Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study

BMJ. 2021 Sep 8;374:n1959. doi: 10.1136/bmj.n1959.


Objectives: To investigate the regulatory handling of cancer drugs that were granted accelerated approval by the US Food and Drug Administration (FDA) but failed to improve the primary endpoint in post-approval trials and to evaluate the extent to which negative post-approval trials changed the recommendations in treatment guidelines.

Design: Retrospective observational study.

Setting: FDA and National Comprehensive Cancer Network (NCCN) reports.

Included drugs: Cancer drugs that received accelerated approval from the FDA and had negative post-approval trials.

Main outcome measures: Regulatory outcomes, including withdrawal, conversion to regular approval, and no action.

Results: 18 indications for 10 cancer drugs that received accelerated approval but failed to improve the primary endpoint in post-approval trials were identified. Of these, 11 (61%) were voluntarily withdrawn by the manufacturer and one (bevacizumab for breast cancer) was revoked by the FDA. Of the 11 withdrawals, six occurred in 2021 alone. The remaining six (33%) indications remain on the label. The NCCN guidelines provide a high level of endorsement (category 1 endorsement for one and category 2A endorsement for seven) for accelerated approval drugs that have failed post-approval trials, sometimes even after the approval has been withdrawn or revoked.

Conclusion: Cancer drug indications that received accelerated approval often remained on formal FDA approved drug labelling and continued to be recommended in clinical guidelines several years after statutorily required post-approval trials showed no improvement in the primary efficacy endpoint. Clinical guidelines should better align with the results of post-approval trials of cancer drugs that received accelerated approval.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Databases, Factual
  • Disease-Free Survival
  • Drug Approval*
  • Drug Labeling
  • Endpoint Determination
  • Humans
  • Neoplasms / drug therapy*
  • Progression-Free Survival
  • Retrospective Studies
  • Safety-Based Drug Withdrawals / statistics & numerical data
  • Time Factors
  • Uncertainty
  • United States
  • United States Food and Drug Administration


  • Antineoplastic Agents