USA — The US Food and Drug Administration (FDA) has issued a draft guidance to help sponsors identify the optimal dosage for cancer drugs in clinical development and in it, the agency recommends a new approach in selecting such dosages for modern, targeted oncology drugs, RAPS news reports.
Historically, dose-finding trials for cytotoxic chemotherapy drugs have been designed to determine the maximum tolerated dose (MTD).
This approach of ‘maximum tolerated dose’ is now being challenged in the United States. Officials at the FDA’s Oncology Center of Excellence (OCE) are concerned that the side effects of some cancer drugs are so toxic that patients stop taking them, writing in a 2021 New England Journal of Medicine editorial that “less is more” sometimes.
That editorial came after the OCE’s Project Optimus, which encourages drug companies to find cancer drug doses that balance tolerability and efficacy.
Around the same time, as part of its accelerated approval of the lung cancer drug sotorasib, the FDA requested that Amgen conduct an additional clinical trial at a lower dose — 240 milligrams per day instead of 960 milligrams per day — with the goal of making the lower dose the default.
The FDA has requested that a report on the findings of this study be submitted by February 2023.
The MTD paradigm applies to drugs that have a steep dose response, have limited drug target specificity, and involve the willingness of patients and providers to accept substantial toxicity to treat serious, life-threatening diseases.
Yet this approach may not be a match for modern oncology drugs, including kinase inhibitors and monoclonal antibodies, which are designed to interact with a molecular pathway unique to an oncologic disease.
FDA states that “these targeted therapies demonstrate different dose-response relationships compared to cytotoxic chemotherapy, such that doses below the MTD may have similar efficacy to the MTD but with fewer toxicities.”
The MTD paradigm “can result in a recommended dosage that is poorly tolerated, adversely impacts functioning and quality-of-life, and moreover, affects a patient’s ability to remain on a drug and thereby derive maximal clinical benefit.”
“Additionally, patients who experience adverse reactions from one treatment may have difficulty tolerating future treatments, especially if there are overlapping toxicities.”
FDA said dose-finding trials that investigate a range of dosages “represent a more informed approach” to identify the optimal dosage.
The agency recommends that sponsors collect and interpret clinical pharmacokinetic, pharmacodynamic, and pharmacogenomic data in selecting the optimal dose.
The guidance states that “dose-finding trials should include pharmacokinetic (PK) sampling and an analysis plan such that PK data are of sufficient quality and quantity to allow an adequate characterization of the PK (e.g., linearity, absorption, elimination) of an oncology drug following the administration of multiple dosages.”
Multiple dosages should be compared in clinical trials to assess activity, safety, and tolerability and to decrease uncertainty with identifying optimal dosages.
Clinical trials should enroll a broad population to allow accurate assessment of the dosages across relevant subpopulations.
To assess safety and tolerability of the dose, sponsors should have pre-specified safety monitoring rules in place to monitor serious adverse reactions.
“The protocol should clearly state what action will be taken if the percentage of dosage modifications or serious adverse reactions is too high,” states the guidance.
“Such actions may include pausing the trial so the safety monitoring committee can review these events, changing the starting dosage for future patients, and/or discontinuing the trial.”
The guidance does not address selecting starting doses for first-in-human trials nor does it address dose optimization for radiopharmaceuticals, cell and gene therapy products, microbiota, or cancer vaccines.
The guidance complements an International Council for Harmonization (ICH) E4 guidance on the dose-response information when identifying the optimal dosage, which was adopted in March 1994.