FDA Project Optimus: Selecting the Optimal Dose for Oncology Therapeutics

Across the spectrum of therapeutic indications, typically, the majority of new investigational drugs are evaluated in randomized dose-ranging clinical trials. These types of clinical trials enable a reasonable understanding of dose-response and exposure-response relationships and provide a rational basis for selecting the optimal dose in subsequent pivotal clinical safety and efficacy trials. In oncology however, fewer dose-finding investigations are traditionally conducted in early clinical development compared to other therapeutic indications. Additionally, oncology dose-finding studies are primarily focused on identifying the maximum tolerated dose (MTD). The MTD is defined as the highest dose of the drug that does not cause unacceptable side effects. This paradigm is predicated on the premise that the dose for oncology products should be set as high as possible to achieve the maximal tumor suppression. In essence, this means that the MTD is largely selected based on safety and tolerability considerations even though a lower dose may be effective. In the age of targeted therapeutic modalities, there is a consensus within the scientific community that the use of the MTD paradigm for oncology therapies is no longer an acceptable approach. The application of the MTD approach in dose selection for oncology products has resulted in the approval of doses that are much higher than the optimal dose level, which violates the FDA’s stated objective of approving the lowest safe and effective dose.

Maximum Tolerable Dose Approach

In a traditional Phase I clinical study design, patients are escalated to a dose that produces a set frequency of clinically relevant, but reversible, dose-limiting toxicity (DLT), which is what helps us determine the MTD. The MTD is the highest dose that most patients can tolerate, usually producing grade three or greater toxicity in less than 33% of patients. The MTD approach stems from the dose-response relationship traditionally seen with chemotherapeutics where more toxicity is associated with more antitumoral activity. However, newer oncology treatment modalities, such as molecular targeted-agents (MTAs) and immunotherapies, often have target saturation limits below the MTD. This suggests that these drugs can be administered at lower doses while achieving similar efficacy and potentially better safety and tolerability profiles relative to the MTD.

What is Project Optimus?

Project Optimus is an initiative being undertaken by the FDA’s Oncology Center of Excellence (OCE) and is intended to bring together various stakeholders from across the pharmaceutical sector including regulatory health authorities, pharmaceutical companies, researchers, and patients to craft a roadmap to guide dose selection for investigational oncology products during drug development. The main goal of this effort is to improve dose selection and the drug development process overall in the oncology space. While a formal guidance on dose-finding trial design for oncology products is not yet available, a white paper entitled “Optimizing Dosing in Oncology Drug Development” was released in 2021 by key representatives from the FDA, academia, patient advocates, and other pharmaceutical industry members. The white paper discusses:

  • current challenges to the implementation of dose-finding studies in oncology
  • opportunities to improve dosing strategies given ongoing challenges
  • expectations for dose-finding studies in the oncology pre-market setting
  • key considerations for selecting appropriate dose optimization strategies in oncology

How Will Project Optimus Effect Clinical Trials in Oncology Drug Development?

Project Optimus is not expected to drastically impact the operations of clinical trials in the oncology space. Nonetheless, it is anticipated that the addition of more dose-finding investigations could increase the costs and timelines of clinical development for some oncology programs. The biggest shift for oncology trials will be the changes to study design and study objectives for achieving an optimal dose. Ultimately, it will be oncology patients who stand to benefit the most from dose optimization with the potential for enhanced quality of life and improved benefit-risk profiles for upcoming products in the oncology pipeline.

Key Considerations for Dose Optimization Strategies

There are many important considerations that go into selecting the optimal dose during first-in-human (FIH) trials and subsequent clinical studies. A few considerations that are especially important for dose selection in oncology therapies include therapeutic properties, the patient population, and supplemental application vs. original submission.

Therapeutic Properties

The therapeutic properties of the drug will influence the selection of initial doses for the dose-finding studies and the methodology for the selection of the dose(s) to be advanced into additional registrational trials.

Patient Populations

Given the heterogeneity in patient populations based on tumor type, disease stage, and comorbidities, it will be pivotal to gain a comprehensive understanding of the various factors that influence drug efficacy and its utility in supporting the selected optimal dose.

Supplemental Application vs. Original Submission

Differences in disease characteristics and patient populations between tumor types and treatment settings (e.g., monotherapy vs. combination therapy) are critical to consider in determining whether any additional dose exploration is necessary for a supplemental application. Prior understanding of exposure-response from the approved original submission may be employed in the study design in situations where additional dose exploration is warranted.


A shift is underway from the use of conventional MTD approaches to improved dose selection strategies for oncology programs. With the help of the FDA’s Project Optimus, a new paradigm will be created that requires randomized studies that evaluate at least two dose levels to support dosing decisions. These studies will improve patient care in oncology by reducing toxicities while maintaining efficacy and ultimately allowing more patients to benefit from treatments for a longer period of time. The ultimate goal is to incorporate dose-finding studies into standard oncology drug development to allow delivery of safe, efficacious, and tolerable doses to patients at initial marketing approval of a new drug. The FDA encourages the pharmaceutical industry to seize this opportunity to work closely with the regulatory health authorities to ensure that all key stakeholders are aligned on the guidelines for the dose-finding design paradigm to ensure a path towards approval. Establishing appropriate dosing regimens to maximize safety and efficacy requires expert analysis of a drug’s pharmacokinetics (PK) and pharmacodynamics (PD). Nuventra is now part of Allucent, who are experts in clinical trial management with decades of experience designing and executing clinical trials in oncology. Allucent’s team of scientists are experts in dose selection, which can be especially challenging for oncology programs. Contact us to learn more about our wide range of services and experience with oncology programs.

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