The DEFINE study: Guidance for Early Phase Dose-Finding trials

This project aims to develop extensions to the Consolidated Standards of Reporting Trials (CONSORT) and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for early phase dose-finding trials.

Background

The SPIRIT 2013 and CONSORT 2010 statements provide minimum guidance for writing protocol and reporting of randomised trials, and have been widely adopted. Several extensions have been developed to further refine the tool for specific types of studies (e.g. adaptive designs and cluster randomised trials).

Existing protocol and reporting guidance do not fully cover features specific to dose-finding. The DEFINE study aims to promote enhance transparency, completeness, reproducibility of methods and the interpretation of results of early phase trials, across all disease areas, and to build on the checklists outlined in the CONSORT 2010 and SPIRIT 2013 statements.

This will be achieved through a staged consensus process involving a broad range of stakeholders, before being widely disseminated for adoption by the wider scientific community.

Increasing efficiency and transparency in early phase trials will translate into a reduction of research waste and, ultimately, improve outcomes for patients.

Methodology

The DEFINE study will develop the dose-finding SPIRIT and CONSORT extensions following the EQUATOR (Enhancing the Quality and Transparency of Health Research) network’s methodological framework through a staged consensus process. It includes:

Conducting literature review and generating candidate items for each DEFINE extensions
Assessing the candidate items with international multi-stakeholders in a two to three stage Delphi survey.
Conducting an international consensus meeting to review the Delphi survey findings
Refining the draft checklist via a pilot run prior to it being finalised, as illustrated below:

DEFINE STUDY: SPIRIT AND CONSORT Extensions development steps.

The team

To ensure the guidance designed is as impactful and as widely adopted as possible, a multidisciplinary team of national and international experts and early phase trial stakeholders has been brought together to drive delivery of the project.

DEFINE Executive committee

Professor Christina Yap, Institute of Cancer Research (Principal Investigator)
Dr Munyaradzi Dimairo, University of Sheffield
Professor Christopher Weir, University of Edinburgh
Professor Adrian Mander, Cardiff University
Professor Thomas Jaki, Lancaster University / University of Cambridge
Professor Jeff Evans, University of Glasgow
Dr Rong Liu, Bristol-Myers Squibb
Associate Professor Shing Lee, Columbia University
Mr Andrew Kightley, Patient and Public Involvement lead
Associate Professor Sally Hopewell, University of Oxford
Professor Johann de Bono, Institute of Cancer Research
Dr Alun Bedding, Roche [CONSORT-DEFINE only]
Professor An-Wen Chan, University of Toronto [SPIRIT-DEFINE only]

DEFINE Research Team

Dr Olga Solovyeva, Institute of Cancer Research
Dr Jan Rekowski, Institute of Cancer Research
Ms Aude Espinasse, Institute of Cancer Research
Ms Dhrusti Patel, Institute of Cancer Research

Collaborators

Dr Moreno Ursino, Université de Paris [SPIRIT-DEFINE only]
Dr John KirkPatrick, Roche [SPIRIT-DEFINE only]

Advisors

Professor Stephen Hahn, Flagship Pioneering
Dr Khadija Rantell, MHRA

Independent expert panel

Professor Deborah Ashby, Imperial College London
Professor Elizabeth Garret-Mayer, American Society of Clinical Oncology [Chair]
Professor John Isaacs, Newcastle University
Professor Melanie Calvert, Birmingham University

Publications

The Dose-Finding SPIRIT (SPIRIT-DEFINE) and CONSORT (CONSORT-DEFINE) extension guidelines have have been published and can be consulted at the links below, or on the EQUATOR network website.

The Dose-Finding SPIRIT (SPIRIT-DEFINE) and CONSORT (CONSORT-DEFINE)guidelines development as well as the rapid methodological (scoping) review protocols have been published and are available from the links below:

The initiation of the work on the CONSORT-DEFINE project was announced in Nature Medicine (Yap et al. The need for reporting guidelines for early phase dose-finding trials: Dose-Finding CONSORT Extension. Nat Med. 2022 Jan;28(1):6-7. doi: 10.1038/s41591-021-01594-1. PMID: 34992264) and is accessible at the link below:

Nature Medicine CONSORT-DEFINE announcement paper.

A methodological review of the quality of reporting of early phase dose finding protocols (Villacampa et al. Assessing the reporting quality of early phase dose-finding trial protocols: a methodological review, eClinicalMedicine, Volume 60, 2023, 102020, ISSN 2589-5370, doi: 10.1016/j.eclinm.2023.102020.) has been conducted and is accessible at the link below:

Assessing the reporting quality of reporting of early phase dose-finding protocols: a methodological review

In partnership with a group of expert patient representatives, a toolkit for creating lay summaries of early phase dose-finding trials, comprising of a template, guidance notes and associated exemple has been created and is accessible at the link below:

DEFINE - Toolkit for lay summaries of EDPF trial results

The development of the SPIRIT-DEFINE and CONSORT-DEFINE extensions ( Solovyeva, O., Dimairo, M., Weir, C.J. et al. Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study. BMC Med 21, 246 (2023). https://doi.org/10.1186/s12916-023-02937-0)has been published and is available at the link below: