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The need for reporting guidelines for early phase dose-finding trials: Dose-Finding CONSORT Extension

Nature Medicine volume 28, pages 6–7 (2022)Cite this article

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To the Editor — Early phase trials (phase I or phase I/II) are studies conducted in healthy volunteers or patients with the aim of determining drug disposition (absorption, distribution, metabolism and excretion), adverse effects, drug exposure, pharmacodynamic biomarker activity and clinical activity. A critical step in treatment development, results from early phase trials directly influence decisions on further trials and whether the selected doses and schedules are sufficiently safe and have promising results on treatment activity.

Often termed dose-finding or dose-escalation studies, early phase trials account for a large number of the trials being run at any given time: a search of ClinicalTrials.gov for phase I studies first posted between 2019 and 2020 returns 8,536 entries, versus 5,162 phase III trials first posted over the same period. The attrition rate throughout the drug development process is high, and the success rate between phase I studies and marketing authorization has been reported as between 9.8% and 13.8% on the basis of several studies1,2, with failure being primarily attributable to either poor tolerability or lack of biological activity (79% of failed studies over the period 2016–2018)3.

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Acknowledgements

This work is funded by a Medical Research Council and National Institute for Health Research (MRC–NIHR) Methodology Research Programme grant: ‘Early Phase Dose-finding Trials: Development of reporting guidance to improve knowledge transfer’ (grant no. MR/T044934/1). C.J.W. was supported in this work by NHS Lothian via Edinburgh Clinical Trials Unit. S.L. was funded through the National Center for Advancing Translational Sciences, National Institutes of Health (grant no. UL1TR001873). T.J. received funding from UK MRC (MC UU 00002/14). This reporting guideline under development is registered on the Enhancing Quality and Transparency of Health Research (EQUATOR) Network database. All the named authors are part of the Dose-Finding CONSORT Extension Executive Committee.

The authors acknowledge the support of E. Garrett-Mayer, D. Ashby, and J. Isaacs, members of the Independent Expert Panel in contributing their expertise and support to this initiative. The authors also thank the late D. Altman for his enthusiasm, inspiration and significant contribution to the initial conception of this work.

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Authors and Affiliations

  1. Clinical Trials and Statistics Unit, Institute of Cancer Research, Sutton, UK

    Christina Yap, Johann de Bono, Aude Espinasse & Olga Solovyeva

  2. Roche, Welwyn Garden City, UK

    Alun Bedding

  3. School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK

    Munyaradzi Dimairo

  4. University of Glasgow, Glasgow, UK

    Jeffry Evans

  5. University of Oxford, Oxford, UK

    Sally Hopewell

  6. Lancaster University, Lancaster, UK

    Thomas Jaki

  7. University of Cambridge, Cambridge, UK

    Thomas Jaki

  8. Patient and Public involvement partner, Lichfield, Staffordshire, UK

    Andrew Kightley

  9. Columbia University, New York, NY, USA

    Shing Lee

  10. Bristol Meyers Squibb, Berkeley Heights, New Jersey, USA

    Rong Liu

  11. Centre for Trials Research, Cardiff University, Cardiff, UK

    Adrian Mander

  12. Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK

    Christopher J. Weir

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  1. Christina Yap
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Contributions

C.Y., J.d.B., M.D., J.E., S.H., T.J., A.K., S.L., A.M. and C.J.W. were responsible for conception and funding; A.E. and C.Y. drafted the manuscript; all authors critically revised the manuscript for important intellectual content and approved the final version.

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Correspondence to Christina Yap.

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The authors declare no competing interests.

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Yap, C., Bedding, A., de Bono, J. et al. The need for reporting guidelines for early phase dose-finding trials: Dose-Finding CONSORT Extension. Nat Med 28, 6–7 (2022). https://doi.org/10.1038/s41591-021-01594-1

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