Despite criticism stemming from contentious biomarkers and failed confirmatory trials, the FDA’s accelerated approval pathway continues to drive therapeutic innovation for some of the world’s most complex and pressing medical challenges.
A History of Impact
Introduced in 1992 during the HIV/AIDS epidemic, the accelerated approval program aimed to address urgent unmet needs. Roche’s Hivid became the first drug approved under the pathway, paving the way for over a decade of groundbreaking HIV treatments. All early antiretrovirals approved through this pathway successfully transitioned to full approval without market withdrawals.
Far from being a shortcut, the program reflects strategic pragmatism, according to Ultragenyx CEO Emil Kakkis. “It would have taken too long to run trials with traditional endpoints, and too many people would have had to get sick and die,” Kakkis explained.
Accelerated Approval in Oncology
The 21st century saw accelerated approval widely adopted in oncology. While high-profile withdrawals, such as Takeda’s Exkivity for lung cancer and TG Therapeutics’ Ukoniq for leukemia, have drawn criticism, the program’s success rate outweighs its failures. Of the 133 accelerated approvals granted for cancer treatments, 106 have demonstrated clinical benefit, with only 30 withdrawn, according to the FDA.
Recent Controversies
High-profile controversies have fueled debate over the pathway’s validity. In 2021, the FDA approved Biogen and Eisai’s Aduhelm, the first disease-modifying Alzheimer’s treatment, despite a near-unanimous advisory committee recommendation against it. The decision hinged on the reduction of amyloid beta plaque in the brain—a debated surrogate biomarker for Alzheimer’s efficacy—and led to the resignation of three advisory committee members.
In June 2023, Sarepta Therapeutics’ Elevidys for Duchenne muscular dystrophy (DMD) gained accelerated approval based on increased micro-dystrophin protein levels. However, skepticism intensified when the therapy failed to meet its primary endpoint in a confirmatory trial just four months later.
The Role of Surrogate Endpoints
Central to these debates is the use of surrogate endpoints—biomarkers that are “reasonably likely” to predict clinical benefit. For Aduhelm, amyloid beta plaque reduction was a contentious marker, with critics arguing that no definitive link to clinical outcomes had been established. Similarly, Elevidys relied on micro-dystrophin levels, despite limited evidence of their functional role in DMD.
In contrast, biomarkers tied to the root cause of rare genetic diseases, such as those used in DMD and other monogenic disorders, are considered more reliable than downstream markers in complex diseases like Alzheimer’s or ALS.
The Broader Impact
While the pathway’s limitations are evident, its proponents emphasize the therapeutic momentum it generates. By providing earlier access to treatments, it incentivizes research and development in areas with significant unmet needs. This is particularly critical for rare diseases and life-threatening conditions where traditional drug development timelines are unfeasible.
As advancements in biomarker science evolve, the accelerated approval pathway remains a powerful—albeit imperfect—tool for fostering innovation and addressing medical challenges that would otherwise remain unmet.
