FDA’s Project Optimus and Dose Optimization in Oncology Trials

FDA’s Project Optimus is changing how oncology doses are optimized. Rather than selecting doses based on efficacy above all else, the goal is to identify doses that maximize the overall benefit for patients.

One2Treat Insights uses Net Treatment Benefit to support this decision by integrating efficacy, safety, tolerability and other clinically relevant outcomes into a single, pre-specified analysis.

How One2Treat Insights supports FDA’s Project Optimus

One2Treat Insights enables sponsors to apply Net Treatment Benefit to dose optimization studies, providing a quantitative framework for comparing competing dose levels.

Using Generalized Pairwise Comparisons, the approach evaluates multiple outcomes simultaneously while preserving their clinical priority. This allows sponsors to assess trade-offs between outcomes, such as increased efficacy at a higher dose versus increased toxicity or reduced tolerability.

One2Treat Insights can help sponsors:

• Compare dose levels across multiple outcomes, including efficacy, safety, tolerability and patient-reported outcomes
• Identify the dose with the best overall benefit-risk profile, rather than automatically selecting the highest tolerated dose
• Quantify trade-offs between efficacy and toxicity using clinically prioritized outcomes
• Generate quantitative evidence for dose selection to support internal decision-making and regulatory discussions
• Apply a consistent analytical framework as the dose strategy evolves from early development through later-stage trials

What is FDA’s Project Optimus?

FDA’s Project Optimus is an initiative to improve dose optimization in oncology by identifying doses that maximize overall patient benefit, rather than simply selecting the maximum tolerated dose (MTD).

Sponsors are encouraged to evaluate efficacy, safety, tolerability and patient experience when selecting doses for later-stage clinical trials. This requires a more comprehensive understanding of dose-response relationships and the trade-offs between potential benefits and risks.

Why is the maximum tolerated dose no longer enough?

Many modern oncology therapies achieve similar efficacy across multiple dose levels, while higher doses may substantially increase toxicity.

Selecting the highest dose patients can tolerate therefore does not necessarily mean selecting the dose that provides the greatest overall clinical benefit.

Project Optimus encourages sponsors to consider the totality of the evidence when selecting a dose, including efficacy, safety, tolerability and patient experience.

From dose optimization to overall treatment benefit

Dose selection often requires balancing competing outcomes. A higher dose may produce greater tumor response but also more frequent or severe adverse events. A lower dose may provide similar efficacy with better tolerability.

Looking at each outcome separately can make these trade-offs difficult to quantify. Net Treatment Benefit provides a way to bring these outcomes together.

Using Generalized Pairwise Comparisons, NTB can compare dose levels across a hierarchy of clinically relevant outcomes. The result is a quantitative assessment of the overall treatment benefit associated with each dose, while preserving the clinical importance assigned to each outcome.

How does Net Treatment Benefit support FDA’s Project Optimus?

NTB complements traditional dose-response, exposure-response, PK/PD, efficacy and safety analyses by providing an integrated assessment of multiple clinically relevant outcomes.

A typical approach involves four steps:

• Define the outcomes
  • Identify the efficacy, safety, tolerability and patient-relevant outcomes that are important for dose selection.
• Prioritize the outcomes
  • Establish their clinical hierarchy before analyzing the results.
• Compare dose levels
  • Use Generalized Pairwise Comparisons to compare patients across the prioritized outcomes.
• Quantify Net Treatment Benefit
  • Determine the overall treatment benefit associated with each dose level.
    

Does Net Treatment Benefit replace traditional dose-response analyses?

No. Net Treatment Benefit complements traditional analyses rather than replacing them. Dose-response, exposure-response, PK/PD, efficacy and safety analyses remain important components of dose optimization.

NTB provides an additional integrated analysis that helps sponsors quantify the trade-offs between multiple outcomes when comparing dose levels.

What is One2Treat Insights?

One2Treat Insights is One2Treat’s GCP validated analytical platform for evaluating treatment benefit across multiple clinically relevant outcomes.

In dose optimization, it can be used to calculate Net Treatment Benefit across dose levels, integrating efficacy, safety, tolerability and other patient-relevant outcomes into a single, clinically interpretable analysis.

This helps sponsors understand the overall benefit-risk profile of competing doses and generate quantitative evidence to support evidence-based dose selection.

References:

• FDA’s Project Optimus
• Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases
• Generalized Pairwise Comparisons in Dose Optimization Oncology Trials: Beyond Safety to Multi-outcome Dose Selection. Alger E, Lin R, Lee JJ, Yuan Y, Yap C.
• Design of a clinical trial using generalized pairwise comparisons to test a less intensive treatment regimen. – Backer MD, Sengar M, Mathews V, et al.