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BackgroundEarly 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).MethodsThe 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.ResultsThe 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.ConclusionsBy 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 registrationSPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network (https://www.equator-network.org/).

Additional file 5. Further details on the statistical analysis plan.

This report summarises findings from a retrospective review of medical records of patients undergoing in-vitro fertilisation (IVF) treatments that inform the redesign of the STOP-OHSS trial (IRAS Number: 298619; SPONSOR Reference: STH20532; REC Reference: 22/LO/0015; ISRCTN: 71978064). The design features of the STOP-OHSS trial, sample size estimates, and the statistical behaviour of the design in addressing the research questions under different assumptions are presented. The limitations of the design and implications of early stopping on trial duration are also discussed. Favourable ethical opinion for the STOP-OHSS Trial was granted by the London-South East Research Ethics Committee.

Additional file 9. Perception of proposed items and sensitivity analysis: Tables A9-1 – A9-3, Figures A9-1 – A9-13. Table A9-1. Summary of categorical and numerical ratings at Round One and 2. Figure A9-1. Percentage of participants changing their numerical scores at Round Two. Figure A9-2. Percentage of participants changing their categorical scores at Round Two. Table A9-2. Number of participants changing their ratings between Round One and Round Two. Table A9-3. Frequency and percentage of perfect agreement. Figure A9-3. Stacked bar plots of candidate item [17 SPIRIT-DEFINE] “Planned dosing regimens presented as a diagram or table, where applicable” by stakeholders. Figure A9-4. Stacked bar plots of candidate item [18 CONSORT-DEFINE] “Planned and delivered dosing regimens presented as a diagram or table, where applicable” by stakeholders. Figure A9-5. Stacked bar plots of candidate item [48 SPIRIT-DEFINE] “Statistical methods for additional analyses” by stakeholders. Figure A9-6. Stacked bar plots of candidate item [69 CONSORT-DEFINE] “Specify if and when results were reported whilst the trial was still ongoing” by stakeholders. Figure A9-7. Stacked bar plots of candidate item [70 SPIRIT-DEFINE] “Where the full trial protocol or the redacted version, with amendments, can be accessed” by stakeholders. Figure A9-8. Stacked bar plots of candidate item [17 SPIRIT-DEFINE] “Planned dosing regimens presented as a diagram or table, where applicable” by Continent. Figure A9-9. Stacked bar plots of candidate item [18 CONSORT-DEFINE] “Planned and delivered dosing regimens presented as a diagram or table, where applicable” by Continent. Figure A9-10. Stacked bar plots of candidate item [48 SPIRIT-DEFINE] “Statistical methods for additional analyses” by Continent. Figure A9-11. Stacked bar plots of candidate item [69 CONSORT-DEFINE] “Specify if and when results were reported whilst the trial was still ongoing” by Continent. Figure A9-12. Stacked bar plots of candidate item [70 SPIRIT-DEFINE] “Where the full trial protocol or the redacted version, with amendments, can be accessed” by Continent. Figure A9-13. Stacked bar plots of candidate item [5 SPIRIT-DEFINE] “Summary of findings from existing correlative biomarker, correlative and associated studies to support planned biomarker sub-study” by Continent.

Additional file 3. Organisations contacted for protocol templates or guidelines and responses.

Additional file 6. SPIRIT-DEFINE and CONSORT-DEFINE items generation for Delphi survey: Table A6-1. Table A6-1. References supporting the proposed candidate items in the DEFINE Delphi survey.

Additional file 11. Qualitative analysis. Table A11-1; Figure A11-1. Table A11-1. Themes and codes identified in the general comments received in Delphi survey. Figure A11-1. Tree diagram of the comments received per theme.

Additional file 8. Delphi survey participants demographics and harmonisation of roles: Tables A8-1 – A8-2. Table A8-1. Demographics of Delphi survey participants. Table A8-2. Harmonisation of participants’ defined roles.

Additional file 7. Toolkit for Lay Summary of EPDF Trial Results.

Additional file 4. Delphi Survey key stakeholder groups and methods of access.

BackgroundIncomplete reporting of the design, conduct and analysis of early phase dose-finding trials can hinder interpretability and reproducibility, and lead to erroneous conclusions on tolerability and efficacy. This methodological review investigates the reporting quality of published trials using broadly the CONSORT 2010 checklist with added items unique to dose-finding trials.MethodsMEDLINE (PubMed) was searched for articles published in 2011-2020. Phase I or I/II trials, with planned interim dosing decisions (de/escalate, stay at the current level or an early stop), which aim to find a recommended dosing regimen(s) for further testing, were included. Data were extracted for 476 randomly selected trials, stratified by cancer/non-cancer settings.ResultsThe key items that are frequently not reported include: n (%) reported cancer(n=238) non-cancer (n=238)Methods Planned/maximum sample size 69 (29%) 105 (44%) with justification 35 (15%) 59 (25%) Recruitment method 19 (8%) 51 (21%) Oversight committees 39 (16%) 90 (38%) roles and structure 17 (7%) 40 (17%) Who makes dose decisions 10 (4%) 39 (16%) Definition of analysis population: dose-determination 108 (45%) 111 (47%) Safety 114 (48%) 129 (54%) key outcomes 100 (42%) 131 (56%) Rationale for starting dose 52 (22%) 42 (18%)Results Baseline demographic and clinical characteristics by each dose level 70 (29%) 148 (62%) Settings and locations where data were collected 86 (36%) 149 (63%) Participant flow diagram/table 85 (36%) 144 (61%) Losses/exclusions for each dose level 30 (13%) 85 (36%)Only 1 (0.4%) cancer trial was randomised compared to 180 (75.6%) non-cancer trials. Notably, very few trials (6.3%) provided accessible protocols. Improvement in the reporting over time is evident in some items, including participant flow and sample size justification.ConclusionImportant methodological features in design, conduct and analysis are frequently omitted. Overall, non-cancer trials appear to be better reported, as mainly randomised, they may have adopted CONSORT 2010 guidance. This review confirms the need for robust consensus-driven guidance for researchers and journals reporting dose-finding trials, to allow accurate assessment of their results to reduce research waste.

In recent years, applications of partial randomisation to research funding processes have received growing attention from meta-researchers and research funders (Woods & Wilsdon, 2021a). Partial randomisation, also known as focal randomisation or random selection, is a method for allocating research funding. It is used in addition to peer review, where peer review has reached its limits and the qualities of applications are largely indistinguishable or ‘equally good’ (Bedessem, 2020). In this article we outline essential considerations for any study of partial randomisation of research funding, and consider scenarios in which RCTs would be relevant. We highlight the interdependence of target outcomes, sample availability and statistical power for determining the cost and feasibility of a trial. For many choices of target outcome RCTs may be less practical and more expensive than they first appear (in large part due to issues pertaining to sample size and statistical power). As such, we also introduce and briefly discuss alternatives to RCTs. It is worth noting that many of the considerations relevant to experiments on partial randomisation may also apply to other potential experiments on funding processes (see Bendiscioli et al, 2021).

Additional file 1. Brief overview of each scenario used in the Costing Adaptive Trials mock costing exercise.

Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised. This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process. The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text. The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites.“To maximise the benefit to society, you need to not just do research but do it well” Douglas G Altman

Additional file 1. Scenarios and guidance pre-revision.

Additional file 8: Appendix H. Example of a CONSORT flowchart for reporting a MAMS adaptive design.

Additional file 7: Appendix G. Example of a CONSORT flowchart for reporting a response-adaptive randomisation adaptive design with frequent randomisation updates.

Additional file 6: Appendix F. Example of a CONSORT flowchart for reporting a population enrichment adaptive design (assuming enrichment was not done at an interim analysis).

Additional file 4: Appendix D. Example of a CONSORT flowchart for reporting 2-stage adaptive design (such as inferential seamless) that use combination test methods.

Additional file 2: Appendix B. Additional examples of Box 13.

Additional file 1: Appendix A. Main ACE checklist available to download.

Additional file 5: Appendix E. Example of a CONSORT flowchart for reporting a population enrichment adaptive design (assuming enrichment was done at an interim analysis).

Additional file 3: Appendix C. Example 2 of Box 14 (Bayesian RAR).

Additional file 9: Appendix I. Box 22 - Dummy baseline table for the TAPPS trial.