Optimizing the design and analysis of clinical trials for antibacterials against multidrug-resistant organisms: a white paper from COMBACTE's STAT-Net

Marlieke EA de Kraker, Harriet Sommer, Femke de Velde, Isaac Gravestock, Emmanuel Weiss, Alexandra McAleenan, Stavros Nikolakopoulos, Ohad Amit, Teri Ashton, Jan Beyersmann, Leonhard Held, Andrew M Lovering, Alasdair MacGowan, Johan W Mouton, Jean-François Timsit, David Wilson, Martin Wolkewitz, Esther Bettiol, Aaron Dane, Stephan Harbarth

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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.
Original languageEnglish
Article numberciy516
Number of pages10
JournalClinical Infectious Diseases
Early online date13 Aug 2018
DOIs
Publication statusE-pub ahead of print - 13 Aug 2018

Keywords

  • randomized clinical trials
  • multidrug-resistant organisms
  • novel biostatistical methods
  • clinical trial design
  • antibacterial drug development

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    de Kraker, M. EA., Sommer, H., de Velde, F., Gravestock, I., Weiss, E., McAleenan, A., Nikolakopoulos, S., Amit, O., Ashton, T., Beyersmann, J., Held, L., Lovering, A. M., MacGowan, A., Mouton, J. W., Timsit, J-F., Wilson, D., Wolkewitz, M., Bettiol, E., Dane, A., & Harbarth, S. (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, [ciy516]. https://doi.org/10.1093/cid/ciy516