The membrane-bound mitochondrial bc 1 complex (b 6 f complex in chloroplasts and cyanobacteria) is a key component of the respiratory and photosynthetic electron transfer chains (see Refs. 1-5 for reviews). It catalyzes the transfer of electrons from ubiquinol to cytochrome c and couples this electron transfer to the vectorial translocation of protons across the inner mitochondrial membrane. It contributes to the proton-motive force, which is subsequently used by the ATP synthase to produce ATP. All bc complexes, from bacteria to higher eukaryotes, contain three subunits forming the catalytic core of the enzyme and carrying four redox centers as follows: the iron-sulfur protein (ISP) 1 with a [2Fe-2S] cluster; the monohemic cyt c 1 ; the dihemic mitochondrially encoded cytochrome b with a low potential b L heme (E m7 around Ϫ50 mV, where E m indicates equilibrium redox midpoint potential) located near the positive side of the membrane; and a high potential b H heme (E m7 around ϩ90 mV) located on the negative side of the membrane. In eukaryotic cells, in addition to these three conserved subunits, as many as eight additional subunits are found whose functions are poorly understood (5). The bc 1 complex catalytic activity is best described by the modified Q cycle (6 -9). Electrons are delivered into a bifurcated pathway at the Q O site. A first electron is transferred from quinol to the ISP (in the so-called high potential electron transfer pathway to cyt c 1 and the soluble cyt c), resulting in the formation of an unstable semiquinone which then transfers a second electron to hemes b L and b H (in the so-called low potential pathway) across the membrane. At the Q I site, on the negative side of the membrane, quinone is reduced to semiquinone by heme b H . Two molecules of ubiquinol at the Q O site are thus required to reduce a quinone to quinol at the Q I site. Although several models have been proposed to account for the bifurcated electron transfer at the Q O site (10 -15), the mechanism at the molecular level is not completely understood. Several threedimensional structures of eukaryotic bc 1 complexes have been obtained in the presence or absence of different inhibitors (16 -19), and more recently, the yeast bc 1 complex structure was obtained at 2.3 Å, including bound water molecules (20). These different structures as well as biochemical and spectroscopic data (21-29) suggest that the extrinsic carboxyl-terminal domain of the ISP carrying the [2Fe-2S] cluster moves between a position close to cyt b (proximal conformation or "b" state) and a position close to cyt c 1 (distal conformation or "c 1 " state), thus solving the apparent incompatibility between distances and rate of electron transfer between the redox centers (16 -19). This movement is made possible by the presence of a flexible "hinge" region (sequence 85 TADVLAMAK 93 in the yeast Saccharomyces cerevisiae) located after the transmembrane domain of the ISP. However, recent data (30, 31) obtained with the cyt b 6 f complex indicate that the ISP l...

Objectives: Medicinal products where active substance, strength, form, or administration route have been modified differ from generic drugs as bioequivalence cannot be demonstrated. In Europe, these 'hybrid' products have a clear registration pathway (Directive 2001/83/EC) requiring investment in pre-clinical and clinical trials. However; beyond the regulatory pathway, pricing and market access remains a national matter and few countries have specific methods to evaluate hybrids; both innovative-and generic-like prices may result. This study evaluated hybrid price differences and consequences for availability of hybrids across Europe. MethOds: Using IMS MIDAS data and the HMA database of registered drugs, we screened 5,000 products to identify 40 hybrid products which were significantly differentiated from the reference product, launched between 2008-2012 and analysed their prices and availability based on sales achieved, versus the reference product within and across 10 European markets. Results: Hybrid prices vary widely, but most frequently, generic rules are applied, limiting the interest of companies to make hybrids available across European markets. There is wide variation in availability of hybrids across markets, suggesting a decision not to launch in markets where prices are particularly unfavourable. Countries applying fixed generic pricing rules appear to have fewer hybrids. Yet where they are launched, hybrids are not classified as generics, so uptake is inhibited by non-substitution rules and prescribing quotas. cOnclusiOns: The lack of clear evaluation criteria and pricing variability within and across countries are barriers to the availability of hybrid products to patients in Europe. To the degree that such products better meet patient needs versus generic medicines, these barriers reduce patient welfare and prescriber choice. In a context where patient-oriented outcomes are increasingly seen as important, hybrid drugs have a role to play given their ability to improve administration, compliance, convenience and in some cases improve safety and efficacy. Consequently, clear rules for hybrid evaluation, pricing and access are desirable as they would improve patient care and reduce uncertainty for hybrid manufacturers.

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