IDEAS home Printed from https://ideas.repec.org/a/plo/pbio00/2004879.html
   My bibliography  Save this article

Preclinical efficacy studies in investigator brochures: Do they enable risk–benefit assessment?

Author

Listed:
  • Susanne Wieschowski
  • William Wei Lim Chin
  • Carole Federico
  • Sören Sievers
  • Jonathan Kimmelman
  • Daniel Strech

Abstract

Human protection policies require favorable risk–benefit judgments prior to launch of clinical trials. For phase I and II trials, evidence for such judgment often stems from preclinical efficacy studies (PCESs). We undertook a systematic investigation of application materials (investigator brochures [IBs]) presented for ethics review for phase I and II trials to assess the content and properties of PCESs contained in them. Using a sample of 109 IBs most recently approved at 3 institutional review boards based at German Medical Faculties between the years 2010–2016, we identified 708 unique PCESs. We then rated all identified PCESs for their reporting on study elements that help to address validity threats, whether they referenced published reports, and the direction of their results. Altogether, the 109 IBs reported on 708 PCESs. Less than 5% of all PCESs described elements essential for reducing validity threats such as randomization, sample size calculation, and blinded outcome assessment. For most PCESs (89%), no reference to a published report was provided. Only 6% of all PCESs reported an outcome demonstrating no effect. For the majority of IBs (82%), all PCESs were described as reporting positive findings. Our results show that most IBs for phase I/II studies did not allow evaluators to systematically appraise the strength of the supporting preclinical findings. The very rare reporting of PCESs that demonstrated no effect raises concerns about potential design or reporting biases. Poor PCES design and reporting thwart risk–benefit evaluation during ethical review of phase I/II studies.Author summary: To make a clinical trial ethical, regulatory agencies and institutional review boards have to judge whether the trial-related benefits (the knowledge gain) outweigh the trial-inherent risks. For early-phase human research, these risk–benefit assessments are often based on evidence from preclinical animal studies reported in so-called “investigator brochures.” However, our analysis shows that the vast majority of such investigator brochures lack sufficient information to systematically appraise the strength of the supporting preclinical findings. Furthermore, the very rare reporting of preclinical efficacy studies that demonstrated no effect raises concerns about potential design and/or reporting biases. The poor preclinical study design and reporting thwarts risk–benefit evaluation during ethical review of early human research. Regulators should develop standards for the design and reporting of preclinical efficacy studies in order to support the conduct of ethical clinical trials.

Suggested Citation

  • Susanne Wieschowski & William Wei Lim Chin & Carole Federico & Sören Sievers & Jonathan Kimmelman & Daniel Strech, 2018. "Preclinical efficacy studies in investigator brochures: Do they enable risk–benefit assessment?," PLOS Biology, Public Library of Science, vol. 16(4), pages 1-11, April.
  • Handle: RePEc:plo:pbio00:2004879
    DOI: 10.1371/journal.pbio.2004879
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2004879
    Download Restriction: no

    File URL: https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.2004879&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pbio.2004879?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Carol Kilkenny & William J Browne & Innes C Cuthill & Michael Emerson & Douglas G Altman, 2010. "Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research," PLOS Biology, Public Library of Science, vol. 8(6), pages 1-5, June.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Airi Jo-Watanabe & Toshiki Inaba & Takahiro Osada & Ryota Hashimoto & Tomohiro Nishizawa & Toshiaki Okuno & Sayoko Ihara & Kazushige Touhara & Nobutaka Hattori & Masatsugu Oh-Hora & Osamu Nureki & Tak, 2024. "Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Dean A Fergusson & Marc T Avey & Carly C Barron & Mathew Bocock & Kristen E Biefer & Sylvain Boet & Stephane L Bourque & Isidora Conic & Kai Chen & Yuan Yi Dong & Grace M Fox & Ronald B George & Neil , 2019. "Reporting preclinical anesthesia study (REPEAT): Evaluating the quality of reporting in the preclinical anesthesiology literature," PLOS ONE, Public Library of Science, vol. 14(5), pages 1-15, May.
    3. M Polyakova & M L Schroeter & B M Elzinga & S Holiga & P Schoenknecht & E R de Kloet & M L Molendijk, 2015. "Brain-Derived Neurotrophic Factor and Antidepressive Effect of Electroconvulsive Therapy: Systematic Review and Meta-Analyses of the Preclinical and Clinical Literature," PLOS ONE, Public Library of Science, vol. 10(11), pages 1-18, November.
    4. Yali Liu & Xingxing Zhao & Yuefen Mai & Xinxin Li & Jin Wang & Lili Chen & Jing Mu & Gengxue Jin & Hongping Gou & Wanting Sun & Yuchen Feng, 2016. "Adherence to ARRIVE Guidelines in Chinese Journal Reports on Neoplasms in Animals," PLOS ONE, Public Library of Science, vol. 11(5), pages 1-12, May.
    5. Kimberley E Wever & Carlijn R Hooijmans & Niels P Riksen & Thomas B Sterenborg & Emily S Sena & Merel Ritskes-Hoitinga & Michiel C Warlé, 2015. "Determinants of the Efficacy of Cardiac Ischemic Preconditioning: A Systematic Review and Meta-Analysis of Animal Studies," PLOS ONE, Public Library of Science, vol. 10(11), pages 1-17, November.
    6. Bettina Bert & Céline Heinl & Justyna Chmielewska & Franziska Schwarz & Barbara Grune & Andreas Hensel & Matthias Greiner & Gilbert Schönfelder, 2019. "Refining animal research: The Animal Study Registry," PLOS Biology, Public Library of Science, vol. 17(10), pages 1-12, October.
    7. Xiao-meng Xu & Guang-yan Cai & Ru Bu & Wen-juan Wang & Xue-yuan Bai & Xue-feng Sun & Xiang-mei Chen, 2015. "Beneficial Effects of Caloric Restriction on Chronic Kidney Disease in Rodent Models: A Meta-Analysis and Systematic Review," PLOS ONE, Public Library of Science, vol. 10(12), pages 1-15, December.
    8. Zhongwei Xu & Bingze Xu & Susanna L. Lundström & Àlex Moreno-Giró & Danxia Zhao & Myriam Martin & Erik Lönnblom & Qixing Li & Alexander Krämer & Changrong Ge & Lei Cheng & Bibo Liang & Dongmei Tong & , 2023. "A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    9. Nathalie Percie du Sert & Viki Hurst & Amrita Ahluwalia & Sabina Alam & Marc T Avey & Monya Baker & William J Browne & Alejandra Clark & Innes C Cuthill & Ulrich Dirnagl & Michael Emerson & Paul Garne, 2020. "The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research," PLOS Biology, Public Library of Science, vol. 18(7), pages 1-12, July.
    10. Vivian Leung & Frédérik Rousseau-Blass & Guy Beauchamp & Daniel S J Pang, 2018. "ARRIVE has not ARRIVEd: Support for the ARRIVE (Animal Research: Reporting of in vivo Experiments) guidelines does not improve the reporting quality of papers in animal welfare, analgesia or anesthesi," PLOS ONE, Public Library of Science, vol. 13(5), pages 1-13, May.
    11. Claudia Kurreck & Esmeralda Castaños-Vélez & Dorette Freyer & Sonja Blumenau & Ingo Przesdzing & Rene Bernard & Ulrich Dirnagl, 2020. "Improving quality of preclinical academic research through auditing: A feasibility study," PLOS ONE, Public Library of Science, vol. 15(10), pages 1-15, October.
    12. Simon Bate & Natasha A Karp, 2014. "A Common Control Group - Optimising the Experiment Design to Maximise Sensitivity," PLOS ONE, Public Library of Science, vol. 9(12), pages 1-12, December.
    13. Laura Maxim & Jeroen P van der Sluijs, 2014. "Qualichem In Vivo: A Tool for Assessing the Quality of In Vivo Studies and Its Application for Bisphenol A," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-16, January.
    14. Beverly S Muhlhausler & Frank H Bloomfield & Matthew W Gillman, 2013. "Whole Animal Experiments Should Be More Like Human Randomized Controlled Trials," PLOS Biology, Public Library of Science, vol. 11(2), pages 1-6, February.
    15. Sarah Driessen & Lambert Bodewein & Dagmar Dechent & David Graefrath & Kristina Schmiedchen & Dominik Stunder & Thomas Kraus & Anne-Kathrin Petri, 2020. "Biological and health-related effects of weak static magnetic fields (≤ 1 mT) in humans and vertebrates: A systematic review," PLOS ONE, Public Library of Science, vol. 15(6), pages 1-18, June.
    16. Constance Holman & Sophie K Piper & Ulrike Grittner & Andreas Antonios Diamantaras & Jonathan Kimmelman & Bob Siegerink & Ulrich Dirnagl, 2016. "Where Have All the Rodents Gone? The Effects of Attrition in Experimental Research on Cancer and Stroke," PLOS Biology, Public Library of Science, vol. 14(1), pages 1-12, January.
    17. Thirumalai Diraviyam & Bin Zhao & Yuan Wang & Ruediger Schade & Antonysamy Michael & Xiaoying Zhang, 2014. "Effect of Chicken Egg Yolk Antibodies (IgY) against Diarrhea in Domesticated Animals: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 9(5), pages 1-14, May.
    18. Bertha Estrella & Elena N. Naumova & Magda Cepeda & Trudy Voortman & Peter D. Katsikis & Hemmo A. Drexhage, 2019. "Effects of Air Pollution on Lung Innate Lymphoid Cells: Review of In Vitro and In Vivo Experimental Studies," IJERPH, MDPI, vol. 16(13), pages 1-15, July.
    19. Emily M Wong & Fern Tablin & Edward S Schelegle, 2020. "Comparison of nonparametric and parametric methods for time-frequency heart rate variability analysis in a rodent model of cardiovascular disease," PLOS ONE, Public Library of Science, vol. 15(11), pages 1-15, November.
    20. Jonathan Kimmelman & Alex John London, 2011. "Predicting Harms and Benefits in Translational Trials: Ethics, Evidence, and Uncertainty," PLOS Medicine, Public Library of Science, vol. 8(3), pages 1-5, March.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pbio00:2004879. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosbiology (email available below). General contact details of provider: https://journals.plos.org/plosbiology/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.