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The Use of External Controls in FDA Regulatory Decision Making

The regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials that typically use a valid comparison to an internal concurrent control. However, when it is not feasible or ethical to use an inter...

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Autores principales: Jahanshahi, Mahta, Gregg, Keith, Davis, Gillian, Ndu, Adora, Miller, Veronica, Vockley, Jerry, Ollivier, Cecile, Franolic, Tanja, Sakai, Sharon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8332598/
https://www.ncbi.nlm.nih.gov/pubmed/34014439
http://dx.doi.org/10.1007/s43441-021-00302-y
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author Jahanshahi, Mahta
Gregg, Keith
Davis, Gillian
Ndu, Adora
Miller, Veronica
Vockley, Jerry
Ollivier, Cecile
Franolic, Tanja
Sakai, Sharon
author_facet Jahanshahi, Mahta
Gregg, Keith
Davis, Gillian
Ndu, Adora
Miller, Veronica
Vockley, Jerry
Ollivier, Cecile
Franolic, Tanja
Sakai, Sharon
author_sort Jahanshahi, Mahta
collection PubMed
description The regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials that typically use a valid comparison to an internal concurrent control. However, when it is not feasible or ethical to use an internal control, particularly in rare disease populations, relying on external controls may be acceptable. To better understand the use of external controls to support product development and approval, we reviewed FDA regulatory approval decisions between 2000 and 2019 for drug and biologic products to identify pivotal studies that leveraged external controls, with a focus on select therapeutic areas. Forty-five approvals were identified where FDA accepted external control data in their benefit/risk assessment; they did so for many reasons including the rare nature of the disease, ethical concerns regarding use of a placebo or no-treatment arm, the seriousness of the condition, and the high unmet medical need. Retrospective natural history data, including retrospective reviews of patient records, was the most common source of external control (44%). Other types of external control were baseline control (33%); published data (11%); and data from a previous clinical study (11%). To gain further insights, a comprehensive evaluation of selected approvals utilizing different types of external control is provided to highlight the variety of approaches used by sponsors and the challenges encountered in supporting product development and FDA decision making; particularly, the value and use of retrospective natural history in the development of products for rare diseases. Education on the use of external controls based on FDA regulatory precedent will allow for continued use and broader application of innovative approaches to clinical trial design, while avoiding delays in product development for rare diseases. Learnings from this review also highlight the need to update regulatory guidance to acknowledge the utility of external controls, particularly retrospective natural history data.
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spelling pubmed-83325982021-08-20 The Use of External Controls in FDA Regulatory Decision Making Jahanshahi, Mahta Gregg, Keith Davis, Gillian Ndu, Adora Miller, Veronica Vockley, Jerry Ollivier, Cecile Franolic, Tanja Sakai, Sharon Ther Innov Regul Sci Review The regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials that typically use a valid comparison to an internal concurrent control. However, when it is not feasible or ethical to use an internal control, particularly in rare disease populations, relying on external controls may be acceptable. To better understand the use of external controls to support product development and approval, we reviewed FDA regulatory approval decisions between 2000 and 2019 for drug and biologic products to identify pivotal studies that leveraged external controls, with a focus on select therapeutic areas. Forty-five approvals were identified where FDA accepted external control data in their benefit/risk assessment; they did so for many reasons including the rare nature of the disease, ethical concerns regarding use of a placebo or no-treatment arm, the seriousness of the condition, and the high unmet medical need. Retrospective natural history data, including retrospective reviews of patient records, was the most common source of external control (44%). Other types of external control were baseline control (33%); published data (11%); and data from a previous clinical study (11%). To gain further insights, a comprehensive evaluation of selected approvals utilizing different types of external control is provided to highlight the variety of approaches used by sponsors and the challenges encountered in supporting product development and FDA decision making; particularly, the value and use of retrospective natural history in the development of products for rare diseases. Education on the use of external controls based on FDA regulatory precedent will allow for continued use and broader application of innovative approaches to clinical trial design, while avoiding delays in product development for rare diseases. Learnings from this review also highlight the need to update regulatory guidance to acknowledge the utility of external controls, particularly retrospective natural history data. Springer International Publishing 2021-05-20 2021 /pmc/articles/PMC8332598/ /pubmed/34014439 http://dx.doi.org/10.1007/s43441-021-00302-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Review
Jahanshahi, Mahta
Gregg, Keith
Davis, Gillian
Ndu, Adora
Miller, Veronica
Vockley, Jerry
Ollivier, Cecile
Franolic, Tanja
Sakai, Sharon
The Use of External Controls in FDA Regulatory Decision Making
title The Use of External Controls in FDA Regulatory Decision Making
title_full The Use of External Controls in FDA Regulatory Decision Making
title_fullStr The Use of External Controls in FDA Regulatory Decision Making
title_full_unstemmed The Use of External Controls in FDA Regulatory Decision Making
title_short The Use of External Controls in FDA Regulatory Decision Making
title_sort use of external controls in fda regulatory decision making
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8332598/
https://www.ncbi.nlm.nih.gov/pubmed/34014439
http://dx.doi.org/10.1007/s43441-021-00302-y
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