Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials:the DEFINE study

Solovyeva, Olga and Dimairo, Munyaradzi and Weir, Christopher J. and Hee, Siew Wan and Espinasse, Aude and Ursino, Moreno and Patel, Dhrusti and Kightley, Andrew and Hughes, Sarah and Jaki, Thomas and Mander, Adrian and Evans, Thomas R. Jeffry and Lee, Shing and Hopewell, Sally and Rantell, Khadija Rerhou and Chan, An-Wen and Bedding, Alun and Stephens, Richard and Richards, Dawn and Roberts, Lesley and Kirkpatrick, John and de Bono, Johann and Yap, Christina (2023) Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials:the DEFINE study. BMC Medicine, 21 (1). ISSN 1741-7015

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Background Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). Methods The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants’ feedback. Results The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. Conclusions By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. Trial registration SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network (

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Journal Article
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BMC Medicine
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17 Jul 2023 12:55
Last Modified:
17 Sep 2023 03:28