Postmarket Drug Safety Timelines Largely Unchanged After FDA Amendments Act

A cross-sectional analysis of nearly 2 decades of US drug approvals challenges assumptions about the long-term impact of the 2007 FDA Amendments Act (FDAAA) on postmarket drug safety oversight.1

Despite granting the FDA enhanced authority to mandate postmarketing studies, revise safety labels, and enforce active surveillance, the FDAAA was not associated with statistically significant differences in the overall time to the first postmarket safety–related action for novel therapeutics.

The FDAAA did not significantly change overall time-to-action trends. | Image credit: Tada Images – stock.adobe.com

These findings were published in JAMA Internal Medicine amid continued scrutiny of accelerated regulatory pathways and the FDA’s growing reliance on postmarket data to manage safety risks.1,2

First Safety Action Was Sooner but Not Significantly

The analysis included 560 novel drugs and biologics approved between 2001 and 2019, with follow-up through 2024.1 Across the full cohort, nearly a quarter of therapeutics (23.2%) underwent at least 1 postmarket safety–related action, such as withdrawals, incremental boxed warnings, or safety communications, with a median follow-up of 12.1 years. Safety-related withdrawals remained uncommon at 1.4%, but incremental boxed warnings and safety communications affected 14.5% and 13.8% of therapeutics, respectively.

Although the FDAAA was designed to strengthen risk monitoring, the study found no statistically significant difference in time to first safety action for drugs approved after the law took effect (time ratio, 0.40; 95% CI, 0.15-1.07; P = .07).

Earlier Actions Within First 5 Years

The FDAAA did not change overall time-to-action trends, but meaningful differences emerged when researchers focused on safety actions occurring within the first 5 years after approval.

Among the 91 therapeutics with early safety events, median time to first action was 3.1 years pre-FDAAA vs 1.8 years post-FDAAA (P = .004), reflecting earlier regulatory response after implementation. Within the study’s context, the authors said, this finding indicates the enhanced safety-related regulatory authorities of the FDAAA were effective. However, they emphasized that the study was not designed for causal inference and that other time-varying factors may have contributed.

“For example, orphan designation was associated with longer times to first postmarket safety-related action, consistent with prior research, illustrating the challenge of detecting postmarket safety concerns when products are used by relatively small patient populations,” they noted. “Similarly, both fast track and breakthrough therapy designation were associated with shorter times to first postmarket safety-related action, consistent with prior research.”

Because these pathways and accelerated approvals allow the FDA to authorize drugs based on more limited evidence—such as single pivotal trials or studies relying on surrogate end points—the findings underscore the importance of strengthened postmarket surveillance for products cleared through expedited regulatory mechanisms, which are increasingly common in the US drug pipeline.

“Nevertheless, FDAAA introduced defined timelines for negotiation of labeling changes and gave FDA the authority to mandate changes if agreement was not reached—a mechanism that did not exist prior to FDAAA that could account for earlier safety-related actions,” the authors said.

Why Were Some FDA Safety Actions Faster Than Others?

The analysis also examined 260 therapeutics approved post-FDAAA after the 2013 introduction of breakthrough therapy designation. Several drug and regulatory characteristics were associated with time to first postmarket safety–related action:

• Small molecule drugs had shorter times to safety actions than biologics (time ratio, 0.24; P = .02)
• Breakthrough therapy (time ratio, 0.10; P < .001) and fast track designation (time ratio, 0.22; P = .005) were associated with faster safety actions
• Prolonged regulatory review (> 400 days) was also associated with shorter times (time ratio, 0.16; P = .02)
• FDAAA-mandated postmarket study requirements at approval were linked to faster safety-related actions (time ratio, 0.35; P = .01)
• Orphan-designated therapeutics had significantly longer times to first safety action (time ratio, 8.29; P < .001), consistent with challenges in detecting safety signals in small populations

References

1. Doernberg H, Wallach JD, Jeffery MM, Mooghali M, Ramachandran R, Ross JS. Postmarket drug safety-related actions before and after the US Food and Drug Administration amendments act. JAMA Intern Med. Published online December 8, 2025. doi:10.1001/jamainternmed.2025.6566
2. Caffrey M. OIG report seeks better oversight, records for FDA’s accelerated approvals. February 3, 2025. Accessed December 9, 2025. https://www.ajmc.com/view/oig-report-seeks-better-oversight-records-for-fda-s-accelerated-approvals