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:	Grace Wangge, Michelle Putzeist, Mirjam J Knol, Olaf H Klungel, Christine C Gispen-De Wied, Antonius de Boer, Arno W Hoes, Hubert G Leufkens, Aukje K Mantel-Teeuwisse
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/41f4581e6bd243c9827bd962f70ffa8c
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spelling	oai:doaj.org-article:41f4581e6bd243c9827bd962f70ffa8c2021-11-18T08:56:36ZRegulatory scientific advice on non-inferiority drug trials.1932-620310.1371/journal.pone.0074818https://doaj.org/article/41f4581e6bd243c9827bd962f70ffa8c2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24040346/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Grace WanggeMichelle PutzeistMirjam J KnolOlaf H KlungelChristine C Gispen-De WiedAntonius de BoerArno W HoesHubert G LeufkensAukje K Mantel-TeeuwissePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e74818 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Grace Wangge Michelle Putzeist Mirjam J Knol Olaf H Klungel Christine C Gispen-De Wied Antonius de Boer Arno W Hoes Hubert G Leufkens Aukje K Mantel-Teeuwisse Regulatory scientific advice on non-inferiority drug trials.
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.
format	article
author	Grace Wangge Michelle Putzeist Mirjam J Knol Olaf H Klungel Christine C Gispen-De Wied Antonius de Boer Arno W Hoes Hubert G Leufkens Aukje K Mantel-Teeuwisse
author_facet	Grace Wangge Michelle Putzeist Mirjam J Knol Olaf H Klungel Christine C Gispen-De Wied Antonius de Boer Arno W Hoes Hubert G Leufkens Aukje K Mantel-Teeuwisse
author_sort	Grace Wangge
title	Regulatory scientific advice on non-inferiority drug trials.
title_short	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_sort	regulatory scientific advice on non-inferiority drug trials.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/41f4581e6bd243c9827bd962f70ffa8c
work_keys_str_mv	AT gracewangge regulatoryscientificadviceonnoninferioritydrugtrials AT michelleputzeist regulatoryscientificadviceonnoninferioritydrugtrials AT mirjamjknol regulatoryscientificadviceonnoninferioritydrugtrials AT olafhklungel regulatoryscientificadviceonnoninferioritydrugtrials AT christinecgispendewied regulatoryscientificadviceonnoninferioritydrugtrials AT antoniusdeboer regulatoryscientificadviceonnoninferioritydrugtrials AT arnowhoes regulatoryscientificadviceonnoninferioritydrugtrials AT hubertgleufkens regulatoryscientificadviceonnoninferioritydrugtrials AT aukjekmantelteeuwisse regulatoryscientificadviceonnoninferioritydrugtrials
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Regulatory scientific advice on non-inferiority drug trials.

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