# New Serious Safety Warnings for Targeted Anticancer Agents After Their Initial FDA Approval

## TL;DR

This study shows that new serious safety risks for cancer drugs can appear years after approval, especially for small-molecule drugs.

## Contribution

The study reveals that new safety warnings for targeted anticancer agents continue to emerge years after FDA approval, particularly for small-molecule drugs.

## Key findings

- New serious safety warnings emerged in updated drug labels of targeted anticancer agents years after initial approval.
- Small-molecule targeted agents received significantly more new warnings compared to monoclonal antibodies.
- Time since approval was a significant predictor of new warnings and boxed warnings.

## Abstract

Knowledge about the tolerability of targeted anticancer agents can improve after their regulatory approval. In this study, we analyzed the emergence of new serious safety warnings in the updated drug labels of targeted anticancer agents that were marketed for at least 10 years. Additionally, possible predictors for their emergence were studied. We found that new serious safety warnings have continued to emerge several years after the initial approval of the targeted anticancer agents, especially small-molecule targeted agents. This research highlights a need for ongoing safety monitoring of targeted anticancer agents. Oncologists, regulators, and payers should be aware of the changing risk–benefit ratios of approved targeted anticancer agents.

Background: New safety concerns about targeted anticancer agents (TAAs) often emerge in the first few years after their initial regulatory approval. Our aim was to determine whether new serious and potentially fatal adverse drug reactions (ADRs) continue to emerge in the updated drug labels of TAAs several years after their initial regulatory approval and whether their emergence can be predicted. Methods: The updated drug labels of TAAs approved by the U.S. Food and Drug Administration before July 2013 were analyzed. Serious and potentially fatal ADRs were identified in the Warnings & Precautions (WPs) and Boxed Warnings (BWs) sections of the updated drug labels. Generalized linear mixed models were used to examine the associations between the number of adverse drug reactions and time, drug type (small molecules vs. monoclonal antibodies), and the availability of companion diagnostics for biomarkers. Results: Among 37 eligible TAAs, 25 (68%) were small molecules and 11 (30%) had available companion diagnostics for the biomarkers. Time was a significant predictor of new WPs (p ˂ 0.001) and BWs (p = 0.008). The updated drug labels of the small molecules received significantly more new WPs (p = 0.042) as compared to monoclonal antibodies. The availability of the companion diagnostics for the biomarkers did not have an impact on the emergence of new ADRs. Conclusions: New serious ADRs of TAAs continue to emerge in updated drug labels several years after their initial regulatory approval. Oncologists, regulators, and payers should be aware of the changing risk–benefit ratios of approved TAAs.