Abstract
Introduction: Commonly accepted standardized sets of outcomes to be measured in clinical trials are still limited. In accordance, outcome measures vary widely between clinical trials even within defined hematological malignancy (HM) entities. Definition of a core outcome set (COS), which represents a standardized agreed set of outcomes that should be measured and reported in all trials for the respective disease of interest may improve this situation. Furthermore, respective COS should address the need of all stakeholders, i.e. not only the views of physicians and industry running the trials, but also the interests of patients and regulators. To perform a task like this, HARMONY - Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms in Hematology - a private-public partnership established in January 2017, including 53 partners and 43 associated partners in 18 different European countries and also 6 patient organizations, poses an optimal platform to define COS for HMs.
Methods: To define COS for 5 selected HMs, it was decided to use the Delphi survey method provided by COMET initiative. Since HARMONY has members of several important stakeholder groups (clinicians, industry, health authorities and patient groups) it was decided to include all stakeholders to participate in the Delphi surveys. A pilot study was implemented for the COS for acute myeloid leukemia (AML) based on which additional Delphi surveys were developed for myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and chronic lymphocytic leukemia (CLL). As starting point preliminary outcome lists were generated based on published reports and available guidelines. Surveys were performed with representatives from each stakeholder group to agree within a pre-defined and iterative process on a COS for each HM. Conditions and criteria were defined in study protocols. Each outcome was rated into 3 categories (1-3 "not important", 4-6 "important but not critical" and 7-9 "critical"). A "consensus-in criterion" was defined if 70 % or more respondents scored the outcome as critically important (7-9) and 15% or fewer rated the outcome as limited important (1-3). To make sure that the patients' voice was heard within the consensus process, a special "patient-important criterion" had been implemented during data analysis. Outcomes ranked with a median of 7 or higher in the patient group were highlighted, showing these are really important for patients. According to a bottom-up-approach, an overarching COS was then created based on the individual survey results.
Results: For the Delphi surveys a total of 365 individuals participated including 126 clinicians (35%), 46 EFPIA members (13%), 177 patients/patient advocates (48%) and 16 regulators (4%). While there was a large overlap of outcomes among HMs, there were also many disease specific outcomes such as leukemia-free survival (LFS) for AML, very good partial response (VGPR) for MM to name only few. In addition, there were sometimes major differences in the assessment of individual stakeholders within an outcome, e.g. between clinicians and patients. Finally, the general COS applicable to all HMs included core outcomes that met the consensus-in criterion for all HMs.
Conclusion: Using Delphi surveys to define specific COS for HMs revealed meaningful results. Based on the bottom-up-approach not only disease specific HM COS could be defined, but also an overarching COS applicable to all HMs. This overarching COS will subsequently not only allow to compare results more easily within a distinct HM subgroup but also results across different HMs. To our knowledge, this is the first multidisciplinary approach to define COS across four different stakeholder groups. These COS should now be a starting point to further refine COS and to apply them within future clinical trials, thereby reducing inconsistencies and bias in outcome-reporting. Results of COS based clinical trials will simplify the development of novel clinical recommendations, which will improve future patient management and clinical patient care in the real-world setting.
Lang: Roche: Honoraria. Ossenkoppele: Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Döhner: Gilead: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Berlin-Chemie: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Ulm University Hospital: Current Employment; Astellas: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Pfizer: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Salles: Genmab: Consultancy; Incyte: Consultancy; Velosbio: Consultancy; Genentech/Roche: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Debiopharm: Consultancy; Allogene: Consultancy; Rapt: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Morphosys: Consultancy, Honoraria; Kite/Gilead: Consultancy; Ipsen: Consultancy; Takeda: Consultancy; Regeneron: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Dreyling: Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Sonneveld: Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Boccadoro: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding. Fenaux: Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Santini: Gilead: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Guillevic: BMS: Current Employment. Calado: Novartis: Current Employment. Sanz: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel, accommodations, and expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Hernández-Rivas: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Barbus: Abbvie: Current Employment. Schulze-Rath: Bayer: Current Employment. Bullinger: Menarini: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Bristol-Myers Squibb / Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Amgen: Honoraria; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.
