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Background. Both ethical and economics concerns have been raised with respect to the funding of drugs for rare diseases. This article reports both the cost-effectiveness of eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and its associated opportunity costs. Methods. Analysis compared eculizumab plus current standard of care v. current standard of care from a publicly funded health care system perspective. A Markov model covered the major consequences of PNH and treatment. Cost-effectiveness was assessed in terms of the incremental cost per life year and per quality-adjusted life year (QALY) gained. Opportunity costs were assessed by the health gains foregone and the alternative uses for the additional resources. Results. Eculizumab is associated with greater life years (1.13), QALYs (2.45), and costs (CAN$5.24 million). The incremental cost per life year and per QALY gained is CAN$4.62 million and CAN$2.13 million, respectively. Based on established thresholds, the opportunity cost of funding eculizumab is 102.3 discounted QALYs per patient funded. Sensitivity and subgroup analysis confirmed the robustness of the results. If the acquisition cost of eculizumab was reduced by 98.5%, it could be considered cost-effective. Limitations. The nature of rare diseases means that data are often sparse for the conduct of economic evaluations. When data were limited, assumptions were made that biased results in favor of eculizumab. Conclusions. This study demonstrates the feasibility of conducting economic evaluations in the context of rare diseases. Eculizumab may provide substantive benefits to patients with PNH in terms of life expectancy and quality of life but at a high incremental cost and a substantial opportunity cost. Decision makers should fully consider the opportunity costs before making positive reimbursement decisions.

Johnson and others, 1 in their response to our recent paper, 2 highlight the need for transparency with respect to economic evaluations within rare diseases. We agree and wish to stress our belief that the same concern must be attached to reimbursement decisions with respect to such diseases. To demonstrate our commitment to such transparency, we would like to take this opportunity to respond to the specific concerns raised by Johnson and others. In addressing the external validity of our model, Johnson and others compare their interpolation of our results to the results of extension studies relating to the use of eculizumab, 3,4 Open-label extension studies in which patients are followed beyond the randomized phase of a clinical trial can be unreliable in assessing the efficacy of therapies primarily due to thelackofacomparatorgroupandpotentialselection bias due to dropouts. 5 At best, such studies may provide useful information relating to safety. The study by Hillmen and others 3 illustrates the concern over dropouts. The number of patients at onset, 195, had declined to 26 patients by 3 years and further to 9 patients by 5 years: the two time frames cited by

This paper describes the application of Kriging metamodeling in multiple-objective simulation optimization. An Arena-based simulation model of an (s, S) inventory system is utilized to demonstrate the capabilities of Kriging metamodeling as a simulation tool. Response surface methodology and Kriging metamodeling are compared to determine the situations in which one approach might be preferred over the other. The optimization approaches described here have the objective of finding the optimal values of reorder point s and maximum inventory level S so as to minimize the total cost of the inventory system while maximizing customer satisfaction. This paper describes two alternative approaches to utilizing Kriging methodology with multiple-objective optimization in simulation studies.

This paper describes a large-scale SLAM II- FORTRAN simulation model of a manufacturing plant that produces pipe valves and fittings. The model represents the functional areas of manufacturing (machining, heat treating, electropolishing, assembly, test and material movement) as well as the production planning and control system. The model allows for experimentation in a variety of areas, including production control, capacity planning, and layout design. Results of model experimentation indicate the advantages of conversion to a new single- floor facility over the existing multi-floor facility, as well as the advantages of a reduction in inventory levels for the plant.

Traditional techniques applied in the analysis of human-centered systems fail to recognize the human- and system-based uncertainties due to imprecision and vagueness of human thinking. A new methodology is needed to cope with ill-defined relationships between people, their machines and environments. The purpose of this paper is to introduce the concept of fuzziness, and to identify the potential applications of fuzzy set theory in the area of human factors. Examples of recent and ongoing studies on the relevant application of fuzzy sets in this area are also given.

Conclusions1. The depressant effects of anoxia on the completely isolated mammalian heart appeared at oxygen tensions well below those tolerated by the intact animal. The heart muscle, therefore, at least as examined in the present experiments, cannot be regarded as a limiting factor in tolerance of the intact animal for anoxia. 2. Increases in cardiac output (of purely cardiac origin) by the isolated heart under anoxia are seen only when C02 is absent from the ventilating gas. The effect appears to be due to the marked elevations in pH seen under these conditions, and, as such, is regarded as a systematic artefact rather than evidence of a direct stimulating effect of low oxygen tensions on the myocardium.