Does Project Optimus Apply to Radiopharmaceuticals?

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officer at Precision for Medicine and former director of the Division of Oncology 2, US FDA, discusses the FDA's new draft guidance on radiopharmaceutical dosing and its relation to Project Optimus.

The FDA recently issued a draft guidance focusing on dosing for radiopharmaceuticals. The publication of this guidance is a response to an ongoing need from the drug development community for a firmer understanding of the FDA’s regulatory expectations as these novel agents are being developed for cancer indications.

This effort traces back to Project Optimus, a framework and guidance put forth by the FDA's Oncology Center of Excellence (OCE) in 2021. Singh notes she was with the OCE for nearly 10 years. Project Optimus has since generated a great deal of discussion and shifting in how companies and drug developers operationalize their early-stage clinical trials.

The fundamental shift under Project Optimus was moving away from the classic sequential dose-escalation design aimed at establishing the maximum tolerated dose (MTD). Instead, the framework called for sponsors to adopt a more holistic, data-driven approach to dosing, particularly for chronic oral therapies. The goal became identifying an optimal dose—one that may not be the highest or most toxic, but that balances efficacy with safety, potentially allowing patients to stay on the drug longer.

At the time of Project Optimus’s initial launch, radiopharmaceuticals were not a key modality in oncology. There had only been a few regulatory approvals. Dr. Singh mentioned she personally oversaw the approval of lutetium Lu 177 dotatate (Lutathera) for neuroendocrine tumors. Since then, the field has seen the approval of blockbusters like lutetium Lu 177 vipivotide tetraxetan (Pluvicto) for prostate cancer, which she describes as a transformative drug.

In recent years, the FDA has seen a significant influx of radioligands and radiotherapeutics coming forward. As a result, the development community has sought clear regulatory frameworks, advice, and strategies for these agents.

The central question that this new draft guidance addresses is: Does Project Optimus apply to radiopharmaceuticals?

The classic paradigm under Project Optimus involves shifting from MTD-finding to a design where sponsors study 2, or sometimes 3, doses in a more robust and contemporaneous fashion during early development. The data from this comparative approach is then used to select the dose to move forward into pivotal trials. The radiopharmaceutical guidance essentially addresses whether this dose-selection framework fits the unique profile of radiopharm agents.

Watch more with Dr Singh.