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Oncologists see relevance to US FDA guidance on optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases. The guidance is intended to assist sponsors in identifying the optimal dosages during clinical development and prior to submitting an application for approval for a new indication and usage.
The regulator noted that this guidance should be considered along with the International Conference on Harmonisation (ICH) E4 guidance on Dose-Response Information to Support Drug Registration when identifying the optimal dosages. It does not address selection of the starting dosage for first-in-human trials nor does it address dosage optimization for radiopharmaceuticals, cellular and gene therapy products, microbiota, or cancer vaccines.
Dose-finding trials which are studies that include dose-escalation and dose-expansion portions with the primary objective of selecting the recommended phase II dose for oncology drugs have historically been designed to determine the maximum tolerated dose (MTD). This paradigm was developed for cytotoxic chemotherapy drugs based on their observed steep dose-response, their limited drug target specificity, and the willingness of patients and providers to accept substantial toxicity to treat a serious, life-threatening disease.
The MTD was identified by evaluating stepwise, increasing doses in a small number of patients at each dose for short periods of time. This was until a pre-specified rate of severe or life-threatening dose-limiting toxicities (DLTs) was observed.
According to Kidwai Memorial Institute of Oncology a state government optimizing the dosage of human prescription drugs is the critical for cancer drug administration. Several reactions manifest too.
Most modern oncology drugs, such as kinase inhibitors and monoclonal antibodies, are designed to interact with a molecular pathway unique to an oncologic disease or targeted therapies. These demonstrate different dose-response relationships compared to cytotoxic chemotherapy, such that doses below the MTD may have similar efficacy but with fewer toxicities.
Additionally, the MTD may never be reached in certain situations. Compared to, for example, cytotoxic chemotherapies, patients may receive targeted therapies for much longer periods, potentially leading to lower grade but persistent symptomatic toxicities, which can be more challenging to tolerate over time.
Nevertheless, the dosage administered in a registration trials designed to evaluate safety and effectiveness. This 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.
The traditional MTD paradigm often does not adequately evaluate other data, such as low-grade symptomatic toxicities, dosage modifications, drug activity, dose- and exposure response relationships, and relevant specific populations defined by age, organ impairment, concomitant medications or concurrent illnesses.
Dose-finding trials that investigate a range of dosages to be further investigated based on clinical data and an understanding of dose and exposure-response. Despite therapeutic progress, most advanced cancers remain incurable, and patients continue to have high unmet medical need for effective and tolerable therapies. Rapid access to safe and efficacious therapies remains critical. Some oncology development programs follow a seamless approach, characterized by rapid transitions between initial dose-finding trials and registration trials to expedite development.
Dosage optimization prior to approval is recommended because delaying until after approval may result in large numbers of patients being exposed to a poorly tolerated dosage or one without maximal clinical benefit.
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