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Observational Study
. 2021 Sep 8:374:n1959.
doi: 10.1136/bmj.n1959.

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

Bishal Gyawali  1   2 , Benjamin N Rome  2 , Aaron S Kesselheim  2
Affiliations
Observational Study

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

Bishal Gyawali et al. BMJ. .

Abstract

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 Of these, 11 (61%) were voluntarily withdrawn by the manufacturer and one (bevacizumab for breast cancer) was revoked by the FDA.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seven) for accelerated approval drugs that have failed post-approval trials, sometimes even after the approval has been withdrawn or revoked.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.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support for the study from Arnold Ventures; ASK is principal investigator on a grant from the FDA to Brigham and Women’s Hospital on an unrelated topic; BG has received consulting fees from Vivio Health, outside the submitted work; BNR has received a grant from Anthem Public Policy Institute and personal fees from Blue Cross Blue Shield of Massachusetts, outside the submitted work; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
Timeline showing dates of accelerated approval, announcement of negative results from confirmatory trials, and regulatory action, if any. Note that pembrolizumab for PDL1+ gastro-oesophageal cancer and nivolumab for hepatocellular cancer were subsequently voluntarily withdrawn by industry in July 2021. AML=acute myeloid leukaemia; CLL=chronic lymphocytic leukaemia; NSCLC=non-small cell lung cancer; SCLC=small cell lung cancer; TNBC=triple negative breast cancer
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