Structured Frameworks to Increase the Transparency of the Assessment of Benefits and Risks of Medicines: Current Status and Possible Future Directions.

Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions.

Refining the benefit-risk framework for the assessment of medicines: valuing and weighting benefit and risk parameters.

A common framework is necessary for the transparent articulation of the benefits and risks of a therapeutic product across disparate stakeholders. The assignment of value and weighting to each component parameter presents challenges deriving from different stakeholder objectives, methods, and perspectives. Building on prior experiences with a validated framework approach, this forum focused on identifying challenges and approaches to the assignment of values and weightings using a case study applied to a hypothetical medicinal product.

Application of the BRAT framework to case studies: observations and insights.

The BRAT Framework is a set of flexible processes and tools that provides a structured approach to pharmaceutical benefit-risk decision making in drug development and post approval settings. A work in progress, it consists of six steps that produce representations of key tradeoffs, with appropriate documentation of the rationale for decisions and the assumptions made in their development. This article describes insights, gained from case studies, into the Framework's performance in a variety of constructed benefit-risk scenarios, focusing on a hypothetical example of a triptan for migraine. The scenarios described illustrate the challenges inherent in arriving at many of the regulatory decisions, including obtaining data for matching populations for all outcomes, finding data of consistent quality, addressing correlated outcomes (e.g., elevated liver function tests and hepatitis rates), dealing with rare but serious adverse events (AEs), and understanding and making decisions based on information for many outcomes simultaneously. The Framework provides a structure for organizing, interpreting, and communicating relevant information, including heterogeneity in results and the quality and level of uncertainty of data, in order to facilitate benefit-risk decisions.

A concise display of multiple end points for benefit-risk assessment.

The assessment and representation of benefit-risk "balance" in pharmaceutical development have become increasingly important. Although the methodologies may vary considerably in complexity, most approaches to benefit-risk assessment require the simultaneous consideration of information pertaining to multiple end points for multiple treatments. However, the lengthy data tables and displays that are frequently used make this assessment difficult. Using an example from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, this note presents a conceptually simple visualization that facilitates understanding of information on multiple points.

[Level of natural autoantibodies to interferon-alpha and characteristics of interferon status during chronic hepatitis and liver cirrhosis].

Level of autoantibodies to interferon-alpha and characteristics of interferon status were studied in 118 patients with chronic diffuse liver diseases (CDLD). During formation of liver cirrhosis in patients with CDLD level of natural autoantibodies to endogenous interferon-alpha increased. During progression of CDLD, decrease of interferon-alpha level and its functional activity were observed as well as change in the ratio between active fraction of interferon-alpha and its inactivated forms towards increase of the latter. One cause of observed decrease in biological functional activity of interferon-alpha in patients with chronic hepatitis and liver cirrhosis was increased titer of interferon-alpha neutralizing autoantibodies in blood. Level of natural autoantibodies to interferon-alpha, its antiviral activity and concentration during chronic hepatitis and liver cirrhosis can be used as markers of disease severity and predictors of its outcome.

[Immunogenetic HLA markers of chronic viral hepatitis].

AIM: To study possible immunogenetic HLA markers of chronic viral hepatitides. MATERIAL AND METHODS: Using the reaction of complement-dependent cytotoxicity by Terasaki, we analysed distribution of leukocytic HLA antigens (loci A, B and C) in 179 patients with chronic viral hepatitides B, C and D in Russians and Kazakhs living in the Astrakhan Region. RESULTS: In the Russian population we discovered a significant positive association of CVHB with HLA-B18, HLA-B35, HLA-B40, HLA-Cw3 antigens, and negative one--with HLA-A2. In Kazakhs with CVHB there was a positive association with HLA-A3, HLA-B18 and negative one--with HLA-A11. Alleles HLA-A10, HLA-B35, HLA-B40 and HLA-Cw3 mark CVHC in Russians. HLA-Cw4 specificity acts as protector in development of chronic HCV-infection. A correlation was found between carriage of some specificities and haplotypes of HLA and activity of chronic HBV and HCV infection. A high risk of chronic delta infection in Russians is associated with HLA-B8 and HLA-B35, in Kazakhs--with HLA-B35 and HLA-D40. There are significant associations between CVHB, CVHC, chronic delta infection and some HLA haplotypes. CONCLUSION: A universal role of HLA-B35 specificity in development of CVH irrespective of hepatotropic virus and patients' nationality is shown.

[Tumor necrosis factor-alpha and interleukin-4 in the blood sera of chronic hepatitis patients]. / Uroven' faktora nekroza opukholi-alpha i interleikina-4 v syvorotke krovi bol'nykh khronicheskim gepatitom.

The concentration of tumor necrosis factor-alpha (TNF-alpha) and interleukin-4 (IL-4) in the blood sera of chronic hepatitis patients was, on the average, reliably higher than in the control group. A more pronounced increase in the concentration of TNF-alpha in the blood sera was observed in patients with chronic hepatitis of viral etiology in comparison with toxic hepatitis. The pronounced cytokine response of type Th2, manifested by the excessive production of IL-4, was typical for hepatitis B virus and hepatitis C virus infections, but not characteristic of hepatitis D virus infection. The replication activity of hepatotropic viruses induced a powerful cytokine response. In the presence of active virus replication in patients with chronic hepatitis B the levels of both TNF-alpha and IL-4 in their blood sera proved to be reliably higher than in patients with hepatitis B virus in the interactive phase.

[The role of cytokines and interferon-alpha in the pathogenesis of chronic diffuse diseases of the liver]. / Rol' tsitokinov i interferona-al'fa v patogeneze khronicheskikh diffuznykh zabolevanii pecheni.

The cytokine profiles were investigated in 171 patients with chronic hepatitis (CH) and in 173 patients with liver cirrhosis (LC). Increasing mean concentrations of IFN-alpha, TNF-alpha, IL-4 and IL-6 in blood serum as well as of the functional (antiviral and cytolytic) activity of IFN-alpha and TNF-alpha were found to be typical of a majority of CH and LC patients. Higher concentrations of IFN-alpha, IL-1, TNF-alpha and IL-6 in blood serum of CH patients are more typical of viral hepatitis versus alcoholic one. The replicative activity of hepatotropic viruses induces a powerful cytokine response. The LC etiology did not have any essential impact, in a majority of cases, on the blood-serum cytokine profile. A low function activity of TNF-alpha in blood serum signifies that the biological effects of the above cytokine are blocked. Finally, such analysis of the parameters of concentrations and functional activity of serum cytokines ensures a more objective evaluation of the pathogenetic disease mechanism and provides for prognosticating its outcome.

[Serum concentration and antiviral activity of interferon alpha in chronic hepatitis and liver cirrhosis]. / Kontsentratsiia i protivovirusnaia aktivnost' interferona alfa v syvorotke krovi pri khronicheskom gepatite i tsirroze pecheni.

Blood serum concentration and antiviral activity of IFN-alpha were studied in 121 patients with chronic hepatitis (CH) and in 115 patients with hepatocirrhosis (HC). The increase in IFN-alpha antiviral activity was revealed in 62% CH patients and in 46% HC patients. In CH patients both the mean indices of blood serum IFN-alpha concentration and its antiviral activity increased. The changes were more expressed in CH having viral etiology (HBV and HCV). For the most CH patients with disease positive dynamics the initially high indices of IFN-alpha antiviral activity were typical. In HC patients with portal hypertension syndrome progress and against the background of increased blood serum IFN-alpha concentration its antiviral activity decreases. With development hepatocellular insufficiency, increasing of disease stage (according to the Child-Pugh classification) the decrease in IFN-alpha concentration and its antiviral activity is noted.

[Concentration and antiviral activity of interferon-alpha in the sera of patient with hepatic pathology]. / Kontsentratsiia i protivovirusnaia aktivnost' interferona-alpha v syvorotke krovi bol'nykh s patologiei pecheni.

The normalization of the antiviral activity of interferon-alpha (IFN-alpha) in the process of the treatment of patients with acute viral hepatitis (VH), simultaneously with the results of other clinico-laboratory tests, reflects the positive dynamics of the process. The prolonged preservation of the elevated level of the antiviral activity of IFN-alpha (up to 6 months and longer) is a prognostically unfavorable sign. In patients with chronic VH the growth of both the average concentration of IFN-alpha in the blood serum and its average antiviral activity can be observed. With the progress of the disease and the formation of the cirrhosis of the liver, the concentration of IFN-alpha in the blood serum remains to be elevated, while its antiviral activity drops.

[Correction of hypercoagulation in head traumas in patients with purulent sinusitis]. / Korrektsiia giperkoaguliatsii pri travmakh golovy u bol'nykh s gnoinym sinusitom.

Hypercoagulation disorders contribute to pathogenesis of purulent sinusitis and craniocerebral trauma. They may result in thrombotic complications. To prevent and correct these disorders we used intramaxillary administration of heparin. This treatment promoted fast regress of hypercoagulatory disturbances of hemostasis: improved plasma recalcification, plasma tolerance to heparin, weakened depression of euglobulin fibrinolysis, stimulated normalization of fibrinogen level. Heparin treatment was contraindicated in intracranial hematomas, recent subarachnoidal hemorrhages.

[Diagnostic and prognostic significance of characteristics of serum interferon antiviral activity in chronic and acute diffuse liver diseases]. / Diagnosticheskaia i prognosticheskaia znachimost' pokazatelei protivovirusnoi aktivnosti syvorotochnogo interferona pri khronicheskikh i ostrykh diffuznykh zabolevaniiakh pecheni.

The interferon (IFN-alpha) level and its antiviral activity were investigated in 236 patients, suffered from the chronic diffuse liver disease (CDLD), including 121 patient with chronic hepatitis (CH), 115 patients with hepatocirrhosis (HC) and 26 patients with acute viral hepatitis (AVH). This permitted to elaborate the pathogenetic and prognostic value of these indices in CH, AVH and HC. The analysis of the variations of IFN-alpha antiviral activity in patients with CDLD in dependence on the etiology, activity of the pathologic process, CH stages by CHild-Pugh graduation, the presence of the portal hypertension and its complications was carried out for the first time. The antiviral activity in the patients suffered from HC with progression of the disease, aggravation of the portal hypertension, development of the decompensation along with persisted elevated IFN-alpha concentration decreased. The main mechanisms modulating IFN-alpha antiviral activity in peripheral blood of the patients suffered from CDLD have been determined. The use of the suggested indices in the combination with other methods of the examining significantly extends the possibilities of the diagnostics, permits to evaluate the reserve possibilities of the organism and to detect the strategy of the immunomodulating treatment. The determination of the IFN-alpha antiviral activity in serum in dynamics is recommended for the control of the therapy of the patients with CDLD and AVH.

[Thymus lipoma complicated by pulmonary artery thromboembolism]. / Timolipoma, oslozhnennaia trombozom legochnoi arterii.

Combination of mediastinum thymolipoma (rare benign variety of thymus tumor) and chronic thrombosis of the main trunk and branches of pulmonary artery is a relatively rare but not occasional combination (location of the tumor in the zone of vascular fascicle, impediment of diastolic heart function because a tumor being equal to the heart enveloped pericardium) resulting in lethal outcome of patient at young age.

[Plasma fibronectin in gastric and duodenal ulcer]. / Plazmennyi fibronektin pri iazvennoi bolezni zheludka i dvenadtsatiperstnoi kishki.

Solid phase enzyme immunoassay was made to measure fibronectin in blood plasma of 132 patients with ulcer and healthy controls. Exacerbations of ulcer occurred in a significant lowering of fibronectin concentration which tended to an increase with ulcer healing. In the scarring phase fibronectin levels returned to normal. A local stimulating action of a plasma fibronectin preparation on scarring of the ulcer defect is validated.

Stochastic modeling and optimization of phage display.

Phage display, SELEX and other methods of combinatorial chemistry have become very popular means of finding ligands with high affinities to given targets. Despite their success, they suffer from numerous sources of error and bias, such as very low initial concentrations of species, non-specific binding, and the sampling of only a tiny fraction of the library at the end of an experiment. To understand the interaction of these errors and to better devise molecular search strategies that take the errors into account, I devise and analyze a highly detailed model of phage display. The model is specifically designed to study the influence of the stochastic nature of each laboratory step. The model includes phage multivalency, multiple classes of targets, and solid-phase equilibrium and washing, yet it is amenable to analytic results and rapid computer simulation. With both analytic and simulation approaches, I: (1) describe the effects of target concentration, phage valency, degree of background binding and other laboratory parameters on the probabilities of phage binding and of being selected; (2) show the effects of an increasing selection stringency strategy and how it results in a tradeoff between rapid library enrichment and high probability of sampling the best ligands; and (3) show how the number of phage sampled for detailed study at the end of a search alters search success. The work concludes with several practical suggestions for the control of selection stringency.

Parallel cone bipolar to on-beta ganglion cell pathways in the cat retina: spatial responses, spatial aliasing, and spatial variance.

An important issue in understanding the retina is finding candidate functional roles for different cell pathways and the details of their anatomy and physiology. We consider various spatial properties of the three main cone ==> cone bipolar cell ==> on-beta ganglion cell pathways in the cat retina and possible roles for the particulars of their anatomy. The cone bipolar cells in these pathways have distinct morphologies and modest differences in their convergence, divergence, densities, and synaptic weighting; and it is unclear whether the pathways differ in their spatial properties or in some other manner. Since differences in spatial processing of cells are best studied on a systemwide level, we developed the multirate filter-based method of retinal modeling, a technique for relating the anatomy of multiple cell layers to its systemic effects. We demonstrate that (1) despite the anatomic distinctions among the three main cone bipolar cell pathways, their spatial responses are essentially identical; (2) despite the spatial averaging in the pathways, there is essentially no filtering of the nonaliasing signal components after the cone layer; (3) instead, this averaging combined with prefiltering by the eye's optics and cone gap junctions prevents spatial aliasing; and (4) the averaging and prefiltering combined allow cell responses to be similar despite significant cell-to-cell anatomic differences.

Adaptive walks with noisy fitness measurements.

Adaptive walks constitute an optimization technique for searching a space of possible solutions, for example, a space of different molecules. The goal is to find a point in space (a molecule) that is optimal or near-optimal in some property, generally referred to as the 'fitness', such as its ability to bind to a given receptor. Adaptive walking, an analog of natural selection, is a powerful technique for searching landscapes. However, errors in the measurements will cause errors in the adaptive walks. Mutant molecules of higher fitness may be ignored or mutants of lower fitness may be accepted. To examine the effect of measurement error on adaptive walks, we simulate single-agent hill-climbing walks on NK landscapes of varying ruggedness where Gaussian noise is added to the fitness values to model measurement error. We consider both constant measurement noise and noise whose variance decays exponentially with fitness. We show that fitness-independent noise can cause walks to 'melt' off the peaks in a landscape, wandering in larger regions as the noise increases. However, we also show that a small amount of noise actually helps the walk perform better than with no noise. For walks in which noise decreases exponentially with fitness, the most characteristic behavior is that the walk meanders throughout the landscape until it stumbles across a point of relatively high fitness, then it climbs the landscape towards the nearest peak. Finally, we characterize the balance between selection pressure and noise and show that there are several classes of walk dynamic behavior.