FDA finalizes guidance on dose optimization studies for cancer drugs

The US Food and Drug Administration (FDA) on Thursday finalized guidance to assist sponsors in finding the right dosage for the newer class of cancer drugs. The agency announced that the update stresses there is no “one size fits all approach” in dosing for these drugs.

FDA said that dose-finding trials for oncology drugs have historically been designed to assess the maximum tolerated dose (MTD), yet this approach is now outdated. The older drugs were cytotoxic, had limited drug target specificity, and patients and providers were willing to accept “substantial” toxicity due to the lack of effective alternatives. Modern oncology drugs, such as kinase inhibitors and antibodies, are developed to interact with a molecular pathway critical to the disease that show different dose-response relationships compared to the traditional cytotoxic compounds.

The guidance addresses the collection of dose optimization strategies, including the collection and interpretation of clinical pharmacokinetic, pharmacodynamic, and pharmacogenetics data, designing trials to compare multiple dosages, safety and reliability, the drug formulation, and subsequent indications and uses of the medicine.

The agency said the guidance complements the International Conference on Harmonisation’s (ICH) E4 guidance on Dose-Response Information to Support Drug Registration issued in November 1994.

The finalized version revises the draft guidance issued in January 2023; the agency received 22 comments on the draft version. (RELATED: NCI official raises concerns about FDA’s cancer drug dose optimization guidance, Regulatory Focus 21 March 2023; FDA details approach for finding optimal doses for new cancer drugs, Regulatory Focus 17 January 2023).

FDA said in a notice that “changes from the draft to the final guidance include emphasis on FDA's availability to provide product-specific advice since there is not a one size fits all approach and clarity on the collection and analysis of key pharmacologic data. In addition, editorial changes were made to improve clarity.”

The finalized version accommodates a comment raised by Novartis and others that the guidance takes a cookie-cutter approach to dosage selection for these drugs. The company said that “dose exploration and eventual dose selection is multifaceted and should not be a ‘one size fits all approach.’”

The revised text in the guidance’s section III on dosage optimization recommendations states that “FDA recognizes that the best approach to determining the optimized dosage(s) for a specific drug development program depends upon a variety of factors including but not limited to the drug class, proposed indicated patient population, and prior knowledge about the drug that is pertinent to dosing. Sponsors are therefore strongly encouraged to discuss their plans for dosage optimization with FDA during formal meetings, including early in clinical development.”

The guidance also includes new text in the background section on the traditional MTD dosing approach, revises the text in the section on trial design to compare multiple dosages, and adds new text in the safety and tolerability section.

This guidance does not address selecting starting dosages for first-in-human trials, dosing for radiopharmaceuticals, cellular and gene therapy products, oncolytics, microbiota, or cancer vaccines, and does not address pediatric drug development.

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FDA finalizes guidance on dose optimization studies for cancer drugs

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