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Early phase dose-finding (EPDF) trials are key in the development of novel therapies, with their findings directly informing subsequent clinical development phases and providing valuable insights for reverse translation. Comprehensive and transparent reporting of these studies is critical for their accurate and critical interpretation, which may improve and expedite therapeutic development. However, quality of reporting of design characteristics and results from EPDF trials is often variable and incomplete. The international consensus-based CONSORT-DEFINE (Consolidated Standards for Reporting Trials Dose-finding Extension) statement, an extension of the CONSORT statement for randomised trials, was developed to improve the reporting of EPDF trials. The CONSORT-DEFINE statement introduced 21 new items and modified 19 existing CONSORT items.This CONSORT-DEFINE Explanation and Elaboration (E&E) document provides important information to enhance understanding and facilitate the implementation of the CONSORT-DEFINE checklist. For each new or modified checklist item, we provide a detailed description and its rationale with supporting evidence, and present examples from EPDF trial reports published in peer-reviewed scientific journals. When reporting the results of EPDF trials, authors are encouraged to consult the CONSORT-DEFINE E&E document, together with the CONSORT and CONSORT-DEFINE statement papers, and adhere to their recommendations. Widespread adoption of the CONSORT-DEFINE statement is likely to enhance the reporting quality of EPDF trials, thus facilitating the peer review of such studies and their appraisal by researchers, regulators, ethics committee members, and funders., Funding: This work is a further extension of the CONSORT-DEFINE study, which was funded by the UK Medical Research Council (MRC)-National Institute for Health and Care Research (NIHR) Methodology Research Programme (MR/T044934/1). The Clinical Trials and Statistics Unit at The Institute of Cancer Research (ICR-CTSU) receives programmatic infrastructure funding from Cancer Research UK (C1491/A25351; CTUQQR-Dec 22/100 004), which has contributed to accelerating the advancement and successful completion of this work., Competing Interests: Example 1“We started with a once a day schedule and allowed for exploration of other dosing schedules according to the decision of the Safety Monitoring Committee (consisting of all principal investigators, the sponsor's medical and safety officers, and an independent expert, who made all decisions regarding patient safety, dose-limiting toxicity (DLT) qualification, dose escalation, and recommended dose definition).”148 This example addresses the composition of the decision making or safety review committee or group but lacks the reporting structure. Example 2“Prior to dosing of the next cohort, the Data Monitoring Committee (DMC), which included two independent clinicians with expertise in immunology/rheumatology and coagulopathies, reviewed blinded safety data from dosing to 14 days and PK [pharmacokinetics] data from at least seven days after the last administered dose within the previous dose cohort.”149 This example addresses the composition of the decision making or safety review committee or group but lacks the reporting structure. Example 3“The Data Monitoring Committee reviewed all available data and evaluated newly emergent safety data including dose-limiting toxicity and provided the Sponsor Safety Committee with recommendations for the next dose level.”54 This example addresses the reporting structure but lacks the composition of the decision making or safety review committee or group. ExplanationEPDF trials typically include frequent interim reviews of accumulated key outcome data and analyses to inform interim decisions, particularly on safety and dose adaptations. The decision-making committee/group typically involves members with relevant specialist expertise to assess an EPDF trial, including clinical (and pharmacological and toxicological, depending on the intervention) experience,150 who may not necessarily be independent from the sponsor.151 It is helpful to specify the composition of people who make decisions in EPDF trials, as their expertise and perspectives can influence the conduct and interpretation of results. Moreover, as the type and composition of decision-making groups vary across different trials, the provision of detailed information may increase transparency, enhance the trial's data credibility, and help readers assess potential biases. Details on the composition of any decision-making committee/group that reviewed key outcomes, such as safety and treatment tolerability, and made or recommended decisions (including dose (de-)escalation, dose expansion, or progression to another phase); summary of its role and reporting structure (see Example 3); and a statement on whether it is independent from the sponsor, funder, or trials team (see Example 1 and Example 2) and competing interests should be provided. It can be helpful to provide a reference to where further details, such as a charter, can be found if they are not in the report. Such an oversight committee/group in EPDF trials could be an individual or a group of members and is sometimes referred to as the safety review committee/group, the dose escalation committee/group, or the data (safety) monitoring committee or board.MD reports a research grant from the UK Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR) Methodology Research Programme (MR/T044934/1) that supported the conduct of the study; JB reports personal fees from Mirati, Insmed, EMD Serono, Ipsen, Merck, Sharp, Dohme, Merus, Bms, Bexion (unpaid), Mekanistic, Agenus (pending), Astellas, Amplia, grants from Abbvie, Astellas, Atreca, Bayer, Dragonfly, I-Mab, Lilly, Incyte, EMD Serono, Pfizer, BMS, Tyra, Totus, Sumitomo Dainippon Pharma Oncology, 23 and me, parthenon/Incendia, Hibercell, Ribosciences, NCI, personal fees from Astra Zeneca, Novocure, Boehringer-Ingelheim, outside the submitted work; OB reports personal fees from Bayer AG, outside the submitted work; MC reports grants from NIHR, UKRI, UK Research and Innovation, Merck, outside the submitted work; JdB reports personal fees from Abbvie, Acai Therapeutics, Amgen, Astellas, Amunix, Bayer, Bioxcel Therapeutics, Celcuity, grants and personal fees from Crescendo, personal fees from Daiichi, Dark Blue Therapeutics, Duke Street Bio Ltd, Dunad Therapeutics, Endeavor Biomedicines INC, grants and personal fees from Genentech/Roche, other from GSK, personal fees from Macrogenics, grants and personal fees from Merck Serono, grants and personal fees from MetaCurUm, personal fees from Moma, grants and personal fees from Myricx, personal fees and other from Novartis, grants and personal fees from Nurix Therapeutics, personal fees from Nuvation Bio, One Carbon Therapeutics Inc, grants and personal fees from Oncternal, Orion Pharma, personal fees from Page Therapeutics, grants and other from Pfizer, other from Takeda, Tango Therapeutics, personal fees from Tubulis GmbH, grants and personal fees from Sanofi, Immunic Therapeutics, outside the submitted work; in addition, JdB has a patent DNA Damage repair inhibitors for treatment of Cancer licensed to AstraZeneca, and a patent 17-substituted steroids useful in cancer treatment licensed to Janssen; TRJE reports grants, non-financial support and other from Astra Zeneca, grants and other from Bayer, Bicycle Therapeutics, Bristol-Myers Squibb, grants from Celgene, grants and other from Medivir, Eisai, grants, personal fees and other from MSD, Nucana, Roche, grants and other from Seagen, grants from Adaptimmune, grants from Astellas, Avacta, Basilea, Beigene, Codiak, CytomX, Immunocore, iOnctura, GSK, Johnson & Johnson, Novartis, MiNa Therapeutics, Lilly, Nurix, Sanofi, Sapience, Starpharma, Sierra, T3P, UCB, Verastem, other from Ascelia, Genmab, grants and other from CV6, other from Chugai, grants from Pfizer, Amgen, BioNTech, Exelexis, Moderna, personal fees from British Journal of Cancer, non-financial support from Immodulon, outside the submitted work; KH reports grants from National Health and Medical Research Council of Australia, outside the submitted work; OK reports the views and opinions expressed in this publication are those of the individual co-authors and may not be understood or quoted as being made on behalf of or reflecting the position of any organisation, committee, working party or group with which the co-authors are affiliated; LM reports personal honorarium from Bayer, personal fees from Eisai, Merck, LifeArc Strategic Advisory Board, unpaid role for Children with Cancer UK Scientific Advisory Board, as ACCELERATE Steering Committee member, ITCC Solid Tumour Steering Committee member, ITCC Industry Strategy Committee member, ECMC Paediatric Network Deputy Lead; RP is an employee and a stockholder in F Hoffmann la Roche; DR reports other from various pharma companies, outside the submitted work; YT has received speaking fees and/or honoraria from Abbvie, Eisai, Chugai, Eli-Lilly, Boehringer-Ingelheim, GlaxoSmithKline, Taisho, AstraZeneca, Daiichi-Sankyo, Gilead, Pfizer, UCB, Asahi-kasei, Astellas, received research grants from Boehringer-Ingelheim, Taisho, Chugai; MU reports personal fees from PTC Therapeutics International Ltd., personal fees from ImCheck Therapeutics, grants and personal fees from eXYSTAT, personal fees from Saryga, grants from Sanofi, other from Novartis, other from Roche, outside the submitted work; CJW reports grants from MRC-NIHR Methodology Research Programme Grant Ref: MR/T044934/1, during the conduct of the study; CY reports grants from Medical Research Council (MRC), Cancer Research UK and Experimental Cancer Medicine Centres, during the conduct of the study, personal fees from Faron Pharmaceuticals, Bayer and Merck, outside the submitted work. The other authors have no conflicts of interest to declare., (© 2024 The Author(s).)

Transparent and accurate reporting in early phase dose-finding (EPDF) clinical trials is crucial for informing subsequent larger trials. The SPIRIT statement, designed for trial protocol content, does not adequately cover the distinctive features of EPDF trials. Recent findings indicate that the protocol contents in past EPDF trials frequently lacked completeness and clarity. To address this gap, the international consensus-driven SPIRIT-DEFINE checklist was developed through a robust methodological framework for guideline development, with the aim to improve completeness and clarity in EPDF trial protocols. The checklist builds on the SPIRIT statement, adding 17 new items and modifying 15 existing ones.The SPIRIT-DEFINE explanation and elaboration (E&E) document provides comprehensive information to enhance understanding and usability of the SPIRIT-DEFINE checklist when writing an EPDF trial protocol. Each new or modified checklist item is accompanied by a detailed description, its rationale with supportive evidence, and examples of good reporting curated from EPDF trial protocols covering a range of therapeutic areas and interventions. We recommend utilising this paper alongside the SPIRIT statement, and any relevant extensions, to enhance the development and review of EPDF trial protocols.By facilitating adoption of the SPIRIT-DEFINE statement for EPDF trials, this E&E document can promote enhancement of methodological rigour, patient safety, transparency, and facilitate the generation of high-quality, reproducible evidence that will strengthen the foundation of early phase research and ultimately improve patient outcomes., Funding: This work is a further extension of the SPIRIT-DEFINE study, which obtained no external funding. The principal investigator (CY) used internal staff resources, together with additional resources from external partners, to conduct this study. The SPIRIT-DEFINE study is a component of the DEFINE project, which also developed the MRC/NIHR funded CONSORT-DEFINE guidance. ICR-CTSU receives programmatic infrastructure funding from Cancer Research UK (C1491/A25351; CTUQQR-Dec22/100004), which has contributed to accelerating the advancement and successful completion of this work., Competing Interests: Example 1“An internal monitoring committee (IMC) will monitor patient safety throughout the study. The IMC will include Sponsor representatives from Clinical Science, Drug Safety, Biostatistics, and Statistical Programming and Analysis. In addition to the ongoing assessment of the incidence and nature of adverse events (particularly Grade 3 events), SAEs, deaths, and laboratory abnormalities performed by the investigator and the Medical Monitor, the IMC will review data supporting the determination of the recommended phase 2 dose (RP2D) and then, at regular intervals during the expansion phase. At the time of each review, the IMC will make appropriate recommendations (e.g., the study should continue as planned, additional analyses should be performed, enrollment should be held pending further safety evaluations). Decisions will be made in consideration of the totality of the available data. Ad hoc meetings may be called in addition to scheduled meetings, as necessary, to provide recommendations on management of any potential new safety signals.”106Example 2“For Part A, the safety review committee (SRC) will be comprised by a sponsor medical representative, the Medical Monitor, a sponsor-independent investigator, and a site representative. For the decision to progress to Part B, an independent statistical consultant and a third party expert will also be included. Key roles of the SRC are as follows:-Before progression to the next cohort, assess the data, decide whether to approve initiation of the next cohort/dose level and to confirm the planned dose or define another dose for use. The data assessed by the SRC is defined in Section 1.1.-After completing its evaluation of the 48 h data for the first 6 subjects per group in cohort, the SRC may request a prolongation of the observation period to up to Day 7 data for later cohorts or other similar adaptions to protect subject wellbeing.-Throughout the trial, assess whether to replace trial subjects permanently discontinued due to safety issues.-Throughout the trial, approval from the SRC will be required prior to resuming any dosing in a “stopped” cohort (see Section 6.6.1). The SRC may call for the opening of a lower dose level cohort.-SRC may make recommendations on increasing the length of the observation periods and additional subject wellbeing calls may be included at the discretion of the SRC. The SRC will act according to its own written procedures described in a charter, and will prepare written minutes of its meetings.”107Example 3“The SMC [Safety Monitoring Committee] is an independent group of at least 3 experts that monitors subject safety and advises DMID [Sponsor]. SMC members will be separate and independent of study staff participating in this trial and should not have scientific, financial, or other conflicts of interest related to this trial. The SMC will consist of members with appropriate expertise to contribute to the interpretation of data from this trial. A quorum will consist of a simple majority. The SMC will hold an organizational meeting prior to enrollment. At this meeting, the SMC will review the charter, protocol, ICF, and safety report template. […] Procedures for SMC reviews/meetings will be defined in the SMC charter. The SMC will review applicable data, including, but not limited to, enrollment, demographics, dosing data, clinical laboratory data, and safety data, at scheduled timepoints during this trial as defined in the SMC charter. The SMC will review blinded aggregate data in the open session of the SMC meetings.”108ExplanationFor EPDF trials, with their focus on risk of harm, their characteristically adaptive nature, and a high number of possible interim analyses, it is key to be transparent in describing who will be involved in decision-making and, if possible, detail how decisions are made. The decision-making committee/group typically involves members with relevant specialist expertise to assess an EPDF trial, including clinical (and pharmacological and toxicological, depending on the intervention) experience,109 who may not necessarily be independent from the sponsor.110 Extensive information on the backgrounds of the committee/group members will increase the trial's credibility and reassure that the decision-making committee/group acts in the best interest of the trial participants. Authors should specify the composition of any decision-making committee/group who will review key outcomes, including safety and treatment tolerability, and make or recommend decisions (e.g., dose escalation/de-escalation, dose expansion, progression to another phase, stopping the trial early for futility). Such groups are sometimes referred to as a safety review committee/group, dose escalation committee/group, data (safety) monitoring committee or board, or similar. Details should include a summary of the role and reporting structure of the decision-making committee/group. A statement should be included addressing whether the decision-making committee/group is independent from the sponsor, funder, or trial team, and any competing interests should be described. Reference should be given to where further details, such as a decision-making committee charter, can be found, if not in the protocol.MU reports personal fees from PTC Therapeutics International Ltd., personal fees from ImCheck Therapeutics, grants and personal fees from eXYSTAT, personal fees from Saryga, grants from Sanofi, other from Novartis, other from Roche, outside the submitted work; GV reports personal fees from Pfizer, MSD, GSK, Pierre Fabrer and AstraZeneca, outside the submitted work; MD reports non-financial support from Sheffield Clinical Trials Research Unit during the conduct of the study; JB reports personal fees from Amplia, Astellas, Bayer, Nested, Mekanistic, Mirati, Merck, Oxford Biotherapeutics, Insmed, Merus, grants from AbbVie, Astellas, Atreca, Dragonfly, I-Mab, Incyte, Eli Lilly, BMS, Bayer, Pfizer, Sumitomo Dainippon Pharma Oncology, Tyra, Totus, 23 and me, Hibercell, Incendia, NCI, Ribosciences, grants and personal fees from Astra-Zeneca, personal fees from Novocure, from Boehringer-Ingelheim, outside the submitted work; OB reports personal fees from Bayer AG, outside the submitted work; MC reports grants from NIHR, UKRI, UK Research and Innovation, Merck, outside the submitted work; TRJE reports grants, non-financial support and other from Astra Zeneca, grants and other from Bayer, Bicycle Therapeutics, Bristol-Myers Squibb, grants from Celgene, grants and other from Medivir, Eisai, grants, personal fees and other from MSD, Nucana, Roche, grants and other from Seagen, grants from Adaptimmune, grants from Astellas, Avacta, Basilea, Beigene, Codiak, CytomX, Immunocore, iOnctura, GSK, Johnson & Johnson, Novartis, MiNa Therapeutics, Lilly, Nurix, Sanofi, Sapience, Starpharma, Sierra, T3P, UCB, Verastem, other from Ascelia, Genmab, grants and other from CV6, other from Chugai, grants from Pfizer, Amgen, BioNTech, Exelexis, Moderna, personal fees from British Journal of Cancer, non-financial support from Immodulon, outside the submitted work; KH reports grants from National Health and Medical Research Council of Australia, outside the submitted work; OK reports the views and opinions expressed in this publication are those of the individual co-authors and may not be understood or quoted as being made on behalf of or reflecting the position of any organisation, committee, working party or group with which the co-authors are affiliated; LM reports personal honorarium from Bayer, personal fees from Eisai, Merck, LifeArc Strategic Advisory Board, unpaid role for Children with Cancer UK Scientific Advisory Board, as ACCELERATE Steering Committee member, ITCC Solid Tumour Steering Committee member, ITCC Industry Strategy Committee member, ECMC Paediatric Network Deputy Lead; RP is an employee and a stockholder in F Hoffmann la Roche; DR reports other from various pharma companies, outside the submitted work; YT has received speaking fees and/or honoraria from Abbvie, Eisai, Chugai, Eli-Lilly, Behringer-Ingelheim, GlaxoSmithKline, Taisho, AstraZeneca, Daiichi-Sankyo, Gilead, Pfizer, UCB, Asahi-kasei, Astellas, received research grants from Behringer-Ingelheim, Taisho, Chugai; CJW reports grants from MRC-NIHR Methodology Research Programme Grant Ref: MR/T044934/1, during the conduct of the study; JSdB reports personal fees from Abbvie, Acai Therapeutics, Amgen, Astellas, Amunix, Bayer, Bioxcel Therapeutics, Celcuity, grants and personal fees from Crescendo, personal fees from Daiichi, Dark Blue Therapeutics, Duke Street Bo Ltd, Dunad Therapeutics, Endeavor Biomedicines INC, grants and personal fees from Genentech/Roche, other from GSK, personal fees from Macrogenics, grants and personal fees from Merck Serono, grants and personal fees from MetaCurUm, personal fees from Moma, grants and personal fees from Myricx, personal fees and other from Novartis, grants and personal fees from Nurix Therapeutics, personal fees from Nuvation Bio, One Carbon Therapeutics Inc, grants and personal fees from Oncternal, Orion Pharma, personal fees from Page Therapeutics, grants and other from Pfizer, other from Takeda, Tango Therapeutics, personal fees from Tubulis GmbH, grants and personal fees from Sanofi, Immunic Therapeutics, outside the submitted work; in addition, JSdB has a patent DNA Damage repair inhibitors for treatment of Cancer licensed to AstraZeneca, and a patent 17-substituted steroids useful in cancer treatment licensed to Janssen; CY reports grants from Cancer Research UK and Experimental Cancer Medicine Centres during the conduct of the study, personal fees from Faron Pharmaceuticals, Bayer and Merck, outside the submitted work. The other authors have no conflicts of interest to declare., (© 2024 The Author(s).)

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the MRC-NIHR Methodology Research Programme for the submitted work. JdB has served on advisory boards and received fees from companies including Amgen, Astra Zeneca, Astellas, Bayer, Bioxcel Therapeutics, Daiichi, Genentech/Roche, GlaxoSmithKline (GSK), Harpoon, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp and Dohme, Pfizer, and Sanofi Aventis; is an employee of the ICR, which has received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, and Vertex (the ICR has a commercial interest in abiraterone and poly (ADP-ribose) polymerase (PARP) inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income); was named as an inventor, with no financial interest for patent 8 822 438, submitted by Janssen that covers the use of abiraterone acetate with corticosteroids; has been chief investigator/principal investigator of many industry sponsored clinical trials; and is an NIHR senior investigator. 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. AM is employed by GSK. TRJE has received honorariums for consultancies (payable to the employing institution) from Ascelia, Astra Zeneca, Bayer, Bicycle Therapeutics, Bristol-Myers Squibb, Celgene Eisai, Karus Therapeutics, Medivir, MSD, Otsuka, Roche, and Seagen and honorariums for speaker’s fees (payable to employing institution) from Astra Zeneca, Ascelia, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Celgene, Eisai, Nucana, Otsuka, MSD, Roche, Medivir, Seagen, and United Medical; has received support of costs of commercial clinical trials (payable to employing institution) from Astra Zeneca, Basilea, Bayer, Celgene, MiNa Therapeutics, Roche, Pfizer, Sierra, Lilly, Eisai, GSK, Novartis, Bicycle Therapeutics, Johnson and Johnson, CytomX, Vertex, Plexxikon, Boehringer, Athinex, Adaptimmune, Bristol Myers Squibb, MSD, Medivir, Versatem, Nucana, Immunocore, Berg, Beigene, Iovance, Modulate, BiolinerX, Merck Serono, Nurix Therapeutics, T3P, Janssen Clovis, Sanofi-Aventis, Halozyme, Starpharma, UCB, Sapience, Seagen, Avacta, and Codiak; has received funding from Cancer Research UK, Chief Scientist’s Office Scotland, and the MRC; and is also the editor-in-chief of the British Journal of Cancer and has an honorary clinical contract with the NHS Greater Glasgow and Clyde Health Board. RP is an employee and a stockholder in F Hoffmann la Roche, and a family member is also an employee and a stockholder of F Hoffmann la Roche. KSH declares grant funding (payable to the employing institution) received by the Medical Research Future Fund (grant 2007425), National Health and Medical Research Council of Australia (grants 2016420 and 2015705), and Heart Foundation of Australia (grant 106607). SH and A-WC 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 MRC NIHR Better Methods, Better Research (MR/W020483/1). MU acted as consultant for eXYSTAT, Saryga, PTC Therapeutics International, ImCheck Therapeutics. MC is director of the Birmingham Health Partners Centre for Regulatory Science and Innovation, director of the Centre for Patient Reported Outcomes Research, and is an NIHR senior investigator. MJC receives funding from the NIHR, UK Research and Innovation (UKRI), NIHR Birmingham Biomedical Research Centre, NIHR Surgical Reconstruction and Microbiology Research Centre, NIHR, Applied Research Collaboration West Midlands, UK SPINE, Research England, European Regional Development Fund DEMAND Hub at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, and the NIHR Birmingham-Oxford Blood and Transplant Research Unit in Precision Transplant and Cellular Therapeutics; funding from Health Data Research UK, Innovate UK (part of UKRI), Macmillan Cancer Support, UCB Pharma, Janssen, GSK, Gilead Sciences, European Commission, European Federation of Pharmaceutical Industries and Associations, and the Brain Tumour Charity; personal fees from Aparito, CIS Oncology, Takeda Pharmaceuticals, Merck, Daiichi Sankyo, Glaukos, GSK, the Patient-Centered Outcomes Research Institute, Genentech, and Vertex Pharmaceuticals outside the submitted work; and lecture fees from the University of Maastricht, Maastricht, Netherlands; in addition, a family member owns shares in GSK. DPR is the volunteer vice president of the Canadian Arthritis Patient Alliance, a patient led and run organisation that derives most of its funding from independent grants from pharmaceutical companies. OB is an employee of Bayer AG. JM is an employee of Cytel (Australia). LS declares grant funding from AstraZeneca, Bayer, Pfizer, Merck, Roche, REPARE, Treadwell, and Janssen; has provided expert testimony for CADTH Health Canada; and also declares ownership of AstraZeneca stock/options. LM received speaker fees from Bayer; co-organiser, chair, and speaker fees at two educational preceptorships (online webinars); advisory board/consultancy honorariums from Tesaro, BMS, and Illumina; and is a member of external data monitoring committees for early phase clinical trials run between Eisai and Merck. RL is an employee and stockholder of Bristol Myers Squibb. JB declares consultancy fees from Mirati, Insmed, Oxford Biotherapeutics, Biosapien, EMD Serono, Ipsen, Merck Sharp and Dohme, Perus, BMS, and Bexion; grant funding from Abbvie, Astellas, Atreca, Bayer, Dragonfly, I-Mab, Lilly, Incyte, EMD Serono, Pfizer, BMS, Transcenta Therapeutics, Tyra, Totus, Sumitomo Dainippon Pharma Oncology, 23 and me, Parthenon, and Hibercell; JB also sits on data safety monitoring committees for Astra Zeneca, Novocure, and Boehringer-Ingelheim. All other authors declare no conflicts of interest.

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work. JdB has served on advisory boards and received fees from companies including Amgen, Astra Zeneca, Astellas, Bayer, Bioxcel Therapeutics, Daiichi, Genentech/Roche, GSK, Harpoon, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp and Dohme, Pfizer, and Sanofi Aventis; is an employee of the Institute of Cancer Research (ICR), which have received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme (MSD), Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, and Vertex (the ICR has a commercial interest in abiraterone and poly (ADP-ribose) polymerase (PARP) inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income)); was named as an inventor, with no financial interest, for patent 8 822 438, submitted by Janssen that covers the use of abiraterone acetate with corticosteroids; has been the chief investigator/principal investigator of many industry sponsored clinical trials; and is a National Institute for Health Research (NIHR) senior investigator. 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. AM is employed by GSK. TRJE has received honorariums for consultancies (payable to the employing institution) from Ascelia, Astra Zeneca, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Celgene Eisai, Karus Therapeutics, Medivir, MSD, Otsuka, Roche, and Seagen; honorariums for speaker’s fees (payable to employing institution) from Astra Zeneca, Ascelia, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Celgene, Eisai, Nucana, Otsuka, Medivir, MSD, Roche, Seagen, and United Medical; support of costs of commercial clinical trials (payable to employing institution) from Astra Zeneca, Basilea, Bayer, Celgene, MiNa Therapeutics, Roche, Pfizer, Sierra, Lilly, Eisai, Glaxo Smith Kline, Novartis, Bicycle Therapeutics, Johnson and 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, Halozyme, Starpharma, Union Chimique Belge, Sapience, Seagen, Avacta, and Codiak; and funding from Cancer Research UK, Chief Scientist’s Office Scotland, and Medical Research Council UK; is the editor-in-chief of the British Journal of Cancer and has an honorary clinical contract with the NHS Greater Glasgow and Clyde Health Board. RP is an employee and a stockholder in F Hoffmann la Roche, and a family member is also an employee and a stockholder of F Hoffmann la Roche. KSH declares grant funding (payable to the employing institution) received by the Medical Research Future Fund (grant 2007425), National Health and Medical Research Council of Australia (grants 2016420 and 2015705), and Heart Foundation of Australia (grant 106607). SH and A-WC are members of the SPIRIT-CONSORT executive group and are leading the current update of the SPIRIT 2013 and CONSORT 2010 reporting guidelines, funded by the UK Medical Research Council NIHR Better Methods, Better Research (MR/W020483/1). MU acted as consultant for eXYSTAT, Saryga, PTC Therapeutics International, and ImCheck Therapeutics. MC is director of the Birmingham Health Partners Centre for Regulatory Science and Innovation, director of the Centre for Patient Reported Outcomes Research, and is a NIHR senior investigator. MJC has received funding from the NIHR, UK Research and Innovation (UKRI), NIHR Birmingham Biomedical Research Centre, NIHR Surgical Reconstruction and Microbiology Research Centre, NIHR, Applied Research Collaboration West Midlands, UK SPINE, Research England, European Regional Development Fund DEMAND Hub at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, and NIHR Birmingham-Oxford Blood and Transplant Research Unit in Precision Transplant and Cellular Therapeutics; funding from Health Data Research UK, Innovate UK (part of UKRI), Macmillan Cancer Support, UCB Pharma, Janssen, GSK, Gilead Sciences, European Commission, European Federation of Pharmaceutical Industries and Associations, and the Brain Tumour Charity; and personal fees from Aparito, CIS Oncology, Takeda Pharmaceuticals, Merck, Daiichi Sankyo, Glaukos, GSK, the Patient-Centered Outcomes Research Institute, Genentech, and Vertex Pharmaceuticals outside the submitted work; has received lecture fees from the University of Maastricht, Maastricht, Netherlands; a family member owns shares in GSK. DPR is the volunteer vice president of the Canadian Arthritis Patient Alliance, a patient led and run organisation that derives most funding from independent grants from pharmaceutical companies. OB is an employee of Bayer AG. JM is an employee of Cytel (Australia). LS declares grant funding from AstraZeneca, Bayer, Pfizer, Merck, Roche, REPARE, Treadwell, and Janssen; has provided expert testimony for CADTH Health Canada; and declares AstraZeneca stock/options ownership. LM received honorariums for speaker fees from Bayer and as co-organiser, chair, and speaker at two educational preceptorships (online webinars); and advisory board/consultancy honorariums from Tesaro, BMS, and Illumina; is also a member of external data monitoring committees for early phase clinical trials run between Eisai and Merck. RL is an employee and stockholder of Bristol Myers Squibb. JB declares consultancy fees from Mirati, Insmed, Oxford BioTherapeutics, Biosapien, EMD Serono, Ipsen, Merck Sharp and Dohme, Perus, BMS, and Bexion; declares grant funding from Abbvie, Astellas, Atreca, Bayer, Dragonfly, I-Mab, Lilly, Incyte, EMD Serono, Pfizer, BMS, Transcenta Therapeutics, Tyra, Totus, Sumitomo Dainippon Pharma Oncology, 23 and me, Parthenon, and Hibercell; and sits on data safety monitoring committees for Astra Zeneca, Novocure, and Boehringer-Ingelheim. All other authors declare no conflict of interest.

Introduction: Early phase dose-finding (EPDF) studies are critical for the development of new treatments, directly influencing whether compounds or interventions can be investigated in further trials to confirm their safety and efficacy. There exists guidance for clinical trial protocols and reporting of completed trials in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and CONsolidated Standards Of Reporting Randomised Trials (CONSORT) 2010 statements. However, neither the original statements nor their extensions adequately cover the specific features of EPDF trials. The DEFINE (DosE-FIndiNg Extensions) study aims to enhance transparency, completeness, reproducibility and interpretation of EPDF trial protocols (SPIRIT-DEFINE) and their reports once completed (CONSORT-DEFINE), across all disease areas, building on the original SPIRIT 2013 and CONSORT 2010 statements., Methods and Analysis: A methodological review of published EPDF trials will be conducted to identify features and deficiencies in reporting and inform the initial generation of the candidate items. The early draft checklists will be enriched through a review of published and grey literature, real-world examples analysis, citation and reference searches and consultation with international experts, including regulators and journal editors. Development of CONSORT-DEFINE commenced in March 2021, followed by SPIRIT-DEFINE from January 2022. A modified Delphi process, involving worldwide, multidisciplinary and cross-sector key stakeholders, will be run to refine the checklists. An international consensus meeting in autumn 2022 will finalise the list of items to be included in both guidance extensions., Ethics and Dissemination: This project was approved by ICR's Committee for Clinical Research. The Health Research Authority confirmed Research Ethics Approval is not required. The dissemination strategy aims to maximise guideline awareness and uptake, including but not limited to dissemination in stakeholder meetings, conferences, peer-reviewed publications and on the EQUATOR Network and DEFINE study websites., Registration Details: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network., Competing Interests: Competing interests: JDB 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, GSK, Harpoon, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals. JDB 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, GSK, 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). JDB was named as an inventor with no financial interest in Patent No. 8822438 submitted by Janssen that covers the use of abiraterone acetate with corticosteroids. He has been the CI/PI of many industry-sponsored clinical trials. JDB is a National Institute for Health Research (NIHR) Senior Investigator. JE has received advisory board or speaker fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Bicycle Therapeutics, Celgene, Clovis, Eisai, Medivir, Nucana, and Roche/Genentech; and has received funding or other support for non-commercial and commercial studies from Adaptimmune, AstraZeneca, Astellas, Basilea, Bayer, Boehringer Ingelheim, Bicycle Therapeutics, Bristol-Myers Squibb, Beigene, Celgene, Codiak, CytomX, Eisai, GlaxoSmithKline, Immunocore, iOncture, Johnson and Johnson, Lilly, Medivir, Merck Sharp & Dohme, MiNa Therapeutics, Novartis, Nucana, Pfizer, and Roche/Genentech, Sanofi, Sapience Therapeutics, Seagen, Sierra, Starpharma, UCB and Verastem. Professor Evans serves as a member of the Clinical Experts Review Panel and Clinical Research Committee for Cancer Research UK, a member of the International Liver Cancer Association Annual Meeting abstracts committee and a member of Pancreatic Cancer Research Fund Scientific Advisory Panel. JE is also a member of the American Association for Cancer Research, the American Society of Clinical Oncology, the Association of Cancer Physicians (UK), the British Association for Cancer Research, the European Association for Cancer Research, and the International Liver Cancer Association. JE is a Clinical Subject editor for the British Journal of Cancer and has received honorarium payable to the employing institution for serving as chair of the Independent Data Monitoring Committee for a phase I trial., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)