USFDA Draft Guidance: Radiopharmaceutical Dosage Optimization and Overall Survival Assesment in Oncology Clinical Trials

On 18th August 2025, the U.S. Food and Drug Administration (FDA) recently published two important draft guidance documents that aim to refine the clinical development of oncology products:

• Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development

• Approaches to Assessment of Overall Survival in Oncology Clinical Trials

These documents provide essential direction to sponsors, researchers, and clinical trial designers working on cancer therapies. Together, they focus on dosage optimization of oncology therapeutic radiopharmaceuticals and on the assessment of overall survival (OS) in oncology clinical trials.

Guidance: Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development

Radiopharmaceuticals (RPTs) are radioactive drugs or biologics administered systemically to treat cancer or palliate tumor-related symptoms. They share properties with both external beam radiation therapy (EBRT) and systemic drugs, but their optimal clinical use and development designs involve unique complexities.

Includes both the administered activity (amount of radioactivity) and schedule (intervals and cycles). An optimized dosage maximizes therapeutic effect while minimizing toxicity.

This draft guidance (August 2025) provides recommendations for identifying optimized dosage regimens of oncology therapeutic radiopharmaceuticals during clinical development.

Key Highlights

• Background Challenge: Historically, RPT dosages were aligned with external beam radiation therapy (EBRT) tolerances. However, EBRT-based limits may not be suitable for RPTs due to differences in radiation properties and delivery.

• Considerations for Sponsors:

  • Participant Population: Trials exceeding EBRT dose limits should focus on late-stage cancer patients with limited life expectancy.

  • Trial Design: Should predefine cumulative administered activity and involve randomized dose-response trials when appropriate.

  • Safety Monitoring: Long-term toxicities (e.g., renal, bone marrow, xerostomia) should be followed for at least 5 years.

  • Dosimetry: Phase 1 studies must include radiation dosimetry to measure absorbed doses and correlate with safety/efficacy outcomes.

In short, this guidance encourages evidence-based, patient-centered dosage optimization while safeguarding long-term health outcomes.

Guidance: Approaches to Assessment of Overall Survival (OS) in Oncology Clinical Trials

OS Definition: The time from randomization until death from any cause. It remains the most objective and clinically meaningful endpoint in oncology. OS is the most objective and meaningful endpoint in cancer clinical trials, reflecting both efficacy (prolonging life) and safety (avoiding life-shortening harm). OS measurement and analysis are affected by long natural history, crossover, subsequent therapies, and intercurrent events (events that occur after treatment assignment and affect the interpretation of the outcome).

Key Highlights

• FDA Recommendations:

  • Pre-specify clear statistical methods to handle crossover and censoring.

  • Ensure sufficient follow-up time to capture survival events.

  • Collect comprehensive patient-reported outcomes to supplement OS data.

  • Consider trial designs that balance early access to therapies with rigorous OS evaluation.

This guidance emphasizes statistical robustness, transparency, and proper trial design to ensure OS is measured consistently across oncology studies.

For full details, refer to the official FDA documents:

• Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development (Draft Guidance)

• Approaches to Assessment of Overall Survival in Oncology Clinical Trials (Guidance for Industry)