Guide Seeks Dose Optimization in Cancer Drug Development
FDA has released a draft guidance entitled “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases,” which is intended to assist sponsors in identifying optimal dosage during clinical development and prior to submitting a marketing application.
The guidance appears to aim at shaking up dose-finding trials for oncology drugs that 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 agency says. However, it notes that “most modern oncology drugs, such as kinase inhibitors and monoclonal antibodies, are designed to interact with a molecular pathway unique to an oncologic disease(s) (i.e., targeted therapies),” and these therapies have different dose-response relationships compared to cytotoxic chemotherapy (e.g., doses below the MTD may have similar efficacy to the MTD, but fewer toxicities).
FDA’s guidance expresses concern that often the dosage administered in a registration trial is the MTD or the highest dosage administered in the dose-escalating trial if the MTD is not defined. “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,” it says. “The traditional MTD paradigm often does not adequately evaluate other data, such as low-grade symptomatic toxicities (i.e., grade 1-2), 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 dosage(s) and select the dosages to be further investigated based on clinical data and an understanding of dose- and exposure-response, represent a more informed approach to identify the optimal dosage(s).”
The guidance also says that dosage optimization prior to approval is recommended because delaying until after approval could expose large numbers of patients to a poorly tolerated dosage or one without maximal clinical benefit. “Furthermore, conducting clinical trials to compare multiple dosages may be challenging to complete once a drug is approved for a given indication.”
The guidance is reminiscent of challenges FDA oncology officials outlined last year (see story) with current PI3K inhibitors. Writing in the 4/14 online Lancet Oncology, FDA Oncology Center of Excellence director Richard Pazdur and other FDA officials dismissed the “current paradigm of using overall response rates in single-arm trials to support accelerated approvals,” and noted that “limited dose-exploration studies were conducted before choosing maximum or near-maximum tolerated doses for subsequent single-arm trials for accelerated approval. Although an exposure–response association exists for adverse events associated with drugs in this class, such an association for efficacy has not necessarily been observed.”
Additionally, the Pazdur article said that the safety concerns have led the officials to recommend a new “framework to re-examine drug development for hematological malignancies, especially those with long natural histories. First, careful dose selection through robust dose exploration should be advocated, preferentially via early randomized trials examining doses and the irrelative safety and efficacy. Patient-reported outcomes should be incorporated into this assessment. Further development of the four currently approved PI3K inhibitors should identify optimal doses as single agents or in combination.”