FDA Weighs In on Optimal Drug Dosing

Oncology drug trials can and should move beyond finding the maximum dose a patient can tolerate and instead determine what is optimal, according to the FDA. The agency issued draft guidance in January to help drugmakers identify the proper dose while assessing safety and efficacy in early-phase trials (see https://www.fda.gov/media/164555/download).

“The impetus for the draft guidance is that for many cancer drugs, the dosage is inadequately characterized prior to FDA approval, which may expose patients to unnecessary toxicity,” says Mirat Shah, MD, with the agency's Center for Drug Evaluation and Research. “The consequences can be that the drug is poorly tolerated at the labeled dosage, preventing patients from starting or staying on a therapy that would otherwise be efficacious.”

For years, some people considered the purpose of phase I clinical trials to be to simply determine how much of a cancer drug patients can tolerate without it killing them. However, Mark Ratain, MD, of The University of Chicago in Illinois, noted that this outdated thinking mainly applies to some early cancer treatments and chemotherapies that have a strong dose–response relationship.

“That was appropriate for nitrogen mustard,” which was one of the main chemical compounds used in mustard gas during World War I. “It's not appropriate for drugs, such as sotorasib [Lumakras; Amgen], that are precisely targeted against a mutant protein [KRAS G12C for sotorasib] that's not expressed in any cells other than the cancer cells,” he says.

Ratain has been part of efforts to develop recommendations for dose optimization, aligned with Project Optimus, which Shah co-leads and that helped draft the guidance (see https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus).

Project Optimus is a multidisciplinary team of scientists with expertise in key aspects of drug dosing that assists the FDA's oncologic disease review divisions in implementing the recommendations to help pharmaceutical companies and researchers move away from the maximum tolerated dose (MTD) paradigm to an optimal dose model.

The draft guidance covers collecting and interpreting data, designing trials, monitoring safety, determining proper dose prior to approval, and potentially adjusting dosing for future indications.

“We recognize that these are broad recommendations and that the right strategy for dosage optimization may be different for different drugs,” says Shah.

The document does not discuss how to select a starting dose for first-in-human trials or dose optimization for radiopharmaceuticals, cellular and gene therapies, microbiota, or cancer vaccines.

Meanwhile, the FDA Oncology Center of Excellence (OCE) is working with drug manufacturers and clinical investigators to incorporate an optimal dosing approach in trials. The OCE has also convened a public workshop to provide specific recommendations to individual drug development programs. Project Optimus will also work with stakeholders in addressing scientific and policy questions to help implement the recommendations.

Both Shah and Ratain say the changes will benefit patients and pharmaceutical companies because establishing the optimal dose prior to FDA approval is much more efficient and cost-effective than needing to change it after approval—or, in some cases, having a drug pulled from the market. For example, the agency can rescind approval if it determines a drug's toxicity outweighs its benefit.

“Optimal dosing will help more patients and keep you from doing a phase III trial at a dose that the FDA at the end of the day says has too much toxicity,” says Ratain. –Aaron Tallent

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