79MO - Developing international consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding clinical trials: The DEFINE (DosE FIndiNg Extensions) study

Background

Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it can be investigated in further trials. Guidance exists for clinical trial protocols and trial reports in the SPIRIT and CONSORT guidelines, respectively. The features of EPDF trials are not well addressed in both guidelines and their extensions. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols and reports.

Methods

The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were further enriched via a review of the published and grey literature, real-world examples analysis, citation and reference searches and experts’ recommendations. Following a 2-round modified Delphi process, an international consensus meeting was held. The resultant SPIRIT-DEFINE and the CONSORT-DEFINE checklists are then piloted prior to being finalised.

Results

Tailored to cover the specific features of EPDF trials, the Delphi survey included new or modified candidate items for SPIRIT (n = 36) and CONSORT (n = 44) extensions. 206 interdisciplinary stakeholders participated in Round 1 from 24 countries, and 151 stakeholders in Round 2. The Delphi results and a subsequent consensus meeting led to the recommendation of 31 and 36 candidate items for the SPIRIT-DEFINE and CONSORT-DEFINE checklists respectively. New items added include starting dose and dosing regimens with rationale, dose [de-]escalation strategies and decision criteria. International stakeholders are currently testing the checklists, and their feedback will be integrated into the final guidelines.

Conclusions

The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address the essential items that should be present in EPDF trial protocols and their reporting of the results. These will promote transparency, completeness and reproducibility of methods and ultimately contribute to reducing research waste and enhancing patient care and safety.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The Institute of Cancer Research.

Funding

Medical Research Council (MRC) and National Institute for Health Research (NIHR) Methodology Research Programme.

Disclosure

J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics; Non-Financial Interests, Personal, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline. A. Bedding: Financial Interests, Personal and Institutional, Full or part-time Employment: Roche; Non-Financial Interests, Personal, Advisory Board, Funding Panel Member: Medical Research Council. T.R..J. Evans: Financial Interests, Institutional, Advisory Board, Advisory Board for GI cancers and melanoma (immune checkpoint inhibitors): Bristol-Myers Squibb; Financial Interests, Institutional, Invited speaker - GI cancers, melanoma, immunotherapy: Bristol-Myers Squibb; Financial Interests, Institutional, Advisory Board - GI cancers, melanoma: Roche/Genentech; Financial Interests, Institutional, Invited speaker GI cancer, melanoma: Roche/Genentech; Financial Interests, Institutional, Advisory Board (Lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board: MSD, AstraZeneca, Medivir, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, Astra Zeneca, Bayer; Financial Interests, Institutional, Advisory Board, Advisory board: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees (and presentation to potential investors): Medivir; Financial Interests, Personal, Other, Support to attend international conferences: Bristol-Myers Squibb, Roche/Genentech, MSD, Nucana, Bayer, Celgene, Pierre Fabre; Financial Interests, Institutional, Advisory Board for Upper GI Cancer: Ascelia; Financial Interests, Institutional, Advisory Board for Oesophageal Cancer: Seagen; Financial Interests, Institutional, Invited Speaker, Educational Grant (supply of study agents) for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Reimbursement of study costs for commercial studies: Astellas, Bayer, Adaptimmune, Bristol-Myers Squibb, Basilea, Celgene, GSK, Eisai, MSD, Roche, Medivir, Nucana, Starpharma, Immunocore, Novartis, Sapience Therapeutics, MiNa Therapeutics, Lilly, Bicycle Therapeutics, Sierra, CytomX, BeiGene, Pfizer, Johnson & Johnson, iOnctura, UCB, Sanofi, Codiak, Avacta, Nurix, T3P; Financial Interests, Institutional, Invited Speaker, support for non-commercial investigator-led study: Verastem; Financial Interests, Institutional, Invited Speaker, reimbursement for costs of commercial studies: Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, reimbursement of costs of commercial study: Seagen; Non-Financial Interests, Personal, Other, Member of Clinical Experts Review Panel/Clinical Research Committee: Cancer Research UK; Non-Financial Interests, Personal, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Personal, Other, Annual Meeting Abstracts Committee: International Liver Cancer Association; Non-Financial Interests, Institutional, Product Samples, Supply of investigational and licensed compounds for a non-commercial study for which I'm Chief Investigator: AstraZeneca; Non-Financial Interests, Personal, Member, Cancer Society Member: American Society of Clinical Oncology, American Association for Cancer Research, British Association for Cancer Research, Association of Cancer Physicians (UK), European Association for Cancer Research, International Liver Cancer Association; Other, Personal, Other, Editor-in-Chief: British Journal of Cancer; Other, Personal, Other, Chair of Independent Data Monitoring Committee for a phase I trial - Honorarium payable to the employing institution: Genmab. S. Hughes: Financial Interests, Personal, Other, Research Consultancy: Cochlear Limited; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal and Institutional, Funding, Research Consultancy: Aparito, CIS Oncology; Non-Financial Interests, Institutional, Invited Speaker: British Academy of Audiology, British Medical Journal, RECOVER Consortium (US NIH); Non-Financial Interests, Personal, Other, Expert Panel Member: HEAR-Eco; Non-Financial Interests, Personal, Member: British Society of Audiology SIG. T. Jaki: Financial Interests, Personal, Funding: Bayer, Novartis; Financial Interests, Institutional, Funding: Roche, Merck, Regeneron. A. Mander: Financial Interests, Personal and Institutional, Stocks/Shares: GlaxoSmithKline; Financial Interests, Personal and Institutional, Full or part-time Employment: GlaxoSmithKline; Financial Interests, Personal, Stocks/Shares: AstraZeneca. M. Ursino: Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Personal, Training: eXYSTAT. C. Yap: Financial Interests, Personal, Advisory Board, Statistical Consultant: Faron Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker at a Training Workshop: Bayer; Financial Interests, Institutional, Research Grant: AstraZeneca, Celgene, Novartis; Financial Interests, Personal and Institutional, Research Grant: Faron Pharmaceuticals. All other authors have declared no conflicts of interest.