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

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/).

Enhancing reporting quality and impact of early phase dose-finding clinical trials: CONSORT Dose-finding Extension (CONSORT-DEFINE) guidance

“…A methodological review of published EPDF trials identified features and deficiencies in reporting to inform the initial generation of the candidate items for CONSORT-DEFINE,2940 based broadly on existing reporting guidelines or recommendations including CONSORT 2010,3738 SPIRIT 2013,46 Adaptive designs CONSORT Extension,18 a checklist proposal for phase 1 dose-finding cancer trials,47 as well as consultation with experts. Further candidate items were generated through the analysis of peer reviewed literature, unpublished or grey literature (eg, regulatory and industry advisory documents), citation tracking, and expert opinion 48…”

“…Two hundred and six participants from 24 countries voted in round one (March-May 2022), and 151 participants voted in round two (May-June 2022) of the Delphi survey. Round two participants were shown the distribution of the item rating as well as their previous rating if they had completed round one 48…”

“…During the Delphi process, 34 of 44 candidate items considered over two rounds of the Delphi survey met the criteria for inclusion in the checklist, leaving 10 items for consideration at the consensus meeting (table S1 in web appendix 1). Further details, including the methods and results of the Delphi process and the qualitative and quantitative analyses, are reported within the DEFINE development process paper 48…”

Ensuring Transparency and Quality of Clinical Trial Reporting in Clinical Pharmacology & Therapeutics: Prospective Trial Registration and Compliance with Reporting Guidelines Are Required for all Clinical Trials

“…A contributing factor to poor reporting quality could be that CONSORT 2010 was not designed for early phase dose‐finding trials with some important elements being either difficult to comply with or missing from the existing guidance. It was recognized that a modified guideline was required to improve reporting of phase I/II trials, especially dose (de)‐escalation trials 13,14 . This has now been addressed with the development and publication of the CONSORT – DosE FIndiNg Extension (CONSORT‐DEFINE) reporting guideline 15 .…”

Let’s make poor reporting of early phase dose finding clinical trials a thing of the past

“…While we anticipated various modifications and additions to the standard Spirit and Consort checklists, what took us by surprise was the sheer number of items that emerged as critically important. Furthermore, while we initially expected participation from around 100 people in the Delphi survey, we were astounded to have 206 participants from 24 different countries contribute to shaping the guidelines2.…”