Radiopharmaceuticals: Project Optimus, Dose Justification, and Dosimetry Weight

In an interview with Targeted Oncology, Harpreet Singh, MD, chief medical officer at Precision for Medicine and former director of the Division of Oncology 2, US FDA, discusses the FDA's new draft guidance on radiopharmaceutical dosing.

Watch part 1 and part 2 of the interview with Dr Singh.

This guidance essentially outlines how and when developers should engage with regulators during the development of these radiopharmaceutical assets. A central theme is a renewed focus on dose justification.

The guidance makes it clear that before advancing to a registrational trial design, sponsors of a radiopharmaceutical must adhere to the principles and framework of the Project Optimus initiative. Radiopharmaceutical development is not exempt from the robust dose selection discussions that are now standard for any oncology asset. Singh views this as a positive step. Adherence to Project Optimus is the right strategy to de-risk programs prior to a registrational design and is critical for patient safety, ensuring that the dosing for any treatment modality is robustly explored.

Regarding data requirements, the FDA is providing guidance on the necessity of integrating data from multiple distinct sources. For radiopharmaceuticals, this integration must include:

1. Dosimetry Data: This is unique to radiopharmaceuticals—Singh notes that you don't see it for oral or immunotherapy drug development. Dosimetry data quantifies the radioactive component of these assets, specifically calculating the absorbed radiation dose and exposure time for critical organs. The primary concerns are with potential long-term bone marrow and renal (kidney) toxicity.
2. Pharmacokinetic (PK) and Pharmacodynamic (PD) Data.
3. Clinical Data: Standard safety and efficacy endpoints.

One specific point of critique and ongoing discussion within the industry is how the FDA will weigh these different data sources. Specifically, there is debate about the relative importance of dosimetry data—which predicts organ exposure—vs the clinical data being generated on a patient-by-patient basis (ie, observed toxicity and efficacy).

Singh believes there is still some "swirl" or debate about where the FDA will ultimately place the weight, and this is a point that will likely be refined as more of these development programs mature and move through the regulatory process.