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FDA Project Optimus from a Medical Writing Submission Lead Perspective

At Certara, we work across a spectrum of therapeutic areas, and, as Regulatory and Medical Writing specialists, we are used to seeing the evaluation of drug doses in early-phase, dose-ranging clinical studies. These studies ultimately enable those of us working on regulatory submissions to get the required understanding of dose-response and exposure-response (ER) relationships  and provide a sensible and rational basis for justifying the optimal dose for a drug. It’s easy, right? (Dosing section in eCTD Module 2.7.3; done!)

What about in the oncology space where there has been a paucity of early-phase, dose ranging studies? The oncology field is challenging and complex; there may be very narrow therapeutic windows, drug resistance, and obviously, an urgency to deliver drugs to patients in need of them. The maximum tolerated dose (or MTD) approach has, historically speaking, completely dominated the oncology dose‐finding paradigm. For dose selection for cytotoxic agents, this MTD approach works. Seeking the MTD is based on the underlying assumption that the higher the dose, the greater the likelihood of efficacy (and toxicity). Dose‐limiting toxicities (DLTs) are predefined in these phase I dose escalation trials, and, based on the DLT criteria, the dose is escalated until the MTD is reached, usually under a classic 3+3 study design (Figure 1).


Figure 1. The typical MTD-driven approach to oncology dosing

But when was the last time you worked on a project for a cytotoxic agent (or at least one without an immune therapy combination arm)? The last few decades have seen an explosion of novel modalities in molecular targeted and immune therapies in oncology drug development. Simply put, finding the right dose for the right patients in targeted and immuno-oncology is extremely challenging.

The MTD design was due to be challenged and has been over the past decade, prompting the FDA’s Oncology Center of Excellence to develop “Project Optimus.” This program aims to address the issues related to dose-optimization in clinical trials that you have started worrying about when writing Phase 3 protocols and Biologics License Applications (BLA) for non-cytotoxic oncology treatments.

FDA’s Project Optimus aims to create a new paradigm; randomized studies that evaluate at least two dose levels to support dosing decisions. This requires changes to the 3+3, MTD-driven study design and study objectives for achieving an optimal dose by replacing 3+3 MTD oncology Phase 1 studies with true dose-finding studies in the development of new, non-cytotoxic oncology agents. The goal is to improve patient care in oncology by reducing toxicities, and mitigating dose modifications and drug holidays, while maintaining efficacy and ultimately allowing more patients to benefit from treatment for a longer period.

At Certara, we partner with our clients, and advocate close contact with the regulatory health authorities to ensure that all key stakeholders are aligned on the guidelines for the dose-finding designs to ensure a path towards approval.  In the meantime, without the backing of Project Optimus-driven dosing studies, we will need to leverage advanced PK/PD exposure-response and physiologically-based PK (PBPK) modeling approaches, non-clinical data, and competitor/class data for our dose rationales. This collaboration will help bridge the gap until trial-tested, dose-finding designs have demonstrated the best doses and regimens for these new classes of oncology agents. To learn more about what oncology drug developers should expect from the FDA’s Project Optimus, please watch this webinar given by my colleague, Dr. Julie Bullock.


What Oncology Drug Developers Should Expect from the FDA’s Project Optimus


About the author

Claire Dyer
By: Claire Dyer

Claire Dyer is a director of submissions and medical writer with experience in multidisciplinary clinical, academic, and corporate environments. She has 20 years of experience in clinical development, including 15 years in medical writing and experience with global marketing applications for both biologics and small molecules, as well as for Investigational New Drug (IND) and Clinical Trial Authorisation (CTA) applications. Claire has led submission teams, including project management, writing submission level documents as well as training and mentoring of junior writers. Her interest in the field of oncology has continued since her PhD in adoptive T cell therapy for lymphoma.

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