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SummaryThis prospective, open-label, postauthorisation safety surveillance study assessed clinically significant inhibitor development in patients with severe haemophilia A transitioning from moroctocog alfa or other factor VIII (FVIII) replacement products to reformulated moroctocog alfa (AF-CC). Males aged12 years with severe haemophilia A (FVIII:C) < 1 IU/dl), > 150 exposure days (EDs) to recombinant or plasma-derived FVIII products, and no detectable inhibitor at screening were enrolled. Primary end point was the incidence of clinically significant FVIII inhibitor development. Secondary end points included annualised bleeding rate (ABR), less-than-expected therapeutic effect (LETE), and FVIII recovery. Patients were assigned to one of two cohorts based on whether they were transitioning to moroctocog alfa (AF-CC) from moroctocog alfa (cohort 1; n=146) or from another recombinant or plasma-derived FVIII product (cohort 2; n=62). Mean number of EDs on study was 94 (range, 1–139). Six positive FVIII inhibitor results, as determined by local laboratories, were reported in four patients; none were confirmed by a central laboratory, no inhibitor-related clinical manifestations were reported, and all anti-FVIII antibody assays were negative. Median ABRs were 23.4 and 3.4 in patients categorised at baseline as following on-demand and prophylactic regimens, respectively; 86.5 % of bleeding episodes resolved after one infusion. LETE incidence was 0.06 % and 0.19 % in the on-demand and prophylaxis settings, respectively. FVIII recovery remained constant throughout the study. No new safety concerns were identified. This study found no increased risk of clinically significant FVIII inhibitor development in patients transitioning from moroctocog alfa or other FVIII replacement products to moroctocog alfa (AF-CC).

Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients. Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

Background Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. Objectives To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. Patients and methods In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept™2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 : 2 to treatment with vatreptacog alfa (one to three doses at 80 μg kg−1) or rFVIIa (one to three doses at 90 μg kg−1). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. Results In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24–48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. Conclusions This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit–risk profile is unlikely to be achieved with vatreptacog alfa.

With the globalisation of economy, companies form alliances with business partners by participating in a virtual enterprises and combine their core competencies for greater impact. However, different organisations have different business processes and information management systems and hence the intellectual cooperation is hindered by conflicts and mis-interpretation of information. This paper examines the issues of creating and managing the content of the information infrastructure that is necessary to support successful operation of the virtual enterprise. The experience is drawn from the GLOBEMEN project of the IMS program. The paper describes the methods of organising and developing a structural analysis on the requirements of content management in the business processes of the virtual enterprise and the tools required for identifying information flow and the systems that people need to perform their tasks and decision-making processes.

The Generic Enterprise Reference Architecture and Methodology (GERAM) defines those methods, models and tools which are needed to identify and carry out change in enterprises. Enterprises need a life-cycle architecture that describes the progression of an enterprise from the point of realisation that change is necessary through setting up a project (or enterprise integration programme) and to implementing the change based on a thorough analysis and design. GERAM is a framework in which all necessary ingredients of this process are identified. GERAM allows one to characterise and compare all particular change methodologies and architectures, or helps in deciding how to combine ingredients of individual architectures and methods. GERAM is the result of generalisation, based on the three most complete enterprise reference architectures: CIM-OSA (Vernadat, 1992), the GRAI Integrated Methodology, GIM (Vallespir et al 1991), and the Purdue Enterprise Reference Architecture, PERA (Williams, 1992), but GERAM extends the scope of enterprise architecture to the life-cycle of Products, Enterprises, Enterprise Integration Projects, and Strategic Enterprise Management. It is also proposed which details of GERAM could be standardised.

The generic enterprise reference architecture and methodology is about those methods, models and tools which are needed to build the integrated enterprise. The architecture is generic because it applies to most, potentially all types of enterprise. The coverage of the framework spans products, enterprises, enterprise integration and strategic enterprise management. The proposal for the architecture follows the architecture itself improving the quality of the presentation and of the outcome. Definitions of generic enterprise reference architecture, enterprise engineering/integration methodology, enterprise modelling languages, enterprise models, and enterprise modules are given. It is proposed how the above could be developed on the basis of previously analysed architectures (and other results too), such as the purdue enterprise reference architecture (PERA) 1 , the GRAI integrated methodology 2 , CIM-OSA 3 , and TOVE 4 . GERAM is meant to unify existing architectures rather than intending to replace them. This is achieved by ensuring that the scope of GERAM spans all areas of consideration in an enterprise.

In multiphoton dissociation experiments on ketene (CH 2 CO) using a UV dye laser emission spectra were observed in the 360–370 nm range. The spectra were seen only with a focused laser beam and consist of lines attributable to emission from rotational levels in the ν ′ = 1 vibrational state of the B 2 Σ − electronic state of the methylidyne (CH) radical. In these spectra rotational transitions to the N ′ = 7 level of the B state from the ground (X) state, ν ″ = 0, were observed. Time-resolved fluorescence measurements on the N ′ = 1, 2, 3, 4, 5 and 6 levels yielded lifetime data contributing to the existing values in the literature. Based on line broadening a lifetime estimate is given for the strongly predissociated N ′ = 7 level.

This paper is a summary of the major technical report (Williams et al., 1993) of the IFAC/IFIP Task Force on Architectures for Integrating Manufacturing Activities and Enterprises. It presents a synopsis of the investigations of pertinent architectures undertaken, and the findings generated relating to the suitability of various architectures for the integration task. It also presents the Task Force's recommendations for achieving a “complete” architecture in terms of the necessary capabilities by “completing” a currently available architecture. The Task Force also outlined how a “best” architecture could be achieved by selecting and combining the best features of the available architectures.

An account is given of the possibilities and limitations of reusing Enterprise Models (EM). Measures are identified which ensure that models are interpreted as intended, thereby controlling the quality of the processes using enterprise models - such as enterprise engineering. A definition of model completeness is presented, based on a pragmatic theory of meaning and theory of communication. New requirements for Enterprise Engineering CASE tools are discussed.

The microwave spectrum of the butadiene-SO 2 complex has been observed with a Fourier transform microwave spectrometer. The rotational constants were determined as A=2793.8856(3) MHz, B=1325.4117(2) MHz, and C=1123.0275(2) MHz. In addition to the normal species, the spectra of eight other isotopic species were assigned. The structure was determined from the moments of inertia of all the isotopic species in a least-squares fitting procedure. The centers of mass of the two monomers are separated by 3.32(5) A with SO 2 sitting above the center of the butadiene plane

Over the next decade there will be revolutionary developments which will profoundly change the manufacturing paradigm. Production will be done in very small batches to supply high quality products. The techniques being developed today will result in much smaller operating plants which should be quickly and easily modified. Will the presently available reference models, which have just reached the maturity for international standardization, satisfy the design requirements of such fast changing structure? The paper summarizes the problems and identifies some ongoing actions.

BDDrFVIII is a B-domain deleted recombinant factor VIII (rFVIII) product for haemophilia A. Manufacture uniquely includes purification chromatography by synthetic-affinity ligand rather than murine-based monoclonal antibody, as well as an albumin-free cell culture process. BDDrFVIII was studied in 204 patients, including 62 subjects

With a plethora of architectures, modelling techniques and methodologies on offer, it is difficult to decide how to begin building an enterprise and achieving seamless integration. This difficulty is most noticeable in consortia that need to deal with government participation. Various government projects have different objectives and agenda. In addition, changes in business environment (or) as well as government policies impose extra conditions onto the project. Failure to comply with the project requirement can lead to loss of business and sometimes unexpected penalty. We use three case studies to show various ways of government involvements in our projects. Based on the experiences of these cases, we discuss how enterprise engineering can help creating and managing the enterprise that can engage government services successfully.