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Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov

OBJECTIVES: This review investigates characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials. DESIGN: Review of adaptive design clinical trials in EMBASE, PubMed, Cochrane Registry of Controlled Clinical Trials, Web of Science an...

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Detalles Bibliográficos
Autores principales: Bothwell, Laura E, Avorn, Jerry, Khan, Nazleen F, Kesselheim, Aaron S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829673/
https://www.ncbi.nlm.nih.gov/pubmed/29440155
http://dx.doi.org/10.1136/bmjopen-2017-018320
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author Bothwell, Laura E
Avorn, Jerry
Khan, Nazleen F
Kesselheim, Aaron S
author_facet Bothwell, Laura E
Avorn, Jerry
Khan, Nazleen F
Kesselheim, Aaron S
author_sort Bothwell, Laura E
collection PubMed
description OBJECTIVES: This review investigates characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials. DESIGN: Review of adaptive design clinical trials in EMBASE, PubMed, Cochrane Registry of Controlled Clinical Trials, Web of Science and ClinicalTrials.gov. Phase I and seamless Phase I/II trials were excluded. Variables extracted from trials included basic study characteristics, adaptive design features, size and use of independent data monitoring committees (DMCs) and blinded interim analyses. We also examined use of the adaptive trials in new drug submissions to the Food and Drug Administration (FDA) and European Medicines Agency (EMA) and recorded regulators’ experiences with adaptive designs. RESULTS: 142 studies met inclusion criteria. There has been a recent growth in publicly reported use of adaptive designs among researchers around the world. The most frequently appearing types of adaptations were seamless Phase II/III (57%), group sequential (21%), biomarker adaptive (20%), and adaptive dose-finding designs (16%). About one-third (32%) of trials reported an independent DMC, while 6% reported blinded interim analysis. We found that 9% of adaptive trials were used for FDA product approval consideration, and 12% were used for EMA product approval consideration. International regulators had mixed experiences with adaptive trials. Many product applications with adaptive trials had extensive correspondence between drug sponsors and regulators regarding the adaptive designs, in some cases with regulators requiring revisions or alterations to research designs. CONCLUSIONS: Wider use of adaptive designs will necessitate new drug application sponsors to engage with regulatory scientists during planning and conduct of the trials. Investigators need to more consistently report protections intended to preserve confidentiality and minimise potential operational bias during interim analysis.
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spelling pubmed-58296732018-03-01 Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov Bothwell, Laura E Avorn, Jerry Khan, Nazleen F Kesselheim, Aaron S BMJ Open Research Methods OBJECTIVES: This review investigates characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials. DESIGN: Review of adaptive design clinical trials in EMBASE, PubMed, Cochrane Registry of Controlled Clinical Trials, Web of Science and ClinicalTrials.gov. Phase I and seamless Phase I/II trials were excluded. Variables extracted from trials included basic study characteristics, adaptive design features, size and use of independent data monitoring committees (DMCs) and blinded interim analyses. We also examined use of the adaptive trials in new drug submissions to the Food and Drug Administration (FDA) and European Medicines Agency (EMA) and recorded regulators’ experiences with adaptive designs. RESULTS: 142 studies met inclusion criteria. There has been a recent growth in publicly reported use of adaptive designs among researchers around the world. The most frequently appearing types of adaptations were seamless Phase II/III (57%), group sequential (21%), biomarker adaptive (20%), and adaptive dose-finding designs (16%). About one-third (32%) of trials reported an independent DMC, while 6% reported blinded interim analysis. We found that 9% of adaptive trials were used for FDA product approval consideration, and 12% were used for EMA product approval consideration. International regulators had mixed experiences with adaptive trials. Many product applications with adaptive trials had extensive correspondence between drug sponsors and regulators regarding the adaptive designs, in some cases with regulators requiring revisions or alterations to research designs. CONCLUSIONS: Wider use of adaptive designs will necessitate new drug application sponsors to engage with regulatory scientists during planning and conduct of the trials. Investigators need to more consistently report protections intended to preserve confidentiality and minimise potential operational bias during interim analysis. BMJ Publishing Group 2018-02-10 /pmc/articles/PMC5829673/ /pubmed/29440155 http://dx.doi.org/10.1136/bmjopen-2017-018320 Text en © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. 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/
spellingShingle Research Methods
Bothwell, Laura E
Avorn, Jerry
Khan, Nazleen F
Kesselheim, Aaron S
Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov
title Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov
title_full Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov
title_fullStr Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov
title_full_unstemmed Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov
title_short Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov
title_sort adaptive design clinical trials: a review of the literature and clinicaltrials.gov
topic Research Methods
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829673/
https://www.ncbi.nlm.nih.gov/pubmed/29440155
http://dx.doi.org/10.1136/bmjopen-2017-018320
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