Evaluating the Impact of Increased FDA Drug Approvals Based on Single-Arm Clinical Trials

Results from randomized controlled trials (RCTs) are the standard in formulary planning and clinical decision-making; however, the focus on rare disease in RCTs presents the ethical concerns of withholding treatment from rare and vulnerable placebo arm populations. Single-arm trials (SATs) have risen in prominence in response which, together with the accelerated approval pathway of the U.S. Food and Drug Administration (FDA), have led to many agents being approved even after just a phase II trial. According to N. Yadav, PhD, and colleagues, this has resulted in “significant unanswered questions” for formulary management.

In their study, presented at AMCP 2022, the researchers quantified drugs approved by the FDA based on SATs and verified a “marked increase” in approvals year-over-year the majority of which “have been in rare and advanced cancers or both such as Mantle Cell Lymphoma (MCL), non-small cell lung cancer (NSCLC), and multiple myeloma (MM).”

The investigators identified and reviewed 318 new chemical entity and biologic agents approved between January 2015 and September 2021 in the FDA drug approval database. The pivotal trails that led to the approval of these drugs were then collected for analysis. Dr. Yadav reported that of the 318 drugs approved in the data period, 51 (16%) were approved based on the evidence of SATs. Of those, nearly half (n = 24; 46%) were approved after a phase II trial, while approximately one quarter were approved after phase III trials (n = 12; 23%). Notably, only five drugs were approved by the FDA in 2015 and 2016, whereas 10 and 14 drugs were approved in 2018 and 2020, respectively. Seven drugs had been approved by the end of the data period in 2021.

Overall, the study’s collaborators presented their findings as a first-step in describing “the growing increase in approval of drugs based on SATs for rare conditions and challenges faced by formulary decision makers on limited evidence.”