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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/).

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. 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. 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.

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.

Background:Patient and carer access to medicines during the last 12 months of life (end-of-life) is critical for control of symptoms, including pain and distress, and for reducing urgent, unplanned use of healthcare services. However, data from our previous studies suggested that prescription, dispensing, supply and associated information given about medicines are experienced by patients as often difficult, demanding, lacking co-ordination, and involves a multiplicity of professionals. Although evidence is suggestive of patient and carer access problems with traditional service delivery systems, including General Practitioner care, little is known about this. Additionally, there are indications that critical sectors of the end-of-life workforce – palliative care nurse specialists and community pharmacists - are currently under-utilised. Furthermore, whilst there are some promising innovations in end-of-life care models, the impact of these on patient access to medicines, as well as their cost-effectiveness comparative to more traditional delivery models, remains largely un-evaluated. Our recent research also suggests that the supply chain ‘upstream’ may be a contributing factor to the complexity and problems with access experienced by patients. Aim:We aimed to provide an evaluation of patient and carer access to medicines at end-of-life within the context of models of service delivery. Design and data sources:Multiphase mixed methods design. 1: Systematic literature review. 2: Online questionnaire survey of healthcare professionals delivering end-of-life care. 3: Evaluative, mixed method case studies of service delivery models, including cost and cost-effectiveness analysis. 4: Interviews with community pharmacists and pharmaceutical wholesalers and distributors. 5: An expert consensus-building workshop. Findings:A systematic review identified a lack of evidence on service delivery models and patient experiences of accessing medicines at end-of-life. 1327 healthcare professionals completed an online survey. Findings showed General Practitioners remain a predominant route for patients to access prescriptions, but nurses and primary care-based pharmacists are also actively contributing. However, only 42% (160) of Clinical Nurse Specialists and 27% (27) of Community Nurses were trained as prescribers. The majority (58% 142) of prescribing nurses and pharmacists did not have access to an electronic prescribing system. Healthcare professionals’ satisfaction with access to shared patient records to facilitate medicines access was low: 39% (507) were either Not At All or only Slightly satisfied. Respondents perceived there would be a significant improvement in pain control if access to medicines was greater. Case studies highlighted differences in speed and ease of access to medicines between service delivery models. Healthcare professionals’ co-ordination facilitated the access process. The work of co-ordination was frequently burdensome, often due to hard-to-access General Practitioner services and unreliable community pharmacy medicines’ stock. Prescription cost differentials between services were modest but were substantial when accounting for the eligible population over the medium term. The supply chain generally ensured stocks of palliative medicines, but this was underpinned by onerous work by community pharmacists navigating multiple complex systems and wholesaler interfaces. Conclusion:Accessing medicines required considerable co-ordination work. Delays in access were linked to service delivery models that were over-reliant on GP prescribing, community pharmacy medicines’ unreliable stock, and Clinical Nurse Specialists’ lack of access to electronic prescribing. Key issues were relationships and team integration, diversifying the prescriber workforce, access to shared records and improved community pharmacy stock. Implications:Greater consideration should be given by service delivery commissioners and managers to implementing named end-of-life care co-ordinators. To expand and diversify the prescriber workforce, funding and support will be required to train more community nurse specialists and generalists to prescribe medicines independently to palliative care patients. Findings suggest all community-based healthcare professionals need access to electronic prescribing systems. Findings also point to the need for greater harmonisation of information technology systems so that all healthcare professionals have access to shared electronic patient records across service organisations’ interfaces. Commissioning telephone support services might offer single-point-of-contact, cost-effective models of provision that co-ordinate medicines access systems, and act as information-giving hubs for end-of-life medicines and services. Greater integration of community pharmacists within the wider community healthcare team to facilitate information-sharing about patients and their medicines is needed. Commissioning of community pharmacy services for palliative care would benefit from a shift to a more standardised core list of medicines, with greater and more even distribution of pharmacies or other community hubs holding stock, accessible out-of-hours. Pharmaceutical wholesalers / distributors need to engage with community pharmacists both individually and collectively for two-way communication about practices that reduce pharmacist work and best support palliative care medicines supply. Given the potential substantial cost differences between services, additional health economics research is required to generate further evidence to inform service provision decisions.