FDA New Therapy Approvals Are Based on Fewer Pivotal Trials

Audrey Zhang, AB

More recent US Food and Drug Administration (FDA) approvals of new therapies have been supported by fewer pivotal trials—and those trials have mostly featured less rigorous, longer trial durations.

New findings from a cross-sectional analysis of 273 drugs and biologics approved by the FDA in the last 3 decades show a shifting priority in pivotal efficacy trial makeup and federal standard for marketing approval. Investigators, led by Audrey D. Zhang, AB, and Joseph S. Ross, MD, MHS, believe their assessment shows a need for increased post-approval drug evaluations.

Zhang, an MD student at the New York University Grossman School of Medicine; Ross, of the Yale School of Medicine; and colleagues sought to understand the influence of the FDA Fast Track designation since its inception in 1988, as it led to the development of other streamlined and circumstantial pathways of regulatory approval for drug makers— Priority Review (1992), Accelerated Approval (1992), and Breakthrough Therapy Designation (2012).

Such pathways are influential in what the investigators call the FDA’s “flexible interpretation” of the required 2 pivotal trial findings in each new drug or biologic submission.

“As a result, the quantity and quality of evidence supporting recent drug approvals is variable, both in terms of the number of pivotal trials and their design features, such as randomization, blinding, choice of comparators and end points, number of treated patients, and trial duration,” they wrote.

To assess the influence of these pathways on the investigative makeup of New Drug Applications (NDAs) and Biologics License Applications (BLAs), the team examined the supporting evidence of approved applications from a trio of three-year periods coinciding with the implementation of the new pathways: 1995-1997, 2005-2007, and 2015-2017.

Therapies were classified by their product type and therapeutic area, as well as by their orphan designations and use of regulatory pathways. Pivotal trial parameters, per indication approval, included use of randomization, blinding, types of comparators, primary end points, numbers of treated patients, and trial duration.

Investigators observed 273 new drugs and biologics approved during the 3 periods: 107 (39.2%) in 1995-1997; 57 (20.9%) in 2005-2007; and 109 (39.9%) in 2015-2017. The observed drugs made up 339 indications across the 3 periods (157 [46.3%]; 64 [18.9%]; and 118 [34.8%], respectively).

The rate of new cancer-related drug approvals nearly tripled over the observed time period, making up 27.1% of the observed new indications from 2015-2017.

The proportion of approvals using ≥1 special regulatory pathway increased from one-third (34.6%) in 1995-1997 to two-thirds (64.2%) in 2015-2017. The proportion of indication approvals receiving an orphan designation tripled over the observed time period (12.7%; 26.6%; 38.1%).

The proportion of ≥2 aggregate pivotal trials supporting each indication approval decreased from 80.6% in 1995-1997, to 60.3% in 2005-2007, to 52.8% in 2015-2017 (P <.001). Predictably, the proportion of just 1 pivotal trial supporting each indication approval increased— from 4%, to 12.7%, to 17% (P = .001).

That said, the proportion of indications supported by ≥1 pivotal trial lasting 6 months increased from 25.8%, to 34.9%, to 46.2% (P = .001).

Investigators questioned whether these trends are driven by changes to baseline drug approval characteristics, or whether the standards needed to secure approval within these strata has evolved.

“Our findings suggest both explanations may play a role,” they wrote.

In a special report by HCPLive® on the rate of novel drug and biologic submissions and approvals in 2018, it was found that the rate of new molecular entity and BLA applications increased by 48% in 2017 than from its annual average since 2012.

The report also showed that the most common pivotal trial patient population sizes for FDA-approved novel therapy applications were 1-300 patients, 301-600 patients, and 3000-plus patients—showing the FDA pathways’ efforts to address both at-need rare disease patient populations, as well as major cardiometabolic and cancer populations.

The FDA provided a statement to HCPLive at the time of the report saying that the recent-years increase in novel drug submissions and approvals is due to the agency’s efforts to provide more information on the submission process, and their expectations as to what constitutes a market-worthy drug.

“An efficient and effective review process that allows for timely responses to FDA questions can help ensure timely patient access to safe, effective, and high quality new drugs and biologics,” the FDA stated at the time.

Zhang, Ross, and colleagues believed their findings show a shifting requirement—fewer pivotal trials are needed under expedited pathways, and longer duration trials compensate for less robust comparators.

“This change has implications for physicians and patients as they consider using newly approved drugs as well as for regulators, given that it suggests an increasing need for continued evaluation of therapeutic safety and efficacy after approval,” investigators concluded.

The study, “Assessment of Clinical Trials Supporting US Food and Drug Administration Approval of Novel Therapeutic Agents, 1995-2017,” was published online in JAMA Network Open.