Structured benefit-risk assessment: a review of key publications and initiatives on frameworks and methodologies.

Introduction The conduct of structured benefit-risk assessment (BRA) of pharmaceutical products is a key area of interest for regulatory agencies and the pharmaceutical industry. However, the acceptance of a standardized approach and implementation are slow. Statisticians play major roles in these organizations, and have a great opportunity to be involved and drive the shaping of future BRA. Method We performed a literature search of recent reviews and initiatives assessing BRA methodologies, and grouped them to assist those new to BRA in learning, understanding, and choosing methodologies. We summarized the key points and discussed the impact of this emerging field on various stakeholders, particularly statisticians in the pharmaceutical industry. Results We provide introductory, essential, special interest, and further information and initiatives materials that direct readers to the most relevant materials, which were published between 2000 and 2013.  Based on recommendations in these materials we supply a toolkit of advocated BRA methodologies. Discussion Despite initiatives promoting these methodologies, there are still barriers, one of which being the lack of a consensus on the most appropriate methodologies among stakeholders. However, this opens up opportunities, for statisticians in the pharmaceutical industry especially, to champion appropriate BRA methodology use throughout the pharmaceutical product lifecycle. Conclusions This article may serve as a starting point for discussions and to reach a mutual consensus for methodology selection in a particular situation. Regulators and pharmaceutical industry should continue to collaborate to develop and take forward BRA methodologies, and by clear communication develop a mutual understanding of the key issues. Copyright © 2015 John Wiley & Sons, Ltd

Allele frequencies of BRAFV600 mutations in primary melanomas and matched metastases and their relevance for BRAF inhibitor therapy in metastatic melanoma

Background: The detection of BRAFV600 mutations in patients with metastatic melanoma is important because of the availability of BRAF inhibitor therapy. However, the clinical relevance of the frequency of BRAFV600 mutant alleles is unclear. Patients and Methods: Allele frequencies of BRAFV600 mutations were analyzed byultra-deepnext-generation sequencing in formalin-fixed, paraffin-embedded melanoma tissue (75 primary melanomas and 88 matched metastases). In a second study, pretreatment specimens from 76 patients who received BRAF inhibitors were retrospectively analyzed, and BRAFV600 allele frequencies were correlated with therapeutic results. Results: Thirty-five patients had concordantly BRAF-positive and 36 (48%) patients had concordantly BRAF-negative primary melanomas and matched metastases, and four patients had discordant samples with low allele frequencies (3.4–5.2%). Twenty-six of 35 patients with concordant samples had BRAFV600E mutations, three of whom had additional mutations (V600K in two patients and V600R in one) and nine patients had exclusively non-V600E mutations (V600K in eight patients and V600E -c.1799_1800TG > AA- in one patient). The frequency of mutated BRAFV600 alleles was similar in the primary melanoma and matched metastasis in 27/35 patients, but differed by >3-fold in 8/35 of samples. BRAFV600E allele frequencies in pretreatment tumor specimens were not significantly correlated with treatment outcomes in 76 patients with metastatic melanoma who were treated with BRAF inhibitors. Conclusions: BRAFV600 mutation status and allele frequency is consistent in the majority of primary melanomas and matched metastases. A small subgroup of patients has double mutations. BRAFV600 allele frequencies are not correlated with the response to BRAF inhibitors

Drivers and outcomes of work alienation: reviving a concept

This article sheds new light on an understudied construct in mainstream management theory, namely, work alienation. This is an important area of study because previous research indicates that work alienation is associated with important individual and organizational outcomes. We tested four antecedents of work alienation: decision-making autonomy, task variety, task identity, and social support. Moreover, we examined two outcomes of alienation: deviance and performance, the former measured 1 year after the independent variables were measured, and the latter as rated by supervisors. We present evidence from a sample of 283 employees employed at a construction and consultancy organization in the United Kingdom. The results supported the majority of our hypotheses, indicating that alienation is a worthy concept of exploration in the management sciences

Relative luminosity measurement of the LHC with the ATLAS forward calorimeter

In this paper it is shown that a measurement of the relative luminosity changes at the LHC may be obtained by analysing the currents drawn from the high voltage power supplies of the electromagnetic section of the forward calorimeter of the ATLAS detector. The method was verified with a reproduction of a small section of the ATLAS forward calorimeter using proton beams of known beam energies and variable intensities at the U-70 accelerator at IHEP in Protvino, Russia. The experimental setup and the data taking during a test beam run in April 2008 are described in detail. A comparison of the measured high voltage currents with reference measurements from beam intensity monitors shows a linear dependence on the beam intensity. The non-linearities are measured to be less than 0.5 % combining statistical and systematic uncertainties.Comment: 16 page

Photoproduction of ϱo on hydrogen with tagged photons between 4 and 6 GeV

We have measured the reaction γp → pπ+π− in the DESY 1 m Streamer Chamber. The dominant ϱo production is analyzed in terms of various models