title: Design of a Randomized Controlled Trial for Ebola Virus Disease Medical Countermeasures: PREVAIL II, the Ebola MCM Study.
abstract: Unique challenges posed by emerging infectious diseases often expose inadequacies in the conventional phased investigational therapeutic development paradigm. The recent Ebola outbreak in West Africa presents a critical case-study highlighting barriers to faster development. During the outbreak, clinical trials were implemented with unprecedented speed. Yet, in most cases, this fast-tracked approach proved too slow for the rapidly evolving epidemic. Controversy abounded as to the most appropriate study designs to yield safety and efficacy data, potentially causing delays in pivotal studies. Preparation for research during future outbreaks may require acceptance of a paradigm that circumvents, accelerates, or reorders traditional phases, without losing sight of the traditional benchmarks by which drug candidates must be assessed for activity, safety and efficacy.
  
  
  
  We present the design of an adaptive, parent protocol, ongoing in West Africa until January 2016. The exigent circumstances of the outbreak and limited prior clinical experience with experimental treatments, led to more direct bridging from preclinical studies to human trials than the conventional paradigm would typically have sanctioned, and required considerable design flexibility.
  
  
  
  Preliminary evaluation of the "barely Bayesian" design was provided through computer simulation studies. The understanding and public discussion of the study design will help its future implementation.
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda.
authors.forename: Lori E
authors.initials: LE
authors.lastname: Dodd
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Proschan
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Neuhaus
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Koopmeiners
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis.
authors.forename: James
authors.initials: J
authors.lastname: Neaton
authors.affiliation: Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Maryland.
authors.forename: John D
authors.initials: JD
authors.lastname: Beigel
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda.
authors.forename: Kevin
authors.initials: K
authors.lastname: Barrett
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda.
authors.forename: Henry Clifford
authors.initials: HC
authors.lastname: Lane
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Davey
mesh_terms: D000354:Africa, Western / Q000453:epidemiology; D001499:Bayes Theorem; D003198:Computer Simulation; D004196:Disease Outbreaks; D029043:Ebolavirus / Q000502:physiology*; D019142:Hemorrhagic Fever, Ebola / Q000453:epidemiology* / Q000628:therapy / Q000821:virology; D006801:Humans; D012107:Research Design
keywords: Bayesian design; Ebola virus disease; adaptive design; clinical trials; emerging infectious diseases