title: Increasing efficiency of preclinical research by group sequential designs.
abstract: Despite the potential benefits of sequential designs, studies evaluating treatments or experimental manipulations in preclinical experimental biomedicine almost exclusively use classical block designs. Our aim with this article is to bring the existing methodology of group sequential designs to the attention of researchers in the preclinical field and to clearly illustrate its potential utility. Group sequential designs can offer higher efficiency than traditional methods and are increasingly used in clinical trials. Using simulation of data, we demonstrate that group sequential designs have the potential to improve the efficiency of experimental studies, even when sample sizes are very small, as is currently prevalent in preclinical experimental biomedicine. When simulating data with a large effect size of d = 1 and a sample size of n = 18 per group, sequential frequentist analysis consumes in the long run only around 80% of the planned number of experimental units. In larger trials (n = 36 per group), additional stopping rules for futility lead to the saving of resources of up to 30% compared to block designs. We argue that these savings should be invested to increase sample sizes and hence power, since the currently underpowered experiments in preclinical biomedicine are a major threat to the value and predictiveness in this research domain.
authors.affiliation: Department of Biostatistics and Clinical Epidemiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Neumann
authors.affiliation: Department of Biostatistics and Clinical Epidemiology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Center for Stroke Research, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Grittner
authors.affiliation: Department of Biostatistics and Clinical Epidemiology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Center for Stroke Research, Charité Universitätsmedizin Berlin, Berlin, Germany.|NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sophie K
authors.initials: SK
authors.lastname: Piper
authors.affiliation: Center for Stroke Research, Charité Universitätsmedizin Berlin, Berlin, Germany.|Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Rex
authors.affiliation: Bio-health Informatics Group, School of Computer Science, The University of Manchester, Manchester, United Kingdom.
authors.forename: Oscar
authors.initials: O
authors.lastname: Florez-Vargas
authors.affiliation: Centre for Health Informatics, Macquarie University, Sydney, Australia.
authors.forename: George
authors.initials: G
authors.lastname: Karystianis
authors.affiliation: Department of Biostatistics and Clinical Epidemiology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Center for Stroke Research, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Alice
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Center for Stroke Research, Charité Universitätsmedizin Berlin, Berlin, Germany.|Department of Public Health and Primary Care, Cambridge Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Wellwood
authors.affiliation: Center for Stroke Research, Charité Universitätsmedizin Berlin, Berlin, Germany.|Center for Transforming Biomedical Research, Berlin Institute of Health, Berlin, Germany.
authors.forename: Bob
authors.initials: B
authors.lastname: Siegerink
authors.affiliation: Meta-Research Innovation Center at Stanford (METRICS), and Departments of Medicine, of Health Research and Policy, and of Statistics, Stanford University, Stanford, California, United States of America.
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
authors.affiliation: STREAM Research Group, Biomedical Ethics Unit, McGill University, Montreal, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kimmelman
authors.affiliation: Center for Stroke Research, Charité Universitätsmedizin Berlin, Berlin, Germany.|NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Department of Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Center for Transforming Biomedical Research, Berlin Institute of Health, Berlin, Germany.|German Center for Neurodegenerative Diseases (DZNE), Berlin Site, Berlin, Germany.|German Center for Cardiovascular Research (DZHK), Berlin site, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
mesh_terms: D035843:Biomedical Research; D012107:Research Design