Priority setting: what constitutes success? A conceptual framework for successful priority setting

BACKGROUND: The sustainability of healthcare systems worldwide is threatened by a growing demand for services and expensive innovative technologies. Decision makers struggle in this environment to set priorities appropriately, particularly because they lack consensus about which values should guide their decisions. One way to approach this problem is to determine what all relevant stakeholders understand successful priority setting to mean. The goal of this research was to develop a conceptual framework for successful priority setting. METHODS: Three separate empirical studies were completed using qualitative data collection methods (one-on-one interviews with healthcare decision makers from across Canada; focus groups with representation of patients, caregivers and policy makers; and Delphi study including scholars and decision makers from five countries). RESULTS: This paper synthesizes the findings from three studies into a framework of ten separate but interconnected elements germane to successful priority setting: stakeholder understanding, shifted priorities/reallocation of resources, decision making quality, stakeholder acceptance and satisfaction, positive externalities, stakeholder engagement, use of explicit process, information management, consideration of values and context, and revision or appeals mechanism. CONCLUSION: The ten elements specify both quantitative and qualitative dimensions of priority setting and relate to both process and outcome components. To our knowledge, this is the first framework that describes successful priority setting. The ten elements identified in this research provide guidance for decision makers and a common language to discuss priority setting success and work toward improving priority setting efforts

Natural Form of Noncytolytic Flexible Human Fc as a Long-Acting Carrier of Agonistic Ligand, Erythropoietin

Human IgG1 Fc has been widely used as a bioconjugate, but exhibits shortcomings, such as antibody- and complement-mediated cytotoxicity as well as decreased bioactivity, when applied to agonistic proteins. Here, we constructed a nonimmunogenic, noncytolytic and flexible hybrid Fc (hyFc) consisting of IgD and IgG4, and tested its function using erythropoietin (EPO) conjugate, EPO-hyFc. Despite low amino acid homology (20.5%) between IgD Fc and IgG4 Fc, EPO-hyFc retained “Y-shaped” structure and repeated intravenous administrations of EPO-hyFc into monkeys did not generate EPO-hyFc-specific antibody responses. Furthermore, EPO-hyFc could not bind to FcγR I and C1q in contrast to EPO-IgG1 Fc. In addition, EPO-hyFc exhibited better in vitro bioactivity and in vivo bioactivity in rats than EPO-IgG1 Fc, presumably due to the high flexibility of IgD. Moreover, the mean serum half-life of EPO-hyFc(H), a high sialic acid content form of EPO-hyFc, was approximately 2-fold longer than that of the heavily glycosylated EPO, darbepoetin alfa, in rats. More importantly, subcutaneous injection of EPO-hyFc(H) not only induced a significantly greater elevation of serum hemoglobin levels than darbepoetin alfa in both normal rats and cisplatin-induced anemic rats, but also displayed a delayed time to maximal serum level and twice final area-under-the-curve (AUClast). Taken together, hyFc might be a more attractive Fc conjugate for agonistic proteins/peptides than IgG1 Fc due to its capability to elongate their half-lives without inducing host effector functions and hindering bioactivity of fused molecules. Additionally, a head-to-head comparison demonstrated that hyFc-fusion strategy more effectively improved the in vivo bioactivity of EPO than the hyperglycosylation approach