TOPLINE:

FDA reviewers flagged trial uncertainties for nearly 80% of cancer drugs approved from 2019 to 2022, but few were reported in journals or National Comprehensive Cancer Network (NCCN) guidelines.

METHODOLOGY:

• The FDA approves most new cancer drugs through expedited pathways, which often leave uncertainties about efficacy and safety, such as reliance on unvalidated endpoints, limited follow-up, or approval based on a single trial. Although the FDA describes these uncertainties in its risk-benefit assessments, clinicians rely on journal publications and clinical guidelines, making accurate reporting of uncertainties in these sources critical for informed prescribing.
• Researchers used Drugs@FDA to identify 52 cancer drugs approved by the FDA from 2019 to 2022. By April 2025, journal publications and NCCN guidelines had referenced 51 pivotal trials covering 48 of these drugs.
• The researchers examined FDA review documents to identify uncertainties related to primary outcomes of pivotal trials, focusing on those included in the FDA’s Benefit-Risk Framework, which the agency considers important to its decisions.
• The primary outcome was the proportion of uncertainties reported in publications and NCCN guidelines. The study also assessed whether drugs with more uncertainties had lower evidence ratings and consensus recommendations in the guidelines.

TAKEAWAY:

• FDA reviewers highlighted a total of 94 uncertainties for 38 (79.2%) cancer drugs. Journal publications reported only 22% (21 of 94) of the FDA-identified uncertainties, and NCCN guidelines cited only 23% (22 of 94).
• For nearly half of the drugs, journals (20 of 38) and NCCN guidelines (18 of 38) omitted all FDA-identified trial uncertainties.
• NCCN guidelines recommended 37% (14 of 38) of cancer drugs with category 1 evidence and 58% (22 of 38) with category 2A evidence, while they did not recommend 5% (2 of 38). The two drugs that were not recommended had the greatest number of trial uncertainties.

IN PRACTICE:

The findings suggested that “clinicians may be unaware of important clinical trial limitations identified by the FDA when making prescribing decisions,” the authors of the study wrote. “To improve transparency and clinical decision-making,” they concluded, “the FDA should make its benefit-risk assessments more accessible and user-friendly. Reporting guidelines should consistently require disclosure of key clinical trial uncertainties, and guideline developers should systematically incorporate FDA assessments into their recommendations.”

SOURCE:

The study, led by Avi Cherla, MSc, London School of Economics and Political Science in London, England, was published online in JAMA.

LIMITATIONS:

Some trials were published before drug approval and might not have reported uncertainties later identified by FDA reviewers. NCCN guidelines may have incorporated updated evidence published after approval that addressed some trial uncertainties.

DISCLOSURES:

The authors did not disclose any funding information. Several authors reported receiving grants or personal fees and having other ties with various sources. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.