A new study co-written by a University of Illinois Urbana-Champaign expert in operations management finds that drugs approved under the U.S. Food and Drug Administration's "Breakthrough Therapy Designation" - a program designed to expedite promising drug treatments to patients - are associated with a significantly higher number of serious adverse events after reaching the market.
The research also finds that one specific FDA safety monitoring mechanism can substantially offset the risk of adverse events, offering policymakers a clear path to improving patient safety while preserving easier access to innovative therapies, said Hanu Tyagi, a professor of business administration at Illinois.
"The Breakthrough Therapy Designation is something that's not going away, because it has proven clinical benefits," Tyagi said. "It's not without risk, but we can optimize it and make it safer, and that's what we set out to do in this paper."
The research was co-written by Rachna Shah of the University of Minnesota and published by the journal Production and Operations Management.
The Breakthrough Therapy Designation was created in 2012 to allow drugs showing early promise in treating serious or life-threatening conditions to move through the FDA approval process faster. The designation has since become an express lane for new drug approvals, particularly in the treatment of cancer.
While the program has been widely praised by patients and firms for accelerating access to new pharmaceuticals, questions have persisted about whether speed is coming at the expense of safety, Tyagi said.
"That criticism was the loudest during the COVID-19 vaccine approval process, and there was also a controversy with a drug that showed promise in slowing down Alzheimer's disease symptoms," Tyagi said. "All of this highlights the speed-safety tightrope that the FDA must walk when approving these potential breakthrough treatments. Obviously, you want to make the most innovative drugs available to patients as quickly as possible while also upholding the medical oath of 'Do no harm.'"
To address these concerns, the researchers examined more than 300 drugs approved by the FDA between 2012-19, tracking safety outcomes using data from the FDA's Adverse Event Reporting System. Drug safety was measured by the number of serious adverse events reported annually, such as events involving death, life-threatening conditions, hospitalization or permanent disability.
"We manually combed through thousands of pages of FDA drug application packets to determine what kind of information was reported, what kind of trials have been run," Tyagi said. "The quality of evidence that the FDA looks at to approve a drug was available to us, but it was buried deep within all this other information, so we had to do a lot of digging to tease out the information we needed."
After accounting for differences in drug characteristics, clinical trial design, sales volume and approval timelines, the researchers found that drugs approved under Breakthrough Therapy Designation experienced an average of 1,722 more serious adverse events per year than non-BTD drugs.
"This represents nearly three times the average annual serious adverse events associated with a typical drug," Tyagi said. "Faster access can deliver enormous benefits to patients, but it also increases uncertainty about safety once drugs are used more broadly in real-world settings."
The study then evaluated whether FDA monitoring tools can mitigate the safety risks associated with expedited approvals.
"Since eliminating the Breakthrough Therapy Designation is neither realistic nor desirable given its documented benefits for innovation and patient access, the study points to practical, evidence-based guidance for improving the program," Tyagi said.
In particular, the authors examined two widely used tools: "Risk Evaluation and Mitigation Strategies," which requires pharmaceutical companies and manufacturers to implement safety plans; and "Boxed Warnings," the FDA's strongest warning label, which alerts physicians and patients to serious risks in bold type on the packaging.
The researchers found that breakthrough-therapy drugs that were subject to REMS experienced approximately 875 fewer serious adverse events per year, cutting the safety gap nearly in half. By contrast, boxed warnings had no statistically significant effect on reducing serious adverse events for breakthrough-therapy drugs, according to the paper.
The findings suggest that safety measures such as REMS, which places the onus on firms and healthcare systems to manage risk, are far more effective than boxed warnings, which rely on prescribers and patients to change their behavior.
"The term 'breakthrough' can create strong expectations of a benefit," Tyagi said. "Warnings alone may not be enough when clinicians and patients think of a drug as transformative. Ultimately, structured safety programs, such as REMS, are much more effective."
Based on their findings, the researchers say that the FDA should consider requiring REMS for all drugs approved under Breakthrough Therapy Designation. Such a policy would preserve the speed and flexibility of the program while substantially improving postmarket safety.
"Our results show that the risks of expedited approval can be managed if the right tools are used," Tyagi said.
