: Tailor acquisition parameters, uptake timing, and analysis criteria to mechanism and tracer behavior.
Site selection & enablement: Identify experienced centers; align pharmacy, radiation safety, and imaging workflows.
Regulatory strategy: Right-size nonclinical packages and submission narratives for exploratory aims. Image interpretation & read planning: Define analysis plans, central reads, and decision thresholds that minimize overreliance on SUV.
Pathway to Phase 1: Integrate findings to sharpen therapeutic design and prioritization.

Final Thoughts

Phase 0 and Phase 1 do different jobs. They are complementary, not interchangeable.

Phase 0 (exploratory IND): Uses very limited human exposure (often microdose/sub‑therapeutic) with no therapeutic intent. The aim is rapid, mechanism‑driven learning—e.g., biodistribution, target engagement, and translational alignment to human biology. It is not intended to characterize clinical safety/tolerability at therapeutic exposures or define dose–response.[1]
Phase 1 (dose‑escalation and early characterization): The initial introduction of an investigational drug into humans to evaluate pharmacokinetics, pharmacologic actions, and characterize safety/tolerability across increasing doses, and—when feasible—gather preliminary evidence of activity to inform Phase 2 design.[2]

Practical implication for radiopharma: Use Phase 0 to decide whether and how to proceed—confirm human targeting, refine indications, and shape imaging/analysis plans. Use Phase 1 to establish the dosing paradigm, safety margins, and operational playbook for subsequent efficacy studies. Treating Phase 0 as a shortcut for Phase 1 invites gaps in dose justification and safety characterization; treating it as a focused translational gate creates a cleaner, faster Phase 1.

Considering a Phase 0 study? Bracken’s experts can help you evaluate whether your design, imaging strategy, and quantitative endpoints are robust enough to guide confident early decisions.