FDA, ASCO propose principles for proper dosing in cancer drug development

The US Food and Drug Administration (FDA) and the American Society of Clinical Oncology (ASCO) have laid out several principles for cancer drug developers to ensure more nuanced dosing. The principles are intended to help sponsors develop drugs that are better tolerated by patients who otherwise might suffer from long-term exposure and toxicity.

Historically, cancer drugs have used the maximum tolerated dose (MTD) or the highest dosage administered in the dose-escalation regimen if an MTD isn’t stated. However, using MTD when determining the proper dosage has significant side effects, including increased toxicity and intolerability for patients. To address the issue, FDA and ASCO held public workshops in 2022 and 2023, and based on stakeholder feedback, have proposed five drug dosing principles that cancer drug developers should consider in a paper published on 24 July.

“At the health system level, the use of MTD and the failure to optimize dosage can derail entire drug development programs,” said FDA and ASCO. “It may lead FDA to not approve an efficacious drug because of excess toxicity, to require label revisions in the postmarket setting, or to remove a drug or indication from the market.

“It is in the interest of pharmaceutical manufacturers to avoid suboptimal dosages and subsequent excessive toxicities, which can lead prescribers to choose alternative therapies for patients and/or abandon use of the drug in their patients,” they added.

To come up with better dosing for cancer drugs, FDA and ASCO have proposed five principles that drug sponsors should consider using. First, they propose collecting and using more expansive patient safety and tolerability data. They said that more expansive safety data could include the type and frequency of adverse events (AE) data, timing of the AEs, and collecting data on lower-grade toxicities.

FDA and ASCO also proposed that sponsors should tailor their drug development plans to the characteristics of the drug and the intended patient population.

"It is important for dosage optimization plans to include a sufficient number of patients to allow for characterization of the dosage-response and exposure-response relationships for both safety and activity; these relationships may be assessed either directly or through surrogates for response,” said the authors. “Investigators and sponsors can base plans on known drug characteristics, including the molecule or agent type, nonclinical dose-response curves for the development candidate and similar therapeutics, target engagement, therapeutic index, safety and tolerability profile, the patient population (eg, older adults v younger populations), and the frequency of the disease.”

They noted that sponsors should consider that current dosage finding study designs tend to use small cohorts of patients, which limits the ability to understand dosage-response relationships. However, different patient traits, such as race, age, and genetics, can affect the dosage response. They also added that trial eligibility criteria can impact the intended patient population, and patient subpopulations may respond to the drug differently.

Another principle that FDA and ASCO have proposed is for sponsors to use modern trial designs when generating data dosage.

“The modern drug development paradigm in oncology should recognize that the MTD is not necessarily the optimal dose and should incorporate both efficacy and safety in choosing an optimal dose,” said the authors. “In the absence of strong nonclinical evidence that the dosage-response relationship does not plateau, the primary goals of modern phase I trials should be determining a range of dosages.”

They noted that this may be achieved by using model-based or model-assisted trial designs followed by dose ranging studies.

FDA and ASCO recommended that sponsors use expanded eligibility criteria in dosage optimization trials so that the post-market results can be more generalizable. They note that some patients may be excluded from the clinical trial for several reasons, such as age, comorbidities, and organ function, that may limit the generalizability of the dosage optimization findings.

Finally, FDA and ASCO proposed that sponsors expand and refine their clinical pharmacology analyses. They emphasized that understanding the drug's pharmacodynamics is critical, which requires a full assessment of the relationships of its dosage and exposure with its efficacy and toxicity.

“While detailed pharmacokinetic studies are traditionally performed as part of phase I trials, population pharmacokinetic studies—including longitudinal assessment in the setting of chronic oral dosing—can also be considered in the context of randomized dosage-ranging phase II studies,” said the authors. “This would enable a clear assessment of exposure-response and exposure-toxicity relationships and evaluation of the magnitude of intraindividual variability, which may affect the therapeutic index of the drug.

“The Division of Pharmacometrics at the FDA can advise on situations in drug development when there is sparse pharmacokinetic sampling and the use of pharmacometric approaches could fill gaps in knowledge,” they added.

ASCO article

FDA, ASCO propose principles for proper dosing in cancer drug development

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