Study: Accelerated approval pathway working as intended in most cases

Regulatory NewsRegulatory News | 10 August 2022 |  By 

Over the last several decades, the US Food and Drug Administration’s (FDA) accelerated approval program has largely been working as it was designed to, with about half the products using the pathway being converted to traditional approvals, according to a recent analysis from a group of authors at Amgen published in Therapeutic Innovation & Regulatory Science.
About half of accelerated approval products went on to receive traditional approval at a median of 3.2 years, Ginny Beakes‑Read, JD, BSN, executive director of global regulatory and R&D policy at Amgen, and colleagues said, but this timeline has shortened to a median of 2.3 years within the last decade.
“The accelerated approval pathway is working effectively to accelerate patient access to treatments for serious or life-threatening diseases or conditions, sometimes when no other therapy exists,” Beakes‑Read and colleagues said.
In their analysis, the authors assessed 278 products or indications approved through the accelerated approval pathway between December 1992 and December 2021, noting the status of those converted to traditional approvals. Beakes‑Read and colleagues also looked at whether approvals were withdrawn, had pending confirmatory trials, pending approvals, dangling approvals or were delinquent approvals.
They found 139 accelerated approvals (50%) were converted to traditional approvals overall at a median of 3.2 years, with 51 of 167 accelerated approvals (30.5%) over the last decade converted to traditional approvals at a median of 2.3 years.
During the same period, 32 accelerated approvals (12%) were voluntarily or involuntarily withdrawn. The median time to withdrawal was 10.4 years for 6 products or indications between 1992 and 2001, a median of 9.7 years for 12 withdrawals between 2002 and 2011, and a median of 3.5 years for 14 withdrawals between 2012 and 2021. The authors attributed the significant decrease in time to withdrawal over the last decade to FDA using Oncologic Drug Advisory Committee (ODAC) meetings to decide if dangling accelerated approvals have a path forward to confirm clinical benefit.
Beakes‑Read and colleagues also found 107 accelerated approvals (38%) were still pending completion of confirmatory trials or awaiting FDA review of the trials; of these, 77 accelerated approvals were on the market for less than 3.2 years, while 30 accelerated approvals were pending for more than 3.2 years. Within these 30 pending accelerated approvals, 22 approvals were determined to be on time, either through original or revised milestones, 5 approvals were dangling, and 3 were considered delinquent.
“The small percentage of drugs whose clinical benefit is ultimately not confirmed should not be viewed as a failure of the accelerated approval program,” the authors wrote. “Rather, they represent an expected trade-off in expediting drug development that benefits patients with serious or life-threatening diseases.”
Addressing criticism of accelerated approval
Beakes‑Read and colleagues referenced the recent criticism of the accelerated approval pathway following several high-profile approvals of products under the pathway, such as Biogen’s Alzheimer’s disease treatment Aduhelm (aducanumab). The controversy prompted the US Department of Health and Human Services’ Office of Inspector General (OIG) to announce in August 2021 it was reviewing the policies and procedures associated with the pathway. (RELATED: FDA defends Aduhelm's accelerated approval, while others call for reform, Regulatory Focus 14 July 2021; HHS OIG to review FDA’s use of accelerated approval pathway, Regulatory Focus 4 August 2021)
FDA officials are also looking to international regulators for ways to align the accelerated pathway to more closely resemble the expedited approval process other global regulators use. (RELATED: FDA officials look outward to improve the expedited drug approval process, Regulatory Focus 31 January 2022)
Critics of the accelerated approval pathway have said the products approved through the pathway don’t always provide evidence of clinical benefit even after traditional approval, and confirmation trials can sometimes take just as long to complete as the pivotal clinical trials.
However, Beakes‑Read and colleagues noted the accelerated approval pathway has worked for most products and indications over the program’s lifespan.
“Concerns voiced recently about the program are based on a small number of examples, and do not reflect overall management of the accelerated approval program over its 30-year history, particularly improvements seen in the last decade in the time from accelerated approval to conversion,” they said.
There have been several suggestions on how to improve the accelerated approval program, including the use of real-world evidence, requiring post approval studies, giving FDA the authority to select post approval study endpoints that demonstrate clinical benefit, and a process to expedite the withdrawal of drugs from the market. (RELATED: Expert proposes changes to accelerated approval reforms in user fee bills, Regulatory Focus 08 June 2022; Health policy experts call for stronger accelerated approval reforms, Regulatory Focus 06 July 2022; Accelerated Approval: Experts weigh in on the role of RWE in confirmatory trials, Regulatory Focus 08 August 2022)
Beakes‑Read and colleagues said accelerated approval program changes made through legislation or other measures “should be based on cumulative experience, not outliers.”
“Any changes must be carefully crafted to avoid creating disincentives that would reduce access to life-saving treatments under the accelerated approval pathway,” they said.
Ther Innov Regul Sci Beakes‑Read et al.


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