title: Deciphering assumptions about stepped wedge designs: the case of Ebola vaccine research.
abstract: Ethical concerns about randomising persons to a no-treatment arm in the context of Ebola epidemic led to consideration of alternative designs. The stepped wedge (SW) design, in which participants or clusters are randomised to receive an intervention at different time points, gained popularity. Common arguments in favour of using this design are (1) when an intervention is likely to do more good than harm, (2) all participants should receive the experimental intervention at some time point during the study and (3) the design might be preferable for practical reasons. We examine these assumptions when considering Ebola vaccine research. First, based on the claim that a stepped wedge design is indicated when it is likely that the intervention will do more good than harm, we reviewed published and ongoing SW trials to explore previous use of this design to test experimental drugs or vaccines, and found that SW design has never been used for trials of experimental drugs or vaccines. Given that Ebola vaccines were all experimental with no prior efficacy data, the use of a stepped wedge design would have been unprecedented. Second, we show that it is rarely true that all participants receive the intervention in SW studies, but rather, depending on certain design features, all clusters receive the intervention. Third, we explore whether the SW design is appealing for feasibility reasons and point out that there is significant complexity. In the setting of the Ebola epidemic, spatiotemporal variation may have posed problematic challenges to a stepped wedge design for vaccine research. Finally, we propose a set of points to consider for scientific reviewers and ethics committees regarding proposals for SW designs.
authors.affiliation: Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Adélaïde
authors.identifier: 0000-0003-2622-5948
authors.initials: A
authors.lastname: Doussau
authors.affiliation: Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Grady
mesh_terms: D035843:Biomedical Research / Q000941:ethics*; D002985:Clinical Protocols; D004334:Drug Administration Schedule; D046129:Ebola Vaccines / Q000008:administration & dosage*; D032984:Ethics, Research; D019142:Hemorrhagic Fever, Ebola / Q000517:prevention & control*; D006801:Humans; D011897:Random Allocation; D016032:Randomized Controlled Trials as Topic / Q000941:ethics* / Q000379:methods; D012107:Research Design; D014611:Vaccination
chemical_list: D046129:Ebola Vaccines
keywords: Biostatistics; Clinical trials; Drugs and Drug Industry; Policy Guidelines/Inst. Review Boards/Review Cttes.; Research Ethics