Radiopharmaceuticals: FDA draft guidance offers tailored approach for optimizing dose

The US Food and Drug Administration (FDA) on Monday released draft guidance to help sponsors determine the optimal dosage for radiopharmaceutical therapies (RPT) used in oncology.

The guidance aims to distinguish dosing recommendations between RPT products and external beam radiation therapy (EBRT), as these are two different methods of radiation treatment for cancer.

In a notice, FDA stated that the process of determining dosing for RPTs has generally been restricted to standard organ absorbed dose limits based on EBRT data. However, due to the differences in physical properties and treatment delivery between RPT and EBRT, those limits may not be as relevant for RPT. Additionally, RPT can potentially lead to delayed, cumulative, and/or irreversible toxicity, which is often not accounted for in traditional dose-finding trials.

The guidance addresses the participant population, trial design, safety monitoring, and dosimetry for dosage optimization trials. Dosimetry is the practice of measuring the absorbed dose of ionizing radiation. It also addresses safeguards to mitigate the risk of unacceptable long-term toxicity from RPT dosages that exceed EBRT limits or previously characterized RPT dosages.

The guidance specifies that trials aiming to define the maximum tolerated dose (MTD) of an RPT or those involving doses that exceed the limits defined by EBRT should be conducted with participants who have a limited life expectancy due to cancer-related mortality. Additionally, these participants must be assessed to determine whether the risk of delayed permanent organ failure is acceptable. The specific participant population suitable for such studies depends on the particular disease and should be discussed with the relevant FDA review division.

In terms of the trial design, the guidance said that RPTs should typically be given for a predetermined number of cycles to reduce the risk of delayed or cumulative toxicity. Protocols should specify a limit on the total administered activity and the corresponding radiation doses absorbed by critical organs, based on available data regarding the organ tolerances specific to RPTs. These limits may vary depending on the product and indication, and they can be adjusted as new data becomes available.

The guidance states that because the onset of radiation toxicity may be delayed by months to years, sponsors should perform safety monitoring against a pre-specified list of late radiation adverse events of special interest (rAESI) for at least five years. “The rAESI list and monitoring schedule should explicitly reflect the drug-specific dosimetry results and a corresponding detailed critical radiation safety analysis plan. RPTs granted approval for cancer indications may be subject to a postmarketing requirement to provide such long term safety follow-up data for FDA review,” FDA writes.

In terms of dosimetry for dosage optimization trials, the guidance states that Phase 1 studies of radioactive drugs must include sufficient data for dosimetry calculations. “Each novel molecular entity should have dosimetry studies performed early in its clinical development program to provide measurements of potential toxicity/efficacy associated with exposure to radiation (e.g., delivered organ absorbed dose and related dosimetric quantities). Dosimetry studies provide a radiobiological context for the clinical efficacy and safety data and support dosage optimization.”

Stakeholders can comment on the draft guidance on www.regulations.gov under docket no. FDA-2025-D-1757 through 20 October.

Draft guidance

Radiopharmaceuticals: FDA draft guidance offers tailored approach for optimizing dose

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