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

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 reco...

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Autores principales: Gyawali, Bishal, Rome, Benjamin N, Kesselheim, Aaron S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group Ltd. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424519/
https://www.ncbi.nlm.nih.gov/pubmed/34497044
http://dx.doi.org/10.1136/bmj.n1959
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author Gyawali, Bishal
Rome, Benjamin N
Kesselheim, Aaron S
author_facet Gyawali, Bishal
Rome, Benjamin N
Kesselheim, Aaron S
author_sort Gyawali, Bishal
collection PubMed
description 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 Of these, 11 (61%) were voluntarily withdrawn by the manufacturer and one (bevacizumab for breast cancer) was revoked by the FDA.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seven) for accelerated approval drugs that have failed post-approval trials, sometimes even after the approval has been withdrawn or revoked.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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spelling pubmed-84245192021-09-22 Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study Gyawali, Bishal Rome, Benjamin N Kesselheim, Aaron S BMJ Research 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. BMJ Publishing Group Ltd. 2021-09-09 /pmc/articles/PMC8424519/ /pubmed/34497044 http://dx.doi.org/10.1136/bmj.n1959 Text en © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Research
Gyawali, Bishal
Rome, Benjamin N
Kesselheim, Aaron S
Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study
title Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study
title_full Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study
title_fullStr Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study
title_full_unstemmed Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study
title_short Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study
title_sort regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424519/
https://www.ncbi.nlm.nih.gov/pubmed/34497044
http://dx.doi.org/10.1136/bmj.n1959
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