The FDA has released new draft guidance to assist pharmaceutical companies in optimizing dosing strategies for radiopharmaceutical therapies (RPTs) in cancer treatment development. The guidance document, titled "Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development," was published on August 18, 2025, and addresses a critical gap in clinical development protocols for this emerging therapeutic class.
Addressing Unique Dosing Challenges
According to the FDA guidance document, RPTs present unique dosing challenges because they share characteristics with both external beam radiation therapy (EBRT) and systemic drug therapy. Traditionally, RPT dosages have been limited to normal organ absorbed dose limits derived from EBRT data. However, the agency notes that differences in physical properties and treatment delivery between RPTs and EBRT reduce the applicability of these established organ absorbed dose limits.
"The optimized RPT dosage, therefore, may be greater than or less than a dosage limited by EBRT organ tolerances," the guidance states. The document emphasizes that radiation absorbed dose limits may also differ between different isotopes or RPTs based on their physical properties.
Flexibility for Higher Dosing Studies
The new guidance provides important flexibility for clinical development by allowing studies of RPT dosages that exceed traditional EBRT organ tolerances under specific conditions. If there is adequate rationale that the optimized dose cannot be identified at lower dosages, sponsors may study administered activities per cycle and cumulative RPT-administered activities that result in absorbed dosages exceeding EBRT organ tolerances.
"Proposals to expose participants to RPT dosages that exceed EBRT organ tolerances or previously characterized RPT dosages could be justified based on existing clinical data or other approaches, as applicable, and should be discussed with FDA during formal meetings, including early in clinical development," the agency states.
Required Safeguards and Monitoring
The guidance emphasizes that trials studying higher dosages must include comprehensive safeguards such as appropriate participant selection, trial design, safety monitoring, and radiation dosimetry evaluation. The document provides detailed considerations for participant population selection, trial design optimization, safety monitoring protocols, and dosimetry requirements for dosage optimization trials.
The FDA notes that RPTs have the potential to cause delayed, cumulative, and irreversible toxicity that may not be captured in traditional dose-finding trials, making these safeguards particularly important.
Clinical Development Context
The new draft guidance is designed to be used alongside recommendations provided in the August 2024 guidance, "Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases." However, it does not cover selection of initial RPT administered activity in first-in-human trials or other aspects such as dosimetry software, fixed versus personalized dosing strategies, and theranostic co-development.
Industry Perspective on Radiopharmaceutical Evolution
Mike Ritchie, chief commercial officer at Champions Oncology, provided context on the evolution of radiopharmaceuticals in cancer treatment. "Radiopharmaceuticals have been used in the past to treat superficial tumors, but they have evolved to treat internal tumors as well," Ritchie explained.
He emphasized the complexity of developing these therapies at scale: "There's so much [that goes] into pharmaceutical development into making something that can be manufactured at scale. It can sit on a shelf for a while. We can administer it to a patient, and it behaves in the way that we want."
Ritchie noted that the field is still in its early stages regarding optimal patient selection: "From the biology perspective, again, we're in our infancy and understanding what are the tumor types, or the molecular cohorts within a tumor that are more sensitive to radio ligands. Like any chemotherapy or any therapy, certain tumors will respond. Others will not. They'll develop resistance."
Regulatory Framework
The guidance document represents the FDA's current thinking on RPT dosage optimization and does not establish binding requirements. Companies may use alternative approaches if they satisfy applicable statutes and regulations. The agency is accepting public comments on the draft guidance through the Federal Register docket system.
