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Historically, oncology drug development followed a straightforward principle: identify the highest dose patients could tolerate without unacceptable side effects, then use that dose in subsequent trials and clinical practice. This maximum tolerated dose (MTD) approach made sense for traditional cytotoxic chemotherapies, where higher doses often increased both toxicity and tumor response. The belief, supported by early evidence, was that more drug equaled more efficacy.
For decades, this "more is better" mindset defined dose selection strategy across the industry. However, as cancer treatments evolved to include targeted therapies, immunotherapies, and other novel mechanisms, this correlation between maximum dose and maximum benefit began to show limitations. Many of these newer treatments exhibit a plateau effect—a point at which increasing the dose no longer enhances efficacy but still heightens the risk of toxicity.
Recognizing the need for a more refined approach, the FDA launched Project Optimus in 2021. This initiative encourages a shift away from MTD-based strategies and toward identifying optimal doses—those that achieve the right balance of efficacy, safety, and long-term tolerability—ultimately improving patient outcomes and supporting more rational drug development.
👉 FDA's New Direction
Project Optimus changes the historical paradigm. Rather than defaulting to the highest tolerable dose, the FDA now encourages sponsors to identify the optimal dose – one that balances efficacy and safety. This shift requires more comprehensive dose-finding studies earlier in development.
Key elements of the Project Optimus principles include:
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Exploring multiple doses to understand the dose-response relationship
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Using randomized, parallel-arm designs in early development phases
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Evaluating both safety and preliminary efficacy across different dose levels within a single indication
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Collecting data over longer treatment periods, not just during initial cycles
This evolution reflects recognition that exposing patients to unnecessarily high doses of cancer therapies can lead to:
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Treatment discontinuations due to adverse events
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Dose reductions and interruptions that compromise efficacy
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Decreased quality of life that may not be justified by marginal benefits
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Challenges in combining therapies due to overlapping toxicities
👉 Impact on Clinical Trial Design
The practical implications of Project Optimus are significant. Rather than find the MTD through a simple dose escalation design, sponsors are now encouraged to:
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Consider multiple dose levels: Multiple dose levels should be considered during dose escalation and expansion, with the objective of estimating measures of safety and efficacy with precision.
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Conduct randomized dose comparisons: Even in Phase 1/2, sponsors should consider randomizing patients to different dose levels to enable direct comparisons and selection of an optimal dose.
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Enroll adequate patients per dose level: While not powered for statistical significance, studies should include enough patients (typically 10-20 per dose) to characterize the exposure-response relationship at multiple dose levels.
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Look beyond initial dosing cycles: Toxicities and efficacy signals emerge over time, so assessment should extend beyond traditional DLT windows.
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Integrate PK/PD and biomarker data: Objective measures of drug exposure and target engagement help build a more complete picture of the dose-response relationship.
As Kyle McBride, Vice President of Biostatistics Consulting, explained during the discussion: "Under Project Optimus, the question isn't how many patients do we need to power this study. These dose-finding studies don't need to be powered for statistical significance. What they need is enough patients per arm to observe clear trends in safety, tolerability, and early efficacy."
Dose optimization is a vital component of clinical development planning under the Project Optimus paradigm; however, the timing of such investigations is not strictly defined. Multiple study designs and timing options are acceptable during early development. While dose optimization doesn't need to be the first study a sponsor conducts, it should be prioritized early in the clinical development program to align with Project Optimus expectations and maximize efficiency. Sponsors may benefit from incorporating dose optimization assessments into Phase 1 or Phase 1/2 trials to streamline development and support robust dose selection.
👉 Real-World Evidence Supporting the Shift
This change isn't purely theoretical. Real-world evidence increasingly shows that the MTD often exceeds what's necessary for optimal treatment. Several approved oncology drugs have undergone post-approval dose optimization studies showing that lower doses maintain efficacy while reducing toxicity.
For example, multiple tyrosine kinase inhibitors have had their recommended doses reduced after approval based on real-world evidence of excessive toxicity. Similarly, some immunotherapy agents have shown equivalent efficacy at lower doses or with less frequent administration.
Real-world data has proven to be a powerful asset in supporting Project Optimus. In cases like immunotherapy, post-approval evidence has shown that lower doses can still achieve the same efficacy observed in clinical trials—challenging traditional assumptions and reinforcing the importance of optimizing, not maximizing, dose.
👉 Implications for Drug Developers
For sponsors developing oncology drugs, Project Optimus requires a shift in both strategy and mindset:
Early Planning: Dose optimization should be considered from the start of development, not as an afterthought.
Regulatory Engagement: Early meetings with FDA are vital to align on dose exploration strategies before pivotal studies.
Cross-Functional Approach: Successful dose optimization requires input from clinical, statistical, pharmacological, and regulatory experts.
Resource Allocation: More complex early-phase studies require greater investment but may prevent costly late-stage failures or post-approval dose changes.
Patient-Centric Focus: Optimizing dose means prioritizing not just tumor response but also quality of life and ability to stay on treatment.
👉 Moving Forward: A Balanced Approach
Project Optimus doesn't mean abandoning the concept of dose-response or ignoring the importance of ensuring adequate drug exposure. Rather, it promotes a more nuanced, evidence-based approach to dose selection that considers both efficacy and toxicity.
As oncology drug development enters this new era of more deliberate, data-driven dose selection, sponsors are being challenged to rethink traditional strategies. Project Optimus is not just a regulatory shift—it’s a call to elevate how we define therapeutic success. At Veristat, we are helping sponsors navigate this complexity with cross-functional expertise in clinical strategy, biostatistics, regulatory science, and real-world evidence. By designing smarter trials from the start, we can identify doses that are not only effective, but truly tolerable—bringing better therapies to patients, faster.