Summary authored by Nathaniel Robinson, MD

FDA and Oncology Product Development

Nathaniel Robinson, MD

Dr. Goulart gave a thorough explanation on the history, goals, workflow, and special programs of the FDA, particularly as it relates to oncology drug development. He started with a detailed history of how the FDA was born, based on the principle that “regulation follows innovation.” What started as a small organization of limited scope has, through a series of at times tragic events related to lack of oversight, grown into a far-reaching regulatory body with broad influence on the market of available medications. The FDA, as he notes, is primarily responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices; and by ensuring the safety of our nation’s food supply, cosmetics, and products that emit radiation. Very importantly, the FDA does not comment on drug prices, does not regulate medical practice, and provides approval for indications, not for drugs.

New oncology products are developed and initially submitted to the FDA as an Investigational New Drug, or IND, based on preclinical and clinical data demonstrating proof-of-concept and initial safety. These INDs are subject to regulatory review and are further developed with early-phase clinical trials when additional safety and activity data are collected. Once the IND is submitted, the FDA will review the data within 30 days and then decide whether the drug is considered “Safe-to-Proceed” to the next level of investigation or if it will require a “Clinical Hold.”

At this point, the IND is subject to further clinical trials, which are generally designed with close collaboration with the FDA. One of the biggest considerations is defining appropriate endpoints. While overall survival is considered a gold standard endpoint, both overall response rate and progression-free survival are considered “clinically intermediate endpoints.” The FDA will consider approval based on clinically intermediate endpoints if the benefit is large, or if they are associated with a significant benefit in patient-reported outcomes and thus are likely to provide clinically meaningful benefit. Once data is collected, a new drug application (NDA) for small molecules or Biologics License Application (BLA) for biologics is submitted to the FDA for approval. After a drug is approved, the FDA will continue post-market monitoring for adverse events and continue to collect safety data.

There are several expedited programs and approval pathways available to investigators with the FDA. Fast Track designation requires clinical or non-clinical data demonstrating the potential to address an unmet clinical need; the primary benefit is to allow for “Rolling Review,” which allows an investigator to submit data on a rolling basis for approval rather than having to wait for all data to be ready. Breakthrough Therapy designation requires clinical data demonstrating substantial improvement over available therapies based on clinical data, and allows for intensive development guidance, an organizational commitment from the FDA, as well as rolling review. Priority Review designation is granted with submission of an NDA or BLA and can be granted by the FDA without a request; this provides a 6 month, rather than a 10-month, review period for regulatory action after filing. Finally, Accelerated Approval, which is a pathway and not a designation, is considered for when a drug might show substantial benefit in a surrogate or intermediate clinical endpoint. It must be for a serious or life-threatening disease, might demonstrate substantial evidence of effectiveness, and assumes some risk that the safety or efficacy data might not be mature. Importantly, a confirmatory trial is required by law afteraccelerated approval is granted.