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Pink Sheet — Premarket Dose Optimization Precedent In Oncology Likely Not Available Yet

Pink Sheet — Premarket Dose Optimization Precedent In Oncology Likely Not Available Yet

The current class of oncology drug approvals may not be the best example of the US Food and Drug Administration’s evolving approach to dose optimization policy.

Agency officials began pushing oncology sponsors more than a year ago to change from looking for the maximum tolerated dose to finding the optimal dose prior to approval.

Because Project Optimus, the name of the FDA Oncology Center of Excellence’s initiative, is still relatively new, the latest oncology approvals may not have been able to fully embrace the new approach.

Julie Bullock, senior VP and global head of clinical pharmacology and translational medicine at Certara and former team leader on the hematology/oncology review team in the FDA Office of Clinical Pharmacology, which is in the Center for Drug Evaluation and Research, said precedent based on the new standard has not necessarily been set yet.

“I tell my clients quite a bit that regulatory lag is real and that you can’t use current approvals sometimes as good precedent,” Bullock said on 14 November during the Friends of Cancer Research Annual Meeting. “The drugs that are in the IND stage that are usually the ones that are confidential are the ones that should be setting the precedent.”

The issue emerged in response to a question about the FDA’s flexibility in evaluating postmarket dose optimization trials. Mirat Shah, a lead for Project Optimus and a lead physician in the FDA’s Office of Oncologic Diseases, which is in the CDER Office of New Drugs, said during the conference that some scenarios may warrant additional dosage work regardless of Project Optimus, but suggested they would be exceptions to the rule.

“We of course understand that Project Optimus started at one point in time and there were products that were in a more advanced state of development when Project Optimus was being implemented,” she said. “Additionally, there might be programs that attempt dosage optimization prior to drug approval, but there are lingering questions that need to be addressed in the postmarketing setting.”

“In both of those situations, we could envision that there might be a postmarketing requirement for further dosage optimization,” Shah added. “But that’s not really the goal. Our goal is for the dosage to be optimized at the time of drug approval.”

Pediatric development may raise more questions about premarket dose optimization. Some Oncologic Drugs Advisory Committee members said postmarketing trials may be an ideal way to optimize pediatric doses.  (Also see “Project Optimus For Kids: US FDA Aims To Improve Dosage Optimization For Pediatric Cancer Drugs” – Pink Sheet, 20 Jul, 2023.)

The idea for Project Optimus emerged in 2021 to support the FDA philosophy that more of a drug is not always better for patients and that the oncology dosing paradigm needed to change.  (Also see “US FDA’s ‘Project Optimus’ Will Encourage Move Away From Conventional Dose-Finding For Modern Cancer Therapies” – Pink Sheet, 26 May, 2021.)

Guidance was released in January that recommended more thorough dosage characterization earlier in development.  (Also see “No Excuses: US FDA Wants Early, Thorough Dosage Optimization For Cancer Drugs” – Pink Sheet, 18 Jan, 2023.)

Premarket Dose-Finding Challenges Remain, But Expected

As part of the effort to optimize oncology drug dosing prior to approval, FOCR convened stakeholders to explore strategies for early phase trial data interpretation to optimize dosing.

The resulting white paper described three points in the process where decisions can be made, as well as how premarket evidence could be considered.

The authors concluded that more studies supporting data extrapolation and best practices for interpreting the data to select an optimal dose are needed. They also said stakeholders should share information to help develop aligned recommendations for data collection and analysis.

Sponsors Adopting Premarket Approach

Shah said stakeholders should not expect the process to be easy.

“It’s important to keep in mind that we are trying to change the way something has been done for many decades so of course it’s expected that there would be challenges,” she said.

But Shah said oncology sponsors already are beginning to incorporate the new policy into their development programs.

“Over the past year, we are seeing many, many more development programs paying attention to drug dosing very early in development,” she said. “Over the next few years we really will be getting to a place where many oncology drugs have dosages optimized at the time of approval.”

Project Optimus launched with single-agent therapies, but OCE Director Richard Pazdur has said combination products also will be subjected to the premarket dose optimization expectation.  (Also see “Project Optimus Is Coming To Cancer Combination Therapy Development” – Pink Sheet, 12 Sep, 2023.)