Biosimilars clinical development program: Confirmatory clinical trials: A virtual/simulated case study comparing equivalence and non-inferiority approaches

AbstractAs part of long term commitment of the Biologicals and Vaccines Committee (B&V) of the International Federation of Pharmaceutical Manufacturers and Association (IFPMA) to provide expert input to the WHO on their recently finalized GUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS (SBPs), and in response to WHO’s request, the IFPMA B&V prepared a clinical case study at a recent WHO workshop in Seoul, Korea. The case study, presented by Mark Fletcher on behalf of B&V, involved a model scenario for a clinical efficacy trial to support the approval of a Similar Biotherapeutic Product (SBP) as part of the required comparative clinical program against a Reference Biotherapeutic Product (RBP). A key goal was to understand and illustrate key clinical and statistical principles, and considerations described in the WHO Guidance for regulatory authorities when designing and implementing WHO guidelines and post-approval regulatory oversight for SBPs.Using this model SBP/RBP pair, an interactive discussion was carried out among the workshop participants on the pros and cons of using equivalence vs. non-inferiority designs to assess the two products’ similarity. Through discussion of the case, the complexity of demonstrating similar efficacy and safety of a SBP vs. RBP for biotherapeutic products is outlined and discussed in the context of the key principles laid out in the recently published WHO GUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS (SBPs). The exercise illustrates the need for a case-by-case approach when interpreting clinical data from SBP dossiers to adequately assure similar efficacy and safety of SBPs for any studied indication

The WIGGUM gene is required for proper regulation of floral meristem size in Arabidopsis

The study of cell division control within developing tissues is central to understanding the processes of pattern formation. The floral meristem of angiosperms gives rise to floral organs in a particular number and pattern. Despite its critical role, little is known about how cell division is controlled in the floral meristem, and few genes involved have been identified. We describe the phenotypic effects of mutations in WIGGUM, a gene required for control of cell proliferation in the floral and apical meristem of Arabidopsis thaliana. wiggum flowers contain more organs, especially sepals and petals, than found in wild-type flowers. This organ number phenotype correlates with specific size changes in the early floral meristem, preceding organ initiation. Genetic studies suggest that WIGGUM acts on a similar process but in a separate pathway than the CLAVATA1 and CLAVATA3 genes in meristem size regulation, and reveal interactions with other genes affecting meristem structure and identity. Analysis of double mutant phenotypes also reveals a role for WIGGUM in apical meristem function. We propose that WIGGUM plays a role in restricting cell division relative to cellular differentiation in specific regions of the apical and floral meristems

Dietary Supplementation with Ethyl Ester Concentrates of Fish Oil (n-3) and Borage Oil (n-6) Polyunsaturated Fatty Acids Induces Epidermal Generation of Local Putative Anti-Inflammatory Metabolites

Clinical reports have attributed the amelioration of chronic inflammatory skin disorders to the presence of certain polyunsaturated fatty acids (PUFA) in dietary oils. To test the hypothesis of a local modulatory effect of these PUFA in the epidermis, the basal diet of normal guinea pigs was supplemented with ethyl esters of either fish oil [rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] or borage oi1 [rich in gamma-linolenic acid (GLA)]. Our data demonstrated that dietary oils influence the distribution of PUFA in epidermal phospholipids and the epidermal levels of PUFA-derived hydroxy fatty acids. Specifically, animals supplemented with ethyl esters of fish oil markedly incorporated EPA and DHA into epidermal phospholipids, which paralleled the epidermal accumulation of 1 5-hydroxyeicosapentaenoic acid (15-HEPE) and 17-hydroxydocosahexaenoic acid (17-HDoHE). Similarly, animals supplemented with esters of borage oil preferentially incorporated dihomogammalinolenic acid (DGLA), the epidermal elongase product of GLA, into the epidermal phospholipids, which also was ac- companied by epidermal accumulation of 15-hydroxyeicosatrienoic acid (15-HETrE). By factoring the epidermal levels of the 15-lipoxygenase products and their relative inhibitory potencies, we evolved a measure of the overall potential of dietary oils to exert local anti-inflammatory effect. For example, the leukotriene inhibition potentials (LIP) of both fish oil and borage oil were greatly enhanced when compared to controls. Thus, the altered profiles of epidermal 15-lipoxygenase products generated from particular dietary oils may be responsible, at least in part, for reported ameliorative effects of oils on chronic inflammatory skin disorders

The SBF Survey of Galaxy Distances. IV. SBF Magnitudes, Colors, and Distances

We report data for $I$ band Surface Brightness Fluctuation (SBF) magnitudes, V-I colors, and distance moduli for 300 galaxies. The Survey contains E, S0 and early-type spiral galaxies in the proportions of 49:42:9, and is essentially complete for E galaxies to Hubble velocities of 2000 km/s, with a substantial sampling of E galaxies out to 4000 km/s. The median error in distance modulus is 0.22 mag. We also present two new results from the Survey. (1) We compare the mean peculiar flow velocity (bulk flow) implied by our distances with predictions of typical cold dark matter transfer functions as a function of scale, and find very good agreement with cold, dark matter cosmologies if the transfer function scale parameter $\Gamma$, and the power spectrum normalization $\sigma_8$ are related by $\sigma_8 \Gamma^{-0.5} \approx 2\pm0.5$. Derived directly from velocities, this result is independent of the distribution of galaxies or models for biasing. The modest bulk flow contradicts reports of large-scale, large-amplitude flows in the $\sim200$ Mpc diameter volume surrounding our Survey volume. (2) We present a distance-independent measure of absolute galaxy luminosity, \Nbar, and show how it correlates with galaxy properties such as color and velocity dispersion, demonstrating its utility for measuring galaxy distances through large and unknown extinction.Comment: Accepted for publication in ApJ (10 January 2001); 23 page

Evaluation of 11C-Acetate and 18 F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2−/− mice in order to facilitate therapeutic translational studies from bench to bedside. Methods 18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2−/− mice (n = 3/tracer) with HCC and 12 m MDR2−/+ control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2−/− (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list. Results Hepatic18F-FDG metabolism was not significantly increased in MDR2−/− mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2−/− mice when compared to MDR2−/+ controls. Serum AFP and LPA levels increased in MDR2−/− mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative. Conclusions Hepatic 11C-acetate PET/CT tracks well with HCC in MDR2−/− mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study 1) HCC emergence/progression in patients and 2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC

Connection between igneous activity and extension in the central Mojave metamorphic core complex, California

This is the published version. Copyright 1976 American Geophysical Union. All Rights Reserved.The development of metamorphic core complexes and associated low-angle detachment faults commonly is intimately associated with synextensional igneous activity. In most areas studied to date, the relation of magmatism to extension is obscured by imprecise dating and by the overprint of later tectonic events. We present data from the early Miocene central Mojave metamorphic core complex (CMMCC) which indicate that extension was accompanied by igneous activity, as reflected by prekinematic, synkinematic, and postkinematic plutons and coeval volcanic rocks deposited in the associated extensional basins. The principal intrusion is an early Miocene granite pluton exposed in outcrops across an area greater than 400 km2. Dikes adjacent to the pluton are common in the Mitchel Range, at The Buttes, and at Fremont Peak. The overall orientation of the pluton and associated dikes is west-northwest, roughly perpendicular to the extension direction. Results of U-Pb analyses on zircon from two pluton and two dike samples yield ages of 20 to 23 Ma. Two other dike samples yield inconclusive results. Synextensional basins formed by detachment faulting during the core complex development. Rocks in these basins compose the Jackhammer and Pickhandle formations and filled an elongate, NW trending trough more than 50 km long. The 40Ar/39Ar ages for tuff beds are as old as 23.8±0.3 Ma near the base of the lower Pickhandle Formation and as young as 21.3±0.5 Ma in the uppermost lower Pickhandle. Hence volcanism and plutonism are coeval. The diversity of intrusive relations relative to the timing and development of the mylonitic fabric in the CMMCC precludes any simple cause-and-effect relationship between magmatism and extensional deformation. Rather, magmatism and extension may have been localized at a releasing bend in a transfer-fault system which links extension in the CMMCC with extension in the Colorado River area to the east

Comparing aging and fitness effects on brain anatomy

Recent studies suggest that cardiorespiratory fitness (CRF) mitigates the brain’s atrophy typically associated with aging, via a variety of beneficial mechanisms. One could argue that if CRF is generally counteracting the negative effects of aging, the same regions that display the greatest age-related volumetric loss should also show the largest beneficial effects of fitness. To test this hypothesis we examined structural MRI data from 54 healthy older adults (ages 55–87), to determine the overlap, across brain regions, of the profiles of age and fitness effects. Results showed that lower fitness and older age are associated with atrophy in several brain regions, replicating past studies. However, when the profiles of age and fitness effects were compared using a number of statistical approaches, the effects were not entirely overlapping. Interestingly, some of the regions that were most influenced by age were among those not influenced by fitness. Presumably, the age-related atrophy occurring in these regions is due to factors that are more impervious to the beneficial effects of fitness. Possible mechanisms supporting regional heterogeneity may include differential involvement in motor function, the presence of adult neurogenesis, and differential sensitivity to cerebrovascular, neurotrophic and metabolic factors

Atmospheric potential oxygen: New observations and their implications for some atmospheric and oceanic models

Measurements of atmospheric O2/N2 ratios and CO2 concentrations can be combined into a tracer known as atmospheric potential oxygen (APO ≈ O2/N2 + CO2) that is conservative with respect to terrestrial biological activity. Consequently, APO reflects primarily ocean biogeochemistry and atmospheric circulation. Building on the work of Stephens et al. (1998), we present a set of APO observations for the years 1996-2003 with unprecedented spatial coverage. Combining data from the Princeton and Scripps air sampling programs, the data set includes new observations collected from ships in the low-latitude Pacific. The data show a smaller interhemispheric APO gradient than was observed in past studies, and different structure within the hemispheres. These differences appear to be due primarily to real changes in the APO field over time. The data also show a significant maximum in APO near the equator. Following the approach of Gruber et al. (2001), we compare these observations with predictions of APO generated from ocean O2 and CO2 flux fields and forward models of atmospheric transport. Our model predictions differ from those of earlier modeling studies, reflecting primarily the choice of atmospheric transport model (TM3 in this study). The model predictions show generally good agreement with the observations, matching the size of the interhemispheric gradient, the approximate amplitude and extent of the equatorial maximum, and the amplitude and phasing of the seasonal APO cycle at most stations. Room for improvement remains. The agreement in the interhemispheric gradient appears to be coincidental; over the last decade, the true APO gradient has evolved to a value that is consistent with our time-independent model. In addition, the equatorial maximum is somewhat more pronounced in the data than the model. This may be due to overly vigorous model transport, or insufficient spatial resolution in the air-sea fluxes used in our modeling effort. Finally, the seasonal cycles predicted by the model of atmospheric transport show evidence of an excessive seasonal rectifier in the Aleutian Islands and smaller problems elsewhere. Copyright 2006 by the American Geophysical Union

A multinuclear solid state NMR, density functional theory and X-Ray diffraction study of hydrogen bonding in Group I hydrogen dibenzoates

An NMR crystallographic approach incorporating multinuclear solid state NMR (SSNMR), X-ray structure determinations and density functional theory (DFT) are used to characterise the H bonding arrangements in benzoic acid (BZA) and the corresponding Group I alkali metal hydrogen dibenzoates (HD) systems. Since the XRD data often cannot precisely confirm the proton position within the hydrogen bond, the relationship between the experimental SSNMR parameters and the ability of gauge included plane augmented wave (GIPAW) DFT to predict them becomes a powerful constraint that can assist with further structure refinement. Both the 1H and 13C MAS NMR methods provide primary descriptions of the H bonding via accurate measurements of the 1H and 13C isotropic chemical shifts, and the individual 13C chemical shift tensor elements; these are unequivocally corroborated by DFT calculations, which together accurately describe the trend of the H bonding strength as the size of the monovalent cation changes. In addition, 17O MAS and DOR NMR form a powerful combination to characterise the O environments, with the DOR technique providing highly resolved 17O NMR data which helps verify unequivocally the number of inequivalent O positions for the conventional 17O MAS NMR to process. Further multinuclear MAS and static NMR studies involving the quadrupolar 7Li, 39K, 87Rb and 133Cs nuclei, and the associated DFT calculations, provide trends and a corroboration of the H bond geometry which assist in the understanding of these arrangements. Even though the crystallographic H positions in each H bonding arrangement reported from the single crystal X-ray studies are prone to uncertainty, the good corroboration between the measured and DFT calculated chemical shift and quadrupole tensor parameters for the Group I alkali species suggest that these reported H positions are reliable