. 2025 Jan 10:79:102988.

doi: 10.1016/j.eclinm.2024.102988. eCollection 2025 Jan.

SPIRIT-DEFINE explanation and elaboration: recommendations for enhancing quality and impact of early phase dose-finding clinical trials protocols

Moreno Ursino^{1

2

3

4}, Guillermo Villacampa^{5

6

7}, Jan Rekowski⁵, Munyaradzi Dimairo⁸, Olga Solovyeva⁵, Deborah Ashby⁹, Jordan Berlin¹⁰, Oliver Boix¹¹, Melanie Calvert^{12

13

14

15

16}, An-Wen Chan¹⁷, Courtney H Coschi¹⁸, Thomas R Jeffry Evans¹⁹, Elizabeth Garrett-Mayer²⁰, Robert M Golub²¹, Christina Guo^{22

23}, Kathryn S Hayward^{24

25}, Sally Hopewell²⁶, John D Isaacs^{27

28}, S Percy Ivy²⁹, Thomas Jaki^{30

31}, Olga Kholmanskikh³², Andrew Kightley³³, Shing Lee³⁴, Rong Liu³⁵, Adrian Mander³⁶, Lynley V Marshall^{22

23}, James Matcham³⁷, Dhrusti Patel⁵, Richard Peck^{38

39}, Khadija Rerhou Rantell⁴⁰, Dawn P Richards⁴¹, Mahtab Rouhifard⁵, Lesley Seymour¹⁸, Yoshiya Tanaka⁴², Christopher J Weir⁴³, Johann de Bono^{22

23}, Christina Yap⁵

Affiliations

¹ ReCAP/F CRIN, INSERM, 5400, Nancy, France.
² Unit of Clinical Epidemiology, University Hospital Centre Robert Debré, Université Paris Cité, Paris, France.
³ INSERM, Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Paris, France.
⁴ HeKA Team, Centre Inria, Paris, France.
⁵ Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, UK.
⁶ Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
⁷ SOLTI Breast Cancer Research Group, Barcelona, Spain.
⁸ Division of Population Health, Sheffield Centre for Health and Related Research, University of Sheffield, Sheffield, UK.
⁹ School of Public Health, Imperial College London, St Mary's Hospital, London, UK.
¹⁰ Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
¹¹ Bayer, Berlin, Germany.
¹² Centre for Patient Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
¹³ Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, UK.
¹⁴ National Institute for Health and Care Research Applied Research Collaboration West Midlands, University of Birmingham, Birmingham, UK.
¹⁵ National Institute for Health and Care Research Blood and Transplant Research Unit in Precision Transplant and Cellular Therapeutics, University of Birmingham, Birmingham, UK.
¹⁶ National Institute for Health and Care Research Birmingham Biomedical Research Centre, NIHR Birmingham Biomedical Research Centre, Institute of Translational Medicine, University Hospital NHS Foundation Trust, Birmingham, UK.
¹⁷ Department of Medicine, Women's College Research Institute, University of Toronto, Toronto, Canada.
¹⁸ Canadian Cancer Trials Group, Kingston, ON, Canada.
¹⁹ Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK.
²⁰ Center for Research and Analytics, American Society of Clinical Oncology, Alexandria, VA, USA.
²¹ Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
²² The Institute of Cancer Research, London, UK.
²³ Royal Marsden NHS Foundation Trust, London, UK.
²⁴ Departments of Physiotherapy and Medicine, University of Melbourne, VIC, Australia.
²⁵ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.
²⁶ Oxford Clinical Research Unit, NDORMS, University of Oxford, Oxford, UK.
²⁷ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
²⁸ NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
²⁹ Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Institute of Health, Bethesda, MD, USA.
³⁰ MRC Biostatistics Unit, Cambridge University, Cambridge, UK.
³¹ Computational Statistics Group, University of Regensburg, Regensburg, Germany.
³² Federal Agency for Medicines and Health Products, Brussels, Belgium.
³³ Patient and Public Involvement and Engagement (PPIE) Lead, Lichfield, UK.
³⁴ Columbia University Mailman School of Public Health, New York, NY, USA.
³⁵ Regeneron, New York, NY, USA.
³⁶ Centre for Trials Research, Cardiff University, Cardiff, UK.
³⁷ Strategic Consulting, Cytel (Australia), Perth, WA, Australia.
³⁸ Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
³⁹ Hoffmann-La Roche, Basel, Switzerland.
⁴⁰ Medicines and Healthcare Products Regulatory Agency, London, UK.
⁴¹ Clinical Trials Ontario, MaRS Centre, Toronto, ON, Canada.
⁴² First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
⁴³ Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK.

PMID: 39877554
PMCID: PMC11773215
DOI: 10.1016/j.eclinm.2024.102988

SPIRIT-DEFINE explanation and elaboration: recommendations for enhancing quality and impact of early phase dose-finding clinical trials protocols

Moreno Ursino et al. EClinicalMedicine. 2025.

. 2025 Jan 10:79:102988.

doi: 10.1016/j.eclinm.2024.102988. eCollection 2025 Jan.

Authors

Affiliations

¹ ReCAP/F CRIN, INSERM, 5400, Nancy, France.
² Unit of Clinical Epidemiology, University Hospital Centre Robert Debré, Université Paris Cité, Paris, France.
³ INSERM, Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Paris, France.
⁴ HeKA Team, Centre Inria, Paris, France.
⁵ Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, UK.
⁶ Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
⁷ SOLTI Breast Cancer Research Group, Barcelona, Spain.
⁸ Division of Population Health, Sheffield Centre for Health and Related Research, University of Sheffield, Sheffield, UK.
⁹ School of Public Health, Imperial College London, St Mary's Hospital, London, UK.
¹⁰ Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
¹¹ Bayer, Berlin, Germany.
¹² Centre for Patient Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
¹³ Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, UK.
¹⁴ National Institute for Health and Care Research Applied Research Collaboration West Midlands, University of Birmingham, Birmingham, UK.
¹⁵ National Institute for Health and Care Research Blood and Transplant Research Unit in Precision Transplant and Cellular Therapeutics, University of Birmingham, Birmingham, UK.
¹⁶ National Institute for Health and Care Research Birmingham Biomedical Research Centre, NIHR Birmingham Biomedical Research Centre, Institute of Translational Medicine, University Hospital NHS Foundation Trust, Birmingham, UK.
¹⁷ Department of Medicine, Women's College Research Institute, University of Toronto, Toronto, Canada.
¹⁸ Canadian Cancer Trials Group, Kingston, ON, Canada.
¹⁹ Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK.
²⁰ Center for Research and Analytics, American Society of Clinical Oncology, Alexandria, VA, USA.
²¹ Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
²² The Institute of Cancer Research, London, UK.
²³ Royal Marsden NHS Foundation Trust, London, UK.
²⁴ Departments of Physiotherapy and Medicine, University of Melbourne, VIC, Australia.
²⁵ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.
²⁶ Oxford Clinical Research Unit, NDORMS, University of Oxford, Oxford, UK.
²⁷ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
²⁸ NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
²⁹ Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Institute of Health, Bethesda, MD, USA.
³⁰ MRC Biostatistics Unit, Cambridge University, Cambridge, UK.
³¹ Computational Statistics Group, University of Regensburg, Regensburg, Germany.
³² Federal Agency for Medicines and Health Products, Brussels, Belgium.
³³ Patient and Public Involvement and Engagement (PPIE) Lead, Lichfield, UK.
³⁴ Columbia University Mailman School of Public Health, New York, NY, USA.
³⁵ Regeneron, New York, NY, USA.
³⁶ Centre for Trials Research, Cardiff University, Cardiff, UK.
³⁷ Strategic Consulting, Cytel (Australia), Perth, WA, Australia.
³⁸ Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
³⁹ Hoffmann-La Roche, Basel, Switzerland.
⁴⁰ Medicines and Healthcare Products Regulatory Agency, London, UK.
⁴¹ Clinical Trials Ontario, MaRS Centre, Toronto, ON, Canada.
⁴² First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
⁴³ Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK.

PMID: 39877554
PMCID: PMC11773215
DOI: 10.1016/j.eclinm.2024.102988

Abstract

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.

Keywords: Dose escalation/de-escalation; Dose-finding; Early phase trials; Phase I; Protocol guidance; SPIRIT; SPIRIT-DEFINE.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**Fig. 1**
Item 6a.1, description of research question(s) and justification for undertaking the trial, Example 1—obtained from the study protocol of NCT04368728, which is available as supplementary material to Polak et al. The example has been adapted—only a portion of the original table is presented here, which has been reshaped into three columns with corresponding rewording.

**Fig. 2**
Item 8a.2, trial design schema to show the flow of major transition points, **(a)** Example 1—obtained from study NCT03150056 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world,**(b)** Example 2—obtained from study NCT03984812 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world.

**Fig. 3**
Item 8a.7, presentation of planned dose levels, **(a)** Example 1—obtained from the supplementary material of Rutherford et al. from *The Lancet Haematology*, reprinted with permission from Elsevier, **(b)** Example 2—obtained from study NCT03594955 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world, The example was masked as displayed in the original protocol.

**Fig. 4**
Item 12, primary, secondary, and other outcomes, Example 1—obtained from study NCT03681860 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world. The example has been adapted; only a portion of the original table is reported.

**Fig. 5**
Item 13, time schedule of enrolment, interventions, assessments, and visits for participants, **(a)** Example 1—obtained from study NCT03101358 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world,**(b)** Example 2—obtained from study NCT02661178 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world.

**Fig. 6**
Item 14, estimated number of participants, **(a)** Example 1—obtained from the supplementary material of Rutherford et al. from *The Lancet Haematology*, reprinted with permission from Elsevier. The example has been adapted—only a portion of the original table is reported here, **(b)** Example 2—obtained from study NCT02865434 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world.

**Fig. 7**
Item 20a.2, for the proposed adaptive design features, statistical methods used for estimation and to make inferences, Example 2—obtained from study NCT02942264 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world.

**Fig. 8**
Item 20c.1, analysis population(s), Example 1—obtained from study NCT03539484 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world.

**Fig. 9**
Item 34, dose transition pathways or dose decision paths, **(a)** Example 1—obtained from study NCT02964507 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world,**(b)** Example 2—obtained from Cole et al, used under the terms of the Creative Commons CC BY licence.

**Fig. 10**
Item 34, dose transition pathways or dose decision paths, **(a)** Example 3—obtained from study NCT03433222 on ClinicalTrials.gov (https://clinicaltrials.gov), a database of privately and publicly funded clinical studies conducted around the world,**(b)** Example 4—obtained from Figure 2 in Kramer et al, reprinted from the *Journal of Stroke and Cerebrovascular Diseases* with permission from Elsevier.

See this image and copyright information in PMC

References

1. Espinasse A., Solovyeva O., Dimairo M., et al. SPIRIT and CONSORT extensions for early phase dose-finding clinical trials: the DEFINE (DosE-FIndiNg Extensions) study protocol. BMJ Open. 2023;13(3):e068173. - PMC - PubMed
1. 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. 2023;21(1):246. - PMC - PubMed
1. Araujo D., Greystoke A., Bates S., et al. Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022. Ann Oncol. 2023;34(1):48–60. - PubMed
1. US Food and Drug Administration Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases guidance for Industry. 2023. https://www.fda.gov/media/164555/download
1. Villacampa G., Patel D., Zheng H., et al. Assessing the reporting quality of early phase dose-finding trial protocols: a methodological review. eClinicalMedicine. 2023;60 - PMC - PubMed

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SPIRIT-DEFINE explanation and elaboration: recommendations for enhancing quality and impact of early phase dose-finding clinical trials protocols

Affiliations

SPIRIT-DEFINE explanation and elaboration: recommendations for enhancing quality and impact of early phase dose-finding clinical trials protocols

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Conflict of interest statement

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