The similarity question for biologicals and non-biological complex drugs

AbstractFor small – low molecular weight – molecule medicines a robust regulatory system has evolved over the years. This system guarantees high and constant quality of our (generic) medicines. Pharmaceutical equivalence and bioequivalence assessment are the pillars under that system. But there are complex medicines where the question of equivalence is more challenging to answer. For biologicals the paradigm of similarity rather than equality (the emergence of ‘biosimilars’) was developed in the past decade. This has been a program where an evolutionary, science based approach has been chosen by the frontrunner regulatory body, the EMA, with a ‘learn and confirm’ character.In addition, there is another group of complex drugs, the non-biological complex drugs, NBCDs, where the generic paradigm can be challenged as well. The NBCDs are defined as: 1. consisting of a complex multitude of closely related structures; 2. the entire multitude is the active pharmaceutical ingredient; 3. the properties cannot be fully characterized by physicochemical analysis and 4. the consistent, tightly controlled manufacturing process is fundamental to reproduce the product. NBCDs encompass product families such as the glatiramoids, liposomes, iron–carbohydrate colloids and many candidates of the group of the upcoming nanoparticulate systems. Following the main principles of regulatory pathways for biologicals (with appropriate product-by-product adjustments), instead of that for small molecules, would be the more logical strategy for these NBCDs.The status and outstanding regulatory issues for biosimilars and NBCD-similars/follow on versions were discussed at a conference in Budapest, Hungary (October 2014) and this commentary touches upon the issues brought up in the presentations, deliberations and conclusions

A Proposed Role of Aeroelasticity in NASA's New Exploration Vision

On 14 January 2004, NASA received a mandate to return astronauts to the Moon, evolve a sustained presence there, then head out into the solar system to Mars and perhaps beyond. This new space exploration initiative directs NASA to develop human and robotic technologies that can deliver payloads larger than Apollo to the Moon, to Mars, and bring astronauts and samples safely back to Earth at costs much lower than Apollo. These challenges require creative aerospace systems. On proposed technology for safely delivering payloads to the surface of Mars and returning samples to Earth involves deployed flexible and inflatable decelerators for atmospheric entry. Because inflatable decelerators provide the entry vehicle more drag surface area at smaller mass than traditional ablative devices, this class of decelerators can potentially accomodate larger mass payloads. The flexibility of these lightweight aeroshells can pose both vehicle and aeroelastic stability problems if not properly designed for the expected flight regimes. Computational tools need to be developed for modelling the large and nonlinear deformations of these highly flexible structures. Unlike wind tunnel testing, an integrated and efficient aeroelastic analysis tool can explore the entire flight environment. This paper will provide some background on flexible deployable decelerators, survey the current state of technology and outline the proposed development of an aeroelastic analysis and capability

Search for the glueball candidates f0(1500) and fJ(1710) in gamma gamma collisions

Data taken with the ALEPH detector at LEP1 have been used to search for gamma gamma production of the glueball candidates f0(1500) and fJ(1710) via their decay to pi+pi-. No signal is observed and upper limits to the product of gamma gamma width and pi+pi- branching ratio of the f0(1500) and the fJ(1710) have been measured to be Gamma_(gamma gamma -> f0(1500)). BR(f0(1500)->pi+pi-) < 0.31 keV and Gamma_(gamma gamma -> fJ(1710)). BR(fJ(1710)->pi+pi-) < 0.55 keV at 95% confidence level.Comment: 10 pages, 3 figure

Search for supersymmetry with a dominant R-parity violating LQDbar couplings in e+e- collisions at centre-of-mass energies of 130GeV to 172 GeV

A search for pair-production of supersymmetric particles under the assumption that R-parity is violated via a dominant LQDbar coupling has been performed using the data collected by ALEPH at centre-of-mass energies of 130-172 GeV. The observed candidate events in the data are in agreement with the Standard Model expectation. This result is translated into lower limits on the masses of charginos, neutralinos, sleptons, sneutrinos and squarks. For instance, for m_0=500 GeV/c^2 and tan(beta)=sqrt(2) charginos with masses smaller than 81 GeV/c^2 and neutralinos with masses smaller than 29 GeV/c^2 are excluded at the 95% confidence level for any generation structure of the LQDbar coupling.Comment: 32 pages, 30 figure

Search for CP Violation in the Decay Z -> b (b bar) g

About three million hadronic decays of the Z collected by ALEPH in the years 1991-1994 are used to search for anomalous CP violation beyond the Standard Model in the decay Z -> b \bar{b} g. The study is performed by analyzing angular correlations between the two quarks and the gluon in three-jet events and by measuring the differential two-jet rate. No signal of CP violation is found. For the combinations of anomalous CP violating couplings, ${\hat{h}}_b = {\hat{h}}_{Ab}g_{Vb}-{\hat{h}}_{Vb}g_{Ab}$ and $h^{\ast}_b = \sqrt{\hat{h}_{Vb}^{2}+\hat{h}_{Ab}^{2}}$, limits of \hat{h}_b < 0.59$and$h^{\ast}_{b} < 3.02$ are given at 95\% CL.Comment: 8 pages, 1 postscript figure, uses here.sty, epsfig.st

Noble gas constraints on air-sea gas exchange and bubble fluxes

Author Posting. © American Geophysical Union, 2009. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 114 (2009): C11020, doi:10.1029/2009JC005396.Air-sea gas exchange is an important part of the biogeochemical cycles of many climatically and biologically relevant gases including CO2, O2, dimethyl sulfide and CH4. Here we use a three year observational time series of five noble gases (He, Ne, Ar, Kr, and Xe) at the Bermuda Atlantic Time series Study (BATS) site in tandem with a one-dimensional upper ocean model to develop an improved parameterization for air-sea gas exchange that explicitly includes separate components for diffusive gas exchange and bubble processes. Based on seasonal timescale noble gas data, this parameterization, which has a 1σ uncertainty of ±14% for diffusive gas exchange and ±29% for bubble fluxes, is more tightly constrained than previous parameterizations. Although the magnitude of diffusive gas exchange is within errors of that of Wanninkhof (1992), a commonly used parameterization, we find that bubble-mediated exchange, which is not explicitly included by Wanninkhof (1992) or many other formulations, is significant even for soluble gases. If one uses observed saturation anomalies of Ar (a gas with similar characteristics to O2) and a parameterization of gas exchange to calculate gas exchange fluxes, then the calculated fluxes differ by ∼240% if the parameterization presented here is used compared to using the Wanninkhof (1992) parameterization. If instead one includes the gas exchange parameterization in a model, then the calculated fluxes differ by ∼35% between using this parameterization and that of Wanninkhof (1992). These differences suggest that the bubble component should be explicitly included in a range of marine biogeochemical calculations that incorporate air-sea gas fluxes.Funding from the National Science Foundation Chemical Oceanography program (OCE-0221247 and OCE-0623034)

Psychology and aggression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68264/2/10.1177_002200275900300301.pd

Technology-Enabled Remote Monitoring and Self-Management - Vision for Patient Empowerment Following Cardiac and Vascular Surgery: User Testing and Randomized Controlled Trial Protocol.

BACKGROUND: Tens of thousands of cardiac and vascular surgeries (CaVS) are performed on seniors in Canada and the United Kingdom each year to improve survival, relieve disease symptoms, and improve health-related quality of life (HRQL). However, chronic postsurgical pain (CPSP), undetected or delayed detection of hemodynamic compromise, complications, and related poor functional status are major problems for substantial numbers of patients during the recovery process. To tackle this problem, we aim to refine and test the effectiveness of an eHealth-enabled service delivery intervention, TecHnology-Enabled remote monitoring and Self-MAnagemenT-VIsion for patient EmpoWerment following Cardiac and VasculaR surgery (THE SMArTVIEW, CoVeRed), which combines remote monitoring, education, and self-management training to optimize recovery outcomes and experience of seniors undergoing CaVS in Canada and the United Kingdom. OBJECTIVE: Our objectives are to (1) refine SMArTVIEW via high-fidelity user testing and (2) examine the effectiveness of SMArTVIEW via a randomized controlled trial (RCT). METHODS: CaVS patients and clinicians will engage in two cycles of focus groups and usability testing at each site; feedback will be elicited about expectations and experience of SMArTVIEW, in context. The data will be used to refine the SMArTVIEW eHealth delivery program. Upon transfer to the surgical ward (ie, post-intensive care unit [ICU]), 256 CaVS patients will be reassessed postoperatively and randomly allocated via an interactive Web randomization system to the intervention group or usual care. The SMArTVIEW intervention will run from surgical ward day 2 until 8 weeks following surgery. Outcome assessments will occur on postoperative day 30; at week 8; and at 3, 6, 9, and 12 months. The primary outcome is worst postop pain intensity upon movement in the previous 24 hours (Brief Pain Inventory-Short Form), averaged across the previous 14 days. Secondary outcomes include a composite of postoperative complications related to hemodynamic compromise-death, myocardial infarction, and nonfatal stroke- all-cause mortality and surgical site infections, functional status (Medical Outcomes Study Short Form-12), depressive symptoms (Geriatric Depression Scale), health service utilization-related costs (health service utilization data from the Institute for Clinical Evaluative Sciences data repository), and patient-level cost of recovery (Ambulatory Home Care Record). A linear mixed model will be used to assess the effects of the intervention on the primary outcome, with an a priori contrast of weekly average worst pain intensity upon movement to evaluate the primary endpoint of pain at 8 weeks postoperation. We will also examine the incremental cost of the intervention compared to usual care using a regression model to estimate the difference in expected health care costs between groups. RESULTS: Study start-up is underway and usability testing is scheduled to begin in the fall of 2016. CONCLUSIONS: Given our experience, dedicated industry partners, and related RCT infrastructure, we are confident we can make a lasting contribution to improving the care of seniors who undergo CaVS