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Regulatory Scientific Advice on Non-Inferiority Drug Trials

The active-controlled trial with a non-inferiority design has gained popularity in recent years. However, non-inferiority trials present some methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how a non-inferiorit...

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Autores principales: Wangge, Grace, Putzeist, Michelle, Knol, Mirjam J., Klungel, Olaf H., Gispen-De Wied, Christine C., de Boer, Antonius, Hoes, Arno W., Leufkens, Hubert G., Mantel-Teeuwisse, Aukje K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764030/
https://www.ncbi.nlm.nih.gov/pubmed/24040346
http://dx.doi.org/10.1371/journal.pone.0074818
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author Wangge, Grace
Putzeist, Michelle
Knol, Mirjam J.
Klungel, Olaf H.
Gispen-De Wied, Christine C.
de Boer, Antonius
Hoes, Arno W.
Leufkens, Hubert G.
Mantel-Teeuwisse, Aukje K.
author_facet Wangge, Grace
Putzeist, Michelle
Knol, Mirjam J.
Klungel, Olaf H.
Gispen-De Wied, Christine C.
de Boer, Antonius
Hoes, Arno W.
Leufkens, Hubert G.
Mantel-Teeuwisse, Aukje K.
author_sort Wangge, Grace
collection PubMed
description The active-controlled trial with a non-inferiority design has gained popularity in recent years. However, non-inferiority trials present some methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how a non-inferiority trial should be conducted. Moreover, in a scientific advice procedure, regulators give companies the opportunity to discuss critical trial issues prior to the start of the trial. The aim of this study was to identify potential issues that may benefit from more explicit guidance by regulators. To achieve this, we collected and analyzed questions about non-inferiority trials posed by applicants for scientific advice in Europe in 2008 and 2009, as well as the responses given by the European Medicines Agency (EMA). In our analysis we included 156 final letters of advice from 2008 and 2009, addressed to 94 different applicants (manufacturers). Our analysis yielded two major findings: (1) applicants frequently asked questions ‘whether’ and ‘how’ to conduct a non-inferiority trial, 26% and 74%, respectively, and (2) the EMA regulators seem mainly concerned about the choice of the non-inferiority margin in non-inferiority trials (36% of total regulatory answers). In 40% of the answers, the EMA recommended using a stricter margin, and in 10% of the answers regarding non-inferiority margins, the EMA questioned the justification of the proposed non-inferiority margin. We conclude that there are still difficulties in selecting the appropriate methodology for non-inferiority trials. Straightforward and harmonized guidance regarding non-inferiority trials is required, for example on whether it is necessary to conduct such a trial and how the non-inferiority margin is determined. It is unlikely that regulatory guidelines can cover all therapeutic areas; therefore, in some cases regulatory scientific advice may be used as an opportunity for tailored advice.
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spelling pubmed-37640302013-09-13 Regulatory Scientific Advice on Non-Inferiority Drug Trials Wangge, Grace Putzeist, Michelle Knol, Mirjam J. Klungel, Olaf H. Gispen-De Wied, Christine C. de Boer, Antonius Hoes, Arno W. Leufkens, Hubert G. Mantel-Teeuwisse, Aukje K. PLoS One Research Article The active-controlled trial with a non-inferiority design has gained popularity in recent years. However, non-inferiority trials present some methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how a non-inferiority trial should be conducted. Moreover, in a scientific advice procedure, regulators give companies the opportunity to discuss critical trial issues prior to the start of the trial. The aim of this study was to identify potential issues that may benefit from more explicit guidance by regulators. To achieve this, we collected and analyzed questions about non-inferiority trials posed by applicants for scientific advice in Europe in 2008 and 2009, as well as the responses given by the European Medicines Agency (EMA). In our analysis we included 156 final letters of advice from 2008 and 2009, addressed to 94 different applicants (manufacturers). Our analysis yielded two major findings: (1) applicants frequently asked questions ‘whether’ and ‘how’ to conduct a non-inferiority trial, 26% and 74%, respectively, and (2) the EMA regulators seem mainly concerned about the choice of the non-inferiority margin in non-inferiority trials (36% of total regulatory answers). In 40% of the answers, the EMA recommended using a stricter margin, and in 10% of the answers regarding non-inferiority margins, the EMA questioned the justification of the proposed non-inferiority margin. We conclude that there are still difficulties in selecting the appropriate methodology for non-inferiority trials. Straightforward and harmonized guidance regarding non-inferiority trials is required, for example on whether it is necessary to conduct such a trial and how the non-inferiority margin is determined. It is unlikely that regulatory guidelines can cover all therapeutic areas; therefore, in some cases regulatory scientific advice may be used as an opportunity for tailored advice. Public Library of Science 2013-09-05 /pmc/articles/PMC3764030/ /pubmed/24040346 http://dx.doi.org/10.1371/journal.pone.0074818 Text en © 2013 Wangge et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wangge, Grace
Putzeist, Michelle
Knol, Mirjam J.
Klungel, Olaf H.
Gispen-De Wied, Christine C.
de Boer, Antonius
Hoes, Arno W.
Leufkens, Hubert G.
Mantel-Teeuwisse, Aukje K.
Regulatory Scientific Advice on Non-Inferiority Drug Trials
title Regulatory Scientific Advice on Non-Inferiority Drug Trials
title_full Regulatory Scientific Advice on Non-Inferiority Drug Trials
title_fullStr Regulatory Scientific Advice on Non-Inferiority Drug Trials
title_full_unstemmed Regulatory Scientific Advice on Non-Inferiority Drug Trials
title_short Regulatory Scientific Advice on Non-Inferiority Drug Trials
title_sort regulatory scientific advice on non-inferiority drug trials
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764030/
https://www.ncbi.nlm.nih.gov/pubmed/24040346
http://dx.doi.org/10.1371/journal.pone.0074818
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