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Systematic review of guidelines for internal validity in the design, conduct and analysis of preclinical biomedical experiments involving laboratory animals
  1. Jan Vollert1,
  2. Esther Schenker2,
  3. Malcolm Macleod3,
  4. Anton Bespalov4,5,
  5. Hanno Wuerbel6,
  6. Martin Michel7,
  7. Ulrich Dirnagl8,
  8. Heidrun Potschka9,
  9. Ann-Marie Waldron9,
  10. Kimberley Wever10,
  11. Thomas Steckler11,
  12. Tom van de Casteele11,
  13. Bruce Altevogt12,
  14. Annesha Sil13,
  15. Andrew S C Rice1
  16. The EQIPD WP3 study group members
    1. 1Pain Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
    2. 2Institut de Recherches Internationales Servier, Suresnes, Île-de-France, France
    3. 3Centre for Clinical Brain Sciences, Edinburgh Medical School, The University of Edinburgh, Edinburgh, Scotland, UK
    4. 4Partnership for Assessment and Accreditation of Scientific Practice, Heidelberg, Germany
    5. 5Valdman Institute of Pharmacology, Pavlov First State Medical University of Saint Petersburg, Sankt Petersburg, Russian Federation
    6. 6Division of Animal Welfare, Vetsuisse Faculty, VPH Institute, University of Bern, Bern, Switzerland
    7. 7Universitätsmedizin Mainz, Johannes Gutenberg Universität Mainz, Mainz, Rheinland-Pfalz, Germany
    8. 8Department of Experimental Neurology, Charité–Universitätsmedizin Berlin, Berlin, Germany
    9. 9Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-Universitat Munchen, Munchen, Bayern, Germany
    10. 10Systematic Review Centre for Laboratory Animal Experimentation, Department for Health Evidence, Nijmegen Institute for Health Sciences, Radboud Universiteit, Nijmegen, Gelderland, Netherlands
    11. 11Janssen Pharmaceutica, Beerse, Antwerpen, Belgium
    12. 12Pfizer, New York, New York, USA
    13. 13Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
    1. Correspondence to Dr Jan Vollert; j.vollert{at}imperial.ac.uk

    Abstract

    Over the last two decades, awareness of the negative repercussions of flaws in the planning, conduct and reporting of preclinical research involving experimental animals has been growing. Several initiatives have set out to increase transparency and internal validity of preclinical studies, mostly publishing expert consensus and experience. While many of the points raised in these various guidelines are identical or similar, they differ in detail and rigour. Most of them focus on reporting, only few of them cover the planning and conduct of studies. The aim of this systematic review is to identify existing experimental design, conduct, analysis and reporting guidelines relating to preclinical animal research. A systematic search in PubMed, Embase and Web of Science retrieved 13 863 unique results. After screening these on title and abstract, 613 papers entered the full-text assessment stage, from which 60 papers were retained. From these, we extracted unique 58 recommendations on the planning, conduct and reporting of preclinical animal studies. Sample size calculations, adequate statistical methods, concealed and randomised allocation of animals to treatment, blinded outcome assessment and recording of animal flow through the experiment were recommended in more than half of the publications. While we consider these recommendations to be valuable, there is a striking lack of experimental evidence on their importance and relative effect on experiments and effect sizes.

    • scientific rigor
    • bias
    • internal validity
    • preclinical studies
    • animal studies
    https://creativecommons.org/licenses/by/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

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      Peer review history and previous versions

    Footnotes

    • Twitter @TimPnin

    • Correction notice This article has been corrected since it was published Online First. ORCIDs have been added for authors.

    • Collaborators The EQIPD WP3 study group members are: Jan Vollert, Esther Schenker, Malcolm Macleod, Judi Clark, Emily Sena, Anton Bespalov, Bruno Boulanger, Gernot Riedel, Bettina Platt, Annesha Sil, Martien J Kas, Hanno Wuerbel, Bernhard Voelkl, Martin C Michel, Mathias Jucker, Bettina M Wegenast-Braun, Ulrich Dirnagl, René Bernard, Esmeralda Heiden, Heidrun Potschka, Maarten Loos, Kimberley E Wever, Merel Ritskes-Hoitinga, Tom Van De Casteele, Thomas Steckler, Pim Drinkenburg, Juan Diego Pita Almenar, David Gallacher, Henk Van Der Linde, Anja Gilis, Greet Teuns, Karsten Wicke, Sabine Grote, Bernd Sommer, Janet Nicholson, Sanna Janhunen, Sami Virtanen, Bruce Altevogt, Kristin Cheng, Sylvie Ramboz, Emer Leahy, Isabel A Lefevre, Fiona Ducrey, Javier Guillen, Patri Vergara, Ann-Marie Waldron, Isabel Seiffert and Andrew S C Rice.

    • Contributors JV wrote the manuscript, mainly designed and conducted the systematic review and organised the process. ES and ASCR supervised the process and the designing and conduction of the systematic review and helped in writing the manuscript. All other authors helped in designing and conducting the systematic review and corrected the manuscript.

    • Funding This work is part of the European Quality In Preclinical Data (EQIPD) consortium. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 777364. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

    • Competing interests None declared.

    • Ethics approval Not applicable.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available on Figshare doi:10.6084/m9.figshare.9815753

    • Open data The data are available at https://figshare.com/articles/SyR_results_guidelines_preclinical_research_quality_EQIPD_csv/9815753.

    • Open materials The materials used are widely available.

    • Preregistration The systematic review and meta-analysis reported in this article was formally preregistered and the protocol published in BMJ Open Science doi:10.1136/ bmjos-2018-000004.

    • Open peer review Prepublication and Review History is available online at http://dx.doi.org/10.1136/bmjos-2019-1000046.

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