Comparison of BRICS-TM Countries' Biosimilar Regulatory Frameworks With Australia, Canada and Switzerland: Benchmarking Best Practices

Objectives: The aim of this study was to identify, compare and evaluate regulatory requirements for the biosimilar development and review processes in BRICS-TM (Brazil, Russia, India, China, South Africa, Turkey, Mexico) countries with mature regulatory systems of Australia, Canada, Singapore and Switzerland. It is hoped that this benchmark study provides an opportunity for BRICS-TM agencies to identify the key areas for improvement in their regulatory processes. Materials and Methods: A semi-quantitative questionnaire was developed covering the different criteria used in biosimilar development and registration process. Eleven regulatory agencies from BRICS-TM and ACSS (Australia, Canada, Switzerland and Singapore) countries were invited to take part in this study. Data processing and analysis was carried out using descriptive statistics for quantitative data and content analysis to generate themes for qualitative data. Results and Discussions: Nine of the 11 regulatory agencies recruited for the study completed the questionnaire. China and Singapore did not meet the deadline due to lack of resources. The organisational structure of BRICS-TM agencies revealed support from external assessors by most of these agencies in comparison with ACSS agencies. There was absence of reliance approach and participation in harmonisation activities across most BRICS-TM agencies. Despite alignment over biosimilarity, the mandate for in vivo non-clinical studies and additional local clinical studies in some of the BRICS-TM countries illustrates a lack of effective implementation of a step-wise approach. Adopting flexible regulatory standards in the sourcing of a RBP (Reference Biologic Product) by BRICS-TM similar to ACSS, will facilitate cost-effective development of biosimilar products. Conclusions: Comparative assessment of the biosimilar regulatory framework of BRICS-TM with ACSS agencies reveals the scope for enhancing efficiency of the regulatory approval process. To achieve this, BRICS-TM agencies should consider relying on reference agencies for alternative review mechanisms such as abridged or verification models, streamlined processes for providing scientific advice to developers and for waiving local clinical studies in-lieu of advanced scientific data.Peer reviewedFinal Published versio

Social interaction and academic performance

In this thesis it was argued that, since almost all activities at school are carried on within a context of on-going social interaction, students' experience of social interaction with teachers and peers constitutes a major part of the high school experience and can be expected to be related to their academic performance and schoolrelated feelings. A review of literature revealed a paucity of information concerning firstly, the adolescent's perspective of within-school social interaction and secondly, the influence which adolescents' experience of such interaction exerts on their academic performance. Accordingly, this study was designed to address the question 'How is adolescents' experience of social interaction with teachers and peers related to their academic performance?' At a general level it was argued that human experience (and the behaviour based upon it) is an outcome of the interaction between personality (which reflects past experience) and current perceptions of the environment. In the light of this it was argued that adolescents' experience of within-school interaction can be conceptualized in terms of the degree of satisfaction they experience in association with needs aroused during interaction with peers and teachers. By their nature social needs are aroused by environmental cues present in interactive situations and are satisfied (or left unsatisfied) by the behavioural exchange which this interaction implies. This theoretical perspective meshed nicely with an available methodology [Stern's (1970) psychometric development of Murray's (1938) needs-press model] and four needs (affiliation, supplication, deference and dominance) were identified as characterizing adolescents' experience of within-school social interaction with peers and teachers. The degree of dissatisfaction which students experience during school interaction with teachers and peers was then inferred from the degree of dissonance they reported in association with these four needs. Two different theoretical perspectives concerning the relationship between need-press dissonance and academic performance were investigated. The first of these adopted a similar approach to earlier studies in this area and argued that need-press dissonance and academic performance would be inversely related. Specifically, it was suggested that perceptions of a high degree of dissonance would be accompanied by the arousal of debilitating state anxiety which would impair academic performance, while perceptions of a low degree of dissonance would not be accompanied by a similar arousal of anxiety and consequently performance would not be impaired. The second perspective attempted to place dissonance associated with social needs into the framework of the expectancy-value theory of achievement motivation and argued that the strength of students’ extrinsic tendency to engage in achievement activities could be inferred from the degree of dissonance they perceived. From this perspective dissonance was viewed as a positive tendency which encourages students to engage in achievement activities i.e. it was argued that dissonance and performance would be positively related. These hypotheses and others derived from them were tested using a variety of multivariate statistical techniques. The results of this data analysis provided limited support for the first of the two major hypotheses mentioned above and evidence was also found to support the prediction that perceptions of dissonance would be related to students’ school-related feelings. In the discussion of these findings it was concluded that the Stern need and press scales are better suited for research into between-school rather than within-school effects and alternative methods of assessing adolescents' experience of social interaction with peers and teachers were suggested

Challenges Faced by the Biopharmaceutical Industry in the Development and Marketing Authorization of Biosimilar Medicines in BRICS-TM Countries: An Exploratory Study

Abstract: Background: Biosimilars are expected to emerge as a rapidly growing segment of the biopharmaceutical industry. However, the biosimilar industry faces multiple challenges and obstacles in developing and marketing these complex products. Divergent regulatory framework in emerging countries adds to repetitive trials and increased cost of biosimilar development, delaying the approval process. Due to such roadblocks, healthcare systems and patients are yet to realize the full benefits of biosimilars. Objectives: The aim of this exploratory study was to specifically identify the challenges faced by the industry in emerging countries including Brazil, Russia, India, China, South Africa, Turkey and Mexico (BRICS-TM), pertaining to biosimilar development and the regulatory approval process. In particular, this study aims to understand the perceptions of industry on the barriers faced by them in terms of complexity, costs for biosimilar development and time-to-market for biosimilar product. Methods: A semi-quantitative questionnaire was designed based on secondary research. A total of 93 industry personnel and representatives from 14 trade associations from the BRICS-TM countries with 15-year minimum experience were identified and invited to take part in the study and participate in interviews, which were recorded verbatim. Data processing and analysis was carried out; descriptive statistics were used for quantitative data and content analysis was employed to generate themes for qualitative data. Results: Of the 107 biopharmaceutical industry and trade association representatives invited to participate in the study, respondents from 33 biopharmaceutical companies agreed to take part and underwent the interviews. The industry personnel perceived biosimilar guidelines and approval processes as being protracted and in a state of evolution. The absence of an abridged approval pathway limited effectiveness of the regulatory process. The biggest hurdles in the development of biosimilar dossiers were the sourcing of the reference biological product and expectations around confirmatory clinical trials by the agencies. The non-comprehensive implementation of a stepwise approach resulting in unnecessary toxicity studies was also reported as a major challenge. The authors recommend further primary research with BRICS-TM regulatory agencies in order to propose a simplified pathway for development and approval. Conclusions: Lack of standardized biosimilar development criteria and regulatory convergence across BRICS-TM agencies has led to challenges in multi-country development programmes for these medicines, in turn impacting the ability of industry to launch newer and more affordable biosimilars.Peer reviewe

Current Regulatory Requirements for Biosimilars in Six Member Countries of BRICS-TM: Challenges and Opportunities

© 2021 Rahalkar, Sheppard, Santos, Dasgupta, Perez-Tapia, Lopez-Morales and Salek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). https://creativecommons.org/licenses/by/4.0/Background: The aim of the study was to identify, interpret, and compare the current perspectives of regulatory agencies in six member countries of BRICS-TM (Brazil, Russia, India, China, South Africa, Turkey, and Mexico) on the different criteria used for biosimilar development and marketing authorisation process. Methods: A semi-quantitative questionnaire was developed covering the organisation of agency, biosimilar development criteria and marketing authorisation process and sent to seven regulatory agencies covering the BRICS-TM countries. All data was kept anonymous and confidential. Data processing and analysis was carried out; descriptive statistics were used for quantitative data and content analysis was employed to generate themes for qualitative data. Results: Out of the seven regulatory agencies included in the study, six representatives provided the responses. The perspectives of these six regulatory agencies varied on a number of aspects relating to the review criteria for biosimilar development and licencing process. The most prevalent model for data assessment is the “full review” of a marketing authorisation application. There is lack of a standard approach across the agencies on sourcing of the reference biological product, in vivo toxicity studies and confirmatory clinical studies. Most agencies restrict interaction with biosimilar developers and any scientific advice is non-binding. The marketing authorisation approval depends on scientific assessment of the dossier, sample analysis and GMP certification. The agencies do not issue any public assessment report specifying the summary basis of biosimilar approval. Conclusion: Regulatory agencies across the six emerging economies are steadily improving the regulatory mechanism in the area of biosimilars. However, there remains scope for increasing the effectiveness and efficiency of the processes by encouraging open and transparent interaction with developers, adopting a flexible approach toward accepting advanced analytical data in lieu of clinical studies and enhancing regulatory reliance amongst agencies. This will help to simplify the new biosimilar development programmes and make them more cost-effective.Peer reviewe

A pilot telephone intervention to increase uptake of breast cancer screening in socially deprived areas in Scotland (TELBRECS):study protocol for a randomised controlled trial

BACKGROUND Breast cancer accounts for almost 30% of all cancers and is the second leading cause of cancer deaths in women in Scotland. Screening is key to early detection. The Scottish Breast Screening Programme is a nationwide, free at point of delivery screening service, to which all women aged between 50 and 70 years are invited to attend every 3 years. Currently over three-quarters of invited women regularly attend screening. However, women from more deprived areas are much less likely to attend: for example in the 3 years from 2010-2012 only 63% of women in the most deprived area attended the East of Scotland Breast Screening programme versus 81% in the least deprived. Research has suggested that reminders (telephone or letter) and brief, personalised interventions addressing barriers to attendance may be helpful in increasing uptake in low-income women. METHODS/DESIGN We will employ a brief telephone reminder and support intervention, whose purpose is to elicit and address any mistaken beliefs women have about breast screening, with the aim that the perceived benefits of screening come to outweigh any perceived barriers for individuals. We will test whether this intervention, plus a simple anticipated regret manipulation, will lead to an increase in the uptake of breast cancer screening amongst low-income women who have failed to attend a first appointment, in a randomised controlled trial with 600 women. Participants will be randomly allocated to one of four treatment arms i.e. 1) Letter reminder (i.e. Treatment as usual: CONTROL); 2) Telephone reminder (TEL), 3) Telephone reminder plus telephone support (TEL-SUPP) and 4) Telephone reminder plus support plus AR (TEL-SUPP-AR). The primary outcome will be attendance at breast screening within 3 months of the reminder letter. DISCUSSION If this simple telephone support intervention (with or without AR intervention) leads to a significant increase in breast screening attendance, this would represent a rare example of a theoretically-driven, relatively simple psychological intervention that could result in earlier detection of breast cancer amongst an under-served group of lower socio-economic women. TRIAL REGISTRATION Current Controlled trials: ISRCTN06039270. Registered 16th January 2014

Main-Belt Comet P/2012 T1 (PANSTARRS)

We present initial results from observations and numerical analyses aimed at characterizing main-belt comet P/2012 T1 (PANSTARRS). Optical monitoring observations were made between October 2012 and February 2013 using the University of Hawaii 2.2 m telescope, the Keck I telescope, the Baade and Clay Magellan telescopes, Faulkes Telescope South, the Perkins Telescope at Lowell Observatory, and the Southern Astrophysical Research (SOAR) telescope. The object's intrinsic brightness approximately doubles from the time of its discovery in early October until mid-November and then decreases by ~60% between late December and early February, similar to photometric behavior exhibited by several other main-belt comets and unlike that exhibited by disrupted asteroid (596) Scheila. We also used Keck to conduct spectroscopic searches for CN emission as well as absorption at 0.7 microns that could indicate the presence of hydrated minerals, finding an upper limit CN production rate of QCN<1.5x10^23 mol/s, from which we infer a water production rate of QH2O<5x10^25 mol/s, and no evidence of the presence of hydrated minerals. Numerical simulations indicate that P/2012 T1 is largely dynamically stable for >100 Myr and is unlikely to be a recently implanted interloper from the outer solar system, while a search for potential asteroid family associations reveal that it is dynamically linked to the ~155 Myr-old Lixiaohua asteroid family.Comment: 15 pages, 4 figures, accepted for publication in ApJ Letter

The discriminatory value of cardiorespiratory interactions in distinguishing awake from anaesthetised states: a randomised observational study

Depth of anaesthesia monitors usually analyse cerebral function with or without other physiological signals; noninvasive monitoring of the measured cardiorespiratory signals alone would offer a simple, practical alternative. We aimed to investigate whether such signals, analysed with novel, non-linear dynamic methods, would distinguish between the awake and anaesthetised states. We recorded ECG, respiration, skin temperature, pulse and skin conductivity before and during general anaesthesia in 27 subjects in good cardiovascular health, randomly allocated to receive propofol or sevoflurane. Mean values, variability and dynamic interactions were determined. Respiratory rate (p = 0.0002), skin conductivity (p = 0.03) and skin temperature (p = 0.00006) changed with sevoflurane, and skin temperature (p = 0.0005) with propofol. Pulse transit time increased by 17% with sevoflurane (p = 0.02) and 11% with propofol (p = 0.007). Sevoflurane reduced the wavelet energy of heart (p = 0.0004) and respiratory (p = 0.02) rate variability at all frequencies, whereas propofol decreased only the heart rate variability below 0.021 Hz (p < 0.05). The phase coherence was reduced by both agents at frequencies below 0.145 Hz (p < 0.05), whereas the cardiorespiratory synchronisation time was increased (p < 0.05). A classification analysis based on an optimal set of discriminatory parameters distinguished with 95% success between the awake and anaesthetised states. We suggest that these results can contribute to the design of new monitors of anaesthetic depth based on cardiovascular signals alone

Phenotypic microarrays suggest Escherichia coli ST131 is not a metabolically distinct lineage of extra-intestinal pathogenic E. coli

Extraintestinal pathogenic E. coli (ExPEC) are the major aetiological agent of urinary tract infections (UTIs) in humans. The emergence of the CTX-M producing clone E. coli ST131 represents a major challenge to public health worldwide. A recent study on the metabolic potential of E. coli isolates demonstrated an association between the E. coli ST131 clone and enhanced utilisation of a panel of metabolic substrates. The studies presented here investigated the metabolic potential of ST131 and other major ExPEC ST isolates using 120 API test reagents and found that ST131 isolates demonstrated a lower metabolic activity for 5 of 120 biochemical tests in comparison to non-ST131 ExPEC isolates. Furthermore, comparative phenotypic microarray analysis showed a lack of specific metabolic profile for ST131 isolates countering the suggestion that these bacteria are metabolically fitter and therefore more successful human pathogens

Urban land planning: The role of a Master Plan in influencing local temperatures

Land use planning (LUP) is central for managing issues related to climatic variation in urban environments. However, Master Plans (MPs) usually do not include climatic aspects, and few studies have addressed climate change at the urban scale, especially in developing countries. This paper proposes a framework with ten categories for assessment of climatic variation in urban LUP. Each category comprises attributes that describe a complex of relationships in influencing local temperature variations. They are analyzed for the case of the Master Plan of Porto Alegre (MPPA), the Southernmost metropolis of Brazil. It is concluded that the MPPA is strongly grounded in climate-related land and zoning coordination, but exhibits weaknesses in building, cartographical and social aspects considered synergistically relevant for tackling problems related to urban climate variation. Furthermore, the MPPA does not contain provisions related to monitoring of local climate and greenhouse gases (GHG) emissions and it is ineffective for improving energy efficiency. Specific MPPA failures stemming from these weaknesses include: an increase of 21.79% in the city's urbanized area from 1986 to 2011 to accommodate a similar increase in population, with significant horizontal sprawl; average temperature rise of 0.392. °C from 1991-2000 to 2001-2010, with statistically significant increases in temperature found since 1931; significant vehicle traffic increases, especially since 2007. From these findings, it is possible to conclude that the MPPA does not offer answers to all the imbalances related to land use, and therefore gives insufficient support to tackle the issue of rising temperatures