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Optimizing the Design and Analysis of Clinical Trials for Antibacterials Against Multidrug-resistant Organisms: A White Paper From COMBACTE’s STAT-Net


de Kraker, Marlieke E A; Sommer, Harriet; de Velde, Femke; Gravestock, Isaac; Weiss, Emmanuel; McAleenan, Alexandra; Nikolakopoulos, Stavros; Amit, Ohad; Ashton, Teri; Beyersmann, Jan; Held, Leonhard; Lovering, Andrew M; MacGowan, Alasdair P; Mouton, Johan W; Timsit, Jean-François; Wilson, David; Wolkewitz, Martin; Bettiol, Esther; Dane, Aaron; Harbarth, Stephan (2018). Optimizing the Design and Analysis of Clinical Trials for Antibacterials Against Multidrug-resistant Organisms: A White Paper From COMBACTE’s STAT-Net. Clinical Infectious Diseases, 67(12):1922-1931.

Abstract

Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge.

Abstract

Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Epidemiology, Biostatistics and Prevention Institute (EBPI)
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Microbiology (medical), Infectious Diseases
Language:English
Date:13 August 2018
Deposited On:27 Feb 2019 16:58
Last Modified:27 Feb 2019 17:10
Publisher:Oxford University Press
ISSN:1058-4838
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/cid/ciy516
PubMed ID:30107400
Project Information:
  • : FunderFP7
  • : Grant ID115523
  • : Project TitleCOMBACTE-NET - Combatting Bacterial Resistance in Europe

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