FDA’s Project Optimus and the Shift in Dose Selection for Oncology Therapeutics: An Update

Across various therapeutic areas, randomized dose-ranging trials are the norm for determining the optimal dose of investigational drugs. However, oncology drug development has long relied on identifying the maximum tolerated dose (MTD), which often leads to doses higher than necessary for efficacy. With the emergence of targeted therapies and immunotherapies, this approach has shown its limitations, prompting the FDA to introduce Project Optimus, a new framework aiming to refine dose selection during oncology drug development.

The FDA’s recent guidance on dose optimization (August 2024) encourages sponsors to integrate robust dose-finding studies earlier in the drug development process. The focus is shifting from the traditional MTD to a more precise determination of the Optimal Biologic Dose (OBD). This approach seeks to balance efficacy with a manageable safety profile, which is especially important for therapies like molecular targeted agents (MTAs) and immunotherapies that often reach target saturation below the MTD. This ensures that treatments are both effective and have fewer side effects, improving the overall benefit-risk profile for patients.

Key Updates from the FDA’s Guidance:

1. Early Phase Dose Exploration: Sponsors should explore a broader range of doses earlier in clinical trials, assessing both efficacy and safety. Dosages in a clinical trial should be supported by data appropriate to the stage of development. Relevant nonclinical and clinical data, e.g. pharmacokinetic (PK), pharmacodynamic (PD), safety, tolerability, dosage convenience and activity) and dose- and exposure-response relationships should be evaluated to select dosing for clinical trials.
2. Optimal Dose Rather Than Maximum Dose: The guidance discourages setting doses based solely on safety (MTD) and encourages consideration of efficacy and tolerability.
3. Focus on Patient-Centric Outcomes: By optimizing dosing, patients experience fewer severe side effects, leading to better quality of life while maintaining therapeutic effectiveness.
4. Randomized Dose-Ranging Trials: The new paradigm will require randomized studies that evaluate at least two dose levels to better support dose optimization during drug development.

In addition, the FDA recommends a variety of efforts to identify optimal dosages:

Clinical Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics

• Include PK sampling and analysis plans in each protocol
• Consider a sampling and analysis plans for pharmacodynamic (PD) and pharmacogenomics data
• Initiate Population PK analysis early as additional data become available to identify specific populations in which the PK demonstrate clinically meaningful differences in exposure
• Evaluate dose- and exposure-response relationships early
• Consider PK, PD, Population PK, dose-response and exposure-response analysis with other data to select dosing for each clinical trial
• Explore additional dosing strategies such as a priming dose and intra-patient dose escalation/de-escalation
• Evaluate the impact of PK, PD, safety, and activity if intrinsic factors are relevant in a given indication
• For oral drugs, evaluate the effect of food on PK and safety early in drug development
• Evaluate the potential for drug interactions with concomitant medications

Trial Designs to Compare Multiple Dosages

• Compare multiple dosages in a trial that’s designed to assess antitumor activity, safety, and tolerability
• Design trials that are randomized and parallel dose-response to compare multiple dosages
• Compare multiple dosages to a registration trial (or as part of a registration trial) by adding additional dosage arms

Safety and Tolerability

• Compare safety and tolerability when selecting dosages for further evaluation or as the recommended dose
• Pre-specify trial stopping rules for excessive toxicity
• Assess frequency and impact of persistent symptomatic adverse reactions, as they may significantly affect patients’ ability to remain on a drug for extended periods
• Evaluate alternative dosing strategies, such as titration, to improve tolerability
• Consider including patient-reported outcomes (PRO) to enhance assessment of tolerability in dose-finding (and subsequent) trials
• Engage with patients and other stakeholders to solicit input on important safety, tolerability, and dosage convenience considerations

Drug Formulation

• Plan various dose strengths to allow for the evaluation of multiple dosages
• Consider the appropriateness of the size and number of tablets/capsules when selecting the final dosage form and regimen
• For parenteral use, consider the appropriateness of the final concentration and volume

Subsequent Indications and Dosages

• Consider relevant nonclinical and clinical data along with established dose- and exposure-response relationships when selecting the proposed dosages to be evaluated
• Use quantitative approaches to support selected dosages for evaluation
• Conduct additional dose-finding if sufficient relevant data are not available to support proposed dosages

What Does This Mean for Clinical Trials?

The FDA’s guidance under Project Optimus suggests more comprehensive and data-driven dose-finding studies, particularly for newer treatment modalities. Although this may increase the complexity and cost of clinical trials, the long-term benefits for patients and the approval of more effective, safer treatments are substantial. Oncology developers must now design their trials to prioritize not just the maximum tolerated dose, but the dose that provides the optimal balance of safety and efficacy.

Impact on Drug Development and Approval

This initiative will encourage early engagement between pharmaceutical companies and regulatory authorities to ensure that the doses selected for pivotal trials are thoroughly evaluated. This evolution in dose selection methodology will likely lead to more refined treatments being approved, which could allow for improved patient outcomes in the oncology space.

At Allucent, we specialize in supporting oncology programs through the integration of pharmacokinetics (PK), pharmacodynamics (PD), and expert trial design. Our team of experienced scientists is well-versed in the challenges of dose selection in oncology, and we are ready to assist your drug development efforts in line with these new regulatory expectations.