Generic drug competition: The pharmaceutical industry “gaming” controversy

Among American adults 20 years and older, 59 percent take at least one prescription drug on a regular basis. Unlike most branded drugs, which are generally drugs that have a trade name and are protected by a patent, off‐patent generic drugs make up approximately 90 percent of prescriptions annually filled in the United States; yet in 2017, generic drugs made up only 23 percent of total drug costs in the U.S. The U.S. Food and Drug Administration has taken the lead in encouraging increased competition in the nation’s prescription drug marketplace, most recently with its release of the agency’s Drug Competition Action Plan, but also with its regulatory guidance and enforcement efforts to eliminate “gaming” of the regulatory process by both branded and generic pharmaceutical manufacturers. Such “gaming” activities include “pay‐for‐delay” agreements involving financial compensation between branded and generic pharmaceutical manufacturers to forestall the emergence into the market of generic pharmaceuticals to compete against a formerly patent‐protected branded drug. A combination of new enabling legislation, federal judicial guidance, and agency regulatory activities show promise in encouraging increased competition in the prescription drug marketplace, with the American consumer the ultimate beneficiary of lower health care costs and improved overall personal health.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152498/1/basr12186_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152498/2/basr12186.pd

Inter-rater reliability of welfare outcomeassessment by an expert and farmers of SouthTyrolean dairy farming

The implementation of an animal welfare assurance programme for dairy cattle in South Tyrol (Eastern Italian Alps) faces particular feasibility constraints due to the outstanding volume of travel associated with routine on-farm audits of remote mountain farms. Therefore, this study aims to estimate the inter-rater reliability of the expert’s and farmers’ welfare outcome assessment regarding recommendations to involve milk producers in animal welfare assurance within South Tyrolean dairy farming. A formal training programme containing a classroom session and an on-farm observation became mandatory for all 188 participating farmers, which was offered by the expert, applied as reference standard. On-farm data collected on the farmers’ cows (dataset of 1719 dairy cows) were compared at animal level. Cohen’s kappa, respectively, weighted kappa, examined for several welfare indicators, range from slight to moderate agreement(k=0.018-0.416;Kw=0.163-0.310). These findings are further confirmed by results at farmlevel (ICC=0.018-0.577). Continuous repeatability checks as part of routine audits are therefore proposed to substantially reduce the variability between the raters and to avoid significant bias in the welfare outcome assessment. In this way, the competence for regular and standardised monitoring could be increasingly transferred to dairy farmers in order to reduce the need for costly and time-consuming inspections by external auditors, which are in long-term perspective also harmful to the alpine environment. Additionally, the promotion of welfare assessment as an instructive management tool would intensify farmers’ commitment to the assessment process

The risk of reintroduction-recirculation of Schmallenberg virus in Belgium in 2012

The Scientific Committee is of the opinion that the risk of reintroduction/recirculation is very high but the impact will be largely dependent upon the in-herd and between-herd seroprevalence. Therefore it is very important to gain knowledge on the seroprevalence of the Belgian livestock. Preliminary results indicate that the seroprevalence can be up to 70% (Netherlands). If such a high seroprevalence is also present in Belgium, circulation of SBV during the vector season 2012 and accompanying clinical symptoms will probably be minimal. Regarding the surveillance for SBV during the vector season 2012, the Scientific Committee proposes to base it on 3 pillar

Carcinogenic and-or genotoxic risks in food; process related contaminants

The Scientific Committee started a self tasking study on carcinogenic and/or genotoxic risks in food. In a first advice (Sci Com Advice 26-2008), the issue was introduced and an overview of relevant carcinogenic and/or genotoxic contaminants in food was presented. This second advice focuses on the group of “process contaminants”, i.e. undesired chemical substances that are formed during food processing processes, such as heating, fermentation, storage. The dietary exposure to these contaminants (in particular of the Belgian population) and the coupled risk, as well as the gaps in the current knowledge are considered. Other aspects, such as occurrence and formation, toxicity, mitigation, etc. are briefly discussed in the annexe of this advice by means of scientific flash cards. Based on the available information following relative ranking is proposed: - First priority: acrylamide, furan, 3-chloropropanediol (3-MCPD) and the 3-MCPD and glycidol esters; - Second priority: benzene, 1,3-dichloropropanol (1,3-DCP), N-nitrosamines (NDMA), polyaromatic hydrocarbons (PAHs); - Third priority: heterocyclic aromatic amines, ethyl carbamate, formaldehyde, semicarbazide, nitro-PAHs. The proposed ranking concerns only the presence of these contaminants in food. However, there might be different, and sometimes more important exposure pathways for the considered contaminants. In addition, it is noted that besides the carcinogenic and/or genotoxic effects, other potentially harmful properties of these contaminants could be relevant (e.g. endocrine disrupting properties)

Plasma bioavailability and changes in PBMC gene expression after treatment of ovariectomized rats with a commercial soy supplement

The health effects of soy supplementation in (post)menopausal women are still a controversial issue. The aim of the present study was to establish the effect of the soy isoflavones (SIF) present in a commercially available supplement on ovariectomized rats and to investigate whether these rats would provide an adequate model to predict effects of SIF in (post)menopausal women. Two dose levels (i.e. 2 and 20. mg/kg b.w.) were used to characterize plasma bioavailability, urinary and fecal concentrations of SIF and changes in gene expression in peripheral blood mononuclear cells (PBMC). Animals were dosed at 0 and 48. h and sacrificed 4. h after the last dose. A clear dose dependent increase of SIF concentrations in plasma, urine and feces was observed, together with a strong correlation in changes in gene expression between the two dose groups. All estrogen responsive genes and related biological pathways (BPs) that were affected by the SIF treatment were regulated in both dose groups in the same direction and indicate beneficial effects. However, in general no correlation was found between the changes in gene expression in rat PBMC with those in PBMC of (post)menopausal women exposed to a comparable dose of the same supplement. The outcome of this short-term study in rats indicates that the rat might not be a suitable model to predict effects of SIF in humans. Although the relative exposure period in this rat study is comparable with that of the human study, longer repetitive administration of rats to SIF may be required to draw a final conclusion on the suitability of the rat a model to predict effects of SIF in humans

Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their revaluation

The threshold of toxicological concern (TTC) approach is a resource-effective de minimismethod for the safety assessment of chemicals, based on distributional analysis of the results of a large number of toxicological studies. It is being increasingly used to screen and prioritise substances with low exposure for which there is little or no toxicological information. The first step in the approach is the identification of substances that may be DNA-reactive mutagens, to which the lowest TTC value is applied. This TTC value was based on analysis of the cancer potency database and involved a number of assumptions that no longer reflect the state-of-the-science and some of which were not as transparent as they could have been. Hence, review and updating of the database is proposed, using inclusion and exclusion criteria reflecting current knowledge. A strategy for the selection of appropriate substances for TTC determination, based on consideration of weight of evidence for genotoxicity and carcinogenicity is outlined. Identification of substances that are carcinogenic by a DNA-reactive mutagenicmode of action and those that clearly act by a non-genotoxic mode of action will enable the protectiveness to be determined of both the TTC for DNA-reactive mutagenicityand that applied by default to substances that may be carcinogenic but are unlikely to be DNA-reactive mutagens (i.e. for Cramer class I-III compounds). Critical to the application of the TTC approach to substances that are likely to be DNA-reactive mutagens is the reliability of the software tools used to identify such compounds. Current methods for this task are reviewed and recommendations made for their application

The identification of a low molecular mass bacteriocin, rhamnosin A, produced by Lactobacillus rhamnosus strain 68

Aims: This study focuses on the isolation and characterization of a peptide with bacteriocin-like properties isolated from Lactobacillus rhamnosus strain 68, previously identified by 16S rRNA gene sequencing and originating from human gastrointestinal flora. Methods and Results: The peptide was isolated from a supernatant of bacteria maintained under restrictive conditions by a combination of ethanol precipitation and reversed-phase chromatography. The molecular mass of the peptide as assessed by mass spectrometry was 6433 center dot 8 Da. An isoelectric point of 9 center dot 8 was determined by 2D-PAGE. The peptide designated rhamnosin A inhibited Micrococcus lysodeikticus ATCC 4698 but did not inhibit Lactobacillus plantarum 8014 or Lact. plantarum 39268. Inhibitory activity against M. lysodeikticus at concentrations used in this study was shown to be bacteriostatic rather than bacteriolytic or bactericidal. Rhamnosin A retained biological activity after heat treatment (95 degrees C, 30 min) but was sensitive to proteolytic activity of pepsin and trypsin. Conclusions: The N-terminal sequence of rhamnosin A, as determined by Edman degradation and in more detail by blast analysis, did not show identity with any currently available Lact. rhamnosus HN001-translated protein sequences, nor any significant similarity with other sequences in the nonredundant protein sequence database. Being a small, heat-stable, nonlanthionine-containing peptide, rhamnosin A should be categorized as a class II bacteriocin. Significance and Impact of the Study: This study describes a partial bacteriocin sequence isolated from Lact. rhamnosus 68 and broadens our understanding of bacteriocins

Harnessing mtDNA variation to resolve ambiguity in 'Redfish' sold in Europe

Morphology-based identification of North Atlantic Sebastes has long been controversial and misidentification may produce misleading data, with cascading consequences that negatively affect fisheries management and seafood labelling. North Atlantic Sebastes comprises of four species, commonly known as ‘redfish’, but little is known about the number, identity and labelling accuracy of redfish species sold across Europe. We used a molecular approach to identify redfish species from ‘blind’ specimens to evaluate the performance of the Barcode of Life (BOLD) and Genbank databases, as well as carrying out a market product accuracy survey from retailers across Europe. The conventional BOLD approach proved ambiguous, and phylogenetic analysis based on mtDNA control region sequences provided a higher resolution for species identification. By sampling market products from four countries, we found the presence of two species of redfish (S. norvegicus and S. mentella) and one unidentified Pacific rockfish marketed in Europe. Furthermore, public databases revealed the existence of inaccurate reference sequences, likely stemming from species misidentification from previous studies, which currently hinders the efficacy of DNA methods for the identification of Sebastes market samples