Studies Highlight Concerns About Accelerated Approval Pathway

The FDA’s accelerated approval pathway has become an increasingly popular way for drugmakers to get novel medications to market. However, the strength of clinical evidence from studies supporting these accelerated approvals is not always high.

Through the accelerated approval pathway, the FDA allows new drugs to come to market that treat serious conditions, based on pivotal trials that use surrogate endpoints or intermediate clinical endpoints that are “reasonably likely” to predict the clinical benefit. Between 2015 and 2022, 159 drug-indication pairs received accelerated approval. Three pairs were excluded due to absence of the product label or FDA review documents in the Drugs@FDA database. Among the remaining 156 approved drug-indication pairs, 77% were supported with evidence from single-arm pre-approval pivotal studies — trials that had no comparators — and 22% from Phase I trials, according to a recent study published by the BMC Medicine journal. The median number of participants in those trials was 92.

Additionally, 61% of the post-approval confirmatory studies were required by the FDA to use randomized controlled trials and 25% had to use clinical endpoints.

During the study period, the drug-indication pairs approved via the accelerated approval pathway almost tripled from 20 (2015–2016) to 59 (2019–2020) but then fell to 36 (2021–2022). The strength of clinical evidence supporting the FDA’s accelerated approvals declined significantly from 2015 to 2020 — as there was a sharp increase in single-arm pre-approval studies and a nearly 50% decrease in the number of participants in these studies. But the strength of clinical evidence supporting accelerated approvals leveled off or bounced back from 2021 to 2022. The researchers suggested that more measures should be taken to improve the accelerated approval pathway.

Another study, published on JAMA Network in April, revealed a similar conclusion after studying only oncology drugs that received accelerated approval. The researchers studied a total of 129 cancer drug-indication pairs receiving accelerated approval from 2013 to 2023. Among 46 indications with more than five years of follow-up, fewer than half (43%) demonstrated a clinical benefit in confirmatory trials, which are post-approval clinical trials measuring a clinical endpoint to confirm a drug’s effectiveness. About 63% of the studied drugs were converted to regular approval, 22% were withdrawn from the market and 15% remained without a definitive outcome. Of the 29 indications converted to regular approval, 69% demonstrated a clinical benefit.

In addition, for the 10 withdrawn indications, the time between accelerated approval and withdrawal decreased from 9.9 years to 3.6 years during the study period. For the 29 indications converted to regular approval, the time between accelerated approval and conversion to regular approval increased from 1.6 years to 3.6 years.

This infographic was reprinted from AIS Health’s biweekly publication Radar on Drug Benefits.