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Review
. 2023 Jul 5;21(1):246.
doi: 10.1186/s12916-023-02937-0.

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

Olga Solovyeva  1 , Munyaradzi Dimairo  2 , Christopher J Weir  3 , Siew Wan Hee  4   5 , Aude Espinasse  1 , Moreno Ursino  6   7   8   9 , Dhrusti Patel  1 , Andrew Kightley  10 , Sarah Hughes  11 , Thomas Jaki  12   13 , Adrian Mander  14 , Thomas R Jeffry Evans  15 , Shing Lee  16 , Sally Hopewell  17 , Khadija Rerhou Rantell  18 , An-Wen Chan  19 , Alun Bedding  20 , Richard Stephens  21 , Dawn Richards  22 , Lesley Roberts  21 , John Kirkpatrick  20 , Johann de Bono  1   23 , Christina Yap  24
Affiliations
Review

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

Olga Solovyeva et al. BMC Med. .

Abstract

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 ( https://www.equator-network.org/ ).

Keywords: CONSORT guideline; SPIRIT guideline; clinical trials; dose finding; early phase.

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Conflict of interest statement

Professor Johann de Bono has served on advisory boards and received fees from many companies, including Amgen, Astra Zeneca, Astellas, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech/Roche, Genmab, GlaxoSmithKline, Harpoon, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, and Vertex Pharmaceuticals.

Professor Johann de Bono is an employee of The Institute of Cancer Research, which has received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GlaxoSmithKline, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, Vertex, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income).

Professor Johann de Bono was named as an inventor with no financial interest in Patent No. 8,822,438 submitted by Janssen that covers the use of abiraterone acetate with corticosteroids. He has been the CI/PI of many industry-sponsored clinical trials.

Professor Johann de Bono is a Senior Investigator at the National Institute for Health Research (NIHR). The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

Professors Sally Hopewell and An-Wen Chan are members of the SPIRIT-CONSORT Executive Group and leading the current update of the SPIRIT 2013 and CONSORT 2010 reporting guidelines, funded by the UK Medical Research Council National Institute for Health Research Better Methods, Better Research (MR/W020483/1).

Professor Jeffry Evans declares the following conflicts of interest:

Honoraria for Consultancies (payable to the employing institution) Ascelia, Bayer, Bristol Myers Squibb, Celgene, Clovis, Eisai, Genentech, Immunova, Jennerex/Transgene, Nucana, Karus Therapeutics, MSD, Otsuka, Roche, Seagen, Medivir, Bicycle Therapeutics.

Honoraria for speaker’s fees (payable to employing institution) Astra Zeneca, Ascelia, Bayer, Bristol Myers Squibb, Celgene, Eisai, GlaxoSmithKline, Nucana, MSD, Roche, Medivir, United Medical.

Support of costs of commercial clinical trials (payable to employing institution) Astra Zeneca, Basilea, Bayer, Celgene, MiNa Therapeutics, Roche, Pfizer, Sierra, Lilly, Eisai, Glaxo Smith Kline, Novartis, Bicycle Therapeutics, Halozyme, Johnson & Johnson, CytomX, Vertex, Plexxikon, Boehringer, Athinex, Adaptimmune, Bristol-Myers Squibb, MSD, Medivir, Versatem, Nucana, Immnuocore, Berg, Beigene, Iovance, Modulate, BiolinerX, Merck Serono, Nurix Therapeutics, T3P, Janssen Clovis, Sanofi-Aventis, Starpharma, UCB, Sapience, Seagen, Avacta, Codiak.

Support to attend international conferences (personal) Bayer, Celgene, Roche, Bristol-Myers Squibb, PIerre-Fabre, MSD.

Dr Sarah Hughes receives funding from the National Institute of Health and Care (NIHR) Oxford-Birmingham Blood and Transplant Research Unit, the NIHR Applied Research Collaboration (ARC) West Midlands, and UK SPINE. Dr Hughes declares personal fees from Aparito Limited, Astra Zeneca, CIS Oncology, Cochlear Limited, and ICON plc. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Dr Moreno Ursino acted as consultant for eXYSTAT, Saryga, PTC Therapeutics International Ltd., ImCheck Therapeutics. He also has projects, ongoing and ended, with Sanofi.

Dr Shing Lee served as a consultant for PTC Therapeutics.

Dr Mander is currently employed by GSK.

All other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Criteria for dropping items between Delphi survey rounds as well as automatic inclusion in checklists
Fig. 2
Fig. 2
Flow chart of the DEFINE Delphi survey
Fig. 3
Fig. 3
Bar plot of the percentage of respondents scoring each item in Round Two. Items in green text had at least 70% of respondents scoring them as “critically important” (scores 7 to 9)
See this image and copyright information in PMC

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