Regulatory Considerations in the Development of Radiation-Drug Combinations.

Radiation therapy remains a fundamental treatment for patients with cancer. Despite an increasing number of targeted molecular therapies that are US Food and Drug Administration (FDA)-approved for the treatment of patients with metastatic disease, there has been very little progress made in terms of drugs used concurrently with radiation. This article reviews the existing regulatory framework in which cancer drugs may be developed for use in combination with radiation therapy from the perspective of the FDA. To briefly summarize: (1) nonclinical studies are a critical first step to ensure that drugs are safe for use in humans; however, additional nonclinical studies of a drug with radiation may not be required before a clinical trial in combination with radiation as long as the safety profile of the drug has been characterized in humans. The FDA determines the quality of evidence required before studying a drug in combination with radiation on a case-by-case basis. (2) Although often impractical to consider late toxicities during dose-escalation, late adverse events should be captured and taken into consideration when determining the final dose and schedule to take forward during drug development. (3) There are a number of expedited programs for cancer drug development, including accelerated approval, a conditional approval that allows for use of earlier clinical endpoints when the data suggests a clinically meaningful improvement over available therapy. (4) The Agency encourages sponsors to discuss their development plan with the appropriate FDA review division in formal regulatory meetings.