Project Optimus: Shifting the paradigm in oncology drug development

In recent years, the U.S. Food and Drug Administration (FDA) has frequently required sponsors to conduct post-marketing trials after approval. These studies or trials have often been completed to obtain additional information on the optimum dosage of a product where the maximum tolerated dose (MTD) had been used for pivotal trials, in addition to providing further insights into safety and efficacy. Project Optimus, introduced in 2021, is an initiative of the FDA’s Oncology Center of Excellence (OCE), aiming to reform the current dose optimisation and dose selection paradigm in early-phase oncology drug development and ultimately improve patient outcomes [1].

The initiative has been specifically designed to tackle the issue of the traditional approach to dose selection, often based on cytotoxic chemotherapy, not always suitable for targeted agents and immunological therapies. This can result in doses that are either too high, leading to unnecessary toxicity, or too low, not providing enough benefit to patients.

Project Optimus objectives

To achieve the overarching goal of the initiative, moving away from the traditional focus on MTD and towards selecting doses that maximise efficacy and minimise toxicity, Project Optimus has several specific objectives, including:

  • Education: The initiative aims to provide initial guidance and resources and set expectations for drug developers about the most appropriate dose-finding and dose-optimisation strategies through publications, workshops and other sources.
  • Innovation: Project Optimus is designed to promote the development and implementation of innovative dose-finding and dose-optimisation strategies that leverage both clinical and nonclinical data, including randomised dose evaluation in the early phases of clinical trials.
  • Collaboration: The project is expected to facilitate early discussions between drug developers and FDA Oncology Review Divisions to review dose-finding and optimisation strategies before conducting registration trials. Various stakeholders, including pharmaceutical companies, academia, professional societies, regulators and patients are invited to help establish a new paradigm that emphasises finding the optimal dose for each patient.

Project Optimus aims to prioritise patient safety by emphasising the importance of selecting doses that not only maximise efficacy but also ensure the safety and tolerability of new oncological drugs for patients. By achieving these goals, the initiative aims to improve the development and approval rate of safer and more effective cancer treatments.

By addressing MTD limitations and enhancing drug development efficacy, Project Optimus seeks to revolutionise the way cancer drugs are developed and dosed. Ultimately, this will enable developers to adapt to the evolving cancer landscape and maximise patient benefit, leading to improved quality of life and outcomes for patients fighting cancer.

Project Optimus challenges

Although the project represents a crucial step towards improving the safety and efficacy of cancer treatments, its implementation faces significant challenges. These include: 

  • Varying stakeholder awareness: The understanding and awareness of Project Optimus differ widely across the industry, with many organisations unsure of when to implement it into their research programmes, even though this is the right course of action.
  • The complexity of clinical trial design: Moving away from the traditional trial design to more advanced ones may prove difficult for some organisations that rely on 3+3 trial design and finding the MTD. This transition requires the adoption of complex methodologies, models and outcome evaluations.
  • Difficulty interpreting guidance: Guidance on certain aspects of the project, such as acceptable Bayesian Optimal Interval boundaries, can be challenging to interpret and act on, with organisations having to make careful evaluations on a case-by-case basis.

Overcoming these challenges requires industry stakeholders to collaborate and communicate openly and clearly. Sharing experiences helps refine strategies and guidelines for implementing Project Optimus. Despite these obstacles, Project Optimus is primed for success, holding promising benefits in improving the efficacy and safety of cancer treatments. The industry working together will ensure successful implementation, ultimately making a difference to patients’ outcomes and quality of life.

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References


1. https://link.springer.com/article/10.1007/s43441-023-00606-1

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